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www.ngpharma.com • Q4 2009

Growth strategy

A personal touch

How Nycomed became one of the big players

Why EMD Serono thrives on community spirit

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Discovery’s golden age

Bull’s-eye

Martin Mackay sees an end to chronic disease

William Chin sizes up therapeutic targets

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MEASURING UP Can individually tailored therapies stop the pharmaceutical industry from unraveling? Page 32

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EDITOR’S NOTE 5

Sizing up the future What role will individually tailored therapies play in the pharmaceutical industry’s new business models?

I

t’s common knowledge that the pharmaceutical industry is in the throes of change. The blockbuster model it has relied upon for decades is no longer viable, but what will take its place? Finding a niche area, perhaps, or going after orphan drugs, or moving into emerging markets.

Or taking the plunge into the rapidly developing field of pharmacogenomics – so-called personalized medicine. Since the Human Genome Project was completed in 2000, excitement has been growing around the idea that someday doctors will be able to design individual treatments based on a specific patient’s genetic make-up.

No more adverse, toxic or even fatal reactions resulting from the lack of – or too much of – a particular enzyme in the patient’s body.

Dosing will be exact, and efficacy will be spectacularly improved.

The key word in this description, of course,

“Genetics is absolutely important to help us understand which are the best targets for drug discovery” William Chin, VP of Discovery Research and Clinical Investigation, Eli Lilly (Page 44)

is ‘someday’. The completion of the Human Genome Project 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. Only a handful of tests are currently available.

There are signs, though, that pharmacogenomics is already being taken seriously within the industry, 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 it as part of, if not the core of, their corporate strategies.

The regulators, in their turn, have begun to require biomarker testing to guide how drugs are prescribed. Two examples of this are testing for infection by a specific HIV subtype that is required prior to the use of Selzentry, and testing

“We have to think through how in a real emergency one could make an H1N1 vaccine available in two months” Andrin Oswald CEO, Novartis Vaccines (Page 68)

for epidermal growth factor receptor expression prior to the use of Erbitux. As biomarker testing often increases efficacy, in addition to reducing adverse events, this practice is likely to become more common.

Even if it can’t solve all of our problems now, science will continue to move forward no matter what the pharmaceutical industry does.

Personalization is a mega trend in many sectors, including healthcare, automotive, transportation, environment and building technologies, and there is no sign that this is about to change. Smart pharma companies will harness this trend, and use it to fashion their own, custom-fitted future. n

Marie Shields Editor

“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” Martin Mackay, President of Global Research and Development, Pfizer (Page 92)

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36 The small company that grew When Håkan Björklund became CEO of Nycomed in 1999, the company was a small, regionally focused operation. Now it ranks among the top 30 in the world

Made to measure As the pharmaceutical industry weighs up its options for the future, how will personalized medicine measure up?

44

84 Up close and personal Reinventing big pharma’s corporate image has been pivotal to EMD Serono’s approach

A bright outlook Lilly’s William Chin on personalized medicine, partnerships and using the company’s PD2 initiative to generate new compounds

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Economies of scales

Medical foods

EXECUTIVE INTERVIEW 52 Eran Gabbai and Ayelet Dilion Mashiah, Do-Coop Technologies Ltd. 62 Scott Clark, Gentris Clinical Genetics, Inc.

64 Klaus Weinberger, Biocrates

80 John Richmond, Bruker Optics Inc. 106 Mary Jo Wojtusik, Waters Corporation 108 René Schwarz, Rockwell Automation 124 David Medina, HP 126 Trevor Heritage, Symyx Technologies, Inc. 134 Richard Malcolm, Acurian, Inc. 138 John Moran, IMS Health

ASK THE EXPERT 71 Peer Staehler, febit holding GmbH 72 Peter Duncan, Definiens AG 82 Ralph McDade, Rules-Based Medicine 91 Dipti Amin, Quintiles 114 Robert Becker, Eurand 132 Ethan Smith, Metastorm

54 INDUSTRY INSIGHT 42 Dave Champagne, Thermo Fisher Scientific 66 Barb Paldus, Finesse Solutions, LLC 96 Steve Cottrell, inVentiv Clinical Solutions 98 Magdalena Tary-Lehmann, Cellular Technology Limited 116 Alfred Sherk, SherTrack 122 Jean Bédard, Alternatives Technologie Pharma 137 Ray Kane, Aerotek Scientific

PROJECT FOCUS 74 Nigel Goode, Aptuit

48 On the up How Jan Lundberg’s R&D efforts are beating the financial downturn

54 Medical foods Richard Isaacson’s overview of an emerging science

68 Gearing up for battle Andrin Oswald and Novartis Vaccines are preparing for the next wave of H1N1

77 Beating cancer Haren Rupani explains the importance of imaging in combating this deathly disease

88 Economies of scales How Pronova’s use of omega-3 has transformed an age-old remedy into a potential blockbuster

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CONTENTS 12 92 Golden age of discovery Pfizer’s Martin Mackay on the merger with Wyeth and why the end of chronic diseases is in sight

IN THE BACK

140 Regional focus:Brazil 142 Events 144 Photo finish Photo finish

100 Faking it Travis Johnson looks at the global problem of counterfeit pharmaceuticals

110 Adapt or perish What the pharmaceutical industry must do to survive

119 Thinking outside the box

ROUNDTABLE DISCUSSION

GSK’s Keith Allen looks at innovative processes in the manufacturing line

59 With Mark Roskey of Caliper Life Sciences and Staf C. Van Cauter of Bioscan Inc.

128 The technical side of business GlaxoSmithKline’s Bill Louv on technology’s role in ensuring successful business solutions Regional focus: Brazil Golden age of discovery

Faking it

92

110

Adapt or perish

100

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GENETIC CULPRIT IN SKIN CANCER Drawing on the power of DNA sequencing, National Institutes of Health researchers have identified a new group of genetic mutations involved in the deadliest form of skin cancer, melanoma. The researchers say the discovery is particularly encouraging because some of the mutations, which were found in nearly one-fifth of melanoma cases, reside in a gene already targeted by a drug approved for certain types of breast cancer.

In the United States and many other nations, melanoma is becoming increasingly more common. A major cause of melanoma is thought to be sun exposure; the ultraviolet radiation in sunlight can damage DNA and lead to cancer-causing genetic changes within skin cells.

In work published in the September issue of Nature Genetics, a team led by Yardena Samuels of the National Human Genome Research Institute (NHGRI) sequenced the protein tyrosine kinase

(PTK) gene family in tumor and had been known about the roles blood samples from people with played by PTK genes in human metastatic melanoma. The sammelanoma. The NIH study was ples were collected by among the first to use the study’s coauthor large-scale DNA seA Steven Rosenberg, a quencing to systemmajor cause of leading expert on atically analyze all melanoma and 86 members of the is thought to be sun chief of surgery at PTK gene family in exposure the National Cancer melanoma samples.

Institute (NCI).

The team’s initial surThe PTK family invey, which involved samples cludes many genes that, when mufrom 29 melanoma patients, identitated, promote various types of fied mutations in functionally imporcancer. However, relatively little tant regions of 19 PTK genes, only

melanoma

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UPFRONT

THE BRIEF

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three of which had been previously imGenetics Branch of the NHGRI’s plicated in melanoma. The researchers Division of Intramural Research. then conducted more detailed analyses “Though additional work is needed of those 19 genes in samples from a to gain a more complete understandtotal of 79 melanoma patients. ing of these genetic mutations and One of the newly implicated their roles in cancer biology, our findgenes stood out from the rest. ings open the door to pursuing speResearchers detected mutations in the cific therapies that may prove useful ERBB4 gene (also known as HER4) in for the treatment of melanoma with 19 percent of patients’ tumors, makERBB4 mutations.” ing it by far the most frequently muIn addition to ERBB4, the retated PTK gene in melanoma. In searchers identified two additional addition, researchers found that PTK genes, FLT1 and PTK2B, with many ERBB4 mutations were located a relatively high rate of mutations in functionally important areas simiin melanoma. Each of these genes lar to those seen in other PTK oncowas mutated in about 10 percent of genes involved in lung cancer, brain the tumor samples studied. cancer and gastric cancer.

NHGRI Scientific Director Next, the researchers Eric Green pointed out moved on to laboratory that such research is Researchers studies of melanoma helping to lay the conducted detailed analyses of cells with ERBB4 mugroundwork for the tations. They found era of personalized that these melanoma medicine. “We enfrom 79 melanoma cells were dependent on vision a day when patients the presence of mutant each cancer patient will ERBB4 for their growth. The have therapies tailored to the melanoma cells also grew much more specific genetic profile of his or her slowly when they were exposed to a tumor. Ultimately, this should lead chemotherapeutic drug known to to more effective and less toxic apinhibit ERBB4. The drug, called laproaches to cancer care,” says Green, patinib (Tykerb), was approved by who directs the NIH Intramural the Food and Drug Administration Sequencing Center, which generatin 2007 for combination use in ed the DNA sequence data for the breast cancer patients already taking melanoma study. the drug capecitabine (Xeloda).

In addition to NIH scientists, the Encouraged by their study results, the team included a researcher from the researchers are planning a clinical trial Johns Hopkins Kimmel Cancer using lapatinib in patients with Center in Baltimore. metastatic melanoma harboring In May 2009, Dr. Samuels’ ERBB4 mutations. The clinical trial group reported in Nature Genetics will be conducted under Rosenberg’s another large-scale DNA sequencdirection at the NIH Clinical Center. ing study of a different group of “This collaborative study represents genes involved in melanoma, the an ideal example of how sophisticatmatrix metalloproteinase (MMP) ed genetic analyses can be translated gene family. This earlier study to the benefit of cancer patients,” found that one gene, MMP-8, says Rosenberg. thought to spur cancerous growth “We have found what appears to actually served to inhibit it. Those be an Achilles’ heel of a sizable share of findings are now helping to shape melanomas,” comments Samuels, melanoma treatment strategies who is an investigator in the Cancer aimed at MMP genes.

NEWS IN PICTURES

A health worker gives a polio vaccination to a child in the Pakistani town of Chaman, as part of the government’s vaccination drive to eradicate the virus

19 genes

Workers at Sinovac Biotech package tens of thousands of doses of H1N1 vaccine in Beijing, China

Nepal’s Prime Minister Madhav Kumar lights a traditional lamp during the opening ceremony of the 27th Meeting of Ministers of Health of South-East Asia

President Obama at a roundtable discussion with healthcare providers, during a visit to the Children’s National Medical Center in Washington

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UPFRONT PROFILE

18 SEVERIN SCHWAN, CEO, ROCHE GROUP Roche’s Severin Schwan began his career as a trainee in its corporate finance division in the early 1990s. His rise to the top rank of the world’s most profitable drug maker has been a fast and relatively fluid climb. Only 42 years old, he is regarded as one of the most successful young businessmen of both the pharma industry and within business as a whole.

His rise to power came as a surprise to many, following his appointment as CEO in 2007.

With a degree in economics and a doctorate in law, Schwan does not have a scientific background. Despite this, he beat Erich Hunziker and William Burns, Roche’s CFO and Head of Pharmaceuticals respectively, to the position.

At the time of his appointment his responsibilities for running diagnostics accounted for only a quarter of group sales.

Schwan’s leadership focus has been on teamwork, whilst also implementing a decentralized structure. With each separate company focusing on specific areas, his success has contributed to that of the corporate structure as he aims to bridge the gaps between new drugs and their counterparts in diagnostics.

Innovation has always been a focus for Schwan, whether he is leading the diagnostics division or within his role as CEO. In his previous role as CEO of Roche Diagnostics, innovation received huge emphasis – Schwan’s policy was that innovation should not be limited to research and development. He believes that to be successful, companies must define new approaches to bringing products to patients.

In July, Roche released an optimistic forecast for the next two years, on the back of its $47 billion acquisition of Genentech, and also said it would provide greater capacity for its H1N1 flu drug Tamiflu. Sales of the drug rose more than 200 per cent in the first half of 2009 to just over one billion Swiss francs ($945 million) and Schwan said the company would be able to meet all orders. He has also said he is expecting cost synergies from the Genentech acquisition.

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MUSCLE LOSS REVERSE

HELP FOR COPD

(FDA). The phase III placebo-controlled trials of roflumilast evaluated the treatment in two 12Nycomed and Forest Laboratories have anmonth and two six-month studies, involving nounced that results of four phase III trials 4500 patients in 10 countries. Details of the results have been published in the prestigious peerof the four studies were published in The Lancet reviewed medical journal The Lancet in August. showing that roflumilast, a The two 12-month studies The studies phosphodiesterase 4 (PDE4) demonstrated that roflumilast showed a reduction inhibitor, improved lung produced a statistically sigin moderate to severe function and reduced exacnificant and clinically releexacerbations by erbations in patients with vant reduction in moderate to severe COPD. exacerbations (lung attacks per patient COPD is an under-diagthat need treatment with sysper year nosed progressive lung disease temic steroids or lead to hospithat may lead to death. Worldwide, talization), even for patients who COPD kills four people every minute and the were also taking long-acting bronchodilators.

World Health Organization (WHO) predicts The studies showed a reduction in moderate that it will be the third leading cause of death to severe exacerbations by 17 percent per paby 2030. The WHO estimates that 80 million tient per year (rate of 1.14 events per year with people have moderate to severe COPD. roflumilast vs. 1.37 per year with placebo, Roflumilast, a once-a-day oral p<0.001). The reduction in extablet, would be the first in an acerbations was irrespecentirely new class of treattive of concomitant ment for COPD if it retreatment with ceives regulatory long-acting betaapproval from the 2 agonists, a authorities in standard Europe (EMEA) bronchodilaand the US tor therapy.

17%

US researchers have published a study in Diabetologia to show how insulin may help turn back the clock on elderly muscle loss.

Providing insulin intravenously and increasing the blood insulin levels to the same amount produced after a meal stimulates protein synthesis and muscle growth in young people, but not in older people. However, giving seniors double the insulin they would normally produce after eating stimulated muscles as it does in young people.

The researchers worked with 14 elderly volunteers to examine the response of thigh muscle to the two different blood insulin levels infused into the thigh’s main artery. Catheters inserted in the femoral artery and vein of each subject allowed calculation of blood flow and muscle protein synthesis. Muscle protein was also gauged using muscle biopsies.

FAST FACT About 1 in every 8 Americans is aged 65 or older –

12.4% of the US population

TRACKING PNEUMONIA A recent World Health Organization study of two strains of pneumonia is providing African governments with their first ever country-by-country figures on the leading global killer of children under the age of five.

The results, which appeared in the September 12 edition of The Lancet, track the rates of pneumococcal (streptococcus pneumonia) and Hib (haemophilus influenza type

b) strains of the infection. They cite four countries – Nigeria, Ethiopia, the Democratic Republic of Congo and Kenya – as having the highest rates of the pneumococcal infection in Africa.

The worldwide figures are expected to help health ministries in more than 72 African and Asian countries expand supplies of highly effective vaccines, reduce costs to about 15 cents per dose, and encourage the introduction of nationwide inoculation campaigns.

Source: www.voanews.com

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Rx IMPORTS PLEDGE

AIDS BATTLE Experts in the battle against we currently face is accurately focusHIV/AIDS and other infectious dis- ing and quantifying what (medieases have met in Pretoria, South cines) a country requires. And the Africa, to discuss ways to more effec- main reason for that is we do not tively deliver anti-retroviral (ARV) have enough information. Even if we medicine. Many believe imhad, that information is not reproving ARV delivery liable,” she said. systems would also Chidzanira says Developing help victims of governments need better systems to fight other infectious to establish relidiseases. able systems to Organizers determine who would also help the struggle against other needs anti-retrovinoted similar diseases challenges face those ral medicine. “Once trying to help victims of you know where the tuberculosis, malaria and other (sick) people are you quantify infectious diseases. They suggested and see how much they require. that developing better systems to And then they (governments) have fight AIDS would also help the to work with an organization with struggle against other diseases. expertise in distribution and logisProject manager Estinah tics. Then they will be able to send Chidzanira of ARV Access for the items to the places where they Africa, which stockpiles and deliv- are required,” she said. ers medicine to African govern- Source: www.voanews.com ments experiencing unexpected shortages, said such shortfalls often occur because of lack of information. “The major problem that

AIDS

Senator Harry Reid, the US imports of Food and Drug Senate Majority Leader, has Administration-approved prepledged that the Senate will look scription drugs; and would allow at plans that would allow US-licensed pharmacies and Americans to re-import US- wholesalers to import these medapproved prescription drugs, icines from locations as varied as whether or not they come up the EU, Japan, Canada, New in the healthcare reZealand and Australia. form debate.

The letter The The guarcomes despite an Senate will look antee, which earlier call in at plans to allow was confirmed June which saw Americans to in a letter sent Senator Reid asto three leading suring the bill’s drugs sponsors of the sponsors that the proposed legislaSenate would vote on tion, confirms that the legislation before movmoves to reassess plans will come ing forward with the massive before year-end. healthcare reform debate currentThe proposed legislation, ly clogging up the Senate. Now sponsored by Republicans John though, it seems there is not time McCain and Olympia Snowe and for this to take place, forcing Reid Democrat Byron Dorgan, would to make further promises to the lift the current ban on re- bill’s sponsors.

re-import

FAST FACT

The CDC estimates that

468,578 people are living with AIDS in the US, 75% of whom are men

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VOTE TO SAVE PHARMA DEAL A proposal to abandon the $80 billion cost-saving deal agreed in June between drug makers and the US Senate Finance Committee’s chairman, Senator Max Baucus, has been rejected by the panel.

According to reports, the amendment to the Finance panel’s health reform bill, which was put forward by Democrat Bill Nelson, was rejected in a 10-13 vote. The amendment would not only have nullified the deal but also would have required the industry to stump up a further $86 billion in cost savings over the next decade.

Under the deal made between Senator Baucus and the Pharmaceutical Research and Manufacturers of America (PhRMA), which Senator Nelson’s proposal sought to overturn, drug makers have agreed to pay 50 percent of the costs of pre-

scription drugs for Medicare patients once they reach the “doughnut hole” coverage gap in the federal programme’s prescription drug benefit.

Officially known as Part D, the coverage gap kicks in when their annual drugs bill reaches $2700 and ends once it hits $6154 – at this point the federal government starts to pay again, covering 95 percent of the enrollee’s drug costs.

Senator Nelson’s proposal, meanwhile, wanted the doughnut hole to be closed altogether on a gradual basis. It would have required drugmakers to supply prescription medications to care beneficiaries at the same prices they charge for enrolees in Medicaid.

FROM THE VAULT In the Q1 2009 issue of NGP, MIKE COLA, President of Specialty Pharmaceuticals at Shire, examined the importance of being different in the dark days of the economic recession, and outlined his role in the business model’s essential component of product focus.

Go to www.ngpharma.com; click on ‘Previous issues’ on the left, then on ‘Issue 15 February 2009’ to read of Cola’s focus on symptomatic conditions.

MRSA TREATMENT Telavancin injections, used for inhibit bacterial cell wall synthesis treating MRSA skin infections, have by interfering with the polymerbeen approved by the US Food and ization and cross-linking of peptidoglycan; telavancin also Drug Administration. The binds to the bacterial injections will be promembrane, disvided as a oncerupting its barridaily treatment, The injections er function. only for adults will be provided as a The recomsuffering from mended dose of complicated treatment for telavancin is 10 skin and skin adults mg/kg administered structure infections by intravenous infusion (cSSSI) caused by susonce every 24 hours for seven ceptible Gram-positive bacteria.

The injectable lipoglycopep- to 14 days. An infusion period of at tide antibiotic is a synthetic deriv- least 60 minutes is recommended ative of vancomycin, the current to reduce the risk for infusion reacstandard of care for cSSSI. tions, often referred to as ‘red Telavancin and vancomycin both man syndrome’.

once-daily

VACCINE READY Health and Human Services Secretary Kathleen Sebelius has told Congress that the nation has taken adequate measures to protect Americans against wider outbreaks of the H1N1 flu strain.

Sebelius also announced the availability by October of initial doses of a new flu vaccine.

Secretary Sebelius says the government will ensure that enough vaccine is available to everyone who wants it as the regular flu season gets underway.

“There will be enough vaccine,” she said. “What we are concerned about is getting it to the priority populations as quickly as

possible and that is what we have asked the states to focus on – how to get pregnant women, children under the age of 24, caregivers of infants, healthcare workers – how to make sure that those folks get to the front of the line if you will.”

As part of its planning for the upcoming flu season, the government ordered 195 million doses of vaccine to be distributed across the country, although individual states make decisions on distribution, including steps to get it to the most vulnerable populations as quickly as possible.

Source: www.voanews.com

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UPFRONT INTERNATIONAL NEWS

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CANCER HOPE A team of Italian researchers, led by Dr Stefania Gonfloni from the University of Rome, has sourced a biological mechanism that explains why cancer treatments can trigger a premature menopause. More astonishingly, the scientists discovered a drug that can block this process. Cisplatin, a compound often found in chemotherapy drugs, was injected into a group of female mice, whilst imatinib, a drug usually given to leukemia patients, was combined with cisplatin and injected into another. The study showed that the mice given the combined treatment remained fertile significantly longer and delivered around twice as many pups as the group who were injected solely with cisplatin.

The scientists have requested that the research, although still in its early stages, be implemented in humans, although there still remain a number of obstacles before this can occur.

COLLABORATION Via its subsidiary Ortho-McNeilJanssen Pharmaceuticals, Inc., Johnson & Johnson has entered into an agreement with Dutch vaccine maker Crucell for the discovery, development and commercialization of monoclonal antibodies, as well as vaccines for the treatment and prevention of influenza and non-infectious diseases. The longterm partnership will focus on new discovery programs for a universal influenza vaccine as well as the development of monoclonal antibodies and/or vaccines directed against up to three other infectious and non-infectious disease targets.

Johnson & Johnson has also purchased 14.6 shares of Crucell, representing approximately 18 percent of Crucell’s ordinary shares, costing them $440.8 million.

CHINESE ONCOLOGY According to a report from Decision Resources Waltham, it is expected that the breast cancer drug market in China will grow from $165 million in 2008 to $298 million in 2013. It is thought that the growth will be the result of an increasing number of incident causes, greater access to medical care, growing individual wealth and an expansion in the use of novel therapies.

The region’s aging population is thought to be a major contributor – there has been an increase of 70 percent in older people between 2008 and 2018. It is also believed that the population’s adoption of a more Westernized lifestyle will contribute to the increasing risk.

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UPFRONT

INTERNATIONAL NEWS

GENERICS LAUNCHED SOHM, Inc, a generic pharmaceutical manufacturer that produces and markets generic drugs has announced the launch of 26 branded generic pharmaceutical products in India. The company has appointed two distributors in Northern India and has included two powerful and highly consumed antibiotics for respiratory diseases.

The product launch also includes anticolds, anti-asthmatics and cough suppressant products, which will be manufactured by the company’s facilities in India with immediate market response and penetration expected. In addition to the two distributors in Northern India, SOHM is in negotiations with two more distributors to introduce the company’s generic drugs to the eastern part of India.

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JOB CUTS Israeli drug maker Teva Pharmaceutical has announced it will be closing one of its Czech factories by the end of the year, cutting around 400 jobs as a result. The company, which currently employs 1700 within the region, has advised that part of the lost jobs would be mitigated by a $58 million investment next year that will boost production at its main plant and create 300 new positions.

Unemployment in the central European country stands at 10.5 million, and has seen a rise of 8.5 percent in August. Teva Pharmaceutical has advised that it will be relocating up to 315 jobs from Ireland to cheaper sites in Eastern Europe or Israel.

HIV VACCINES Trials of sanofi pasteur’s ALVAC vaccine and AIDSVAX, a vaccine developed by VaxGen, have gained huge media coverage and much hope. The six-year trial, now in phase III, has involved more than 16,000 adult volunteers in Thailand and has shown signs of effectiveness in preventing HIV. The combination of the two treatments is reported to have lowered the rate of HIV infection by 31.2 percent, when compared with placebo.

In the analysis, 74 placebo recipients became infected with HIV compared to 51 in the vaccine regimen arm, a statistically significant result. The combo had no effect on the amount of virus in the blood of volunteers who became HIV-infected during the study, more details from which will be presented at the AIDS Vaccine Conference (October 19-22) in Paris.

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UPFRONT COMPANY NEWS

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PROTEIN BIOMARKER AND TARGET VALIDATION SERVICES

The pharmaceutical industry is looking toward biomarkers and enhanced target validation as key solutions to the drug development problem. The role of biomarkers spans all aspects of drug discovery and development. It has been recognized that integration of biomarkers through the different phases of drug development can yield safer drugs with enhanced therapeutic efficacy in a cost-effective manner. Biomarkers also provide the critical link in translational medicine (bench to bedside) and are essential for the realization of personalized medicine. The ability to discover putative protein biomarkers increases every year with improved discovery platforms in multiple disciplines.

However, because commercially available assays for protein biomarkers will not support all of these objectives, there is a bottleneck in biomarker development. That is the ability to develop assays in an acceptable timeframe in order to begin to validate putative biomarkers to moving viable candidates forward.

NextGen Sciences’ platform has a solution that greatly 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. This knowledge accelerates the development of robust, accurate and precise multiplexed assays suitable during all phases of clinical development.

NextGen Sciences’ high quality, comprehensive protein profiling services, which include the identification and characterization of clinically relevant proteins, facilitate better pharmaceutical target selection and validation with the aim of reducing compound attrition rates. The technical know-how and experience allows rapid insight to target validation studies and the delineation of off target effects.

NextGen Sciences’ biomarker and target validation services offer a way to improve drug development for all therapeutic areas.

DRUG MANAGEMENT WARNING A new report from the American College of Physicians suggests there is strong backing from US doctors for newly approved prescription drugs to be labeled with a symbol indicating they are new.

The report also stressed there was a call for direct-toconsumer (DTC) advertising for new drugs to be limited for the first two years after approval.

These recommendations make up part of six proposals being put forward by the College to the Food and Drug Administration (FDA) in an effort to help improve the ability of the approval and monitoring of new drugs.

The moves come following a barrage of reports that reveal the FDA as being grossly under-funded, highlighting how a limited regulatory authority and insufficient organizational structure has been ineffective in regulating the safety and effectiveness of new and approved drugs.

In its defence, the FDA did take measures to make improvements following the Institute of Medicine (IoM) report in 2005 that its ability to approve and monitor drug safety had been compromised by, among other issues, a lack of regulatory authority; but according to the ACP, problems remain.

TOP 10

Biggest pharmaceutical companies by sales, September 2009

1 2 3 4 5

6

7 8 9 10

Pfizer

GlaxoSmithKline

sanofi-aventis

Novartis

AstraZeneca

Johnson & Johnson

Merck

Roche

Eli Lilly

Wyeth

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WORLD PERFORMANCE

SHRINKING WORKFORCES

Pharmaceutical companies around the world currently have different levels of success in each country. In America, the market is forecast to suffer a decline in 2009, while the top five European firms are only expected to see a two or three percent increase, with Japan seeing a growth of just four or five percent, according to IMS Health, the global drug sales tracking agency. More than 53,000 jobs have been eliminated in 2009 globally by MNC drug companies, almost double that in 2008.

But despite global multinational drug makers slashing their workforces to reduce their costs, their Indian counterparts are on a hiring spree. The top 10 domestic drug companies recruited 200-250 professionals annually over recent years. The number has now gone up almost five times.

GlaxoSmithKline, the largest multinational player in India, added 300 people in 2009 to enlarge its sales team to 2100 people. Sources said other MNCs such as Pfizer, Astra Zeneca and MSD Pharma were also recruiting sales people in large numbers to boost business in Indian shores.

Eli Lilly & Co. is planning to cut 5500 jobs over the next two years as the firm seeks to cut costs and bring new drugs to market more quickly as its bestsellers go off-patent.

The move will see the Indianapolis-based firm reducing its workforce by as much as 14 percent – to 35,000 – by the end of 2011. However, that total excludes hiring in high-growth emerging markets and in Japan.

Eli Lilly is not alone. In fact, the nation’s pharmaceutical indus-

FAST FACT

In August, the number of unemployed people in the US increased to

14.9 million

try announced more than twice as many job cuts through August of this year as it did during the same period in 2008, at least according to a study from outplacement firm Challenger,

Gray and Christmas.

According to the study, the number of cuts in 2009 now totals 53,000 jobs, which is significantly more than the 24,880 that were cut last year.

The news from Eli Lilly sees the firm hoping to cut annual costs by $1 billion per year as the firm plans to restructure itself into five new units: cancer, diabetes, established markets, emerging markets, and Elanco, its animal health business.

Eli Lilly CEO John Lechleiter

EXPANDED CANCER IMAGING CAPABILITIES Imagine having the ability to monitor cellular events such as tumor progression and metastasis in live mice. Thanks to a newly installed image monitoring system at The Jackson Laboratory–West in Sacramento, California, that concept is now a reality. The JAX In Vivo Services group has recently added an IVIS Lumina Imaging System to its suite of high throughput phenotyping test platforms.

The group delivers target validation and efficacy testing in mouse models of human disease. The addition of the imaging system can monitor cellular activity through bioluminescent or fluorescent reporters in live mice. The system is physically calibrated and measures absolute light emitted from an animal; thus results obtained from different mice, experiments or labs over the course of time can be meaningfully compared.

By leveraging its cancer research experience and its extensive collection of immunodeficient mouse strains, the Laboratory has developed orthotopic transplant models of human cancer that incorporate the new imaging system.

These models allow longitudinal evaluation of tumor development before, during and after treat-

ment, as well as the detection of small tumor and micrometastases, offering an excellent preclinical strategy to assess tumor response and recurrence.

JAX In Vivo Services are very customizable. Clientprovided cancer cell lines can be imported and used to develop new orthotopic models. Standard protocols can be used, routine procedures can be modified to match clients’ requirements, and/or protocols can be transferred from the literature.

For more information, visit www.jax.org/jaxservices/invivo or contact JAX Services at jaxservices@jax.org, 1-800-422-6423 or 1-207-288-5845.

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SEPRACOR ACQUISITION Japanese pharmaceutical company Dainippon Sumitomo Pharma has announced plans to acquire US-based Sepracor in a deal worth $2.6 billion.

The deal, which has already been unanimously approved by the boards of both companies, will see DSP, currently Japan’s seventh largest drugmaker, pay $23 per share of Sepracor. This represents a 48 percent premium on Sepracor’s average stock price over the last six months and 27.6 percent more than the Massachusettsbased group’s closing price on September 1.

Most importantly, though, the signal suggests a real move from DSP into the US market.

A desire to move into international markets is obvious, given that the Japanese market has experienced growth at a much slower rate than other major pharmaceutical markets across the globe. Now, in return for their payment, DSP will get hold of Sepracor’s drug Lunesta (eszopiclone), for the treatment of insomnia in adults, Xopenex (levalbuterol), which is indicated for the treatment of chronic obstructive pulmonary disease and asthma, and another COPD drug Brovana (arformoterol).

MAIL ORDER SURVEY A new survey reveals considerable issues pertaining to the state of the service given by mailorder pharmacies, which is leaving many patients in the US without their prescribed medicines.

According to the study, conducted by the National Community Pharmacists Association (NCPA), 63 percent of patients who are required by their health plan to use mail order pharmacies complained they had experienced late delivery; that’s compared to just 28 percent of those who had

a choice of pharmacy.

Worryingly, a massive 48 percent of those respondents who were mail-order customers said they had had to go without medications because of late delivery, adding that they had routinely had to pay for prescription drugs twice – once for the mail order and again when the mailorder purchase did not arrive in time and they were forced to seek out community pharmacies for emergency refills.

ABBOTT HEART DEAL FAST FACT

Abbott has announced an agreement to ac- medical devices portfolio,” said John M. quire the outstanding equity of Evalve Inc, a Capek, Abbott’s Executive Vice President, Californian company that has developed a Medical Devices. proprietary system which enables percuta“Evalve is on the cutting edge with its neous repair of cardiac valves. non-surgical approach to treating structural This deal sees Abbott estabheart disease. With this breakthrough lish a presence in the growing mitral valve repair technology, The area of non-surgical treatphysicians will be able to offer acquisition of the equity inlcudes an ment for structural heart their patients a minimally invaupfront payment of disease, in which physisive alternative to open heart cians use catheter-based surgery – not unlike the oppordevices to repair or replace tunity that stents provided more basic structural components than two decades ago for the treatof the heart such as mitral and aorment of coronary artery disease.” tic valves.

The acquisition of the equity includes an “The acquisition of Evalve will provide upfront payment of $320 million in cash, plus Abbott with leading technology in the an additional payment upon completion of emerging field of minimally invasive heart certain regulatory milestones, for a total of up valve repair and further broadens Abbott’s to $410 million.

$320 million

80,000,000 people in the United States have one or more forms of cardiovascular disease

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BLAME GAME

health insurance industry was considered to be more to blame.

A new report reveals that as many as 84 percent of While a separate report, conducted by Americans blame the pharmaceutical industry for the CNN/Opinion Research Corp, revealed that twocountry’s healthcare woes. thirds of Americans who watched President The Harris Poll, which was carried Obama’s impassioned speech to out in August, was conducted to disCongress in support of his plans for More than cover just what Americans blame for healthcare reform are now on his the problems currently facing the side, the findings of The Harris Poll believe the industry healthcare system in the US. brings bad news to pharma’s door. deserves a great deal According to the findings, the pharOther groups identified in the of blame maceutical industry came in second in poll that are facing the blame included the blame game – and more than Republicans in Congress (74 percent), 50 percent believed the industry business (72 percent), hospitals (70 percent), deserves a great deal of Democrats in Congress (69 percent), and doctors blame. Only (61 percent), but none of these saw more than 30 the percent of Americans believing they deserved a “great deal of blame.”

The proposed healthcare reforms certainly still have a long way to go, but the outlook is positive, especially considering that about one in seven Americans watching his address changed their opinion on the healthcare plan.

50%

COMPANY INDEX Q4 2009 Companies in this issue are indexed to the first page of the article in which each is mentioned.

Accuri Cytometers, Inc. 57 Acurian, Inc. 8, 134, 135 Aerotek 13, 35, 137 Alternatives Technologie Pharma 122, 123 Aptuit 74, 75 AstraZeneca 48 AT Kearney 110 BD PreAnalytiX 95 Biocrates Life Sciences AG 64, 65 Bioscan Inc. 15, 58, 59 Bruker Optics Inc. 80, 81 Caliper Life Sciences 59, 61 Cellular Technology Limited 98, 99 Definiens AG 72, 73 Do-Coop Technologies Ltd. 52, 53 Eli Lilly 44 EMD Serono, Inc. 84 Eurand 10, 114, 115 febit holding gmbh IFC, 71 Finesse Solutions LLC 66, 67 GE Healthcare 29 Gentris Clinical Genetics, Inc. 6, 62, 63

GlaxoSmithKline 119, 128 HP 124, 125 IMS Health 138,139 International Anti-Counterfeiting Coalition 100 inVentiv Clinical Solutions 96, 97 MDS Nordion 25 MedImmune 48 Metastorm Inc. 132, 133 Natoli Engineering Company, Inc. 121 NextGen Sciences 24, 77 Novartis 68, 77 Nycomed 36 Pharma Search Partners 87 Pilgrim Software 131 Pfenex Expression Technology 79 Pfizer 92 PricewaterhouseCoopers 32 Pronova BioPharma 88 Quintiles 91 Restek Corporation 31 Rockwell Automation 4, 108, 109, IBC

ROPACK 105 Rules-Based Medicine, Inc. 82, 83 Sartorius Stedim Biotech 113 SherTrack, LLC 116, 117 Singulex 51 Symyx Technologies, Inc. 126, 127 The Jackson Laboratory 26, 27 The Missouri Partnership 143 Thermo Fisher Scientific 41, 42, 43 TMF Corporation 102 University of Miami 54 Waters Corporation 106, 107, OBC Wheaton Science Packaging 118

HIGH STRESS As the H1N1 swine flu virus spreads rapidly through the Northern Hemisphere, doctors and other health care professionals face a heavierthan-usual workload, even with-out a flu pandemic.

Studies show, up to 60 percent of physicians in the United States suffer to some degree from burnout – physical and emotional exhaustion. The stress on doctors can cause medical mistakes, so the universities that train America’s doctors are looking for ways to prevent it.

So many children are coming to emergency rooms with flu-like symptoms that many hospitals have set up tents where they can diagnose and treat flu patients while keeping them away from other patients and hospital staff.

Even without a pandemic to add to the workload, doctors are busier than ever. In Rochester, New York, primary-care physician Michael Schneider has seen the stress from his work increase steadily over the past 30 years. “It’s something lost when we have phones ringing, consultants calling, computer screens flashing,” he says.

A recent report by the Mayo Clinic says up to 60 percent of American physicians at times suffer symptoms of fatigue and depression. The research shows that when doctors are overworked or depressed, they are more likely to make mistakes – even errors that could cost people their lives.

Source: www.voanews.com

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COVER STORY

Made to

measure

With pipelines running dry and fortunes ďŹ&#x201A;agging, the pharmaceutical industry is weighing up its options for survival. Could individually tailored treatments be the answer? By Marie Shields

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t

he pharmaceutical industry is at a crossAccording to Tony Pillari, PwC’s Director, Healthcare Advisory roads. Business models are changing, and Services, the report was developed for three key reasons. First was the smart companies are looking for ways to level of deal activity in that sector, which PwC feels is significant and likemaximize their R&D investment. As blockly to increase in the coming years and create a multitude of business opbusters fall by the wayside, or at the very portunities. least become much less common, what will Second was the growing importance of diagnostics in the practice of take their place? One answer could lie in the medicine and in the emergence of personalized medicine. And third were rapidly emerging field of personalized medthe many exciting advances that that have been made in recent months in icine, or pharmacogenomics. the field of personalized medicine, such as the recent announcement by This is not personalized medicine as it Complete Genomics of the $4000 genome. is often defined in healthcare – the need to In PwC’s definition, a personalized medicine diagnostic is any tool that consider an individual patient’s unique lifestyle and medical history, and how allows for the generation of data that is then used to tailor strategies for prethis impacts on his or her response to treatment – rather, this type of personvention and care to the needs of the individual. Such tools would include comalized medicine aims to develop drug therapies that have efficacy within narpanion diagnostics, early diagnostics and prognostics. rowly targeted groups of patients, based on each person’s genetically Tailoring the treatment to the patient is not an entirely new idea. programmed reaction to the drugs.

What’s different about this definition, says Why can two people take the same medPillari, is the specificity and accuracy that ication, and have completely different readvances in genomics and proteomics and The potential benefits of pharmacogenomics sponses? One may have severe side effects, a whole host of related technologies now could include: and the other none at all. Or the treatment make possible. may lead to remission in one, and seem to “We now have a much deeper under■ The ability to make better medication choices. have no effect in the other. standing of many diseases, including comEach year, roughly 100,000 Americans die from One of the reasons behind this variety of plex diseases like cancer, at the molecular adverse reactions to medications, and more than results is the variations we inherit in our genetlevel, and our knowledge continues to two million are hospitalized. Pharmacogenomics ic make-up. Pharmacogenomics uses this gegrow,” he says. “That kind of understandmay be able to reduce the number of adverse netic information to study how individuals ing simply wasn’t possible before. As a rereactions by predicting who is mostly likely to react to medications. Variations in genes can sult, the way we treat disease, including react badly to a particular drug. determine how we respond to treatment, in a how we design treatment options for pa■ Safer dosing options. similar way that genetic variations cause differtients, has changed to a point where trial Standard doses used today can prove toxic to ences in eye or hair color. For example, if you and error will hopefully be replaced by trial those with certain genetic make-ups. Using have a genetic variation that causes a drug to and success.” pharmacogenomics, doctors may be able to stay in your body longer than normal, this may Pharmaceutical companies looking to predict which dose will work for which patients. cause unwanted side effects. maximize success rates will be able to deResearchers are working to identify these termine which subsets of patients would be ■ Improvements in drug development. genetic variations, and then match them with more likely to respond positively to their Pharmacogenomics may help drug companies responses to medications, so that physicians can drugs. This happens to some extent albetter focus their drug development programs, by take this into account when prescribing drugs. ready, with companies often targeting subpredicting in advance which people will have In addition to the usual information such as sets of patients if initial trials with larger adverse reactions to a drug before it is tested. These weight, age, medical history and how any relagroups don’t yield the expected results. people can then be excluded from clinical trials. tives may have reacted to the same medication, AstraZeneca, for example, did this with its Source: www.mayoclinic.com doctors in the future may be able to take into acanti-cancer drug Iressa. In 2004, a large count your own personal genetic make-up. randomized study failed to demonstrate a survival advantage for the drug in the treatment of non-small cell lung canGrowth area cer, but it has since been shown to be effective in patients with mutations reThe field of personalized therapies – and the diagnostics used to develop lating to epidermal growth factor receptor (EGFR). them – is growing so rapidly that PricewaterhouseCoopers recently released Ideally, as AstraZeneca’s EVP for Discovery Research Jan Lundberg ‘Diagnostics 2009: moving towards personalized medicine’, the first in a sepoints out, R&D organizations should work out beforehand which groups of ries of annual reviews of deal activity in the in vitro diagnostics sector and sigpatients are likely to benefit, rather than waiting until the drug has been denificant events for personalised medicine. veloped and then looking for people it can help.

Reaping the benefits

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PwC’s Pillari believes specialized therapies can help pharmaceutical companies improve their bottom line. “The blockbuster model has been the predominant model in the pharmaceutical industry for quite some time and until recently, has been very successful. However, the poor return on R&D investment realized 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 move to specialized 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 specialized therapy delivers to a specific subset of patients.”

sent 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 personalized 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 personalized medicine. “If you’re really talking about the Holy Grail of personalized 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.” In the course of his travels around the world, Followwill has asked many people in the industry when they think Mixed feelings that day will come, and has received answers as varied as in 10 or 15 years to There are some within the industry who see a potential downside to the as long as 100 years. advent of personalized medicine. David Lathbury, AstraZeneca’s Director of The version of personalized medicine as it exists today has proven popProcess Chemistry, believes it will only help big pharma improve its ular with regulators. In some cases, they now insist on biomarker business models if it translates to a much more reduced cost of testing to guide drug prescribing. Tony Pillari believes their development. If it doesn’t do this, he says, the simple net premain concern is efficacy. He points to 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 rea year die from adverse ceptor that HIV subtype uses to attach to and infect reactions to The following genetic tests are currently in medications, and more white blood cells. use. They help guide dosing and prevent than 2 million are “Similarly,” he says, “testing for epidermal growth toxic levels of medication from building up in hospitalized factor receptor expression is required prior to the use of patients who lack certain enzymes.

Erbitux because Erbitux binds to EGFR and blocks certain growth factors that ultimately promote the expansion and spread ■ Cytochrome P450 test. This group of enzymes are of tumors. We believe this practice will become more common, as everyresponsible for metabolizing more than 30 types of one in the healthcare value chain, from regulators to pharma to providers to medications. The test can determine dosing and effect of patients to payers, appreciates the benefits of improving drug efficacy as well some antidepressants, anticoagulants, proton pump as reducing the frequency of adverse events.” inhibitors and a number of others.

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 ■ Thiopurine methyltransferase test. This enzyme breaks deal-flow between the pharmaceutical and diagnostics industries, because down the chemotherapy drug thiopurine, which is used to while the existing pathway for drug approval and reimbursement is clear and treat leukemia and autoimmune disorders. well-established, this is less true for diagnostics and even less true for drugs and diagnostics developed in tandem.

■ UGT1A1 TA repeat genotype test. This test detects a Pillari does point out that there are a number of encouraging initiatives variation in a gene that affects the UGT1A1 enyme, which under way, including by the FDA and the Critical Path Institute, to better dedetermines how the body breaks down irinotecan, a drug fine the pathway for drug and companion diagnostics development. As this used to treat colorectal cancer. pathway becomes clearer, and the risks associated with such strategy are mitigated, he expects deal-flow between the two to increase.

■ Dihydropyrimidine dehydrogenase test. This enzyme Frost & Sullivan’s Followwill points out that personalization is a breaks down the drug 5-fluorouracil and is a commonly megatrend in many sectors, including healthcare, automotive, transused chemotherapy medication. portation, environment and building technologies. For this reason he predicts that personalization will also increase within the pharmaceutical Source: www.mayoclinic.com industry, as it strives to find new business models to secure its future.

100

Americans

Testing time

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THE BIG INTERVIEW

THE SMALL COMPANY THAT

grew

Once a minor force in the world pharmaceutical market, Nycomed became a major player following its acquisition of Altana Pharma in 2006. CEO Hรฅkan Bjรถrklund tells Marie Shields how the company is positioned to meet the challenges of its extraordinary growth.

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W

hen Håkan Björklund became CEO of Nycomed in 1999, it was still a relatively small company based in Denmark. Then in 2007 Nycomed acquired Altana Pharma, and almost overnight the combined company was catapulted into the top 30 in the world. What has it been like to oversee such a huge transformation?

“You rapidly forget how it used to be,” Björklund says with a chuckle.

“You think that where you are today is the most natural thing on earth. But when I compare the figures, I realize that we are about 12,000 people now, and we were fewer than 2000 people in 1999. And of course we have considerably more subsidiaries as well. What it means is that you need to change your management style from being directly involved in a lot of things to having a more overseeing attitude.

“I have many very competent collaborators and experts in every field.

There is no need for me to be involved in the details. I look upon myself as more responsible for strategy and for creating the culture in the company, which is absolutely essential, especially when you’ve been through a merger like ours with Altana. You need to create a winning culture where people are proud of being with Nycomed; where they feel empowered and where they are happy to go to the work every morning, and thereby are contributing more and having a good time as well.”

You can’t institute a big change like the Altana merger without meeting some challenges, however. Björklund says the most obvious of these was the fact that Altana was twice the size of Nycomed – like David buying Goliath. In addition to coping with the size issue, Björklund’s other aims for the new company were to make the culture more open and to change its R&D structure.

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“I think a lot of people in the former Altana organization were questioning the new strategy,” he says. “They wondered if it would work, and also would we do what we said we intended to do. It took a lot of effort in the beginning to convince people that yes, this strategy would work, and that we were very committed.

“Our other challenge was that we had to reduce costs significantly, which inevitably means reducing the number of employees, which is never a fun thing to do. It’s always nicer to open a new plant than to close a plant.

Fortunately, the Altana organization was aware of the fact that they would have needed to restructure even if they had not been acquired, so there were no surprises when we said we would reduce the number of employees and thus cut spending.”

“This is not the time to get scared and withdraw; this is the time to take market share”

of money was spent developing follow-up compounds and me-too compounds, with a new patent life but with limited medical advantage compared to what was on the market. But you were still fine – you could get a decent price for it and you could take market share. That is no longer the case. The market will go with the generics as long as you don’t have a significant advantage with a new compound.

“For instance, to launch a new statin today – or maybe even more difficult, to launch an expensive new protein pump inhibitor – when you have generics out there at a fraction of the original price is going to be very, very difficult. That’s going to change the R&D model, and medical utility will be absolutely essential. If you cannot prove that your new product adds medical benefits, and hopefully also reduces costs for society, you will not be able to convince the payers that they should pay for it. That process has been going on for quite some time in Europe, and I’m convinced that it will also come to the United States.

“So R&D will need to be more focused, and if anything, the R&D part will be reduced. Sales organizations will also be smaller: we’ve seen that happening now for a number of years, and there is still more to come. Access to doctors is becoming more difficult, and it just does not pay off to have these huge armies of sales reps any longer, not in the mature market.”

Merger trend

Partnerships

Björklund talks about his career path as “a long and winding road from academia to pharmaceuticals.” He started out as a medical student at the Karolinska Institutet in Stockholm in the mid 1970s. He describes himself at that time as a basic scientist, and his intention was to remain in academia. But in 1984 he saw a job advertised at Pharmacia for a scientist to lead a small biology group focusing on ophthalmology, which is how he got into the pharmaceutical industry.

He moved up the ranks of R&D before switching to the commercial side, running Northern Europe for Astra before it became AstraZeneca. From there it was but a short step up to his current position.

Having gone through the merger experience with Altana has given Björklund a unique perspective on the recent trend of mega-mergers that have swept through the global pharmaceutical industry. “There is a difference between these mergers and the previous mega-mergers,” he emphasizes. “This time around, cost-cutting will be absolutely essential in order to make them successful, whereas previously people always talked about how with a bigger R&D organization, one plus one would equal three.

“I don’t think the mergers have anything to do with the current financial situation. They are more about developments in the pharmaceutical industry that have been going on for a number of years. If you look at the 10 biggest companies, they have lost market share as a group over the last five to 10 years.

There are exceptions, of course – Roche is one of them. But the idea of ‘the bigger, the better’ no longer applies.

“So cost-cutting is important, and if we look outside in the market, the pressure on our industry is totally different than it used to be, and this will also mean that we need to be more cost-effective.”

It’s a well-known fact that the global pharmaceutical industry is facing some serious challenges in the immediate future, including an upcoming wave of patent expiries and a scarcity of new blockbusters. Björklund says that in order to cope with these issues, the industry needs to shrink.

“The industry needs to be more selective in R&D. It used to be that a lot

Nycomed’s own pipeline strategy is somewhat unusual for a big pharma player. Rather than producing the majority of new compounds internally, it has chosen to create four-fifths of pipeline growth through in-licensed products. Björklund points out that the biotech industry has grown exponentially over the past two decades, with a huge number of potential new products in different phases of development.

“Most biotech companies will not have the resources to bring these products to the finishing line on their own; they need a partner at some stage in development. There is also reason to believe that the biotech industry – which in most cases is small and entrepreneurial – has been more effective in developing new drugs than the big R&D organizations and big pharma companies.

“When it comes to creativity, I don’t think there is an advantage of scale – it could actually be a disadvantage of scale. If you put together more people in an organization, they do not necessarily become more creative; maybe it’s the other way around.

Because to be creative you have to think outside of the box, and it’s probably easier to do this in a small biotech organization.”

Björklund also explains that when he started at Nycomed in 1999 it was obvious to him that the company did not have the resources to do its own discovery research, which made in-licensing a necessity. After the merger with Altana, Nycomed did gain an R&D organization, which it intends to maintain, because early stage in-licensing requires the company to have its own R&D capabilities in order to evaluate and work on what it’s bringing in.

“When you bring in a pre-clinical project you need to have a lot of these functions yourself,” Björklund says. “And that four-fifths is not written in stone. Whether that’s 60 percent, 70 percent or 80 percent, only the future will tell. Of course we hope that our own discovery research will also be productive, but we don’t depend on it. We assume that the majority of the products will come from the outside,” he continues with a smile, “although if my own scientists prove me wrong, I’ll be extremely happy.”

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Pursuing an in-licensing strategy naturally meant having to make changes to Altana’s existing R&D structure. One major impact was the significant reduction of the pre-clinical unit. Nycomed also outsources a lot of its clinical work to avoid having a large fixed cost structure internally. When an interesting phase III project comes along, the company is able to ramp up clinical trials with the help of external partners. Björklund puts it this way: “I like to have the brain power inside the company, whereas the people doing the clinical trials and monitoring can to a large extent be outsourced.”

Nycomed’s strong emphasis on partnerships and external collaboration extends beyond R&D and into marketing. “In R&D, most of our partnerships are earlier stage projects from smaller biotech companies,” Björklund says.

“But we also pursue collaboration on the marketing side, where we out-license products. The biggest product we have out-licensed is Pantoprazole to Wyeth in the United States. We’ve also recently completed a deal with Baxter around TachoSil, which they will launch in the US, and we’ll do some of the development for the US market together.

“A large part of our product portfolio in Russia is in-licensed. Our biggest partner there is Merck Serono, where we acquired their portfolio and have been very successful in growing it. I always tell my people that partnership, regardless of whether it’s in-licensing or out-licensing, R&D or marketing, is absolutely essential. We’re not big enough to do everything on our own, and we should only do the things in which we can add value, and in many cases someone else can add more value.

“Partnership is a skill; you need to be good at it, and you need to approach it with the attitude of, ‘I need my partners.’ It’s never easy with partnerships, because you don’t always get your way. There is a famous quotation by Winston Churchill that I often paraphrase, in which he says that the only thing worse than fighting a war with allies is to fight

it without them. Maybe it’s difficult to work with partners, but it’s more difficult to work without them.”

Focus on growth Nycomed has had a strong presence in Russia-CIS since the early 1990s, and even before that under the old Soviet Union. Since 2000, its Russian sales have grown from $25 million to $480 million. As Björklund explains, emerging markets are becoming increasingly important for the pharmaceutical industry as a whole. “Growth in the pharma industry is coming from two places: emerging markets and specialist products in the more mature markets. We have been successful in Russia-CIS, and we’ve also got a strong presence in Latin America.

We believe in investing in these markets. We’ve also clearly stated that we would like to expand in Asia, where we’re not sufficiently strong.

“I always tell people, both internally and externally, that if you’re in the emerging markets you need to be in, you have to be willing to ride the ups and downs. Now we’re seeing an economic crisis, which of course is hitting the emerging markets a little more than the rest of the world. This is not the time to get scared and withdraw; this is the time to take market share. For example, in Russia, yes, we have been hit by currencies, but we’re still growing in local currency and we’re taking market share. You have to be resilient and persistent.”

Closer to home, Nycomed has two products that are nearly at the marketing stage: Instanyl and Daxas. Instanyl is a nasal spray of fentanyl, the short-acting opioid that has been on the market for some time. The nasal form is new, and is indicated for the treatment of breakthrough pain in terminal cancer patients.

These patients normally have a fentanyl patch, which treats the day-to-day pain from which they suffer, but many also experience breakthrough pain.

The advantage of fentanyl in a nasal form is that it of-

veloping Rather than de IP APPROACH ly, fourSH al ER rn N te RT in PA ds A new compoun its of rated ity ne or ge aj the m e growth is med’s pipelin fifths of Nyco nsed products through in-lice

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fers a very quick onset of action because it’s rapidly taken up into the bloodstream, so pain relief begins within five minutes. Fentanyl is also quickly eliminated from the bloodstream. Björklund says Instanyl has seen a lot of interest, both from specialists and from the authorities.

Instanyl is a specialist product, to be used primarily in cancer clinics and hospices, and also at home. The second product, Daxas, is a little further away from the market, but Björklund says it offers a bigger commercial opportunity.

“Daxas is a possible phosphodiesterase-4 inhibitor, so it acts in the inflammatory cascade in patients with COPD – smoker’s disease. These patients are suffering from an inflammation, which in many cases leads to exacerbation of the condition. In some cases, people have to be admitted to hospital.

“COPD is a huge disease worldwide: it’s the fifth largest killer, with many millions of patients affected. Currently we don’t have any good anti-inflammatory treatment for COPD. Most patients will be treated with inhaled corticosteroids, which were originally developed for asthma and are very effective in countering the inflammation that asthmatics suffer from. But they are considerably less effective in COPD, because the inflammation in COPD is different.

Daxas is a once-daily tablet, the first anti-inflammatory that has been specifically designed for COPD.” According to Björklund, clinical trials have shown that Daxas offers a significant reduction in exacerbations and a significant improvement in lung function. When Daxas is added on top of the bronchodilators that most COPD patients are treated with, it gives a further improvement in lung function.

Expiry date The good news around Daxas could not come at a better time: Nycomed desperately needs a new superstar to bolster its product list. The patent on Pantoprazole, the company’s biggest product, expired several of months ago in most European markets and is due to expire in the US in 2011. This will inevitably lead to a decline in sales, and Björklund says this was one of the reasons why the cost-cutting exercise was necessary after the Altana acquisition.

“We needed to prepare ourselves for a time without patent protection on Pantoprazole,” he emphasizes. “Although more than 40 percent of our Pantoprazole sales do come from markets where there is no patent protection or where there has not been patent protection for a long time, so we’re convinced that we’ll be able to maintain a significant portion of our sales. Even though we will lose sales with the patent expiry, Pantoprazole will remain the largest selling product for us for the next few years. But it’s important that new products are coming along to compensate for the eventual drop in Pantoprazole sales.”

Nycomed has taken the unusual step of launching its own generic version of Pantoprazole in partnership with Wyeth here in the US, even though the drug’s patent has not yet expired there. In the American market, it is not unheard of for generics manufacturers to create copycat versions of patented drugs, with the assumption that they will be able to invalidate the patent in a court case.

In the case of Pantoprazole, Björklund says that the first generics were launched in the US about 18 months ago. Nycomed immediately countered with a lawsuit, but because of the legendary slowness of our legal system, the lawsuit is still ongoing and the generic versions are still being sold. “We’re convinced the patent is enforceable and strong,” Björklund underlines, “and that we will eventually prevail in the courts. But the reason we launched the generic was to counteract those that had already been launched, and thereby be able to compete more strongly in the market as it is now.”

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In private In contrast to many of its big pharma competitors, particularly in the US, Nycomed is privately owned. Other non-public European-based companies tend to be family-controlled, but Nycomed’s main shareholders are two private equity firms, Nordic Capital and DLJ Merchant Banking.

Given the current state of the global economy, has private ownership helped insulate the company from market fluctuations? Björklund says it has.

“We’ve been privately owned now for 10 years by various groups, and it has served us very well, because it has allowed us to focus on building long-term value in the company. We don’t need to focus on the next quarterly result. It has also aligned the interest of the shareholders and management: everyone has the same ambitions to grow the company and create value. There are no politics.

“When it comes to the culture, I think it has also been good in the sense that we’ve been able to be considerably more open in a private equity-owned company than if we were a publicly owned company, because I don’t need to worry about following the rules of the stock exchange in terms of what I can and can’t communicate. I can tell my people what we think and how things are going, which I could not do in a public company because of the risk of it getting into the public domain and having an impact on the stock price. It’s easier to be open in a private company.”

Of course privately owned companies do not have the same requirements around transparency as public companies do, but Björklund says the information Nycomed publishes doesn’t differ from that of its public rivals. “If you read our annual report, which we publish and which is readily available, you won’t see any difference in the way we report compared to a public company.

“We’re just as transparent and open with everything. You can even find my salary in there. We are reporting as a public company, and also preparing for the possibility that in the future we may go public, which is not out of the question.” Björklund won’t be drawn on when this might happen, saying only that the situation in the financial markets will need to stabilize before the idea is given serious consideration.

When asked what the future holds for Nycomed, Björklund’s response is an optimistic one. He doesn’t foresee any restructuring as a consequence of the current recession, and he points out that the financial crisis has affected emerging markets in Eastern Europe, because of the weakening of currency that has taken place there. The economic downturn has also had an impact on GDPs in the Baltic countries, which decreased by 15 percent in the first quarter of this year.

“That is also affecting peoples’ ability to buy drugs,” Björklund continues.

“But it’s not dramatic, and this industry is relatively resilient to downturns. So I’m not so worried about the financial crisis – at least not in the mid term or long term.

“On the other hand, within the big five EU countries, I think the pharmaceutical industry will see very little growth, and it will be primarily in specialist products and only certain of them. The growth will come from Eastern Europe and from Russia-CIS: emerging markets.”

In the case of his own company, Björklund’s optimism does not seem misplaced. Nycomed, the small company that grew, seems to have its place among the top 30 pharma players firmly established. And who knows, if it continues to play its cards right, in a few years it could be knocking on the door of the top 10.

Håkan Björklund is Chief Executive Officer of Nycomed. Before joining Nycomed, Björklund was Regional Director at Astra (now AstraZeneca), and was President of Astra Draco from 1991 to 1996. He is a member of the Board of Directors of Atos Medical AB, Coloplast and Danisco A/S and holds a PhD in neuroscience research from the Karolinska Institutet, Sweden.

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INDUSTRY INSIGHT

Facilitating data management at an enterprise level The beneďŹ ts of an integrated and purpose-built LIMS solution. By Dave Champagne

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harmaceutical companies can no longer afford to delay the implementation of next generation tools to help them manage the increasing amount of data generated by their organizations. Working with multiple, disparate systems with minimal to no integration is no longer an option.

Pharmaceutical companies need tools that help them improve enterprisewide communications, reach critical decisions faster and produce timely, accurate reports on how compounds are progressing, all while maximizing return on investment, shortening the pipeline life cycle and cutting costs. The challenge is to successfully streamline and integrate the flow of data so that management has the information they need to make timely decisions. The solution begins with a purpose-built, enterprise-level laboratory information management system (LIMS).

The challenge With drug development times of approximately 15 years and subsequent costs approaching $2 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. Enterprise level LIMS are key contributors in this effort. Delivering advanced functionality that is specific to each stage of the drug development process, sophisticated, purpose-built LIMS streamline processes and help reduce costs, and present organizations with unique integration opportunities. Purpose-built LIMS provide superior capabilities by delivering real-time analysis and reports, facilitating regula-

tory compliance and product quality, integrating with the companyâ&#x20AC;&#x2122;s broader network and providing secure access to key data throughout the organization.

Historically, industry standard LIMS have only delivered 30-40 percent of specific functionality targeted to each userâ&#x20AC;&#x2122;s needs, requiring extensive customization to make that LIMS function in that particular setting. Such customization 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 outdated and/or costly proprietary languages has been particularly troublesome in the pharmaceutical industry. In addition, pharmaceutical laboratories normally 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.

The growing mandates of global regulatory compliance and longterm 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 customization, validation and implementation periods, in many cases lasting 36 months or more, have become routine, resulting in decreased productivity. However, with the increasingly higher costs of bringing a new drug to market,

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CONNECTS In response to 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. 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 systems, and the interoperability necessary to transform data into relevant business drivers. In facilitating this enterprisewide integration of systems, management will have the information they need to have early insight into how pipeline drugs or compounds are progressing on a routine basis, and 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.

pharmaceutical manufacturers cannot afford to delay the implementation of next generation tools that will make them more productive.

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. The objective of purpose-built LIMS solutions is to deliver as much domainspecific functionality as possible that addresses the critical needs of the laboratory and delivers the increased enterprise-level access that multisite/multi-user organizations are looking for. According to the same Frost & Sullivan report, market growth indicators for LIMS solutions providers are focused on providing customers with not only purposebuilt LIMS that are fully integrated with other laboratory equipment, but also LIMS that easily align with global enterprise solutions.

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. Modern LIMS serve as common platform frameworks that other informatics solutions, instrumentation, enterprise systems and enterprise communications tools can plug into to share common functions, without having to build them from scratch for each product.

Conclusion 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. LIMS can help pharmaceutical companies to respond with more certainty to the many unforeseen challenges that can often make or break a company. Enterprise 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. LIMS help bring key business knowledge originating in the laboratory to management at all levels of the enterprise.

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 enterprise will facilitate better planning, data quality, collaboration and end-to-end report generation, all with the goal of providing management dashboard views of key business metrics, which are essential to effectively run operations, and thereby enabling management to have the critical data they need before, not after, any point of crisis.

Integrated LIMS At Thermo Fisher Scientific, we have developed a portfolio of LIMS that meet the needs of customers at every stage of the drug development process. Th is is particularly true in the pharmaceuticals industry where laboratory requirements are unique in research and development, discovery, and manufacturing. There is no single system that could answer the unique needs of these laboratories, so it is important to develop, with the help of individual customers, purpose-built LIMS for each area of the pharmaceutical value chain.

Purpose-built 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

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. Champagne’s career includes 13 years at Lotus Development Corporation and two roles as Chief Executive Officer for early-stage software companies.

For more information about Thermo Scientifi c informatics solutions, please call + 44 161 942 3000, email marketing.informatics@thermofisher.com or visit www.thermo. com/informatics. Thermo Scientific is part of Thermo Fisher Scientific, the world leader in serving science.

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FEATURE INTERVIEW

Abright

outlook

Natalie Brandweiner talks to Lilly’s William Chin about personalized medicine, partnerships, and using the company’s PD2 initiative to generate new compounds.

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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 increasingly demanding that drugs become safer, signaling a shift in balance between benefit and risk. The industry is also facing continuous skepticism 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 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 issue, 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. “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 in-

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cludes cancer, metabolic diseases and neurosciences, or whether it’s leaders in chemistry, toxicology, ADME, experimental medicines/translational medicine and program/medical. I count on the excellence of these leaders to join in as a team to achieve our tasks, so my style is that I trust my colleagues. I am 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 the input of as many people as we can get, within reason, to be able to make the best decisions. I believe in diversity of experience and 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.”

Academic achievements 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 program, 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.

“Genetics is important to help us understand what are 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, based on our uncomplete 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

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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 the genetics division is how to utilize this kind of information to help us choose targets in a more intelligent way,” says Chin.

His focus during his time at Harvard, whether he practiced as a physician, researcher or educator, was always the patient. His realization 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.

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, which 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.”

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.

“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, because they can’t afford it or governments or third-party payers are not willing to reimburse for it, then we really haven’t done anything.”

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Networking He also underlines 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; in other words, everybody has a 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 self-sufficient.

However, we realized 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 bringing together the talent that’s present throughout the world. That seems like a very ambitious goal; there are a lot of ideas and compounds out there in the scientific community that remain untapped but could really help patients.

“What this program 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, 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 another assay. Instead of focusing on a specific molecular target, it’s looking at a cell behavior.”

Approximately 60 institutions and laboratories have signed onto 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

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activities interesting enough, Lilly will then engage in a discussion and have a certain amount of time in which it can agree or disagree with the investigator in 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 academics 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 Lilly has 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 potential drugs for our patients,” says Chin.

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Personalized medicine

Eli Lilly headquarters in Indianapolis

in its clinical pipelines

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 multiple 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 tumor 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 this to be a part of the approach that we can take in terms of personalized 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 and or benefit and so probably shouldn’t take this medicine,” says Chin.

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 organization of staffing 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 organized well, if they’re not working together in an optimal way as part of a true team, then you’ve lost the benefit. Lilly has created 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/PD, experimental medicine and medical work together in a cluster concept of activity.

“Four or five years ago I wanted to reorganize our group because I felt that we had groups that were much too large. They’d created silos that diminished the synergies that I thought we could have by having more integration, and so we created smaller groups called drug-hunting teams. This is largely the biologists; the groups were much smaller and focus on specific areas such as diabetes or psychiatric diseases.

“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 have 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 optimization of proteins for large molecules has been supported by its additional acquiring of Structural Genomics, a technology used 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 partnerships. “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.

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 School and Chief of the Division of Genetics and Senior Physician at the Brigham and Women's Hospital, Boston.

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DRUG DISCOVERY

ON THE UP AstraZeneca’s Jan Lundberg tells NGP how his company’s R&D efforts are beating the financial downturn.

I

n a time when companies in many industries are struggling, UK-based AstraZeneca’s half-year pre-tax profits rose by 27 per cent to $5.611 billion. Part of this unexpected jump was attributed to a 33 percent leap (to $1.129 million) in second quarter sales of Crestor, the cholesterollowering drug.

Jan Lundberg, AstraZeneca’s Executive Vice President of Discovery Research, believes this is down to Crestor’s superior performance compared to its competitors. “If you look at the available information from various trials, I think it’s very fair to say Crestor is the most effective statin to lower LDL cholesterol (C),” he says. “At the same time it also raises HDL-C with an effect that is maintained across the dose range, which is different from some other statins, where HDL declines with dose.

“There are some very exciting recent data where the accumulating evidence suggests that Crestor has a very positive impact on arteriosclerosis, preventing its progress, even potentially reversing some of its effects. It also reduces mortality in cardiovascular disease in a recent study in patients with low to normal C levels but at increased CV risk due to age and elevated levels of an inflammatory marker, CRP, to the Crestor effect. This was seen at LDLC levels, which at the baseline level today are considered normal. This data

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adds to the body of evidence showing that ‘lower is better’ in terms of LDL-C and shows that treatment with CRESTOR can achieve LDL-C levels significantly below what is defined as normal today.”

Another recent boost to AstraZeneca’s pipeline is the vaccine the company is developing for the H1N1 virus. A number of big pharma companies are currently developing a vaccine for pandemic H1N1 and AstraZeneca has a vaccine that is licensed for use in the US. AstraZeneca hopes theirs will stand out because of its novel delivery method – through a nasal spray rather than injection. Lundberg is quick to acknowledge that MedImmune, the biologicals arm of AstraZeneca, moved quickly to develop this novel technology in the face of a growing global pandemic.

“At a high level I would say that it’s a matter of getting the right yield so you can deliver a significant amount of doses as quickly as possible and our technology delivers many doses per egg. Secondly it’s about timing of delivery alongside that for seasonal flu. We have to get the vaccine out as soon as possible before the pandemic escalates, but also remind people of the importance of getting a seasonal flu vaccination as well. Many believe the nasal delivery technology would provide benefit in the event of a true pandemic, enabling mass vaccination without the need for needle preparation or dis-

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posal. Of course it is also very important to comply with regulaal business models change and as progress in technology and science make tory requirements, and our MedImmune colleagues have done a this possible. great job in the swine flu vaccine area.”

This applies particularly in oncology, as he explains: “In oncology we have Those who are worried about the upcoming winter flu seathe ability to analyze tumor biopsies or blood samples for their respective tumors. son will be relieved to hear that in Lundberg’s estimation, We can let science drive the benefits for patients both in relation to maximizing AstraZeneca has a “very competitive delivery time horizon” for the potential for clinical effect and also reducing risk. It’s still an evolution, but the the vaccine. trend is very clear.

Another piece of good news for AstraZeneca has been the “A key aspect will be to identify these opportunities early enough. With performance of its blood-thinning drug, AZD6140/Ticagrelor Iressa, we only established which patients would respond when the drug was al(Brilinta), which was shown to reduce heart attacks and deaths ready on the market. It would be better if we could do this at the time of, or even more than standard therapy with sanofi-aventis SA’s and Bristolbefore, nominating compounds to the clinic in a new area. We could analyze this Myers Squibb Co.’s Plavix. The data came from the Plato study tumor population to see if there are specific pathways that are particularly prone of more than 18,000 patients, whose findings were presented at to be more responsive, and then design the compounds against these paththe European Society of Cardiology meeting in Barcelona in late ways and select patients in early clinical trials that could be maximally reAugust. sponsive, based for instance on genetic analysis of tumor biopsies.”

Lundberg is understandably enthusiastic about Brilinta’s Lundberg points out that even in the last couple of years, there have been success. “We have suspected for some time that because of its very major developments in personalized healthcare and combined diagnostics. He rapid onset and smaller degree of variability in the anti-thrombothighlights the CNS area of Alzheimer’s disease, where the pathophysiology is inic effect than the current market leader Plavix, Brilinta would have creasingly known, based to a large extent on genetic analysis of patients with a beneficial outcome for patients. That was exactly what the Plato hereditary Alzheimer’s. “Here we have a PET ligand as a new diagnostic tool,” trial showed, namely that Brilinta was superior to Plavix in reduche says, “and you can see if patients have accumulated amyloid in the brain, ing cardiovascular events after the initial myocardial infarction. Not which is a strong signal that the risk of developing Alzheimer’s is high. You can only did it reduce events, but it also improved overall survival.” With typical understatement, he continues, “Plavix is Jan Lundberg is Executive Vice one of the biggest products on the marPresident, Discovery Research ket today, a major product globally, and at AstraZeneca, a position he has held since the Astrato have a substance like Brilinta that Zeneca merger in 1999. He is a member of the Senior beats Plavix’s efficacy without comproExecutive Team reporting to mising safety is quite good.”

David Brennan, CEO. The company also recently reLundberg has a medical education from the University ceived approval in Europe for its anti-cancer drug, of Gothenburg and was a Iressa. “With new science we could show finally that professor at the Department of Pharmacology at the Karolinska Iressa has a positive effect in patients with non-small Institute in Stockholm before joining Astra AB. He has cell lung cancer,” Lundberg says. “This is a very sepublished more than 500 vere disease, and Iressa had good effects for those scientific articles, mainly related to mechanisms of cell signaling patients with mutations relating to the epidermal in the nervous, cardiovascular and respiratory systems. He is a growth factor receptor. They had particularly good highly cited author. responses and a much better quality of life compared to the traditional cytotoxics that are tested for that indication. This is an illustration of personalized healthcare success in the oncology arena.” 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.

Genetic target “There are some new agents coming in, which are tested to prevent accuContinuing in the vein of drugs targeted at genetically defined patient popmulation of or to deplete amyloid, which offer a way of combining diagnosis and ulations, AstraZeneca is also developing a PARP inhibitor, which inhibits DNA potentially following the effects of anti-amyloid treatments and correlating that repair. “Patients with hereditary breast and ovarian cancer of the BRCA 1 and 2 with improvement in cognition, again taking a personalized healthcare treattype are particularly responsive to the PARP inhibitor,” Lundberg explains. “We ment approach. have very promising phase II data in this area and we are pushing forward as rapidly as we can. This agent would be combined with a genetic test for this particular patient population and it’s likely the response would be very high.”

Lundberg believes treatments developed for specific patient populations will become more common within the pharmaceutical industry, as tradition-

Partnership AstraZeneca, like many of its competitors, places a strong emphasis on partnership and externalization, which bring with them the benefits of a much

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broader coverage for R&D portfolios.

“This allows us to capture successful new ideas, for instance with clinical signals or technology platforms, which we can then utilize in early research. “It’s a fundamental part of the way we operate. The better compounds and more validated disease mechanisms we have, the more we’ll reduce the risk of clinical failure.

“We want to get more products to the market and have a broad opportunity to choose from various agents that we push into late stage, more expensive trials. This should give us a higher chance of success overall, if we can choose and compare the best compounds in-house and externally in parallel.

“It also gives us an opportunity to leverage our scientific R&D organization that can improve on our partners’ ideas and help with designing trials and regulatory strategies, in addition to coming up with much better follow-on compounds if needed. We can also use some of our novel agents to produce combination products with a partner, which we have recently done with Crestor, where we are working with Abbott on a Crestor plus Trilipix combination for a broader approach to dyslipidemia than just LDL lowering and HDL elevation. That will help us to access the best combination to benefit patients.”

Lundberg also cites a recent example for novel agents, in which AstraZeneca was sitting on a very good compound in oncology

This approach has brought the company a significant amount of success; one example being the recent approval of its type 2 diabetes drug Onglyza in the US, which was developed jointly with Bristol-Myers Squibb. AstraZeneca has also submitted other phase III products for licensing applications that have been partnered.

Opportunities

One of the motivators driving companies to work more collaboratively may be the uncertain state of the financial markets, which could limit funding for projects. But Lundberg maintains that the recession has not yet had a major effect on R&D within AstraZeneca key facts the pharmaceutical industry.

• Focuses on six therapy areas: cancer, “We are a long-term business. There cardiovascular, gastrointestinal, infection, are scientific opportunities there to be exneuroscience, and respiratory and inflammation. ploited because we have so much unmet • Active in more 100 countries, with a growing medical need remaining. One cannot look presence in emerging markets, including China. upon the pharma industry as a short-term • Corporate office based in London, UK, with major fix. We are here in the long term to create the R&D sites in Sweden, the UK and the US. drugs for which we know there will be cusAdditional R&D sites in Canada, France, China tomer demand; just think about the increase and India. in the aging population.

• Employs more than 65,000 people (51 percent in “Most people are very interested in Europe, 32 percent in the Americas and 17 percent their personal health, which includes politiin Asia, Africa and Australasia). cians as well. We appreciate that financial • Employs 12,000 people in its R&D organization, pressures and regulatory hurdles are inwith 17 principal R&D centers in eight countries. creasing, but in the end this is a very spe• Maintains 26 manufacturing sites in 18 countries. cial industry where the customer needs • Sales in 2008 totaled $31.6 billion. will not go away. Science is evolving, • R&D investment totaled over $5 billion. along with our understanding of most diseases, so there are opportunities to improve treatment. The customer base is also increasing, with the economy still growing in Asian countries, for example, so the demand is likely to increase.”

Lundberg does pinpoint one potential area of concern: if the biotech industry doesn’t get enough financing, this could reduce external opportunities, particularly for new technologies, which would have a negative impact on the development of new drugs. This is why many big pharma companies have taken an increasing interest in venture capital funding of early biotech companies, to ensure there is a next generation of new technologies and innovations coming out of the industry.

Increasing regulatory hurdles are also proving a challenge. “I can understand that society has the right to demand very safe drugs,” Lundberg says, “and also that for one pathway and Merck had a compound for another cancer pathway. Now we show differentiation versus current drugs on the market. We are adopting and the two companies are working together to combine these compounds to poelevating the bar for what we think is a real winner for the future, trying from early tentially have an even better effect on the tumors. Lundberg says it’s about havdiscovery and onwards to understand what are the regulatory and payer needs that ing strong internal research and also realizing that there are a number of global we need to comply with. Of course we also need to be in a constant discussion with opportunities in the scientific arena that you can capture and be part of, which regulators, to understand what benefit/risk balance is reasonable for a particular in the end will benefit not only the company but also patients. indication so that patient access is not unnecessarily delayed.”

“One cannot look upon the pharma industry as a short-term fix. We are here in the long term to create the drugs for which we know there will be customer demand”

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EXECUTIVE INTERVIEW

Overcoming obstacles in drug development Eran Gabbai and Ayelet Dilion Mashiah of Do-Coop Technologies describe a new technology that is turning the tide in the pharmaceutical industry.

What challenges face the pharma industry?

Ayelet Dilion Mashiah. R&D is in trouble because of shrinking pipelines. To fund new research you need sustained revenue from previous drugs. But the number of new drugs is dropping, because of R&D obstacles that kill a drug before the clinical trials. It’s a vicious cycle spiraling into a crisis.

Which obstacles are fatal for a new drug?

Eran Gabbai. The worst are poor efficacy and toxicity. Many new compounds are hydrophobic, only solubilized with an aggressive solvent.

After pre-clinical success, the high toxicity of the solvent requires a different vehicle for the

Eran Gabbai is the inventor of Neowater and the entrepreneur who founded Do-Coop Technologies Ltd, of which he is President and CEO.

Ayelet Dilion-Mashiah is the VP of Business Development and CFO of Do-Coop Technologies Ltd.

clinical phase. That change can undermine earlier data and cause unpredictable results.

If you overcome those, you hit a third obstacle – the behavior of intracellular water, which is different from bulk or lab water. Those differences are generally misunderstood and in vivo efficacy in humans can be affected as a result.

These obstacles are so prevalent that around 75 percent of drug discoveries are shelved as impractical. Some 60 percent of these failures are from solubility issues alone.

ADM. Pharma companies are losing $80 billion a year, just from solubility setbacks.

EG. The beauty of Neowater is that it overcomes all these obstacles. Neowater shifts the physical and chemical properties of bulk or lab water. Its proprietary structure is nontoxic, inert and remarkably stable, so it can be the vehicle for both in vitro and in vivo testing.

Best of all, Neowater resembles intracellular water in handling both hydrophobic and hydrophilic compounds. Its compatibility with the natural biological environment also reduces the need for co-solvents or surfactants used in drug formulation, reducing toxicity levels while enhancing compound efficacy.

How would you categorize Do-Coop’s business value for the pharma industry?

ADM. Neowater works unlike any other drug delivery system. But because Neowater is generic, it provides the optimal vehicle for many compounds with only minimal customization.

Companies can register new IP with existing API (active pharmaceutical ingredients), based on an extended therapeutic window.

Additionally, Neowater was submitted to the FDA for compound integration without needing a separate toxicity control. Companies using Neowater-based compounds will see faster, more cost-effective progression.

EG. With a single delivery vehicle, efficient use of R&D capital rises, as do the discoveries that can become viable. Neowater also provides better hydration and bioavailability in formulations, greater control in sustained-release formulas, and long-term stability in stored products.

What successes has Do-Coop had so far?

ADM. We partnered with Champions Biotechnology, who are developing oncology drugs.

They were hunting everywhere for a solubilizer for SG410, their benzoylphenylurea (BPU) sulfur analog. It was a ‘brick’ compound with no therapeutic window at all.

Using Neowater, Do-Coop enabled a liquid formulation that can be taken for in vivo studies, with at least the same activity as with DMSO. Champions will have early Biomerk Tumorgraft results for Neowater-based SG410 by late 2009.

“R&D is in trouble because of shrinking pipelines. To fund new research you need sustained revenue from previous drugs” As an example of using existing API, we connected a third party with a reformulated cyclosporine (based on Neowater) as an immuno-suppressive agent for eye treatment. Allergan owns the IP for cyclosporine eye drops, but because Neowater extends its therapeutic window with a formulation that doesn’t intrude upon Allergan’s IP, new IP could be created.

Incidently, the cyclosporine was originally an in-house POC. We are not a drug producer.

We license Neowater technology, merging Neowater IP with our customers’ IP. Our business model is receipt of royalties and milestone payments only. The pharma companies reap the other rewards.

EG. In the end, our society benefits from medical advances that can be brought to market for lower cost, in less time and with fewer glitches along the way. So we all win with Neowater.

For more information please visit: www.docoop.com or email: business@docoop.com

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DRUG DISCOVERY

Medical foods: overview of an emerging science

By Richard Isaacson

M

edical foods offer physicians an additional tool for approaching and managing various medical conditions. They can help improve the symptoms and/or slow the progression of a specific chronic condition, and they are complementary to approved pharmacologic therapies. As the number of available medical food therapies increases, so must an understanding of their function and benefits to enable proper use. This article aims to provide a comprehensive overview of medical foods.

Examples of medical foods Medical foods are available for a wide number of common medical, neurological and psychiatric conditions.

Many address the metabolic processes associated with a disease to help improve or slow progression.

Alzheimer’s disease Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia and it is predicted to reach epidemic proportions by the late 21st century. AD is an excellent model of a well-studied neurodegenerative disease with many severitydependent potential targets of a medical food. A prominent feature in AD is the disturbance of the cerebral metabolic rate of glucose or regional cerebral hypometabolism. As this hypometabolism is an early and progressive event, it is reasonable to target this avenue in AD therapy. A first-in-class medical food for the clinical dietary management of the metabolic processes associated with mild-to-moderate AD was recently released. This represents the first new therapeutic agent in the AD market in over five years and helps to satisfy an unmet need for “targeted therapy” for AD patients.

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Axona safely and effectively supports the nutritional requirements of patients with mild-to-moderate AD. The therapy is a proprietary formulation of medium-chain triglycerides (MCTs) (specifically caprylic triglyceride) that is digested and metabolized in the liver to produce ketone bodies. Ketone bodies are naturally occurring compounds produced by the body at low levels. After being metabolized in the liver and released into the bloodstream, these ketone bodies provide an alternative energy source for brain cells to help improve functioning.

Clinical studies have demonstrated that this novel approach to the management of AD can safely improve cognitive function and memory. On average, patients with AD who received Axona experienced significantly improved ADAS-Cog (Alzheimer’s Disease Assessment Scale – Cognitive subscale) scores (P < 0.05) at day 45, and in apolioprotein E (ApoE4) genotype negative patients at day 45 and

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Definition As defined by the Orphan Drug Act (1988 Amendment), a medical food is “a food which is formulated to be consumed or administered enterally (orally) under the supervision of a physician, and which is intended for specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” These therapeutic agents are a heterogeneous group of formulations which comprise a relatively new category of medical protocols defined by Congress, and are subject to regulation by the US Food and Drug Administration (FDA).

The distinctive nutritional requirements of medical foods towards a specific disease must be supported by solid laboratory and clinical data as well as by product performance. The clinical rationale of medical foods is thus subject to scrutiny by medical evaluations and objective determinations of efficacy. This increased surveillance of medical foods by the FDA is reflected in the requirements of the Generally Regarded As Safe (GRAS) designation, the highest FDA standard of safety given to foods which all components of the formulation must satisfy. Additionally, and unlike over-the-counter dietary supplements, they require the supervision and prescription of a physician to be obtained.

Medical foods and dietary supplements are discrete regulatory classifications and are not interchangeable. The former must be shown, by medical evaluation, to meet the distinctive nutritional needs of a specific, diseased patient population being targeted, prior to marketing. In contrast, dietary supplements are intended for normal, healthy adults and require no pre-market efficacy tests. In addition, medical foods require physician supervision and a prescription. To summarize, medical foods are medical products for a specific nutritional purpose as opposed to dietary supplements which are a consumer product to supplement the diet and maintain good health and regular function.

day 90 (P < 0.05). Axona has also been studied in patients with agerelated memory loss, and is currently being studied as a targeted therapy for improving quality of life measures for AD patients.

Osteopenia and osteoporosis The nature of osteopenia and osteoporosis is one of the more clear-cut disease spectrums for the focus of medical food development. Elderly female patients are most often affected by the serious sequelae of this disease (predominantly fractures) and its associated disability can be quite limiting. The elderly often do not successfully meet the nutritional requirements of Vitamin D and calcium necessary for the prevention of osteopenia and osteoporosis. Fosteum has demonstrated a clinically effective combination of Vitamin D/calcium supplementation with soybean derivatives (known to partially simulate the protective effect of estrogen through mimicry). A randomized clinical trial performed in Italy with over 380 post-menopausal patients over two years demonstrated a significant reduction in bone turnover evidenced by statistically significant improvement in bone mass density (BMD) scores.

Osteoarthritis Limbrel, another medical food, also places its focus in the musculoskeletal system by targeting the metabolic processes involved in osteoarthritis and joint degeneration. An interesting aspect of the therapeutic mechanism is its dual mode of action, which involves inhibition of both the inflammatory pathways well-defined in osteoarthritis (cyclooxygenase, lipoxygenase) as well as antioxidant properties which slow disease progression at the level of the involved joints themselves. In large, double-blind, placebocontrolled clinical studies in the United States and Japan, Limbrel administration has resulted in statistically significant improvement in all primary clinical endpoints (functional mobility, functional stiffness and functional joint discomfort).

Open-label studies have also been performed with similar positive results. The endpoints were validated by the patientscored Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), an established questionnaire designed to assess severity and patient disability due to knee and hip arthritis symptoms.

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In contrast, the efficacy of prescription drugs that make disease-specific claims must also be supported by clinical/scientific studies (such as animal toxicity, phase I/II, large phase III/IV, and post-marketing clinical studies) designed to highlight potential safety issues, while also being pre-approved by the FDA. This escalation of government supervision reflects the formal medical food claims, which refer to the “nutritional or dietary management of a specific disease or its metabolic processes,” whereas a prescription drug claims “curing, treating, preventing or mitigating the effects of symptoms of a spe-

outpatient setting, however, medical foods are primarily aimed at slowing the progression of chronic, progressive diseases by modulation of the disease process via continuous, long-term administration. Given the wide array of possible targets for therapy, it is not difficult to envision that a significant number of diverse medical foods have been developed despite their relative novelty.

The role of neurotransmitter modulation by exogenous therapeutics is still a controversial one. However, spurred by the market need for adjunctive, nonaddicting agents to assist patients with acute and chronic pain-related complaints, formulations have been developed which are intended to do just that. Theramine is a medical food engineered to stimulate production of neurotransmitters that are well-understood to inhibit CNS pain signaling, such as serotonin, GABA and norepinephrine. It also claims to facilitate PNS inhibition of inflammatory neuropeptides and Substance P, well-characterized signaling molecules for the perception of localized pain. The extrapolation of a possible improvement of the patient’s baseline pain tolerance with Theramine administration makes this a consideration for healthcare practitioners that manage pain syndromes.

While medical foods are not as familiar to physicians as drugs, the potential benefits and risk/benefit ratio should be discussed with patients. These agents may provide a therapeutic complement to currently available pharmacologic therapies. It is likely that in the future, our knowledge about the underlying mechanisms and potential benefits of medical foods will be further elucidated. Additional well-designed, randomized, placebo-controlled studies are warranted in diverse areas.

“Medical foods can help improve the symptoms and/or slow the progression of a specific chronic condition, and they are complementary to approved pharmacologic therapies”

cific disease.” Therefore medical foods represent a unique hybrid of therapeutics, and although sometimes prescribed in conjunction with conventional pharmaceuticals or supplements, nonetheless represent an entirely different scientific and medical approach to managing diseases.

Healthcare professionals may already be familiar with medical foods intended to support or even fully substitute the nutritional needs of hospitalized or critically ill patients who cannot meet them, such as those with malabsorption syndromes. These enterally administered therapeutics form an important subset of short-term therapies the inpatient clinician has at their disposal to acutely facilitate healing and improve outcomes. In the

Depression Deplyn (L-methylfolate) is an orally administered prescription medical food intended for the dietary management of suboptimal folate levels in depressed patients or hyperhomocysteinemia in schitzophrenia patients. L-methylfolate can be used as adjunctive therapy for depressed patients with suboptimal folate levels in order to regulate the synthesis of trimonoamine neurotransmitters (serotonin, norepinephrine and dopamine). Studies have suggested that concomitant treatment along with selective-serotonin reuptake inhibitor (SSRI) medications may improve response to SSRI therapy.

Central nervous system disorders Another related pair of medical foods branded Sentra AM & PM bridges the seemingly disparate indications between cognitive modulation and management of sleep and pain disorders.

Acetylcholine, a ubiquitous neurotransmitter in humans and the target of the Sentra AM therapeutic, is thought to have an important role in memory formation and cognition, as well as in the arousal component of circadian rhythm regulation. There is also casual, less-well studied links between acetylcholine deficiency and improper modulation of pain signaling in the central nervous

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Richard Isaacson is Assistant Professor of Neurology and Medicine, and Associate Chair of Education at the University of Miami Miller School of Medicine.

system (CNS). In the peripheral nervous system (PNS), acetylcholine deficiency also has an implicated role in sustained muscle contraction, making its supplementation potentially useful in the management of chronic pain and fatigue syndromes.

Sentra AM is purely a cholinergic modulator, providing supplementation in choline and acetylcarnitine which are both acetylcholine precursors. Its claims include the ability to increase amounts of acetylcholine at the molecular level. Small doubleblinded trials with emphasis on imaging data conducted by the manufacturer have demonstrated increased choline in the CNS of treated patients versus selected subjects. The indication thus spans entities as variable as fibromyalgia, sleep/arousal dysregulation syndromes and cognitive decline. Sentra PM focuses on the rebalancing of the excitatory/inhibitory axis of the neurotransmitter milieu, placing its indication within the realm of sleep onset and maintenance regulation. It provides a balanced ratio of precursors-to-neurotransmitters important in sleep onset (serotonin) and maintenance of normal sleep cycles (acetylcholine and glutamate). Eight open label trials demonstrating improved activation of the appropriate PNS (parasympathetic) response in symptomatic patients are reported by the company.

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ROUNDTABLE

Streamlining the drug discovery process Caliper Life Sciences’ Mark Roskey and Bioscan Inc.’s Staf C. Van Cauter tell us how to reduce R&D costs and increase efficiency.

What technologies can companies use to help reduce the cost of drug discovery?

Mark Roskey. One approach to reducing the cost of discovery is to gain more specific pharmacologically relevant information about a candidate drug earlier. Molecular imaging is emerging as a key technique to reduce costs by enabling researchers to test candidate drugs in animal models earlier in the discovery process.

High value and high-throughput longitudinal efficacy studies can be carried out in mouse models using cost-effective optical imaging technology, which can provide detailed molecular information on how much compound is specifically modulating a target. The ability to do rapid dosing studies using fewer animals and the reduced requirement for histological follow-up are also key to reducing cost and getting better quality drugs into clinical testing.

Technologies like IVIS deliver molecular imaging data with high throughput and calibrated precision to meet the demands of drug development on a commercial scale. IVIS has aided the discovery and development of more than five FDA-approved therapies and an increasing tally of compounds in clinical trials.

Staf C. Van Cauter. A major factor in the high cost of drug discovery is the high attrition rate of promising drug candidates at a late stage in the process.

Today, only about 10 percent of investigational new drug (IND) applications for new molecular entities submitted to the FDA progress beyond the investigational phase I. The success rate is even lower in oncology (less than five

The panel

Mark Roskey is currently Senior Vice President of Biology R&D at Caliper Life Sciences. He has a PhD in Microbiology from the University of Notre Dame and completed a postdoctoral fellowship in Molecular Immunobiology at Harvard Medical School. Roskey has more than 20 years’ experience developing tools and technologies designed to accelerate drug discovery.

Staf C. Van Cauter is Executive Vice President of Bioscan Inc., Washington, DC. Prior to joining Bioscan, Van Cauter was Corporate Vice President and Chief Technology Officer of Packard BioScience Company until its acquisition by PerkinElmer, Inc.

percent). The problematic issues that underlie this low rate of approval of new drugs include the lack of tools that can accurately predict the efficacy and toxicity of new agents.

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I believe that translational molecular imaging technologies such as PET/CT and SPECT/CT offer the unique ability to improve the efficiency of this process by enabling a seamless transition from pre-clinical animal testing into human clinical trials. The FDA and other regulatory agencies are facilitating this transition with the recognition of the phase 0 micro-dosing clinical trial phase. I believe that the ability of imaging biomarkers with PET and SPECT across the traditional pre-clinical and clinical gap will translate into improved sensitivity in delineation of viable drug candidates, thus reducing the number and costs of failures.

With looming patent expiries, pharmaceutical companies need to be more efficient in R&D to stay ahead of the competition. What tools can they use to help streamline their drug discovery process?

SVC. With the recent introduction of the new nano-nuclear imagers, such as the NanoSPECT and NanoPET (Bioscan, Inc., Washington, DC), it is now possible to obtain images from mice – 1500 to 2000 times smaller than humans – with virtually the same detail as can be obtained with human PET and SPECT scanners in the clinic. By combining nanoliter volumetric resolution with picomolar detection sensitivity, these tools can now be used early and throughout the entire drug discovery process. This includes validating therapeutic targets in mouse models of human diseases, optimizing candidate agents and providing proof of concept for these agents in larger animal models, enhancing the mechanistic understanding of drug or drug combinations, and even distinguishing, early on, responders from non-responders.

Therefore, these tools can clearly be used to streamline the entire drug discovery process.

MR. The R&D discovery process can be streamlined by linking early phase target identification and screening with the rapid evaluation of safety and efficacy parameters in animal models. By decreasing the turnaround time between identifying new lead molecules and validating efficacy in vivo, candidate drugs can be triaged much more quickly.

Specific tools to accomplish this include higher quality compound identification and profiling platforms to ensure upfront activity, and tools such as molecular imaging, which can be used to effectively link in vitro activity to in vivo efficacy.

Getting drugs into animals sooner streamlines the development process. A complete in vivo optical imaging platform makes this approach feasible because it is cost effective to use in a high-throughput mode early in the discovery process.

Drug firms are facing increasing demands for compliance from regulatory bodies. What tools can they use to help meet these requirements?

MR. Pharma companies are now starting to implement quality by design (QBD) processes and metrics earlier in the discovery process as an approach to generate the appropriate supportive data and ensure downstream compliance with regulatory standards. These QBD processes are being implemented on standardized laboratory robotics and analytic tool platforms designed for reproducibility and high quality analytical data generation.

One specific tool that is being implemented in this format is the LabChip GX platform. This microfludics-based, high-throughput, protein characterization and analysis platform rapidly generates very reproducible and high quality data supporting QBD approaches and generating appropriate data for regulatory submission. Leading biotechnology and pharmaceutical

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companies have adopted this platform as a component of their QBD systems used specifically to characterize and QC protein therapeutics and follow-on biologicals.

SVC. By pointing to the location in the body of diseased tissue and monitoring the effects of therapeutic agents over time, the non-invasive PET and SPECT imaging techniques allow experimentation in a physiologically relevant tissue context, thereby avoiding the artifacts and pitfalls often associated with tissue processing in ex vivo and in vitro assays.

As the FDA points out, the search for a new drug can only be confined to a laboratory test tube until the point at which research is aimed at discovering “what a drug does to the body.” After that, animal testing is required to find out “what the body does to the drug.” Given the high failure rate of compounds entering clinical testing, and the ability of PET and SPECT imaging to test drug candidates as they move through the entire development process, I believe that non-invasive testing with these technologies, in combination with biomarkers for efficacy and toxicity, is critical to make the development of medicines faster, better and safer.

How do you see the future of drug discovery developing in the next few years?

MR. Drug discovery scientists are recognizing the multifactorial nature of disease as well as the biological redundancies that have evolved to compensate for inhibition of a particular molecular target. As such, future discovery efforts will be increasingly focused on more complete characterization of the complex biology of a particular disease. Technical approaches to inhibit, activate and monitor molecular effects on pathways in relevant animal models will drive the more rapid development of successful candidate drugs.

In vivo imaging of cellular pathways using optical reporters is becoming a significant trend in molecular imaging. Monitoring the signaling process in whole animals using IVIS provides the most relevant readout from a complex set of interactions. IVIS data also co-registers with more translational modalities to provide a direct link to dosing regimes and clinical trials.

As new drugs are accelerated from pre-clinical testing into clinical trials it becomes increasing important to establish relevant companion biomarkers, including optical imaging biomarkers, which will be used to monitor dosage, efficacy, development of drug resistance and identify responding patient populations.

SVC. I believe that the concerning downward trend in regulatory approval for new drugs can be reversed by the use of appropriate tools for imaging biomarkers. Many novel drugs fail at a late stage because they have not been tested at earlier stages in a relevant physiological environment of living specimens, or they fail because they may have been tested in inappropriate patient populations, thus not being able to demonstrate the clinical benefit that is required for marketing approval.

Many of these challenges can be overcome by using non-invasive PET/CT and SPECT/CT micro-imaging tools throughout the process. These tools enable us to visualize disease biology at the nano-volume level and to monitor and quantify the effect of candidate therapeutics on disease pathology with picomolar sensitivity. Such tools can therefore identify therapeutic and toxic effects early and assist with the selection of optimal patient target populations, thus significantly improving the chances for success in drug discovery.

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EXECUTIVE INTERVIEW

A TARGETED APPROACH

In what ways can researchers use the information generated by this process?

SC. Researchers can use this information to make decisions in clinical development. Not only can microarray technology determine the normal versus diseased profi le, this technology can be used to examine the effects of compounds used to treat the diseased state.

Clinical researchers can then evaluate a go or no-go decision for the compound based on the treated and untreated profi les. In addition, clinical researchers can use this information to help design therapies to decrease or increase protein levels by altering gene expression. For example, if a gene is over-expressed, silencing RNA or interfering RNA therapies could be used to block much of the diseased RNA from being translated into protein thus reducing protein levels to a more normal state.

How does DNA microarray technology help researchers learn more about conditions Scott Clark tells NGP why microarray technology is proving such as heart disease, infectious disease beneficial for drug discovery. and cancer?

SC. DNA microarray technology can aid What are the specific applications of miSC. Comparative analysis of genes from disresearchers in examining many genes sicroarray technology within the drug discoveased and normal cells can help identify premultaneously, which reveal linkage between ery process? dictive biomarkers for early disease diagnosis polymorphisms and disease as well as linkScott Clark. Microarray technology is providand predict the proteins synthesized by the age between polymorphisms. These profi les ing new opportunities for growth in the drug diseased genes needed can help in disease screendiscovery process. Thousands of genes/alleles for the development of ings, which may help with can be examined simultaneously for gene extargeted therapies. Aldownstream therapies. For pression profi ling or genetic alterations, such though DNA microarray example, in patients with caras SNP or copy number variations. Microarray technology can deterdiac disease such as long QT, technology can be used in pharmacogenomics mine genetic alterations DNA microarray technology to examine correlations of drug response with in diseased cells versus can identify certain polymorDNA polymorphisms or alterations in gene exnormal cells, not all of phisms for that disease. Using pression. Microarray technology is used in toxithese alterations affect this information, certain cogenomics by examining responses to toxicant gene expression or propharmaceuticals would be exposures that can be used to prevent adverse tein synthesis of the contraindicated if the medicaScott Clark has more than 16 years effects in clinical populations. Yet another apgene. However, comtion prolongs QT. For cancer of experience at pharmaceutical plication would include the use of genome wide paring gene expression researchers, DNA microarray and clinical research companies in technology assessment and association studies to examination genetic dislevels with DNA mutatechnology can help identify applications, assay development, laboratory management and ease’s such as Alzheimer’s disease, which can tions in the same target polymorphisms associated project management. Clark joined reveal novel genes involved in the disease. genes can determine with certain cancers as well Gentris Corporation in September 2001 as Laboratory Director and what genetic alterations as identify polymorphism in was promoted to Chief Scientific Officer in July 2008.

How does the use of microarray technology affect RNA levels. An drug metabolism enzymes. in the comparative analysis of the genes increase or decrease in The identification and downfrom a diseased and a normal cell help in RNA levels can indicate stream result of this analysis the identification of the biochemical contoo much of a protein being produced, not is adjustment of a patient’s therapy to develop stitution of the proteins synthesized by the enough protein being produced or an altered a personalized medicine that will be efficadiseased genes? protein being produced. cious and safe.

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EXECUTIVE INTERVIEW

Emerging genomics Klaus Weinberger explains the potential of metabolomics to revolutionize 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 recognized 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.

nogenic diseases, which 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.

Are there other practical applications of metabolomics?

KW. The range of potential applications is wide and varied. Besides neonatal screening, metabolomics is currently applied in biomarker and diagnostics research and in drug

“Metabolomics is the systematic identification and quantification of metabolites in a biological sample” Is there already a proof-of-concept for metabolomics?

KW. The proof-of-concept for targeted metabolomics was fi rst 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 revolutionized 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 mo-

development. It can be used to uncover new drug targets, prioritize lead compounds and assess drug toxicity, enabling the development of novel, smarter and safer drugs. At the same time, metabolomics will help identify individuals likely to benefit from a given therapy.

Yet, the diagnostic potential of metabolomics is not confi ned to metabolic disorders.

For example, metabolomics may help identify individuals at risk of diabetes, and it will have a broad range of applications in diseases such as cancer, chronic kidney disease and neurologic disorders. Another success for metabolic markers has been the ability to diagnose renal, liver and heart organ transplant rejections.

Also, metabolomics is widely used in nutritional 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.

What is your vision for the future of metabolomics?

KW. Metabolomics has the potential to revolutionize diverse areas of life. A thorough understanding of disease-related metabolic processes will allow us to utilize new markers for both diagnosis and therapy. Importantly, these markers will be able to be identified from samples that are easily obtainable by non-invasive procedures using readily accessible biofluids, such as plasma or urine.

Assessment of the metabolic characteristics of individual patients will lead to the development of personalized treatments and enhance the benefit a given therapy has for an individual patient. Metabolomic analyses will become part of the standard repertoire of laboratory diagnostics in both human and veterinary medicine.

Apart from its medical applications, however, other aspects of daily life, such as healthy nutrition or optimized exercise, will also be addressed by metabolomics. Thus, by analyzing a person’s specific metabolic reactions towards food intake or exercise, it will be possible to customize 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 optimization 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.

Klaus Weinberger is a biomedical scientist with particular expertise in metabolomics infectious diseases, public health and immunology. Before joining Biocrates, he led a research group at the University of Regensburg.

Weinberger holds an MSc in biophysics, biochemistry and microbiology, and a PhD in medical microbiology from the University of Regensburg.

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INDUSTRY INSIGHT

Searching for the holy grail of single-use solutions

By Barb Paldus

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any biotechnology companies are transitioning their stainless steel infrastructure to single-use or disposable systems in order to reduce scaleup costs and facility capital expenses. As singleuse bioreactors have matured, their market acceptance has rapidly expanded. The move to disposables is, in many instances, driven by reduction in sterilization and cleaning requirements, improved plant flexibility for multi-product manufacturing, reduced product changeover costs and faster time to market for new products. As the average titer (g/L) produced continues to increase, the size of bioreactor vessels required in manufacturing will decrease; this trend will further accelerate the transition to disposable bioreactors in production environments.

In order to fully enable the single-use paradigm, the automation software, hardware and single-use sensors must be designed specifically for this application. Automation hardware systems used with single-use bioreactors must be flexible, in order to adapt to the different processes that can be run in a multi-product facility. Hardware must be user-friendly and plug-and-play with a wide variety of external equipment, such as pumps, scales and off-line analyzers. In addition, and especially for CMO customers, the bioreactor control system must have a modular design, allowing fast and easy reconfiguration of the bioreactor train for different bioreactor sizes and types, as well as different processes or cell lines, such as batch, fed-batch or perfusion.

Automation software should allow rapid scalability of a process through advanced process models and smart algorithms, as well as ease of data collection and analysis. The software should allow easy process reconfiguration through drop-down menus without any programming, and allow the user to save and load process recipes for accelerated process scale-up or transfer. The software should be vessel agnostic, so that it can be used with glass vessels and single-use rocker or stirred-tank bioreactors, to provide a seamless integrated solution from R&D through production. For true scalability, the software must be developed with GAMP5 methods and therefore be validatable for cGMP applications.

Single-use sensors, to date, are the critical missing element for upstream bio-processing. Specifically, there is a significant need for disposable sensors for dissolved oxygen, pH, temperature and pressure, which are pre-inserted into the single-use bioreactor bag and gamma irradiated with the bag so that the entire system arrives sterile, and the time from unpacking the bag

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to inoculation is minimized. Smart sensors which arrive in the bioreactor pre-calibrated and thereby minimize operator time during process setup, are the industryâ&#x20AC;&#x2122;s ideal.

A visionary supplier will provide turnkey, configure-toorder measurement and automation solutions for different single-use bioreactor types. This supplier will also provide full support for its systems, including installation, training, validation packages (FAT, SAT, IQ/OQ), leachables/extractables certifications for all single-use components, and service/ maintenance programs. Moreover, this supplier would have cell culture capability and be able to provide complete bioreactor and sensor solutions, and also cell line development and media optimization services, in order to minimize the risk to an enduser of transitioning a process to single use, and scaling up pro-

â&#x20AC;&#x153;Single-use sensors are the critical missing element for upstream bio-processingâ&#x20AC;?

duction. Taking one last step, this supplier would also be able to provide complete, single-use solutions for downstream applications and optimize the entire process end-to-end with yield modeling.

Today, there is no such ideal supplier. Several alliances in the industry have formed, but no true one-stop-shop has yet emerged. In addition, most suppliers have a very limited cGMP installed base and track record in single-use systems, and have not made serious inroads into single-use downstream processing. The single-use flexible factory concept remains the holy grail.

Nonetheless, in the next few years, especially with the ongoing industry consolidation between larger and smaller players, we expect that such an ideal supplier will eventually emerge. n Barb Paldus was most recently the CTO of Picarro, a company she founded in 1998. At Picarro, she was responsible for technology strategy, research and business development, which led to a solid-state Cyan laser product in 2003 and cavity ring-down spectroscopy products in 2004. Paldus is currently a partner at Skymoon Ventures. She received both her PhD (1998) and MSEE (1994) degrees in electrical engineering from Stanford University, and her BS (1993) in electrical engineering/applied mathematics from the University of Waterloo.

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VACCINES

Gearing up for battle Novartis Vaccines’ Andrin Oswald tells NGP how the company is preparing for the next wave of H1N1 mutations, and why a new manufacturing process is needed to provide faster vaccinations.

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s the winter months draw near and seasonal influenza begins to dominate headlines, Novartis Vaccines began the process of shipping its vaccine to US healthcare facilities several weeks ahead of schedule. Andrin Oswald, CEO of Novartis Vaccines, explains the company’s desire to provide the opportunity for early vaccination.

“Since we did not know whether healthcare officials would want to vaccinate seasonal and H1N1 together or separately, it was clear to us that if we shipped seasonal quickly, we could get it out of the way before the H1N1 vaccination would have to start,” he explains.

Novartis provides approximately 30 million doses to the US each year, and this year intends to provide the same amount as last year. “When we started H1N1 vaccine production, we decided that since we didn’t know exactly how the pandemic would play out, it would be responsible to produce the same amount as was needed last year. That’s what we did, and then we switched to H1N1.”

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Providing an H1N1 vaccine was always going to be essential, but it was still uncertain whether this would be combined with a seasonal vaccine or if it was to be given separately with a three-week interval. Oswald explains that the ambiguity surrounding the H1N1 vaccine has brought forward seasonal vaccines.

“Once the H1N1 vaccine becomes available in October, you don’t want to have to wait another three weeks because you’re still vaccinating seasonal. So in principle, seasonal now could be vaccinated ahead of H1N1, and when H1N1 becomes available, we could immediately start that program as well.”

Novartis’ clinical trial for the H1N1 vaccine began in July, and since then, Oswald explains, the first set of data has become available, which was published in the New England Journal of Medicine in September. He notes that the first data from other clinical trials are also now available, and although they have not yet been published, they have been communicated to the respective health authorities in order for them to make the appropriate decisions.

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into the relevant immune cells, which both boost the immune response to the vaccine “You can produce more because normally the antigen production is the limiting factor for the volume we can produce,” says Oswald. “With the adjuvant you can probably stretch that by a factor of four. It also helps to boost supply, but that’s not the only reason we use the adjuvant. We also use it because it allows for better cross-protection, especially in a situation where one doesn’t know when and how the virus will mutate. Having an immune response that gives you some protection even against mutated forms of the virus is very valuable.

“For flu vaccines some adjuvants – such as aluminum – don’t work well, so there was a need for a new adjuvant, and this new class, called squalenebased adjuvants, are very effective. Our adjuvant has been on the market in Europe for 12 years with more than 45 million people vaccinated, so we have by far the longest safety history and from that point of view can clearly say that the adjuvant is unique,” he underlines.

Novartis’ work in vaccine development has certainly not gone unnoticed.

The company has been awarded two contracts by the US government for the future purchase of H1N1 bulk vaccines and is expecting several other orders to follow. Oswald explains that in September, the company is already sold out beyond the end of 2009. “We are not giving the exact data on specific orders because we leave it up to the respective governments to be in charge of communication, but we expect that we can produce 80 to 100 million doses by the end of the year, and for the time being we have more demand than we can deliver.”

Pandemic preparation The vaccine was created at a fairly rapid pace, thanks to a system that exists to prepare for a pandemic as much as possible. Oswald notes that in Europe the company has a pandemic vaccine already filed and approved under a mockup file, so in principle when a new virus develops, the file can be approved immediately once a pandemic is declared.

“We also have technologies that allow us to Andrin Oswald operate as quickly as possible, in particular in our cell-based manufacturing system, by which one could gain a couple of weeks of speed over the traditional egg-based manufacturing and by that make a new vaccine available somewhat earlier. In the case of a severe pandemic, a few weeks can make a big difference,” says Oswald.

Novartis Vaccines’ proprietary adjuvant, MF59, also plays a role in pandemic preparedness. MF59 is the first oil-in-water influenza vaccine adjuvant to be approved for use and commercialized in combination with a seasonal influenza virus vaccine. It works in two ways: by recruiting immune cells to the injection site and by promoting the uptake of antigen

“It is very likely that we will see different mutations in H1N1 in different parts of the world” H1N1 mutation However, developing a vaccine for H1N1 is not straightforward. Experts have speculated that the virus is likely to mutate into a more virulent, deadly form when the winter flu season starts, and Oswald agrees with this. “It will happen because flu viruses do mutate,” he explains. “We see that with the seasonal flu viruses as well. They normally mutate when there is pressure for them to, which is at the time when a fair number of the population has already been infected; because if the virus hits someone who already has some protective antibodies, then it is under pressure to mutate to survive and keep going. I would expect mutation to happen not in the first wave but in a second wave of the pandemic, when maybe 20 to 30 percent of the population has already been infected and has some protection.

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“Then we normally see the virus drifting and making small mutations to become more virulent to survive. That doesn’t necessarily mean that the virus becomes more pathogenic or more severe; that is not necessarily the case. It’s just different. Even if you’ve had the earlier form you could get it again, and of course the people that didn’t have it would still get it. It wouldn’t necessarily be more severe, but it’s a challenge to the vaccine because the mutations could make it somewhat less effective. Hence, our belief that with an adjuvant one has a higher chance of vaccinating with something that would still protect if these small mutations happen.

“When these mutations happen we will develop a new vaccine, particularly addressed against that mutated virus, but that takes a couple of months, so there is a significant window until a new tailored vaccine becomes available. It is also very likely that we will see different mutations in different parts of the world; we see that with seasonal flu as well. There may be one mutant that will start to spread in the US and a different one in Europe and a third one somewhere in South America, and given that we cannot develop tailored vaccines for each of these regions, the adjuvant allows you to give some broader protection.

“We are now responding to this pandemic as well as we can, but we will have to ask ourselves the question: how do we prepare better for future pandemics? The avian flu, for example, is not completely off the table, and a more severe pandemic can definitely hit us more or less anytime. It’s not about creating panic, that’s not what we want. What we want is to make sure we’re so well-protected that there is no need to panic.

“Our systems today have significant shortfalls in terms of us being able to protect the world population against a severe pandemic. We should learn from the current exercise and be able to quickly come up with as many better solutions as are needed for the future. I would love to see more of the debate shifted over towards that,” he says.

Oswald suggests that prevention could be enhanced by a more efficient production capacity, noting the current pressure of shipping vaccines to developing countries. If there’s not enough capacity for the countries that have invested and built this capacity, how can we expect it to be available for other countries that have not done so? His solution is to build a sustainable production system that can supply the entire world, adding, “That should not

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Cell culture manufacturing Novartis Vaccines is currently the only company that has a licensed cell culture-based technology to produce influenza vaccine antigen. Since many viral strains cannot replicate in chicken eggs, cultivating viruses using a cell line offers the possibility of a more robust virus production and seed strain development that more closely matches circulating viruses, which could potentially translate into a more immunogenic and effective response.

The use of cell-based manufacturing enabled Novartis to cut weeks off the time required to begin H1N1 vaccine production. First results achieved with the A(H1N1) wildtype strain show the significant time savings of cell-based production over the traditional egg-based manufacturing approach, confirming the value of cell-based production in pandemic situations.

happen by forcing donations in a pandemic, but it should happen so that the capacity would be available.”

He also argues for bigger and better investments into new technologies, again citing the shortfalls of egg-based production. “We need the financial incentives for companies to be attracted by that, because with a lower demand and lower prices in many countries for seasonal flu, we simply cannot afford to aggressively invest into new technologies, so we have to think about how to address this and how to create the right incentives for innovation.

“Finally, from a patient point of view, there are still too many hurdles that stop us from being really quick. We have to think through with the different authorities and regulators how in a real emergency one could make a vaccine available in two months. That’s possible, but we would have to cut out some of the hurdles if a pandemic were to be severe,” concludes Oswald.

With not much time left before the winter flu season begins, it remains to be seen how the industry will cope with the crisis. Novartis’ preparedness for the pandemic and its mutations means it is already one step ahead of the game.

ASK THE EXPERT

A new level in next generation sequencing Peer Staehler tells NGP how the molecular profiling of large patient cohorts is enabled by high-throughput sequencing.

T

he capacities of modern next After all non-hybridized fragments are washed generation sequencing (NGS) away, the enriched target DNA is eluted and technologies have been catacan be directly applied to NGS platforms. pulled to a new level during the The microfluidic chip architecture reduces past two years. The remaining the volume and amount of DNA needed for limitations for large-scale molecular profi lNGS. The eluted DNA can be directly applied ing, which include throughput, cost, data to next generation sequencers and enables management and automation issues, can now studies without the bias of PCR-amplification be circumvented by a brand new technology, or other methods currently on the market. enabling deep re-sequencing of selected parts HybSelect offers unmet advantages: short of the genome. Febit is offering this new powhands-on time (minutes instead of hours), a erful technological solution, which provides high degree of reproducibility and unmatched all the required features: robust automation, parallelism in selecting several genomic samsimple assay workflows and manageable data ples at a time. pipelines.

Recent applications Th is highly automated and capable techIn several biomedical studies of early nology from febit is called HybSelect. The access customers over the past months, Hybextended multiplexing capability and high Select demonstrated superb enrichment facdegree of automation of HybSelect make it tors and deep sequencing coverage for a broad an affordable way to conduct NGS for large range of diseases and cancer-related human cohort studies of hundreds or thousands genes and genomic regions. of patient samples. Such Scientists at the TGen Institute comparative and meaningin Phoenix, Arizona, are currently ful large-scale studies can using HybSelect’s sequence capture help the pharmaceutical technology to discover diagnostic and diagnostic industry to biomarkers for Alzheimer’s disease, develop enhanced knowldeveloping a set of markers for edge about the genesis and monitoring disease progression. progress of diseases. The Researchers at the German improved understanding Cancer Research Center in Heidelresulting from individual berg, Germany, used HybSelect molecular profi ling holds to perform an NGS study on the potential for further Peer Staehler has acted as the Chief Scientific Officer samples from approximately 200 personalized therapies. at febit holding gmbh for patients. They identified a specific over 10 years. As co-inventor of the Geniom Technology Sequence capture microRNA marker associated with as well as co-founder of the company itself, Staehler doubled survival rates in a certain The core of HybSelect is an expert in the biochip type of cancer. An ongoing study is a highly efficient microsector and benefits from his many years of experience in at the Saarland University, Gerfluidic biochip that uses the biotechnology industry. many, investigates malignant brain robust automation, fast procancer by deep-sequencing of the cessing and high-density 100 most relevant genes. microarrays as a binding matrix. The biochip HybSelect will be one of the workhorses is synthesized with capture probes (oligofor the detection of novel tumor markers at the nucleotides) specific to the genomic region of newly developed Biomarker Discovery Center interest in a particular research project. They (BDC) in Heidelberg, Germany. The BDC is serve as bait for the desired DNA-fragments.

currently working on about 20 oncology and five inflammatory disease-related projects that are using febit’s technology together with ABI and Illumina next generation sequencers.

Moving forward HybSelelect will allow the characterization of exons from hundreds of genes involved in complex diseases. Currently, the identification of new tumor-specific mutations as well as aberrant non-coding RNAs (ncRNA), like microRNAs, is under way. The determination of novel markers in comprehensive large-scale studies will be an important step towards standardized diagnostic assays as well as the development of new ‘personalized’ pharmaceuticals and the investigation of new therapeutic delivery models.

Febit will stay at the forefront of cancer research with the 2Mb exon cancer biochip released this summer and a 30Mb biochip planned for release in 2010. The demand for comprehensive and effective technologies like HybSelect will grow dramatically alongside the expanding understanding of biologic pathways and genetic regulation.

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ASK THE EXPERT

The challenges of biomarkers The implementation of biomarkers for patient stratification to improve oncology-targeted therapies is still an extremely challenging endeavor with limited success.

By Peter Duncan

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lthough we are now beginning to benefit from the genetic, genomic, and proteomic discoveries made over the last decade, the implementation of biomarkers for patient stratification to improve diagnostics, prognostics and companion assays for oncology targeted therapies is still an extremely challenging endeavor with limited success. This is due to many factors, including the lack of implementation of true systems-based approaches in clinical development to achieve multiplexed, multi-parametric, phenotypic profiling of protein biomarkers and corresponding tissue microanatomy.

Accurate prediction of biological events, whether it be disease prognosis, toxicity or therapeutic response, will become increasingly similar to how we predict other multivariate phenomena; for example, the weather. 100 years ago farmers had to rely largely on qualitative, non-integrated

“This oversimplification of the problem further inhibits our abilities to make strides in diagnosis” methods such as a weathervane, cloud patterns and an almanac for identifying weather trends.

Today, when one wishes to see the weather forecast, a visit online to any one of a myriad of weather-related websites provides a variety of images and quantitative information at our fingertips. Multivariate modeling integrates several factors (such as images, temperature, barometric pressure, wind speed and historical data) yielding accurate weather forecast information, which we are then able to make decisions with.

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There is no doubt that our efforts in ‘foresuch as Herceptin, response rates are still lower than casting’ biological events could benefit from a desired even among patients who have been classisimilar approach. However, at the present time, fied as potential responders via a companion assay, we are often looking for ‘silver bullets’ that will fasuch as immunohistochemistry. Although a parcilitate medical decisions, drug prioritization or ticular patient may have an over-active angioclinical trial enrichment. In the press, we often genesis-related biomarker that shows up in the read about a single gene or protein that is responimmunohistochemical test, there is currently litsible for cancer. This kind of over-simplification tle opportunity in the clinical development of the problem further inhibits our abilities to process to stratify patients by utilizing the simake strides in diagnosis, prognosis and drug demultaneous measurement of biomarkers that velopment. belong to multiple pathways. These other pathCompounding the problem is the fact that ways may be compensating when the original the current sequential clinical drug target is inhibited, leading development paradigm does not to the low response rates we are facilitate the development of faced with today. multivariate assays that can aid a A few solutions might be better understanding of how for the FDA to facilitate a clinmultiple signal transduction ical development process that pathways can affect the progresis more interactive than sesion or therapeutic response of quential, which could facilitate an individual’s unique cancer. true systems-based, multivariThis is because in order to develate approaches. Additionally, op these kinds of assays for a spefurther guidance for in vitro dicific patient set, pathologists agnostic multivariate index asPeter Duncan joined Definiens need access to patient tissue samsays (IVDMIAs) is needed.

AG in December of 2008 as ples from the specific clinical trials Bio-pharmaceutical drug deGlobal Director, Marketing and Business Development, which they are conducting. Phase velopers, cancer research cenLife Sciences. In this capacity, Duncan manages external III clinical trials usually include ters, technology providers and collaborations with leading adequate patient numbers for clinical service labs should cancer centers, industry partners and biomultivariate assay development. work together more closely, pharmaceutical companies.

He has over 15 years of However, by the time clinical trisynergizing efforts where posexecutive sales, marketing als are in phase III, it is too late to sible. As described in the article and business development experience spanning the develop a training model, validate in ‘Imaging is Key to Success in analytical chemistry, biotechnology, and diagnostic the model and then run an addiTranslational Research and industries. He holds a BS tional prospective study to Drug Development,’ image indegree in Biochemistry from the University of Vermont. demonstrate feasibility under telligence solutions that can be FDA guidance. As such, bioimplemented across the entire pharmaceutical companies are biomedical continuum will forced into a dynamic that often only considers the also be needed. Further, we should accept that target in question (Her2/neu and EGFR) or related complex biological problems will require sysmolecules within the pathway that the therapeutic tems-based approaches to understand them as agent seeks to perturbate. The result is that even opposed to approaches based on an oversimplithough we have examples of personalized medicine fication of the underlying biology.

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PROJECT FOCUS

Risk assessment across the drug development process

By Nigel Goode

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isk assessment in drug development is often discussed at the clinical trial level. From in vitro studies to phase I, II and III trials through to market applications, clinicians measure safety, tolerability, toxicity, side effects and a variety of other factors related to the mechanisms and safety profi le of a given drug. However, beyond risk assessment at the clinical level, quality risk assessment across all stages of the product life cycle is critical to minimize and avoid risk to development programs and patient safety.

Quality risk assessment procedures and techniques at the operational and scientific level are fairly standard, but true forwardlooking quality risk assessment involves adopting and employing a holistic operating approach to include people, procedures and equipment; conducting regular internal auditing; and developing action plans to ensure that opportunities to impact risk are identified and acted upon.

cords and a variety of other categories. During this process, they should also ensure that their strategic partner has an ongoing commitment to and processes around risk assessment and management, and that the organization continuously seeks ways to improve its people, procedures and equipment to minimize and avoid risk to its clients’ programs and the patients at the end of the line.

A holistic operational approach to risk assessment is the most effective way to ensure the quality of client data and development activities and to protect patients. By identifying potential scenarios of breakdowns in any given system, it is possible to predict what could happen if things went astray, and address those possibilities before they would ever become a reality. A holistic approach not only isolates a potential risk at a single point in a piece of equipment, but also takes a systemic view of the entire network of equipment, pro-

cedures and protocols within the facility, and the expertise of the people involved in the process. It involves making sure the people in our labs and facilities have a working knowledge of not only just how to do the work, but also knowledge of why we do things the way we do to make informed decisions when executing on our clients’ projects.

Aptuit’s commitment to quality risk assessment places an emphasis on internal auditing, internal and external transparency, preparing risk assessment reports and policies based on ongoing analysis, and taking action on areas we identify that would benefit from improvement. Forward-looking risk assessment is vital to the success of drug development, and it is part of a deep commitment to the success of our strategic partnerships. It is ultimately a commitment to the industry in which we operate, as along with the potential risks involved in drug development efforts comes the potential of big rewards for science, our businesses, healthcare, and ultimately and primarily, patients.

Nigel Goode is the Senior Director of Aptuit’s Active Pharmaceutical Ingredient division, where he is focused on the quality of the company’s development and manufacturing services. He has over 30 years of experience in pharmaceutical research and development.

“Quality risk assessment across all stages of the product life cycle is critical to minimize and avoid risk to development programs and patient safety”

Drug developers that engage with a strategic outsourcing partner not only tap into the potential to reduce timelines and address specific issues with a compound’s drug profi le, but also quality risk assessment throughout the drug development process that can have great impact on the success of the overall program.

Drug developers audit their outsourcing partner at the onset of the relationship in relation to regulatory standards, delivery to promise re-

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IMAGING

BEATING CANCER Tumors continue bypassing cell pathways while molecular biologists doggedly try to understand how cancer works. Haren Rupani explains why we are still in the infancy of our cancer knowledge, and the importance of imaging in combating the deadly disease.

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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 imaging 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 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 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.

“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 response, 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.

“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 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-center organization con-

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ducting multi-regional trials poses challenges for imaging. Rupani notes one as being standardization 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.

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

“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” “Standardization 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 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. Standardization is the most critical, and there are a lot of challenges that come in trying to standardize because you have different equipment, you have different ways of calibrating the machines, and that becomes a process. Standardization 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 regulatory 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.

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, 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. Th is 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 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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BRUKER EXEC_4August 30/09/2009 15:08 Page 80

EXECUTIVE INTERVIEW

Quality control John Richmond tells NGP about process analytical technologies for the pharmaceutical industry.

How does Bruker’s approach to process analytical technology align with the FDA principles?

John Richmond. The FDA announced their guidance on process analytical technology (PAT) in 2003. Since then, many pharmaceutical companies are utilizing modern spectroscopy techniques for multivariate data acquisition for process and end-point analysis.

Bruker adopts a science- and risk-based approach to any potential PAT implementation.

We will discuss with the end-user the critical quality attributes and how we propose to monitor and control these. We will discuss the implementation in detail with the end-user, identify potential technology solutions and in many cases carry out proof-of-principle trials. We will support this with extensive documentation and validation procedures, including onsite IQ/OQ/PQ. Finally, we will support method development and suggest relevant validation procedures for these methods.

“What a PAT solution does is test either continuously or more frequently during manufacture to reduce the risk on moving to the next stage”

Why are online, real-time methods important for quality control?

JR. Conventional laboratory-based measurements focus on testing the quality of materials at the end of each manufacturing phase, with the aim of reducing the risk on moving to the next stage. However, if that manufactured material is out of specification (OOS), there is very little that can be done. It is not possible in this case to induce quality by testing after the fact. What a PAT solution does is test either continuously or more frequently during manufacture to reduce the risk on moving to the next stage. This is very beneficial and will result in better product consistency, no OOS materials, reduced batch cycle times, more efficiency and ultimately lower cost of manufacture. The eventual aim is for reduced work in progress (WIP) and real time release (RTR).

Please describe a few case studies where Bruker technology has been implemented in a PAT solution.

JR. Bruker is the world’s leading supplier of successful PAT solutions, and we have many examples of implementation where the end-user has been able to file a method with the FDA based upon Bruker technology measuring a critical quality attribute (CQA). We are able to monitor CQA for incoming raw

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materials, blending, granulation, drying and on finished products. In API manufacture, we use infrared and raman spectroscopy to determine reaction end points and to monitor and control crystallization and distillation processes. These non-destructive spectroscopy techniques are already used in various industries for process monitoring applications.

Three areas I’d like to concentrate on are blend homogeneity, content uniformity and check weighing. In the blending process, Bruker has developed novel technology based on NIR diode array technology, packaged in a small wireless system that is easy to implement. This technology gives a real-time output of blend uniformity, as well as measuring percentage of API and percentage of magnesium stearate. For content uniformity, Bruker has developed a unique online tablet analysis system, which combines traditional physical measurements (hardness, weight) with chemical composition (content uniformity). This integrated analyzer has been used by the major pharmaceutical companies to measure tablet cores, and this methodology has recently been filed with the FDA. The third area to mention is implementation of time domain NMR for online contact free check weighing of vials and pre-filled syringes in the packaging area. This non-destructive method provides a fast, through-the-packing measurement of the pharmaceutical compound directly. These are just three examples that demonstrate the ‘fit-for-purpose’ implementation of Bruker technology as part of a PAT solution.

Bruker offers many technology platforms for PAT – we are not trying to make one technology fit every application. We evaluate each potential application and offer a technology that is fit-for-purpose. Instead of a traditional vendor relationship with our customers, we have more of a partnership, where key scientists and engineers from Bruker become part of the overall project team. By being involved at every stage from initial consulting to eventual implementation, we are able to help manage the project and the expectations, to ensure success. n

John Richmond joined Bruker Optics in 2000 and is currently Vice President, Business Development. He has been working in the area of process near infrared spectroscopy since 1988 and has experience in developing and implementing solutions in the pharmaceutical, chemical, and petrochemical and food industries.

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ASK THE EXPERT

Biomarker assay development

By Ralph McDade

D

iscoveryMAP v 1.0 is RulesBased Medicine’s (RBM) newest and most comprehensive biomarker assay, measuring 189 clinically relevant proteins from a single 500 microliter sample of serum or plasma. The service offers drug developers broad coverage of the most physiologically relevant pathways, providing key biological information, leads for further study and support for go/no-go decisions. The sheer number of important analytes in a single test increases the odds of identifying new protein biomarker patterns in almost any drug development or diagnostic discovery project.

We developed DiscoveryMAP because when it comes to identifying meaningful biomarker patterns, more data is better.

DiscoveryMAP was designed in response to requests from our biopharma customers who recognized the value of combining our various human MAP services into a single comprehensive assay.

There are a host of benefits with this new service. DiscoveryMAP utilizes RBM’s proprietary multi-analyte profi ling (MAP) platform to quantify key blood-based biomarkers representing dozens of important biological pathways. With this platform, customers receive the most robust, quantitative data compared to any other available proteomic service or platform technology. All samples are processed in RBM’s CLIA-certified lab using proprietary reagents and soft ware to give the most accurate and reproducible protein measurements.

Second, multiplexing allows all of these assays to be processed from a 500 microliter sample of serum or plasma, compared with single-plex platforms, such as ELISA, which would require 10 to 15 milliliters of sample. And fi nally, all samples are processed on an industrialized,

automated platform that enables the discovery rations to develop diagnostic and companion of biomarker patterns made up of multiple diagnostic applications based on patterns deproteins, many with small, yet reproducibly tected with DiscoveryMAP. detected, changes.

Using the RBM approach, researchers While being a cost-effective way to meaare able to quantitatively interrogate a larger sure 189 analytes, it’s also the first step of a pronumber of proteins in order to identify biocess that can yield a new custom panel tailored marker patterns on which to focus further for each customer’s needs. DiscoveryMAP research. To illustrate the effectiveness of includes biomarkers known to be important in this approach, 30 years ago researchers found the major disease indications for drug develthat blood cholesterol was a good marker for opment. Once a pattern is discovered, we can cardiovascular risk. Unfortunately, elevated convert those biomarkers into a new custom cholesterol only identified roughly 50 percent panel for high-throughput sample processing of the at-risk population. Eventually, research in clinical trials as a service from RBM or supuncovered the role of lipoproteins (HDL and plied to the customer as an optimized kit. And LDL) which showed better predictive value since all of our work is done than cholesterol alone. on a clinically-validated platToday, research has idenform, our biomarker pattern tified 25-30 blood-based discoveries are more easily markers that provide even applied throughout remainbetter predictive value ing clinical trials. in assessing cardiovascuThese benefits are more lar risk. The problem is than theories. DiscoveryMAP that measuring all of these has already been successfully markers has been prohibiused in the discovery of new tively expensive and unrelidiagnostic biomarker panels. able. Applying multiplexing RBM’s partnerships with technology, the RBM apPsynova Neurotech, Satoris, proach provides drug Ralph McDade is the Strategic Development Officer for RulesInc., and leading academic developers and researchers Based Medicine and has held this researchers have yielded diwith a cost-effective and repost since the company’s inception in 2002. He was formerly the Chief agnostic biomarker patterns producible way to measure Scientific Officer for Luminex Corporation from 1996-2002, that have been validated with dozens of relevant clinical where he was closely involved multi-site sample collecmarkers and pinpoint the with the development of xMAP technology. He received his PhD in tions for applications such as biomarker patterns that are Microbiology from the University of Texas Southwestern Medical School neuropsychiatry, neurodegeneither directly involved in in 1980. erative disease, nephrology, the disease process or are immunology and cardiology. useful surrogate markers.

RBM is also partnering with When those patterns can several pharmaceutical companies to develop be reliably measured, the efficiency of drug companion diagnostic products. Looking development is accelerated while achieving forward, RBM is seeking additional collabogreater efficacy and safety.

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FIROUZ_4August 01/10/2009 10:47 Page 84

FEATURE INTERVIEW

Up close and personal Reinventing big pharma’s corporate image has been pivotal to EMD Serono’s personalized approach. President and CEO Fereydoun Firouz tells NGP’s Natalie Brandweiner about the company’s drive to innovate, its community spirit, and its participation in the conversations around healthcare reform in the United States.

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s President and CEO of EMD Serono, Fereydoun Firouz chise, have an out-of-pocket personal pay. That means it is a cash segment, so is driven by the belief that innovation is fundamental to patients may have to pay with their own money. It’s not fully insured in cersuccess in the biopharmaceutical industry. Innovation is tain states, so we’re seeing some decline in that segment of our business, as the cornerstone of the company’s business model, driven people must make choices,” he explains. by a pipeline that includes late stage-products, unique partnering models, and a growing R&D organization foCommunity focus cused on delivering future medicines.

Firouz believes the business drives the prerogative of a successful bioIn the limelight is EMD Serono’s late-stage pipeline, primarily its invespharmaceutical company to become part of the community in which it opertigational short-course oral multiple sclerosis drug, cladribine. For Firouz, ates, and he certainly proves to be a man of his word. EMD Serono has cladribine is the essence of innovation, with the potential to be the first oral, immersed itself in a number of collaborations with its patients, employees and short-course therapy to treat MS. communities: the company supports many local and national organizations, “As a leader in the area of multiple sclerosis, we believe that if approved, including the American Cancer Society and the National Multiple Sclerosis cladribine could possibly transform the way people living with relapsing MS Society. approach their therapy options.”

In order to better impact the local community near its Boston location, This drive to innovate may be hampered in the short term by more the company is involved with initiatives to train the next generation of scienproactical concerns. In common with many others within the industry, the tists, such as the Massachusetts Biotechnology Education Foundation’s recent financial downturn has not left the company completely untouched.

BioTeach program, which aims to integrate biotechnology into every school Firouz points out that EMD Serono is an employer, and is limited by conin Massachusetts. straints every employer faces in difficult “We don’t behave like a standalone times. “Acting with fiscal responsibility company in our community and only take Partnership during these times is important to ensure a care of our business,” says Firouz. “We need EMD Serono’s agreement with Fast Forward, a sustainable business in the future and in to be active within our community and wholly owned subsidiary of the National the healthcare business. It also impacts, to help, and as we grow we want the commuMultiple Sclerosis Society, was announced on a certain extent on the drug reimbursenity around us to grow and to benefit also.”

May 1, 2009. The collaboration, which committed ment system in America,” notes Firouz.

Why has EMD Serono placed such an $3 million, is aimed at supporting innovative, “As a commitment to ensuring patients emphasis on community values? As a subearly-stage projects to develop therapies to have access to our products through our pasidiary of Merck KGaA in Darmdstadt, prevent treat or reverse nervous system damage tient assistance programs, we are also in a Germany, it is able to run an efficient, in multiple sclerosis (MS). Fast Forward had fierce competition across our formulary pomore community-focused operation withalready received strong presence in the earlysitions on the insurance business, and that is out the corporate mindset of big pharma. stage development for MS with its ongoing important for us to manage.

The company has a long history of corporesearch funding; it was agreed that Merck KGaA “The economy has obviously had an rate social responsibility and for the orgawould provide up to $19 million in total funding. impact on our business model: some of our nization this is key to being a successful compounds, mainly our infertility fran-

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biopharmaceutical company.

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â&#x20AC;&#x153;The key to innovation is developing compounds that are differentiated and have clear clinical benefitâ&#x20AC;?

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Firouz’s tenure with the organization spans nearly 20 years. His leadermarket. The second kind of partnership we do, which is quite a breakthrough, ship abilities first came to prominence during his stint as Vice President of is with certain investment arms of patient advocacy groups, such as Fast Latin America for Serono SA, where he oversaw the successful launches of Forward. multiple products and the company made the transition from a pharmaceu“Fast Forward, a wholly-owned subsidiary of the National Multiple tical to a biotech company.

Sclerosis Society, is a collaboration centered on supporting early-stage re“I learned a great deal from my time in Latin America, from when we search in the areas of multiple sclerosis, and there’s a certain amount of inbegan synergizing our manufacturing capabilities that were based at that time vestment earmarked to drive this goal. We are now in the process of screening in raw material collection. We were trying to shut that down because we had some of the proposals that are coming to us, and a cross-organizational comalready gone to a biotechnology platform and had introduced the first genermittee between Fast Forward and EMD Serono will look at these proposals ation biotech products in the region, beginning with our multiple sclerosis and will make the appropriate decisions to advance those compounds to a product, Rebif,” he says. later stage of development.”

The company continues to be a leader in the Latin American market, exThe third type of partnership is purely R&D, as Firouz explains. “An expanding and introducing new products. Under Firouz’s leadership, its Rebif ample of this is the collaboration with MD Anderson within our oncology therapy for relapsing remitting MS patients was approved by the FDA in the pipeline, focused on early stage compounds. They evaluate the potential of US in 2002. His experiences in global regions including Latin America, and compounds and then we decide together if we want to develop them for any the Middle East have helped him shape the culture and success of EMD specific indication,” he says.

Serono.

This type of collaboration is reflective of EMD Serono’s own R&D orgaAs part of his current day-to-day responsibilities, Firouz takes advantage nization, in which compounds are discovered and evaluated for their longerof the company’s size and its experience in the sector to understand and take term clinical value. EMD Serono’s activities are heavily focused on oncology, part in the conversations surrounding healthcare reform. Firouz believes that as well as neurodegenerative diseases. The company has its neurodegeneraone of the main current issues is whether sufficient incentives can be providtive research operations in a new facility in Cambridge, Massachusetts, where ed to the industry in order to drive innovation, so that patients can get the cutit is hiring scientists across different disciplines to strengthen its global neuting-edge, life-changing treatments they need. rodegenerative platform. One of the core principles of the research organizaNeither has the company ignored the emerging tion is to also focus on disease trend toward tailored therapies. Firouz notes the imprevention, and reversal – underExpansion portance of recognizing this. “One way we think about standing the pathology behind the In April, 2008, the company announced a personalized medicine as bringing the biomarker disease to ultimately help people live planned investment of more than $75 angle into the debate, and we are quite active in that. healthier lives, Firouz explains. million at its Billerica research facility in One of our drugs in oncology, Erbitux, for example, Despite the economic downMassachusetts. The investment is due to which is marketed outside of the US by Merck KGaA, turn, EMD Serono’s future looks create more than 100 new jobs. On March is being targeted at tumors bearing a normal or ‘wildpromising. In a time when health30, 2009, EMD Serono announced its plans type’ KRAS gene. As an R&D organization, we have care reform is on almost everyone’s to expand its research capabilities and open wholeheartedly embraced personalized medicine and lips, the change of system is sure to a new site in Cambridge, Massachusetts. its value to the customer, the payer. We see that as a bring those companies making the The site incorporates the company’s drug critical advantage, and we have instituted that in our major breakthroughs, such as a podiscovery activities in neurodegenerative R&D and commercial organizations.” tential oral therapy for MS, into the diseases and will accommodate almost 50 limelight. “We need to be part of that scientists to work at the location.

Partnering up dialog, and that is going to be our EMD Serono undertakes three types of partnership: the typical one with another biotech pharma company, with an arm of a patient advocacy group, and with an academic institution.

“We are not limited to partnering with a smaller biotech company or a bigger pharmaceutical company,” Firouz explains. “An example of this is our partnership with the Canadian biotech company, Theratechnologies. We are working toward bringing a compound to the US market, a growth releasing hormone for the indication of lipodystrophy. The commitment is a followthrough to our HIV franchise that we have only in the United States. It’s public that the filing at the FDA has happened, and our partner is working to bring the compound to the market.

“That’s the type of partnership we’ve done with a biotech company, successfully expanding a franchise where we have the know-how, where we already have product expertise, and then delivering a late-stage compound to

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first step,” says Firouz. “We support a balanced approach to reforming healthcare, and we want the administration to be successful in that.

“We also want to continue to tap into the resources that we have in Boston, in the northeast and the whole of the country, and that would mean strengthening our position in R&D and having more yielding investments in the United States, having products that are going to cover unmet medical needs and bring options to patients. We’ll be continuing on that path as we go forward.”

In Firouz’s view, the key factor that will pull the industry through the financial crisis is innovation: “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,” he concludes. n

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NEW PRODUCTS

ECONOMIES OF SCALES The benefits of essential fatty acids have long been established, but introducing them into the pharmaceutical sphere is a relatively recent phenomenon. Hilda Steineger explains how Pronova’s use of omega-3 from fish oil has transformed an age-old remedy into a potential blockbuster.

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orway has traditionally used fi sh oil as a natural remedy, most notably cod liver oil, but it wasn’t until the late 1970s that a Danish scientist discovered that the large intake of fats by Eskimos meant they did not have the normal correlation of cardiovascular problems that are seen in the Western world. Further analysis of the types of fat uncovered large quantities of omega-3, and the understanding of its cardiovascular properties was born.

“There has been a lot of scientific research in Norway on lipids and omega-3s since the late 1980s,” explains Hilde Steineger of Norwegianbased Pronova BioPharma. “Between the late 1980s and early 1990s, Norsk Hydro looked into omega-3 to produce it in a very high concentration, and this is what makes our product different than the supplements from those you can buy in the pharmacy: we have a much higher concentration of omega-3. A normal supplement would be somewhere between 30-50 percent concentration, while our product is above 90 percent concentration of omega-3.

“At that time, Norsk Hydro, which is a large conglomerate in Norway, fi led patents on this concentration and they started to do clinical trials.

When they started they had an open mind about which indication and diseases this could be used towards, and what they observed was that it was quite effective on lowering triglycerides. So that was one of the indications that we ended up going forward with in the clinical trials.”

Steineger also notes the work of a large cardiologist group in Italy, the GISSI Group, who began work on the effects of omega-3 at a similar time. They also began studying the effects of omega-6 and if it would work, as well as studying whether similar results could be produced from Vitamin E.

Clinical trials Following this, the GISSI Group then took the lead with Pronova and began performing large-scale clinical trials, with over 7000 postmyocardial infarction patients. For instance, patients who had previously experienced heart attacks would receive either a placebo drug, omega-3

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Omega-3 Popularly known as fatty acids, omega-3s are a group of unsaturated acids that have a final carbon-carbon double bond in common. Awareness of their benefits to health has grown over the last few decades, and as a result, the number of foods enriched in omega-3 fatty acids has increased – such as milk and eggs that can be naturally enriched.

They were deemed ‘essential’ when scientists found that they were indispensable to normal growth in young children and animals.

or Vitamin E to determine the effects. The Vitamin E groups proved to show no effects, whilst the highly concentrated omega-3 groups showed tremendous effects on all-cause mortality, new cardio arrests and heart attacks, as well as on sudden deaths.

Most astonishingly, the trials showed a four to five percent relative risk reduction in sudden death groups and a 20 percent reduction in allcause mortality. Steineger notes that these results were responsible for the formation of the basis of post-myocardial infarction in Europe, the other indication present being a lowering of triglycerides.

She explains the results of omega-3 on cardiac prevention as being due to a regulation of heart rhythms – electrocardiac signals – in the body.

“On cardiac prevention, you must remember the human race has eaten fish for hundreds of thousands of years, so we have the metabolism and the system in place, and fish oil and omega-3 are involved in an extremely high number of different pathways in the body,” says Steineger.

“There are many modes of action of this drug; we can’t pinpoint one and say, ‘Th is is one of them. Th is is how it works.’ We can pinpoint several, but which of these modes of action is the most important is difficult to say. However, on the prevention of cardiac events, we believe that this is a regulation of heart rhythms, electrocardiac signals.

“How would that come to be? Well, it’s believed that every cell membrane of phospholipids has lipids in it, and if you exchange the lipids from saturated or monounsaturated with polyunsaturated, they get more liquid: the membranes get more fluidity. The more saturated fat is, the harder it gets.

“If you then go to the other extreme and have a polyunsaturated fatty acid, like omega-3, and you incorporate this into the phospholipid layers it has been shown that the lipid layer will get a higher fluidity. Th is fluidity has an effect on the electrocardiac channels, such as the calcium potassium channels conducting the electric signals between the cells.

That’s one change in the phospholipid layer and how that might change electrocardiac signals.

“There is a lot of research that shows there is potential in omega-3, but it all depends on the clinical trials that you do to support your product”

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“After the GISSI-Prevenzione study, the GISSI Group also performed a study reported in 2008 called the GISSI Heart Failure Study. There they showed the reduction in all-cause mortality to be around nine percent this time; however, heart failure patients are quite sick and are on a lot of different drugs, so it was an add-on therapy and not a switch. Th is is the mode of action on the cardiac prevention.

“The lowering triglycerides is a bit more complicated in the sense that natural or fatty acids are natural ligands for PPARs. When the fatty acids bind to PPARs, the PPARs then regulate a lot of different metabolic pathways, stimulating the uptake of triglycerides in the blood and reducing the body’s own production of triglycerides, and also increasing the metabolism of fatty acids and triglycerides. So it has quite a lot of different modes of action, which all together give a reduction in the very high triglyceride group, because there’s differentiation on how high levels you have with triglycerides. Therefore, in the very high triglyceride we see a 45 percent reduction of triglycerides, which is comparable to Niaspan and Tricor, but without having the same side effect profi le,” explains Steineger.

Regional attitudes Pronova’s omega-3 product, known as Omacor in Europe and Asia and Lovaza in North America, is the first and only EU- and FDA-approved omega-3 derived prescription drug. It is indicated in Europe for lowering all forms of triglycerides, as well as for use in post-myocardial infarction patients; whereas in the US it is indicated only for lowering very high triglycerides. However, the US market is expanding, following a recent re-launch. Reliant Pharmaceuticals launched Lovaza in 2005, and when GSK bought Reliant in 2007, a different sales team was put together, the sales force was doubled and the product was relaunched three months later – creating a bigger market. However, Steineger believes the pick-up rate to be the same at home as it is abroad, regardless of the long tradition of omega-3 use in Norway. In fact, the greatest market currently for Pronova is the Mediterranean.

“They already eat a lot of fish there, so you would think that they wouldn’t need extra fish oil or extra omega-3, but the perception that fish oil and omega-3 are good for you is easier to penetrate there than in the more northern European countries,” says Steineger.

Although there is no scientific proof, she alludes to the fact that in a region where the intake of fish oil is already high, having extra is considered even more beneficial. It is this approach towards omega-3 that has received tremendous attention within the US, and she explains GSK is promoting the product “very well and very professionally, it’s one of the growth drivers for GSK for the moment.”

So how is this steering the future of Pronova? Steineger explains that this area is due for even more growth, and there is certain to be a greater market in the future for these marine-derived omega-3 products.

“We have just scratched the surface of the potential, but it will of course be dependent on clinical trials and what we can prove. Omega3 has been coupled up with CNS diseases, like depression, Alzheimer’s

“The human race has eaten fish for hundreds of thousands of years, so we have the metabolism in place to process omega-3” and also dementia, as well as having shown to have anti-inflammatory effects. There’s a lot of research that shows there’s potential in omega3, but of course, it all depends on the clinical trials you do to support your product. We have a business model whereby we don’t perform large clinical trials ourselves; it’s our partners that perform them,” explains Steineger.

The timeframe for looking into such other potential applications is still uncertain. She notes that there is still a lot to do on the cardiac prevention and on the lowering of triglycerides, in the sense of harvesting all the potential. There is also a large clinical trial, known as ORIGIN and driven by sanofi-aventis, which includes Pronova’s product in two of the arms, and involves 12,000 pre-diabetic patients.

The remainder of 2009 looks promising for Pronova, and with March end-user sales hitting $1.1 billion, the company is aiming for blockbuster status for Omacor/Lovaza, and as Steineger says, “there are not many products that can do that.”

Hilde Steineger has served as Head of Investor Relations at Pronova BioPharma since 2007. Before that, Steineger was Senior Associate at NeoMed Management from 2006 to 2007, Business Development Consultant at Maxfield/Amino from 2003 to 2006 and Senior Financial Analyst at Nordea Securities from 2001 to 2003. She graduated with a PhD in medical biochemistry from the University of Oslo.

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ASK THE EXPERT

Late phase studies: an early priority

By Dipti Amin

L

ate phase research has sometimes been viewed as less of a priority than the earlier trials required for product registration.

In the past, this has meant lost opportunities to expand product labels, demonstrate product value and monitor safety – and a limit to a biopharmaceutical company’s ability to realize a product’s full commercial potential.

Today, biopharmaceutical companies are feeling pressure from numerous sources – demands of a competitive marketplace to develop drugs more cost-effectively and to squeeze revenue from them, combined with a new level of regulatory scrutiny surrounding post-marketing commitment studies. The demand for these studies puts a significant strain on companies to meet the regulatory requirements and manage the expense of complex protocols.

However, this challenging environment also presents opportunities for innovators.

Visionary pharmaceutical and biotech companies are recognizing the opportunity to expand revenues at earlier stages in a product’s lifecycle through greater investment in strategic late phase studies that are intelligent, cost effective and market savvy designs. The results of such trials bring valuable insight about real-world product use and clinical practice patterns.

In addition to the studies to expand the product’s uses, pharmaceutical companies are also increasingly faced with post-marketing

commitment studies, as a requirement for apincluding: strategic understanding of the study proval or continued marketing of their prodobjectives and design options to achieve goals; ucts. While the purpose of these studies is to knowledge of the complex nature of the results comply with regulations and generated and how to maximize provide additional informathe data analysis during and tion about safety, effectiveness after the trial; in-depth unand optimal use, if approached derstanding of the operational strategically biopharmaceutical issues involved in managing companies can also gather imlate phase studies; expertise in portant and useful differentiatthe disease or therapeutic area; ing data about their product. global capabilities coupled There is great interest in with local market expertise; fitpost-marketing safety surveilfor-purpose data management lance, driven by public demand tools; and access to appropriate for safer products and more patients and investigators.

Dipti Amin is the transparency. Th is is reflected This approach yields qualSenior Vice President and Global Head of in increased regulatory emity data to satisfy regulators and Quintiles Late Phase and Safety Services phasis on drug safety, such as payers. It provides validated unit. Educated in the the mandatory risk manageassessment of safety and other United Kingdom, Amin earned professional ment plans (RMPs) in place in outcomes in real-world settings. degrees through GKT Medical School Europe, and the US FDA Risk These multiple, fit-for-purpose of the University of Evaluation and Mitigation data analyses, including comparLondon. She earned graduate degrees and Strategies (REMS), Risk Miniative effectiveness, can enhance diplomas in medicine, surgery, family mization Action Plans (Riskpublication output and reach planning, obstetrics MAPs), and authority over more prescribers. Implementaand gynecology, child health and clinical post-marketing surveillance. tion at the earliest possible stage pharmacology.

The changing regulatory in the product lifecycle can proclimate is making it necessary vide a welcome boost to product to collect better safety data to answer increasrevenues at a time when the cost of developing ingly detailed questions about drug risks and new products is at an all-time high. perform more comprehensive analyses within a Biopharmaceutical companies are facing growing cost containment/reduction environment. Late pressures. From Library_Late-Phase v5.ppt LatePhase_ phase research requires a specialized approach, PodPresentation.pptx

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RESEARCH

Martin Mackay, Pfizer’s President of Global R&D, explains how in the age of tailored therapies, the end of all disease could be in sight.

M

artin Mackay assumed his role as Pfizer’s President of Global Research and Development in 2007, but being an internal candidate for the position, he had thought hard about his responsibilities and aims long before his appointment.

Working within the company, his main objective was to understand why, as an R&D department, Pfizer was not getting its return on investment, and how as a department they could address that.

Plan of discovery 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 fivepoint 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 organization. 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 our scientific and drug discovery point of view. This resulted in Novartis 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 toptier 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 the fact that this area often receives the least attention, he notes how it received 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 while we had always had collaborations, again, it was a case of taking it to the next level. In our five largest therapeutic areas we formed therapeutic area scientific advisory panels, each led by a leading academic, and in turn those academics have a number of really top-notch scientists. This group works directly with the leaders of those five therapeutic areas – whom we call chief scientific officers – and that has really gained us access to the very best minds.

“We’ve got terrific talent within Pfizer, and a great history of drug discovery,” explains Mackay. “However, most discoveries happen outside because even with our terrific budgets it’s relatively small compared to

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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 with some of our competitors.

“We’ve focused on attacking the issues of productivity that have dogged the industry and have engaged 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 that 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-center 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 scrutinized, but I like to think we scrutinize 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.”

Personalization

n age overy

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 this, 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. “Therefore for any patient that takes 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 around 18 months 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 patient got the treatment. 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 lung carcinoma. We showed how in a particular group of patients with nonsmall cell lung carcinoma that 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.

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

Essentially they couldn’t feel any pain, and whilst that sounds 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, this NaV 1.7 channel, was the gene responsible for the condition. We also did other genetic analysis; there’s another condition where people are acutely aware of pain: even at the slightest touch they feel it quite badly, and 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 launched a very large program in the UK 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, but also was an acute eye right in the beginning to get to the right patient population,” he says.

has moved in the last few years on to the next plane, which is much more selective screening but still using the power of numbers and the power of combinatorial chemistry.

“Most of our new projects, certainly from a small molecule perspective, start in this way, and it’s really very impressive how we’re using computational biology and computational chemistry to narrow down on the types of chemicals that make great medicines.”

Discovery methods Pfizer’s methods for discovery have also matched its products. In the early 1990s the company was one of the leaders in high-throughput screening.

Mackay notes that during his early days with Beecham Pharmaceuticals, in the 1970s, chemists would only make a few compounds a week. As time has gone on and tests have become more high tech, there is greater accuracy in the correct chemical matter in addressing particular targets, and this has become achievable on a much greater scale.

Medicinal chemists could now make tens of thousands of compounds rather than the previous few, with the biologists matching this with the creation of assays that could tests hundreds of thousands of compounds, referred to as high-throughput screening.

“There’s a whole host of different ways we screen millions of compounds, which gives you a much earlier clue as to the type of chemical matter that you’re going to have to work on, to come up with what will be a medicine,” Mackay says.

“Interestingly there are very few occasions now that we run a high-throughput screen. We have a file of about three million what 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 selected parts of the files.

“For example, let’s say the target is a kinase target, which is a particular type of enzyme in the body that is very well known to be a good source of new medicines. We can now have a targeted library purely for kinases and if we’re starting any de novo kinase we will just screen against those compounds first before ever going to the full file. So high-throughput screening

Future of discovery Staying at the forefront of drug discovery in an industry of giants is no mean feat, but Pfizer’s merger with Wyeth is sure to stand them in good stead.

The deal is due to close over the next three months, and the results of this will give what Mackay describes as a huge boost to the R&D department.

“Point three of the five-point plan was to become top-tier in biotherapeutics. Wyeth has a really impressive record in both biotherapeutics and prophylactic vaccines, so when you ask what will set us aside and what I’m optimistic about, I see us being a really terrific company in small molecule drug discovery and development, in biotherapeutics, and in prophylactic vaccines, which really gives us the span of the modalities that we will need to attack disease.

“The head of R&D at Wyeth, Michael Dohlsten, is joining Pfizer, and Michael and I have decided to split R&D into two components, a small molecule group and a large molecule group. I will lead the former and he will lead the latter, but these groups are inextricably linked and we have a golden mission to really attack the diseases that dog us. I truly believe that by the end of the century we will cure most of the diseases that plague us, and it’s our challenge in an R&D environment to make that happen in our lifetimes.

“We have never had a better chance to do that, and Michael and I are on an absolute mission to be a forefront R&D organization that really addresses the needs in oncology, Alzheimer’s disease, diabetes, pain and inflammation, and we’ve never had so many tools at our fingertips to be able to do this. I’m very optimistic about the future of medicine and our role in it.” n

“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”

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Martin Mackay is President of Global Research and Development at Pfizer.

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INDUSTRY INSIGHT

Preserving flexibility in outsourcing clinical services

BY STEVE COTTRELL

E

very manufacturer and developer of pharmaceutical, biotech and medical device products is being challenged on many fronts by today’s market issues.

The events of each day bring potential impact on any strategic plans and require manufacturers and suppliers alike to change strategy in timing, resourcing or whether or not to modify or cancel projects. All of these uncertainties require a different set of skills than traditional processes have demanded.

We are all being forced to manage shortterm success while looking for ways to fundamentally change the development process. Now more than ever, this requires a high degree of agility with respect to how resources are deployed. Many of the historical resource choices remain available to execute clinical development projects, including executing the entire program internally utilizing in-house staff and contractors, engaging a network of clinical development ser-

vice providers that offer niche services or a complete turnkey approach utilizing a traditional clinical research organization (CRO).

Successfully executing these strategies requires top talent at both the manufacturer/developer and service provider level. Identifying that talent and, more importantly, retaining them is more challenging than ever before. The traditional outsourcing model has provided significant value. However, excellence in clinical development is still being sought. The decision is much less ‘if’ alternative solutions will be utilized, but ‘how’ they will be utilized.

A complete turnkey approach will continue to provide the least control over the clinical process to the manufacturer/developer; however, the project manager must have a clear development plan and cost for all services must be contemplated. Furthermore, clients must have strong trust in their service provider in order to avoid costly change fees.

Niche providers or consultants also offer high flexibility and value when managed closely.

This strategy can produce highly qualified personnel within a short period of time; however scalability can be an issue if the niche provider has limited resources.

The functional service providers (FSP)

model in clinical development has many definitions and has fallen in and out of favor over the past three years. A number of firms hold strong expertise within various functional disciplines which provides a variety of benefits to clients.

The pressure to deliver greater efficiencies by utilizing any of these service levels is here to stay and will continue to expand over time. This is forcing both manufacturers and service providers alike to look for greater opportunities for improved coordination of services not often seen in the past. The opportunity to coordinate investigator meeting management with medical education companies and online meeting services results in a highly interactive and effective process.

In addition, proactively managing the impact of a risk evaluation mitigation strategy (REMS) requirement on trial design, revenue forecasting and patient access as well as utilizing on-call nurses to drive clinical understanding of a trial, assistance with patient recruitment or support of a REMS offering can impact speed and effectiveness.

Finally, having a service provider that can easily access marketing teams early in the process to drive a holistic approach to molecule development, while conducting market and therapeutic analyses to help determine asset valuation in combination with the scientific teams that are performing the clinical development, will provide a stronger asset valuation package for sale of the asset or valuation of the organization Taking the time to evaluate these strategies in combination with the traditional outsourcing tools will ensure all the potential ‘gaps’ in clinical development are filled appropriately and the product potential is maximized.

As the choices are made to pursue one avenue or another, one thing is fairly certain: Companies who effectively integrate a sound outsourcing strategy, while leveraging all the tools available to them, will clearly lead within their respective markets. Successful integration of a dynamic outsourcing strategy with a firm that has the depth, breadth and operating philosophy to fit your needs will deliver quality, timeliness and strong cost savings. n Steve Cottrell is the Executive Vice President of inVentiv Clinical Solutions, responsible for Resourcing Operations and Business Development. Cottrell has 20 years of experience in the disciplines of CRO services, online training/learning services, outsourced sales and marketing functions and consulting. He resides in the Somerset, NJ offices of inVentiv.

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INDUSTRY INSIGHT

of the response. ELISPOT is extremely sensitive, with detection limits of 1 in 500,000 cells or better. Th is is an order of magnitude more sensitive than ELISA, CBA or ICS. ELISPOT further assesses the functional characteristics/differentiation states of T-cells, per cell cytokine productivity and frequency and quality of T-cell immunity, and their changes under physiological stimulation conditions.

The robustness of the assay allows use of cryo-preserved samples, facilitating high throughput testing of batched samples collected at different time-points, which is a great advantage in clinical trials. ELISPOT assays can be validated under GLP-compliancy with multiple cytokines and test systems.

Cellular Technology Limited (CTL) specializes in GLP-compliant ELISPOT testing ELISPOT assays offer unique qualification for cytokine-based for pre-clinical and clinical trials, involving immune monitoring and standardization strategies. the measurement/characterization of T-cell responses in various species. For example, ssessing immunogenicity is cellular or a radiological readout. Secretion ELISPOT is ideal for Th1/Th 2 analysis, meaa challenge in the biopharof cytokines by T-cells could be used as a biosurement of per cell cytokine production and maceutical industry as an marker. An assay for monitoring CMI via such direct ex-vivo cytotoxicity assays. Testing for increasing number of new biomarkers should perform identically with simultaneous secretion of one or more proddrugs and vaccines aim to fresh or previously frozen samples. Further, ucts, such as T-cell functional avidity studies elicit a response from the cellular component it should be standardized, enabling interor epitope mapping, are just a few areas where of the immune system, such as T–cells. Some study comparisons of data in multi-center or ELISPOT assays are used. of the challenges include measurement of a large clinical trials. High CTL’s GLP laboratory has vaccination’s effectiveness and early detecthroughput testing is nechigh-throughput capability, altion of adverse effects. There is also a need for essary to accommodate lowing us to significantly accelrepresentative biomarkers and establishment the needs of clinical studerate the development process of correlates of protection for novel vaccines ies, involving high-volume for drugs and vaccines entering aiming to elicit cellular immunity. testing of hundreds of the clinical testing phase, as well Cell-mediated immunity (CMI) is a samples using automated as subsequent immune monitorcritical component during immunological data read-out equipment. ing. CTL also provides laboratoresponses, involved in infectious diseases, ELISPOT is an ideal ry services for processing whole cancer and autoimmunity. Research into corassay system for immune blood and cryo-preservation of relates of protection has exposed limitations of monitoring of cytokines lymphocytes for later functional Magdalena Tary-Lehmann is vaccine approaches relying solely on antibody secreted by T-cells. The assay testing.

Co-Founding Scientist and Chief Scientific Officer for responses to confer protection against pathoELISPOT assay estabCTL not only has a GLPCellular Technology Limited (CTL). She provides guidance gens, such as HIV and smallpox. Immune lishes the quality of an compliant laboratory operation, and oversight for technical monitoring and biomarker screening can be immune response, such but also specializes in developoperations, ensuring the ongoing scientific excellence implemented during all pre-clinical and clinias the type of products ing and manufacturing image of the company. Over the past 10 years, she has worked with cal phases of drug and vaccine development.

T-cells secrete in response analysis-based high throughput clients and regulatory agencies To increase chances of successfully detecting to a vaccine candidate or 21 CFR Part 11 compliant instruto develop and validate reference samples and controls biomarkers for use in future clinical studies, drug, allowing the difmentation and soft ware. With for use in regulated immune monitoring assays. the readout system must have high resolution ferentiation between Th1/ our expertise in both ELISPOT and must be compliant with good laboratory Th 2/Th17 (CD4+ T-cells) testing and instrumentation, practice (GLP) regulations. and Tc1/Tc2 (CD8+ T-cells) based on cytokine CTL is uniquely qualified to be at the forefront What is a biomarker? A biomarker is a signatures. It establishes the quantity of the of cytokine-based immune monitoring and nonclinical endpoint used to predict a clinical secreted cytokine product in response to an standardization strategies. course or response, which can be molecular, antigen or vaccine and reveals the magnitude Contact CTL at info@immunospot.com or call 1.216.791.5084.

Monitoring of cell-mediated immunity

A

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COUNTERFEIT MEDICINES

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

C

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 tooth brushes 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 developing a brand name that consumers recognize and that they place trust in. If someone can copy a product closely enough, and use the name and the good will 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 and don’t really consider all of the other facts, unfortunately, sometimes with very bad consequences.”

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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 $2 billion for the state, and in excess of $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 $200 billion a year, to as high as $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 word, 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 is mind-boggling.”

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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 the product that has no active ingredient whatsoever, and has no medicinal affect. These sorts of products, whether it’s a small amount of the active ingredient or a product with no active ingredient, 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 that 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 10 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 10 percent of the world drug supply could be composed of either counterfeit or diluted pharmaceutical products. It’s been less of 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 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.”

Travis Johnson on the government’s international trade report: The Special 301 Report is produced each by the Office of the United States Trade Representative puts out every year, 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 it’s 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.

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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 organization, offering anti-counterfeiting programs designed to increase protection for patents, trademarks, copyrights, service marks and trade secrets.

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.

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 within the 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 find any number of places where they can obtain what they think are in many cases, the real thing.

“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 Johnson feels that the situation for counterfeit pharmaceuticals is at a crossroads. Laws around the world have improved and the industry has made a major move forward in acknowledging and addressing the problem. He does believe, however, that there are areas require additional focus on 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 $30 million worth of counterfeit pharmaceuticals were intercepted by customs out of $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 $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 child labor, 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

Building quality Mary Jo Wojtusik explains the benefits of using a Quality by Design approach.

What are the benefits of a Quality by Design (QbD) approach for chromatographic method development?

Mary Jo Wojtusik. Quality by Design is all about building quality into a product or process by focusing on gaining scientific understanding and knowledge during the development process, and having a goal of reducing variation and consistently producing a quality product. Liquid chromatography is the preferred analytical technology for final product testing and release and is also used throughout the entire drug development process. Using a QbD approach for chromatographic method development builds robustness into a method during the development phase that can be carried forward through manufacturing, eliminating the costs and delays associated with having to redevelop and revalidate unreliable methods.

“Developing quality methods the first time allows for problem-free validation, transfer and operation” How does using a QbD approach lead to quality or fit-for-purpose methods?

MW. QbD, as I mentioned, focuses on gaining scientific understanding.

Guidance documents from both the US Food and Drug Administration (FDA) and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) state that the information and knowledge gained during the development process should provide sufficient scientific understanding to support establishment of the design space, specifications and controls. Design space, as defined in the guidance documents, is the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. It is very reasonable and easy to think of a chromatographic separation as a process with various inputs and parameters such as type of column, mobile phase composition and pH, flow rate and temperature, with all of these inputs and parameters interacting simultaneously to effect a separation of the sample constituents. The process of developing a valid design space investigates all of the chromatographic interactions that participate in achieving the desired method and includes an evaluation of robustness. Achieving the de-

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sired optimal method performance and ensuring that the method is robust so that it will continue to perform for the life of the product is the definition of a quality method.

What is the role of regulatory authorities in extending the application of QbD principles to chromatographic method development?

MW. The regulatory authorities recognize that robustness is a key attribute of any analytical method. The ICH guidance document, ICH Q2B Validation of Analytical Procedures: Methodology (November 1996) states “the evaluation of robustness should be considered during the development phase….” The challenge for chromatographic methods is that there has been no good way to do this. Robustness is evaluated during the validation phase where we are essentially testing it in to the method rather than building it in. So, the intention of the regulatory guidance document is to recommend an approach that builds robustness into a chromatographic method while the method is being developed.

What do you see as the future of complementary analytical technologies?

MW. The focus in the industry is on shortening drug development times while reducing operating costs. I see the path forward as being driven by the integration of technologies that streamline and automate the chromatographic method development workflow and incorporate Quality by Design principles to achieve the necessary productivity improvements and cost reduction. At Waters, we have been working with one of our software partners, S-Matrix Corporation, a developer of advanced software that automates R&D experimental work according to QbD principles and methods, to bring together the superior chromatographic performance of the Waters ACQUITY UPLC system and our industry-leading chromatography data software, Empower 2, with S Matrix Fusion Method Development software to provide an integrated and automated, Quality by Design method development solution that dramatically reduces the amount of time that it takes to development a method and uses an approach that ensures that a robust, fit-for-purpose method is developed. Developing quality methods the first time allows for problem-free validation, transfer and operation, thereby eliminating the time and cost associated with having to redevelop and revalidate chromatographic methods. n Mary Jo Wojtusik joined Waters Corporation in 2007 and has more than 15 years of experience in bringing innovative analytical and process-scale products and solutions to the pharmaceutical and biotech industry. As Business Manager for Pharmaceutical Development at Waters, Wojtusik works closely with customers and industry experts developing solutions that meet their scientific and critical business needs.

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EXECUTIVE INTERVIEW

Tools for streamlining the manufacturing process René Schwarz tells NGP why manufacturing execution systems are important for achieving operational excellence.

What are the chief advantages offered by manufacturing execution systems?

René Schwarz. During previous years, pharmaceutical and life sciences companies have faced a multitude of new challenges. Economic pressures, changing regulatory environment and portfolio pressures are demanding answers. Corporate initiatives like Lean manufacturing, Six Sigma programs and real-time enterprise have been established to achieve operational excellence. Life sciences companies often define operational excellence as the organizational capability to simultaneously meet regulatory and productivity requirements. Manufacturing execution systems (MES) can provide the tools and support methods to achieve operational excellence by providing visibility, tracking and control.

How can pharmaceutical and life sciences companies use manufacturing execution systems to streamline their manufacturing processes and achieve operational excellence?

RS. One of the major concerns of pharmaceutical and life sciences companies is the cost of compliance. MES can help by enforcing processes and specifications, as well as reduce the time required for batch report reviews and effort for investigations. It enables paperless production by eliminating paper batch records and other documents, such as equipment logbooks and standard operating procedures from the shop floor.

Another issue is the time a company requires to launch a new product. Using MES can reduce scale-up times from product development through clinical to commercial manufacturing by employing standards like general and site recipes, as well as reusable building blocks. In fact, these concepts can improve time-to-recipe in general and they help to establish and propagate best practices, which is key for continuous improvement.

Decisions about where a product is manufactured can be a critical cost factor. MES can provide

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value by simplifying the so-called tech transfer, the transfer of a master recipe from one site to another.

What specific types of MES software tools are most useful in helping companies uphold production while maintaining the highest quality?

RS. For quite some years, the application customers’

directly from equipment and sensors to ensure its correctness. In any case an integrated exception management manages deviations from processes or specifications, which is key for review by exception. With that, significant reductions in batch review cycle time and effort for investigations related to deviations can be achieved.

realize the quickest return-on-investment with has In addition, manufacturing intelligence and been weigh and dispense, which is unlikely to performance management tools offer sophisticatchange in the near future. The weighing operator is ed reporting and data analysis capabilities as well guided through pre-defined workflows, which as dashboards, and with that can help to turn the helps to reduce operator errors. Error-prone and data that has been gathered during production time-consuming calculations are history. into valuable information – information that is Furthermore, the software compiles a comprehenvital to establish further processes improvements. sive weighing report that includes all information required by regulation. Material, equipment and How do you expect the use of MES to develop within the pharmaceutical industry in the future? personnel involved in the weighing process are RS. MES has been primarily tracked. The software enforces adopted by larger pharmaceuprocesses or specifications and tical companies and for their manages deviations in a GxPlarger sites. However, best compliant manner. Weigh and practices that have been estabdispense ensures compliance lished throughout past years, with regulations, while it can combined with technology significantly save time and reinnovation, will further reduce cost. duce cost of deployment as However, what pharmawell as total cost of ownership ceutical and life sciences com(TCO) for MES. With that panies are striving for today is the entry point becomes low electronic batch recording enough to make MES reality (EBR). After achieving paperRené Schwarz is the Product for smaller pharmaceutical less production in the weighManager of FactoryTalk Pharma companies’ respective smalling booths, the next step is Suite. René has been working for more than 20 years in various er sites. eliminating the paper still preroles developing software products and solutions tailored to Furthermore, the phardominant in the manufacturthe needs of the life sciences maceutical industry will coning and packaging area. EBR industry. His domain knowledge covers product and process sequently pursue trends like presents electronic instrucdevelopment throughout clinical to commercial primary and process analytical technology tions on a screen to the opersecondary manufacturing.

(PAT) and quality by design ator and ensures that the (QbD). Best practices and batch documentation is alstandards have been develways complete and correct. oped by industry associations, suppliers and cusManual data entry is limited to the absolutely nectomer themselves and MES will follow with essary and always checked against specifications supporting functionality and interfaces. and limits. If possible, process values are gathered

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FUTURE TRENDS

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t’s no secret that things in the pharmaceutical industry are far from rosy. Patents expiring, pipelines drying up, blockbusters thin on the ground. Aft er years of progress and breakthrough treatments – not to mention high profits – something is clearly wrong. A recent report from global management consulting fi rm A T Kearney, ‘Pharmaceuticals out of balance: Reaching the tipping point,’ authored by Jonathan Anscombe, Michael Thomas and Omar Sawaya, gets to the root of the problem by identifying the industry’s current ‘tipping points’.

The report points out that the pharmaceutical industry has enjoyed one of the greatest success stories in recent history. “The industry has created technologies that have redefi ned the concept of old age. Vaccines have eradicated diseases such as polio and smallpox, and research in genetic medicine has led to huge gains in the treatment of lethal diseases such as cancer and AIDS.” On the business side, the authors say, the industry accounts for 20 percent of all global R&D investments, and generates revenues of more than $700 billion.

What, then, has gone wrong? As the report points out, even as healthcare budgets are rising, drug sales in most developed markets

are forecast to be flat. “Spending on sales and marketing in the United States,” it goes on to say, “has increased 13 percent a year over the past eight years, while return on that investment has dropped by 15 percent.”

Efforts to improve efficiencies through cost-cutting and consolidation have not solved the problem, and shareholder returns are plummeting. And the future, according to Anscombe, Thomas and Sawaya, also looks bleak. Pricing pressures are increasing across the globe, and even the US has become a challenging market.

The authors believe these problems are symptoms of a shift in the nature of healthcare systems. They say healthcare is out of balance, and so is the pharmaceutical industry. “Each company in this innovationbased industry will soon face a choice of either playing in ever-smaller niches or re-asserting its position as a key partner in improving global healthcare outcomes,” they maintain. “Th is new role will require companies to move away from selling molecules and toward addressing health needs; to look away from traditional markets; to be driven by the way their therapies are used, rather than by the discoveries they’ve made; and to restructure away from the integrated models that have dominated the industry to more fluid forms that allow companies to respond to new challenges across the value chain.”

ADAPT OR PERISH A new report from management consultants AT Kearney highlights what the pharmaceutical industry must do to survive.

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The report’s authors believe these increasing problems are a sign that the industry is approaching a time of rapid change. They have identified three interrelated ‘tipping points’ relating to what the industry sells, to whom, and how it should organize itself. Below, we summarize their descriptions.

From therapies to service models The fi rst tipping point relates to the pharmaceutical sales model, which until now has assumed that the prescribing doctor is the primary decision-maker, making decisions based solely on the doctor’s perception of patient need. Th is assumption has led to the current model of investing heavily in sales and marketing to influence doctors.

But physicians are subject to many outside influences: the constraints of formularies, the influence of guidelines, the prompts delivered by IT systems, the incentives offered by fi nancial mechanisms. All of these are driven by payers and regulators or by providers responding to payer costs and political pressure.

The report outlines how, which drug is prescribed is becoming increasingly less important to pharmaceutical companies than whether a drug is prescribed at all. For example, where patients move through

expensive levels of treatment – from NSAIDs to DMARDs to biologics – a company providing biologics could benefit more by persuading payers to allow their earlier use than by trying to prove that their drug is more effective than a competitor’s.

Another issue is increasing elasticity in pricing. The traditional view is that selling a drug more cheaply does not mean more volume because doctors do not prescribe based on price, but this is changing with the growing influence of payers. However, the way payers perceive value is different from the way pharmaceutical companies do.

The authors also point out that over the past few years, there has been a dramatic change in what payers want to achieve. Rarely are drugs the only intervention used to treat a disease: payers are often more interested in the effectiveness of the treatment pathway than the clinical effectiveness of a particular drug in a clinical trial.

However a pharmaceutical company chooses to defi ne a drug’s value, it will need to be demonstrated in a way that is compelling to payers.

While phase III randomized control trials can demonstrate the clinical value of a therapy in a controlled environment, payers need to know how it will perform in the real world before providing funding.

The problem with many drugs is not their efficacy, but the lack of patient compliance. The report states that within six months of agreeing to take a prescribed drug, about 50 percent of patients stop taking it – and this holds true even for those with life-threatening illnesses. As the focus shifts increasingly to payer needs, a service model in which drugs are actually used will confer a competitive advantage.

“Over the past few years, there has been a dramatic change in what payers want to achieve”

From niches to mass markets

The US dominates the pharmaceutical industry, with more than half of all drug sales and R&D spend. Because of this, much R&D focuses on those areas that are important to the US market, and prices also reflect what the US market will bear.

As the US market begins to falter, developing markets are emerging as the new engine of growth. Ninety-six percent of population growth in the next 50 years is expected to occur in developing countries, which at the same time are experiencing a dramatic increase in diseases – such as diabetes – that are more common in the developing world.

The developing world is characterized by high levels of self-pay and very little in the way of public health systems. However, spending per capita is growing, and the report’s authors feel that most countries will develop some form of comprehensively funded healthcare system as soon as they can afford to. They say that emerging state-funded systems will need to develop cost-effective solutions to these new health problems, but will not be prepared to pay Western prices.

As the US tightens up on pricing and developing markets continue to grow, volume at a lower cost will become increasingly attractive.

Anscombe, Thomas and Sawaya think pharma companies should forget their obsession with high-priced solutions focused on the US market and establish prices to maximize revenue over a drug’s life cycle and across

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“The traditional model of a globally integrated pharmaceutical industry will struggle to survive” global markets. They believe that the industry will be forced to view emerging markets in a new light: not just as an opportunity for lowering R&D costs or demonstrating market commitment, but as a source of lowprice breakthrough innovation.

Making connections The report argues that against this new world order, the traditional model of a globally integrated pharmaceutical industry will struggle to survive – it will be too large, unwieldy and unfocused to connect payers, providers and potential partners in the many markets it seeks to serve.

It notes that the most successful companies of the future will shift from being R&D driven to being market-driven, and this will require a complete rewiring of their organizations.

The challenge for pharmaceutical companies will be choosing the therapy areas on which to focus. The authors believe the current trend to specialize in specific niches will accelerate, with even the biggest companies building expertise in a few selected clinical areas.

The requirement to integrate drugs into delivery models and demonstrate value in the real world will introduce new requirements to build broader relationships with healthcare systems and form partnerships with local providers. A new kind of sales and marketing organization will be needed, with traditional sales forces dramatically reduced in favor of localized market access organizations.

With the move toward service delivery, companies will need to have closer integration between researchers and marketers. Researchers will increasingly need to understand not just the science of the disease, but also the operational, human and political barriers to effective treatment.

Innovative solutions will increasingly encompass establishing delivery platforms that unite multiple technologies.

Sources of innovation are also becoming more diverse. The report’s authors point out that new biomedical centers are emerging in places such

as Singapore and Shanghai.

The proportion of drugs that are in-licensed is increasing, and inlicensing is happening earlier in the product development process. Companies will also need to seek out low-cost, breakthrough innovations, which are more likely to occur in the developing world.

The shift toward mass market solutions will also introduce a dramatically different dynamic to the supply chain. Anscombe, Thomas and Sawaya underline the fact that when margins are 80 percent or more, working capital, manufacturing costs and distribution costs have little impact on profitability. The advise companies to look closely at their manufacturing and distribution models to help drive down supply chain costs.

Future manufacturing and supply-chain organizations will have to be more streamlined to bring more therapies into mass production quickly and cost-effectively. The authors expect to see outsource manufacturing continue to grow, not just in late life-cycle or periphery technologies, but also for core technologies.

A consequence of the need to Jonathan Anscombe is a focus on specific capabilities means partner and co-head of AT Kearney’s pharmaceutical that new types of companies will and healthcare practice. operate in the space currently occuMichael Thomas and Omar pied by integrated pharmaceutical Sawaya are principals in the global pharmaceuticals and companies. Value-delivery compahealthcare practice. nies will focus on specific therapies in certain countries, and will gear their value propositions in response to local market needs. Health innovation companies will develop and leverage technologies in as many applications as possible to gain a return on investment at a reasonable cost, thus maximizing profit.

The report conlcludes that the pharmaceutical company of the future will have to decide which of these functions it wishes to deliver, and with which companies it needs to partner to access world-class capabilities.

Competitive advantage will come from the ability to connect these capabilities to address critical health needs on a global scale.

For more information on the full report, please see www.atkearney.com.

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ASK THE EXPERT

SUCCESSFUL PRODUCT COMMERCIALIZATION

ROBERT BECKER

T

he breadth and depth of Eurand’s oral technology platforms enables us to combine and adapt the technologies to the drug substance, turning difficult drug candidates into easyto-administer products for patients. Our expertise lies not only in our proven oral pharmaceutical technologies, but also in our capabilities ranging from formulation development and analytical testing, to small batch GMP-manufacturing and full scale commercialization. These key attributes, paired with scientific professionalism and patent protection on our technologies and formulations, attract our partners and allow us to extend and maximize the market potential of our partners’ therapies, whether prescription or over-the-counter.

With increasing challenges facing drug discovery, we see the life cycle management strategy for product portfolios becoming more important for all of our pharmaceutical partners. Generating products with key differentiating benefits, gaining clinical and regulatory approvals and enabling patient convenience are all important considerations that must be achieved when developing new formulations of existing drugs.

At Eurand, we address these issues by assessing a variety of existing drug features such as API properties, physical characteristics of the desired dosage form and in vivo requirements, to name a few. Our R&D team then determines and tests the most appropriate technology or combination of technologies to apply that will produce an optimal formulation with enhancements such as increased bioavailability, custom release profi les and patient-friendly organoleptic properties.

When working with pharmaceutical partners, our aim is to convene as a single project team, aligning on the goals and objectives of the project. Key to this approach is a communication pathway promoting teamwork. Strong management support, the use of metrics and continuous improvements are implemented effectively to provide an environment that fosters success.

Whatever the size of our partner, the approach is similar. We work with our partners to completely understand the market requirements and the desired product profi le. We then create a comprehensive development plan that combines our scientific resources with clinical and regulatory expertise, which includes a program designed to achieve the product timing and budgetary targets required by our partners. Our partners value the ability to be a part of the process every step of the way – for example, the develop-

masking technology, which provides a coating that encapsulates drug particles, forming an inert barrier between the medication and the taste buds while still allowing the drug to dissolve in the stomach. The Microcaps coating technology employs a distinctive coacervation process and can also incorporate spray coating, creating polymeric membranes of differing porosity and thickness to encapsulate drug particles. Because the coated particles have a very small size, the formulation can be created to have a smooth and pleasant ‘mouthfeel’ for patients.

Through successful partnerships such as this, Eurand adds value to pharmaceutical brand portfolios while continuing its commitment to develop and commercialize products that better address patient needs.

Eurand develops, manufactures and commercializes enhanced pharmaceutical and biopharmaceutical products based on pro-

“With increasing challenges facing drug discovery, we see the life cycle management strategy for product portfolios becoming more important for all of our pharmaceutical partners” ment deliverables are jointly reviewed at key milestones in order to allow the partner to track the program appropriately and make timely adjustments, if necessary.

Developing Lamictal ODT Some of the most common reasons for poor patient compliance with drug therapy are poor taste and difficulty in administering the drug. Our goal was to work with GlaxoSmithKline to provide an effective formulation of the product that is pleasant tasting, easy-to-swallow and convenient. The development of Lamictal ODT came as a result of our collaborative process.

We used our AdvaTab ODT technology, which makes use of our proprietary granulation and tableting processes that allow the tablet to disintegrate rapidly in the mouth without chewing or the need for liquid. We combined this with our Microcaps taste-

prietary technologies, and has developed successful alliances with leading pharmaceutical and healthcare companies. We recently co-developed a new formulation of Lamictal (lamotrigine) with pharmaceutical partner GlaxoSmithKline. Approved by the United States Food and Drug Administration (FDA) in May 2009, Lamictal (lamotrigine) ODT (oral disintegrating tablets) represents Eurand’s fifth FDA-approved drug since 2001.

Robert Becker is Chief Research Officer of Eurand and oversees all research and formulation development activities worldwide.

His background includes senior management positions at Biogen Idec GmbH, Lilly Research Laboratories and Boehringer Ingelheim.

Becker holds a degree in Chemistry and a PhD in Physical Chemistry from the Technical University of Munich, Germany.

For more info please visit www.eurand.com

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INDUSTRY INSIGHT

Process innovations for operational excellence The pharmaceutical industry has made dramatic contributions to improving the quality of life around the world, yet it finds itself under tremendous pricing pressure for its products, says Alfred Sherk.

T

his pressure is compounded by fi ndings of a recent McKinsey & Co. analysis of the pharmaceutical industry that, “the internal rate of return (IRR) on small-molecule R&D is now around 7.5 percent, which is less than the industry’s cost of capital”. While increasing the pace of innovation could elevate returns, operational excellence has become a strategic necessity for the long-term vitality of the industry. Operational excellence, stated simply, is minimizing waste while maximizing customer value.

Relative to other complex manufacturing industries, there are two egregious top-level measures of operational efficiency that can be effectively used to drive operational excellence.

The first measure is end-to-end throughput time of the production life cycle from the first chemical reaction through distribution.

The second is the total amount of inventory.

“Operational excellence, stated simply, is minimizing waste while maximizing customer value” At the beginning of Toyota’s long journey to becoming Lean, their leadership focused on removing inventory and wait-time from their manufacturing processes. At that time, their end-to-end cycle time was in the range observed in the pharmaceutical industry today.

Excessive throughput time is caused by the

lack of synchronization of key processes or operational complexity that is being ineffectively managed.

Novartis’ continuous manufacturing paradigm, a ever, the operational processes component of their Lean prothat need to be addressed for gram, has led to the reduction meaningful end-to-end cycle of their overall throughput time and total inventory are usutime from 550 days to 200 ally global and cross-functional days for some of their major Alfred Sherk is the founder in reach. A central tenet of the products, and they see the and CEO of SherTrack, a quality movement is the unopportunity to get it to just provider of innovative, predictive analytic solutions derstanding that every process one month. If Novartis can for synchronizing supply with has its capability limits; step achieve this level of perdemand. He is a past member changes in performance require formance, the implied proof the Technical Advisory Board for Michigan State process innovation. In this case, ductivity gains are gigantic.

University’s Graduate School it is the enabling work processes Moreover, every operational of Business and is a limited that need to be re-thought. decision they make will be partner in North Coast Technology Investors LP. Recent innovations in apbetter informed by real cusplying predictive analytics to tomer demand. customer demand signals and Total inventory is also how they can be propagated down the supply very high in the pharmaceutical industry. and production chain have allowed the adopAccording to a recent IBM study, inventory tion of the Lean pull process in operations turns are just 3.4 times industry wide. Unlike that previously were deemed too complex to most other industries, the lives of patients are use the Kanban type process. Demand-driven potentially at risk if a pharmaceutical is not manufacturing builds on the Lean pull model available when needed. However, inventory and extends it beyond assembly operations ties up fi nancial capital, which is increasingly into complex manufacturing. Furthermore, expensive as a result of the credit crunch. advances in probabilistic algorithms have led From an operational excellence perspective, to significant performance gains in complex excess inventory frequently masks incapable production operations, in terms of on-time work processes. Reducing inventory exposes delivery, overall equipment effectiveness and these incapable processes and affords opporinventory. Innovations in predictive analytics tunities to redesign them. and probabilistic algorithms offer pharmaThe Lean Six Sigma movements provide ceutical producers new options in their drive the framework and tools to identify waste and to operational excellence. methodically address operational issues. How-

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PACKAGING

Thinking

outside the box

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 optimization 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 standardizing 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 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

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of green and black belts to facilitate new projects, who as a result have made kets to standardize, but at least we can try and do something for the EU. strong progress, despite the recent industry hurdles set by regulatory bodies There must be something we can do as a pharma industry – there are a lot and their new guidelines. of influential people within it, but only time will tell if we can influence the “The regulatory bodies are causing a bit of a stir at the moment, whether regulatory bodies.” it’s child-resistant packaging, new track-and-trace legislation or Braille. It’s Allen explains that the possibility for European harmony is more likely interesting; it’s certainly a massive challenge. than some of the Asia-Pacific countries, For example, with the secondary packs we which often require additional packaging ICH Guidelines have to put reimbursement labels on, as well and a flow wrap, amongst other things.

The International Conference on Harmonization as counterfeit features, tamper evidence and However, the quality of standards is not an of Technical Requirements for Registration of Braille; combined with the new leaflet legisissue that tends to greatly differ, and doesn’t Pharmaceuticals for Human Use (ICH) is a unique lation it could all result in increased pack pose too much of a problem at present. project that brings together the regulatory sizes. We have reduced the number of leaflets GSK, like every pharma company, needs authorities of Europe, Japan and the United and cartons, and standardized, but the new to reduce costs to compete, he explains. “We States and experts from the pharmaceutical legislation is making it more difficult. We’ve need to produce more packs of high quality industry in the three regions to discuss scientific had to introduce more components, bigger and with less resources. At the moment, it is and technical aspects of product registration. cartons and bigger leaflets, so unfortunately working, but there is a period of continual The purpose is to make recommendations we’re now going the other way. It’s building change. Change is good, change is healthy, on ways to achieve greater harmonization in the a lot more complexity into our process,” exbut we’ll also need some stability. Hopefully interpretation and application of technical plains Allen. we can get there. Changes in the ICH guideguidelines and requirements for product lines have affected us, but you expect that in registration in order to reduce or obviate the need Challenges the pharma industry, and all pharma compato duplicate the testing carried out during the He notes the challenges of incorporating nies should be geared up to cope with these research and development of new medicines.

Braille within the packaging: the height and requirements.” profile of the dot and the technology that is However, despite these worries, Allen (Source www.ich.org) needed in the manufacturing process either by doesn’t view the future in terms of restricting embossing the dots during the carton manuregulatory constraints or the crumbling effacturing process or by screen printing on labels or cartons. fects of the economic crisis. He talks of the innovative process, QBD, Lean Currently the only legislation for dot height is for Italy, which stands at Six Sigma and Design of Experiments, and the need for them in the indus130 micron; all other markets have a target height of 100 micron. “At the motry. The main change, he predicts, is outsourcing. “We’re slowly getting ment, we can achieve that, but the new guidelines are asking for possibly there with the non-value adding activities, and like the asset management around 200-micron dot height, and we’d be very pushed to actually make that because you start getting a lot of bursting of the carton board, and that can affect the printed text,” says Allen.

“Instead, we’re looking at the possibility of labeling the packs with Braille, or reverting to a rotary type application to replace embossing, but again there is the challenge of ensuring that every single pack Keith Allen is Technical Manager of Packaging Technology at GlaxoSmithKline. has the correct Braille information, and all dots are present.”

Working as a global company also sets difficulties in the manufacturing process. Allen notes the trace-andand maintenance I do see a lot more of that happening, but you need to retrack feature and new packing lines, that GSK has had to install purely for the tain your expertise at the sites. You can reduce head count by outsourcing, Italian market requirements. “One of the concerns right now is that we’ve inand there are lots of savings to be made, but you must have your experts; troduced all this new technology for one market, and that other markets that you need to retain the knowledge.” also take reimbursement labels, such as France and Belgium, will require a difAs the challenges mount across the board, it is becoming apparent that ferent process, and hence different equipment. those companies with innovative R&D departments who are able to meet re“Ideally, if it’s possible, we want one process for all markets, at least one quirements that will continue successfully. How many companies in the infor the EU. We’re not expecting the US, Japan or possibly the Zone 4B mardustry will be able to do that remains to be seen.

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

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INDUSTRY INSIGHT

Going the extra mile Wouldn’t it be nice if the pharmaceutical supply chain could comply with cold chain regulations from manufacture to end-user?

By Jean Bédard

T

he cold chain concept refers to all resources that are required to maintain temperature-sensitive pharmaceutical products within temperature limits as specified by manufacturers, from production to final distribution, down to the end-user or patient (last-mile distribution). Compliance requirements for storage and distribution of temperature-sensitive products have been edited by many organizations, including World Health Organization (QAS304.068), Health Canada (IDGPSA, Guide-0069) and United States Pharmacopoeia (USP <1079>).

While a great emphasis is put on the control and monitoring for storage and transport conditions from the manufacturers to the wholesalers, a lot of work has still to be done for the very last-mile distribution steps. In 2008, between 17 and 37 percent of healthcare suppliers were found to expose vaccines to inappropriate storage conditions, especially in temperature, with storage equipment being too cold rather than too warm.

However many retailers, healthcare professionals and end-users are still unaware of the new management and compliance challenges for the last-mile distribution of pharmaceuticals. Today, guidelines and standards tend to contain the whole supply chain, including the very last-mile components like pharmacists and healthcare professionals. Boards of Pharmacy started to install cold chain storage and distribution guidelines. For shipments from pharmacies to patients or end-users, procedures and documentation for receiving and storage of products are required, with all documents and records being adequately maintained. Further, temperature standards should be installed and storage temperatures should be monitored and controlled. Actions should be taken when temperature deviations occur.

To help pharmacies and other institutions in maintaining good cold chain control,

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Alternatives Technologie has developed simple and effective solutions: • Procedures and documentation: A kit of preformatted procedures and documentation is available and can be rapidly adapted to pharmacies, in regard to the receiving, storage of drugs, storage equipment and shipping/delivering processes. Self-auditing templates and training materials are also provided.

• Storage equipment: The pharmacist has to possess refrigerated equipment to store products between 2°C and 8°C, whether it is a domestic refrigerator or a laboratory refrigerator (avoid ‘bar’ type refrigerators). In order to know the performance of the equipment and to comply with regulations, we have developed a mapping tool kit (protocol, data loggers and procedures) to perform temperature distribution studies of refrigerators.

• Temperature control and monitoring: To meet financial challenges and make it affordable, we’ve introduced solutions that enable us to monitor the storage temperature (equipment, shelves) without investing a lot of money on heavy monitoring systems and having to manage hardware, software and databases. A vendor-hosted web wireless monitoring system continuously monitors the temperature inside the pharmacy’s storage areas and equipment. The pharmacists simply have to install the wireless temperature sensors and plug in the reader module.

Then individual and secured monitoring accounts can be set up through a common web

portal. Current and historical temperature data are readily accessible under secure session from a central database. Furthermore, the pharmacist can configure his account and temperature alarms. To help pharmacists we have also created a vendor-hosted data logger management system based on the same model.

• Delivering and shipping container: A kit of pre-qualified reusable portable containers is offered to pharmacies, with different sizes and different temperature ranges available.

Such containers are equipped with condi-

Jean Bédard is Chief Executive Officer for Alternatives Technologie Pharma Inc. and holds a MBA in Bio-industry Management. Since 2003, he has led the company and its impressive team of cold chain and track and trace management experts, and has managed more than 100 cold chain compliance programs in the Life Sciences and Healthcare sectors.

tioning material kits in order to maintain the products during delivery and distribution to the end-users. Additionally, individual conditioned bags with temperature-sensitive products are available to end-users.

With these new products and services adapted to the last-mile actors, there is no reason not to have a complete and secure supply chain that can protect the integrity of medicines and preserve all their therapeutic properties from raw material to the end-users. It’s time for these last-mile actors to jump on the cold chain train to make sure that their patients get the right and secure medicine to help them stay healthy.

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EXECUTIVE INTERVIEW

Prescription: technology NGP speaks with HP’s David Medina to find out how IT can help the life science and pharmaceutical industry face some of today’s biggest challenges.

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offer organizations the ability to securely collaborate on research projects irrespective of their location, providing virtual access to the resources they need for effective data and process sharing.

Cloud computing also offers possibilities not yet imagined to enhance collaboration across the healthcare ecosystem.

odern life science research is largely a function of traditional research techniques. However, the advent of the genomic revolution has brought with it a raft of new data sources and types, such as DNA sequencing, genomics, proteomics, imaging and even sociological data that has now become a critical part of research. As a result, successful life science research has increased its dependence on information technology.

What role does information technology play in a life science organization's strategy to improve the efficiency of the drug discovery and development process?

David Medina. IT is an extremely important element in the biopharmaceutical industry’s quest to improve the efficiency of drug discovery and development. In addition to reducing IT costs, pharma CIOs are being asked to bring the power of information technology to bear on the business issues faced by the industry. Information technology has been applied to many of the problems faced in conducting clinical trials. Electronic data capture has had a rapid uptake due to its ability to speed the process of gathering and analyzing clinical trial data during the conduct of the trial, rather than waiting for the end of the trial to review and clean up all the data related issues. Of course, IT has also had an essential role in the collaboration, analytics and data gathering required during the discovery process. From target search, through processes such as HTS and HCS, the role of high performance computing is absolutely critical to the success of drug discovery. There is also an oncoming tsunami of data resulting from the application of the latest life science research methodologies. Cost-effective, properly applied IT will be required to manage these data sets.

How do you envision information technology being used to stimulate collaboration be-

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There has been much discussion about the im-

David Medina is Worldwide Life Science and Pharma Segment Executive for HP. He is experienced in helping companies bring drug and device products to market, has held leadership positions with Quintiles Consulting (Regulatory Affairs Certification), Medical Manager, Confer Software and Dianon Systems and is a member of the CDISC Advisory Board.

tween life science organizations and the rest of the healthcare ecosystem such as providers and payers?

DM. Effective collaboration must cut across the boundaries of each member of the healthcare ecosystem. This entails sharing information and processes in a seamless fashion both within and between enterprises. Technologies such as service oriented architecture offer healthcare ecosystem the opportunity to share data and link processes. For example, initiatives such as caBIG use this approach to enable interoperability between organizations involved in cancer research. IT technology will also allow different organizations to collaborate on common processes and develop knowledge networks with individuals regardless of organizational boundaries. Thin-client technologies also

pact of next generation sequencing and other high data rate instrumentation in the field of life science research. What do you see as the challenges to industry from these new developments in the field of life science research?

DM. The most pressing challenge that these new technologies pose to the industry is around management of the huge data sets that these instruments will churn out. When this is coupled with an evolving business and regulatory environment that is also driving longer retention periods for data, one can see that the costs for storage will grow, as well as the need for new technologies and techniques that can effectively manage and analyze this research data. The follow on set of challenges will revolve around the efforts to aggregate these data with clinical and other types of life sci-

“The most pressing challenge that these new technologies pose to the industry is around management huge data sets” ence data in order to gain the highly sought after insights upon which the advancement of the life sciences depend. These challenges include everything from high contact data management to the tricky issues around semantic interoperability between dissimilar systems, including both data and controlled vocabularies.

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EXECUTIVE INTERVIEW

them across globally dispersed, virtual teams that combine specialty know-how and expertise under a single umbrella. These virtual organizations require sharable soft ware, on-demand content in the context of scientific workflows and effective collaboration tools that are always ‘on’, and easy to switch off. The bottom line is that R&D labs today are searching for ways to do more with less, and the demand for assured ROI has never been greater. Lower-cost, faster data processing in the cloud can address these baseline customer concerns.

What are the barriers to adopting a hosted informatics solution?

TH. Data security, IP protection, reliability and customizability are concerns raised by some, but uneasiness around these issues is fast disap-

SEEDING THE CLOUD Trevor Heritage discusses the value of hosted informatics in life sciences R&D. Are Symyx’s life sciences customers ready for cloud computing?

Trevor Heritage. Industry as a whole is moving very rapidly to cloud computing – supplementing, and in some cases even replacing traditional, license-based soft ware with subscription-based, on-demand Soft wareas-a-Service (SaaS) offerings. This new approach lets companies focus on their core competencies, on operational agility and cost savings. I see life sciences organizations making a similar rapid shift to what I call ‘hosted informatics’. In this paradigm, high-value scientific information and applications are hosted online and made available to many customers in a multi-tenant environment. It’s a pay-as-you-go approach that offers overall cost savings, easier deployment, easier access and improved flexibility in managing internal operations, partners and contract research organizations (CROs). Hosted informatics is especially helpful in the biopharma sector where mergers and acquisitions are a part of every-day life. It can take months to sort out the network deployments necessary to integrate globally dispersed teams into a newly merged organization. With hosted informatics, all you need is an internet connection and a password for instant access to shared scientific information, tools and workflows.

What is driving the traditionally conservative life sciences industry into the cloud?

TH. Labs today generate enormous amounts of information. Turning experimental results into timely, actionable information that drives better decisions, more effective workflows and more successful pipelines is a huge challenge. Today’s emphasis on outsourcing and global project teams makes information-driven R&D all the more daunting. Outtasking to CROs is decentralizing pharma R&D operations, distributing

pearing as people become more familiar and comfortable with hosted solutions. Safe, secure online banking and document storage are commonplace today, and the success of ventures like Amazon, Google Docs and Salesforce.com is prompting pharma to investigate and increasingly invest in cloud solutions. In fact, pharma has been using cost-saving, hosted solutions in its clinical and sales/marketing activities for some time now. Suppliers like Symyx who offer hosted solutions are not challenging pharma to do something they don’t want to do. Rather, we’re partnering with pharma, providing a time- and cost-saving alternative approach to more effective laboratory workflows and outsourcing.

What kinds of hosted informatics applications do you see pharma adopting?

TH. Our customers are interested in deploying hosted electronic lab notebooks along with cloud-based chemical registration, chemical inventory management, work order management and R&D data management services augmented by project dashboards with real-time analytics. I envision a secure, hosted informatics environment where pharmaceutical, biotechnology and chemical companies, their partners and CROs, can collaborate effectively and with reduced overhead and costs. For example, a hosted chemical registration service can significantly reduce the costper-compound-registered while also lowering the total cost of ownership of a chemical registration system. The hosted system also streamlines outsourcing by enabling R&D organizations to turn on and turn off thirdparty collaborators quickly and efficiently. For pharmas concerned by the one-size-fits-all reputation of the SaaS model, hosted informatics solutions actually come in a variety of shapes and sizes, ranging from remote management of a preconfigured server that sits in the customer’s environment to a completely hosted solution accessed via a web browser. Flexible deployment options like this improve support for distributed project teams, reduce installation costs, accelerate start-up times and provide quick payback periods for investments in hosted informatics solutions. The convergence of information-driven R&D and hosted informatics in the cloud is an exciting prospect.

Trevor Heritage is president of Symyx’s software division, a provider of scientific software solutions for enhancing laboratory productivity, collaboration and innovation within the life sciences, consumer products, chemicals and energy industries.

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TECHNOLOGY

THE

SIDE OF BUSINESS GlaxoSmithKline’s Bill Louv tells Natalie Brandweiner of technology’s role in ensuring the company’s success.

s CIO of GlaxoSmithKline, Bill Louv is the steward of more than $1.1 billion of IT investments that are made every year

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by the company. Making sure that the multi-center global pharma company receives a high level of ROI on these investments 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 organizations.”

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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er it’s in h t e h w , o d rything we g or any of the e v e s in p r acturin gy unde “Technolo evelopment, manuf ations” d discovery, commercial organiz “We don’t bring them all together into one prioritization,” 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 software that is specific to them, and they’re prioritizing that against other types of spend within R&D. They are prioritizing it against in-licensing an early phase compound or conducting another clinical trial.”

Times are changing, and GSK is aware of 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 that 80 percent of patients look online for medical information, with an additional 80 percent of doctors stating the internet to now be a critical component to their practice of medicine. The effects of this on customer focus can only be a good thing.

Cloud computing Cloud computing is a form of computing in which scalable and virtualized 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.

ine.

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o Bill L

of CIO

hKl t i m S o

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“Customer focus sounds like an obvious and easy thing, but it’s not at all,” says Louv. “Although 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 the 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 first of all figure 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 restrictions. If we stay focused on what’s right for the patients and the doctors, we will be able to figure 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 is extending into all aspects of the industry. Louv explains its critical role in personalized medicine in the developing or discovering of genetic markers, which involves large datasets; large not only in respect to the number 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.

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“We have big investments in both hardware and software 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 fastmoving part of IT. This problem is being solved as we speak, and a lot more can be done now with multiple terabyte-sized 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 points out 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.

“This is a core problem we’ve been wrestling with for years, and we’ll continue to wrestle with it for many more years. Things 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 digitize 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. If you capture the data earlier, it opens up all kinds of opportunities to share it among the scientists.

tegrated platforms that cover lots of different processes and activities, but you’re always going to be able to find 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 find the best and then cobble them together. Other people have the philosophy that they should get an integrated suite, eliminate all those interfaces and just follow the 80/20 rule. They think, ‘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. You have to take each case by itself and you don’t want to get hung on your own philosophical statements.”

Future 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 infiltration 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 analyzing a startup company such as a biotech company, a 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 centers. So we’re not only moving to their software, 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.

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.”

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 with securing funding becoming too tough. The technology sphere in general is preparing itself to welcome the arrival of the cloud computing phenomenon, and Louv notes that there are ways to achieve this without a significant outlay of capital.

“There’s some trauma on the organization 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.”

“Our company scientists have been using collaboration tools and collaborative databases for a decade, and using them effectively” “Just like everybody else, we’re always looking for ways to leverage search engines, to crawl around the company and to find things, but it’s something that we’ll continue to wrestle with. The other challenge, the collaboration piece, is different. This 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 externalized – that is, so much of R&D is done through partnerships – this collaboration goes on across the firewall as much as it does within the company, which creates additional challenges for an IT organization.

“We have several projects that change the security philosophy in the company: if you’re inside the firewall, you are trusted, and if you’re outside the firewall, you are distrusted. That model doesn’t work anymore, so what you have to do is go back, and your line of defense 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 different platform issues caused by the varying software needed for research areas. He notes how the problem often becomes a philosophical debate between whether you should use integrated platforms or best-of-breed systems. “There are some software companies that offer in-

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ASK THE EXPERT

Automating life sciences SOPs

By Ethan Smith

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ife sciences organizations often overlook active process compliance as part of process initiatives. Compliance is typically considered only to ensure inclusion of process steps in workflows and SOPs to address 21 CFR Part 11, GCP, GAMP or other regulatory requirements. The missing piece for sustainable compliance is the automation of business processes (SOPs essentially) in a controlled way – a way that ensures that the appropriate steps, rules and other compliance factors are clearly documented and enforced during process execution. Effective deployment of process modeling and business process management (BPM) soft ware has helped a number of the world’s largest life sciences companies successfully accomplish this – on a relatively short timeline and for a reasonable cost.

The fi rst step is to model mission-critical processes, analyze them, and defi ne standard global processes with regional differences where required by regulations. Traditional, static, ‘wallpaper’ process models will not suffice.

Software For life sciences companies traditionally dependent on SOP documents, deviations and waivers, leveraging an integrated process analysis and BPM soft ware suite provides process discipline and compliance that delivers real value in a number of ways. These include: reduced SOP deviations through enforced process adherence; reduced or eliminated SOP waiver forms; and real-time process visibility and information capture to monitor process compliance.

Benefits also include readily available process documentation and having the ability to easily update processes and implement process changes when needed. The solution exists today to help life sciences companies achieve and maintain active process compliance across the enterprise. Metastorm is an enterprise soft ware company focused on delivering business improvements through effective business architecture, process analysis and process automation technology.

Connecting Effective process models must connect together within a defined taxonomy to ensure complete process paths, and be easily consumable across the enterprise for collaboration. They must also include associated documents and content – such as SOPs, forms and work instructions – and be accessible in role-specific views for end user consumption. From there, process execution elements are added to the business flows using BPM soft ware – user forms, dashboards, integration services, role hierarchies and more – bringing the process to life.

BPM is being used by top global pharmaceutical organizations to implement processes in new and more effective ways. Th is is enabled by the ability to take process models and associated requirements elements directly from the modeling tool into the BPM automation engine, which significantly shortens process design and deployment timelines and ensures documentation consistency.

The direct linkage from the process models, SOPs and other documentation to process execution is how active process compliance is achieved. Executing processes on a BPM soft ware platform implicitly means that users are required to follow the prescribed flow and make decisions only as permitted by their defi ned role and authority in the organization. All of the process information is captured by the BPM soft ware and exports into standard documentation formats to provide validated evidence of process compliance.

Ethan Smith is the Director of Life Sciences Solutions at Metastorm. Ethan has extensive experience in business process consulting, including enterprise BPM strategies and centers of excellence utilizing Metastorm ProVision and Metastorm BPM. He has driven process initiatives across R&D, sales operations, incentive compensation, physicians spend management and compliance functions.

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EXECUTIVE INTERVIEW

Driving ROI analysis Richard Malcolm explains how to get the best ROI in patient recruitment.

basis, either a weekly or biweekly, you should look at the number of enrolled patients, and look for trends in the number of enrolled patients, including number enrolled per week and total number enrolled in the study, versus the planned enrollment or versus the predictive model that has been provided to you by the recruitment program.

“Patient recruitment is going to stop being a black box ” What trends do you see occurring over the next decade that will impact not only ROI but patient recruitment in general?

Why is ROI such a hot topic in patient recruitment today?

Richard Malcolm. There are more and more requests from senior management at the larger pharmaceutical companies to show the value of the money that’s being spent on patient recruitment and ultimately, to show the return on investment. Cost pressures have been impacting the pharmaceutical industry for several years now, and there has been continued pressure to speed up the very expensive development process to try and get drugs to market as soon as possible, to get revenues as quickly as possible, and to get as much patent-protected revenue as possible.

Do the individuals who are randomized into a study come from the sponsor or the site’s own sources, or do they come from the recruitment program?

RM. What you really want to be able to do regardless of whether you’re using newspaper advertising, television commercials or direct mail, is to be able to demonstrate on a regular basis – and regular basis being either weekly or biweekly – that the external recruitment program is contributing a measurable number of enrolled patients and that that contribution is additive or on top of the site’s normal recruitment contribution.

We’ve seen when we’ve done these programs and

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RM. Patient recruitment is going to stop being a black box and is going to start being much more of an analytical metrics driven process, and the reason is that without those kinds of metrics it’s impossible to make any kind of meaningful assessment of whether or not you got a good return on investment, of whether or not you spent the tracked them very closely that the external remoney well. It’s increasingly difficult for the study cruitment program does, in fact, enhance the team or the recruitment specialist at the pharmanumber of patients that wind up being enrolled ceutical company to be able to go back to their per week or enrolled per management and say, “Here month so that you get an adis what I spent, here’s what ditive effect rather than a reI’ve got and here’s the net fiplacement effect. nancial impact for our company.”

What are some of the metThere will be much rics sponsors should considmore attention given to er when measuring ROI? doing some really solid fiRM. The recruitment organinancial analysis to show the zation should be able to probenefits of spending money vide you with a set of on patient recruitment. expectations that are driven People are interested in off of a predictive model. If knowing and understanding Richard Malcolm is Chief Executive they’ve done a lot of this and getting a stronger sense Officer of Acurian. He brings over 22 work, they should have a very of how good of a spend this years of experience in healthcare management to the company. high degree of confidence of is. Also, there will be a greater Malcolm was previously VP, Business Development, for ICON what their recruitment curve likelihood that recruitment Clinical Research, served as is going to look like, how long programs will need to worldwide head for what is now Quest's central laboratory, and held it’s going to take before ranachieve enrollment objecsenior management and consulting roles at GlaxoSmithKline and startdomized patients start showtives within a desired timeup pharmaceuticals. ing up in the study from the frame, so not only will you be external supplier, what the driven by generating the paflow will be, and what the tients that a pharmaceutical process needs to look like to hit not only the encompany hopes that the external recruitment rollment objective in terms of number of individprovider can bring in, but also within a timeuals, but the target date. And then on a regular frame, and this will drive the ROI analysis.

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INDUSTRY INSIGHT

Meeting staffing needs in an economic downturn Ray Kane explains how these challenging times have affected staffing in the life sciences industry.

S

taffi ng needs in the life sciences industry during this current economic climate differ from what they have been in recent years. In the past, consolidation of big pharma companies has been limited and contracted work was less than prominent in this industry. But that was then and this is now.

Although the life sciences industry has proven to be more resilient than other industries during the current economic downturn, it certainly has felt the heat.

Earlier this year, the national unemployment rate reached its highest level since December 1983. The recession has changed the direction of the life sciences industry, resulting in the consolidation of big pharma companies and internal layoffs, forcing companies to be creative when it comes to fi nding solutions to fit their hiring needs.

Many companies have chosen to partner with staffi ng companies that utilize contract or contract-to-hire models to staff projectbased needs. Contract positions have the potential to develop into long-term opportunities in the future, assuming there is a sufficient backlog of work.

Partnering with a staffing company Companies within the life sciences industry have specifically begun to partner with staffi ng fi rms that specialize in the industry – such as Aerotek – to augment their staff through contract hiring. As a leading inter-

Ray Kane is Vice President of Sales for Aerotek Scientific. He has more than 13 years of experience in the staffing industry with Aerotek, dedicating the past six years to its Life Sciences and Health division. As Vice President of Sales in Life Sciences and Health, Ray manages national sales strategies and executes staffing services.

national staffi ng provider, Aerotek offers the flexibility to add staff to meet an immediate need, while allowing companies to maintain their bottom line.

A working relationship with a staffing provider allows life sciences companies the financial flexibility to spread out the cost of an employee over the contract period, in addition to the ability to focus on increasing its drug pipeline instead of concentrating on hiring full-time talent. Hiring an employee on a contract or contract-to-hire basis offers a flexible cost cushion,

• Aerotek, headquartered in Hanover, Md, is a leading provider of technical, professional and industrial staffing and program services.

• Established in 1983, Aerotek is an operating company of the Allegis Group, the largest provider of staffing services in the United States.

• For more information, please visit www.aerotek.com/sciences

because the cost to hire contract employees can be significantly less then hiring and training a full-time employee. Plus, Aerotek assumes the responsibility for associated contract employee costs such as healthcare, insurance and retirement benefits, among others.

For example, contract positions are currently gaining popularity in the life sciences industry, specifically during the recent hike in mergers and acquisitions of the larger pharma companies, and the internal layoffs that have been forced to occur as a result. As new projects develop, these companies must secure the appropriate personnel to work on projects in a timely manner.

Staffi ng companies can do just that, by providing qualified contract staffi ng employees with an agreed start and end date, which will alleviate the need to lay off employees after the completion of a project. Hiring employees on a contractual basis can also open doors to potential future employment opportunities, such as converting an employee to a permanent position after the contract period is complete.

“Aerotek offers the flexibility to add staff to meet an immediate need, while allowing companies to maintain their bottom line” While the consolidation of big pharma companies has recently subsided, the life sciences industry has yet to see the full effect of these acquisitions. In the meantime, big pharma companies need to decide how to properly balance internal layoffs in respect to project-based work. Contract staffi ng is an option that warrants careful consideration for short-term and long-term solutions that will have lasting benefit, no matter what the economic climate.

The economy will begin to turn around at some point and some indicators are showing that it may be sooner rather than later. The companies that are best positioned will be able to reap the benefits sooner.

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EXECUTIVE INTERVIEW

PHYSICIAN

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John Moran looks at how value delivered to offices can be used as a key metric of sales force performance.

STRENGTHENING SALES SUCCESS What’s the current state of the physician-sales rep relationship?

John Moran. Physicians continue to cut back on time spent with pharmaceutical sales representatives in the office during practice hours. This is in response to increasing patient loads, escalating administrative requirements, and tighter formulary restrictions. IMS Health physician research conducted in the first half of 2009 indicates that physicians are giving office access to fewer, select reps on the basis of who delivers more value to the physician and staff. Physicians define value in very specific ways, and these vary according to the physician’s specialty, size of practice, geography, characteristics of patients under care and certain personal preferences.

A three-year longitudinal analysis of IMS value metrics shows that value received correlates more strongly with prescribing preference and market share than traditional sales force effectiveness (SFE) metrics, which overemphasize the mechanics of the rep-physician interaction. By identifying the primary drivers of value for distinct segments of physicians, and adding these to activity metrics, US sales forces can reverse the gradual decline in strength of relationship with physicians and achieve greater field productivity.

Why haven’t traditional SFE initiatives improved these relationships?

JM. Since the early 2000s, when more systematic evaluation of sales forces using physician research was coined, companies have invested millions in understanding the quality of their selling effort. Today, just about every major US pharma or biotech company evaluates SFE by gathering physician feedback about rep interactions. Typically, a company will spend $3 million to $5 million per year to capture and analyze these data.

Th is does not include the cost of internal resources to manage, interpret and communicate results, and it also excludes the opportunity cost of focusing the field on things that do not drive market share.

According to commercial executives interviewed about SFE initiatives, few have been able to point to significant ROI on these initiatives.

Executives identify two primary reasons for this: research fi ndings are not specific enough or geographically focused to be actionable; and these fi ndings do not inspire the confidence and trust of the sales force. Given this disappointing track record, managers have lowered their expectations of SFE. What was originally implemented as a tool to drive rep productivity and measurable share gain has become comparative research that provides general ‘strategic’ insights about physician interactions.

Worse, there is a proliferation of published industry rankings of sales forces, which is usually broken out by primary care and specialists that leave managers with contradictory insights about who really is performing well and why. Commercial organizations clearly need better metrics and analytics to explain and predict market share, which generate specific guidance for improving performance.

Focusing on things that your customers value most and implementing actions to improve your delivery is an exciting way to re-energize SFE and deliver stronger, more improved ROI. Companies focused on transforming SFE into value for the customer are surpassing their competitors.

What questions should be considered for tracking SFE? JM. SFE, or customer effectiveness, metrics were largely developed when companies deployed selling models heavily weighted to reach-and-frequency. With few exceptions, metrics have not kept up with the sweeping change in how prescribing decisions are made or forced upon prescribers.

Companies that rely solely on traditional SFE metrics are not leveraging all the information that exists about physicians, reimbursement, patients and group practice influences.

A rigorous, high-impact, customer value-based approach should

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significant amounts of data, but little proof. The type of proof that generates excitement in the field requires advanced local-level influence analysis, considering promotion, reimbursement and practice influences. The third obstacle is not making fi ndings relevant for district managers. Perhaps the greatest cost of traditional SFE measurement isn’t the cost of the research, but the lost revenue from not pursuing true, verifiable drivers of prescribing. Finally, the fourth obstacle is not paying enough attention to the physician-sales rep relationship. IMS estimates that fewer than five percent of US commercial organizations routinely track their biggest intangible asset – relationships with physicians.

Furthermore, through extensive tracking research with thousands of physicians, IMS has identified four categories of rep behavior that help explain relationship strength and ability to influence prescribing.

These include building a mutually beneficial relationship, as physicians seek reps that are valuable to them and their practice; removing prescribing barriers as commercial organizations need to understand why prescribers can’t write their brand and remove these obstacles; engaging in valuable information exchange, as physicians and staff value learning and a perception of objectivity; and customizing information, tools and resources to the practice, as this drives access and additional opportunities to be valuable.

consider several key questions to establish a cross-functional discipline of excellence, such as how many of the metrics have been set based on historical notions of what used to drive prescribing behavior? Have these metrics been statistically tested to determine if they move share today?

When was the last time you interviewed physicians to get their perspective on what reps should be measured on? Are you using a methodology that relies on physicians’ ‘intent to prescribe’, not today’s advanced patient level data, as a way to predict impact? Are you measuring customer performance at the local level and communicating these results to district managers? What significant actions have resulted from your SFE measurement program in the past 6-12 months?

Experience alone is not enough to drive decisions. There is a new requirement for a higher standard of evidence, including data, analysis and fact-based insight.

What are successful companies doing to improve SFE? JM. The leaders of these companies are overcoming four common value obstacles. The first obstacle is an organizational mindset that treats SFE as a process check rather than a competitive differentiator. The goal of SFE research should be to fi nd ways to increase market share locally – either at the territory or district level. A second obstacle is generating John Moran is Global Leader for the Commercial Optimization Center of Excellence for IMS Health. He has more than 20 years of Rx, OTC and consumer marketing and sales experience spanning a broad range of marketing and sales disciplines. Moran works with many of the world’s top pharma organizations, developing new commercial effectiveness models with emphasis on strategies that enable greater customer focus and value.

How can companies better equip their sales reps to enter the physician’s inner circle?

JM. Companies can do three things to better equip their reps. First the role of the representative must be defi ned in terms of value delivery. Reps who deliver high value have more advanced and different skills compared to traditional selling model reps. Understanding the key drivers of value is critical for each specialty area, so that skills can be tuned to exact customer needs and motivations. Two, commercial organizations need to shift focus from rep activity to value received by prescribers. Value delivery is not just the responsibility of the sales organization. Marketing, managed markets and analytics must be equally involved to provide reps with the tools and information needed to be successful. Finally, create a business case to drive the implementation of value-focused execution.

Due to the limited impact of traditional SFE programs in the past, many sales and marketing organizations are skeptical of new measurement and tracking initiatives. Since a customer-value focused program goes beyond general information to provide specific market share opportunities and quantifies the impact of improving, a business case can be reviewed with commercial leaders to drive organizational commitment.

What is at stake?

JM. While physicians today are providing less access to their practices than ever before, they are allowing entry to a select number of reps who they believe are providing true value. A customer value program focused on the items valued most by physicians and designed to increase rep productivity can achieve significant results. Despite four common value obstacles, specific steps can be taken to re-energize SFE and deliver ROI. Companies committed to transforming SFE into value for the customer are gaining entry into ‘inner circles’ and an invaluable leg-up on the competition.

For more information, please contact jmoran@us.imshealth.com

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IN THE BACK

REGIONAL FOCUS: BRAZIL

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An emerging market, Brazil is receiving investments in the pharma industry, both at home and abroad.

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ocated in South America, Brazil is the fi ft h largest country globally by geographical area and occupies nearly half of the region, 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, São Paulo and Rio de Janeiro, which is one of the megalopolises in the world.

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 fi rms such as GSK, Roche and Novartis establishing operations there. AstraZeneca’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.

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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 destabilize the

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IN THE BACK REGIONAL FOCUS: BRAZIL

economy. The National Medicines Agency has ions that introduced a number of regulations have resulted in costs to the indus-try, 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 $1 billion

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from the industry annually. thes constraints, the market Despite these is generally becoming more sophisticated and has recovered its leadership in the region and is beginn ning to mirror other emergm ing markets, such as Russia and China, in regards to export and production opportunities.

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 $217 million, with generics accounting for two thirds of that. In April 2009, sanofi-aventis announced it 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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INTHE BACK

INTERNATIONAL EVENTS

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A roundup of upcoming conferences and events across the globe.

Dusseldorf

Dublin

Boston

Kiev

European Biomarkers Summit Nov. 5 – Nov. 6, 2009 Barcelona, Spain

Barcelona

Reporting Failure Investigations and Process Deviations Nov. 11 – Nov. 13, 2009 Dublin, Ireland

World Drug Delivery and Formulation 2010 Jan. 26 – Jan. 27, 2010 Radisson BLU Scandinavia Hotel, Dusseldorf, Germany

www.cfpie.com

www.ddfevent.com

R&D Leaders Forum 2009 Nov. 9 – Nov. 11, 2009 The Marriott Long Wharf, Boston

Pharmacovigilance Dec. 14 – Dec. 16, 2009 The Rembrandt Hotel, London

www.phacilitate.co.uk

www.management-forum.co.uk

Process Validation for Drugs and Biologics Jan. 28 – Jan. 29, 2010 The Desmond Hotel & Conference Center, Malvern, PA

www.selectbiosciences.com/ conferences

www.cfpie.com

Ukrainian Pharmaceutical Forum Nov. 10 – Nov. 11, 2009 Kiev, Ukraine

Vaccine Forum Washington Jan. 25 – Jan. 27, 2010 The Grand Hyatt, Washington

www.adamsmithconferences.com

www.facilitate.co.uk/bv

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An umbrella hangs next to graffiti about H1N1 influenza on a street wall in Mumbai on September 9, 2009.

PHOTO FINISH

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