NGP EU 9

COVER NGPEU9 2_apr09 09/03/2010 16:19 Page 1

www.ngpharma.eu.com • Q1 2010

KEEPING IT LEAN How Novartis Pharma is streamlining its technical operations Page 40

BACK ON TRACK Martin Mackay on improving the ROI on Pfizer’s R&D Page 80

Taking it personally Why pharmaceutical companies are lining up to customise medicines for specific genetic groups Page 28

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FROM THE EDITOR 5

The personal touch Can pharmacogenomics cure the industry’s ills?

P

ersonalisation is a major trend in many sectors, including healthcare, automotive, transportation, environment and building technologies, and the pharmaceutical industry is no exception. Combine this trend with the challenges currently facing big pharma – the death of the blockbuster model, an epidemic of patent expiries, dry pipelines – and it’s clear that the business model the industry has relied upon for decades is no longer viable.

Many companies are dealing with these issues by finding a niche area, going after orphan drugs, or moving into emerging markets. Personalisation, in the form of the rapidly developing field of pharmacogenomics, is another promising avenue.

Pharmacogenomics holds out the potential for medicines to be tailored to an individual’s genetic make-up, offering the vision of a world without adverse reactions resulting from the lack of – or too much of – a particular enzyme

“In the long term, what we fundamentally need as a society and human beings will prevail and the truly innovative things will be rewarded” Joe Miletich, Senior Vice President, Research and Development, Amgen (Page 32)

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in the patient’s body. Dosing will be exact, and efficacy will spectacularly improved.

But we’re not there yet. The completion of the Human Genome Project in 2000 was only the beginning. It will take scientists years to decode every genetic variation and then work out how this will affect reactions to a particular medicine. The number of tests currently available can be counted on the fingers of one hand.

The potential of pharmacogenomics is, however, being taken seriously both by big pharma companies and by regulators such as the FDA and the EMEA. According to a recent report by PricewaterhouseCoopers, Diagnostics 2009: Moving towards personalised medicine, a number of pharmaceutical companies have indicated that they plan to incorporate pharmacogenomics as part of, if not the core of, their corporate strategies.

Biomarkers are a case in point. The regulators have begun to require biomarker testing to guide how drugs are prescribed, and as this testing often increases efficacy in addition to

reducing adverse events, the practice is likely to become more common. Although as Amgen’s SVP of R&D Joe Miletich points out in this issue, biomarkers are not magic bullets, they are merely tools that help indicate whether a compound is doing what it should.

Even if it can’t solve all of our problems right now, the science of pharmacogenomics will continue to move forward, and smart companies will want to be along for the ride.

Whether or not it proves to be a miracle cure, personalised medicine is here to stay and will play a vital part in the pharmaceutical industry’s future.

“Last year in the United States, seizures of pharmaceutical products alone were up over 150 percent from the previous year” Travis Johnson, Vice President and Director of Legislative Affairs and Policy, International AntiCounterfeiting Coalition (Page 64)

“More and more our early discovery portfolio is predicated on a genetic analysis that shows some genetic validation” Martin Mackay, Senior Vice President and President, PharmaTherapeutics R&D, Pfizer (Page 80)

Marie Shields, Editor

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CONTENTS 7

28

80 Back on track Martin Mackay, Pfizer SVP, outlines his plan to improve the real returns on the drug giant’s R&D investment

Miracle cure?

There’s no denying that the pharmaceutical industry is in flux, if not downright turmoil. Can the emerging field of pharmacogenomics provide a life-saving tonic?

32

40 The Lean solution

The innovation agenda

Carmen Doran and Domingo Traver work to improve process efficiency at Novartis Pharma

Joe Miletich, Amgen’s Senior Vice President for Research and Development, looks at the pressing need for novel compounds in pharmaceutical R&D

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CONTENTS 9

92

Dai Hayward, CellAura

ROUNDTABLE DISCUSSIONS 47 Manufacturing With Liam O’Brien of ESP, Debra Shumar of 3P Partners and SherTrack’s Alfred Sherk 73 Waste-water With Michael Costello of Siemens Water Technologies and Veolia’s Michel Bouvet 102 Biomarkers With GlaxoSmithKline’s Aiden Flynn, Eurofins Medinet’s Edwin Janssen and Michael Pisano of NextGen Sciences, Inc. 125 Clinical trials With NNIT’s Philip Puls and Onorach Ltd’s Christene Leiper 137 Marketing With Jo Spadaccino of Cohn & Wolfe London and Rob Halkes of Van Spaendonck Management Consultants

TROUBLESHOOTERS 58 Martin Svantesson, Geodis Wilson 70 Rebecca Vangenechten, Siemens 130 Kirk Nielson, Iris Global Clinical Trial Solutions

ASK THE EXPERTS 52 Ian Cox, JMP 60 Manfred Zurkirch, Dividella 62 Marcel Velterop, Dr Reddys Laboratories 78 Andrew Thompson, Eurand

122

Fixing the failure rate

38 The importance of integration Dave Champagne evaluates the integration benefits of enterprise-level LIMS

90 Multiplexed assays enter drug discovery labs

By Bernhard Ronacher, Anagnostics Bioanalysis GmbH

54 On the frontline of disease prevention

94 Making the vital connection

Rene Labatut outlines the challenges of developing new vaccines

GSK’s Paul Matthews looks at the challenges of combining imaging and drug development

64 Get real

100 Culture development

Travis Johnson looks at the global problem of counterfeit pharmaceuticals

RBM’s Dominic Eisinger on immune system monitoring in clinical trials

76 The whole package

110 Hunting down cancer

GSK’s Keith Allen examines innovative processes in the manufacturing line

Novartis’ Haren Rupani explains the importance of imaging in combating cancer

86 Getting personal

112 Step up to the MIQE

Lilly’s William Chin explains how the company is using tailored therapeutics to improve outcomes for patients

Towards real-time PCR in drug discovery, with Bio-Rad’s Richard Kurtz

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CONTENTS 10

IN THE BACK

116 All change

142 Towards transparency

Raafat Fahim looks at why a more efficient business model is needed for the industry

Tina Kohnstam of Caudex Medical Ltd explains the importance of best practise standards

122 Fixing the failure rate Celgene’s Kamal Shah on why most new compounds fail to progress beyond clinical trials

144 Patient-centric commercialisation Quintiles’ Justin van Gennep on entering ‘the new health’ era

132 The force is with you Why sales force effectiveness is taking top priority

Brazil 156 Travel focus: Brazil 158 Roundup: Upcoming conferences 160 Final word by Vivian Hunt, McKinsey

134 Measuring the probability of commercial success

146 The technical side of business GlaxoSmithKline’s Bill Louv outlines technology’s role in ensuring successful business solutions

With Mike Rea, IDEA Pharma

EXECUTIVE INTERVIEW 68 Jozsef Repasi, Ubichem Plc 84 Holger Kissel, Taconic 92 Dai Hayward, CellAura 108 Klaus Weinberger, Biocrates 114 Rita Cortvrindt, EggCentris 120 John Hall, Quintiles 128 Michael J Butler, Xceleron 140 Tom Haskell and John Moran, IMS 150 Matt Sawtell, GE Healthcare 152 Petter Mörée, Umetrics 154 Ethan Smith, Metastorm

144

Justin van Gennep, Quintiles

Making the vital connection

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NGP Europe Summit 2010 The NGP Summit is a three-day critical information gathering of the most influential and important executives from the pharmaceutical industry.

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UPFRONT 14

DOES HOMEOPATHY WORK? Homeopathy is a 200-year-old system of treatment that uses highly diluted substances – sometimes so none of the original product is left – that are given orally in the belief that it will stimulate the body's self-healing mechanism.

The homeopathy industry is worth around GBP£40 million in the UK, and around €400 million in both France and Germany. While

this may seem small compared to the mammoth size of the pharmaceutical industry, real drugs have to be proven to be effective before being licensed in the UK – something the homeopathy industry does not have to prove, and something they would be entirely unable to prove.

Recently, the UK’s House of Commons Science and Technology Committee said using public money on homeopathic remedies could no longer be justified. The cross-party group said there was

no evidence beyond a placebo efby the medical establishment. fect, when a patient gets better beSales of homeopathic and ancause of their belief that the throposophical medicines grew by treatment works.

60 percent between 1995 In medicine it is and 2005, from €590 recognised that some million in 1995 to people will get better €775 million in because they believe 2001 and to €930 the treatment they million in 2005.

Value of homeopathy industry in France take is going to work.

Because of homeand Germany The MPs said the NHS opathy's impressive should not fund treatand growing popularity in ments on this basis. They argued Europe, this alternative treatment the effectiveness was often unpreposes a significant threat to condictable and involved a deception ventional medicine.

€400 million

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UPFRONT 15 UK manufacturers and supHomeopathy is particularly porters of homeopathy disputed popular in France, where it is the the report from the House of leading alternative therapy. In Commons Science and 1982, 16 percent of the population Technology Committee, saying used homeopathic medicine, rising the MPs had ignored important to 29 percent in 1987, and to 36 evidence. percent in 1992. In 2004, 62 perSupporters believe the remecent of French mothers used dies help relieve a range of minor homeopathic medicines in the preailments from bruising and vious 12 months. A survey of swelling to constipation and inFrench pharmacists was conductsomnia, but the MPs said homeed in 2004 and found that an asopathy was basically sugar pills tounding 94.5 percent reported that only worked because of faith. advising pregnant women to use There have been previous homeopathic medicines. warnings from the World Health The German government Organization, which said last year mandated that all medical school that people with conditions such curricula include information as HIV, TB and malaria should about natural medicines. not rely on homeopathApproximately 10 peric treatments. cent of German docNick tors specialize in Beeching, a spehomeopathy, with of German doctors cialist in infectious approximately 10 specialise in diseases at the percent more prehomeopathy Royal Liverpool scribing homeopathic University Hospital, remedies on occasion. said at the time to the BBC: A cross-sectional survey “Infections such as malaria, HIV was conducted in a large random and tuberculosis all have a high sample of 516 German outpatient mortality rate but can usually be care physicians with qualifications controlled or cured by a variety of in 13 medical fields representative proven treatments, for which of a basic population of 118,085 there is ample experience and scistatutory health insurance physientific trial data. cians in November and December “There is no objective evi2005 as part of a national healthcare dence that homeopathy has any survey. In this survey, 51 percent effect on these infections, and I were in favour of CAM use (26 perthink it is irresponsible for a cent were very much in favor, 25 healthcare worker to promote the percent were in favour). This suruse of homeopathy in place of vey found that 38 percent of the proven treatment for any lifemedical doctors prescribed homethreatening illness.” opathic medicines.

A survey done by Bristol In the UK, the NHS spends Homeopathic Hospital found that around GBP£4 million every year 70 percent of patients said their on homeopathy and the British health improved after treatment. government supports four NHS However, while the MPs said that Homeopathic Hospitals - Bristol, patient satisfaction is important, Glasgow, Liverpool and London. they concluded that it isn't proof While over 400 GPs in the UK regthat a treatment works, the British ularly refer patients to homeopathpaper The Guardian reports. ic clinics.

NEWS IN PICTURES

A copy of the 2000-page healthcare bill, part of US President Obama’s renewed efforts for healthcare reform

10%

Swiss drugmaker Novartis appoints former Head of Pharmaceuticals Joe Jimenez as Chief Executive

Algerian public health workers striking in Algiers over salaries and working conditions

Demonstrators call for the release of 43 arrested health workers outside the Court of Appeals in Manila, Philippines

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MERGER CLOSES Despite declining sales, Pfizer reported a 26 percent jump in third-quarter profits, as planned cost cuts offset massive industry lags. Pfizer Inc., already the world’s largest pharmaceutical company, has been a hot topic in the news recently thanks to the completion of its $68 billion acquisition of Wyeth, which closed in October. Now, with reports showing net income in the firm's most recent quarter at $2.88 billion – up from $2.28 billion a year earlier – Pfizer is riding high again.

With the acquisition now complete, Pfizer now employs 4500 former Wyeth employees at facilities in Collegeville and Great Valley.

However, Pfizer has already made moves to consolidate quickly now that the merger – announced in January – has been finalised.

AID TO HAITI On 12 January, Haiti was rocked by the largest earthquake ever recorded in the area. The incident has sparked a call for emergency aid across the world, and now, thanks to Novartis, the pharmaceutical industry is getting on board too. According to reports, global pharmaceutical firm Novartis is, through its local organisations in countries throughout the region, set to provide the equivalent of over $2.5 million in immediate emergency aid for victims of the disaster. Reports show that this support will include both direct financial aid to relief agencies working in Haiti, as well as donations of essential medicines, including antibiotic and pain relieving drugs.

MERCK PROFITS Whereas Novartis has had steady Q3 profits, Merck & Co. has posted a huge profit margin due to higher than average sales and the sale of a business.

A large part of that income came from the sale of half of the Merial animal health business so that regulators would approve Merck’s plan to buy New Jersey neighbour Schering-Plough Corp. That sale alone saw the company reap an impressive $1.7 billion (after tax), but even without it, profits would still have been up 58 percent from the year before.

As a result of its profitable year, Merck is moving up from number eight to number two on the pharma power ladder with its pending $41 billion acquisition of Schering-Plough.

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HIV FIGHT Abbott has announced FDA approval of a new tablet formulation of antiretroviral medication Norvir. According to reports, the move will help Norvir – which is used in combination with other medications to treat HIV– to boost the fight against the disease.

The new tablets, which can be stored at room temperature and do not require refrigeration, will hopefully make treatment more convenient for patients. According to reports, while the new tablet and the Norvir softgelatin capsules both contain 100 mg of ritonavir, and the rate the drug is absorbed is different, Abbott say there is no requirement for dosage change.

What’s more, all forms of Norvir, including the soft-gel capsule and liquid form, will remain available in the US.

PREVENTION STUDY Researchers have revealed that Africans who took AIDS drugs were far less likely to infect their partners with the virus. The study, presented at a meeting of AIDS experts, is one of the first to show so clearly that the drugs can prevent infection as well as keep patients healthy. It could boost efforts to provide the AIDS drugs to people, especially in the hardest-hit countries in Africa.

There is a debate over whether treating patients also reduces the likelihood that they will infect others. It is an important point as governments and non-profit groups spend billions on treatment and prevention programmes.

AUSTRALIAN PHARMA According to companiesandmarkets.com Australian pharma is regarded as the second most attractive market for investment in the Asia Pacific region, behind Japan. While its expanding and ageing population, excellent access to medicines and fast-recovering economy (among other factors) provide opportunities to multinationals, entry and earnings potential is counteracted by the government’s cost-containment measures, best illustrated by its efforts to keep the wide-ranging Pharmaceutical Benefits Scheme (PBS) drug subsidy programme affordable through price cuts and the use of generics.

Over the next 10 years, therefore, we forecast that spending on pharmaceuticals – including all prescription and over-the-counter (OTC) medicines – will increase at a compound annual growth rate (CAGR) of 3.16 percent in local currency terms.

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DRUG INFO PLEDGE A call for new initiatives to complete Commission proposals that would liberalise European controls on the provision of prescription drug information to patients has come courtesy of Europe’s new Health Commissioner-designate.

John Dalli, who is the Commissioner-designate for Health and Consumer Policy (SANCO) in President Jose Manuel Barroso’s new Commission, has told ministers that the current draft directive

needs to be reassessed. According to Dalli, “Patients have the right to have access to proper information on prescribed medicines. We have to reassess the proposal and put a better one on the table.”

If successful in his nomination, Dalli would also be taking on responsibility for the European Medicines Agency, and in his written answers to the ENVI panel he says he is looking forward to the upcoming evaluation report on the Agency’s functions.

FROM THE VAULT In the Q3 2009 issue of NGP, Håkan Björklund tells of Nycomed’s acquisition of Altana Pharma and how the company meets the challenges of its extraordinary growth.

Go to www.ngpharma.eu.com, click on ‘Previous issues’ underneath ‘Magazine’, choose ‘Issue 8, July 2009’ and scroll down to ‘Cover stories’ to read about the importance of partnerships in Nycomed’s strategy.

COMMUNICATION, COLLABORATION AND CULTIVATION Physicians often turn to key opinion leaders (KOL) for knowledge and advice on specific drugs. Interacting with these high-credibility contacts in a structured and targeted manner thus becomes increasingly important for pharmaceutical companies. The KOL management communication strategy of pharmaceutical companies is rarely uniformly executed, however. A systematic approach to KOL’s needs to involve all customer-facing business functions should be incorporated in the overall CRM strategy in three key areas: communication, collaboration and the cultivation of relationships.

Communication with KOLs is all about timing the right message to the right person.

Finding the right KOL in a therapeutical area is best done by segmentations based on direct feedback factors, such as a number of annual publications and appearances from the ones closest to the individual physicians, which are most often field sales. The CRM system needs to capture this information and link it to the ongoing segmentation process.

Collaboration is important to KOL management as interactions with KOLs include everything from the participation in clinical trials to the KOL speaking at events. With a userfriendly CRM system as the backbone, pharmaceutical companies get an easily navigatable 360-degree view of these key contacts. The CRM system should furthermore interact seam-

lessly with the most commonly used IT platforms, such as Microsoft SharePoint Portals and mail clients such as Microsoft Outlook.

Finally, KOL management is a cultivated process – something you do with your key contacts, not to them. Thus your processes and especially your CRM system should be easily adaptable to accommodate changes in the behaviour of your contacts. A good example of this high adaptability is Microsoft Dynamics CRM, in which CDM Optimize is built.

Focusing on communication, collaboration and cultivation in the CRM system helps you build the foundation of successful KOL management.

For more information please visit www.cdm.com

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GROWTH FOUNDED ON RELATIONSHIPS SI Associates continues to see its life sciences consulting business grow, with industry-leading levels of customer retention and referral and an expanding global reach. Recently selected to partner with global top-five pharmaceutical and medical device companies in improving the cost and capability profile of their supplier bases, SI also continues to support its clients in getting safe and efficacious new products to market as quickly as possible.

In the first couple of months of 2010 SI has commenced work on four new, client-strategic pieces of work. The first, an extension of scope on a supplier development project with a leading global pharmaceutical company, will extend existing double-digit million-dollar cost savings across all operating divisions. SI is also commencing work with another global pharmaceutical business to help their development operation reduce time-to-market by implementing the principles of operational excellence and Quality by Design. In the third new project, SI has begun working with a major medical equipment manufacturer to

improve the capability of its supply chain, reducing cost and improving quality. The firm’s consultants have also started work with a US-based pharmaceutical business to help optimise a drug development project, again using the principles of QbD and Design for Six Sigma in an ‘applied’ fashion.

“This success reflects the contribution that our consultants make when working closely with our client partners as part of their team, building relationships based on performance, respect and trust”, said Harry Clark, SI’s Managing Director.

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FEREYDOUN FIROUZ, PRESIDENT AND CEO, EMD SERONO Acting fiscally responsible during these times is important to ensure a sustainable business in the future and in the healthcare business. It also impacts, to a certain extent, the drug reimbursement system in America.

The economy has obviously had an impact on our business model: some of our compounds, mainly our infertility franchise, have an out-of-pocket personal pay. That means it is a cash segment, so patients may have to pay with their own money. It’s not fully insured in certain states, so we’re seeing some decline in that segment of our business.

The key to innovation is developing compounds that are differentiated and have clear clinical benefit on efficacy, safety and convenience. We’re fortunate in that we have those products in the market and our pipeline is about creating those types of compounds.

As a commitment to ensuring patients have access to our products through our patient assistance programs, we are also in a fierce competition across our formulary positions on the insurance business, and that is important for us to manage.

We don’t behave like a standalone company in our community and only take care of our business. We need to be active within our community and help, and as we grow we want the community around us to grow and to benefit also.

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THE CURSE OF GLOBALISATION Counterfeit drugs are today a big concern to the pharmaceutical industry and endanger the public health worldwide.

FT-NIR spectroscopy offers a tool for the quick and cost-effective detection of fake drugs. Many products of our daily life are nowadays traded over the internet. Even medicines can be ordered discretely on the internet with a delivery directly to the doorstep. The dark side of the internet drug trade is obvious: many websites offer drugs without prescription and of unverified origin. One major problem with fake drugs is that the counterfeiter has no knowledge on how to copy a drug accurately, and sometimes, they do not even try. In Asia more than 50 pecent of counterfeit malaria medicines contain no active ingredient and even trusted and verified online pharmacies unknowingly sell these counterfeit drugs. Many customers and authorities examine at present whether a global testing of drugs is possible. FT-NIR spectroscopy is the most promising technology and already well established for pharmaceutical quality testing. The big benefit is that FT-NIR spectrometers like the MATRIX-F system of Bruker Optics can be taken into the field. By using mobile units, networks can be built up for a nationwide fight against counterfeit drugs.

In 2001 the Chinese State Food and Drug Administration initiated a research project to evaluate the NIR technology for this task. In the meantime, more than 350 FT-NIR systems are built in small vans scrutinising drugs all over China.

This way it can be ensured that legal drug providers have no counterfeits in their portfolio. Already on day one, the first counterfeits were found in legal pharmacies. Other countries will copy the example of China. With the help of modern analytical technologies at least the legal distribution channels can be made substantially safer, for the wellbeing and the security of the people.

FAST FACT

Increased regulation to cope with the influx of counterfeit medicines could cost between

€2 billion and €4 billion per year

IDENTIFYING WEAK SPOTS The new version of the Trebing & Himstedt OEE (overall equipment effectiveness) best practice makes downtime and failure analyses easier than ever before. Based on SAP MII, the smart KPI solution of the SAP Special Expertise Partners for Life Science enables monitoring of production processes in real time, as well as identification of weak spots with a few well-targeted clicks.

Data from various information sources on the shop floor and throughout the company are processed as respectively relevant and depicted via a web browser in a clearly arranged display – in the required form of visualisation and degree of detail. In this way, the OEE solution monitors and analyses machine efficiency by means of KPI calculation, failure analyses and monitoring of the production process.

A flexible role concept enables different views and selective evaluations: workstation views for machine operators and machine group and workstation views for shift supervisors, and a complete view of all plants, equipment and machine groups for site managers. This means, for example, that machine operators are constantly able to check their compliance to performance standards in real time via aggregated dashboards on the shop floor.

Site managers, on the other hand, can also run detailed error analyses over a certain period of time. The OEE best practice provides the following evaluation and analysis tools: KPI calculation, detailed downtime, failure and quality analysis with top 10 lists, quantity and time-based total-vstarget analyses, and overviews of orders and machines. The KPI solution also supports Lean manufacturing strategies inside the enterprise.

For more information, please visit www.t-h.de

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UPFRONT 24

OUTSOURCING

GSK JOB CUTS

Leading British-Swedish pharmaceutical company AstraZeneca has announced that it is to cut 8000 jobs worldwide as it embarks on one of the biggest shake-ups seen in the industry’s history.

According to analysts, the job cuts are likely to result in the loss of 1500 jobs in the UK, where AstraZeneca has research and development (R&D) operations in several locations. Analysts

GlaxoSmithKline is expected to announce thousands of job losses. The UKbased pharmaceutical giant is reportedly likely to follow in the footsteps of other drug companies, including key rival AstraZeneca – who announced similar cuts recently – by announcing cuts.

Like many big pharma companies, GSK is facing the harsh reality that several of its blockbuster drugs are either about to lose, or have already lost, their patent protection in Western countries, with the US and European governments continuing to bear down on medical costs. The announcement is likely to continue the push by GSK to reduce the workforce in the US and Europe, while continuing to expand in Asia.

FAST FACT

Autism is the fastestgrowing developmental disability, with a

1148% growth rate

have also speculated that the pharmaceutical giant will shed as many as 3500 posts from its R&D facilities across the globe as it tries to cut costs.

The reasoning behind the cuts is to save money. The overall plan is to outsource more of AstraZeneca’s research and development function – a division largely defined as the heart of any pharmaceutical company – to pharmerging markets such as China.

AUTOMATED TUBE DECAPPER ENHANCES LAB PRODUCTIVITY Hamilton Company, world leader in fluid measurement, introduces the DeCapper – an automated instrument for the opening and closing of screw-capped tubes. The programmable DeCapper opens a row of 12 tubes simultaneously, increasing productivity over one-at-a-time methods and providing more flexibility than systems that decap 96 tubes at once.

The instrument operates from outside to inside rows, eliminating the possibility of drip contamination that can occur with the 96-tube decappers. Built-in torque monitoring ensures a consistent seal and reports the exact location in the event a tube is not completely sealed. After removal, the caps are placed on a separate, removable cap holder, which enables batch processing. Ideal applications for the DeCapper include storage of biological materials like DNA, cells, blood, tissue and plant materials as well as compound library storage in drug discovery research.

The DeCapper can operate as a standalone system or controlled by the MicroLab Venus One software, for integration with Hamilton Robotics’

automated pipetting workstations. For added flexibility, the DeCapper remains available for manual runs without removing it from the integrated workstation. It is also an ideal accessory for the sample access manager platforms from Hamilton Storage Technologies, including the company’s -20˚C and 80˚C storage systems.

“Our new DeCapper adds functionality to Hamilton systems and also works well in standalone use,” commented Jason March, dealer product business unit manager for Hamilton.

“It delivers the combination of flexibility and throughput that all labs are looking for today.”

Hamilton Company is a leading worldwide supplier of precision liquid handling equipment, laboratory automation and storage systems, serving customers in academic and private research laboratories, pharmaceutical and clinical diagnostic companies and governmental institutions. Hamilton maintains headquarters in Reno, Nevada and Bonaduz, Switzerland, both of which house R&D and production facilities.

For more information, visit www.hamiltoncompany.com.

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FAST FACT The International Diabetes Federation estimates that there are

246 million adults with diabetes

COMPANY INDEX Q1 2010 Companies in this issue are indexed to the ďŹ rst page of the article in which each is mentioned.

EggCentris 114, 115

Metastorm 4, 154, 155

Siemens Water Technologies 73, 75

Eli Lilly 86

Nabi Biopharmaceuticals 116

Skyscan 96

Amgen 32

ESP 47, 48

NextGen Sciences, Inc. 102, 104

Taconic 6, 84, 85

Amphora Research 99

Eurand 11, 78, 79

NNIT IFC, 125, 127

Thermo Fisher Scientific 37, 38

Anagnostics Bioanalysis GmbH 90, 91

Eurofins Medinet. 102, 107

Novartis 110

Trebing & Himstedt 22, 23

Farmak 67

Novartis Pharma Technical

Ubichem Plc. 2, 68, 69

Aventis Pasteur 116

Frost & Sullivan 28, 132

Operations 40

Umetrics 83, 152, 153

Biocrates 108, 109

GE Healthcare 150, 151, OBC

Onorach Ltd 124, 125

Van Spaendonck 137

Bio-Rad Laboratories, Inc. 13, 112, 113

Geodis Wilson 58, 59

Pilgrim Software 149

Veolia 72, 73

GlaxoSmithKline 76, 94, 102, 146

Pfizer 80

Xceleron 128

Burkert 27

Hamilton 24, 25

PharmaFlow 21

Xenogen Biosciences Corporation 84

Caudex Medical Ltd 142, 143

IDEA Pharma 134, 135

PricewaterhouseCoopers 28

CDM 18, 19

IMS 140, 141

Quintiles 120, 121, 144, IBC

Celgene Corporation 122

International Anti-Counterfeiting

Rules-Based Medicine 100, 101

CellAura 92, 93

Coalition 64

SanMed 132

Cohn & Wolfe 136, 137

Iris Global Clinical Trial Solutions 130

Sanofi Pasteur 54

Corbett Accel 130, 131

JMP 8, 52, 53

SherTrack 47, 50

Dividella 60, 61

McKinsey 160

SI Associates 19, 42

Dr Reddys Laboratories 62, 63

Meettheboss.com 139

Siemens 70, 71

3P Partners 46, 47 Aegis Analytical 57

AstraZeneca 28

Bruker Optics 22, 119

Burkert AD.indd 1

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COVER STORY

MIRACLE CURE?

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In an ailing industry desperately casting about for a way to save itself, the rapidly emerging field of pharmacogenomics could provide a life-saving tonic.

By Marie Shields

T Reaping the benefits The potential benefits of pharmacogenomics could include: The ability to make better medication choices.

In the UK, 10,000 people a year die from adverse reactions to medications.

Pharmacogenomics may be able to reduce the number of adverse reactions by predicting who is most likely to react badly to a particular drug.

Safer dosing options.

Standard doses used today can prove toxic to those with certain genetic make-ups. Using pharmacogenomics, doctors may be able to predict which dose will work for which patients.

Improvements in drug development.

Pharmacogenomics may help drug companies better focus their drug development programs, by predicting in advance which people will have adverse reactions to a drug before it is tested. These people can then be excluded from clinical trials.

Source: www.mayoclinic.com

here can be no denying the fact that the pharmaceutical world is in flux, if not downright turmoil. The old blockbuster model has fallen by the wayside, and even the big players are seeking a cure, with some gobbling up their rivals in an attempt to boost flagging pipelines. But there is another option that could be a lifesaver for the industry – pharmacogenomics, also known as personalised medicine.

Personalised medicine in healthcare is defi ned as the need to consider an individual patient’s unique lifestyle and medical history, and how this impacts on his or her response to treatment. In pharmaceuticals, however, personalised medicine aims to develop drug therapies that have efficacy within narrowly targeted groups of patients, based on each person’s genetically programmed reaction to the drugs.

The foundation of this type of personalised medicine is the fact that two people can take the same medication and have completely different responses: one may have severe side effects, and the other none at all. Or the treatment may lead to remission in one person, and seem to have no effect in the other.

One reason for these different outcomes is the variation in our inherited genetic make-up. Genetic variations can determine how we respond to treatment, similarly to the way they cause differences in eye or hair colour. For example, if you have a genetic variation that causes a drug to stay in your body longer than normal, this may cause unwanted side effects.

Researchers are working to identify these genetic variations and match them with responses to medications, so that physicians can take this into account when prescribing drugs. In addition to the usual information such as weight, age, medical history and how any relatives may have reacted to the same medication, doctors in the future may be able to take into account your own personal genetic make-up.

The field of personalised therapies – and the diagnostics used to develop them – is growing so rapidly that at the end of last year PricewaterhouseCoopers released Diagnostics 2009, the fi rst in a series of annual reviews of significant events for personalised medicine.

According to Tony Pillari, PwC’s Director, Healthcare Advisory Services, the report was developed for three key reasons. First, the level of deal activity in the in vitro diagnostics sector, which PwC feels is significant and likely to increase in the coming years, creating a multitude of business opportunities.

Second, the growing importance of diagnostics in the practice of medicine and in the emergence of personalised medicine. And third, the many exciting advances that have been made in recent months in the field of personalised medicine, including those related to diagnostics.

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Testing time The following genetic tests are currently in use. They help guide dosing and prevent toxic levels of medication from building up in patients who lack certain enzymes.

Cytochrome P450 test. This group of enzymes are responsible for metabolising more than 30 types of medications. The test can determine dosing and effect of some antidepressants, anticoagulants, proton pump inhibitors and a number of others.

Thiopurine methyltransferase test. This enzyme breaks down the chemotherapy drug thiopurine, which is used to treat leukaemia and autoimmune disorders.

UGT1A1 TA repeat genotype test. This test detects a variation in a gene that affects the UGT1A1 enyme, which determines how the body breaks down irinotecan, a drug used to treat colorectal cancer.

Dihydropyrimidine dehydrogenase test. This enzyme breaks down the drug 5-fluorouracil is a commonly used chemotherapy medication.

Source: www.mayoclinic.com

In PwC’s definition, a personalised medicine diagnostic is any tool that allows for the generation of data that are then used to tailor prevention and care strategies the needs of the individual. Such tools would include companion diagnostics, early diagnostics and prognostics.

More accuracy Tailoring the treatment to the patient is not an entirely new idea.

What’s different about this new definition, says Pillari, is the specificity and accuracy that advances in genomics and proteomics and a whole host of related technologies now make possible.

“We now have a much deeper understanding of many diseases, including complex diseases like cancer, at the molecular level, and our knowledge continues to grow,” he says. “That kind of understanding simply wasn’t possible before. As a result, the way we treat disease, including how we design treatment options for patients, has changed to a point where trial and error will hopefully be replaced by trial and success.”

Pharmaceutical companies looking to maximise success rates will be able to determine which subsets of patients would be more likely to respond positively to their drugs. This happens to some extent already, with companies often targeting subsets of patients if initial trials with larger groups don’t yield the expected results. AstraZeneca, for example, did this with its anti-cancer drug Iressa. In 2004, a large randomised study failed to demonstrate a survival advantage for the drug in the treatment of nonsmall cell lung cancer, but it has since been shown to be effective in patients with mutations relating to epidermal growth factor receptor.

Jan Lundberg, formerly AstraZeneca’s EVP for Discovery Research and now head of R&D at Lilly says that even in the last couple of years there have been major developments in personalised healthcare and combined diagnostics. He highlights the CNS area of Alzheimer’s disease, where the pathophysiology is increasingly known, based to a large extent on genetic analysis of patients with hereditary Alzheimer’s. “Here we have a PET ligand as a new diagnostic tool,” he says, “and you can see if patients have accumulated amyloid in the brain, which is a strong signal that the risk of developing Alzheimer’s is high. You can follow the accumulation of amyloid and potentially prevent amyloid deposits or reduce them if they are already there, which is likely to influence the disease.

“There are some new agents coming in, which are tested to prevent accumulation of or to deplete amyloid, which offer a way of combining diagnosis and potentially following the effects of anti-amyloid treatments and correlating that with improvement in cognition, again taking a personalised healthcare treatment approach.”

Lundberg believes treatments developed for specific patient populations will become more common within the pharmaceutical industry, as traditional business models change and as progress in technology and science make this possible.

This applies particularly in oncology, as he explains: “In oncology we have the ability to analyse tumour biopsies or blood samples for their respective tumours. We can let science drive the benefits for patients both in relation to maximising the potential for clinical effect and also reducing risk. It’s still an evolution, but the trend is very clear.”

Earlier analysis Lundberg does point out, however, that ideally R&D organisations should work out beforehand which groups of patients are likely to benefit, rather than waiting until the drug has been developed and then looking for people it can help.

“A key aspect will be to identify these opportunities early enough.

With Iressa, we only established which patients would respond when the drug was already on the market. It would be better if we could do this at the time of, or even before, nominating compounds to the clinic in a new area.

We could analyse this tumour population to see if there are specific pathways that are particularly prone to be more responsive, and then design the compounds against these pathways and select patients in early clinical trials that could be maximally responsive, based for instance on genetic analysis of tumour biopsies.”

PwC’s Pillari believes specialised therapies can help pharmaceutical companies improve their bottom line. “The blockbuster model has been the predominant model in the pharmaceutical industry for some time and until recently, it has been very successful. However, the poor return on R&D investment realised by that model over the past few years, in terms of new drugs developed and introduced into the marketplace, has been well documented, as has the number of drugs coming off patent in the next few years.

“As a result, and quite understandably, pharmaceutical companies are very concerned about pipelines and future revenues. In this context, the

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move to specialised therapies is relevant to the pharmaceutical industry for two reasons. First is the potential to reduce drug development time and costs and increase success rates through enriched clinical trials.

“These are trials that only include those people who, based on the analysis of their make-up at the molecular level, are most likely to respond to a given drug. Second is the opportunity to move to a ‘niche buster’ model, that is, one that generates revenue because of the value a specialised therapy delivers to a specific subset of patients.”

There are some within the industry who see a potential downside to the advent of personalised medicine. David Lathbury, AstraZeneca’s Director of Process Chemistry, believes it will only help big pharma improve its business models if it translates to a much more reduced cost of development. If it doesn’t do this, he says, the simple net present value calculation means that companies won’t make money. “If you can very quickly identify the target groups, if you can get through phase III with, for example, 200 patients, then absolutely it will be a benefit. But if you’ve got to go through the same process before you identify that population, it could be very difficult.”

Lathbury says that where personalised medicine could make a difference is in dosing regimens, which could help drive through a better result.

“We tend to give everyone an average dose, that’s the way most clinical programs are designed. If better titration of dose will reduce adverse events, increase compliance and get a better return on the drug, those steps I think we can take.”

Then there’s the view we could go much further. Dorman Followwill.

Partner and VP, Healthcare EIA for Frost & Sullivan, describes his idea of the ultimate version of personalised medicine. “If you’re talking about the holy grail of personalised medicine, it would be walking into a physician’s office, pulling out a smart card that has your genotype on it, and having them plug it into their system and then diagnose you or dispense medication for your genotype.

“Estimates of when we might achieve that vary from 10 to 15 years, to as long as 100 years. However long it takes, we will see increased personalisation over time because that is a mega trend in the world today. In my role, I get to look at some of the 360-degree views of many industries produced by our team, and the topic of personalisation comes up big time

What are biomarkers?

Biomarkers can be a sign of a normal/abnormal process, or of a condition or disease. For example, blood pressure is widely accepted as a biomarker because large epidemiologic databases exist demonstrating a correlation between elevated blood pressures and adverse cardiovascular outcomes. This has been supported by the numerous placebo-controlled studies showing an effect on stroke and coronary heart disease outcomes from lowering blood pressure.

US FDA Pharmacogenomics Guidance further defines three categories of biomarkers: exploratory, probable and known valid.

Markers are included in these categories based upon available scientific information.

in healthcare, in automotive and transportation, and in environment and building technologies.”

Popularity The version of personalised medicine as it exists today has proven popular with regulators. In some cases, they now insist on biomarker testing to guide drug prescribing. Tony Pillari believes their main concern is efficacy. He points the testing for infection by a specific HIV subtype that is required prior to the use of Pfizer’s Selzentry treatment, which he says is based on the fact that Selzentry blocks the specific receptor that HIV subtype uses to attach to and infect white blood cells.

“Similarly,” he says, “testing for epidermal growth factor receptor (EGFR) expression is required prior to the use of Erbitux because Erbitux binds to EGFR and blocks certain growth factors that ultimately promote the expansion and spread of tumours. We believe this practice will become more common, as everyone in the healthcare value chain, from regulators to pharma to providers to patients to payers, appreciates the benefits of improving drug efficacy as well as reducing the frequency of adverse events.

Yet despite the fact that the clinical case for developing companion diagnostics is strong, the PwC report points out that there has yet to be significant deal-flow between the pharmaceutical and diagnostics industries, because while the existing pathway for drug approval and reimbursement is clear and well-established, this is less so for diagnostics and even less so for drugs and diagnostics developed in tandem.

Pillari does point out that there are a number of encouraging initiatives underway, including by the FDA and the Critical Path Institute, to better define the pathway for drug and companion diagnostics development. As this pathway becomes clearer, and the risks associated with such strategy are mitigated, he expects deal-flow between the two to increase.

However you look at it, and even with its potential downsides, there is no backing away from pharmacogenomics, with its potential to bring once-dead drugs back to life by allowing them to be repurposed for new populations. In a beleaguered industry suffering from the twin ills of dry pipelines and no blockbusters, personalised medicine could provide a life-saving shot in the arm.

Source: www.c-path.org

Biomarkers can be further divided into the categories of predictive or prognostic. A prognostic biomarker is associated with the likelihood of an outcome (eg. survival, response, recurrence) in a population that is untreated or on ‘standard’ (non-targeted) treatment.

A predictive biomarker can predict differential effect of treatment on outcome. A predictive biomarker is a biomarker that is present prior to an event occurring and which predicts that outcome. For example, the KRAS oncogene can be considered a negative predictive biomarker for response to treatment with the EGFr (epidermal growth factor receptor) class of drugs since it can identify which patients are unlikely to respond to treatment with an EGFr inhibitor.

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MILETICH_mar10 09/03/2010 14:59 Page 32

THE BIG INTERVIEW

The

INNOVATION

AGENDA

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Joe Miletich tells NGP why in these uncertain times, it’s more important than ever for pharmaceutical R&D to pursue novel compounds.

I

n common with most top 20 pharma companies, Amgen rode the wave of blockbuster success in the late 1990s and early 2000s, but now finds itself staring at the twin threat of patent expiries and a lack of big earners coming out of the drug pipeline. Amgen’s answer is to “reignite” its innovation engine. But what does this actually mean?

In its largest sense, any change can be labeled as innovation. But as Joe Miletich, Amgen’s Senior Vice President for Research and Development points out, you’re not going to get very far by doing things the same way they’ve always been done. In this way, innovation is essential to a company’s survival.

His definition of the term ‘innovation’ as it is used in the current context of drug discovery means not just bringing in change but bringing in change at a very significant level: changing the practice of medicine and changing what people understand and believe about what can be done in disease conditions.

“That’s the highest level of innovation when you’re in the drug discovery and development business,” says Miletich. “You want to change the way people think about a disease and make things possible that weren’t possible before.

“I think society truly wants our industry to focus on the highest level of innovation, but in our current climate there are a couple of things that are acting against that larger goal. The first is a fear of being reckless and having an insufficient regard to safety; and the second is a concern about how we are going to pay for it, because it’s very costly to be this innovative.

“The only reason people might be reluctant to be highly innovative now is because of a worry that we’re at a temporary phase where the concerns about safety and reimbursement have become so prominent in our thinking that what we would normally expect as rewards for innovation might not be there.”

The long game Miletich believes it is more important than ever to be innovative in the current climate. He underlines the obvious fact that discovering and developing drugs is a long cycle business: the time from an original idea until a drug reaches the market might be 12 or 15 years. Companies work constantly to reduce that time, yet at the same time ever more stringent safety and efficacy requirements act to increase it.

He remains optimistic, however, that the need for innovation will win out in the end. “In the long term,” he says, “what we fundamentally need as a society and human beings will prevail and the truly innovative things will be rewarded. When you think about this as a long-cycle business, as a company we need to pay attention to that and bet heavily on it.

“That doesn’t mean we won’t do anything that isn’t the most highly innovative thing we can think of. There are very practical benefits to being innovative on a less expansive scale, and we do make improvements to

medicines. We’ve done this in the past, and we’ll continue to do so where it brings benefit.

“It’s all in how you weight your portfolio. We weight our portfolio so that roughly two-thirds of what we’re doing are highly innovative things. It’s a conscious choice. We make the choice to do that and then set ourselves up so that we can find people in our own research labs and in all the connections we make with small companies and with academic collaborators around the world – find those innovative insights that will help change the practice of medicine.”

A major focus of Miletich’s role at Amgen is to oversee the translation of drugs from discovery through early stage clinical trials. He points out that at Amgen, translational medicine is not limited to early clinical trials and biomarker research.

“Of course we have a terrific medical sciences group that places an enormous emphasis on biomarkers and we concentrate on our experiments in people to discover whether that fundamental idea that we started with back in the research labs actually does have enough impact in human biology to let us change the practice of medicine.

“But that’s not the only thing that’s important when you’re trying to

“This is an unusual time to be in the pharmaceutical industry: our fears and concerns are at a peak at the same time that our hopes and aspirations are also at a peak” translate that original idea. You also have to understand how to make a molecule at large scale, how to formulate it and what the attributes are that will become important in human biology, and how you would recognise if you needed to make something that was changed.

“You have to incorporate all you learned from your pharmacokinetics and drug metabolism studies to know and appreciate the characteristics of those molecules and how they behave, and you certainly have to understand all of your toxicology assessments so that you can clearly make a weighted judgment about what risk you will expose patients to and become very convincing and fluent and provide appropriate scientific evidence about the safety factor that you’re employing when you embark on those experiments.

“Even more than all of that, when you integrate your learning from all of these different sciences that go into what molecule you want to make and how it performs, as well as what actually happens when you do this in biology, you can learn a great deal more. You can learn a great deal about how things work in the human body.”

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Miletich and his team work to integrate the different sciences needed to move a candidate molecule forward and develop it with the optimal properties for a potential human therapeutic, in order to learn as much as they can about what goes on in human biology and to carry out the most informative experiments. They then use that information to make judgments about how to weight the portfolio and where to make the investments that are the most likely to pay off with the greatest benefit to people.

Challenging times

HAN MORE T

17 MILLIONE

S HAV Producing breakthrough drugs that PATIENT AMGEN radically change the way we look at disD AN RECIEVE ICINE ease might be every R&D team’s dream, MED but what about the challenges in then bringing that drug to market? Only about one in every 10 drug candidates that enter clinical trials are eventually approved by the FDA, and the cost of all these failed drugs is another major challenge for the industry. How can pharma companies raise their success rates and cut down the amount of money spent Joe Miletich is clearly a man who loves his job: He moved into the pharmaceutical industry in his enthusiasm shines through when he talks conducting trials for drugs that never 1999, taking a position at Merck in the about his responsibilities as Amgen’s Senior come to market? toxicology group and then heading up the Vice President for Research and Development.

“Companies may understandably company’s worldwide pre-clinical development . try to reduce drug discovery and develMiletich certainly boasts a varied career In 2002, Miletich joined Amgen, and for the opment to a methodology that can be background: after completing an MD and a first four years was responsible for repeated for project after project,” PhD in molecular biology at Washington discovery research all the way through the Miletich says. “There is great efficiency University, he trained in internal medicine at first introduction of medicines into people. the University of California, San Francisco, in doing that so you don’t relearn how Since 2006 he has focused on translational then went back to Washington University to do things, and we do that when it is medicine. To top it all off, he is also a board where he was a faculty member for 18 years . certified clinical pathologist. appropriate as well and have no qualms about it. Where things are repetitive and we can learn to do them in a repeatable, efficient fashion, we do that at every opportunity.

“Every one of these innovative projects, important, but you continuoushowever, is a new adventure. It’s a pioneering discovery, and in order to oply review your portfolio and continuously monitor what the opportunity actimise how much you can do with the resources you have you need to make tually looks like relative to your original idea and adjust your investments decisions all along the way about what your level of investment is going to be. accordingly.”

“That means that when you integrate all this information that’s coming Miletich says that when this is done well and a good stable of candidates in in real time as you’re in this early stage of drug development, you should is selected at the very beginning, a fraction of these emerge quite early as havhave a sense, if you’re paying attention to all the information you have, about ing very promising characteristics that can then be invested in heavily and what your likelihood of success is, and about what your potential for doing pushed aggressively and quickly, thanks to the conviction that this drug good in how many people might be. My firm belief is that you should adjust should be developed and made available as fast as possible. your investment to those opportunities as you see them in real time.

“With some, another fraction, you find the idea simply wasn’t good “You don’t just set up a drug discovery and development organisation enough or your molecule wasn’t good enough, and when you find that early and turn a crank. You learn how to turn the cranks very efficiently where it’s 34 www.ngpharma.eu.com

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you can stop that investment, rethink what you want to do, and see if there’s an adjustment you can make. Then there’s a group in the middle, which can encompass 40-50 percent of the molecules, where you discover that there’s something else that you need to understand before you can gauge the value of the opportunity. For these candidates, you adjust and modify your investment and decide what that next piece of information is to allow you to make a decision about whether it’s worth investing in or not.

“You have to manage this portfolio in a very dynamic way. When you do that, you’ll increase your overall success rate, and you’ll increase the efficiency of the resource base you use. I’m optimistic that in another five or six years we will be able to point back and say it did result in an improved success rate.”

Although Miletich makes this process sound quite straightforward, in reality it is anything but. He explains that for a typical project at this stage there can be as many as 1000 different work streams. His team could be working on 30, 40, or 50 different projects and many of those work streams are interconnected, so that one that’s about to begin depends on the results from another one that has just been completed, which makes managing this resource base in real time an incredibly complex project management task.

Biomarker targets The use of biomarkers is often touted as essential weapon in this struggle to cut waste by ensuring more drugs hit their targets, but Miletich is quick to point out that biomarkers are not magic bullets. “Biomarkers are just tools,” he says. “They allow you to gauge whether you’re doing what you wanted to do and whether it’s as impactful as you wanted it to be.

“Sometimes when people talk about biomarkers, they make it sound as

though they can solve all our problems, and that it’s the biomarkers themselves that are important. But in fact the important thing is deciding what you want to do, what your idea is, whether it works and whether it is impactful.

Biomarkers help you determine whether you’re doing that or not, and you have to have a full toolset of biomarkers to do that.

“One of the things that might not be evident to people who aren’t familiar with the business is that while in human medicine we have a large number of tests that are available through physicians and hospitals and we have a lot of imaging tools, those tools, assays and tests were developed for very specific purposes and often don’t answer the questions we’re asking now.

“So we have to set up new assays, new tools, new tests, and we have to understand how they perform in populations of people. All that work has to start very early on because it can take years to set up. Our goal is to always have those tests and assays in place by the time we are ready to do that experiment in people.”

All of this hard work has resulted in some interesting drug candidates moving through Amgen’s pipeline, including an osteoporosis drug known as AMG-785, which is now in phase II trials and about which Miletich is very excited. “We’re investigating AMG-785 along with our partner UCB, to find out what dose and schedule of this new therapeutic will enable us to restore a good level of baseline bone health to women with moderate to severe osteoporosis, and we’re also studying it in a phase II trial where we’re looking at very hard-to-heal fractures. In particular, we’re looking at fractures that happen in the tibial plateau, the top of the lower leg bone.

“Fractures there can often be problematic, not healing adequately or taking too long to heal. We’re investigating AMG-785 to see if we can improve

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Happy anniversary the speed or quality of healing in that setting.”

Amgen has a large number of therapeutic candidates in phase II trials in oncology, as well as a portfolio of molecules being studied in a variety of inflammatory and autoimmune diseases, including an extensive program of molecules in asthma. The company recently licensed a molecule from Cytokinetics and is studying patients with severe congestive heart failure to improve heart function.

“We’ve also recently introduced an antibody called AMG-145, which helps us lower cholesterol levels in patients that can’t otherwise reach target,” Miletich says. “We’re in phase I studies with that molecule. So we’re making some meaningful ventures into the cardiovascular arena, again where we’re using mechanisms that have never been explored in human biology, to do things in ways that were never possible. We continue to have new efforts in the diabetes, such as the deal we concluded in December with Array BioPharma to license their glucokinase activator, which is a very promising molecule that, if it is successful, will allow treatment of diabetes in a new and meaningful way as well.”

When asked how he sees pharmaceutical R&D developing over the next couple of years, Miletich smiles, and calls it an intriguing question. “In one sense if you take the pulse of the industry, there are pressures there that are unprecedented: concerns around safety, around reimbursement, around the

36 www.ngpharma.eu.com

In 2010 Amgen celebrates its 30th anniversary, having been established as a corporation on April 8, 1980.

Since then, the company has grown to become one of the world’s leading independent biotechnology companies.

• More than 17 million patients have received an Amgen medicine • The company has a presence in nearly 50 countries • Its focus is on discovering, developing and making human therapeutics • It specialis–es in innovative medicines for serious illness and is a pioneer in protein therapeutic manufacturing

productivity of the industry as a whole.

“At the same time, from someone in my position the prospect of doing important things for patients who suffer from grievous illnesses has never, ever been better, and it feels like a very unusual time to be in the pharmaceutical industry: our fears and concerns are at a peak at the same time that our hopes and aspirations are also at a peak, and no one knows how this will play out.

“If you look at previous examples of how humankind has reacted in other situations that are even remotely parallel to this, I would say that there will be tremendous advances, and there will be some things that we can’t predict that will take place in ways we can’t foresee. My guess is that some time over the next 10 years we might see some consolidation in the industry, but we’ll also see out of the next four or five years of effort some winning scenarios emerge, and those companies that are nimble and can adapt and that aren’t afraid of the opportunities will manage to be highly successful even though there are great concerns about the pressures on the industry at the moment.

“I hope, and will work diligently with all of my colleagues here at Amgen to ensure, that we are one of those companies that emerges with the success rate that’s necessary to move on to even greater things.” n

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INDUSTRY INSIGHT

The importance of integration Dave Champagne evaluates the integration benefits of enterprise-level laboratory information management systems.

E

nterprise-level integration is particularly relevant in today’s business climate where near instantaneous response is required by pharmaceutical companies to protect the public and the environment. Seamless enterprise-wide integration is a necessity because it enables key knowledge originating in the laboratory to be available to management in real time. As such, the world of laboratory informatics is changing to meet the needs of pharmaceutical companies, which are continually searching for ways to reduce costs, accelerate time-to-market and respond to increasing regulatory requirements.

Enterprise-level laboratory information management systems (LIMS) can help to streamline the flow of information successfully, providing companies with the information they need in today’s business climate to make critical business decisions.

Historically, industry standard LIMS have only delivered 30-40 percent of specific functionality targeted to each user’s needs, requiring extensive customisation to make that LIMS function in that particular setting. Such customisation is commonly only possible through the use of proprietary programming languages that are developed and provided by the LIMS vendor. The combination of minimal industry-specific functionality and often out-dated and/or costly proprietary languages has been particularly troublesome in the pharmaceutical industry. In addition, pharmaceutical laboratories often create their own user documentation, design documentation, validation scripts and help fi les. As a consequence, the implementation of LIMS in various laboratory settings has been, almost without exception, a long, costly and painful process not only during installation, but also in operating and maintaining the system over the years.

With pressure to cut costs, shorten the pipeline lifecycle and maximise return on investment, pharmaceutical companies need tools that help them improve enterprise-wide communications, reach critical decisions faster and produce timely, accurate reports on how compounds are progressing. Working with multiple disparate systems with minimal to no integration is no longer an option.

The growing mandates of global regulatory compliance and long-term data traceability, as well as the complexity of laboratory testing and emphasis on batch versus sample management, have forced pharmaceutical manufacturers into lengthy, expensive adaptations of generic LIMS to meet their specific

requirements. Extensive and costly customisation, validation and implementation periods, in many cases lasting 36 months or more, have become routine, resulting in decreased productivity. With the increasingly higher costs of bringing a new drug to market, pharmaceutical manufacturers cannot afford to delay the implementation of next generation tools that will make them increase productivity.

Today, global deployments of LIMS solutions have become more consistent and more rapid. The implementation of purpose-built LIMS across the enterprise allows for more simplified system upgrades, minimised project risks, and enhanced compliance. In addition, industry-specific solutions facilitate enter-

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prise-wide application and training. These multifaceted benefits help lower the total cost of ownership of the solution, which is critical to pharmaceutical companies that are under ever-increasing pressures to contain costs and increase efficiency. Th is goal can be achieved by integrating the LIMS with instrumentation and enterprise systems, which can facilitate the global harmonisation of business processes, automation of operations and consolidation of data management in a single system, allowing for near-instant decision-making.

Purpose-built integration solutions With drug development times of approximately 15 years and subsequent costs approaching US$2 billion (€1.5 billion) by 2010, pharmaceutical companies are increasingly in search of processes that can help them consistently deliver a return on investment during the patent life of a drug. LIMS are key contributors in this effort. Delivering advanced functionality that is specific to each stage of the drug development process, sophisticated, purposebuilt LIMS streamline processes and costs and present organisations with unique integration opportunities. These LIMS provide superior capabilities by delivering real-time analysis and reports, facilitating regulatory compliance and product quality, integrating with the company’s broader network and providing secure access to key data throughout the organisation.

When the required functionality is built into the base system as standard, it eliminates the need for user-specific customisations during implementation. This, in turn, results in reduced validation time, shortened deployment and easier ongoing support. Purposebuilt LIMS for pharmaceutical applications are particularly relevant. According to the 2008 Strategic Analysis of the US Laboratory Information Management Systems Market, by Frost & Sullivan, preconfigured solutions with test methods for specified industries, will drive growth across all markets. The more functionality included in the core product out of the box, the less risk, lower costs and less time involved in the implementation, validation and support of the applications. According to the same Frost & Sullivan report, market growth indicators for LIMS solutions providers are focused on providing customers with not only

purpose-built LIMS that are fully integrated with other laboratory equipment, but also LIMS that easily align with global enterprise solutions. At Thermo Fisher Scientific, our objective in developing purpose-built LIMS solutions is to deliver the domain-specific functionality that addresses the critical needs of the laboratory and also delivers the increased enterprise-level access that multi-site/ multi-user organisations are looking for.

In response to the needs of our customers and these market growth indicators, Thermo Fisher Scientific has introduced a new informatics initiative aimed at bridging the gap between laboratory-generated data and the enterprise-level information that is required for mission critical management decisions.

agement will have the information they need to have early insight into how pipeline drugs or compounds are progressing on a routine basis, and they will also have the critical data they need before, not after, any point of crisis that may affect operations, shareholder value or the safety of the consumer.

A LIMS fully integrated with laboratory instruments and enterprise systems can help bring key business knowledge originating in the laboratory to management at all levels of the enterprise. By effectively integrating laboratory informatics data and providing management key with business knowledge, laboratory informatics can elevate the role the laboratory plays in day-to-day mission critical decisions. LIMS can help pharmaceutical

“These multifaceted benefits help lower the total cost of ownership of the solution” Because of the breadth of our company’s product offerings, and our strategic partnerships, we are uniquely positioned to offer Thermo Scientific CONNECTS, an enterprise-level solution set that allows companies to more fully integrate the work of the laboratory into the enterprise. CONNECTS enables our customers to extend the business of science from the laboratory throughout the enterprise, providing both the integration of instruments and system and the interoperability necessary to transform data into relevant business drivers.

Seamless enterprise-wide integration is a necessity because it enables key knowledge originating in the laboratory to be available to management in real time. Integrating the laboratory with the enterprise will facilitate better planning, data quality, collaboration and endto-end report generation, all with the goal of providing management dashboard views of key business metrics, which are essential to effectively run operations. By investing in this enterprise-wide integration of systems, man-

companies respond with more certainty to the many unforeseen challenges that can often make or break a company.

Modern LIMS serve as common platform frameworks that other informatics solutions, instrumentation, enterprise systems and enterprise communication tools can plug into to share common functions, without having to build them from scratch for each product. As such, a coherent strategy that can integrate data from a LIMS, chromatography data system (CDS), enterprise resource planning (ERP), manufacturing enterprise system (MES), electronic laboratory notebooks (ELN), and other sources across the enterprise is a key business driver for pharmaceutical companies.

Dave Champagne was named Vice President and General Manager of Thermo Fisher Scientific’s Informatics business in April 2005. He joined Thermo Fisher in April 2003 as Director of Global Services for Informatics, and was later promoted to Commercial Director for the company’s Informatics and Services division.

Please visit www.thermo.com/informatics for more information about Thermo Scientific Informatics solutions.

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LEAN SIX SIGMA

The Lean solution Following in the footsteps of many other industries, the pharmaceutical industry has begun to embrace the concepts of Lean and Six Sigma in its manufacturing operations.

Here, Carmen Doran, Global Operational Excellence Champion, and Domingo Traver, Head of Supply Chain Excellence and IQP for Novartis Pharma Technical Operations, tell us about their company’s progress in implementing these processes.

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Carmen Doran of Novartis Pharma Technical Operations explains how the unique combination of Lean and Six Sigma is bringing about significant performance improvements through the work of the company’s global and local IQP Champions.

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s Global Operational Excellence Champion, Carmen Doran supports all 23 sites for Novartis Pharma’s technical operations as well as the global support functions, by providing a systematic training and certification programme across the organisation. This aims to foster a culture of operational excellence (internally referred to as IQP: innovation, quality and productivity). She comments that operational excellence in Novartis Pharma covers a wide range of topics, tools and techniques, which allow flexibility in identifying the best approach for a specific problem or opportunity.

“The philosophies of Lean and Six Sigma represent a way of thinking and looking at a prob-

lem, in order to understand the root cause(s) and then solve the problem in a sustainable manner,” she explains. “This approach is different to the traditional management styles focusing on short term ‘quick fix’ solutions rather than on identifying the problem correctly and ensuring the solution is effective and sustainable long-term. We try to use this approach across all areas of the business.”

Initially set out as two different methods, Lean and Six Sigma are very much interlinked and constantly evolving, a development that Doran notes to be present in Novartis Pharma technical operations. She explains how previously projects would solely use Lean and focus on reducing waste, or would apply a Six Sigma approach to reducing variability. “The Lean phiContinues on page 44

Carmen Doran is Global Operational Excellence Champion in Novartis Pharma Technical Operations.

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Domingo Traver of Novartis Pharma Technical Operations talks about the satisfaction he derives from the successful implementation of Lean and Six Sigma in the pharmaceutical supply chain.

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ealthcare markets around the world are rapidly evolving and pharmaceutical companies need to be prepared to address these changes. For example, regulators and payers are becoming more challenging while patients are taking a more active role in their disease management. All of this affects the pharmaceutical business, where increasing efficiencies can support the future growth.

As Domingo Traver explains, rather than reinventing the wheel, it makes sense for pharmaceutical companies to draw lessons from what their counterparts in other industries have already done. He describes how the processes of Lean and Six Sigma – pioneered by Toyota and Motorola respectively – have taken hold within the Technical Operations organisation at Novartis Pharma, where he is Head of Supply Chain Excellence and IQP. “The idea was first that we implement Lean to reduce waste in our processes, and then apply Six Sigma to reduce variability; it’s a two-step process,” he explains. “We have implemented the Lean phase, and in certain areas, such as quality assurance, we have also begun to apply Six Sigma. For example, Lean has been implemented in the different operational units, it is now time to link all of these units together.

IQP is the internal name: innovation, quality and productivity for the operational excellence or continuous processing program.”

In his role at Novartis Pharma, Traver looks after logistics and IQP, as well as leading the multimarket network for supply chain.

He points to the fact that the current level of regulation and quality control within the pharmaceutical industry has a direct impact on the development and implementation of new efficiency processes. While regulation is necessary to ensure the safety of the end products, Lean and Six Sigma can additionally help to support the overall processes.

“For example,” Traver points out, “existing procedures may show that a particular process takes eight hours. By understanding your internal processes and applying Lean techniques, you will be able to demonstrate improvements and hence reduce the time required. Lean, therefore, challenges your current processes and technologies while at the same time making them more efficient.”

Another challenge can lie in implementing such changes across an entire organisation, which is why the Technical Operations unit at Novartis Pharma started with several pilot

programs. After the successful implementation of these pilots, the initiative has now been rolled out across global functions, such as supply chain.

Creating change Prior to taking up his current position, Traver was Functional Champion IQP for Novartis PharmOps Spain, where he was principally in charge of deploying IQP and aligning IQP efforts with the global Technical Operations’ vision and strategy. He was leader of the Lean – POO (Process Oriented Organisation) project that ended with the implementation of the new organisational structure in Barbera in May, 2007.

“It was a very interesting project, because it included two elements,” he recalls. “One was the pure implementation of Lean Six Sigma – hence, applying the techniques and helping the teams understand what these techniques mean and how to use them. The other element was about POO, which was aimed at changing the organisation’s culture and mindset in regard to how people approach business operations.

Among others, this included a change in management tools as well as business understanding.

“We used the Kotter model, starting with the ‘burning platform’. This allowed us to see how people behaved differently after POO had been initiated a number of weeks previously. This was really exciting to me, as you could see how the organisation as a whole had improved .

“You have different people behaving in different ways; for example, some may be afraid of change. Generally, there will always be 10 percent of people who are quite change resistant.

However, you can manage this 10 percent by demonstrating how the other 90 percent benefited from new processes and a new culture. I was very happy that despite the challenges we managed the turn-around.”

Traver feels that Lean and Six Sigma have a strong future within the pharmaceutical industry, as well as in other industries.

He points out that there are many areas in which these concepts are yet to be introduced.

“Lean Six Sigma helps us to improve our processes and to reduce variability. It is really helpful in many industries, and yet there are parts of the world that still have not taken advantage of it. So I would say overall that there is a lot of future in this yet.”

“Lean Six Sigma helps us to improve our processes and to reduce variability”

Domingo Traver is Head of Supply Chain Excellence and IQP for Technical Operations at Novartis Pharma AG.

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losophy is to have flow through the process and to do this, you need to have processes you can rely on. A stable and reliable process is then the foundation for continuous improvement. So Lean and Six Sigma go hand in hand to achieve operational excellence.

“We look at the flow of value all the way through our processes down to the customer, whoever the customer may be; in our case, this is ultimately the patient. If we look at some of the supporting functions like HR, we’ve been applying the Lean and Six Sigma way of thinking to these processes, going through the steps of identifying the problem, understanding the customer needs and root causes of the problem and then finding the solution which matches to those. By doing so, we are for instance ensuring the improvement and sustainability for recruitment processes where the benefiting customers are actually both the employee and the business.

“We apply the same approach in non-manufacturing environments as we do in production.

It’s a natural progression that we need support functions aligned to the new way of working and thinking in manufacturing. Like a lot of companies, Novartis started to apply these methodologies and philosophies in the manufacturing area first, and now the ideas are spreading to the rest of the business. In manufacturing it’s very easy to see the processes and to work on the processes because that’s what is right in front of your eyes. In other business areas, some of the work we do focuses on simply making the process transparent,” explains Doran.

As a global IQP champion at Novartis, Doran explains how she has a lot more requests to provide Lean support than she has time for; these come from people who have heard about Lean through their colleagues or through seeing the benefits themselves. In order to accommodate what Doran explains as a “pull system” for IQP support, Novartis has its IQP champions across the world, operating different skills in different areas and matching the business needs with the company’s resources.

“We often use an external pair of eyes on a process. That external view may come from another internal function, another manufacturing site or a global function. Novartis has a strong network of people across the globe, all with different backgrounds, but all working on Lean and Six Sigma in a rather unified manner. They are capable of implementing various problem-solv-

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ing tools and methodologies in projects and of linking them together to create a culture leading towards operational excellence,” she explains.

Pharma Technical Operations has successfully handled some natural resistance to change and to the use of these new processes thanks to strong leadership endorsement, although Doran admits that there are still some people who are coming round to the idea. Enthusiasm for a new project, she points out, is often created upon seeing the results. If a person working on a project has enjoyed it and demonstrated good results, then others can judge for themselves.

Expansion As a global company, Novartis Pharma Technical Operations has sites located across the US, Europe and Asia. Prior to taking up her current role, Doran worked in the company’s recently opened Pharmaceutical Operations site in Singapore. She explains that there are variations in the take-up of Lean Six Sigma across different locations, but not always in the way you might think. “The difference for us in terms of adoption is not necessarily the culture but the maturity of the site. When you have a site which has been around for 50 years where you have people with a lot of history at that site, then it takes a different approach for them to change their way of thinking than if you have a brand new site like Singapore. For them, everything is new.

“We can show them results from other sites, and there isn’t that resistance to change because they understand how it works together in the overall business model. So rather than people’s cultural differences, adoption depends on the lifecycle of the site,” says Doran.

In order to meet the challenges that often accompany such implementations, she calls upon the company’s network of IQP champions: each site has a single point of contact for all best practice sharing. “If I have a site in China that needs some input from a site in the US, they can directly contact the local IQP champion and ask about the results and learnings.”

Communication between the multiple sites is essential, and is facilitated by the central IQP team. Doran places most emphasis on the power of speech and interactions between people, and explains that although Novartis publishes its IQP project results on the internal website and in newsletters, most results are seen from the effects

of a strong network. Monthly teleconferences with IQP champion networks, ad hoc teleconferences and regular meetings focus on the challenges facing the site, the successes, their goals and what’s in store for the future.

“Although the sites are on the same journey, they’re all at different stages, but they’re all looking for alignment through our operational excellence scorecard. We have a very clear strategic direction for operational excellence in Novartis Pharma Technical Operations which allows all of the sites to move in the same direction.

That's one of the reasons we’ve been successfully able to turn those challenges along the journey at a site into something that has been enjoyable and rewarding.”

Novartis Pharma is certainly not alone in facing these challenges. The pharmaceutical industry has been dogged by pressures to reduce costs in light of the recent economic crisis. “We could focus on cost, but the better way is to focus on the speed and the agility of the processes,” explains Doran.

“One of the biggest concerns for all pharmaceutical companies is the speed at which they are able to adapt to change. A lot of our processes can be improved, and maybe we haven’t had the challenge that some of the faster-moving consumer industries have had in terms of reaction to market requirements. Those companies who can respond quickly to the market needs by being flexible and reducing their cycle times, both in manufacturing and in development, will be the ones who can overcome these challenges.”

Added pressures come from the highly regulated nature of the industry. “None of us would want to take medicine if it wasn’t highly regulated,” says Doran. However, she notes that the pharma industry must also recognise that it is not alone in terms of the level of regulation it must undergo, pointing to the aerospace industry as facing similar challenges. To combat these concerns, she points out that there are opportunities to collaborate more closely with regulatory agencies such as the FDA, which welcomes positive changes.

“At the end of the day, what I feel has made the Lean and Six Sigma thinking successful for us is the combination of the technical process improvements, cultural aspects and a clear strategic direction which fosters, for all involved, a passion to strive for operational excellence,” she concludes. n

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ROUNDTABLE

Reducing

waste

NGP gathers some of the industry’s leading experts to discuss the importance of Lean and Six Sigma in pharmaceutical manufacturing.

What are your definitions of Lean and Six Sigma? How do they differ from each other?

Liam O’Brien. Lean relates to best practice, procedures and processes that optimise resources and give results in the fastest possible way while achieving cost reductions. It has a particular focus on eliminating waste and non-value add activities. Six Sigma is based on statistical analysis; it includes a project methodology and project organisational structure for expeditiously achieving the goal of efficient, high quality (low defects) production. Lean Six Sigma (LSS) combines both Lean and Six Sigma and translates into a process, that is both responsive and capable of achieving high quality consistently.

Debra Shumar. Lean is described as a method to reduce or eliminate waste in those processes that do not add value to the fi nal product being produced. Six Sigma is a method to reduce variation of products, improve capability and to help reduce defects in manufacturing, development and service organisations. Both have very specific structured approaches to improve customer satisfaction by efficiently delivering the right products at the right time, in the exact quantities with repeatable and measurable results.

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Both disciplines differ in the way in which inefficiency and problems are solved. The key is in learning which tool is used and in what situation. Lean is used for the reduction of wasteful activities usually in a production environment. The use of such tools and techniques include pull systems, leveling, Kanban, quick changeovers, value stream mapping, small lots, and transportation and logistics. Six Sigma uses a defi ned methodology called DMAIC (defi ne, measure, analyse, improve, control) to reduce the variation within processes, measAlfred Sherk is the founder and urement, fit and timing, which CEO of SherTrack, provider of innovative, predictive analytic causes defects and in turn creates solutions for synchronising waste. Both disciplines are vital supply with demand. He is a past member of the Technical to any organisation’s continuous Advisory Board for Michigan State University’s Graduate improvement strategy. Depending School of Business and is a on the emphasis of the organisalimited partner in North Coast Technology Investors LP. tion’s strategy for improvement, both tools can be used to improve any process or product needing improvement.

Alfred Sherk. Lean is an approach for the fundamental examination of an organisation’s processes necessary to execute its mission. Th is focus on process stems from the understanding that every process has a capability limit. Lean drives efficient operations by eliminating low value activities and reengineering high value creation processes to improve their capabilities.

Performance breakthroughs derive from innovations in the underlying Debra Shumar is President processes for delivering value. For and Founder of 3P Partners, a DL Shumar & Associates example, Ford’s assembly line inCo. LLC. 3P Partners provides th innovative approaches, novation in the early 20 century services and software transformed manufacturing, while solutions in quality, cultural transformation, Lean and Apple’s iPod (built on the digitaliSix Sigma management, and supply chain risk management sation of sound) transformed the for improving business, music industry. Six Sigma is a dataoperational and workplace performance. driven methodology for improving process capability as measured by key performance indicators (KPIs).

Six Sigma methods help defi ne what is important (value added) about a process, and what changes bring processes closer to their underlying process capability limits. Six Sigma brings a deep appreciation for the impact of variation on the execution of processes.

What are the potential advantages and challenges involved in implementing Lean and Six Sigma in pharmaceutical manufacturing?

AS. Process innovations in pharmaceutical manufacturing are bur-

dened by the realities of regulatory fi lings and control. Significantly changing the underlying pharmaceutical manufacturing process is challenging and risky. However, innovations in the enabling processes (such as the order-to-fulfi lment process) for manufacturing offer great potential for important improvements in end-to-end manufacturing time, agility and responsiveness to changes in demand. The complexities of pharmaceutical’s underlying manufacturing processes create challenges for conventional Lean and Six Sigma methods and tools. Effectively mastering this process complexity is a critical success factor for breakthrough performance gains.

LO’B. The advantages of LSS in pharmaceutical manufacturing are much the same as in any other industry – reduced cost, improved quality, more consistent product, elimination of non-value-add activities, reduction in recalls and Liam O’Brien is a leading manufacturing execution customer complaints, and rationsystem (MES), process alisation of the supply chain. A and automation solutions specialist within the life particularly significant one for science industry. In a career spanning more than 30 the pharmaceutical industry is the years, he has had extensive potential to reduce the lifecycle for commercial and project management experience. drug development in terms of time O’Brien is also a founding member of ESP, which and cost. specialises in implementation The LSS methodology provides of MES. a mechanism for improvement, trouble shooting and problem solving and allows performance to be monitored, measured, trended and reviewed. Since LSS uses statistical analysis to address root cause and problem resolution, it fits in with the culture and modus operandi of the drug development community, which uses statistical techniques for all aspects of drug development and testing. Though these principles are well accepted throughout the broader pharmaceutical community, pharmaceutical manufacturing remains prone to the ‘quick fi x’ approach to solve the immediate problem.

The existing quality assurance and regulatory culture and practice appear to support Six Sigma with annual product reviews, corporate standard procedures for corrective action and preventive action and a significant effort applied to statistical analysis of critical parameters and trends within manufacturing. However, since these tend to be islands of activity without much joined up thinking and are often

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perceived to be necessary activities to satisfy a regulatory or quality requirement, the opportunity to effectively use these existing activities as part of a real process improvement effort is often not fully utilised.

LSS offers a methodology for incorporating these activities in a process improvement effort that is fully integrated with manufacturing as well as quality and regulatory.

DS. As pharmaceutical companies are challenged to reduce their costs in an effort to help reduce the overall healthcare costs to businesses and individuals and have a sustainable business model, implementing these two methods within an organisation is vital. Utilising Lean and Six Sigma can help a company prevent, reduce or eliminate recalls due to errors in the manufacturing and business processes. Realising or acknowledging where the organisation is truly performing is the challenge of leading the implementation of such tools and techniques.

Leadership’s involvement at all levels within the organisation is important for constancy of purpose and success. If the entire organisation is not engaged, then creating a culture of improvement will become another flavour of the month exercise. People will revert back to their comfort zones and all monies spent will be lost.

What tools and techniques can pharmaceutical companies use to ensure a smooth roll out of Lean and Six Sigma in their manufacturing operations?

DS. It may not be thought of as a tool but communication will be the most important attribute or behaviour throughout the organisation for a smooth roll out. Communication must be open and free across the organisation. Gathering proper data from assessments to determine the effectiveness and efficiency of the performing organisation will be critical. Engaging all employees by using teams that are cross functional and implementing one or two departments at a time will give the best opportunity to gain those necessary fi rst wins for overall success.

Report outs with weekly updates on projects, measuring results and sharing success and miscues with all employees of the organisation is important, so that it is apparent that the process is moving forward with success.

AS. Advances in predictive analytics and digital plant modelling provide important new capabilities for understanding and improving manufacturing process capability. Our research has shown that the enabling processes for manufacturing operations are usually the limiting factor for overall performance capability. Furthermore, predictive analytics enables the use of the very efficient Lean pull process in complex operations. Innovations in these enabling processes should significantly improve a pharmaceutical company’s capabilities, especially in emerging markets with less predictable demand.

The analyse phase of the Six Sigma DMAIC (defi ne, measure, analyse, improve and control) process is the most problematic in tackling complex facilities. Advanced digital plant modelling provides the vehicle for thoroughly analysing a facility’s capabilities and accurately evaluating the impact of process changes with no operational risk. It provides a system’s view of pharmaceutical manufacturing operations rather than just addressing manageable sub-processes.

LO’B. There are many tools and techniques than can be utilised, but for LSS it is important to note that for many people it is a very different methodology and a very different way of working. The biggest challenge can be achieving the mindset change that is required for LSS to succeed in the organisation. The rollout out of the programme must be well communicated to employees and fully supported by senior management. Training for success is of paramount importance as LSS can be misused for processes that are not well defi ned and hence can become burdensome. It’s most important to identify and prioritise the key projects in your organisation that will improve performance in achieving compliance, waste elimination or process productivity.

How do you see Lean and Six Sigma developing in the pharmaceutical industry in the future?

AS. The leading pharmaceutical companies are embracing the culture of operational excellence as reflected in the growing appreciation of Lean and Six Sigma. We expect that the re-examination of core business processes will lead to step-changes in process capability for those companies that can master complexity and execute systematic changes in their core processes. Other industries that operate globally can provide useful insight into the nature of valuable process changes.

Strong and engaged leadership is essential for identifying and adapting cross-industry advances to achieve competitive advantage in their own operations and markets.

LO’B. In these challenging times, pharmaceutical organisations cannot afford to ignore LSS. Expectations of customers, regulators and shareholders have grown and the industry must respond quickly to improve productivity, work more efficiently and implement changes to remain productive and profitable. To achieve the benefits of LSS, organisations will have to leverage from the existing quality and regulatory culture within the industry as well as incorporating more recent initiatives such as process analytical technology, quality by design and more extensive use of computer technology as a quality tool.

LSS can be employed across almost all aspects of the pharmaceutical business. For many, especially manufacturing, it has already proved itself in cost reduction and process optimisation but its application across areas such as research and development, quality management, human resources, fi nancial, and sales and marketing remain relatively untapped. As a result of the flexibility of the application, LSS has placed itself fi rmly into the day-to-day operations and will be here to stay for many years to come.

DS. Lean and Six Sigma are structured disciplines with tools and techniques to drive sustainability and profitability. They are not the only answer to moving the industry forward but for pharmaceutical companies to continue they must become more efficient at all phases: R&D, clinical trials, production and sales and marketing. Becoming more efficient in the R&D process and potentially reducing the time to clinical trial, costs can be reduced significantly. Building a culture of sustainability with everyone focused on continuous improvement using the methodologies of Lean and Six Sigma will separate the competition significantly.

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INDUSTRY INSIGHT

STRICTLY SIX SIGMA? Ian Cox examines how to get the most from Six Sigma.

“The dynamic visualization used in visual Six Sigma allows practitioners to use their understanding of the specific data context, and the patterns they can see in the data itself, to start to quickly and easily get to the root of an issue, whether working on trouble shooting or improvement.”

A previous article for NGP [http://www.ngpharma.eu.com/article/ Managing-variation-uncertainty-and-risk] talked about leveraging data to help acquire the new process understanding that drives improvements and innovations in the development and delivery of pharmaceutical products. It’s fair to say that Six Sigma occupies a special place within this agenda, particularly in manufacturing operations and distribution.

So this is an article about getting the most from Six Sigma.

Because the genesis of Six Sigma was 24 years ago, and because it has been subject to change and development, Six Sigma can be difficult to pin down. Characterisations range between: ‘A way to transform a company’, ‘A way to create processes with no more than 3.4 defects per million opportunities’, and ‘A project-based improvement approach delivering undisputed benefits’.

For this discussion, think of Six Sigma as: ‘The management of variation in relation to performance requirements’. Th is makes a convenient separation of ‘what’ we need to do (meet the performance requirements) from ‘how’ we need to do it (by managing variation using data). For reasons of space, we won’t deal so much with the ‘what’ part, just assuming that the performance requirements are known.

Historically, Six Sigma training and practice has focused too much on so-called ‘confirmatory data analysis’ (CDA), and this is unfortunate for two reasons. One is that, green belts, black belts and master back belts notwithstanding, training people to do CDA well, if it is possible at all, takes a lot of time and energy.

The second is that, as data from operations increase in volume and complexity, the methods taught and used rapidly run out of steam and may even be misleading. In contrast, the dynamic visualisation used in VSS allows practitioners to use their understanding of the specific data context, and the patterns they can see in the data itself, to start to quickly and easily get to the root of an issue, whether working on trouble shooting or improvement.

Visual Six Sigma is intuitive and powerful, and, compared with the traditional Six Sigma curriculum and practice, is much easier for most people to get to grips with. It can revitalise your Six Sigma initiative if it is stalled, and if you are just starting out, it will allow you to be data-driven in situations where traditional Six Sigma starts to run out of steam. As PAT and QbD take root, these situations will be the norm rather than the exception.

Ian Cox works in the JMP Division of SAS as the European Marketing Manager for JMP. He worked for Digital and Motorola in the 1980s and has consulted on how best to use data for more than 20 years. He is co-author of Visual Six Sigma – Making Data Analysis Lean (Wiley, in press). For more information visit www.jmp.com

Attention to detail Perhaps ironically given the way it arose, Six Sigma has not given enough attention to the way that people are actually able to work with and exploit data. Within the DMAIC process (design, measure, analyze, improve and control), there are many places where we need to work with data. Th is process will only operate well if we recognise fully what we have to work with and what we are trying to accomplish.

Visual Six Sigma (VSS) is a set of three strategies for removing waste from the process of exploiting data, making it leaner and more efficient and effective [Visual Six Sigma: Making Data Analysis Lean, Ian Cox et al, Wiley and SAS Business Series, 2010], and taking better recognition of what practitioners are actually capable of. The fi rst and most important strategy is to use the dynamic visualisation that software like JMP provides to literally see the sources of variation in the data that has been collected.

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MANUFACTURING

ON THE FRONTLINE OF DISEASE PREVENTION In this excerpt from an interview with NGP’s sister media channel, MeettheBoss TV, Sanofi Pasteur’s Rene Labatut tells Victoria Newing about improving manufacturing process efficiency, and the challenges of developing vaccines for new diseases.

Sanofi Pasteur is the largest company in the world devoted entirely to human vaccines. How do manufacturing processes differ across the globe?

Rene Labatut. Sanofi Pasteur’s manufacturing processes use the same standards but different processes for the same specialty and the same therapeutic queues. We have three Tetanus processes, for example: one in Canada, one in the US and one in France, and now because of the recent acquisition we have one in India too.

The difference in these processes is historical: they come from the original companies. Now when we are developing a process, even if we have several manufacturing units, at the end it’s notably true in formulation. The processes are the same; the challenge in this field is to keep it the same because along the life of a process in a different unit, you always

have circumstances where people make minor changes. So you have to be very strong on your change control policy.

There is a system called a process book, which is an electronically organised reference where people fi nd the detailed description of what they have to do. It is web-based, so any information can be accessible in less than six minutes; and there is exactly the same reference for people who are running the same process in two locations.

It’s anticipated that the demand for new and existing vaccines will double by the year 2012. What measures are you taking to ensure that Sanofi can deliver and meet market demands?

RL. Four or five years ago we engaged in a strong investment policy. On a yearly basis we invest between €350 million to €400 million, and have

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built a huge inactivated polio vaccine capacity in Lyon, France. We have more than doubled our flu capacity in the US for seasonal flu and the formulation/fi lling in the US has also been extended. We have invested close to €150 million in this unit, and we have also invested very heavily in Normandy, France, to do formulation, as well as fi lling and packaging for distribution of vaccines on a worldwide basis.

Now we are also leveraging all the capacity we have at the group level, notably in packaging because it’s less specific for vaccines. We have a plan to invest more than €250 million to build a new dengue unit; and there is also an ongoing plan to develop new vaccines for diseases that are not yet covered by vaccination programmes.

What new approaches are needed to drive manufacturing processes more efficiently and to overcome the complexities of new vaccines?

RL. New vaccines for new diseases can be more complex to produce because they have processes that are more complicated, such as new conjugates or new formulation types, which are more difficult to manage. The other way around is to design your product approach – this can be more complex for something like the dengue vaccine, which is a chimeric vaccine – but the management of the process by itself is not so complex.

The way you manage your cell and the interaction between the cell and the virus is difficult, but in comparison to a classical inactivated polio vaccine, the process itself is simpler because the complexity has moved into the product itself and the construct will simplify after the process.

“We want to drive our processes instead of following them; when you drive you are in control” A vaccine is a preventative medicine; when you inject a vaccine into someone they are not sick yet, and the worst thing you can do is to make them sick using the vaccine. So the level of attention you pay to safety is very high.

Th is ties in with the trend of moving to a more preventative type of medicine from a curative one, and requires a different way of thinking.

The only area where the risk/benefit ratio is very high is in therapeutic vaccines, but mostly these type of products are the last line of defence or therapeutic use where the risk is death within six to nine months, so it’s a different story.

You’re an advocate of the software solution process. Can you elaborate on the benefits that this can offer a company like Sanofi ?

RL. We want to drive our processes instead of following them; when you drive you are in control. When you are following, you are just reporting what’s happened, which is not really the mindset we should have. We want to go to a QBD-type approach and have a consistency of output of our process; consistency of results versus the classical consistency of

Background: Rene Labatut Rene Labatut has 22 years of experience in the biotechnology sector across a variety of disciplines. NGP asked him how this insight has helped in his current role as Vice President of Global Manufacturing Technology at Sanofi Pasteur.

“My experience has helped me in two ways. First, to have the right level of humility – there are a lot of things you have to learn and you can be surprised every day; the biotech world is like that. And also to always be looking at the big picture; sometimes I need to go into very detailed things, but I must always have the ability to go back and forth between the different levels of vision, as well as to build a vision of what’s next based on experience and extrapolation between things.

“My key mission is to be the guardian of industrial knowledge for the company. To be a guardian is a dynamic thing and not a passive one; not keeping things as they are, but moving them into what they should be in the next 20 years. It’s transferring new products from R&D to manufacturing: taking them from phase II up to commercial launch.

“This also involves being in charge of continuous improvement for any manufacturing process, as well as technological innovation. That’s my primary responsibility. Besides that and within that, there is all the techno transfer between internal sites and also between Sanofi Pasteur and our partners.”

settings. There is a lot of classical approach in secure process control.

Following critical parameters step-by-step independently of each other assumes that if you take a given step the result of this step will not influence the step after. In our process there is a lot of difficulty, and it’s not mathematically accurate to say that the steps are independent.

We have to consider the process as a rule, with interconnection between steps; and the result of what happened in step one will have an effect on what will happen in step six or eight and can be corrected by what will happen in step 10.

You need to have the overall behaviour; and this type of soft ware is trying to address that, looking at the overall process and how it behaves and interlinks. And instead of having a critical parameter only on one step, you have a cluster on different steps. But it’s based on a mathematical model like genetic algorithm, which is a learning-type process. And

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the way we use it, notably on high frequency products, enables us to look at what happened in the early stages of the process for some parameters.

We must then predict, based on all the models, where it will end if we don’t correct the settings and diagnose what will be the appropriate corrective setting we have to put in place before the end of the process. Then we can be sure that we are very close to the point where we want to end in terms of product quality and product yield.

How does the manufacturing process help drive the need for innovation?

RL. The innovation I’m focusing on centres on discovery work in vaccines. We now face the challenge of being able to do this in an economically viable way and also in volume, in terms of the number of doses produced at a reasonable cost. They must be affordable on a worldwide basis, which is not a niche market for most of these products. We need to innovate to make this possible, to extrapolate directly what’s done at the lab bench scale. We cannot do it at the large scale that we need, so there is some innovation there to be driven by us.

We also need to improve processes and assure process performance. We need to think about doing it differently – changing and applying new technology or a new way of thinking, leading into new manufacturing technology even for existing products. The big drive behind that is that you can manufacture a certain way, and put the cost of goods at a value of 10. The number has no real value, it’s just to give an order of magnitude. If you want to sell that in Western Europe, that’s fi ne. But if you want to address it on a worldwide basis and encompass developing areas, you have to bring your 10 down to under one; and to do this you have to have a technology breakthrough.

There are different ways to achieve this. First, you think of the classical approach of applying Lean to your manufacturing process or getting rid of things that don’t make sense or are just there because of history or habits. The second step is to maximise the value of what you get out of the things that it still makes sense to do.

What drives the performance of the process, in terms of product and making yields? The huge leverage it yields. If you understand very well how your complex biological system is working, then you can apply a method or attune the way you drive your process to increase. Just by managing the biological organism we handle its physiology very closely and see how it behaves when it becomes invasive in the body, then use the defence mechanism as a leverage to obtain the product we want versus when it is in a comfortable situation doing regular things.

How is innovation formalised and managed at Sanofi Pasteur?

RL. In order to manage innovation, we have had to sort out what the fields of innovation are. We are looking at what we have in the pot from discovery down to commercial. What is the overall portfolio of products in the company, the ones that are at the early stages, as well as the ones we are manufacturing? We’re working on the type of processes and the technology we are using from the early microorganism down to the fi nal box – looking at where the needs for technology are in the company and also in terms of order of magnitude in the market.

First, we are looking at needs we have not covered by existing technology: where we have developed something, where it applies and what is the value for the company according to the span, focus or depth into a certain product. That’s the needs part.

We are also scanning what’s going on in different areas of the industry, not only in pharma, but also food and microelectronics. We are scanning what’s going on in universities and at the very early stages, looking at where it can apply and where it can make a difference; in doing so, we want to develop technology. Our technical teams are evaluating continuously with biotech teams or with universities, several of which we have contracts with.

What role do issues such as the relationship between development costs and drug prices play in the transfer from R&D to operations?

RL. If you take too long in transferring from R&D to operations costs will increase: any time you take will be costly and this will have an impact on the cost of the goods. If you fi nd ways to speed up this transition or transfer, normally you will reduce the cost at the end and you have more leverage to be able to negotiate or provide the services with a better price.

That said, to be able to transfer quickly from R&D to operations, you need to have a very specific approach on the R&D development level because things that are a little bit fuzzy or not totally developed will induce a lot of rework during the transfer or just after the transfer, and that doesn’t help to keep costs at an optimised level.

Sanofi ensures that we’re optimising that process by mostly imposing a quality by design mindset, starting in phase I. The pharmaceutical development of new products is jointly managed by the VP of R&D and myself, and to ensure the team diagnoses in phase I or phase II the critical quality attribute of any product, the critical process barometer associated with the system.

Then there is also preparing the scale-up algorithm: starting to optimise upfront as much as we can yield reliability and the capability of processes to eliminate what can be damaging for the operation afterwards; and also to help minimise the investment needed.

Rene Labatut is Vice President of Global Manufacturing Technology, Sanofi Pasteur.

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Aegis Analytical Ad.indd 1

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TROUBLESHOOTER

Cross-divisional integrated solutions The supply chain has become a competitive edge, a sales argument and at the same time, a key area for cost cutting activities. Time to market plays a significant role for the future. By Martin Svantesson

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ross-divisional solutions will be a major factor for success in the future global pharmaceuticals supply chain. End-to-end integrated solutions are the true competitive edge. The forwarding industry needs to focus more on integrated solutions, meeting up with expectations from pharmaceutical companies that seek to have crossdivisional solutions.

The pharmaceutical supply chain is experiencing great development, where the industry is going from decentralised decision-making and functional focus to a truly integrated and value-added supply chain model where cross-functional focus and centre lead strategies are focus areas.

Warehouse strategies play a significant role for the supply chain and the potential markets served. The pharmaceutical industry is seeking true long-term partners that have the ability to offer all areas of logistical activities, distribution and warehousing.

The pharmaceutical industry has become aware of the significant advantage of operating their supply chain from warehousing to effective road freight, air freight or ocean freight, linked with the most up-to-date communication platforms.

The traditional business relationship between logistics suppliers and pharmaceutical companies is changing.

Historically, there has been a clean cut between different solutions: warehousing, air freight, ocean freight and road freight. Future partnerships will span these different areas, becoming one integrated solution.

A true global logistics provider must be able to offer these cross-divisional solutions, tailored to any region of the globe the customer chooses. It is simply not good enough only to offer top quality air freight solutions if you can not offer a warehouse operation tailored to customer needs.

The market demands global solutions and customers are requesting the ability to order correct quantities and lower inventory levels. This brings a change to the order profi le; orders are becoming smaller and production changes accordingly. This is a challenge for the distribution of pharmaceuticals. Consolidation possibilities that can meet with the lead-time demands of the end customer are highly valuable.

A change of routines in the supply chain can have dramatic effects if not properly implemented at all levels.

With clear communication, the cost of change reduces dramatically. Global harmonisation enhances the possibility of maximising effects in a supply chain.

It is the harmonisation and interaction between the pharmaceutical company, freight forwarder and carrier that makes the supply chain successful. There are regional variances in infrastructure that determine how the supply chain is operated.

A true cross-divisional activity achieves several synergies for both parties. The fi nancial benefits are far greater than if a customer operates with three or four different partners for warehouse, air freight, ocean freight and road freight services.

The logistics provider will become more integrated into the pharmaceutical company and its full supply chain.

Better understanding of pharmaceutical companies’ demands and needs will Martin Svantesson is Vertical secure a robust service level and at the Market Director of Geodis Wilson Pharmaceuticals. He has 15 years’ same time keep costs down. experience in global distribution and For communication between parholds a Master’s degree in supply chain management. Svantesson’s ties to become more effective, a suitable role is to develop Geodis Wilson’s pharmaceutical distribution communication platform is a must. Th is solution/proposal for existing and could take some time for both parties to potential pharmaceutical customers, as well as to harmonise a global adjust to, but once up and running, it approach within Geodis Wilson in regard to pharmaceutical handling acts as the glue between the parties. according to GDP standards.

Cross-divisional partnering tends to be for a period of three to five years, which falls in line with changes that are ongoing in the current business climate, including long-term partnering and fewer partners.

Geodis Group’s global strategy is to meet the future trends for cross-divisional demand in the pharmaceutical industry. Geodis has several partnerships up and running where a full control, cross-divisional set-up is operated. We see the benefits of this type of approach and seek to partner with more pharmaceutical producers or wholesalers.

Geodis Group stands in the forefront of end-to-end, cross-divisional solutions for pharmaceuticals.

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Geodis AD.indd 1

26/2/10 11:01:29

ASK THE EXPERT

Innovation and possibility Manfred Zurkirch outlines future trends in pharmaceutical packaging.

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he pharmaceutical packaging market is constantly advancing and has experienced significant growth in the past few years.

However, it’s important to differentiate between the growth of packaging material volumes and the equipment market. Packaging material will keep pace with the general expectation for the pharmaceutical market, which has experienced very moderate growth of one to four percent per annum in areas such as the US and Western Europe, and about 10-15 percent per annum in the so-called pharma emerging countries such as Brazil, South Korea, China, Russia and Turkey.

One would most probably also need to distinguish between prescription (Rx), generic (Gx) and over-the-counter (OTC) drugs. For example, packaging volumes for generics will still go up but the price pressure will be fierce, whereas for Rx products this will be a bit more mitigated.

In the equipment market (such as machinery), on the other hand, it clearly depends on the machine concept.

Under the current cost pressure, site consolidations and overall equipment effectiveness programmes are gaining high priority within pharma companies. This means that growth perspectives for versatile, flexible and efficient machines are still promising. We are therefore optimistic about substantially participating in the future growth of the pharma industry.

In terms of the impact of continuous innovations to pharmaceuticals themselves (powder applications, pre-filled syringes and so on), in general there is a symbiotic relationship between a packaging solution and the packaging equipment. If new, innovative products enter the market, the new packaging solution can ideally be processed on the same installed machines. We will be seeing a heavy trend towards harmonising pack styles and the upgrading and retrofitting of existing equipment to ensure the capability to pack all the new innovations coming online.

Pharmaceutical companies depend on reliable and efficient packaging to protect the quality and security of their products. There are three different fields of action to optimise quality and security for pharmaceutical products.

Firstly, various features can be built into the packaging material; for instance, RFID chips, hidden printed patterns and holograms.

Secondly, there are numerous possibilities to be incorporated into the packaging solution. Ideally the packaging development department of the equipment supplier starts to discuss the requirements with the pharmaceutical company

very early in the process. Depending on the company’s priorities, packaging solutions can be designed that factor in physical product protection, volume (critical for cold chain products), compliance, tamper evidence and convenience requirements. Last but not least, there are elaborate control mechanisms on every packaging machine to ensure that no bad product leaves the production line. This is mainly accomplished with a sophisticated process flow on the machine, including a lot of sensors and cameras.

Future trends in pharmaceutical packaging depend heavily on the kind of drugs to be packaged and their distribution channel. For Rx drugs, I envision that due to their high value there will be more and more very small batches.

Pharma companies do not want to stock these products, resulting in a large focus on quick changeover. Additionally, these products need high physical protection and small volumes because they often go into the cold chain.

For generics, I believe we will see two contradictory trends. Obviously, the intense cost pressure will continue and favour simple, cheap solutions. However, in order to continue to make money, some generics producers will differentiate themselves via an innovative and appealing packaging solution. In the realm of OTC products, we have yet again a different playing field. These packaging solutions have to be self-explanatory, attractive and, not surprisingly, large enough to be seen on the shelf. In summary, I foresee a lot of innovation in the next few years, because in general a strong competitive environment boosts innovation, to ensure survival of the fittest.

“If new, innovative products enter the market, the new packaging solution can ideally be processed on the same installed machines”

Dr. Manfred Zurkirch is Managing Director of Dividella AG, which he joined in 2006 from a leading Swiss technology group, where he was Business Unit Manager, and previously VP of Marketing and Sales. His expertise covers the capital equipment industry, and through his extensive sales activities he has an excellent knowledge of international markets.

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ASK THE EXPERT

The pharma industry in the new decade Marcel Velterop explains the rise of collaborative working in the industry.

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he year 2009 was a momentous year in many ways, but it will always be remembered for the economic turmoil that impacted almost every country and every industry across the globe. The pharmaceutical industry once considered itself largely safe from downturns and the macro economic cycle, but last year’s events left none in doubt that there are few safe havens in such traumatic times. As the new decade begins, it seems the worst of the troubles from 2009 are beginning to dissipate and economies are returning to something that looks more like normality. But what legacy have these events left on the pharmaceutical industry and how does it move forward with confidence to meet the challenges of healthcare in the 2010s?

Some of the macro changes and trends have been openly discussed; there will be less dependency on the blockbuster model, with smaller therapeutic areas gaining much needed attention and ‘pharmerging markets’ becoming the key growth markets for the industry.

There is another level of re-alignment being undertaken by the industry. Long established norms are being challenged and replaced. The high cost to develop new drugs was once justified by high clinical attrition rates and supported by the generous rewards earned from blockbusters. Today the cost of drug development is seen as a target for reduction; how can clinical success rates be improved, materials be sourced more effectively and time lines be reduced?

Working capital is another example; historically it may not have been a frequently debated topic in pharma board meetings, but now our industry has de-stocked in both com-

mercial and clinical phases. Nor do we expect panies has become the new trend. Similarly, it to see manufacturing organisations rebuilding is advanced technologies, such as catalysis and their inventory stocks and plant capacity just biotechnology and enhanced manufacturing in case. However it is not just fi nancial and capabilities, that will reduce the environmental research efficiencies that are being challenged, burden from pharmaceutical manufacture. environmental and sustainability performDr Reddy’s Laboratories and its CPS busiance is set for radical reform. Pharma has long ness has withstood well the recent economic been aware of its need to manufacture with turmoil. Over the last year we have learnt that care, but it is now time to consciously reduce our inherent capabilities allow our customers and eliminate waste by design. to effectively outsource their clinical trial reHow does the pharma industry address quirements and develop effective strategies for the seemingly impossible: produce more incommercial phases and lifecycle management. novative pharmaceuticals, using less capital, Also we see that that our technological capain a shorter time, with the bilities, more now than ever smallest possible ecological before, are necessary to meet footprint? The refocusing of the increasing demands of internal R&D resources is economic efficiency and enalready apparent with many vironmental responsibility pharma companies looking and sustainability. to biotechs as a richer seam of So how does the pharma new candidates. Conducting landscape of 2010 compare clinical primary and secondwith the previous decade? ary manufacturing exterCertainly it is clear that the nally is simple and effective industry will be re-building in reducing working capital itself in an innovative and certain to continue as an way; which is relevant and outsourcing trend. sustainable to meet future Greater attention will be healthcare needs. But these Marcel Velterop is Vice President of Global Sales and Business given to lifecycle management new structures will require Development at Dr Reddys and outsourcing of commerdifferent foundations and Laboratories S.A. Velterop joined Dr Reddy’s Laboratories in January cial APIs and drug product support; Dr Reddy’s CPS 2004 as European Director of Sales and Marketing. He currently heads manufacture to third parties intends to be one of those the global business development to allow focus on the core foundations working even team for Dr Reddy’s CPS business, which caters to innovator pharma activities of discovery and closer together with cuscompanies. marketing. This strategy has tomers to enable the rapid the added advantage of opendevelopment and supply of ing up older products to newer chemical and unique and relevant pharmaceuticals, at lower processing technologies in-sourced at a lower costs to meet the needs of existing and emeroverall cost. Collaboration with generic comgent patient populations.

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COUNTERFEIT MEDICINES

GET REAL

Travis Johnson of the IACC talks to NGP about the global problem of counterfeit pharmaceuticals.

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ounterfeiting is a major problem across many industries, and it’s getting worse. According to Travis Johnson, Vice President and Director of Legislative Affairs and Policy for the International Anti-Counterfeiting Coalition, in the 30 years since the association was formed, there has been significant growth both in terms of volume and diversification of counterfeited items. “Back in the 1970s and 1980s counterfeiting was largely a concern for apparel companies and luxury goods brands,” he says.

“The stereotype of the fake handbag, or $20 Rolex that someone would be selling on the street corner. Since then we’ve seen the expansion of the counterfeiting problem into every possible product sector. We have members from the automotive section, the music industry, video games, movies, computer soft ware – and pharmaceuticals. Any product sector you can think of, even things like toothbrushes and shampoo.”

If it seems surprising that anyone would bother to counterfeit a toothbrush, Johnson explains that at a basic level, counterfeiting is not so much about the product but about the name attached to it. “In many cases, companies have spent millions of dollars and many years develop-

ing a brand name that consumers recognise and that they place trust in.

If someone can copy a product closely enough, and use the name and the goodwill that the legitimate companies have developed, a consumer may be more willing to buy that product than a no-name brand. Unfortunately, the more popular your brand is, and the more well-trusted it is, the more likely someone could be fooled into buying a fake product.”

Johnson explains that the easiest way to spot a counterfeit product is traditionally the fact that you’re paying significantly less than you would expect to be paying for it – that, and the location where it’s being sold.

He cites pharmaceuticals as a good example of this. “You wouldn’t normally expect to see someone selling prescription drugs unless they’re a pharmacist, no matter what the outlet, whether it’s a bricks-and-mortar traditional type store or over the internet. If you buy prescription drugs over the internet without a prescription, that’s an obvious tip-off that it’s not a legitimate product. They’re either selling counterfeit product, or stolen or misdirected product. In any case it’s a product that you have no way of knowing whether it was properly stored whether it’s been tampered with or diluted. Many people think they’re getting a good bargain

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301 Report and don’t really consider all of the other facts, unfortunately, sometimes with very bad consequences.”

A big problem When asked about the scale of the counterfeiting problem within the pharmaceutical industry, Johnson demurs. He says it’s one of the most common questions he is asked, and also one of the most difficult to answer.

“Of course, the counterfeit market is an illegal black market activity,” he points out. “Obviously, the people selling counterfeit items tend to not fi le things like their tax returns, or a statement of profit. In many cases they’re not declaring any income from it, which ties into another issue of depriving the government of legitimate tax revenue.

“Th is in turn gets back to consumers in the form of reduced availability of government services. Back in 2004, the comptroller of New York did a study that estimated that lost tax revenue from the sale of counterfeit and pirated goods, whether it was unpaid sales tax, unpaid business income tax or unpaid employment taxes, was upwards of US$2 billion for the state, and in excess of US$1 billion for the city. To make that a bit easier to grasp, the tax revenue they lost out on could have been used to hire up to 40,000 new public school teachers.”

Johnson says that worldwide, across all industries, the estimates of the value of counterfeit trade range from over US$200 billion a year, to as high as US$700 billion a year. However, he reiterates that it’s very difficult to know how close these figures are to the actual number, since the only real source of hard data is the amount of counterfeit product seized by customs agencies and other law enforcement agencies.

“Last year in the United States, seizures of pharmaceutical products alone were up over 150 percent from the previous year,” he points out.

“While we would like to think that that’s a result of improved work by law enforcement and customs, and a good portion of it may be, I think it’s a fair assumption that the increase in seizures is closely tied to an increase in the overall traffic as well. One of the problems that we run into with the seizure of counterfeit and illicit goods is that the easiest way, and probably the most accurate way of identifying shipments is the physical inspection of the goods.

“In many cases, when individuals are importing illicit goods they falsify documentation, they attempt to disguise the original source of the goods, which makes it significantly more difficult for customs personnel to spot a red flag and know that this is a shipment they should take a closer look at. With the quantity of goods moving around the world, the amount of manpower it would take to physically inspect all of the goods and significantly improve the possibility of detecting and intercepting those shipments would is mind-boggling.”

Drug specific While the methods used by counterfeiters of pharmaceutical products don’t differ significantly from those used in other industries, Johnson explains that there are some additional challenges in the ability to identify product as legitimate or counterfeit. “With counterfeit drugs, we have a couple of different categories that we see. There is product that has the right active ingredient, but not necessarily the right amount, or the right formulation. Then there is product that has no active ingredient

Travis Johnson on the US government’s international trade report: The Special 301 Report is put out every year by the Office of the United States Trade Representative, and focuses on international intellectual property enforcement and general trade enforcement throughout the world.

It’s often referred to as the US government’s blacklist, because its focus in the past has been fairly critical of countries where intellectual property protection was not seen as robust as it is in the United States and most of western Europe.

The list is broken down into several tiers, the highest being priority foreign country. Any country that is declared a priority foreign country on the 301 watch list requires the US Trade Representative to initiate an investigation and potentially bring a trade case against them. Countries like China and Russia generally top the list.

whatsoever, and has no medicinal effect. With those sorts of product, whether it’s a small amount of the active ingredient, or a product with no active ingredient they tend to be the formulations that are favored by the counterfeiters, because you may get a slight medical benefit from using those products, or no benefit whatsoever, but at least there is no negative effect.

“Obviously if people start showing up dead, the likelihood of scrutiny is going to significantly increase. But if somebody has high cholesterol or high blood pressure, and they’re taking a pharmaceutical they think is real but there’s no real medicinal effect from the product, then if they happen to die there’s a high likelihood that it’ll just be attributed to the fact that they were already sick.”

In pharmaceuticals, Johnson explains, there are also products which are not exactly counterfeit as such, but that may have been moved into a gray market area; for example, where product that was intended for sale in one particular region has been diverted to a third country. In some cases, there are also formulations that are slightly different, which may not have been tested or approved for distribution in that particular market. The labeling may be different and may not contain all of the information, or it may not be in the right language for that country.

“With the diversion of medicines, we also see in some instances the dilution of product,” Johnson says. “Particularly with medications that come in a liquid form, whether glass ampoules or vials you’ll see a single dose of the product diluted down to create a significantly less powerful version of the drug, which can be sold as ten dosages, or 100 dosages.

Th is would of course provide far less medical benefit if any benefit at all.

In some cases, the weaker form of the drug may end up leading to a more resistant strain of the disease it is meant to treat.”

Despite the significance of these issues, Johnson says that in the past there have been complaints that the pharmaceutical industry hadn’t been vocal enough about counterfeiting. “The World Health Organization released statistics suggesting that as much as ten percent of the world drug supply could be composed of either counterfeit or diluted pharmaceutical products. It’s been less an issue in the more developed countries, but in some countries, such as Nigeria, we’ve seen rates of upwards of 80 percent of counterfeit or tainted pharmaceuticals, which

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IACC history The International Anti-Counterfeiting Coalition was founded in 1979, in Washington, DC. Its mission is to combat counterfeiting and piracy by promoting laws, regulations and directives designed to render the theft of intellectual property undesirable and unprofitable. It serves as an umbrella organisation, offering anti-counterfeiting programmes designed to increase protection for patents, trademarks, copyrights, service marks, trade dress and trade secrets.

“In many cases, they are sadly disappointed – but they are also fairly lucky, assuming that what they’re getting doesn’t cause serious complications or medical problems. I think they’re far happier to get ripped-off even though they may end up with a serious medical problem resulting from the fact that they didn’t want to pay for the real thing.”

Future outlook The association began as a collaboration between a number of apparel and luxury goods companies in the US and Europe.

These companies were seeing more and more counterfeit products entering the market, and they decided that the problem had become so large that no individual company had the time or resources to be able to devote to it. The founder companies decided to pool their resources and work together to push for positive legislative change, and to raise the profile of the issue with government officials and law enforcement.

One of the coalition’s first successes was the passage of the Trademark Counterfeiting Act of 1984, which was the first federal criminal law regarding trademark counterfeiting.

means that some of the people who are in most need of medicines are being helped the least.

“In the past few years, the pharmaceutical industry has begun taking steps to educate the public about the risks of counterfeit products, working with groups like the Pharmaceutical Security Institute, which collects and aggregates data from pharmaceutical companies about enforcement and the international trafficking of counterfeit drugs. Or the Partnership for Safe Medicine, which does a fantastic job of providing public awareness information, alerts about reports of medications that have shown up in certain areas.

Work needed “Pharmaceutical companies have taken significant steps in dealing with the issue,” Johnson concedes. “I think they should be commended for it. However, there’s still quite a bit of work to do, both in the pharmaceutical industry and industry in a broader sense. There are still many people who are not aware that counterfeiting is an issue.”

Johnson quotes a Gallup survey that showed that upwards five to eight percent of respondents were either certain or fairly sure that they had purchased counterfeit pharmaceuticals. Although the drugs may have been purchased from such unlikely sources as street vendors or flea markets, those surveyed seemed to have few concerns about the safety or effectiveness of the drugs. Their overriding concerns instead being lower cost, and the ability to buy treatments for potentially embarrassing medical conditions without the need to get a prescription or consult a doctor. Johnson points to the ‘embarrassment factor’ as one explanation for the growth in counterfeit drug sales over the internet.

“In the past, we would see the general trafficking of counterfeit pharmaceuticals that have been manufactured in one country and shipped to another country, where another individual would deal with the rest of the distribution chain from the large shipment down to the individual buyer. Now, with the ease of access that the internet offers, individuals can just hop online, do a search on Google, and fi nd any number of places where they can obtain what they think is the real thing.

Johnson feels that the situation for counterfeit pharmaceuticals is at a bit of a crossroads. Laws around the world have improved and the industry has made a major forward move in acknowledging and addressing the problem. He does believe, however, that there are areas which require additional focus in the coming years.

“One of the main areas we need to look at is continuing to educate the public. Last year in the US, approximately US$30 million worth of counterfeit pharmaceuticals were intercepted by customs out of US$300 million in total counterfeit goods that came into the country. Some of the economic estimates for the actual total market for counterfeit goods in the United States is upwards of US$200 billion.

“There’s clearly a demand from consumers for cheap products. If that demand wasn’t there, it wouldn’t matter how many factories were operating wherever in the world producing the products, they would have nowhere to sell them. By educating the public and letting them know the real reasons why they should not be using counterfeit products, whether pharmaceuticals or otherwise, could go a long way in making a dent in that number.

“Many people look at it as simply an economic issue, and mainly a concern for large corporations. They don’t see how the counterfeit trade is affecting them personally; they don’t think about things like the loss of tax revenue, or the fact they’re missing out on government services because the government can’t afford to hire new teachers, or to fi x the roads, or provide other important services. They often don’t think about the fact that the factories that are producing these things often use like child labour, for example. There’s a sense of ‘me fi rst’ and the idea that big companies can afford to lose a little money. They’re not aware of the true cost of counterfeit products, both to themselves and to society as a whole.

“We need to bring the message to consumers about all the reasons why they should not be supporting counterfeiters, whether it’s their own health and safety, or the fact that people are losing their jobs, or the impact on the economy. By doing that, we can make a real impact on the spread of counterfeiting.

Travis Johnson is Vice President and Director of Legislative Affairs and Policy for the International Anti-Counterfeiting Coalition. He serves as the principal lobbyist for the association, both with Congress and state legislatures, with a particular focus on issues related to trademark enforcement, including counterfeiting and infringement. Internationally, he tackles issues such as trade enforcement and international trade policy, including cooperative work for trade enforcement between the US government and other governments, and customs rules and regulations in the United States and the EU.

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EXECUTIVE INTERVIEW

Material management Jozsef Repasi explains the importance of chemistry services in drug development.

What are the main challenges currently facing those charged with sourcing chemicals for use in pharmaceutical drug development?

Jozsef Repasi. Over the last couple of years the requirements of customers of CROs have changed substantially – putting increasing pressure on service providers to improve prices and reduce lead times. Therefore, sourcing of starting materials has become a critical part of the activities of CROs. In the early discovery phase, chemical suppliers are providing excellent and very rapid service, supplying starting materials from stock within a couple of days. However, sourcing of the same chemicals for late preclinical and early clinical work can be a major challenge. As a result of the ongoing economic crisis, European trading companies have reduced their stock levels substantially, so most of the materials have to be sourced from Indian and Chinese suppliers. There are good and reliable Asian suppliers, but materials from the same source are often offered by a number of companies. Unfortunately, the originally agreed lead times are frequently not met.

Nowadays, the buyers of CROs are working under extreme time pressure as their work has a substantial impact on the success of the company and its reputation. In order to secure the timely supply and good quality of the critical starting materials, it is sometimes necessary to dual source materials in order to minimise the risk of late delivery or quality problems.

JR. In my experience, the priorities of large and medium-sized pharmaceutical companies are very different when looking for service providers, and this has a fundamental impact on the success of the cooperation.

Large pharmaceutical companies frequently base the decision on the size and FTE rate of the service provider. One should wonder if it’s possible to develop a CRO of a few thousand people which functions efficiently in a few years. It could be argued that a company needs years of organisational development to achieve this. European and American service providers were established after years of such development, so, on the whole, they are able to provide fast, good quality and reliable service.

In early discovery, cheap service en masse can be sufficient for large pharmaceutical companies, but as the drug development progresses, flexibility and honest communication in timely fashion will get higher priority. The on-time service of the chemical supplier will greatly influence the work of other service providers.

A delay in toxicology or clinical phase can cost an order of magnitude more for the pharmaceutical company than the price to manufacture the drug substance. As a result, some pharmaceutical companies use different supplier evaluation methods in different phases of development; that is, reliability, trust, price, speed, and flexibility are weighted differently in each phase.

It is vital that pharmaceutical compounds, and the processes and procedures that surround them, are compliant with all relevant legislation. How can companies ensure this is the case?

JR. As Ubichem is a small company with approximately 100 employees, it is more efficient for us to use external experts to guarantee that we are compliant with all the relevant regulations. The external experts are responsible for providing information about any changes on a monthly basis and our colleagues are evaluating the changes and preparing plans to allow us to meet them. We also have an in-house system regarding internal monitoring and distribution of the legislation. Our colleagues responsible for the regulatory compliance regularly participate in training and conferences to keep their knowledge up to date, but they are also highly motivated and continuously developing themselves through self-education.

How did Ubichem’s Pharma Services Division come to be recognised as a Centre of Excellence for global chemistry services?

JR. Ubichem Research, which provides our pharma services, was created in Hungary in 1996. Since then, continued investment in people and facilities means that we now offer a comprehensive range of chemistry services to support the development programmes of our pharmaceutical and biotech partners around the world. An experienced team, with particular expertise in heterocyclic and organometallic chemistry, ensure that we minimise the risks associated with the scale-up of medicinal chemistry routes. Our passion for chemistry is matched by a pragmatic approach to innovation, enabling us to create new opportunities and add value to our clients’ projects. Th is, coupled with reliability and excellent problem-solving skills, makes Ubichem a preferred partner for many pharmaceutical and biotech companies.

What should pharmaceutical companies look for when searching for a chemistry partner to help accelerate their drug discovery and early development programmes?

Jozsef Repasi is Managing Director at Ubichem Research Ltd and Director of Ubichem Plc. He has held his Managing Director position since the creation of the company in 1996.

Repasi earned a masters degree in science, specialising in pharmaceutical chemistry at ELTE, in 1986 and has more than 20 years of experience in pharmaceutical reserach and development.

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TROUBLESHOOTER

Hung out to dry?

Rebecca Vangenechten explains the importance of delivering a freeze drying step-change for the pharmaceutical industry.

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roblem: “Siemens is at the forefront of accelerating process analytical technology (PAT) implementation in pharmaceutical manufacturing. Now Siemens is teaming up with the University of Ghent (UGent) to study how PAT can help pharmaceutical companies gain better efficiency and control when they freeze dry their products.”

Freeze drying, or lyophilisation, is an important part of the manufacturing process of many pharmaceuticals, especially in the fast-growing area of biotech production.

By removing water, the product becomes more stable. But this end stability is dependent on the product remaining stable during the drying process itself. Freeze drying is a complex, time-consuming and, thus for the pharma industry, expensive, multiple-step process during which the starting material, in solution form, undergoes several transformations leading to the end dry product.

In most manufacturing environments we see that the only information that is being monitored during lyophilisation is process data on the parameters of the freeze drier and not what is actually happening with the product itself. The result is that any degeneration of the product during the process can only be identified and rectified by in-process sampling – which is difficult given the vacuum conditions. Instead, end quality testing is mostly used today, whereby those vials that are of an unsatisfactory quality are eliminated. Throwing away the bad vials costs money.

Understanding and continuously monitoring what is taking place within the product during the actual freeze drying process can not only ensure product quality is maintained but can also provide a much more optimal management of the process itself. During lyophilisation, it is crucial to ensure that the endpoint of all intermediate process steps is reached before the next process step is initiated and to monitor the solid state of the freeze dried product.

disturb the normal freeze drying procedure. They do not allow monitoring of all critical process aspects, do not improve understanding of the product behaviour during the process and/or cannot characterize the intermediate and end product quality parameters, which are essential for real-time product release.

Drawbacks of current practice

Next steps

Until now, several process analysers have been developed and used in industry allowing the in-line and real-time determination of the freeze drying step-end points. These include thermocouples, manometric temperature measurements and use of vapour pressure methods. However, these systems are mainly based on the continuous monitoring of the product temperature, the water vapour content, or pressure changes inside the freeze-dryer chamber.

These existing techniques are also mostly indirect and often

Siemens and UGent are working collaboratively with manufacturers who are taking a keen interest in deploying this technology and combining it with SIPAT to achieve real-time release in their own freeze drying processes. The potential is there for a step change in this crucial and, increasingly important, stage in pharma and biotech production. n

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SIPAT: making real-time release possible Siemens is building on the study to deliver this goal of making real-time monitoring and real-time product release possible for manufacturers. We are combining the UGent approach, which is not done in real time as the data is collected after the process has finished, with our SIPAT software which links analyzers and PAT tools into one single system architecture.

“Existing techniques are also mostly indirect and often disturb the normal freeze drying procedure”

SIPAT makes it possible to collect analytical data in real time and use it with additional process data in a model that gives continuous predictions on the quality of the batch. Most importantly, it enables companies to have a control strategy in order to deliver advanced process control and achieve robust, right first time manufacturing. With SIPAT it is possible to act during the run of the process to correct a batch if any parameters are going wrong. Instead of having end-testing, in which some product is lost or even a whole batch if quality turns out not to be correct, manufacturers can be confident that the integrity of the product has been maintained throughout the freeze drying.

Rebecca Vangenechten is a Life Sciences Industry Consultant with Siemens. She is responsible for business development life sciences US and focuses on innovative technologies, including Process Analytic Technology (PAT).

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ROUNDTABLE

Waste-water solutions Michael Costello of Siemens Water Technologies and Veolia’s Michel Bouvet discuss waste-water management and its role within the pharmaceutical industry.

What are the specific challenges currently facing the area of wastewater management within the pharmaceutical industry?

Michael Costello. Specific challenges include increased regulation, reduced volume limits, limits on specific contaminants and rapidly rising costs. There are three main drivers associated with waste-water treatment: lowering operating costs, adhering to regulatory requirements and operating in an environmentally friendly manner.

Lowering operating costs is imperative for all organisations to remain competitive. Lowering these costs, however, must never lower product safety or product quality.

Adhering to regulatory requirements can be challenging as requirements become more stringent and more specific. Operating in an environmentally friendly manner is the responsibility of the industry as we share the natural resources and environment of our communities.

Capital costs for waste-water solutions can be expensive. Total cost of waste-water solutions must be factored into operating budgets. Understanding current and future regulations, waste-water technologies that are available and selecting the right water partner will ensure the most cost-effective and safe operation.

Michel Bouvet. Regulatory changes and possible impact of anticipated regulatory changes drive strong waste-water treatment improvements.

Pharmaceutical contaminants can cause long-term problems; this is a fact. But very little attention has been given to the potential contribution of metabolites. Challenges are no longer in COD reduction, which only represents a global pollution measurement; they are in detection of contaminants and metabolites. This will require strong R&D partnerships between pharmaceutical industry and water companies to achieve dedicated, quick responses. Moreover, it is not only water but also sludge quality from waste-water treatment that remains an issue as contaminants and metabolites could be adsorbed into it. Consequently, existing and future technologies and environmental strategies must take into account

the entire cycle of waste streams. New waste-streams strategy include specific treatment of high polluted streams such as on site decontamination (oxidation, thermal treatments) as well as concentration of streams for outside destruction.

The pharmaceutical industry requires several kinds of high quality water for product manufacturing. How can companies ensure they have a sufficient supply of water where it is needed?

MC. The most important factor for any pharma manufacturer is to ensure that they have sufficient supply and sufficient quality of their feed water, which depends on selecting the right partner for their water needs. The right partner will have a full portfolio of technologies, trained staff and, most importantly, experience with local installations with similar challenges.

Many water solutions providers have a limited technology portfolio that can severely limit the options available to the pharma manufacturer.

Choosing the right partner with a full line of products and technologies and experienced personnel allows the pharma manufacturer and the water solutions provider the opportunity to design the most effective solution to ensure proper performance while maintaining budgets. Lastly, it is important not to isolate the projects into design islands (such as pretreatment, make-up, storage and distribution and waste treatment), but rather approach the overall water system holistically.

Whether the feed water is surface water or groundwater, private or municipal, or highly specialised, it is critical to design the water system around the pharma manufacturer’s specific needs.

MB. Quality is driven by both experience and compliance with the latest standards, without compromising process security and product quality.

From WFI to clean steam or PW, large companies like Veolia can provide package systems for PW or distribution skids after having them tested by our commissioning team prior to shipment (factory acceptance test

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After some years in R&D related to micro pollutant evolution and degradation in soil and water, Michel Bouvet has been involved in industrial water treatment, especially in the areas of corrosion, scaling, fouling and waste-water treatment improvement.

Nowadays, he’s more specifically in charge of sales management related to water and waste-water for the European industrial sector and is engaged in the way of sustainable development.

(FAT). We have also developed a comprehensive mobile range of solutions for implementing quick and flexible solutions related to demand.

Our large range of equipment, as well as the size and global nature of our company allow us to provide a fast response with to respect with all pharmaceutical standards.

The industry is also facing increasingly stringent regulations for its effluent waste water. In your view, what is the best way for pharmaceutical companies to ensure they comply with these regulations?

MC. Ensuring waste-water compliance includes three critical factors: understanding current and future regulatory requirements, understanding technology choices, and selecting the right waste-water partner.

Like ensuring feed water performance, waste-water performance should not be looked at individually but rather as part of the overall water programme in a manufacturer’s plan. Quite often, the waste-water of one operation can become the feed water of another operation with minor fi ltration or treatment. Th is approach can drastically reduce the volume of waste-water produced (saving waste disposal costs) as well as drastically reduce the feed water requirements for production (saving raw water costs). Interestingly, the water quality in manufacturing can usually be improved through this process.

There are many case studies and examples of this success available for review by pharma manufacturers interested in this type of comprehensive water management programme.

MB. The constant evolution of environmental regulations as well as the problem of public image, global awareness about sustainable development, and other reasons push pharmaceutical companies to reinforce and to show the public their sustainable development strategy. We have been engaged for several years in sustainable development. The protection of the environment and the management of water resources as well as waste-water treatment are the key elements of Veolia’s core business.

Therefore, strong regulation and continuous solution improvements are a must for us. And with the help of our R&D facilities, we can provide the right answer for the best economic value. Th is includes not only water discharge limitation targets but also water make-up and consequently discharge volume reduction. When it is feasible, recycling and reuse of water will reduce our water footprint and provide substantial savings.

Th is implies the necessity to build strong partnerships with water companies to develop new tools to drive those evolutions.

How do you see the field of pharmaceutical waste-water management developing over the next few years?

MC. It is clear that regulations for contaminant levels will continue to advance, lowering the allowable discharge limits of specific contaminants.

Th is advancement will come as we better understand the health implications of industrial waste-water on our communities and environments.

Th is advancement will also come with newer manufacturing processes and new drug products such as biotechnology and nanotechnology. The cost of water, and the cost of waste-water disposal, will continue to rise for the foreseeable future.

Perhaps the biggest impact on waste-water regulations is the specific contaminant management rather than general wastewater treatment.

Waste-water systems are likely to become more specialised in targeting and treating critical waste compounds to very low trace levels to avoid negative health and environmental impacts.

Specialised products engineered to achieve advanced fi ltration performance on specific contaminants are already available, and will likely become more prevalent in waste-water treatment programmes. Experience and empirical data, as well as embracing innovation, are necessary elements for a water solutions provider to lead the industry.

Michael Costello is Global Director of Life Sciences at Siemens Water Technologies.

Costello directs the water and waste-water business for pharma and life sciences for Siemens and has over 25 years of process experience in pharma. Costello has developed new solutions, patented technologies and designed hundreds of pharma facilities all over the world.

MB. Waste stream management becomes more and more complex to achieve due to both regulatory evolution and new pharmaceutical molecules to remove.

We think those partnerships will integrate the whole water cycle: new molecules will require new specific water qualities we must be able to produce with the right equipment. Th is will require anticipation and the need to share information. And those new molecules must be removed before discharge.

Consequently, the partnerships will be global and will require strong commitments. We must be able to bring contractual guaranties not on the life of equipment but on water quality (guaranties of results) all along the equipment lifecycle.

Th is must be done according to a certain number of criteria that are unanimously emphasised in the pharmaceutical sector such as improvement of employees’ safety and health, management of industrial risks and development and use of less polluting energies.

In short, waste-water management will be included in a more ambitious sustainable management target that should take into account utilities management.

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Allen ED_11jan10 09/03/2010 14:44 Page 76

PACKAGING

The whole package The financial crisis and increasing regulatory restrictions make the pharma industry a tough battleground. GSK’s Keith Allen tells NGP why innovative processes in the manufacturing line and ensuring regulatory harmony will create the winners in the industry.

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s Technical Manager of Packaging Technology, Keith Allen’s day-to-day responsibilities require analysis of primary packaging materials and their development, ensuring that they function properly on the line. He works very closely with engineering and production to ensure that the materials used are compatible, and working with new processes such as Lean Sigma, Quality by Design and Design of Experiments.

“It’s very important to get online with your engineers and experiment with the machines to understand what effects the equipment has on the material prior to any optimisation or development studies,” he explains. “We perform the full validation process as well, and are getting a lot smarter with

that. We’re doing a lot more matrix-type testing, bracketing, especially when it comes to stability, getting the materials developed that little bit quicker and then introduced into production.

“So the manufacturing process is quite varied; we work very closely with our suppliers, mainly primary contact suppliers such as Alcan, looking at the specifications and making sure that they can meet our requirements, as well as working closely with them to reduce costs and looking at ways of standardising the materials and components.

“We’ve got a really good relationship with primary and secondary vendors, such as Alcan and Chesapeake. They are very good companies to work with who do supply a range of high quality products, and we’ve made some

“The regulatory bodies are causing a bit of a stir at the moment, whether it’s childresistant packaging, new trackand-trace legislation or Braille”

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great progress with them in terms of cost saving and process improvements.

Years ago it was all about whoever could provide the cheapest components, but now it’s a strategic partnership, working with them to reduce costs and improve efficiencies.”

GSK operates a number of newer processes. Allen notes that the company has Lean Six Sigma applicants, with a strong operational excellence team of green and black belts to facilitate new projects, who as a result have made strong progress, despite the recent industry hurdles set by regulatory bodies and their new guidelines: “The regulatory bodies are causing a bit of a stir at the moment, whether it’s child-resistant packaging, new track-and-trace legislation or Braille. It’s interesting; it’s certainly a massive challenge. For example, with the secondary packs we have to put reimbursement labels on, as well as counterfeit features, tamper evidence and Braille; combined with the new leaflet legislation it could all result in increased pack sizes. We have reduced the number of leaflets and cartons, and standardised, but the new legislation is making it more difficult.

We’ve had to introduce more components, bigger cartons and bigger leaflets, so unfortunately we’re now going the other way. It’s building a lot more complexity into our process,” explains Allen.

ICH Guidelines The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.

The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.

(Source www.ich.org)

Challenges

pharma industry – there are a lot of influential people within it, but only He notes the challenges of incorporating Braille within the packtime will tell if we can influence the regulatory bodies.” aging: the height and profile of the dot and the technology that is Allen explains that the possibility for European harmony is more likely needed in the manufacturing process either by embossing the dots than some of the Asia-Pacific countries, which often require additional packduring the carton manufacturing process or by screen printing on aging and a flow wrap, amongst other things. However, the quality of stanlabels or cartons. dards is not an issue that tends to differ greatly, and Currently the only legislation for dot doesn’t pose too much of a problem at present. height is for Italy, which stands at 130 micron; GSK, like every pharma company, needs to reall other markets have a target height of 100 duce costs to compete, he explains. “We need to promicron. “At the moment, we can achieve that, duce more packs of high quality and with less but the new guidelines are asking for possibly resources. At the moment, it is working, but there is around 200-micron dot height, and we’d be a period of continual change. Change is good, very pushed to actually make that because you change is healthy, but we’ll also need some stability. start getting a lot of bursting of the carton Hopefully we can get there. Changes in the ICH board, and that can affect the printed text,” guidelines have affected us, but you expect that in says Allen. the pharma industry, and all pharma companies “Instead, we’re looking at the possibility should be geared up to cope with these requireof labeling the packs with Braille, or reverting ments.” to a rotary type application to replace emHowever, despite these worries, Allen doesn’t Keith Allen is Technical Manager of Packaging bossing, but again there is the challenge of enview the future in terms of restricting regulatory conTechnology at GlaxoSmithKline. suring that every single pack has the correct straints or the crumbling effects of the economic criBraille information, and all dots are present.” sis. He talks of the innovative process, QBD, Lean Six Sigma and Design Working as a global company also creates difficulties in the manof Experiments, and the need for them in the industry. The main change, ufacturing process. Allen notes the trace-and-track feature and new he predicts, will be outsourcing. “We’re slowly getting there with the nonpacking lines that GSK has had to install purely for the Italian market value adding activities, and like the asset management and maintenance I requirements. “One of concerns right now is that we’ve introduced all do see a lot more of that happening, but you need to retain your expertise this new technology for one market, and that other markets that also at the sites. You can reduce head count by outsourcing, and there are lots take reimbursement labels, such as France and Belgium, will require a of savings to be made, but you must have your experts; you need to retain different process, and hence different equipment. the knowledge.”

“Ideally, if it’s possible, we want one process for all markets and As the challenges mount across the board, it is becoming apparent at least one for the EU. We’re not expecting the US, Japan or possithat it is those companies with innovative R&D departments who are able bly the Zone 4B markets to standardise, but at least we can try and to meet requirements that will continue successfully. The number of comdo something for the EU. There must be something we can do as a panies in the industry able to do that remains to be seen. n

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ASK THE EXPERT

Commercial success Examining the potential of drug delivery products in emerging markets.

ANDREW THOMPSON

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s economic, demographic and social changes sweep through the developing world, pharmaceutical companies are looking beyond the leading industrial nations (the ‘G7’) to the growing potential of emerging markets. PriceWaterhouseCoopers estimates that the Gross Domestic Product of the ‘E7’ – the seven major emerging countries which include Brazil, China, India, Indonesia, Mexico, Russia and Turkey – will triple over the next decade, and by 2020 could account for close to 14 percent of a projected global pharmaceutical market of $800 billion.

Disease profiles in emerging markets are evolving to more closely resemble those of developed countries, shifting from infectious disease control to management of more chronic conditions such as cancer, diabetes, and respiratory and cardiovascular disease. According to the World Health Organization, in the US only 12 percent of deaths from cardiovascular disease occur in working-age people, compared

with 28 percent in Brazil, 35 percent in India and 41 percent in South Africa. There is a growing market for products that address unmet medical needs in these countries; and those that also enhance therapeutic benefits such as dosing regimens and targeted dosage forms (such as via drug delivery technologies) greatly increase the potential for commercial success.

As emerging markets become more developed, local companies are growing more sophisticated and looking not only to license in fi nished products from Europe and the US, but also to develop their own pharmaceutical products and expand life cycle management options, making them potentially attractive partners. Additionally, multinational pharmaceutical companies are seeing the developing world as a key to potential life cycle extension for their own products. Generally, regulatory dossiers such as a US Food & Drug Administration (FDA) approval or an EU Certificate of Pharmaceutical Product (CPP) meet the standards of developing countries, and could over time become the benchmark for regulatory approval in emerging markets.

With more than 20 products sold in over 50 emerging countries since 2002, Eurand has demonstrated success and experience over the last decade in providing technologically advanced products to partners addressing unmet medical needs in these markets. Eurand’s successful record with the FDA, including recent

Selected Eurand Products Marketed in Emerging Markets, 2002-2009 Country

Partner

Finished Product Name

Technology

Korea

Green Cross

C-Mate

Diffucaps® extended release

Korea

Daewoong

Bonelax ER

Diffucaps® extended release

Korea

Boryung

Rino Ebastel

Diffucaps® extended release

Russia

Solvay

Olicard

Diffucaps® extended release

Singapore

GSK

Panadol

Microcaps® taste masking

Taiwan

Invida

Coracten

Diffucaps® extended release

Supplied technology component

Supplied final product

approval of several products, has resulted in strong data packages that can help streamline registration timelines for these partners. The launch of a once-daily formulation of the muscle relaxant cyclobenzaprine in Korea in September 2009, for example, came just 17 months after fi nalizing the licensing deal with a major local pharmaceutical company, Daewoong, in April 2008. Approved by the FDA in 2007 and marketed in the US by Cephalon as AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules), the product uses Eurand’s Diff ucaps technology and reduces the need for patients to take multiple daily doses of cyclobenzaprine while improving the safety profi le and tolerability of the drug by reducing the levels of somnolence associated with the standard immediate release (IR) drug formulation. In addition to Korea, a pharmaceutical market that increased 8.5 percent from 20072008, Eurand has also fi nalized deals with local companies to market cyclobenzaprine ER in Turkey, South Africa and Israel, where growth over the same time period was 12.9 percent, 7.8 percent and 5.3 percent respectively.

Assessing emerging markets Review of emerging markets is a very dynamic process, and perceptions and direction can often change. Companies seeking to succeed in these markets must be armed with substantial information, prepared to create local partnerships for the long term, and willing to be flexible and creative in their planning.

Eurand’s experience has led to the development of an intensive process for assessing each market, working closely with local partners to leverage their understanding of market dynamics. Key factors in this process include assessment of the region’s healthcare system, trading environment and taxation issues, the local competitive landscape and therapeutic class analyses, as well as a review of regulatory, pricing and reimbursement practices.

With the right information, the right products and the right partners, companies that make the investment now can successfully tap into the great potential of emerging markets.

Andrew Thompson has 25 years’ experience in international marketing and operations in the pharmaceutical industry, including increasingly senior positions at ICI Pharmaceuticals, Glaxo Wellcome and Spanish pharmaceutical group Almirall. In 2007 he joined Eurand, where he is responsible for the company’s pharmaceutical technology business outside the US.

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FEATURE INTERVIEW

on

track Martin Mackay fills NGP in on his plan to improve the ROI of Pfizer’s R&D.

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M

artin Mackay became Pfizer’s President of Global Research and Development in 2007, moving to Senior Vice President and President, PharmaTherapeutics R&D following the completion of the company’s merger with Wyeth in October 2009.

Having taken on the initial role of President of R&D, his main objective was to understand why Pfizer was not getting adequate return on investment in R&D, and how as a department they could address that.

Mackay explains the implementation of what he describes as his “highly tactical plan” from day one. “The first day I was in the job I laid out my five-point plan, which people thoroughly enjoy at Pfizer, and it was a very simple plan based on everything that we had learned over a period. It basically came down to executing what we had in the pipeline.

“The simple first thing was to deliver the late-stage portfolio. At the beginning of 2007 we had eight entities in phase III; by the end of 2008 we had 26 entities in phase III. That first part of the plan of delivering was very important and as part of that we made some commitments to what we were going to deliver as an R&D organisation. We did that on March 5, 2008, and we’ve been very public about them. We’re on track to deliver on all of these publicly made commitments, something that we hadn’t done before.”

The second part of the plan was to make sure the company was working in the right areas: those of the highest medical need and those that could be attacked from a scientific and drug discovery point of view.

This resulted in the company cutting its portfolio considerably to focus on areas that would be best for patients and for the company.

MacKay notes the third part of the plan was to focus on becoming a top-tier company in biotherapeutics. Historically, Pfizer has focused on small molecule drug discovery with a large biotherapeutics pipeline, but Mackay wanted more, and to take the company to the next level. His fourth agenda was to increase productivity. Despite this receiving the least attention, it required the biggest amount of effort, particularly in terms of improving attrition.

“The fifth part of the plan was to access external science much more productively and efficiently, and whist we had always had collaborations, again, it was a case of taking it to the next level, explains Mackay. “In our five largest therapeutic areas we formed therapeutic area scientific advisory panels, each lead by a leading academic and in turn those academics having a number of really top-notch scientists. This group works directly with the leaders of those five therapeutic areas – we call them chief scientific officers – and that has gained us access to the very best minds.

“We’ve got terrific talent within Pfizer, and a great history of drug discovery.” However, most discoveries happen outside because even with our terrific budgets it’s relatively small compared to everything that’s invested in the life sciences. I’m very pleased with the number of great collaborations that we have, both with academia biotech and even with some of our competitors.

“Over that period we’ve focused on attacking the issues of productivity that have dogged the industry and have engaged with our colleagues, and I have to say they’ve risen to this task. I couldn’t ask for more effort and more

result coming out of our laboratories, and obviously all the people who support that have been really excellent.”

In addition to improving the company’s problem areas, Mackay has also been determined to address those external challenges that face every pharma company. He notes the increase in regulatory hurdles, and the company’s response to this of running more patients in its studies. “We have always had a very simple philosophy that our drugs have to be both safe and effective, and we put a lot of effort into making sure they are,” he explains.

Pfizer’s work with agencies across the world and its multi-centre operations does not come without its challenges, but Mackay notes that providing the company continues to produce good medicines, they will be approved through the regulatory process. “Sure, there will be discussions and meetings and appropriately the data will be scrutinised, but I like to think we scrutinise our own data more than anybody else does,” he says. “We’re on the cusp of the golden age of drug discovery and of producing medicines that are going to alter the nature of disease.”

Personalised medicine Discovering and developing the right medicines and ensuring the right patients receive these is Mackay’s essential goal; Pfizer’s laboratories now examine, very early on in the process, the patient population that will best be served by each medicine. “This is going to be a real change for the true benefit of patients in the near future,” he says.

Pfizer’s portfolio of pipeline products currently spans 11 therapeutic areas, ensuring the tailored therapies approach is begun in the very early stages of clinical development. Mackay gives examples of drugs both in the market and also within early stage clinical development. Selzentry, which is also known as maraviroc, is Pfizer’s CCR5 antagonist for the treatment of HIV/AIDS. Mackay explains how the virus enters the immune cells of some humans via the CCRF receptor, but there is another portal of entry, for which the company has an assay that it conducts before treatment starts.

“This ensures that the virus actually would enter the patient by this receptor,” explains Mackay. “For any patient taking Selzentry, we essentially know that it’s going to be effective because of this test that we do beforehand.

Selzentry was the first new mechanism in HIV/AIDS for a decade. We launched it around two years ago, but right from the beginning (and I was there on day one of this project) we had an eye on making sure that the right patients got the treatments. I’d like to think that in future the vast majority of the compounds we launch will have aspects in them of this.

“We have a very interesting approach in oncology now for non-small cell carcinoma. We showed how in a particular group of patients with non-small cell lung carcinoma, our phase I compound worked remarkably well and better than anything else that is currently being used, and we were able to isolate a particular genetic translocation in that group of patients. We’ve subsequently partnered up with Abbott on a diagnostic that will identify those patients ahead of time.

“Another example that demonstrates how we approach diseases or conditions from a discovery perspective, which is a particular programme called

“I truly believe that by the end of the century we will cure most of the diseases that plague us”

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NaV 1.7, is a sodium channel approach that we have in the pain area. We did some seminal work with leading academics in the United Kingdom, looking at a family in Pakistan who had what’s called a chronic indifference to pain. They couldn’t feel any pain, and while that sounds like a good thing it’s actually a really terrible thing. It leads to mutilation of fingers and the like, because children growing up can’t feel the normal sensory touches that protect us.

“The seminal work that led to the identification of the problem was that the sodium channel, the NaV 1.7 channel, was the gene responsible for the condition. We did other work in genetic analysis: there’s another condition where people are acutely aware of pain; even at the slightest touch they feel it quite badly. Again this was when the NaV 1.7 channel was implicated, so here we had genetic validation both in terms of a loss of function and a gain of function. We started a programme in the UK whereby we launched a very large program because we thought this was a leading target in pain treatment.

“More and more our early discovery portfolio is predicated on a genetic analysis that shows some genetic validation, and also has an acute eye right in the beginning to get to the right patient population,” he says.

Inpact of the Pfizer/Wyeth merger

In November, Pfizer announced that it would close six R&D facilities in the US and the UK, reducing its global capacity by over a third, following completion of its acquisition of Wyeth.

Units in Princeton, New Jersey; Rouses Point and Plattsburgh, New York; Sanford and Research Triangle Park, North Carolina, as well as two in Gosport and Slough in the UK, would cease operations.

The firm told Reuters that: “While these changes are expected to bolster productivity and reduce costs, they will result in staff reductions."

Drug, biologics and vaccine R&D will be focused at five main sites: Cambridge, Massachusetts; Groton, Connecticut; Pearl River, New York; La Jolla, California; and Sandwich in the UK. Other facilities in San Francisco, Cambridge, UK and Shanghai, China will conduct the development of monoclonal Discovery methods antibodies in a move that In the early 1990s, Pfizer was one of Biopharmaceutical R&D head the leaders in high-throughput screenMikael Dolston said would ing. Mackay notes that during his early transform the firm into the days with Beecham Pharmaceutical, in world's leading biopharma Jeffrey Kindler, CEO of Pfizer and Bernard Poussot, CEO of the 1970s, chemists would only make a manufacturer.

Wyeth, appear at a news conference discussing the planned merger of their companies. Pfizer acquired Wyeth for $68 few compounds a week. As time went “This new structure puts billion, creating the world's largest biopharmaceutical company. Pfizer in the best position to on and tests became more high-tech, there was greater accuracy in the correct conduct cutting-edge research chemical matter in addressing particuwithin and beyond our own lar targets, and this became achievable on a much greater scale. laboratories and to deliver a portfolio of high-impact Chemists can now make tens of thousands of compounds rather than the medicines to patients.” previous few, with biologists matching this with the creation of assays that Martin Mackay, president of PharmaTherapeutics R&D, could tests hundreds of thousands of compounds, referred to as highagreed with the advantages of the new set-up, explaining that: throughput screening.

“Moving forward on our aggressive timeline, we are analysing “There’s a whole host of different ways we can screen millions of comthe combined portfolio and prioritizing research projects that pounds, which gives you a much earlier clue as to the type of chemical matwill address unmet medical need and bring Pfizer’s scientific ter that you’re going to have to work on, to come up with what will be a and competitive advantage to the benefit of patients.” medicine,” he says.

Source: www.in-pharmatechnologist.co “Interestingly there are very few occasions now that we run a highthroughput screen. We have a file of about three million that we believe to be excellent compounds and we can run those and a whole array of different types of screening technologies, but much more we use computation and seing but still using the power of numbers and the power of combinatorial lected parts of the files. chemistry.

“For example, let’s say the target is a kinase target, which is a particular “Most of our new projects, certainly from a small molecule perspective, type of enzyme in the body that is very well known to be a good source of new start in this way, and it’s very impressive how we’re using computational bimedicines. We can now have a targeted library purely for kinases and if we’re ology and computational chemistry to narrow down on the types of chemistarting any de novo kinase we will screen just against those compounds first cals that make great medicines.” n before ever going to the full file. So high-throughput screening has moved in Martin Mackay is Senior Vice President and President, PharmaTherapeutics Research & Development at Pfizer. the last few years on to the next plane, which is much more selective screen-

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EXECUTIVE INTERVIEW

In line with in vivo Taconic’s Holger Kissel explains the significance of in vivo treatments, and tells NGP how researchers are providing efficient and reliable forms of study.

How can quality animal models and services help accelerate research and improve market position?

Holger Kissel. Using in vivo models earlier in drug discovery will generate physiologically relevant data to be used for target identification and assessing the safety of the target. Drug selection guided by early access to in vivo data will be more likely to achieve clinical success.

In addition, translational mouse models, in which target proteins or entire pathways are humanised, provide a toolbox for testing compounds in vivo before entering the clinic. As a result, using these advanced mouse models in combination with established in vitro tools in pharma R&D, should contribute to reducing drug attrition in clinic trials and help to increase the success rates of drugs making it to market.

How will your acquisition of Xenogen Biosciences Corporation expand Taconic’s drug discovery services?

HK. Th is acquisition gives us the ability to integrate model generation, phenotyping and in vivo compound testing, thereby providing a complete research service to our clients – be it the identification of new targets, target validation, compound profi ling or even repositioning of existing drugs. Also, the existing expertise at Xenogen Biosciences (now Taconic) will allow us to build a strong portfolio of services in a specific therapeutic area, such as using Taconic’s luciferase imaging technology in the area of oncology and non-invasive monitoring of tumour development. In combination with our translational mouse models, such as our panel of humanised transADMET mice, this will provide high value for our customers.

Within the family of Taconic companies we can now integrate state-of-the-art model generation services, efficient contract breeding

services and quality control of animals, as well as the analysis of these in vivo models. Th is enables us to provide phenotypic and pharmacologic data to our clients on any target gene or compound provided to us by our partners.

How is genetic integrity and strain harmonisation of laboratory mice and rats ensured?

HK. Genetic quality assurance of a mouse or rat strain becomes imperative for the success of scientific experiments. To accomplish this, a genetic monitoring (GenMon) programme

present the same characteristics at all different sites, therefore, a harmonisation program should be in place.

How does Taconic work alongside researchers to conduct an efficient and reliable in vivo study?

HK. For the generation and analysis of complex in vivo models and their phenotypic analysis, we see ourselves as a scientific partner of researchers in the pharma industry. We have a very dedicated scientific project management team being the single contact for all project re-

“We can now integrate state-of-the-art model generation services, efficient contract breeding services and quality control of animals”

that is intertwined with a breeding programme needs to be in place. Inbreeding programmes are designed to maintain the purity of a genetic background strain and should be designed to prevent crossbreeding and genetic drift. Outbreeding programmes on the other hand ensure maximum heterogeneity. In most cases, genetic monitoring programmes are based in DNA technology such as microsatellites and or single nucleotide polymorphisms (SNPs). In both scenarios genetic backgrounds are determined by a unique DNA fi ngerprint.

For genetically modified mice their genotype should be verified.

An important component of a breeding program is assuring that existing colonies of a strain at geographically distant sites should

lated inquiries. Th is team manages the entire project from design to execution to delivery of data. Th rough this personal interaction on a project level we have always been very flexible in considering a customer’s desire and are able to quickly communicate progress or any arising issues. With many of our long standing pharma partners we do have frequent scientific meetings on site to discuss the status of all running projects, as well as presenting them with new technologies and services Taconic is about to offer.

Dr Holger Kissel joined TaconicArtemis in 2005. In 2008 he joined the newly founded Global Business Development team at Taconic. He is responsible for keeping Taconic current regarding the emerging needs of the global biomedical community and for the commercialisation of developing technologies into new products.

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Getting personal

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William Chin tells Natalie Brandweiner how Eli Lilly is using tailored therapeutics to improve outcomes for patients and boost its bottom line.

E

li Lilly and Company is well established in its R&D success. Currently ranked 122 in the Fortune 500, it has 56 potential drugs in its clinical pipelines.

Armed with an array of knowledge and tools, Lilly is sizing up its disease targets. However, this is not an easy task given the current economic climate, as well as the patent expiry pressures and safety hurdles beginning to weigh down almost every major drug firm.

The company is facing a number of pricing pressures, due to the loss of exclusivity on many of its drugs combined with the simultaneous shortening of drug life spans. The public is also increasingly demanding that drugs become safer and safer, signalling a shift in balance between benefit and risk. The industry is facing continuous scepticism regarding its productivity. Regardless of the investments Lilly has made, there have been certain periods, such as during 2007, in which low points are evident.

As the Vice President of Discovery Research and Clinical Investigation, William Chin is the man leading the company’s drug developments, battling against the many industry pressures and media misgivings. Chin says the real challenge, both at Lilly and within the industry, is to continue to maintain a flow of high-quality molecules to test and to understand what kinds of molecules will be able to help treat disease in patients.

“That is going to be a key challenge,” he says, “but to do this in a more efficient and effective way unfortunately takes too long and costs too much to get the drugs that we get, and so we need to improve that. What I’ve been trying to do in that process is to take a group of very talented scientists, including physicians, and bring them together to join in on this process of making the whole journey better and more effective.

“In terms of my management style, I’m very fortunate to have really outstanding leaders in the various fields, whether it’s biology, which includes cancer, metabolic diseases and neurosciences, but also leaders in chemistry, toxicology, ADME, experimental medicines/translational medicine and programme/medical. I count on the excellence of these leaders to join in as a team to achieve our tasks, so my style is I trust my colleagues. I am, myself, proud of my own integrity and I hope that others would follow that. My decision-making style is a participatory one. I’m a firm believer that we need all the input of as many people as we can, within reason, to be able to make the best decisions. I believe in diversity of experience, of background, to be able to come together to provide the input so that we can make the best decisions for our own portfolio and for our products.”

Personalised medicine The idea of tailored therapeutics – providing the right drug at the right time and for the right patient – is gaining support industry-wide.

However, Chin notes that often Lilly’s commercial colleagues would prefer that he and his team think in terms of expanding the business rather than from a patient perspective. In order to create good outcomes for all, Chin says Lilly has taken deliberate steps to ensure that every project that is started has a multiple of outcomes.

The first of these is improving outcomes for individual patients – understanding how the drug will excel against any others that are on the market, and looking at which patients will benefit more than others. The second outcome involves incorporating biomarkers, which allow researchers to follow both the efficacy of treatments in animals, as well as human subjects and patients. Chin provides an example of how this can be applied in cancer drugs: “In colorectal cancer, for example, there are a number of agents that have been shown to be effective, including an antibody against the EGF receptor known as cetuximab. It’s been shown that this drug is useful in patients with colorectal cancer, if you have a certain gene called K-RAS. If there is a normal copy of that gene in the tumour in these patients, then you have a better likelihood of response with these agents, but if you have a mutated or abnormal form of K-RAS, then it is not likely that you’ll benefit.

“The FDA, as well as the EMEA, has allowed us to be a part of the approach that we can take in terms of personalised medicine. That’s a really good example of how this is going to be applied.

Sixty percent of individuals with colorectal cancer have a normal form of K-RAS, which means 40 percent through this testing wouldn’t respond or benefit and so probably shouldn’t take this medicine,” says Chin.

Prior to joining Lilly, Chin was a member of the faculty at Harvard Medical School for 25 years and is proud of the achievements made during his academic career. His research in the nuclear hormone receptor field illuminated the process by which hormones work to regulate events in cells and pathways in the body. He also led a genetics programme, one of the first in adult medicine in the United States, established 23 years ago.

A pioneer indeed – at that time, genetics was thought of as a pediatric department, one that would be responsible for postnatal genetic diagnosis, for example.

“I learned that genetics is absolutely important to help us understand which may be the most important targets for drug discovery,” he explains. “One of our challenges is that we need to be better at choosing targets for drug discovery, and part of the difficulty of this is, again,

“What we are trying to find out is how can we share in knowledge, share in work, share in the risk of projects and hopefully, then, share in the reward”

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based on our incomplete knowledge of disease causation or pathogenesis.

Genetics helps us begin to tease that out a little bit more.

“A classic example is an enzyme called PCSK9, which is a gene that regulates LDL cholesterol receptor function. As a result, it then follows the body’s levels of LDL cholesterol, and we know how important that is in the cause of atherosclerosis. So we know that individuals who have defective PCSK9 genes have very low levels of cholesterol, and associated with that is almost absent cardiovascular disease and atherosclerosis.

“Conversely if you have too much of this activity then you can have the reverse. So, you can see how we might imagine that this could be a good target in addition to our statins. That’s our standard treatment these days: diet, exercise and statins for control of cholesterol in the body. If you had a small molecule or an antibody that blocked the activity, or decreased the amount of PCSK9, you could mimic what happens in these few rare individuals who have the defect as a part of a genetic condition.

So what I learned from my activities as head of genetics division is how to really utilise this kind of information to help us choose targets in a more intelligent way,” says Chin.

Chin says his focus during his time at Harvard, whether he practiced as a physician, researcher or educator, was always the patient. His realisation of the huge amount of unmet medical need propelled him to look for solutions; as a scientist, Chin notes that the greatest of discoveries are made through serendipity. “In order for you to have great innovation you’ve got to create a climate to allow our scientists to be able to almost play a little bit,” he says.

William Chin

He notes the tendency, due to tighter budgets and time constraints, to rush through discovery developments, but says the correct atmosphere and environment must be created in order for those random acts to occur that often provide the most insight. Because he is no longer a scientist working in an academic environment, but is head of a corporate department, Chin must be aware of these constraints, as he points out, “After all we do have a business to run, and we do need to make sure that we provide this flow of innovation to our patients and shareholders.”

Patient focus Lilly is currently keen to promote its phenotypic drug discovery initiative, PD2. The company’s success in drug development over the last several years is more than apparent – a large number of molecules have been tested in both human subjects and patients. Determined to continue in its success, the company is doggedly providing this stream of information, transforming itself in order to meet the industry challenges Chin has already noted.

“One answer is to focus on patients,” explains Chin. “We like to talk about improved outcomes for individual patients. We know that even if we have the most innovative drug but our patients have no access to it, for whatever reason, because they can’t afford it or governments or thirdparty payers are not willing to reimburse for it, then we really haven’t done anything.”

He also notes the importance of providing patients with tailored therapies, and the need for collaboration in order to understand these new ideas. Collaboration has long been a trend within the pharmaceutical industry, but Lilly is now entering into much deeper partnerships, sharing risks as well as rewards.

Chin explains that this is called a FIPNET – fully integrated pharmaceutical network – which encompasses collaborative partnerships with academics, biotech companies and government agencies, or even with larger pharma companies.

“Another level is to have shared risk and reward, so in other words, everybody has a bit of stake in the game as opposed to just paying a group for services. And the third level is to take an equity position in our partner company,” he explains.

“We made Lilly a FIPCO – a fully-integrated pharmaceutical company – that is both self-contained and selfsufficient. However, we realised that we’re going into an era where this may not be the best approach, and so we are morphing towards a network approach, a FIPNET. “As part of this FIPNET, we think that PD2 is an opportunity to increase our innovation flow by basically bringing together the talent that’s present throughout the world. That seems like a very ambitious goal, but there are a lot of ideas and compounds out there in the scientific community that remain untapped but could really help patients.

“What this programme does is provide free testing of compounds that are designed by largely academic investigators, that may be very different than the kinds of compounds that we normally have; they’re tested in four or five assays, which are called antitypic assays. Normally in our business we decide on a particular target, such as a molecular target,

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and then find molecules for that target. Whether they’re small or large molecules, we then test to see whether they work in biochemical and cell assays and then ultimately in animals.

“If that does well and it’s safe enough, we then move these molecules into humans. One of the assays is to see how compounds affect cell proliferation, how cells multiply and so on. So you can see how this would be very valuable in cancer.

“We have another assay that looks at what we call angiogenesis, which is the production of new blood vessels. Many cancers are very good at making new blood vessels and depend on that in order to thrive; our job is to find drugs that block new blood vessels in formation, and so that’s anothnother assay. Instead of focusing on a specific molecular ular target, it’s looking at a cell behaviour.”

Approximately 60 institutions and laboratories have signed into PD2, providing opportunity to have their molecules tested. If at the end of the testing there is enough mutual interest, the molecules are novel enough and the activities interesting enough, Lilly will then engage in a discussion h and have a certain amount of time in which it can agree or disagree with the investigatorr in

Eli Lilly headquarters in Indianapolis

PD experimental medicine and medical work together in PD, a cluster concept of activity.

“About four or five years ago I wanted to reorganise our group because I felt that we had groups that were much too large. That they’d created silos that diminished tthe synergies that I thought we could have by having more integration, and so we created smaller groups called drugin hunting teams. This is largely the biologists; the groups were hun much smaller and focus on specific areas such as diabetes or psychiatric diseases. psychiatri “These smaller groups would have with them a set of colleagues in chemistry and so on, and they would work together to provide more flexibility, with the ability to respond to changes more rapidly. In large part it has allowed us to do that, and I believe this has been a reason why we have been more successful lately in our pipeline,” explains Chin.

He also reiterates that a continued focus on patient outcomes, as well as FIPNET, are other factors behind the company’s success, before citing the fourth reason as being the result of “a rare company that has a true balance of therapeutic modalities focusing on small and large molecules”.

Most pharma companies have largely focused on small organic molecules as drugs, and those drugs mostly been taken orally in the form of a pill. However, Lilly is opting to take a different direction, focusing on large molecules such as antibodies, peptides and therapeutic proteins to treat disease. Lilly’s recent acquisition of Applied Molecular Evolution to aid the company with the optimisation of proteins for the large molecules has been supported by its additional acquiring of Structural Genomics, a technology used as a structure for finding new molecules.

Chin finally describes the company’s focus on being excellent partners, understanding that the future depends not on doing things as a sole company, but through collaborative partnership. “What we are trying to find out is how can we share in knowledge, share in work, share in the risk of projects and hopefully, then, share in the reward,” he concludes.

Approximatly 60 institions and labratories have signed in to PD2

order to proceed with a research contract.

“If we agree not to continue, the investigator gets all the data and gets to publish at will, which becomes a way of increasing our knowledge base for everybody. In this sense, this is a model of open collaboration with a much larger network of scientists that increases the likelihood of innovating. This will provide what I like to call a win/win/ win – it’s a win for our partners, our academic and other collaborators, because they get more information about their compounds and improve our overall knowledge base. It’s a win for Lilly because we have access, potentially, to ideas that we might not have, and we create relationships with investigators that we might otherwise not have had. Most importantly, the third part of the win is that ultimately we hope this will lead to new therapies and treatments for our patients,” says Chin.

Meeting challenges Chin explains that the success of these developments is Lilly’s strategy to meet the considerable challenges that continue to dominate the industry. For Chin, the correct organisation of staffi ng is necessary to ensure the company remains ahead of its competitors. “I have an outstanding scientific and physician staff and ultimately it starts there: if you have the best people in the business then you at least stand a chance of being hailed to be competitive, but you can have all the best people in the world and if they’re not organised well, if they’re not working together in an optimal way as part of a true team, then you’ve lost the benefit.

What Lilly has done is to create an environment where our biologists working in cancer and neurosciences are working closely with our chemists and our toxicologists; and our folks who work on ADME, PK/

William Chin is Vice President of Discovery Research and Clinical Investigation at Eli Lilly and Company. He also serves as a member of the company’s senior management council. Prior to joining Lilly in January 1999, Chin was Professor of Medicine and Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical and School Chief of the Division of Genetics and Senior Physician at the Brigham and Women’s Hospital, Boston.

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INDUSTRY INSIGHT

Multiplexed assays enter drug discovery labs How multiplexed technologies can increase productivity if they produce reliable, consistent data and eliminate tedious and error-prone manual work in the laboratory.

A

nagnostics Bioanalysis GmbH is a high tech startup based in St Valentin, Austria, which specialises in developing microarray based systems and protein and DNA assays for research and routine diagnostics. Founded in 2005, Anagnostics has developed a unique cylindrical microarray, the patented hybcell, and built a completely automated system around it, the hyborg.

Dr Bernhard Ronacher, inventor of the hybcell and co-founder of Anagnostics Bioanalysis, points out: “Working with traditional array-based systems was quite frustrating. Complex microarray handling with various manual processes, lack of robustness and the lack of kinetics measurements did not lead to productive work and satisfactory results. Therefore Anagnostics developed the hybcell technology with the objective to eliminate these limitations. We wanted to provide a highly productive system which generates superior quality results, and is easy to use.”

“Due to the technology’s flexibility the application areas are virtually unlimited” Easy handling and automated work flow The design of the hybcell allows for great versatility, if required. The specially developed surface of the cylindrical microarray allows binding of DNA as well as proteins, which is a significant difference to most other multiplexed or microarray systems on the market.

However, once an assay is established, the whole process is standardised and easily per-

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The use of fluorescence detection with specific fluorophores provides highest selectivity at high sensitivity. Even high throughput experiments can be conducted completely automated through the combination of the 4.000- spot hybcell surface and the 96 sample capacity, a completely unique capability.

DNA applications focus on the determination of DNA melting curves and on-spot reactions (primer extension, compact sequencing, nano-preparative DNA target enrichment). A ‘PCR-likeprotocol’ has been developed, aiming to combine a two step PCR and microarray hybridisation process into a single assay, but in a highly multiplexed manner. This protocol dramatically reduces the complexity and required time of many DNA microarray applications.

The time required for one complete multiplexed Dr Bernhard Ronacher, a assay ranges from 10 to about molecular biologist, geneticist and 90 minutes. biochemist, developed the hybcell microarray technology. He headed A number of technical the molecular diagnostics laboratory of Lambda GmbH, notes describing the developed where he established the DNA assays and applications can be chip and array technology and in 2001 the first Austrian biochip, accessed on Anagnostics’ webParoCheck, was filed for patent. At the university, he uncovered the site.

formed in any laboratory by standard technical personnel.

Anagnostics’ hyborg system is a fully automated and integrated device for processing and analysing the cylindrical hybcells. The hyborg integrates sample loading module, microfluidics module, thermocycler, hybridisation station and fluorescence scanner in a single device trough automation. All processing steps – from temperature profiles or exchange of liquids to multi-colour scanning – are freely configurable by the scientific user and controlled and documented by the hybwiz and hybcon software platforms.

Intuitive software tools

Efficient operation of any lab equipment is key in today’s data intensive lab routine.

Anagnostics maintained utmost flexibility of the system but did not want to burden lab technicians with complex software tools. As a result, two software interfaces were developed, one for the assay developers, hybwiz, and one for system operators, hybcon.

That way the scientist or operator can focus on the task at course of infection by Rhino hand. Both solutions do inteviruses, responsible for the common cold. His work was grate seamlessly, of course.

Outlook fundamental in the development of anti-viral agents and was Due to the technology’s Anagnostics developers rewarded by the European flexibility the application areas have successfully worked with Hoechst Foundation. are virtually unlimited. a number of partners both in However, in the research appliacademic institutions as well cation space Anagnostics’ focus lies on kinetic proas in pharmaceutical drug discovery laboratotein applications, such as multiplexed measurement ries to prove the hybcell technology’s capabiliof on/off rates in protein-antibody binding experities and the performance of the hyborg system. ments (e.g. in biomarker studies, high throughput This new and revolutionary hyborg system for selection of antibodies based on affinity, antibody multiplexed DNA and protein assays is now QC) or kinetic measurement of protease activities. commercially available. n

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EXECUTIVE INTERVIEW

Back to the future Dai Hayward explains how binding assays have held onto their dominance.

What is CellAura doing with fluorescent technology?

Dai Hayward. CellAura designs and synthesises pharmacologically validated fluorescent ligands.

It does this through a deep understanding of how to combine a fluorophore, a linker and a biologically active ligand to deliver optimal performance for a wide variety of assay formats. Fluorescent technologies have become the gold standard for a significant majority of cell-based bioassays used in drug discovery. However at the crucial interface between chemistry and biology – the ‘binding assay’ – radioisotopes have held onto their dominance despite the ever increasing safety, operating and waste disposal overhead issues of using radioactive materials in these assays on a large scale.

This has been because low molecular weight drug-like molecules were challenging to label with fluorescent probes. The fluorophore usually has a large molecular weight compared to the parent ligand, often dramatically altering the pharmacology of the parent ligand in both potency and efficacy at the receptor. This has been a specific issue for the monoamine family of G-protein coupled receptors (GPCR’s) whose orthosteric ligands are low molecular weight organic molecules. Consequently, high-throughput screening (HTS) for GPCR active molecules has become dependent on functional cell-based formats that read out activity of second messengers, signalling pathways and DNA response elements downstream of receptor activation or blockade. The Achilles heel of these formats is that many test molecules which appear as active from the HTS campaign subsequently turn out to be working downstream of the target receptor when counter screened in small scale radioligand binding assays or alternative cell-based formats (false positives).

How will CellAura Technologies solve this problem?

DH. Our fluorescent ligands are labelled with a

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‘red-shifted’ fluorophore that can be used in parallel with other cell-based readouts that emit their fluorescence in the green region of the visible spectrum, such as calcium mobilisation using Fluo4 based assays, receptor internalisation with GFP tagged receptors or GFP tagged betaarrestin complementation. CellAura has developed a solution to the above challenge through its unique combination of expertise in synthetic chemistry and molecular pharmacology to produce high quality fluorescent reagents as tracers for G-protein coupled receptors (GPCRs). As a result, drug discovery scientists can now determine fluorescent binding and function in the same assay reducing the amount of counter screening required from a cell-based HTS campaign.

Many of the platforms you have validated are automated fluorescent microscopes used for high content analysis/screening. Can CellAura ligands be used for HCA/S? DH. Yes. The capabilities of HCS have been expanding over the last five years and our technology synergises very well with HCS. Drug

discovery scientists are increasingly realising that appropriately designed and executed HCS can reduce both false positive and false negative rates (molecules working through alternative mechanisms to the targeted pathway) to the traditional target-based screening previously described. Secondly most HCS assays have used fluorescent antibodies (for ‘fix & stain’ formats) or engineered fluorescent proteins (for ‘live cell’ formats) that Dai Hayward has an international target intracellular mechareputation, developed over 25 years, Do CellAura ligands require nisms. The addition of in the creation and growth of chemistry-based businesses with specialised analytical inCellAura’s fluorescent ligands application in a number of markets.

In 2003 he won the prestigious strumentation to quantify targeting cell surface recepGolden C award from the their binding to receptors? tors enables the tracking of Commercial Marketing and Development Association of the DH. No. We have been able to signalling pathway initiation USA for business development across a wide variety of frontier work with customers and inat the receptor level, effectively technologies. He is also an alumnus strument vendors to demonwe bring ‘targeting’ to phenoof the Prince of Wales’ Business and Environment Programme. strate the quantification of typic assays.

CellAura ligand binding on We know from our valimany of the analytical platdation experiments that fluoforms that drug discovery scientists will already rescent ligands deliver an increased level of have in their laboratories: Zeiss LSM510, sensitivity compared to radioligand binding. This ImageXpressULTRA, ImageXpressMICRO, enables the measurement of binding and function Opera, IN Cell Analyzer 3000 System, at the single cells level and, with suitable autoArrayScan VTI HCS Reader, 8200 Cellular mated microscopes, to analyse sub-cellular doDetection System (FMAT;), FLIPRTETRA and mains. Thus we have an expectation that we can we continue to work towards demonstrating work with physiological expression levels in prithat CellAura ligands function on all other mary cells and are currently looking for partners commercially and academically relevant platwith which to validate this concept and to co-deforms. velop sub-type specific ligands. n

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IMAGING

Making the vital connection NGP talks to GSK’s Paul Matthews about the unique challenges posed by the combination of imaging and drug development.

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eing the Vice President for Imaging at GSK is not just a job for Paul Matthews. Speaking to him, it is immediately clear that he is passionate about the opportunity to bring chemical imaging to the heart of drug development. As he explains, this is not because it is just another test, but because it creates greater confidence in drug development, particularly at the early stage.

He notes the current challenges of a high attrition rate in the industry – when attrition is late in the drug pipeline it’s both extremely expensive and time-consuming, and is not doing either the patients or the industry itself any good as a result. “We’d like to bring confidence in decision-making early and we can do this by trying to study pharmacology in humans in the same ways that we’ve become accustomed to and with the same detail of information we’ve been accustomed to getting in pre-clinical species. In order to do this, we need to have powerful non-

invasive approaches to quantitative physiology and pharmacology. Th is is what imaging is really all about,” explains Matthews.

“While I speak of imaging in the context of drug development, it’s not about developing pretty pictures, although that’s a side benefit. It’s about providing quantitative information related to where a molecule might move in the body in a biodistribution study, molecular interactions of a putative drug with its target, or about physiological responses of the human tissue. Th is is what imaging can bring to us and its confidence in decision-making is the impact.”

He describes the current relationship between drug development and imaging as an “interesting period of marriage”. Matthews adds that the technology connecting the two has been missing for some time, at least in principle, but what has really been missing is the connection of drug development in the hands of people who understand how to use the information that’s derived from investigation and those with an expertise in imaging.

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“Bringing imaging to drug development isn’t just about going down a checklist,” he says. “It’s about developing powerful questions and then fi nding the technology that answers those questions and not different ones. Previously, the limits placed on the ability of the imaging to have an impact on drug development happened through parties who were not engaged with the same agenda. A company would go to an academic site or an external CRO, who had a limited understanding either of the problems of drug development or the specific problems of a molecular series.

“Here, what we’ve been able to do is actually merge clinical teams developing drugs with teams delivering this high-level pharmacological and physiological data, so the two have a common language. The questions can be translated across. The tools can be suited to the problem.

And that’s what is beginning to make these studies have impact rapidly. To give you a flavor for this, in the last seven months we’ve done as many studies with the opening of the imaging center and bringing it up to full speed, as GSK did in a similar area over the previous couple of years, and that’s because we can make things move much faster, do studies that count and bring value to the company and, ultimately, to patients.”

pipeline and communicating the science of drug development to the user population. But they’re all wrapped up together. It’s about making science the core of drug development and being transparent about how the information is used in the process,” he says.

Matthews explains that actively promoting this course of communication throughout the organisation is something that the senior executives within GSK’s R&D department are attempting to do. He notes that one key element that has been taken into account is to create working teams that are small enough to speak together, are co-located and have a limited agenda, which allows issues to be fully aired and done so openly amongst larger segments of the group.

These groups have been named development performance units, or DPU. Matthews explains that the major drug development units, either the larger units or the former Centers for Excellence in Drug Discovery (CEDDs, have been divided up into these DPUs. The size of each unit ranges between 40 and 70 people, all of whom are located on single sites, and this allows for face-to-face communication on a regular basis. However, although this brings many advantages to the communication process, Communication by dividing up a big organisation into smaller R&D is one of the key functions in which units the risk remains of failure to communiPaul Matthews is Vice President for Imaging at science and the business of pharma are merged, cate between each DPU. GlaxoSmithKline and Head of the GSK Clinical Imaging Centre. and ensuring communication between the “To some extent, this is helped by organtwo is essential. However, this is no easy task. ising clusters of DPUs together as CEDDs, or Matthews explains that communication is the units in oncology,” says Matthews. “For our number one challenge facing any large organisation; there being three pharmaceuticals, where the leadership regularly meets together with a issues that each organisation must face. “One is a communication across leader of the CEDD or unit in order to develop coordinated strategies and R&D itself to help this very broad organisation learn to optimise its abilprovide a communication strategy that, again, is limited to a relatively ity to work together, so that we don’t have individual drug units pursuing manageable number of players who can meet regularly, face to face. similar problems without knowing about each other.

“You can understand that I’m a great fan of trying to get human-to“The second area of communication is perhaps even more critical human contact to make those communications. Now, fi nally, what we’re if we’re to transform the industry, and that’s to communicate the needs trying to also do is create structures that move across DPUs and CEDDs of late-phase development into early phase and to merge the problems and begin to share what is learned from one with the others. These take that late phase will encounter in the clinic into the early development a variety of forms; they’re suited to the problems that they’re trying to decision-making. And, in turn, to use the science from early developaddress.” ment to translate out to late phase, to help defi ne the populations that are Challenges targeted for a new treatment, the way studies are designed and also the Matthews provides an example of GSK’s peer review forum – a way in which the potential benefits are communicated. group of senior clinical scientists who meet on a weekly basis to review “That leads to the third communication problem. Making drugs new protocols coming through drug discovery. The review is voluntary, is fundamentally a very complex scientific effort. We need to get away although it is taken up by almost every unit moving protocols forward, from the notion that every drug hitting the same target is equivalent and and provides feedback on the science and attempts to help create the communicate the potential differentiation of our molecules, which we’re strongest protocols possible. In doing so, the hope is that expertise is working towards from the very beginning of discovery way out past the brought across from one unit to bear on the problems of another. stage at which it’s marketed.

Another challenge that continues to increase is the identification of “We need to help physicians and patients understand the differences disease areas that are being pursued across DPUs or CEDDS. Matthews between drugs within the pharmacopoeia, but also the differences benotes that discussion groups are coming together to look at the strategy tween the way drugs may act in different kinds of people. Th is is a new for the company in terms of the science and the relatively autonomous type of agenda that we’re going to have to grasp. I’ve mentioned three: units that lie beyond that. communicating with R&D, communicating between early and late-stage

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He also notes that there are a number of higher-level mechanisms that are set up to provide scientific feedback in the form of scientific advisory boards that sit above the CEDDS and DPUs, in which learnings are shared so the best science can be produced, as well as to allow a good accountability for safe clinical practice and trials. “It’s not a solved problem. It has to be addressed at multiple levels using different approaches.

One of the things that we’re trying to grasp is making person-to-person contact the foundation of this, because that’s ultimately what’s effective,” says Matthews.

Internal communication is essential for better science and employs an equally critical role for the wider public – more information communicated on the same level of efficacy and depth of R&D has the potential to cut down on health scares. Matthews explains that some recent examples of this have been generated by the pharmaceutical industry itself – by failing to communicate the science well to the news media who misunderstand as a result.

So how is this to be remedied? Matthews believes that it will be a slow process, but one in which GSK can be confident and successful.

“First, we’ve got to create an open, transparent industry. We have to be able to communicate why we’re pursuing the areas that we are. We have to communicate the importance of science and objective thinking being at the basis of our decision-making. And, fi nally, we have to be able to communicate this science, the results of clinical trials for example, in a fully open and transparent fashion.

The goals of the CIC include to: • Accelerate effective drug discovery and development in GSK • Establish a centre of excellence with a critical mass of imaging expertise • Develop and utilise imaging methods for novel molecular targets from the GSK portfolio • Characterise the distribution and pharmacokinetics of novel drug candidates in man • Characterise key human diseases represented by the GSK portfolio • Develop and implement novel methodologies for the above

GSK Imaging Centre In partnership with Imperial College and the UK Medical Research Council, GSK has built a Clinical Imaging Centre (CIC) at Hammersmith Hospital in London, UK. The CIC houses leading imaging scientists and state-of-the-art PET and MRI equipment. The imaging centre partnership is one of the largest industry-university collaborations.

“At the same time, we have to be willing to engage our scientific community and even the public in very open feedback. We have to get away from KOL meetings that are stacked with people who we think are going to provide us the right answers. We have to go out and fi nd the people who are going to be able to comment the most robustly and provide the strongest opinions on what we’re trying to do. That’s GSK’s commitment now. By having open science, by communicating the results of trials and the rationale leading up to them in an open public forum, we can increase the quality of the science, because now it’s being tested against the best the scientific community has to offer.

“We can also help the public have more confidence that decisions aren’t being made behind the backs of everyone, that things aren’t being hidden. Finally, we have to continue to address the issues of scientific ethics and business ethics throughout the process. We have to make sure that the motivations of the people we have involved, both within the company and outside, are transparent and appropriate.

“We have to appreciate the tremendous responsibility that has been vested in the pharmaceutical industry to be the primary bringers of new therapies to the public. We have to recognise that we have a pact with the public who depends on our drugs, with the shareholders who are supporting the company, to be ethical in everything we do. If we begin to stray from that, we’re only going to hurt ourselves.

“GSK has taken these values very strongly to heart; they’re a core of what we’re all about. An example of this is our peer review group that vets every early stage protocol going through, trying to provide good scientific input. Th is group includes not just GSK staff but also external scientific advisers, who are independent of the drug pipeline of progression and who can openly look at our science and provide us with the clearest documented feedback that we can get from them,” he says.

Technology GSK has a track record of turning such fi ndings into powerful and marketable drugs; Matthews explains that drug development must not only have strong communication to be successful but also be collaborative. “We’re in a very special place; we’re at the interface between preclinical science and clinical science, trying to translate the fi ndings from our pre-clinical colleagues into pharmacology in humans to help provide confident decisions moving forward.

“We see that as our space. Again, we try to be fi rm, open scientific critics of the development program; we try to ensure that we’re asking

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powerful questions that will either help a molecule move forward, if it’s appropriate, or kill a molecule if there is good reason to stop the development.”

To take on this challenge, GSK has a range of scientists participating in development; this range is varied and they do not all share the same scientific agendas. Th is allows the project to be objective rather than being carried away by the need to move a molecule on to the next stage. Bringing together scientists from different backgrounds is vital so as they don’t carry the same biases to the problem. GSK’s aim is to create an independent development unit, contributing to drug efforts in multiple CEDDs, DPUs and units.

GSK’s overall strategy is divided into three priorities – to grow, deliver and simplify each specific role in each area of responsibility. Matthews explains the importance of simplicity: “When companies grow, there is an effort to address many problems – communications, governance, coordination – but what they inevitably do is create more and more rules, so it becomes increasingly byzantine.

“Our goal, as a group within GSK that is trying not just to conceive clinical trials, but to execute them, and not just ordinary clinical trials,

but trials that put a premium on speed and efficiency, our job is to try to identify the hairballs that we can throw out of the mix to try to help us move more quickly. So simplification is something that becomes critical to our business case.

“We depend on being able to move rapidly from solutions to one problem to the challenge of solving another. If we’re mired by bureaucracy and unnecessary complexity, our mission is going to be severely limited. So simplification is something we’re taking to heart. We’re continuously re-examining all of our processes and the way we relate to our partners; we’re trying to bring out unnecessary elements to do all the simple things like cutting meetings, making meetings more focused, but also to try to make all of our processes as simple, transparent and needs based as possible.”

Growing the company is also important – translating value into growth is the company’s strategy. By growing in quality rather than quantity, GSK can bring greater value to the market. Matthews explains that the focus is on making more rational, early-phase decision-making, which will drive better drugs for patients.

He envisions delivery as having a sense of urgency, which permeates throughout the organisation. Interactions between DPUs and CEDDs are fast-paced, making the drug development timeline significantly shorter.

“We’re trying to bring more patients into the organisation in regular discussions about what the patient needs, so that we can show the bench scientists what it is like to have the disease that we’re trying to work on.

“We’re also trying to bring an intelligent plan to drug development so that we don’t repeat things that don’t need to be repeated. So urgency, and bringing science and a considered development approach to the problem, is how we’re trying to bring delivery.

“Our belief is that with a rational development process, with a science-based development process and with a very open and transparent approach to that science, we’re going to ensure that the molecules that we’re moving forward deserve to be moved forward, and that we address efficacy and safety issues that need to be highlighted at the earliest stages possible. Th is limits the amount of resources, ultimately, that we may waste. And in the end, it is going to deliver products of real value to the market.”

“By communicating the results of trials and the rationale leading up to them in an open public forum, we can increase the quality of the science”

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INDUSTRY INSIGHT

CULTURE DEVELOPMENT Dominic Eisinger discusses an easy, reliable and cost-effective solution to immune system monitoring in clinical trials.

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ruCulture is Rules-Based Medicine’s proprietary blood culture system that provides reliable monitoring of the immune system in clinical trial applications. When combined with RBM’s comprehensive panel of 46 cytokine and chemokine immunoassays (TruCultureMAP v1.0), TruCulture can provide valuable insight into how a disease or therapy affects an individual’s immune status.

Using TruCulture, the immune system can be readily sampled within a standard blood collection tube. TruCulture maintains all cellular components throughout culture, which is an advantage when probing the immune system outside of the body (ex vivo). Minimising sample manipulation is important as exemplified by the variability and high failure rates seen with blood transported to central labs for peripheral blood mononuclear cells (PBMCs) cultures. By instantly mixing whole-blood with media, stimulants and or test substances in an enclosed sterile environment, TruCulture has an extremely low failure rate.

TruCulture is the fi rst standardised, fully closed, whole-blood culture system developed for the clinical setting that does not require cell culture facilities or specialised personnel. The system incorporates a three ml blood collection tube containing cell culture media optimised for this purpose which can contain test substances such as drug candidates, drug metabolites or immune modulators. Blood is drawn by standard phlebotomy directly into the collection tube media for an immediate and controlled initiation of whole-blood cell culture. After incubation overnight in a 370oC heating block, blood cells are physically separated from the culture media by insertion of a valve separator. The culture media can be stored and shipped frozen for analysis of signalling proteins and high quality, non-degraded RNA can be obtained from the cells for gene expression analysis.

Probing the immune system with whole blood is reliable and consistent, as all of the key elements of the immune system including cellular (granulocytes – neutrophils, basophils, eosinophils, lymphocytes, monocytes, NK-cells), pseudo-cellular (red blood cells, platelets), and subcellular components (such as enzyme inhibitors, complement system and kininogens) are present. Both innate and adaptive immune

system responses can be measured with TruCulture. The reproducibility of TruCulture now allows one to assess an individual’s immune status before and after introduction of the experimental portion of the protocol.

Common applications for TruCulture in the drug development setting are drug safety, drug efficacy and pharmacodynamics (PD). An example of a safety application would be the Tegenero incident in 2006 when a CD28 superagonistic antibody (TGN1412) was administered to healthy phase I volunteers. Within minutes, a single intravenous dose induced a systemic cytokine storm leading to multiple organ failure. All of the young men survived this lifethreatening event. The biologic in question had been tested in both rats and monkey with little indication that at its given dose it had a safety issue. It would have been preferable to test this biologic in the safe and controlled environment of an ex vivo study, such as TruCulture.

Pharmacodynamic biomarker discovery with TruCulture in phase I trials can also be a valuable tool. As the complexity of the immune system is guided by soluble mediators such as cytokines and chemokines, it is not surprising to fi nd that the expression of such mediators can correlate directly or indirectly with drug mechanism of action. In subsequent validation studies, these candidate biomarkers may become important for understanding drug efficacy or useful for patient stratification.

TruCulture makes ex vivo immune monitoring in clinical trials possible and can facilitate a successful biomarker strategy by interrogating a large number of targets thus identifying patterns on which to focus further research. By applying multiplexing technology, the RBM approach provides drug developers and researchers with a cost-effective and reproducible way to measure dozens of relevant clinical markers and to pinpoint the biomarker patterns that are involved either directly in the disease process or are useful surrogates. When these patterns can be reliably measured, the efficiency of drug development is greatly accelerated.

“Probing the immune system with whole blood is reliable and consistent, as all of the key elements of the immune system are present”

Dominic Eisinger is the Director of Strategic Development for Rules-Based Medicine (RBM). He joined in 2006 as part of the business and scientific management team. He is a noted international authority on protein arrays and prior to joining RBM, he was President of Multiplex Biosciences, a multiplex immunoassay services company. He received his PhD in stem cell molecular biology in 1994.

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ROUNDTABLE

BIOMARKER

TECHNOLOGIES NGP talks to three industry experts about the challenges of using biomarkers in drug development.

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What challenges are pharmaceutical companies likely to encounter when using biomarkers in drug development?

Edwin Janssen. While the pharmaceutical R&D has shifted focus towards biomarkermediated drug development, the regulatory authorities are still hesitant to accept biomarker-based evidence for approval of drugs. The acceptance of a biomarker’s clinical utility, therefore, is highly depending on acceptance by the scientific and clinical community to support a claim. Needless to say that the efforts put into qualification of a biomarker can be a cash burn. From a regulatory perspective, the clinical development teams should be aware that the applied biomarker requires rigorous analytical assay validation in order to understand the analytical limitations. Unfortunately, this awareness is sometimes lacking, but can severely obstruct the drug development programme in terms of time and additional costs. In case a global study is conducted, standardisation of the applied biomarker assay becomes critically important. Only the production of consistent biomarker data enables critical decision-making and requires that the same procedures are applied among different test facilities.

Michael Pisano. The role of biomarkers spans all aspects of drug discovery and development and the pharmaceutical industry is looking towards biomarkers as one key solution to the drug development problem. When one thinks about molecular markers one thinks about genomic markers and protein markers. While genomic data can be gathered very quickly with lots of data and patient testing, protein markers will more likely be more informative, but it has been said that working with proteins is difficult. One reason proteins are often overlooked as good candidate markers is that a bottleneck exists in protein biomarker development, namely, the ability to develop assays in a timeframe acceptable to move viable candidates forward in line with the therapeutic compound. Another challenge is high quality sample collections, but I will not address this in this forum.

Aiden Flynn. There are a number of issues with biomarkers in drug development. In some cases, biomarkers may have been collected as

Aiden Flynn has spent the past eight years at GlaxoSmithKline where he is a Director of the group providing statistical support for clinical biomarker studies. Prior to joining GSK, he worked as a lecturer in the Department of Oncology at University College London, where he obtained his PhD in Biophysics.

part of a study that was designed for another purpose. So the analysis relating to the biomarker is exploratory or hypothesis generating. In this case, the study can involve the evaluation of a large number of biomarkers and it can be problematic to efficiently identify biomarkers that are clinically meaningful. Whilst these exploratory analyses are a much needed part of fi nding new biomarkers, they can be costly, resource intensive, time consuming and yet have a low probability of success.

There is a lack of understanding of the range of potential clinical biomarker applications and also uncertainty around the evaluation of the utility of biomarkers in those applications. In addition, it is not clear how the use of biomarkers will affect the development programme, whether there is the need to develop a diagnostic and how drug regulators will view the use of the biomarker. With this added uncertainty, developers may choose not to invest or commit to the co-development of biomarkers. Lastly, there is the issue of poor biomarker data reproducibility, quality and standards. The lack of defi ned biomarker data standards can prevent the integration of biomarker data with other clinical data and poor quality and reproducibility compounds the difficulties with identifying and implementing biomarkers in clinical studies.

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How can these challenges be overcome?

AF. One of the key areas that can help overcome some of these challenges is a clear biomarker strategy to be used in the early planning and integration of biomarkers in the clinical development plan. Where possible, biomarkers should not be an add-on to a study.

Rather, study designs should be scrutinised to ensure that they provide a reasonable chance of success for biomarker research. In addition, biomarkers should be considered as an integral part of the entire development programme.

However, we should accept that there may also be scenarios where biomarkers have little or no impact, such as the use of biomarkers to explain variability in drug response when there is no evidence of unexpected variability.

We should try to focus our efforts relating to use of biomarkers by using existing knowledge of disease, drug and current biomarker technology to identify realistic opportunities where biomarkers can make a difference. With regards to data reproducibility, quality and standards there is no easy solution other than to say that the entire biomarker research community needs to work together to ensure that biomarker data is fit for purpose.

EJ. A good understanding of how the biomarker assay will be used during drug development is pivotal to allow critical decision-making. Th is requires good coordination and communica-

Michael Pisano is President and CEO of NextGen Sciences, Inc. He has more than 18 years experience in the pharmaceutical industry with senior positions held in RPR Pharmaceuticals, Aventis Pharmaceuticals and Genomic Solutions.

Pisano was co-founder and President of Proteomic Research Services, Inc. and is now Chief Scientific Officer of NextGen Group and President and CEO of NextGen Sciences, Inc.

tion between the translational and clinical development teams to clearly define the purpose of the biomarker assay, early in the drug development process. Proof that a biomarker reflects a clinical benefit will take costly and lengthy clinical trials. Working together in consortia enables us to share costs in the development and qualification of biomarkers. A qualified biomarker, eventually, will facilitate drug development across the industry. Good examples of the outcome of such an endeavour are the recent qualification of novel human kidney safety biomarkers, led by the Critical Path Institute, and the demonstration of adiponectin as a predictive biomarker for type 2 diabetes, as demonstrated by the Biomarker Consortium.

In the Netherlands, we have the TI-Pharma and CTMM initiative, for example.

MP. The ability to discover putative protein biomarkers is always increasing with im-

proved discovery platforms in all therapeutic areas so there is no issue in fi nding new putative markers. The issue is having the biomarkers and assays ready for a clinical study.

Th is requires the biomarker programme to be an integral part from early discovery and the ability to rapidly develop assays to allow putative biomarkers to be validated in the timeline required. NextGen Sciences’ mass spectrometry-based platform significantly shortens the assay development time relative to more conventional platforms such as immunoassays. Biomarker projects are supported by NextGen Sciences’ proprietary biomarkerlibrary, which contains catalogues of proteins from a variety of biological fluids, tissues and cell lines from pre-clinical models to human. Th is knowledge accelerates the development of robust, accurate and precise multiplexed assays suitable during all phases of clinical development.

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What specific methods and tools can companies use to increase the successful application of biomarkers in the evaluation of drug therapies?

EJ. Within our laboratory we do see an increased demand for analysis of cellular drug responses. Although challenging in terms of analytical and biological variations, cellular drug responses are key in providing early proof of concept. PBMCs, or whole blood assays, can be good surrogate sources to assess in vivo target exposure in patients, establish proof of concept, and ensure optimal clinical development. Proteomics and biomarker imaging technologies are important in drug development as well. To what extent proteomics and imaging tools will be successfully integrated in early or late stage drug development programmes remains to be seen. In terms of sensitivity, reproducibility, throughput and cost-efficiency, ligand-binding assay formats do still fi nd their greatest utility in monitoring drug safety and efficacy, particularly during late stage development.

Promising approaches also include the use of miRNA-based biomarkers, which embody novel diagnostic and prognostic biomarkers.

Analysis of disease-related miRNAs from the blood may represent a promising approach for monitoring of disease progression and drug efficacy.

AF. It is hard to specify methods or tools that can generally improve the successful use of biomarkers across all the potential clinical applications. One approach is the use of modelling, simulation and decision trees to estimate the probability of success for the range of development options and study designs where biomarkers are being considered. Th is approach helps project teams focus on what they are trying to achieve and to understand the options and implications. It is also important to have access to a biomarker knowledge base that includes disease and drug specific information, scientific and regulatory developments in biomarker research and case studies describing biomarker applications. Such a tool would be a very valuable resource.

MP. There is no specific method or tool that will increase the successful application. Instead it is the application of a systematic approach. In

other words, two things need to happen; first, as new technologies emerge there is often the ability to detect what could not be detected previously and second is to look at signatures whether that be multiple proteins or combinations of proteins, genes and metabolites or images with protein signatures. As complex as biology is it should not be expected that single entities will paint a complete picture.

How do you see the use of biomarkers in the pharmaceutical industry developing over the next five to 10 years?

MP. The pharmaceutical industry will integrate biomarkers to help understand the mechanism of a disease, to aid the development of therapeutics, as diagnostics and in personalised medicine. The integration of biomarkers through the different phases of drug development can yield safer drugs with enhanced therapeutic efficacy in a cost-effective manner. Pre-clinical and clinical applications of biomarkers include safety, patient selection in a drug trial, measuring drug efficacy, monitoring response and adverse events and studying alternative indications for a drug in development. Biomarkers are critical in helping to reduce costs in the drug discovery and development process. Biomarkers can be used as a way to rescue drugs that have failed in development and even those that have been withdrawn from the market.

EJ. Because of the ongoing advances in biomarker research and qualification processes, many more biomarkers are likely to become accepted.

Accordingly, these biomarker assays need to be validated for their application in clinical trials. The recent qualification of novel kidney safety biomarkers already paves the way for central laboratories to encourage sponsors and investigators to analyse these injury response biomarkers to demonstrate drug safety. The recent validation of circulating tumour cell measurements has also shown its suitability for routine assessment of drug efficacy in metastatic (breast) cancer patients. Epigenetic factors, such as histone deacetylation or promotor region methylation can be expected to become important in oncology, and be used on a more routine basis as well.

Central laboratories are likely to become outsourcing partners for successfully integrat-

Edwin Janssen joined Schering-Plough (formerly Organon), following several years of postdoctoral experiences. At Schering-Plough, he participated in the discovery, development and implementation of biomarkers in lead optimisation programmes and proof of concept studies. Since 2009, Janssen has been the Head of the Biomarker and Biopharmaceutical Group of Eurofins Medinet.

ing biomarker assays in drug development programmes in the years to come. The support by the central laboratory of many clinical studies with a broad variety of biomarker applications will become valuable in advising sponsors on the type of biomarkers and the analytical limitations of these assays.

AF. A lot of biomarker research in recent years has been driven by the ability of biomarker platforms to generate increasingly large volumes of biomarker data. However, we are still developing the capabilities to perform the best analysis of these data. These analysis methods need to go beyond the traditional statistical approaches used in clinical trials. They need to account for the biological relationships in the biomarker data as well as the statistical associations with the clinical data. Over the next few years statisticians, bioinformaticians, computer scientists and others will be working together more to develop methods for use in clinical biomarker research. These methods will open up many opportunities such as the use of a combination of biomarkers, clinical information and environmental variables for predictive modelling. When we develop these tools, we’re going to see a more integrated, informed and pragmatic approach to the use of biomarkers.

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EXECUTIVE INTERVIEW

Emerging genomics Klaus Weinberger explains the potential of metabolomics to revolutionise diverse areas of life.

What does the term metabolomics stand for?

Klaus Weinberger. Metabolomics is an emerging field in functional genomics that is increasingly being recognised as the functionally most relevant discipline in this area. Metabolomics is the systematic identification and quantification of metabolites, such as amino acids, sugars or lipids in a biological sample. Sample matrices range from cell, tissue or organ specimens to bodily fluids, such as plasma, serum, urine or CSF. Is there already a proof-of-concept for metabolomics?

KW. The proof-of-concept for targeted metabolomics was first delivered in clinical diagnostics, namely in neonatal screening for inborn errors of metabolism. In the late 1990s, the diagnosis of inherited disorders in amino-acid metabolism, such as phenylketonuria, or fatty acid oxidation disorders, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, was revolutionised by the use of mass-spectrometric assays.

The idea was to quantify specific sets of amino acids and acylcarnitines to diagnose specific metabolic disorders, and it worked, laying the foundation for what we are now referring to as ‘targeted metabolomics’. The transition from expensive, monoparametric assays to simultaneous diagnosis of 20-30 monogenic diseases, which

What is your vision for the future of Are there other practical applications of metabolomics? metabolomics?

KW. The range of potential applications is wide and KW. Metabolomics has the potential to revoluvaried. Besides neonatal screentionise diverse areas of life. A ing, metabolomics is currently thorough understanding of disapplied in biomarker and diagease-related metabolic processes nostics research and in drug dewill allow us to utilise new markvelopment. It can be used to ers for both diagnosis and therauncover new drug targets, pripy. Importantly, these markers oritise lead compounds and aswill be able to be identified sess drug toxicity, enabling the from samples that are easily development of novel, smarter obtainable by non-invasive and safer drugs. At the same procedures using readily actime, metabolomics will help cessible biofluids, such as plasidentify individuals likely to ma or urine. benefit from a given therapy.

Assessment of the metaYet, the diagnostic potenbolic characteristics of indiKlaus Weinberger is a biomedical scientist with particular tial of metabolomics is not convidual patients will lead to the expertise in metabolomics fined to metabolic disorders. development of personalised infectious diseases, public health and immunology. Before joining For example, metabolomics treatments and enhance the Biocrates, he led a research group at the University of may help identify individuals at benefit a given therapy has for Regensburg. Weinberger holds a risk for diabetes, and it will have an individual patient.

MSc in biophysics, biochemistry and microbiology, and a PhD in a broad range of applications in Metabolomic analyses will bemedical microbiology from the University of Regensburg. diseases such as cancer, chronic come part of the standard kidney disease and neurological repertoire of laboratory diagdisorders. Another success for nostics in both human and metabolic markers has been the ability to diagnose veterinary medicine. renal, liver and heart organ transplant rejections.

Apart from its medical applications, howAlso, metabolomics is widely used in nutriever, other aspects of daily life, such as healthy

“Metabolomics is an emerging field in functional genomics that is increasingly being recognised as the functionally most relevant discipline in this area” was co-pioneered by one of the founders of Biocrates, has taught us some very important lessons for future clinical applications that will ultimately lead to significant medical and commercial benefits.

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tional science to determine the effects of specific diets, and it is being employed in environmental research and monitoring to assess the risks of pharmaceuticals, pesticides and household or industrial chemicals.

nutrition or optimised exercise, will also be addressed by metabolomics. Thus, by analysing a person’s specific metabolic reactions towards food intake or exercise, it will be possible to customise dietary schemes and training programs.

Metabolomics will also impact on industrial bioprocesses, such as the cell-based production of therapeutic proteins or nutritional supplements, and it will facilitate the optimisation and monitoring of exploited biological processes.

Overall, metabolomics will develop into a powerful analytical tool that will do much to promote the scientific, medical, and economic progress of our society. n

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IMAGING

HUNTING DOWN CANCER

Tumours continue bypassing cell pathways whilst molecular biologists doggedly try to understand how cancer works. Haren Rupani explains why we are still in the infancy of our cancer knowledge.

Haren Rupani

I

maging techniques in the sphere of oncology have aided the monitoring of cancer and developed in turn. Traditionally the way a cancer responds, as Haren Rupani, Global Head of Oncology Clinical Imagings at Novartis, explains, is evaluated by traditional anatomic imagining, which is done either by CAT scan, ultrasound or MRI. “Th is determines whether the tumor is present or not and whether it’s shrinking, which has typically been what the FDA or the regulatory authorities have been allowing us to do because there has been a long history. So these are time-proven methodologies of imag-

ing techniques, which the regulatory authorities allow for evaluation.”

He explains how imagining has developed from anatomic, the more traditional method, due to a change in paradigm in terms of incorporation of functional imaging. “The modalities of functional imaging are those such as PET scanning and DCMRI. It enables

exploratory imaging rather than traditional anatomical imaging,” says Rupani.

Exploratory techniques Novartis is endorsing such developments and Rupani cites a number of their benefits and the reasoning for the company’s adoption of exploratory techniques. Traditionally they are used during the early phases to enable the physician to discern whether the trials are on track and how they may be working. Rupani notes the commonest reason, therefore, is for early response, as well as proof of concept and a proof of mechanism.

“I’m hoping that at a government level there is also increased interest and investment into research and development” us to look at how the tumor is behaving rather than if the tumor is present or not. Exploratory imaging from the regulatory perspective is not something that you can use for a primary endpoint. It can only be used for a secondary or exploratory endpoint, the reason being that these have not been validated as to reflect what the patient outcome is. That’s the nature of

“The other area is to be able to evaluate an optimal biological dose rather than a maximum tolerated dose, so that is another very important function. You do not want to give medicine to a patient in excess of what is actually needed, you want to reduce the toxicity,” he says. “The other basic role, a very important role, is patient stratification. I’ve already mentioned tumor re-

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sponse, proof of concept, proof of mechanism, patient stratification, optimum biological dose versus maximum tolerated dose – these are the common indications to help us make decisions.

“At Novartis, 75 percent of the time we have conducted the early response. In approximately 10 percent of our trials we’re also evaluating for optimal biological dose. The real goal for me and for Novartis, as well as the entire pharma industry, is getting the right medicine for the right patient in the right dose, and so that can be summarized as patient stratification. Th is is the ultimate goal, and imaging may not be the right tool for patient stratification because of the advantages and disadvantages of imaging.

machine as well as mine. That’s a very simplistic way of putting it. So when you’re doing that at 50, 60, 70 trials, you cannot have the 100 pounds being measured as 70, 80 or even 200 pounds. Standardisation is the most critical, and there are a lot of challenges that come in trying to standardise because you have different equipment, you have different ways of calibrating the machines, and that becomes a process. Standardisation remains number one.

“Number two, how do you deliver the radio tracer? Radio tracers always have their half life, so different radio tracers have different half lives; the shorter the half life the more difficult it becomes to deliver that to the various sites. Also, what if it is not FDA or regula-

“Cancer is much smarter than we are right now, it’s a formidable enemy and we do not know all the tools that cancer has”

and from a patient point of view you want to look at that. Everybody will become a patient one day. Th is is something that we cannot afford not to do, so as a society it becomes important to know what are our priorities are.

Do we want to spend money in research and development or not?

“On an individual basis for pharma, there are different approaches. There are companies that do invest and there are companies that do not invest, so I’m blessed at Novartis that there is a lot of importance given and we are investing this. This is going to be long, it is going be expensive, and it’s going to be often frustrating, but Novartis has got the long-term view in terms of investing into this technology. I’m hoping that at a government level there is also increased interest and investment into research and development so that cost does not become an issue; it’s a question of priorities. It all depends what we want to spend our money on.”

Discovery difficulties “Biomarkers can be divided into imaging and tissue biomarkers; so you take a blood sample, you take a biopsy of the tumor and you can conduct a lot of testing, and that’s basically what tissue biomarkers are. So imaging and tissue biomarkers are all exploratory modalities that I use. We do not know which one is the most effective one and for what; only time will tell which, or both, of them will be useful in patient stratification. The commonest reason why we use exploratory imaging is for early response to the drug.”

Challenges However, the rise of almost every pharma company to a multi-centre organisation conducting multi-regional trials poses challenges for imaging. Rupani notes one as being standardisation and another as being visibility, being unable to locate the radio tracers that would be potentially done. He notes that 80 percent of exploratory imaging is with PET imaging, and the tracer is needed in order to deliver that. The fi nal challenge is that of fi nancial issues.

“Standardisation is very important,” explains Rupani. “To give an analogy, if I have a weighing machine and you have a weighing machine and I have a 100 pound weight, that should measure 100 pounds on your weighing

tory approved, like an EMEA in Europe, then before you can inject that into a human you need an investigation, a new drug application, which is a laborious, long process. So the practicality and feasibility of doing studies with radio tracers, which has not been approved for human use, has its own challenges.

“The last factor is cost. These are not cheap things to do so it’s important to know what you are getting out of them. Typically exploratory imaging using PET scanning is always done in a subset of people; you cannot obviously do it in all the patient population because of the cost factor,” he explains.

Rupani adds that keeping the cost in check is attributable to efficiency – the right patient, the right medicine, the right dose. He notes imaging to not only be expensive, but also timeconsuming: before the regulatory authorities approve surrogate markers, allowing Rupani and his team to replace and evaluate them, the validation process fi rst takes a long time. “Th is is such a huge task to overcome that there’s no single person or single entity, be it the government, manufacturers or the industry, that can have the expertise and the resources to do this alone. It has to be a pooled thing,” he says.

“However, society as a whole cannot afford not to do it. Unfortunately, all of us will either have cancer or heart disease, one of the two,

It is no new phenomenon to understand the difficulty of cancer drug discovery, regardless of fi nancial challenges. Rupani joined the pharma industry with a background in radiology and nuclear medicine, having to learn molecular biology during his entry. “The thing that fascinates me about each and all of us, is that we have 100 trillion cells in our body.

When you look under the microscope and the way the cell functions, we cannot understand it – there are more than 100 different cell pathways. Although now the medications are based upon targeting a cell pathway, we attack one of the 100 pathways that are occurring and we know that sometimes multiple therapies work better than just one therapy because now we are targeting two or three pathways.

“Depending upon how the tumor develops, cancer figures out a way of bypassing these pathways. It figures out the ways of becoming not responsive to what you’re giving, so we are at our infancy in our knowledge of molecular biology, how cancer works. Cancer is much smarter than we are right now; it’s a formidable enemy and we do not know all the tools that cancer has. Until we make progress in this it’s going be a long battle,” he concludes.

Haren Rupani is the Global Head of Oncology Imaging at Novartis.

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NEXT BIG THING

Step up to the MIQE When it comes to real-time PCR in drug discovery, Richard Kurtz believes that MIQE guidelines will help create a clear path.

ver the years, polymerase chain reaction (PCR) has evolved into a readily automated, high throughput quantitative technology. Real-time quantitative PCR (qPCR) has become the industry standard for the detection and quantification of nucleic acids for multiple application, including quantification of RNA levels.

But a lack of consensus among researchers on how to best perform and interpret qPCR experiments presents a major hurdle for advancement of the technology. This problem is exacerbated by insufficient experimental detail in published work, which impedes the ability of others to accurately evaluate or replicate reported results.

In extreme instances, incongruous pre-assay conditions, poor assay design and subjective data analysis methods have led to the publication of irrelevant or misleading data. The original 2002 paper on measles, mumps and rubella (MMR) provided evidence that supported a link between the MMR vaccine and autism. Later examination established that the original conclusions were based on flawed real-time PCR data. Subsequent publications have convincingly demonstrated there is no plausible link between the vaccine and autism, but the debate and doubt continues outside of the scientific community and MMR vaccination rates have dropped in several countries.

Accurate qPCR testing can help companies avoid pursuing the wrong compound or target.

Providing sufficiently detailed reports of experimental design in early stage drug discovery research can potentially save millions of dollars by not wasting man-hours or reagents. The Minimum Information for Publication of Quantitative RealTime PCR Experiments (MIQE) standards can help companies and researchers avoid these drug development pitfalls.

MIQE’s goal is to restructure the current approach to qPCR data reporting into a consistent format that encourages detailed auditing of experimental processes, analysis and results whereby the

O

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technical quality of the work and reliability of the conclusions can be evaluated. Implementing these guidelines is imperative in continuing the growth of qPCR into an accurate and reliable nucleic acid quantification technology.

MIQE promotes the careful examination of qPCR results to enhance integrity of submissions to peer-reviewed journals, consistency between laboratories and experimental transparency. Adoption of and compliance with these guidelines will help researchers more accurately report data and replicate experiments, ultimately saving time and money.

direct import of data from the system to the software. The combined solution provides researchers with the flexibility to handle both small and large experiments as well as combine data from different experiments using qbasePLUS software as the repository database.

As the industry continues to recognise the importance of the MIQE guidelines it will become increasingly necessary to ensure that laboratories and corporations are following them. Simplifying compliance facilitates not only drug discovery and development, but basic biological research. Investing

“In extreme instances, incongruous pre-assay conditions, poor assay design and subjective data analysis methods have led to the publication of irrelevant or misleading data” When it comes to providing scientists with the tools to be MIQE-compliant, Bio-Rad Laboratories, Inc. is paving the way. Recently, Bio-Rad entered into an arrangement with Biogazelle to exclusively distribute the qbasePLUS data analysis software with its CFX96™ and CFX384™ real-time PCR detection systems, a programme that enables users to annotate their experiments with MIQE-compliant experimental details. The qbasePLUS software, in combination with these real-time PCR systems, provides customers with improved accuracy in their qPCR experiments and speeds up standardised data analysis. qbasePLUS software allows for the elimination of erroneous data, normalisation to remove samplespecific non-biologic variation, and inter-run calibration, which can remove the technical variation between samples analysed in different runs. By enhancing the reliability of the qPCR data, qbasePLUS conforms to MIQE. Using the CFX96 and CFX384 real-time detection systems with qbasePLUS software accelerates research through automated, fast calculations and

in a qPCR system and failing to follow guidelines that will ensure that quality data is being produced may result in a wasted investment.

It can be anticipated that additional qPCR vendors will soon offer solutions to assist researchers in maintaining MIQE compliance. Top instrument makers and reagent vendors are supporting the thought leaders working to expand MIQE awareness and compliance. Bio-Rad has trained sales and support staff to help researchers comply with the guidelines. They share this training through educational meetings focused on MIQE. Quality data is paramount for the successful development and potential approval of a drug candidate. Following MIQE will help strengthen the quality qPCR data needed to move a candidate forward. Plus, it may avoid the devastation of finding out the focus was on the wrong target or having a drug candidate fail. n Richard Kurtz is Senior Marketing Manager at Bio-Rad Laboratories. Prior to joining Bio-Rad, Kurtz served as Field Applications Manager for MJ Research Incorporated.

Kurtz earned his PhD from Northwestern University and a BA in Molecular Biology from Colgate University.

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EXECUTIVE INTERVIEW

Pharmaceuticals and fertility Rita Cortvrindt explains how the analysis of a drug’s effect on fertility reproductive functions can speed up pharmaceutical development.

Why is it important that pharmaceutical companies screen compounds for their influence on fertility and embryonic development?

Rita Cortvrindt. Until now reproductive effects (female and male fertility, embryo toxicity and neonatal development) of a NCE are usually not taken into account during drug discovery or lead selection. However the reproductive system is susceptible to toxicities throughout almost the entire life span of an individual, with specific vulnerabilities during the different stages. A normal reproductive function is not only necessary to guarantee a successful procreation but also determines hormonal balance and influences the sense of an individual’s well being. Early characterisation of potential reprotoxic effects is therefore of utmost importance. As there are now a number of in vitro bioassays available to screen the reproductive targets, requiring only minute amounts of product, reproductive toxicity screening can easily be incorporated in the early drug discovery process.

“Reproductive toxicity screening can easily be incorporated in the early drug discovery process” How can engaging the services of a contract laboratory specialising in the analysis of reproductive function help pharmaceutical companies to speed up the development of new drugs?

RC. Reproductive health is characterised by long-term processes determining hormone homeostasis, gamete quality and reproductive capabilities of the offspring and is very sensitive to all kinds of external factors, such as light, tem-

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the mechanism of action and NOAELs at the perature, noise and handling. To assure solid target (organ) level, necessary for the prediction and reproducible test outcomes a specialised faof the in vivo harmful effect. The real advantage cility is required. Only dedicated staff and scienof these innovative bioassays, besides only retists with an in-depth knowledge of all the quiring minute amounts of compound and underlying physiological processes can warrant being quicker than in vivo studies, is that the efthe correct assessment of the reproductive function. fect can be predicted and still fit into the drugThis holds true for in vivo studies but even more so discovery process. EggCentris has already for the performance of in vitro bioassays. developed a battery of this Standard reprotoxicity type of multi-parametric testing is based on a set of exbioassays, each representing a pensive long-lasting in vivo target organ. studies requiring vast amounts of compound, usually perHow does EggCentris conformed late in the drug-development process, risking a late tribute to the achievement discovery of devastating reproof reduction, refinement ductive effects. Incorporation and replacement of animal of a battery of innovative in experimentation (3R princivitro bioassays evaluating the ple)? main targets of the reproducRC. EggCentris was founded tive system during drug diswith the aim to offer the incovery and lead selection will dustry in vitro bioassays that reduce that risk and advance can assess the reproductive Rita Cortvrindt is CEO and founder of EggCentris. She the drug-development process function while applying the acquired expertise in the field of substantially.

3R principle. Long-term reproductive biology/medicine and toxicology over the last 20 years. Her main focus was on the development of innovative vitro methods that closely mimic the in vivo physiology. With EggCentris she aims to contribute to the 3R principle.

What are the advantages of in vitro versus in vivo testing?

RC. In vitro test are usually characterised as being simple, quick, cheap and high throughput. However this type of simple cell culture systems are not very informative for most of the reproductive (t)issues. The target cells of the reproductive organs continuously differentiate and if used in a static state are prone to give false results. Relevant in vitro bioassays aiming to evaluate the reproductive function have to mimic the physiologic process of the target organ, implying long-term multi-parametric tissue cultures. They generate data sets covering several primary endpoints, allowing pinpointing

multi-parametric tissue cultures systems holding the key elements of the target organ were designed and shown to be highly predictive. Since they closely mimic the physiological processes, they reveal a physiological (in vitro) response to the tested compounds. A very dedicated and well-designed in vivo study will only be performed when no in vitro alternative is available to answer the question.

EggCentris R&D focuses on extending its battery of in vitro bioassays so that all the target organs of the reproductive system can be covered, ultimately enabling us to entirely assess male and female fertility and embryo development in vitro. n

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DRUG DISCOVERY

All change Raafat Fahim of Nabi Biopharmaceuticals explains why a new, more efficient business model is needed to cope with the increasing challenges facing the industry.

R

aafat Fahim has long been a fi xture in the pharmaceutical industry. Prior to his role at Nabi Biopharmaceuticals he held a 14-year tenure with Aventis Pasteur before it became a part of sanofi, and it was here in the leading vaccine manufacturer of the world that he developed his concept of developing research to market. By converting research findings into manufactured solutions and implementing them into the market, Fahim found a more efficient business model to cope with the rising industry challenges.

He attributes much of his thinking to his time at Aventis Pasteur: “It certainly provided a wide scope of experiences that I’m using today in my current role as Chief Executive of Nabi – a biotech with a vaccine development pipeline. In this I am able to interact and use my experience in the many areas that Nabi needs, both research and development, as well as from a business development perspective,” he explains.

Challenges

Fahim points to the example of when this occurs: the concept can be invented in a short period of time but then it often takes five or six years to go through the various stages of regulatory and compliance process.

“You can have an idea of what works or you’ve tested in the lab and in small animals and maybe discovered in a couple of years, but then it takes you another six years to get to the stage where you can apply for marketing authorisation,” he explains.

Th is is usually a problem for small biotech companies and this is often an area in which they don’t excel in, he says, as the company is unlikely to be developed for manufacturing or engineering but for discovery and research; what Fahim describes as “the fun part”. The problem is a practical one that all biotech companies face and each must endure the necessary length of time to go through the regulatory process to arrive at the fi nal stage.

“The best advice one can give is to realise what you don’t know very early on,” says Fahim. “Most companies, when they get early successes in research and discovery, think and believe that now they can do anything and don’t recognise that getting to the next stage of manufacturing, compliance and the regulatory process is actually a completely different set of expertise that you need to start preparing for earlier. That is probably one of the biggest problems facing most small biotech companies: that they don’t realise early enough what they don’t know and the experience they lack within the company.”

Th is is not the only challenge facing small biotech companies; the pharmaceutical industry also has to face problems within pharmacy supply chains. Fahim notes efficiency as one challenge; the pharma industry, although it has grown substantially in recent years and is recognising it is now well established, still remains far less efficient than other industries. He points to the automotive industry, as well as the chemical and food industries, and the success in these in getting the supply chain down to the minor details.

“The pharmaceutical industry has enjoyed, for a long period of time, a reasonable return on investment and a reasonable margin for their product, and they were less concerned about cost and efficiency. They recognised that a few years back, but are not yet at the stage that they could be or should be, from my perspective anyway,” he says.

“So many companies have gone bankrupt, even though they have a very good product, because they are unable to continue to develop”

Now is the time a wealth of experience is needed to cope with the industry’s challenges.

Bioinformatics are enabling researchers to identify more numerous and complex targets than ever before, and pharmacies are fi nding that they’re also unusually constrained in their ability to turn research findings into manufactured solutions through the market. Although R&D is much further ahead in its game than manufacturing and not facing the constraints of regulatory processes, it still has its hindrances. Fahim explains that on a daily basis certain things may work in a good way but are often unable to be applied in practice due to regulatory constraints; the rigorous side to this is ensuring that manufacturing continues consistently and in a compliant way.

“Compliance is one of the biggest elements facing biotechs. They innovate very well, but then when it comes to regulations and compliance the brakes are put on their development simply because of the need for a rigor in manufacturing. These are the kind of things that one faces on a daily basis. Having the technology is one thing, but what you can do with it is another. For the most part pharmaceutical companies, and in my case vaccine companies, have understood, digested and accepted that it’s a reality and are coping with it reasonably well.”

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“There is no doubt it will change. That I can guarantee you because with the pressure on the pharmaceutical industry to control costs, they are now recognising and facing more of a challenge to become more efficient. And they are actually coping with it now and addressing it in a big way. They are taking the right steps, maybe a bit later than they should have; but nevertheless they are doing that now.”

Efficiency Driving efficiency within Nabi is of primary importance to Fahim.

Still in the development stage, the company is preparing itself for consistency in manufacturing and preparing for commercialisation. The first stage is ensuring the drug can be produced correctly and with equality, and the second stage is then to drive consistency, he explains. Nabi has not yet had to face the second stage, but Fahim has already begun examining it; his previous role with Aventis Pasteur taught him to look at such issues very carefully.

“I started to look at that and see how we can do it in the future but I don’t have to face it for another two-to-three years or so, fortunately.

The most important thing for us now is to make sure we can do it and to make sure that I can produce the material. Efficiency becomes a secondary issue at this stage but planning for efficiency is defi nitely important.

“We’re now looking at the supply chain, what is the best way to handle the various contract manufacturing organisations that we’ve working with to make them more efficient and to be responsive to the needs that we have in the future. So you can consider that we are in the planning

phase, as opposed to the implementation phase today,” says Fahim.

Economic recession There are certain challenges that face every pharmaceutical company, regardless of size or stage of development. The economic recession impacted the ability of companies to ensure the security or consistency of supply chains and has driven home the need for efficiency in a big way. Pharmaceuticals and biotechs may be two completely different industries but the challenges they face both derive from the same financial dilemma. The pharmaceutical industry has seen the big issue of control of costs and pricing of pharmaceuticals whereas within the biotech industry this is much more dramatic. The pharmaceutical industry is still reasonably profitable but the biotech industry is less so.

“The pharmaceutical industry is one of the industries that has been least impacted, so to speak, by the fi nancial crisis, although they are facing the challenges themselves. For biotech, however, it is dramatic,” says Fahim. “If a biotech company now wants to raise money for the next stage of development or discovery they are doing, it is almost impossible to get anybody to back it up now.

“So many companies have actually gone bankrupt, even though they have a very good product, or sold their companies or products at a significantly reduced price simply because they are unable to continue to develop. That’s a major problem that we’re currently facing. We were fortunate that we had cash in the bank so I didn’t have to go and raise money otherwise I could be facing the same fate as others have.”

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Without money in the bank, Fahim explains that the situation is nothing other than a crisis. He advises that if a company has product but no cash, the most feasible move would be for them to partner with larger pharmaceuticals that may be interested in their technology. This is often easier said than done, with large pharma companies wanting to take advantage of the smaller companies dilemma and wait for the price of such a deal to become cheaper. Without public funding or private backing there is little option other than a partnership.

One big issue shaping the industry is the number of acquisitions that have been conducted recently, Pfizer and Wyeth being just one example.

But is this proving to be a help or a hindrance during these difficult times? Fahim states that he prefers to be the optimist, advocating that the trend is not necessarily a bad thing and not one that will necessarily stifle innovation. “It may actually make it more efficient,” he says. “And in the current realities of price control of pharmaceuticals, that is a very good thing. That’s one way to cope because the pharmaceutical industry has been inefficient so far.

“To drive efficiency is very good. Now, does it impact negatively on innovation? It potentially may have a negative impact, but the overall impact would be positive, in essence, and would drive more efficiency in the pharmaceutical industry. It’s not a bad trend. It depends how far it goes. You don’t want to end up with one huge pharmaceutical company in the world, and we have regulations in place to prevent that from happening.

Ensuring that smaller companies can still compete against these merged giants is innovation, says Fahim. He notes that there is no longer any doubt that large pharma’s ability to drive innovation fast or wide enough is stunted compared to the past. “Each one of them was fully dependant on their own organic growth for innovation. It is clear that they have failed miserably.

“They have a huge infrastructure that makes the cost of innovation very, very high, stifles innovation with the various committees that they had too, and the various triage of projects that they have. On the other hand, biotech has shown, categorically, that it can develop very fast and in a nimble way. That’s whybiotech has been gobbled up by the big pharmaceutical companies, be it the products or the companies as a whole. So there is no doubt that biotech has driven innovation over the past 15 years and will continue to do that in the future.”

“The best advice one can give is to realise what you don’t know very early on”

Innovation Innovation is essential for a company to stay ahead of the game: it has proved to be a critical piece of the drug discovery model. Fahim explains that at the centre of Nabi’s innovation is a drive towards areas that are of significant unmet medical need and that are unique. “I can go and discover the next antibiotic, but guess what; there’s a lot of other companies doing the same thing.

“The best way for a biotech to be unique, and survive and strive is to get into areas where there’s still significant unmet medical need but that’s

not very crowded. The vaccine that we are looking at within Nabi, which I consider to be a very good example of that unmet medical need which is not crowded, is a nicotine vaccine.

“There are still 1.3 billion people smoking in the world and we know how bad smoking is. And, therefore, a nicotine vaccine, which is a unique technology and a unique drug, is a huge unmet medical need with huge market potential. We are the leaders; so obviously, we have found that area to be attractive very early on.

“The other vaccine we have is against the flu coccus aureus, which is the superbug everybody hears about. Again, there is no vaccine on the market for it, so it’s a huge unmet medical need, has huge market potential and is not a crowded area. To me innovation has to be a huge unmet medical need with huge market potential and not crowded, so you can make your mark in the field.”

Driving and managing that level of innovation throughout the company is Fahim’s responsibility as CEO. The best way to do this, in his opinion, is to ensure that the scientists have enough freedom to develop the concepts and ideas they have, although this is often prohibited by the constraints of costs and resources. If possible, this is the model he believes to work well. A very heavy structure will stifle innovation, which is to be avoided at all costs.

Fahim explains that efficiency is the future; the most important development for the pharmaceutical industry over the next few years is to drive efficiency and become lean in the supply chain. He argues that the examples of extracting a lot more cost out of the current state of inefficiencies are plentiful. “It’s a wise thing for the pharmaceutical industry to start paying even more attention than they are today to the current potential for more price controls over the industry. That becomes, probably, one of the biggest things they need to look at carefully,” concludes Fahim.

Raafat Fahim is President and Chief Executive Officer, Nabi Biopharmaceuticals. He most recently served as Chief Operating Officer and General Manager. His career includes 14 years with Aventis Pasteur where he developed several vaccines from early research to marketed products.

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Quintiles ED_11jan10 09/03/2010 14:50 Page 120

EXECUTIVE INTERVIEW

The perfect storm John Hall tells NGP about the unique challenges facing the biopharmaceutical industry.

What are the burning issues in the biopharmaceutical industry?

John Hall. There is a new health landscape in which the rules are changing on all fronts. Patients are taking more control over decision-making about their treatments, with access to a wealth of information available at their fingertips on the web. There is greater emphasis on safety from both regulators and consumers. Furthermore, there is a greater value consciousness on the part of both patients and payers. This means that there is a heightened need for different types of data for the changing stakeholder groups that goes beyond the data traditionally gathered for the regulatory authorities. It is now vitally important to consider these needs and to do so early in the drug development process.

These drivers have contributed to ‘the perfect storm’ for biopharma companies. Going forward, it is easy to envision how the impending ‘patent cliff’ will serve to heighten the pressure the industry faces. Specifically, from 2009-2014, an estimated €94 billion branded revenues will go generic. At the same time, funding for biotechs remains under heavy pressure in a capital constrained economic environment.

What is the principal driver for change?

JH. Pharmaceutical companies need to re-exam-

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incorporated into phase II or III clinical trials, the real goal of these studies remains getting the drug licensed and it is imperative that this goal is not compromised by building in too many more objectives. Hence the need to have a longer term strategic clinical plan that includes late phase or post-marketing studies.

These studies are concerned with what the product actually looks like in real life, rather than in the highly selective context of a mainstream clinical trial. For example, in a real-world setting patients may have several diseases and be taking several therapies at once. To pursue late-phase development effectively, though, requires specific expertise that goes beyond that employed in the traditional phase III setting. Expertise is required in areas such as PROs, health economics, statistics and outcomes research and, as with all forms of research, the key success factor is designing the studies correctly from the outset.

What options are there for late-phase studies?

JH. There are far too many to list; however, options include using nurses and patients to help fill out a drug’s profile post-approval. ine the way they manage the lifecycle of their Sponsored nurses not only play a crucial role in drugs, in particular the role of late phase studpatient education and compliance with theraies, if they are to differentiate their products py, they can also collect outcomes data from and build a comprehensive value proposition hospital databases under contract. Patients can in an increasingly saturated and payer-domialso contribute through media such as the nated marketplace. If they don’t take up this iGuard online medical monitoring service, challenge, the payers themselves will be only too which was launched in 2007 with start-up happy to step into the breach funding from Quintiles. The and at the end it will largely service now has over two milcome down to price. lion users.

Ultimately, however, Why is lifecycle management what is required is a major important? change in thinking to ensure JH. Ultimately it comes down that there is a continuum of to real lifecycle development. studies that encompass both The concept of value has the more traditional and the widened to encompass not just more innovative approaches whether a drug is safe and and which will provide the ‘works’ but other key factors right data at the right time to such as how it performs against satisfy the needs of the inthe current gold standard of creasing stakeholder groups.

John Hall is Vice President, Global care, cost-effectiveness, longIt is only by thinking strategiMedical Affairs, Epidemiology and Outcomes Research for Quintiles. A term risk management and satcally early on in the developformer practising physician, he brings over 25 years of experience isfying reimbursement criteria. ment process that the in development and While elements of value biopharma industry will be able commercialisation strategy, having served in medical affairs with Eli to continue to develop new and creation, such as patient-reLilly, Glaxo, Allen and Hanburys and an independent consulting better medicines that deliver real ported outcomes (PROs) or company. patient benefits.n quality-of-life measures, can be

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CLINICAL RESEARCH

Celgene Corporation’s Kamal Shah looks at why most new drug compounds fail to progress beyond the clinical trial stage.

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espite all the scientific advances made over the past couple of decades, one of the main challenges in the pharmaceutical industry remains the failure of many drugs to reach successful registration and approval. According to Kamal Shah, Head of Global Trials Safety Surveillance for Celgene Corporation, the number of drugs that progress from discovery to approval hasn’t changed much, in terms of the failure rate still being very high.

“The pharmaceutical industry needs to come to a consensus and perhaps learn from the past and figure out where the biggest failures are occurring,” Shah says. “There are usually ample warnings from discovery all the way to the registration and approval process, but somehow the people working on these projects are missing them. This could be because they are focused on their own career aspirations.

“If you look at the development of a compound, most of the people who start working from phase I or earlier are in charge of that compound,

and the failure of that compound could affect their career development.

The flipside of that is that they may hype up the compound rather than thinking more scientifically and perhaps more critically about its chances of success or failure. If the drug succeeds, of course, everybody working on it gets the rewards, so it’s a catch 22 as to how to get away from that model.

“I’m sure other scientific areas have the same problem, and they have found a way of lessening it. If there was independent review in the middle of or at every stage of the trial, it might make this process more successful.

We can’t eradicate the failure rate completely, of course, but if it could be reduced by only 10, 20 or 30 percent, that’s a huge amount of research money going somewhere else.”

The other challenge Shah points to is that certain countries, primarily the US, are paying for a lot of the innovation in research and discovery, which is not necessarily compensated when the resulting drugs move into other markets.

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“In poorer countries where government resources are stretched, this is understandable,” he says, “but for developed countries there is a need to share the burden of development rather than it being placed on only one or two countries. There are a lot of countries that can afford to pay, and they need to come together, just like the EMEA has become one body. I’m sure if the organisations like the FDA, the EMEA and the Department of Health worked together, they could come up with some formula of how to divide the expenses.”

Safety first Patient safety is obviously a critically important consideration in clinical trials, and awareness is certainly not a problem within the industry, as Shah points out: “It’s not a question of whether people are aware of safety in clinical trials, because if somebody’s living in today’s world, I’m sure they’re reading the paper, looking at the compound and probably most of them are involved in answering the questions from the regulatory agency about safety.

“The challenge on the clinical trial side is that efficacy is the driving force. Safety brings bad news occasionally to the table, and that’s one of the reasons it has not been accepted as a member of the core team, maybe just by default. The bearer of bad news is never welcome anywhere, but the teams need to look at this and the critical approach of how can you ignore safety, because drugs are approved now based on the benefit-risk ratio rather than just efficacy.

“In order to reach an acceptable level of safety, you have to make sure that safety is fully in tune and working right from phase I trials into human, all the way through. There are a lot of challenges involved in improving safety and listening to the dose selection as well as all the risk mitigation strategies that make a potential failure down the road less likely.”

It has become almost impossible to separate safety from efficacy in clinical trials, because regulatory agencies now ask for a benefit-risk assessment as a combination. “The problem there is that the assessment of acceptable risk is never well defi ned,” says Shah. “For many major diseases it’s not very difficult, but there is no consensus amongst different regulatory agencies in North America and Europe and Asia, for example.

“The regulatory agencies worldwide are attempting to come up with a formula for assessing and giving a number to the benefit-risk, but that’s another big challenge. You can put a number on efficacy, and if you reach that, you succeed. With safety, things need to be considered on an individual basis: drugs have idiosyncratic reactions and some behave differently in, say, a patient who is compromised in liver function or renal function. Th is has to be individualised and acted upon.

It will be very difficult to come up with a fi xed number where you say, ‘Okay, this is the benefit-risk ratio, and if the number is one, then the drugs get approved or not.’ It’s an evolving science in terms of how to perfect it.”

International outlook Another change in the clinical trial landscape has been the number of trials being conducted internationally. In Shah’s view, international trials are a very good way of making sure the drug is exposed to varieties of populations and individual country practices and habits as well as individual genetic considerations that may be brought in by different parts of the world.

He underlines the fact that the opening up of certain areas, such as Latin America and Southeast Asia, has brought more diversity to the trial population, making it easier to get drugs accepted worldwide. However, he also points to the challenges that develop through the need to satisfy local agencies and regulations and practices, which can occasionally throw a wrench into proceedings.

Despite this, Shah sees the internationalisation of clinical trials as a continuing trend within the industry. “A lot of companies are trying it.

It allows them to get good enrolment from a lot of areas outside of traditional, research-based centres. They also get exposure to patients who are not controlled in the same fashion and so might help indicate how the drug might react when it gets marketed, so you have better population exposure.”

Another thing that Shah sees evolving in the next five or 10 years is the development of more collaborative partnerships with local expertise, either internally or acquired through partnerships with service providers. He predicts that service provider industries are going to continue to grow in terms being the source of doing a lot of trials.

“The question is whether they will be able to maintain the talent pool, which keeps changing,” Shah says. “Quality of service is never guaranteed for the duration of the trial, even with the best companies.

“Personally, I also feel there is a strong need for collaboration between academic centres and pharmaceutical companies, because most of the targets are being developed or invented or discovered at academic centres, and then the development of the compound goes to the pharmaceutical industry.

“There needs to be stronger, more collaborative efforts between the academic centres that can bring a lot more science to the table, rather than just a faster approach to the development process, and maybe can help in selecting the best candidate, rather than just a candidate. There are academic centres that can bring more partnership to the table, even for conducting trials, which is right now one of the biggest reasons for failure. Trials could be conducted either in collaboration with or maybe even independent of the pharma industry, which gives the potential for a better success rate.

“The active involvement of large academic centres, the involvement of good research physicians and the people who are at the forefront on the treatment side of the disease, would bring a lot to the drug development and clinical trial process.”

“Trials could be conducted either in collaboration with or maybe even independent of the pharma industry, which gives the potential for a better success rate”

Kamal Shah is Head of Global Trials Safety Surveillance at Celgene Corporation..

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ROUNDTABLE

IT SOLUTIONS IN CLINICAL TRIAL MANAGEMENT NNIT’s Philip Puls and Onorach Ltd’s Christene Leiper on how to optimise performance management by delivering better analysis and planning tools.

Thanks to rising costs and longer development cycles for new drugs, data, shorten the length of time taken to run clinical studies, and reduce pharmaceutical R&D departments are facing an increasingly chalthe time to get new medicines to market. lenging business environment. What strateMake certain that the study design meets all gies can pharma companies use to help meet the questions being asked to prevent any protothese challenges? col variations occurring.

Philip Puls. NNIT recommends companies Crucial steps to ensure the success of studto evaluate their overall clinical development ies are site selection and engagement. As it process with the aim to optimise each step for takes time to achieve the required number of maximum efficiency and alignment to the overpatients, pharma companies have to develop a all process. A cornerstone of the outcome is setplan for successful enrolment, bearing in mind ting up a company-wide IT strategy with strict the challenges such as geographical location, executable elements. Th is requires a breakdown before devising their approach. They also need of silos and a reinvention of the clinical landto defi ne an acceptable cost per patient, which scape. Companies must defi ne a larger vision means defi ning a budget. Principal Investigators and architecture, develop improved processes can accelerate recruitment by screening patient based on identified gaps, build business cases for records, by using ICD-9, an international claseach chosen project area, and then initiate the sification of diseases, or by assessing ‘billing projects in the best sequence. codes’, thus identifying the disease. Referring The approach from NNIT, called eCliniphysicians can refer their patients for screening. cal, is not dictating a single solution that fits all To assist the physician, a dedicated staff member Philip Puls is Senior Programme Manager at NNIT. He has 20 years of experience in the life sciences companies; it recognises that all companies have can complete this task effectively. industry specialising in the implementation of varying organisational restrictions and specific standard solutions in clinical development. He has a deep pharmaceutical business understanding, challenges, which must be taken into consideraWhat specific tools can companies use to high regulatory and technical expertise and has worked as a Project Manager with CDW, eClinical tion. Based on careful analysis, the objective of create a more flexible clinical trial manageprocess optimisation, EDC and safety system the NNIT eClinical process is maximisation of ment process? implementation projects. benefits for the R&D organisation according to CL. Companies need to apply intuitive technolothe priorities. gies so that data from various sources in different countries can be converted into a common, accessible format. These technologies should be flexible, familiar, and user-friendly so that clinical Christene Leiper. Use an outsourcing model that involves working with collaborators can manage and share information concurrently anywhere innovative CROs who have specific services designed to produce robust

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in the world. Web technology makes it easier for clinical trial managers to fi nd, update, and share the right information where and when they need it. By having all this information at their fi ngertips, clinical trial managers can make the best decision about continuing a trial, stopping a trial, or adding an amendment to the protocol.

to the inconsistencies in the way people input their data. Moreover, existing technologies use widely differing data standards and this hinders integration. The result is that clinical site managers waste a great deal of valuable time converting critical data fi les into usable formats, thus increasing the risk of human error.

Life sciences companies need to apply efficient technology solutions to help manage the flow of information at investigator sites. These solutions must promote collaboration between remote clinical researchers all over globe and enable data exchange across technological boundaries. Solutions need to be flexible but also secure so that intellectual property is available to the right people at the right time.

PP. At NNIT we believe two types of tools can facilitate more flexible and agile system landscapes. The first tool focuses on the organisational ability and maturity. The organisational tool comprises standardisation and a governance model for enforcement and development of standards. The second tool is based on the introduction of new components into the application landscape, more specific single repositories for sourcing and maintenance of master and meta data connected with a service oriented architecture (SOA) allowing easy access across all applications.

The SOA approach enables plug-and-play of soft ware products, which ideally allow access to the best of breed solutions enabling optimal processes and functionality and also creating the necessary flexibility. Another solution featuring end-to-end integration is to sign up with a full suite provider that covers EDC/CDMS, CTMS, CDW, BI and safety system, with the expectation Professor Christene Leiper has over 25 years of that they can provide the required architecture experience in clinical research. She is President of Onorach Ltd., a CRO located in Scotland and functionality in a timely fashion.

How do you see the use of IT solutions in clinical trial management evolving over the next few years?

CL. IT Solutions will continue to optimise performance management by delivering better analysis and planning tools. Companies can apply soft ware that improves their ability to make timely, informed decisions in all areas whether clinical R&D, manufacturing, operations or fi nance.

Soft ware will become an important strategic tool for clinical trial management and will carry much greater weight in developing processes to increase clinical efficiency and optimise costs/ with a global focus. The company philosophy value for money. Soft ware provides the tools enis to engage with clients as a clinical trial partner and it has experience in site selection abling you to monitor performance against the Why has it become necessary to move away and management. Prof. Leiper can be contacted at christene.leiper@onorach.com key milestones such as investigator selection, site from legacy systems towards a modular archiinitiation etc; combine your plans and budgets in tecture based on browser/web access across order to clarify spending, predict expenses, and organisational and geographical areas? maximise fi nancial capital leverage; and better PP. The short answer is high total cost of ownership (TCO), low user satisfaction, lack of cross company collaboration plan and analyse key performance indicators (KPIs) which will certainly and inability to get access to best of breed solutions. The current situation improve the effectiveness of contracts. for many companies can be summarised in the following issues: significant delay in access to data, difficulties to create a clear picture of historic PP. There will be a single sign-on to a clinical portal from any client or current performance/results, the creation of integrated reports of data (Windows/Mac, PDA/Smartphone) from any corner of the world. The is slow and resource intensive, while resource and portfolio management user interface will be a browser of choice with a common look and feel is rudimentary. Th is is caused by having data in multiple, non-integrated for all the systems. The portal will provide access for in-house as well silos, data keys and in formats that are inconsistent between systems. as external resources to share data and information. It will be con‘Old’ systems don’t support new ways of working because they are not nected to the company’s document repository, clinical data repository, flexible enough and built on old technology. User interfaces are not inoperational data repository, safety data repository and provide access tuitive and adaptive to business processes and therefore require specialito a number of preconfigured reports with drill down capabilities all sation. In the cases where bespoke interfaces have been established to relevant for the job held by the user. Th is will remove a large workload facilitate data exchange, the companies fi nd that it now becomes an even for trial managers, with respect to create and distribute progress rebigger task to maintain and support the users. ports of trials.

Furthermore, a number of predefi ned workflows will be available CL. Pharmaceutical companies often use multiple data sources such to secure fast and seamless execution of key business processes which as ERP, Microsoft Project or Excel spreadsheets to defi ne and manage often will be event driven. Finally key business processes will be autoclinical trial processes. However, these systems have their limitations not mated by use of metadata, enabling fast and reliable report generation only because the data is so complex to access or understand, but also due and data pooling.

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EXECUTIVE INTERVIEW

Defining improved efficiency The use of 14C tracers – and ultra-low level analysis – is the future of effective drug development, says Michael J. Butler.

What is interesting about the use of 14C tracers in drug development?

Michael J. Butler. Taking a fit-for-purpose approach using a 14C tracer in combination with ultra-sensitive accelerator mass spectrometry (AMS) can benefit contemporary efforts to make early drug development more effective and less costly. We’ve found that the 14C tracer/AMS combination can provide unique insight in phase 0 (microdose), phase I and phase II clinical studies when combined with rigorous sample preparation.

Typically small molecule drugs have been labeled with 14C for the purpose of tracking (tracing) closely those events that could not be followed as easily without the tracer. For this to work, the amount of 14C tracer added must be such that it does not perturb the behavior of the larger (non-labeled) pool being studied or traced.

An example of a traditional study using a 14C tracer is the so-called human mass balance study performed at a pharmacological dose level.

Such studies form part of regulatory submissions.

This type of study typically employs a dose of 100 µCi, 3.7 MBq of radioactivity. Such levels can be measured by scintillation counting, a traditional analytical technique.

How does the traditional use of 14C tracer differ from what you do at Xceleron?

MJB. The biggest difference is derived from the specificity and sensitivity we can achieve with the 14C tracer/AMS combination we use. AMS measures isotope ratios in the femto- to attogram per mL range. This is many orders of magnitude more sensitive than traditional methods used to measure 14C or indeed methods such as LC-MS/MS used to measure un-labeled drugs.

What benefits does the 14C tracer/AMS combination confer on drug development?

MJB. Uses have changed with time as our customers have become comfortable with the technique. However, the the14C tracer/AMS combination is entirely complimentary and synergistic to traditional techniques such as scintillation counting and LC-MS/MS. The earliest use our customers made of the 14C tracer/AMS combination was in the conduct of human regulatory mass balance studies but using 14C tracer at significantly lower specific activity than traditionally. We have conducted such studies at 100-200 nCi (3.7-7.4 kBq) radioactivity dosed, or

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1000 lower than the levels described above. This approach has been taken to overcome inherent molecular instability resulting from radioactive decay. We have also used the sensitivity of AMS to measure later time-points, of several days in studies of long half-life drugs when the levels of drug drop below the detection limits of traditional analytical methods. We have been conducting these types of studies since Xceleron was formed 12 years ago. As far as we know, there are seven drugs on the market which were approved using Xceleron data from such studies.

Another common use of the 14C tracer/AMS combination is in the conduct of phase 0 microdose studies. Our customers tell

“The early insight from these studies is provided at only a small increase in the cost of a traditional phase I study” us that they are particularly valuable to provide very early go- nogo decisions, particularly for anti-infectives where pharmacokinetics can be pivotal for the drug’s action. Most recently, we see demand from customers to use phase 0 studies for purposes other than straightforward investigations of systemic PK. For example, we have conducted phase 0 drugdrug interaction studies. We have also investigated drug transformations in isolated cell populations and drug disposition in CSF, skin blisters and other compartments. Xceleron has conducted phase 0 microdose studies regularly for 10 to 12 years.

The area of greatest new interest in the use of the14C tracer/AMS combination is in clinical phase I. In particular, our clients are interested in getting insight to metabolite safety and fundamental kinetics such as absolute bioavailability. We have conducted studies in this area over the years but interest has grown significantly in the past year or so.

Why so much interest in the use of the14C tracer/AMS combination in clinical phase I studies?

MJB. From what our customers tell us, it comes down to two things: Most importantly, the the14C tracer/AMS combination facilitates a clinical study design which is optimally suited to the issue under investigation; secondly, such

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example. That early insight can enable critical go-, nogo decisions for compounds which suffer from poor bioavailability and would require extensive downstream formulation development.

You mentioned metabolite safety. How can that be investigated in phase I? MJB. We’ve worked with our clients to design a screening approach that identifies potential human-specific or disproportionate metabolites. In this approach, we add a very low level of 14C-drug to the oral dose. We then collect plasma and excretory samples and profile them for metabolites. Using pooled samples, we can keep the analysis to a minimum thereby reducing overall cost. We refer to this study as our MIST approach, named after the US regulatory guideline.

How cost-effective are these phase I approaches?

MJB. The insight provided at such an early stage has the potential to save our clients significantly by halting development of a compound with unfavorable characteristics or guide the ongoing development of an appropriate candidate.

The early insight from these studies is provided at only a small increase in the cost of a traditional phase I study. In the case of the IV-PK study, the IV dose can be administered without additional non-clinical safety data. Safety data for the oral route of administration is sufficient. Furthermore, formulation of the intravenous dose at such a low level is trivial, taking intravenous formulation off the critical path. This is significant as many contemporary assets are pretty insoluble.

By using flexible protocol designs in phase I, these studies can be incorporated into existing phase I SAD or MAD designs, or as part of a fed/fasted phase I approach. studies can be conducted at a small financial increment to the funds already committed to the clinical phase I investigation.

What is optimal about these studies?

MJB. The best example is a design that has long been advocated to gain absolute bioavailability and other fundamental pharmacokinetic parameters.

We often refer to this as an IV-PK study. An intravenous 14C-dose is given contemporaneously with an extravascular therapeutic dose. For example volunteers may be dosed orally as usual. An IV dose is then administered at a much lower level (≤ 100 μg) compared to the oral dose and is given, for example at the Tmax. The IV dose is so low that it does not contribute significantly to the overall systemic drug concentration to which the volunteer is exposed.

What is the advantage to conducting an IV-PK study in phase I? MJB. An IV-PK study can characterize the effect of first pass metabolism, for

Are the 14C tracer/AMS combination studies in phase I covered by regulations?

MJB. Yes, our metabolite screening approach is derived from FDA’s ‘Safety Testing of Drug Metabolites’ (MIST) guidance. This approach has recently been reinforced in the new ICH M3 guidelines adopted at the beginning of this year. ICH M3 also makes provision for IV-PK studies. IV tracer studies which require only µg levels of drug do not require separate IV toxicity data.

Can the concept be applied to biologics?

MJB. Yes, Xceleron have been working with biologics for several years and has developed techniques for 14C labeling. n Michael J. Butler is Chief Executive Officer of Xceleron. He has 20 years’ experience in science-driven businesses in Europe, US and Asia, and he has been President, Scientific Operations and Chief Scientific Officer with Aptuit, Group Vice President at MDS-PS and Group Director, Business Development for Huntingdon Life Sciences.

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TROUBLESHOOTER

An untapped opportunity How to motivate patients who aren’t ready, by Kirk Nielson.

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et’s say for the sake of making my point clear, that you have completed your early enrolment strategic planning, finalised your protocol and conducted all of your site initiation visits, and you are wrapping up the coordinator training session on the last day of your investigator meeting. Oh, and let’s not forget that your primary investigators are perfectly comfortable with the somewhat aggressive, eight-patients-per-month enrolment goal you just presented. Do you feel you have things pretty well covered?

Now, imagine how it might feel if at that very moment, I tapped you on the shoulder and informed you that only 50 percent of the patients your investigators (or CROs) have earmarked for this trial are actually ‘ready’ to participate in your study. Does that feeling intensify when you realise that the actual percentage could be as low as 20 percent?

Imagine the potential cost savings you could amass if you were able to drive that percentage up 10 or even 20 percentage points across your entire pipeline. Better yet, think of the possible savings a 10 percent increase in ‘ready’ patients would amount to if applied to the nearly 50,000 phase II and III clinical trials currently registered on clinicaltrials.gov. Feeling better?

The good news is that there is a proven approach to motivating patients locked in this ‘non-ready’ state to change. The bad news is that it is not exactly just-in-time behavioural change.

The approach used for driving this change in behaviour is called the Transtheoretical Model of Change (TTM). This model, commonly referred to as Stages of Change, involves a set of health psychology strategies for addressing patient ambivalence or resistance to change.

TTM assesses an individual’s readiness to act on a new behaviour, and provides strategies to direct an individual through the various stages to adoption and sustained behavioural change (maintenance).

There are five stages of change that make up the core constructs. These integrated stages form a continuum of motivation centred around ‘readiness to change’. Movement along this continuum occurs by successfully completing (outcome measures) the process of change within each specific stage. The stage construct is important because it represents a temporal dimension. Change implies phenomena that have occurred over time. This is very different from other theories of change, often considered a point in time or an event. It is important to point out

that the TTM model focuses on the individual’s decisionmaking process.

The five stages of change include: precontemplation – there is no action expected in the foreseeable future, usually measured as the next six months; contemplation – there is an intention to change in the next six months; preparation – there is an intention to take action in the immediate future, typically within the next month; action – there has been an overt modification to the existing behaviour within the past six months; and maintenance – there is a planned effort to prevent relapse, estimated to last from six months to about five years.

In addition, the model includes a relapse pathway, which is not a stage, but signifies a return from action or maintenance to an earlier stage.

“Early implementation of the Transtheoretical Model should be considered for recruitment for almost any phase II or III trial where enrolment rates are expected to be low” The model includes a series of intermediate/outcome measures, which allow for greater monitoring of change over the five stage transitions, and therefore better optimisation of the process of change. While a more detailed description of the model is required to gain a sound understanding of how it produces the motivation necessary to change behaviour and maintain that change, early implementation of the Transtheoretical Model should be considered for recruitment for almost any phase II or III trial where enrolment rates are expected to be low or study recruitment difficult. The model’s success stems from its recognition that different individuals will be in different stages and that appropriate intervention must be developed for everyone.

Finally, due to its patient-focused design and more intrinsic, motivational approach, the Transtheoretical Model can also help drive greater participant retention rates, another area of challenge in many of today’s complex clinical trials.

Kirk Nielson is Senior Vice President and Managing Director of Iris Global Clinical Trial Solutions™. Nielson leads the Intelligent Trials™ Practice, uniquely motivating sites, subjects and sponsors to drive enrolment success in challenging clinical trials, including early strategic consulting with sponsors to more effectively optimise their site enrolment activities.

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MARKETING

The force is with you With patent t t expiries i i and d generic i competition ttiittii on th tthe h rise, i th the h pharmaceutical h ti l iindustry d t iis b being scrutinised like never before. As a result, sales force effectiveness is taking top priority.

By Matt Buttell

“There is no such thing as a no-sale call. A sale is made on every call you make. Either you sell the client some stock or he sells you a reason he can’t buy. Either way, a sale is made; the only question is: Who is going to close? You or him?”

These are the words of Ben Affleck’s character Jim Young in the 2000 movie Boiler Room – a dark and intense drama depicting the perils of working on a highly pressured, highly paid sales floor at a suburban investment fi rm.

While the movie is a dramatisation of what life is like as a cold-call salesman, the ‘boiler room’ concept that goes hand-in-hand with sales is nothing new to the pitching floor. Of course, outside the world of fi lms, while the reality for the sales force may not be half as ruthless, it is just as dramatic. And not least for the pharmaceutical industry. That’s because the industry is currently at a crossroads, facing the very real problem of patent expiries and the rise of generic substitutions – and the pharmaceutical sales force is top of the critical agenda.

The challenges facing the pharmaceutical industry in 2010 are multi-faceted and have already been well publicised. For one, a slowdown

of growth levels within mature markets is leading to a refocusing for the industry – in particular, Big pharma – that sees future profits lying in emerging markets such as China and India: markets that have been dubbed by the media as ‘pharmerging’.

As such, the pressures on the sales forces of pharmaceutical companies are great, not least as many of pharma’s biggest markets are now saturated with sales representatives. A direct result of this sees the industry’s selling techniques becoming increasingly ineffective and the industry is now being forced to embrace the reality that this model guarantees neither growth nor future profitability.

Instead is the argument that there is a new opportunity presenting itself to the industry: the realisation that moving beyond sales force growth and mass promotion and into a new era of sales force effectiveness.

Denied access According to the Pharmaceutical Sales Force Effectiveness Strategies report published by Business Insights last year, the social, demographic and economic context in which the pharmaceutical industry operates

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is changing dramatically, with huge implications for the industry as She believes that the most successful future pharmaceutical sales a whole. Dr. Ksenija Jakovcic, a Business Development Manager at organisations will include a significant variable component and will be SanMed and author of the report, notes how these challenges will have engineered for agility and for greater cost effectiveness. “A solution for the major ramifications for the way in which pharmaceutical companies future is to establish a smaller internal sales organisation composed of the market and sell the medicines they develop over the coming years. highest performing sales reps. To build in flexibility, this fi xed resource The study aims to highlight how the pressures associated with would be supplemented by variable resources provided by controlled sales these challenges impact market efficiencies and discusses the idea that, organisations (CSOs), whose expertise is in the rapid deployment and recurrently, no aspect of pharma operations is under as much scrutiny as deployment of custom profile sales teams.” the sales and marketing function.

What’s more, the pharmaceutical industry, which has long been deOne of the biggest issues facing the pharmaceutical sales force is scribed as counter-recessionary – a fact largely based on the assumption the fact that while the perceived benefits of high return on investment that people will always need drugs regardless of the state of the economy – have, in the past, been a key driver for companies to increase numbers, has shown signs of being far from invincible. According to analysts, whilst the reality has meant that a surplus in the number of reps. That, alongthe recession-proof theory might be true at a surface level, a more granular side a raft of new pressures – including busier physicians, the proliferaanalysis reveals dissimilarities between different segments of the industry. tion of new drugs, greater competition among companies that produce For instance, the providers of branded drugs, blockbusters and the and market drugs and evolving customer dynamics – has seen the ROI newest treatments tend to make long-term investments in R&D, and have on detailing decline. high sales and marketing costs as a result, while those manufacturers of What’s more, the pharmaceutical industry remains somewhat cautious off-patent, older drugs – usually manufactured at a much lower cost than about the concept of change, a fact underlined by Dorman Followwill, Vice the branded molecular rivals – typically operate off a lower R&D cost base, President of Healthcare EIA at Frost with smaller sales, marketing and & Sullivan. In an interview given at budgets in tow.

Side effects the Next Generation PharmaceutiThis issue has only been exacResearched and organised by eyeforpharma, a division of a cal Europe summit last year, Follow erbated by the ongoing recession private company headquartered in London, the Sales Force will used the analogy that, over the and global economic crisis. As such, Effectiveness Summits for 2010 go a long way to highlight the last 30 or 40 years, the pharmaceuticompanies are asking themselves importance this topic is bringing to the industry. cal industry has operated more like if this is the time to be investing in The first summit will be held in Barcelona in April and aims to the automotive industry, something pharma sales or not as the industry give attendees a real insight into how change is impacting the he defines as an “interesting crossrefocuses its ideas on the way to apindustry. Keynote speakers will share knowledge designed to industry comparison,” given the sigproach the sales floor. transform the pharmaceutical business model from product focused to customer-facing. nificant meltdown the US automotive However, the industry’s bottom industry experienced last year. line (profit) remains the bottom A second summit will be held in New Jersey in Ma, tackling “Obviously the pharmaceutical line, and it is clear that big pharma similar issues for the US market. industry doesn’t want to see itself is going to have to change its sales at that point, so there is a lot of model – though whether this will angst and worry currently circulating in the pharmaceutical world,” he come about as a want or a desire to change, rather than a necessity, renoted. “Nonetheless, the industry remains incredibly slow to change.” mains to be seen. In the end, the pressures the industry is facing – such In fact, warns Followwill, until pharmaceutical companies shift as saturated markets, declining margins, increased pressure from generic their focus, change for the industry is unlikely to happen at all. “The competition and fewer blockbusters – mean that cost cuts are inevitable, industry is largely geared ruthlessly toward the fi nancial market and and eventually that has to include cuts within the sales force. shareholder values, which have to be driven on a quarterly basis. MeetThankfully though, as change does slowly begin to envelop the ing analyst expectations remains the number one metric for a pharma pharma industry, the Hollywood mentality of sales force effectiveness, at CEO, and as long as that remains the case, there won’t be a gigantic least, seems to disappearing. amount of change. The pharma industry is probably not going to look The general consensus is that success lies in striking a balance bethat different in 10 years’ time.” tween ‘soft skills’ and ‘hard skills’, and analysts say that emotional intelligence – which includes attributes such as listening skills and dressing and New ideas behaving in a professional manner – is required just as much consultative Jakovcic, meanwhile, only echoes Followwill’s thoughts, explaining selling skills (CSS), which include knowledge about the product, the medithat while caution certainly does remain, the industry is slowly begincal condition it treats, and – in the end – the skill to close the deal. ning to explore new ideas and innovative sales models. “Although only So, maybe Ben Affleck’s speech as Jim Young in Boiler Room shows seven percent of surveyed respondents believe that new sales models some truth after all, but for the ‘Always Be Closing’ mantra of years will be rolled out in the next two years, the majority of interviewees gone by, it seems the number’s up. And in its place, perhaps the usually expect that focused pilot projects will indeed gradually pave the way to static pharmaceutical industry will adopt a new ABC of sales: ‘Always new business models,” she writes.

Be Changing’.

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NEXT BIG THING

Measuring probability of commercial success

By Mike Rea

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he term ‘attrition’ is traditionally applied to R&D, suggesting the positioning itself. However, that is the first clue: looking for a single an unpredictable loss of agents in the pipeline. However, when ‘metric’ that works across all brands is impossible – like attempting to tune only one marketed drug in four repays its investment, a review a piano by tightening or loosening all the strings at once. A prognostic of the most avoidable ‘attrition’ – that of products launched must allow for each brand to be measured against its own objectives, and with low to zero probability of commercial success – is essential. The huge within its own context. question has become: “Can we predict the commercial success or failure of It is also essential to look beyond the checklist: for example, simply a drug before launch?” ‘having’ a positioning is not predictive of success or failure; having a high Commercialisation quality is significantly more powerful as a quality positioning, however, is a component of successful brands and one predictor for market success (or failure) than tactical or promotional that is lacking in unsuccessful brands. Positioning quality is therefore a marketing. Commercial decisions including indication, TPP, defi nirobust, causative and predictive component. tion of ‘efficacy’ and positioning, Developing a robust progall need to be made as early as nostic is then about identifying The problem of context phase I; however, the industry has an exhaustive set of components, struggled to test the quality of the all of which must be present, and High unmet need Saturated SoV market ‘Normal’ distruibution underlying strategy. of testable individual quality, to The tactical mix has a causaproduce an objective yardstick tive positive or negative impact on that has both validity and reprosuccess; however, if the strategic ducibility. elements are not optimised, any There are two ways to apply effect is diminished – they modify prognostic evaluation to a stratea product’s success or failure, but gic plan: with complex feedback, they don’t decide which it will be. or using a standardised scale.

Investment Investment Investment An excellent promotional proMany internal planning processes gramme will still struggle if the already rely upon internal ‘experts’ © 2005 IDEA Pharma Consulting positioning, segmentation and to provide feedback; however, they messaging are ineffective (or low are typically limited by time and geared), where a basic programme may suffice if these strategic compoexternal validation, limiting a full review and producing ‘group think.’ nents are high geared.

This is an important consideration in an era where analysts and senior Gearing also applies to the context into which a drug is launching. management need to know more than the clinical data to make a judgment You can’t directly compare the effect of one drug’s marketing with another, about a brand’s prospects. Many recent high-profile compounds that have even in the same class, because the context differs. For example, the kind delivered against their clinical objectives have spectacularly underperof market into which the drug launches affects the way that investment formed in the market. works: a product launching with desirable attributes into an area of high unmet need will have a very different return curve than one launching into Predicting the future: three strikes… a saturated market.

Measuring probability of technical and regulatory success is already Some have said ‘it is impossible to measure quality’ in strategic maran essential component of pharmaceutical development, yet three of four keting, and that the ‘x’ factors are indefinable. In pharma, however, drawproducts that survive this challenge are still not returning their investment. ing conclusions from success or failure is objective. Forensic case studies Now that those products can be diagnosed pre-emptively, the excuses for of disruptively successful compounds, or unpredicted failures, as well as launching another Exubera or Relenza are going to be harder to deliver. average performers, yield many lessons.

The complicating factor in pharma is the contingency – a compound’s Mike Rea has worked in international pharmaceutical marketing for over 20 years, and has developed global marketing solutions for most of the world’s top 10 pharmaceutical positioning is contingent upon the quality of the market research, and companies. He has led the strategic direction of over 50 pharmaceutical brands since founding IDEA Pharma. strategic assumptions, as well as the quality of the process of deriving

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ROUNDTABLE

UTILISING U D S G THE MEDIA Two industry i d t experts t tell tte NGP GP P how h life lif sciences i companies i can maximise i i the th benefi b fitts of communications. nicati

In an era of increasing diversifi cation of print, broadcast and

tion gadget. We prudently might state that there are too many cases in

online media outlets, how can life sciences companies maximise

which the drive to message must have overwhelmed the intention to listen and engage, let alone collaborate. And yet, these are the better options for continuous business in life sciences.

the efficiency and impact of their communications channels?

Jo Spadaccino. Gone are the days where one size fits all – it’s now time for the industry to embrace a more targeted, insight-driven approach with its audiences. Regular customer research is key to ensuring a deep understanding of each target market’s media preferences as the landscape evolves. Of equal importance is ensuring expertise to understand how each media outlet operates and how to effectively engage in dialogue with them. An active relationship with each outlet, directly or via a strong agency, is a must. Measurement is the other piece to this jigsaw, with most PR practitioners today advocating a much more sophisticated approach to demonstrating results which focuses on changes in belief or behaviour. Common sense will tell us that continuous evaluation of activity will result in greater future efficiency – the challenge is to ensure that budget is protected for this in the face of pressure to prioritise for short-term gain.

Rob Halkes. Communication technology has made anything possible.

Information, communication and interaction can be continued over time and place, publicly as well as privately. It offers new opportunities to engage with everyone a company needs to.

However, we rather see the continuation of just getting the message out there than a more fundamental approach, although there are prudent attempts to use the new media.

The thing to do is to reflect on the company’s position as a centre to its own network of different actions with different stakeholders.

Strategic questions might be asked as to what kind of communication activity might create better conditions for the business. A thorough analysis of needs and wishes of protagonists in it and a basic approach of designing is crucial to step beyond just trying a new communica-

What specific strategies should life sciences companies employ to ensure they get the maximum benefit from digital communications channels such as social networking sites and blogs?

RH. The new digital channels present three formats with different consequences: the web 1.0, web 2.0 and web 3.0 formats. They present three approaches to communication: just sending out information; communicate, interact and collaborate, and fi nally, to do so in a specific personalised way. The 1.0 and 2.0 formats regard information and interaction in the public sphere, like blogs, twitter and communities: open to all. The 3.0 format specifies the technology to collaborate and interact at private issues not desired to be made public. It is in this context that experience co-creation is designed to suit the personal intentions of the customer. Th is is a basic need of patients: personalisation of possibilities and facilities to one’s own health. Experience co-creation offers the opportunity to life sciences to partner with other healthcare constituents to optimise healthcare itself. It will result in communities in which the patient will fi nd a private, reliable and trusted context to cope with his condition. Also, to choose between facilities construed to help him learn, be coached and comply with the therapy.

To build such a context for the patient, partners in healthcare will need to structure multidisciplinary cooperation and the processes of care itself. With this, the empowered patient will be able to grow into trusted self management with his disease. It generates the opportunity to go beyond one’s product positions so as to benefit from accumulated knowledge and information concerning the medication.

JS. There are some great examples of life sciences companies who have

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found their confidence and place in cyberworld – which, let’s face it, is just like the regular world. Yes, there are regulatory and technical considerations, and yes, there is a need for internal policies and expert advice to navigate the pitfalls, but at its most basic we should be thinking about digital strategies as part of the overall communications strategy, not as something that stands alone.

Jo Spadaccino is Healthcare Director at Cohn & Wolfe London, a global strategic public relations consultancy.

Spadaccino partners with her clients to navigate this complex marketplace using a whole range of integrated communication tools. She is passionate about creating, building and protecting the reputations of organisations and their brands.

As with off-line communications activity, successful digital strategies are those that have a reason for being. It’s not about being on Twitter, ‘because it sounds good’, it’s because the business goals and audience insight tells us this is the best way to engage. Engagement is the key word here. Generating meaningful conversations, through creation of legitimate and compelling content in a place where target audiences can fi nd it, will get you a long way.

What effect has the increasing globalisation of health-related organisations had on communications strategies within the life sciences sector?

JS. As companies and the world around them become global, so the need to communicate a common unifying message about its core mission, products and services also grows. A globally led strategy has important benefits in terms of stronger positioning and branding, as well as more efficient use of resources. The best global communication programmes clearly lay out the goal and direction after taking a helicopter view of the marketplace.

Turn-key materials help under-resourced markets to reach out to their audiences, whilst leading on issues and crisis situations provides a strong and consistent voice. And yet, it can be easy to forget that it’s the systems that are globalised – not the audiences. Platform strategies must be equally supported by strong tailored national strategies that work within different health systems, regulations and cultures. Any programme that attempts to overlook the importance of local dynamics is still not going to go far.

RH. Worldwide web communities have been set up on a small scale, to co-research new developments of promising compounds. More effort is given to new, digital ways to relate to target groups. Th is has been directed to the design of websites, email campaigns, e-detailing and set up of patient communities. Some experiments with pharma twitter accounts are done to get experience with it, be it that those accounts are mostly followed by market specialists and scarcely by patients or doctors.

But, the focus of reaching out is product related and promotional by nature. One must learn that engagement and collaboration has a different basis of interaction than promotion: support, authenticity and information about the disease and on how to cope appear to be more relevant then product information. Besides, it is the question whether company accounts will gain enough trust as opposed to those from healthcare providers and peers. Partnerships are necessary. Moreover, the EC acknowledges that there’s a need to rethink the role of medication information health care. It holds in promise for the business, if life sciences companies can take it up wisely.

How do you see the field of healthcare communications developing in the next few years?

RH. New structures of multidisciplinary partnership around patients will emerge that exploit digital opportunities to the max. New designs of integrated care around consumers and patients, from prevention up to telemedicine and home automation, will be implemented. It will change healthcare structurally. Partnerships between healthcare providers and stakeholders will continue for a long time. The sooner life sciences and pharma will accommodate their communication strategies, the sooner they become a self-evident partner to other stakeholders and prevent themselves from drift ing into a commodity market.

Rob Halkes has been a consultant to the market of pharmaceutical and life sciences for 20 years. He works at strategic change, innovation and professional development with executive, marketing, sales and medical management. In the pharmaceutical industry he is currently developing value innovation as a new business model.

JS. We are currently in the midst of a total game change for healthcare communications. Life sciences companies are redefi ning their business models in the absence of blockbuster drugs, the era of personalised medicine is upon us, and the way audiences old and new interact with companies is also shift ing. Couple that with an evolving media landscape and we have a completely new era for healthcare communications before us. As a result, we will begin to see more blurred boundaries between the various marketing disciplines, as siloed operations will lack the required responsiveness. Programming must be audience-led and this will require a higher level of market and audience insights; equally, ignoring the need to forge long-term partnerships in order to build trust and collaboration will come at a high price. From a consultancy perspective, there will be more demand for integrated strategic expertise in specialist areas in addition to fl awless tactical execution.

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Where Future Leaders Learn

8/3/10 09:45:25

EXECUTIVE INTERVIEW

Understanding the new prescribing influences Tom Haskell and John Moran of IMS’ Innovation Lab discuss how to evaluate new factors driving prescribing decisions.

What new factors are affecting prescribers’ medication choices?

Tom Haskell. The list is growing exponentially, but we can classify them into three general categories: those that are managed-care driven, patient-driven and technology-driven.

The influence of managed care extends beyond the use of generics to include the impact of tier position in drug choice and of noncompliance caused by prior authorisation requirements. A more educated patient population has a strong voice in therapy and medication decisions. And physicians are relying more heavily on the internet through electronic medical journals, e-detailing and physician networking sites. These new influences will differ in the degree and duration of their impact and sorting out the high-value activities from the ‘trendy’ ideas is the challenge.

How have these new channels complicated things for manufacturers?

John Moran. Companies are increasingly moving to regional commercial models and figuring out how best to use traditional channels differentially across regions, which is complex enough. If not done well, adding new channels to the mix could make the process unmanageable for a regional business unit. Also, these various influences do not impact healthcare practitioners uniformly.

Figuring out the rate and pace of impact regionally and by specialty poses an opportunity to maximise brand performance in the near and long term.

What is the role of headquarters, versus each region in adopting these channels?

TH. It is up to the headquarters’ commercial

analytics and market research functions to vet new influence sources, qualitatively and quantatively, and then to give specific deployment recommendations to regional units (and even the national franchise). Of course, recommendations should be made in conjunction with the regional business unit’s strategy and operating approach. For example, a region focused on obtaining preferred status for second-line therapy will benefit most from deploying channels that education healthcare practitioners and payers on patient flows and treatment patterns.

Determining how much to invest in which channels involves asking, ‘Which influences act where, what level of support should be reallocated from traditional channels and how should investment performance be measured’? These types of questions are

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strategic, rather than quantitative, and can only be answered with customer insights.

Do these new channels represent any opportunity for manufacturers?

TH. Most defi nitely. To the extent that companies can select and deploy local activities in these channels, they can drive stronger customer relationships, optimise their P&L through more efficient brand spending and improve brand usage. Companies that understand the rate and pace of a channel’s impact regionally and by specialty can maximise brand performance in the near and long term.

What specific metrics can be derived from these research methods?

JM. Traditional metrics such as brand share and volume can be applied to some, but not all, new influences. Others require new performance metrics such as penetration, treatment rates, disease intervention rates and patient compliance/adherence. We’re testing research questions now, but have identified some ‘givens’, such as brands operating under new commercial models must have a way to regularly assess the strength of the prescriber’s relationship to the brand and the corresponding value it delivers.

Also, the believability of the brand’s message should be measured in light of other influences that either support or contradict the brand’s value proposition. Particularly in today’s highly connected environment, companies must be attuned to how an influence supports or undermines corporate communication and education efforts. Finally, measures should address the dual drivers of cost containment and comparative effectiveness. While measuring the impact of a pharmaceutical brand on patient outcomes and cost is still in its infancy as a commercial business practice, new metrics of cost and value are taking shape.

TH. Often models produce results that aren’t intuitive. In one study of coupon usage among patients in a specialty-focused disease area, IMS found that certain coupon types and offers significantly influenced the follow-on adherence of patients. It was reasonable to assume that couponing would have an impact on new patient share, but an impact on patient adherence was a surprise. This fi nding has significant by accounting for the ‘lifetime value’ of the patient brought into the franchise.

What must companies do to adopt appropriate new performance metrics?

TH. First and foremost, they need to develop a richer dialogue with their customers through a combination of primary research and rep interactions. Fortunately, they can fund such research by migrating other, more traditional primary research activities, such as awareness, trial and usage studies, to secondary data sources. A good starting point for using new metrics is to apply them initially only to new influences. Eventually, they can then be extended to traditional promotion and education activities.

How can companies assess the impact of these new channels?

JM. In general, there are three types of measurement methods that can be used, although there isn’t one right way to assess the impact of an influence channel. Often, multiple models are required to best explain the impact on prescribing. First, there are analyses at the healthcare practitioner level that compare the prescribing behavior of test and control groups. This is only possible, of course, if you can identify through secondary or primary research which practitioners have What other tips do you have for companies been exposed to the new influence.

Can you give an example of a measurement as they focus on new influence factors?

The second type is regional-level modelof a new influence that produced surprising JM. The fi rst step is to expand or redeploy reing, which includes a strategic framework for search activities so that companies can mearesults? understanding the future impact sure the extent of practitioners’ of influences that are working exposure to new influences and together. This entails modelthe resulting behavioral change. ing the influence’s contribution Brand managers should then to sales, gathering sentiments look for gaps between the refrom participants, obtaining a search fi ndings and their brand perspective from the field, and plan. Each year, they should then deploying the activity seincorporate a few promotional lectively and tracking its actual ‘R&D’ elements into the brand impact. The third type is chanplan so that they can keep on nel-level assessment. With this, top of new channels. Once influprimary research is integrated ences are identified, prioritised with new-to-brand prescribing and included in the brand plan, metrics and value assessments tracking and assessment can to identify how the influence begin. The organisation will affects HCP satisfaction, loyalty have to add a few key perforJohn Moran leads the US Innovation Tom Haskell is Director, US Innovation and prescribing. The results are mance indicators, such as brand Labs for IMS. He serves as an advisor to Labs for IMS Health. In this role, he pharmaceutical clients across a range of directs the development of new, used to prioritise programme penetration, productivity and commercial disciplines, designing and creative solutions for pharmaceutical structuring solutions to meet clients’ and biotechnology clients in the R&D, efforts or to implement regionadherence, to the brand dashkey commercial challenges. He holds a clinical and commercial spaces. Haskell specific programmes that inboard to monitor the spread of BS in Chemistry from Carnegie-Mellon is a graduate of Harvard University, University and an MBA from the majoring in Applied Mathematics and crease customer value in lagging an influence and to track how University of Pittsburgh.

Computer Science. geographies. the brand is responding.

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INDUSTRY INSIGHT

Towards transparency Tina Kohnstam explains the importance of good publication practice in the pharmaceutical industry.

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en years ago, major concerns about the quality of clinical trial reporting threatened to damage the reputation of the pharmaceutical industry and industry-sponsored research. Issues included publication bias (the failure to publish negative data), ‘ghost writing’ and the relationship between the science and the commercial interests of sponsor companies.

The publication of guidelines for good publication practice (GPP) was the first attempt to redress this situation and establish best practice for reporting studies by the biopharmaceutical industry.

GPP has now been revised and updated (GPP2) and its provisions will have profound effects on the way that pharmaceutical companies work with external authors and investigators to communicate their data. It now covers all forms of communication (not just peer-reviewed publications), medical device and biotechnology companies as well as the pharmaceutical industry. The guiding principles of integrity, completeness, transparency, accountability and responsibility must be observed and be seen to be observed by the audience.

One outcome of GPP2 will be to finally lay to rest the issue of ghost writing. The role of authors has been clarified by endorsement of the ICMJE (International Committee of Medical Journal Editors) authorship criteria, accompanied by a requirement to acknowledge all other contributors. The acknowledgements will have to state not only who the contributors were, but also what they did. The exact nature of any support, financial or otherwise, will therefore be clear to all. A broad definition of conflict of interest is given and authors are advised to disclose any such conflicts regardless of the requirements of the journal or congress.

What will GPP2 mean in practice? Companies and their communication agencies need to review their current practices to ensure GPP2 compliance. Academic institutions are leading the way but the industry must also play its part.

Authors must now assume a more central role than before, acknowledging their responsibility and accountability for communications bearing their name. Good working relationships will be critical to making sure that all parties collaborate in a balanced, transparent and open way.

Beyond publications, wider relationships and interactions with key experts are also changing. While it is necessary, and indeed desirable, that key experts retain their independence and their credibility, tighter regulations have reduced the frequency and level of interactions.

Many feel that this is to the detriment of both parties.

The pharmaceutical industry is a major source of funds for research and education, both of which are valued by physicians. Industry-sponsored activities provide opportunities for peer-to-peer dialogue between healthcare professionals that would probably not otherwise happen. Just as concerning is the potential negative impact on clinical trials and evidence-based medicine. Reduced interaction between key experts and the industry may lead to poorer study designs with less robust findings and missed opportunities for directing future research.

“The pharmaceutical industry is a major source of funds for research and education, both of which are valued by physicians” External advice and validation need to be broad based.

Patients are better informed than ever, but patient advocacy groups have indicated that there is still an overwhelming need for better educational materials, so why not work with them? Further, many patient groups believe that they are best served through the transparent interactions between key experts and the pharmaceutical industry. The overarching theme is that the industry must act and be seen to be acting in the interests of patient care; involving patients not only makes good business sense, it is logical and ethical as well.

Looking into the future, I believe that we will see wider recognition of the benefits of working with the pharmaceutical industry, but on a different footing. The separation of science and marketing will continue, and there will be renewed focus on working towards better patient outcomes. The emphasis on transparency, exemplified by GPP2, provides tangible evidence that the industry has cleaned up its act and left any unethical practice firmly in the past. A new era beckons.

Tina Kohnstam is the Global Medical Director at Caudex Medical, leading a team of specialist medical writers and editors in Caudex offices in Europe and the US. As a former physician, Kohnstam is ideally placed to understand and guide the complex interactions between the industry and the medical profession.

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THE NEXT BIG THING

Patient-centric commercialisation Justin van Gennep explains how alternative models for healthcare delivery will improve patient compliance and provide valuable, real-world outcomes data.

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e’re entering an era of ‘the new health’, which is Quintiles’ perspective on the fastmorphing world of biopharma where the rules are changing on all fronts. Among the many challenges now facing biopharma companies is the issue of demonstrating the value of their products to the specific expectations of an increasingly powerful group of payers. Meeting these high expectations and demands for accountability has been exacerbated by obstacles that limit market access and reimbursement, which increases the challenge of building a business case for premium pricing on branded drugs and therapies.

In the complex and fragmented European healthcare environment, biopharmaceutical companies are struggling to obtain market access for new products. Unlike in the United Kingdom, for example, where most reimbursement decisions are made at the national level, the healthcare landscape of the rest of Europe consists of a number of local and regional decision-makers who are becoming increasingly powerful in determining which products get reimbursed and which do not. In countries such as Spain and Italy, reimbursement decisions are slightly more regionally oriented, in the sense that there is a strong push for the regional payers to be more independent from the central government. This means that these local payers have a bigger say on how their healthcare budget is spent, and what criteria they use to determine reimbursement. So it’s not enough for a product to obtain a central EMEA registration – in countries where pharma can’t get a central reimbursement decision, they have to be mindful that one region may choose to cover a product but another region may not. This requires an overall strategy designed to bring convincing data to these regional decision–makers that will be meaningful to them.

The challenge for the industry, therefore, is to demonstrate the value of its products in a meaningful manner, which resonates not only with patients and providers, but with regional payers as well.

Regardless of where they are located, payers are now demanding pay-for-performance. To make an accurate deter-

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mination of the viability of a drug, they will require data that provides market access information such as economic arguments, quality of life metrics and data from head-to-head trials. Payers will want to analyse traditional clinical data as well as the market access data to prove that a drug is a significant step forward in terms of therapeutic performance, and more importantly, economic value. Therefore, combining patientcentric healthcare services with real-world health outcomes data direct from the marketplace will be a critical component for success for biopharmaceutical companies looking to commercialise a new product.

Justin van Gennep, serves as Quintiles’ Senior Vice President and Head of EMEA Commercial Solutions. He joined Quintiles in 1998, bringing more than 25 years of experience as a business leader in the pharmaceutical industry. Dr van Gennep earned his medical degree from the University of Amsterdam and has participated in postgraduate programmes including the INSEAD Executive Programme (IEP) and a postgraduate course in Pharmaceutical Medicine UWIST.

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To succeed in ‘the new health’, pharma must provide payers with as much outcomes data as possible. Although phase III trial results are a necessary and appropriate component, real-life outcomes data from patients observed in normal circumstances are the most meaningful.

Furthermore, regional-level outcomes data from the population within the region where reimbursement is sought would be ideal. Outcomes data out of Italy, for example, would be far more convincing to Italian payers than patient data from Scandinavia.

The question then becomes how can pharma obtain the information it desperately needs to demonstrate the value of its products? One model with considerable promise for obtaining better outcomes data is in-home healthcare delivery. In health systems such as the United Kingdom and the Netherlands, independent healthcare specialists make visits to patient’s homes and help them properly administer their prescribed medications. In-home healthcare delivery not only helps to increase patient compliance, it affords the opportunity to document health outcomes from a very controlled environment. With such real-world outcomes and safety data, biopharmaceutical companies can then be better equipped to provide payers with information that will resonate with them. In a model such as this, pharma is no longer just selling a product, but providing a fully integrated service.

Some companies are already experimenting with home healthcare models, but most traditional biopharmaceutical companies do not have the expertise to deliver on this type of service. Direct patient care is not a core function of the industry due to its inherent conflict of interest and the fact that it can be better delivered by an independent expert. Furthermore, physicians would be very reluctant, and rightfully so, to hand over patient treatment to a pharmaceutical company. But an independent resource with the knowledge, skills and systems in place to collect and analyse patient outcomes data can be an indispensable ally in demonstrating the value of pharmaceutical products to payers.

Additionally, early in-home healthcare providers have been geared more toward compliance and patient ease than they have toward collecting outcomes data. Indeed, most of these providers have never even incorporated health outcomes into their business models, and as such, are ignoring an important element for the future development and distribution of medicines. Because demonstrating value to the appropriate stakeholders is of critical importance for commercial success, it is imperative that the industry leverages every possible tool it can to collect the real-world outcomes data that payers are now demanding.

Quintiles is paving the way to use in-home healthcare to collect real-world data via its joint venture with healthcareat-home in Germany, and its plans to expand these industry-

‘The new health’ ‘The new health’ is both the movement toward an ideal state and the destination.

It is defined by the challenges that biopharma executives are struggling to resolve, by the expanded stakeholder group, and by the promise of better health for humans through high-quality, accessible products and treatments that enable people to live healthier lives. It is not simply a landscape in which faster and cheaper ensures a competitive advantage.

It marks a moment in which public health, multi-stakeholder collaboration and access to quality and affordable medicine must be factored into every decision – from how drugs are developed and delivered to assessing their value, and to how they are brought to market as safely and efficiently as possible. ‘The new health’ presents unmistakable risks for biopharma, yet offers unmatched opportunities for those who can navigate those risks, usher in a new paradigm of drug development and put into operation a more innovative business model.

leading patient-centric services throughout continental Europe. A key centrepiece of this partnership is collecting regional outcomes data, applying proper analytics to it and furnishing customers with information that helps to create a strong economic argument for reimbursement.

Through an understanding of the European marketplace and the complexities of the various healthcare systems, combined with Healthcare at Home’s robust infrastructure and expertise, Quintiles will usher in a new model of pharmaceutical commercialisation in which patient-centric services and the collection and extrapolation of outcomes data will lead to better care for patients, and better returns for the industry.

Pharma is indeed in the midst of a massive paradigm shift, and a new way of bringing innovation to market must be found. A new commercialisation model is necessary, one that takes into account the needs of the new decision-makers and, most importantly, the new decision requirements needed to have a successful commercial product. By leveraging real-world data from real-world patients, pharma can better prepare itself to meet these requirements and seize the opportunities of ‘the new health’ successfully. n

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TECHNOLOGY

The technical

side of business

GlaxoSmithKline’s Bill Louv tells Natalie Brandweiner about technology’s role in ensuring successful business solutions, and the responsibility of ensuring the company’s success.

A

s CIO of GlaxoSmithKline, Bill Louv is the steward of more than €800 million of IT investments that are made every year by the company. Making sure that the multi-centre global pharma company receives a high level of ROI is Louv’s responsibility, for as he explains: “Technology underpins everything we do, whether it’s in discovery, development, manufacturing or any of the commercial organisations.”

Responsibility

The success of the company and its entire operations are dependent on some form of IT, with the department facing the huge task of leveraging technology to solve business problems. Louv notes that those on his team, working at the interface of the company’s various business operations and technology, do so with a passion in this very applied role. Knowing which new technologies to pursue and how to integrate these into the company’s processes is critical. Half of GSK’s investment is directed to a central enterprise shared service form of IT, with the other half becoming embedded in all of its different business areas, such as R&D, manufacturing and the vaccine group.

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“We don’t bring them all together into one prioritisation,” says Louv. “If you look at R&D, they take advantage of the core plumbing of IT, but they also have a significant amount of money for soft ware that is specific to R&D, and they’re prioritising that against other types of spend within R&D. They are prioritising it against in-licensing an early phase compound or conducting another clinical trial.”

Times are changing, and GSK is quick to note the online presence of its customers and prescribers; like the rest of the world, the number of those in the pharma industry transacting business online is increasing. Louv explains how 80 percent of patients look online for medical information, with an additional 80 percent of doctors stating the internet to now be an absolutely critical component to their practice of medicine. The effects of this on customer focus can only be a good thing.

“Customer focus sounds like an obvious and easy thing, but it’s not at all,” says Louv, “however the internet and other technology now means we have much more immediate and regular feedback from our customers. It’s a big challenge for many reasons, not least of which is that we’re a highly regulated industry. We had a very significant discussion with the Corporate Executive Team, which is the CEO’s management team, and the philosophy here is to fi rst of all fi gure out what serves the patient. Figure out what the right thing is to do for patients and for doctors and then try to do that within the regulations and legal

“Our company scientists have been using collaboration tools and collaborative databases for a decade, and using them effectively” restrictions. If we stay focused on what’s right for the patients and the doctors, we will be able to fi gure out some way to engage them where they want to be engaged, which is in the social media forums, as well as the internet and other electronic forums. For us to be silent in a world where customers are expecting to be able to interact in these ways is not beneficial.”

Tailored therapies Technology’s role is extending into all aspects of industry trends.

Louv explains its critical role in personalised medicine in the developing or discovering of genetic markers which involves large datasets; large not only in respect to the numbers of observations but also the number of dimensions in each observation. Technology aids the process in understanding which genes are on and off over time under different situations, crunching a vast amount of data.

“We have big investments in both hardware and soft ware that you need for storing all this data, moving it out of storage and into active memory to run mathematical algorithms against them. It’s a huge IT challenge to deal with those giant datasets, we’re always investing in that area and it’s a fast-moving part of IT. Th is problem is being solved as we speak, and a lot more can be done now with multiple terabytesized datasets,” he says.

However, implementing this information across the whole R&D process does not come without its challenges, certainly in the importance of maintaining good communication between researchers, external partners and collaborators. Louv notes the problem of data integration, having the data on any particular compound in a multitude of datasets, which often proves difficult for scientists attempting to pull all this data together.

Cloud computing Cloud computing is a form of computing in which scalable and virtualised resources are provided into an internet infrastructure. The creation of the ‘cloud’ typically incorporates infrastructure as a service (IaaS), platform as a service (PaaS) and software as a service (SaaS), as well as other technologies that need the internet to provide sufficient services for business applications. Professor Ramnath Chellappa who described it as, “A computing paradigm where the boundaries of computing will be determined by economic rationale rather than technical limits” was the first to use the term in academia.

“Th is is a core problem we’ve been wrestling with for years, and we’ll continue to wrestle with it for many more years. Th ings are better, but it will always be an interesting challenge. Some of the progress we’ve made, such as data warehousing, is done because the tools are better.

Another thing we are doing is to digitise data earlier; so for example, we have something called the Electronic Lab Notebook, and now all of our early discovery experiments are captured electronically rather than in the old paper notebooks. So if you capture the data earlier, it opens up all kinds of opportunities to share it among the scientists.

“Just like everybody else, we’re always looking for ways to leverage search engines, to crawl around the company and to fi nd things, but it’s something that we’ll continue to wrestle with. The other challenge, the collaboration piece, is different. Th is is an area where GSK R&D has always been a bit ahead of the competition. Our company scientists have been using collaboration tools and databases for a decade, and using them effectively.

“There are always new tools and interesting new things to try, and now since so much of R&D has been externalised – that is, so much of R&D is done through partnerships – this collaboration now goes on across the fi rewall as much as it does within the company, which creates additional challenges for an IT organisation.

“We have several projects that change the security philosophy in the company; if you’re inside the fi rewall, you are trusted, and if you’re outside the fi rewall, you are distrusted. Th at model doesn’t work anymore, so what you have to do is go back and your line of defence has to fall back to particular applications or even databases within applications. Whether you’re internal or external is no longer thought to be a good indicator of whether you can be trusted or not trusted,” explains Louv.

Added to this are the various platform issues caused by the different soft ware needed for research areas. He notes how the problem oft en

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“Technology underpins everything we do, whether it’s in discovery, development, manufacturing or any of the commercial organisations”

becomes a philosophical debate between using integrated platforms or best-of-breed systems. “There are some soft ware companies that offer integrated platforms that cover lots of different processes and activities, but you’re always going to be able to fi nd some niche provider who has a better system for some subset of those requirements.

“Some people have the philosophy that for each area you should fi nd the best and then cobble them together. Other people have the philosophy, ‘Hey, get an integrated suite, and eliminate all those interfaces, and just follow the 80/20 rule. It’s probably going be good enough, and it’ll be a lot simpler and a lot cheaper.’ We lean toward the latter: we buy integrated platforms and use the 80/20 rule. However, we are by no means doctrinaire about it. Some would say not disciplined, but I would say not doctrinaire. You have to take each case in isolation and you don’t want to get hung on your own philosophical statements.”

Future Technology as a constantly changing phenomenon is hard to predict, but Louv explains how he assesses the recent trends within what he describes as the turbulent pharma industry in order to move forward in the future, both as a department and a company. “IT is in a fascinating place in that we are a big cost, so there’s great interest in lowering our cost,” he says.

“At the same time, we’re a significant part of every solution that people come up with, whether it’s to decrease cost through automation, to drive a new commercial model or a new R&D paradigm, it always requires IT investment. We’re in this really challenging era now of whatever we do we have to keep doing, but at a lower cost to liberate money to invest in driving other parts of the company.

“There’s some trauma on the organisation because on average it’s a very exciting and dynamic environment. However it does, of course, mean a disadvantage or pain to people who work on a particular technology or who work in a particular part of the company where those projects are being starved whilst other parts we’re growing very fast, and that creates tension, but it’s exciting. It’s the way you have to do things in order to be successful, but it’s not always easy to manage.”

He attributes a portion of this to the economic situation; although unsure of the extent, Louv points to the change in attitude toward large capital projects becoming too tough. The technology sphere in general is preparing itself to welcome the arrival of the cloud computing phenomenon, and notes that there are ways to achieve this without a significant outlay of capital.

Cloud computing is set to change the way in which technology is used and the cost benefits that can be leveraged by those companies who use it. As Louv notes, its infi ltration into big pharma could be a slow process, but GSK is educated on technology’s importance and its responsibility in delivering successful business solutions.

“If you were analysing a startup company such as a biotech company, that’s not going to spend any capital on IT if they can help it, you will find them making use of the cloud much more than you’ll find in big pharma. We do make use of it: we’re moving our entire email, calendar and company intranet portal into the Microsoft data centres. So we’re not only moving to their soft ware, we’re adopting their online service and this is one that’s going to ring the bell all the way around better, faster and cheaper,” says Louv.

Bill Louv is CIO of GlaxoSmithKline.

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EXECUTIVE INTERVIEW

Optimising your laboratory assets GE Healthcare’s Matt Sawtell looks at the tools pharmaceutical companies can use to ensure they maximise their R&D dollars.

Pharma companies are striving to reduce costs without affecting quality, yet few have capitalised on the optimisation of their laboratory assets. Why is this the case?

Matt Sawtell. The pharma and biotech industries have for a long time focused on driving cost down and continuously improving manufacturing, through widespread adoption of Lean and IT initiatives. However, there has been minimal focus on adopting these bestin-class approaches in R&D, leaving pharma companies at the ‘early adopter’ stage when it comes to laboratory asset management.

On the vendor side, companies in this space have been slow to evolve away from the standard service delivery structure. The step change needed now is to adopt an outsourcer/ chief technology officer approach. Th is would enable pharma companies to realise the value of a combined technology, IT, Lean, process and business intelligence offering in the management of laboratory assets in R&D. Once this approach is adopted both the vendor and pharmaceutical company can form a true strategic partnership, ensuring each operational project makes an impact not only on hard cost savings and simplification of operating models, but also significantly improves the efficiency and productivity of scientists to focus on core activities.

What benefits does a complete laboratory asset management programme offer?

MS. The industry is being advised to streamline R&D groups to small focused teams with more emphasis on ensuring R&D dollars are spent on drug development rather than non-core activities. Pharma is looking to outsource more of these non-core activities and a complete lifecycle laboratory asset management service will enable them to take advantage of integrated services, technologies and tools, going way beyond an extended service contract.

Although R&D is project-based and therefore more difficult to process map than manufacturing, there are many opportunities for improvement. The key initially is to

gain visibility of every process and laboratory asset, including a complete understanding of where all assets are, how often they’re used and moved, and the workflows they’re used in.

At GE Healthcare, we have created an effective life sciences services solution, built around a change acceleration programme (CAP) enabling fast and effective change, combined with data-driven decision-making that provides a roadmap of when, how and where to drive that change. In addition, as these programmes cover the entire lifecycle of an asset, support is offered right through from purchase planning to disposition.

analysis, they have certainly not maximised the benefit these tools can bring. Going over and above this, GE Healthcare’s asset management service programmes offer resources such as analysis of workflow and waste, data analytics designed to measure service quality, and benchmarking data to ensure spend, service levels and other variants, which are best in practise.

Rather than supplying simple service level analysis, business intelligence gives insight into how assets are used, and an understanding of their value if unused, to support decisions around redeployment or disposal. In addition, insight into fi nancing options and advice on asset purchase enables companies to really maximise CAPEX. How do you see the area of laboratory asset management developing in the future?

MS. The current economic environment is

“The current economic environment is forcing pharmaceutical companies and their suppliers to think differently about how to drive performance and make their business model more agile” What tools can companies use to optimise the management of their laboratory assets?

MS. Although many pharma companies have already adopted measures on a low level, such as asset tracking, spend and asset utilisation

forcing pharmaceutical companies and their suppliers to think differently about how to drive performance and make their business model more agile. With M&A activity showing no signs of easing off, all companies are looking to redefi ne their business practices in order to address both present and anticipated future market challenges.

Laboratory asset management providers need a deeper and faster adoption of learnings from other industry sectors, such as the aircraft industry, through reliability centre maintenance, IT outsourcers’ service agnostic approach and industry partnerships to enable IP creation. Service organisations are morphing into ‘services’ solution providers, offering consultative tools, technologies and change processes to become a more integral part of the pharmaceutical operating model.

In this environment, strong organisations will thrive under the challenge of producing more aligned services and solutions. As Darwin once said, “It is not the strongest of the species that will survive, or the most intelligent. It is the most adaptable to change.”

Matt Sawtell is Director Of Global Operations, Scientific Asset Services – Life Sciences, GE Healthcare.

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EXECUTIVE INTERVIEW

Improving workflow Petter Mörée discusses the importance of process analytical technologies.

What challenges are pharmaceutical companies currently facing in terms of streamlining their manufacturing processes?

Petter Mörée. Based on Umetrics’ experience it is the interaction, or rather lack of interaction, between soft ware, hardware, measurement systems and infrastructure that is the major challenge in streamlining the manufacturing process. For existing processes there is a strong drive to integrate soft ware and measurement systems into hardware, such as granulators. Umetrics works with a number of suppliers to ensure that all available data from a process can be collected and used for multivariate process analytical technology (PAT) models. An additional challenge is that many processes consist of a series of unit operations that are often not one-to-one concerning size, therefore splitting and pooling of material is necessary.

What are the four levels of PAT, as defined

by Professor Svante Wold? Why do they require different multivariate tools?

PM. Level 0 – Design of Experiments (DoE) also referred to in ICH Q8. DoE is often used in the development of new processes and products and leads to an increase of information and decrease of experiments. With the design space concept there has been an increase in DoE activities and also a need for improvements in DoE soft ware so that the risk of failure can be accurately calculated and visualised.

Level one – Off-Line PAT is the use of analytical techniques that are faster than traditional wet chemistry. A common technique is NIR that requires multivariate calibration but many of the newer methods are also spectroscopy based and benefit from the use of MVA. Level two – At-Line PAT, could for instance be the use of raw material characterisation. If knowledge is gained for raw materials or intermediate products, operations can be adopted to compensate for these variations. At-line PAT means working very close to the process, usually by process operators, measurements

and soft ware need to be adopted to a process environment.

Level three – On-Line PAT, use of real-time tools for one or few unit operations with the ability to react to process variation in real time rather than react to variation in quality attributes.

Level four – Entire process PAT (super model).

Th is is the combination of all of the above levels where one focus is to enable the prediction of fi nal quality attributes using relevant data from the entire process.

For levels three and four, there is a need for very flexible soft ware that can handle both different types of data and large data amounts.

Online soft ware adds an additional level of complexity where multivariate technology is one part in a total infrastructure that has to function seamlessly.

purposes. These models open up the possibility for release of intermediates. Dependent on the process, saving can be quite substantial; one example is 40 percent yield improvement on a 30-year old process.

How do you see the use of PAT developing in the future in the pharmaceutical industry?

PM. Based on Umetrics’ work in non-regulated areas, we believe this will also increase in importance within pharmaceutical productions. PAT control strategies will be introduced where the process adjusts for variations in environment, equipment and materials to keep output constant and optimal, not keeping the process locked. In the same way as pharmaceutical industries have interacted with and learnt from other industries for batch processes, Umetrics predicts that this will happen for continuous processes. Most of

“For existing processes there is a strong drive to integrate software and measurement systems into hardware” In what specific ways could a pharmaceutical company use multivariate technology software to improve its workflow?

PM. The goal of the development projects has been to establish a design space that gives a reliable production and thereby avoid timeconsuming analytical measurements. The feedback, although somewhat limited, is that the strategy works but one still needs to establish the exact balance in how much should be handled by multivariate models from the process and how much by traditional analytical techniques.

For old processes, Umetrics has established multivariate models that can be used in real time (in- at- or online) for monitoring and prediction and, in some cases, control

the tools and the soft ware are already available for PAT within continuous processes and, in Umetrics’ view, the transition to continuous process will accelerate.

Measuring the entire particle size distribution and defi ning quality with the d50 is throwing away information. Quality described by PCA or related methods is slowly gaining acceptance. Umetrics has a customer that uses PCA plots to decide which batches to send to which customers. In our view this will become more common.

Petter Mörée is Director of Online Products for Umetrics.

Mörée has a technical background with an MSc in technical chemistry with a specialisation towards chemometrics. After his MSc he joined Umetrics in 1998 as an application specialist and has for the last nine years worked towards PAT and QbD with increased responsibilities.

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EXECUTIVE INTERVIEW

Streamlining regulatory submissions Ethan Smith explains how to automate submission document processes for strategic advantage.

Regulatory submissions are critical to every life sciences organisation. What does it mean to automate them?

Ethan Smith. Given the fact that submission documents contain the content upon which regulatory agencies make decisions, recommendations and ultimately grant approvals, they are in fact one of the most – if not the most – important sets of documentation for every life sciences organisation. While this point is widely accepted, the processes by which these documents are produced, reviewed and approved before submission are not always well understood or documented and often depend heavily on manual intervention and heroics to meet submission deadlines, despite the fact that these deadlines are typically known many months in advance.

Automating the planning, writing, scientific review, quality assurance, approval and issuing processes using business process management (BPM) soft ware entails web-enabling the work steps involved, capturing critical information about both the content and process logistics and then using this information as the basis for resource planning, performance metrics, and ultimately process improvement.

There are several key benefits gained from a BPM solution, including timely access to and incorporation of clinical data, shortened review cycles, improved global resource management and productivity, and significant transaction cost savings. And ultimately, BPM enforces adherence to submission deadlines, which in turn contributes to strategic advantage.

How does the automation of the submission document processes with BPM relate to content management solutions employed by life sciences companies?

ES. A common myth is that BPM and content management are competing disciplines – which is absolutely false. Content management is a competency and set of technologies that are complemented and extended through the utilisation of a BPM solution. With re-

spect to submission document processes, the content management solution remains the secure, validated repository for controlled documents and associated content. The business processes for creating and processing said content and documents is what BPM handles – essentially providing a process wrapper around the validated content management repository.

By extracting the business process from the physical content artifacts, the business processes become much more agile and controllable by the business, without the risks and costs associated with custom changes to validated enterprise content management applications. Once the business processes have been defi ned, the BPM application can access controlled documents by way of hyperlinks to ensure the version control features are not altered while also providing business users immediate access to the working documents associated to a specific process in a seamless fashion. Th is approach takes advantage of the strengths of both technologies to empower the business to better manage and control the business processes and activities while simplifying the maintenance and management of the validated content management system for IT.

pressures are forcing life sciences companies to look for ways to globalise their operations for sustainable operational cost reductions.

“A common myth is that BPM and content management are competing disciplines – which is absolutely false”

Automating submission document processes offers a unique way to take advantage of lower offshore resource costs while at the same time improving turnaround times for the submission documents. By virtue of the fact that the automated processes are accessible online, work items can be handled by any resource regardless of location with complete visibility to management. Not only does this allow companies to more effectively leverage offshore resources, but it also enables work items to ‘follow the sun’ and be worked on across Globalisation is a key tenet of time zones to maximise Ethan Smith sets the strategy for the life sciences regulatory enworking hours in a 24-hour Metastorm’s life sciences solutions globally. He has over 10 years vironment today and is likely period. These two advanof experience consulting to the to become more important tages make processes both industry and solving processrelated problems to create tangible over time. How does BPM supfaster and cheaper while at business value. port globalisation? the same time providing ES. With the many challenges management with clear the industry faces today, globalisation is visibility into where each document resides at one of the key opportunities for life sciences any point in time and giving them the ability companies in two major ways. With growing to reprioritise and reassign work with ease. disease incidence and increased access to care BPM makes all of this is possible while still in emerging markets, globalisation represents maintaining the content in the same validated a key growth segment. At the same, rising cost repository where it has always been.

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REGIONAL FOCUS 156

Heating up An emerging market, Brazil is receiving investments in the pharma industry, both at home and abroad.

B

razil is the fi ft h largest country globally by geographical area and occupies nearly half of South America, boasting a population of almost 200 million. Separated into states based on historical and conventional borders, as in the US, the states have autonomous administration but with much less independent power – criminal or civil laws can only be voted for by the federal bicameral Congress.

The southeast region is much richer than the rest in terms of total economic output. It is also the most densely populated region and incorporates the country’s two largest cities, Rio de Janeiro and São Paulo, which is one of the largest megalopolises in the world.

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Pharmaceutical market Recent economic reforms have given the country a new potential for international investment, and as a result, Brazil has been identified as an emerging market for the pharmaceutical industry.

The year 2008 saw government investment in R&D programs and mergers in the industry create a large pharma structure similar to that in the US. The market is performing strongly, which is encouraged by high GDP per capita, with the generics sector seeing the most growth. Many of the US top 10 companies are penetrating Brazil as a region to establish subsidiaries and set up manufacturing operations.

Nearly 20 percent of the companies operating in the Brazilian market are foreign investors, with major drug firms such as GSK, Roche

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and Novartis establishing operations there. AsraZeneca’s sales in Brazil grew at double that of the retail pharmaceutical market in 2008, providing the company with a market share of 3.3 percent.

The distribution sector is beginning to consolidate itself, with many of the major distribution companies announcing plans for expansion. However, many companies have found themselves facing increasing regulatory measures, which are starting to destabilise the economy. The National Medicines Agency has introduced a number of regulations that have resulted in costs to the industry, and certain practices such as third-party manufacturing are now becoming increasingly difficult to operate. The region operates the highest amount of taxes on medicines in the world – the Brazilian federal government collects over US$1 billion from the industry annually.

Despite these constraints, the market is generally becoming more sophisticated and has recovered its leadership in the region and is beginning to mirror other emerging markets, such as Russia and China, in regards to export and production opportunities.

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Pharma companies The Brazilian pharmaceutical market accelerated in 2008, registering an increase of 9.5 percent year-on-year.

Medley, a family-owned pharma company, is Brazil’s third largest pharma company and its number one generic company. In 2008 the company’s sales amounted to US$217 million, with generics accounting for two thirds of that. In April 2009, sanofi-aventis announced its plans to buy Medley in a deal that is likely to turn the major French drug firm into Latin America’s top generics manufacturer.

Grupo EMS Sigma Pharma was established more than 40 years ago and has become the leading pharma company in Brazil. The company has two industrial plants in São Bernardo do Campo and Hortolândia, in the state of São Paulo, and has committed itself to success via its focus on R&D. Grupo EMS was also the first company to export medicines out of the region and into Europe, as well as being the first to produce medicine products in fractioned packaging and generics.

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INTERNATIONAL EVENTS 158

A roundup of upcoming conferences and events across the globe.

Karachi

Munich

Future Directions in Pharmacy Education March 24, 2010 University of Reading Reading, UK www.beta.pharmacyplb.com/development /events-and-courses.asp

Seoul

Sixth Health Asia 2010 International Exhibition and Conference April 2 – 4, 2020 Karachi Expo Center Karachi, Pakistan www.health-asia.com/

ADMET Europe April 8 – 9, 2010 Holiday Inn, Munich City Centre Munich, Germany www.selectbiosciences.com/conferences/A DMET2010

Next Generation Pharmaceutical Summit Europe March 29 – 31, 2010

11th European Symposium on Controlled Drug Delivery April 7 – 9, 2010

Global Healthcare & Medical Tourism Conference 2010 April 13 – 16, 2010

Hotel CampoReal Golf Resort and Spa Oeste Region, Portugal www.ngpsummit.eu.com

Hotel Zuiderduin Egmond aan Zee, The Netherlands www.escdd.eu

Coex Intercontinental Seoul Seoul, South Korea www.asiamedicaltourismcongress.com/in dex.php

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London

Las Vegas

St. Petersberg

Next Generation Pharmaceutical Summit The Boulders Resort Scottsdale, Arizona April 26 – 28, 2010 www.ngpsummit.com

Strategies Against Counterfeit Medicines April 26 – 28, 2010 Maritim Hotel Wurzburg Wurzburg, Germany www.counterfeit-conference.org

Oeste

Armada Speciality Pharmacy Summit May 4 – 7, 2010 The Wynn Hotel Las Vegas, NV www.armadasummit.com

Russian Pharmaceutical Forum May 19 – 21, 2010 Corinthian Nevsky Palace St. Petersburg, Russia www.adamsmithconferences.com

RNAi & miRNA World Congress May 5 – 7, 2010,

APS - FIP Vaccines 2010 June 8 – 9, 2010

Boston Park Plaza Hotel and Towers Boston, MA www.selectbiosciences.com/conferences/R NAiWC2010

Royal Pharmaceutical Society of Great Britain London, UK www.apsgb.co.uk/Events/20100608/defau lt.asp

FINAL WORD

Closing the gap

By Vivian Hunt

T

he pharmaceutical industry is navigating a major change in industry structure and behaviour. We are passing through a time of changing patient and customer expectations – they have a shared urgent need for quality medicines and technologies that deliver both innovation and broader access. It is now critical to fi nd a way to deliver on all of these objectives.

The following series of articles will address four inflection points where we believe a radically different approach will support the European pharmaceuticals industry to better deliver innovation, access and quality. In each case we feature proprietary research and will profi le the characteristics of successful models.

The first topic, Tackling the issue of failing research productivity, is abstracted below and directly addresses the drivers and potential responses to falling research productivity.

Future issues will address three further topics: Transforming clinical insight and development, Building relationships: paths to true clinician and customer loyalty and, finally, If not now, then when?, a challenging look at market access and the opportunity for managers to better meet patient and customer needs.

Tackling the issue of failing research productivity McKinsey has set out to understand what drives research productivity from the bottom up: from the lab itself. We conducted proprietary research with world class serial innovators from academia and industry, and identified how the world’s most productive labs innovate.

We were able to construct a fingerprint for these top labs, which can be used to diagnose any lab focused on practical research.

The core elements of the fingerprint of top labs We identified a common set of activities and behaviours adopted by the leading research labs.

Strategic choices: Top labs have a clear long-term strategy, which directs critical decisions. Th is is well understood across the lab and guides day-to-day prioritisation. Labs fall short by failing to articulate what they will be known for, or failing to communicate their strategy to the broader team.

Talent management: Top labs look to build a diverse talent pool, invest in continuous development, and do not tolerate underperformance. Often, average labs recruit from a small number of sources, and refuse to hold researchers accountable for performance levels.

Differences between labs It is important to recognise that one size does not fit all. In our research we did not identify any labs displaying all of the best practice activities of a top lab. However, the research did identify many similarities in the approaches of labs conducting quite different types of research.

We appreciate that there are intrinsic differences between certain types of labs. In particular, academia and industry labs have fundamentally different requirements for the research they conduct over how they build teams and how they organise themselves.

These differences were consistently observed

“This research has identified the common approaches the world’s top labs take to make their research activities productive” Portfolio and project management: Top labs keep close managerial control of their projects, and aim to create synergies across the portfolio. Problems can occur when projects are not regularly reviewed, or if they continue for some time after a termination decision.

throughout our assessments. However, the underlying principles that our research has uncovered can be applied broadly across many sectors where innovation is driven by laboratory-based research.

How to use these insights Problem solving approach: Top labs own a few scientific problems, and are hypothesisled throughout. They actively encourage innovative side projects and allow teams significant autonomy – elements that are missing from many average labs.

This research has identified the common approaches the world’s top labs take to make their research activities productive, from the lab level up. We believe our findings can act as the basis for a comparative assessment of research labs in academia and industry, particularly those focused on biomedical research.

Collaboration: Top labs develop a strong sharing culture, encourage joint problem solving and collaborate with external labs extensively. Average labs offer only limited external collaborations, and do not provide the optimal physical environment to encourage sharing of ideas.

Vivian Hunt is a Director in McKinsey’s Global Pharmaceuticals and Medical Products Practice.

Colleagues Mubasher Sheikh, Michael Edwards and Mark Beards (London Office) lead McKinsey’s global SuccessLab project.

We hope you find this series of articles both challenging and helpful as you navigate the road ahead. For further information, please see our full article at www.ngpharma.eu.com/article/Tackling-the-issue-offailing-research-productivity/ or contact successlab@ mckinsey.com

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