Pharma Focus Asia - Issue 08

Strategy

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Expert Talk

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Research & Development |

Clinical Trials

Issue 8

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Manufacturing

2008

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IT

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Clinical Trial Supply Chain Key to Success

P h a r m a F o c u s A si A

ISSUE - 8 2008

Getting from Challenge to Change How far, how fast?

Business Intelligence in Pharma A key enabler of industry transformation

Biopharmaceutical Manufacturing The challenges

P h a r m a F o c u s A si A

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Foreword

Clinical Trial Supply Chain

Key to success “One of the most important factors in successfully conducting clinical studies is the efficient management of clinical study supplies.” – BearingPoint

T

he key to the success of a drug development programme is the effective management of clinical trials. Clinical trials today are bigger, more complex, spread across multiple sites and conducted in ever-shrinking timelines making their management a daunting task. However, optimal management of Clinical Trials Supply Chain could play an important role in conducting successful clinical trials.

Lack of proper infrastructure at study sites, regulations, availability of qualified study personnel, frequent changes in the trial design and uncertainty in the demand of clinical supplies due to unpredictable patient retention are some of the major challenges in conducting a clinical trial. Nonetheless, adapting to the changes induced by internal and external factors to ensure completion of the trial within the stipulated time frame and budgets is important and this is where a Clinical Trial Supply Chain’s role becomes critical to the success of a trial.

Clinical trials account for 50-70 per cent of the total spending on bringing a new drug to market and take an average of 10 years to be completed. According to a BearingPoint study, each day saved in the clinical development stage can contribute US$ 600,000 for a niche drug and US$ 8 million for a blockbuster drug in revenues every day. An efficient Clinical Trial Supply Chain ensures that all variations arising out of the huge disconnect that exists between the clinical trial supply demand planning, forecasting and the supply process are accounted for and dealt with in real time.

Aala Santhosh Reddy Editor

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Unleashing the Industry’s True Potential

48

Closed loop clinical trial supply chain R S Kumar, Senior Manager, Life Sciences Practice, BearingPoint, USA

Clinical Supplies

55

Adapting to trial demand Catherine Hall, Supply Chain Coordinator, Pfizer Global Research and Development, Supply Chain Management, USA

Clinical Trial Supply Chain

58

Streamlining information management Douglas Meyer, Senior Director, Aptuit Informatics Inc., USA

Strategy Global Risk Management Meeting the challenge

06

Nayan Nanavati, Vice President, Peri-Approval Clinical Excellence, Americas, PAREXEL International, USA

Indian Patent Law

Relevance to global pharmaceutical industry

18

Vijay Soni, Executive Vice President - IP, Glenmark Generics Inc., USA

Drug Development Challenges

22

Harjit Singh, Senior Development Consultant, Clinical Research, UK

Research & Development Getting from Challenge to Change How far, how fast?

10

Christopher-Paul Milne, Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

Sustainable Drug Discovery

Orchid Research Laboratories Ltd., India

14

Andre Hoekema, Senior Vice President, Corporate Development, Galapagos, The Netherlands

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27

Uma Ramachandran, Vice President - Medicinal Chemistry Mrinalkanti Kundu, Associate Director - Medicinal Chemistry

Galapagos’ alliance strategy

Antibacterial Research Bright future?

Targeted Delivery Photosensitiser conjugated gold nanoparticles Maung Kyaw Khaing Oo, Doctoral Candidate in Materials Science Hongjun Wang, Assistant Professor, Biomedical Engineering Henry Du, Professor and Director of Chemical Engineering and Materials Science Stevens Institute of Technology, USA

31

Contents 35

The staffing challenge

Adjuvant Systems

D Thomas Oakley, President and CEO, Bridge Laboratories, USA

Next stage of rational vaccine design

Nathalie Garçon, Vice President, Head of Global Adjuvant Center for Vaccine Development, Global Vaccine Development GlaxoSmithKline Biologicals, Belgium

Early Formulation Shortening the development timelines

Manufacturing 38

79

Controlling Production Process Incorporating analytical methods

Solvay Pharmaceuticals B.V., NCE Development Center, The Netherlands

43

Zhenping Zhu, Vice President, Antibody Technology, ImClone Systems Incorporated, USA

82

Holger Grohganz, Assistant Professor, Pharmaceutical Technology Jukka Rantanen, Professor, Pharmaceutical Technology University of Copenhagen, Denmark

Process Analytical Technology Application in precipitation processes

Clinical Trials Personalised Healthcare Hitting the mark

Moving from R&D to Manufacturing Excellence Bart Moors, Business Consultant, Pharmaceutical Industry SEA, Siemens AG, Belgium

Jan Möschwitzer, Senior Pharmaceutical Scientist, CPD-PSA Han Op’t Land, Head of the Biopharmaceutical Platform

Enhancing Antibody-based Cancer Therapy

Outsourcing 75 CRO Services to China

61

Shannon A Graver, Global Studies Operations Manager, PDOC Stefan J Scherer, Senior Biomarker Program Leader Angiogenesis, PDEO

84

Marjatta Louhi-Kultanen, Research Lecturer, Docent in Industrial Crystallization, Department of Chemical Technology, Lappeenranta University of Technology, Finland

Information Technology

F Hoffmann-La Roche, Switzerland

Proteomic Biomarkers Transforming drug development

65

Daniel Chelsky, Chief Scientific Officer, Caprion Proteomics, Inc., Canada

Global Clinical Development Reducing Japan’s drug lag

Business Intelligence in Pharma A key enabler of industry transformation

88

Alan S Louie, Research Director, Health Industry Insights, an IDC Company, USA

69

Toshiyoshi Tominaga, Director, International Planning, Minister’s Secretariat, Ministry of Health, Labour and Welfare, Japan

Biopharmaceutical 92 Manufacturing The challenges

Rustom Mody, Director, Quality and Strategic Research, Intas Biopharmaceuticals Limited, India

Human Antibody Discovery VelocImmune - A novel platform Sean Stevens, Associate Director, Inflammation and Immune Diseases, Regeneron Pharmaceuticals Inc., USA

72

Public Private Partnerships

94

Joseph Manoj Victor, Senior Research Analyst, Healthcare Practice, Frost & Sullivan, India

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Issue 8

2008

Senior Product Manager and Editor : Aala Santhosh Reddy

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isk management for prescription pharmaceuticals is both a high priority and a significant challenge for the biopharmaceutical industry today. Numerous incidents involving the safety and risks of marketed pharmaceutical products in recent years have brought the issue to the forefront

of public attention and regulatory scrutiny in the United States, Europe, and elsewhere around the world.

In 2007 alone, nearly a dozen major pharmaceutical products were either withdrawn from the market or placed under stringent prescribing restrictions because of safety concerns. These product

Global Risk Management Meeting the challenge A changing regulatory environment and difficult targets present significant challenges for biopharmaceutical companies seeking a balanced approach to risk management.

Nayan Nanavati Vice President, Peri-Approval Clinical Excellence, Americas, PAREXEL International, USA

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failures risked the health of patients, damaged the public trust of both the biopharmaceutical industry and government regulators, and represented investment losses of billions of dollars for the companies involved.

This issue of drug safety and risk is compounded by another significant

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problem: the inappropriate prescribing of medicines, which is a major cause of adverse drug reactions. For example, one recent study showed that 29 per cent of elderly patients received one or more inappropriate prescriptions medicines1.

Despite these statistics, substantial progress has been made in recent years to reduce risk and improve drug safety within the pharmaceutical industry.

Risk management plans are rapidly becoming a prerequisite for regulatory approval outside the US, and are gaining momentum within the FDA as well. However, there is clearly a need for continued investment by pharmaceuti1 Simon et. al.; Journal of the American Geriatric Society, 2005

cal companies to implement proactive, integrated risk management strategies to help ensure that new products provide the appropriate balance between patient benefit and risk. Achieving that balance is particularly difficult in light of the strong public demand for new therapies to address complex, lifethreatening conditions such as cancer and Alzheimer’s disease. In addition, the evolving regulatory environment concerning risk management has created its own challenges as a result of the sometimes-conflicting approaches in the US and Europe.

Understanding the challenges

One of the biggest risk management challenges faced by the pharmaceutical industry today is the complexity of the diseases being targeted. Most of the potential treatments for these conditions involve new classes of compounds or new approaches such as biologic and genetic therapies—all of which involve risks that are not fully understood. Many of these diseases are also chronic conditions that impact multiple parts of the body, making the biological effects of any new treatment regimen more difficult to predict.

Added to this challenge is pressure from a competitive global marketplace and a demanding public to bring innovative therapies for these devastating diseases to market as quickly as possible to benefit patients. In addition to concerns regarding recent market

Issues of drug safety and risk ­­– Recent statistics A study published in the Archives of Internal Medicine in 2007 showed that serious adverse events for prescription drugs reported to the US Food and Drug Administration (FDA) increased by nearly 260 per cent between 1998 and 2005. Fatal adverse drug events rose by 270 per cent over the same period.

These increases were four times greater than the growth in total outpatient prescriptions during that time2.

2 Thomas J. Moore; Michael R. Cohen; Curt D. Furberg; Serious Adverse Drug Events Reported to the Food and Drug Administration, 1998-2005; Arch Intern Med 2007 167: 1752-1759

withdrawals, public perception of drug safety and risk has also been influenced by growth of drug liability litigation.

These pressures require biopharmaceutical companies not only to carefully determine which products to bring to market, but also, importantly, to ensure that they have the right safeguards in place and have developed a proactive, comprehensive safety model and risk management strategy.

The issues of risk and safety must be understood in the context of the clinical trial process. For instance, the largest Phase III clinical trials typically enroll a few thousand patients. These trials provide significant data on the safety

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and efficacy of the compound for the target indication in its intended population, but it is important to recognise that these studies cannot answer every single question about a product’s risks and side effects.

The key for the biopharmaceutical industry—as well as the public and the regulatory agencies—is to learn as much as possible about the risks of each product within a reasonable period of time, then make a market decision about the product that carefully weighs its benefits compared with its risks.

One step that many pharmaceutical companies are taking in order to enhance their understanding of product benefits versus risks is to expand their clinical trial programmes during the peri-approval process. This is done by continuing to gather important safety and efficacy data during the time after a product has been submitted to a regulatory agency for review. This allows a company to gain additional data about a product and work with the agency during the review process to refine a product’s safety profile and understand its risks more thoroughly. This process helps the agency and the company to agree on product labelling that reflects the appropriate level of risk.

Post-marketing pharmacovigilance programmes also play a vital risk management role. These programmes typically monitor the use of a product in a larger population and gather data on reported adverse events to ensure that a product’s benefit / risk profile remains acceptable, or if changes need to be made to better manage its use.

Education programmes for healthcare professionals about proper prescribing criteria are another important way that pharmacovigilance programmes help maintain safe product usage.

Regulatory challenges

While the regulations governing risk management are crucial to ensuring the safety of marketed pharmaceutical products, they also present a challenge

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to the biopharmaceutical industry as it tries to manage risk on a global scale.

The FDA and the European Medicines Agency (EMEA) are leading the way in actively promoting improved drug safety by providing a framework of laws and regulations designed to help companies better manage the risk of their products throughout their lifecycles.

The challenge comes from the ongoing evolution of these regulations.

Although both the FDA and the EMEA are trying to achieve the same basic goals—protecting public health through better risk management of

Essential questions to understand a drug’s risks Are there rare events that will only manifest themselves when more people take the drug?

Are there specific risks for certain populations, such as younger or older people, or those with other conditions?

Will there be issues if the drug is taken in combination with any of the thousands of other pharmaceuticals on the marketplace, or with OTC products?

Are the risks different if a drug is taken over a long period of time for a chronic condition?

biopharmaceutical products—they have taken somewhat different approaches.

While the regulations are beneficial in many ways, they also can make compliance more difficult and more costly for the biopharmaceutical industry.

Since 2005, the FDA has produced guidances on Premarketing Risk Assessment, the Development and Use of Risk Minimisation Action Plans (RiskMAP), and Good Pharmacovigilance Practices. The guid-

ances stress the importance of early risk assessment and risk minimisation, with an emphasis on uncovering safety issues during clinical trials and providing adequate safety data to the agency to evaluate risk-benefit of drugs submitted for approval. However, as regulations are still evolving, so are their practical applications within the FDA’s divisions, with each division having a somewhat different approach than the other. As a result, risk management planning by biopharmaceutical companies must currently be pursued on a case-by-case basis.

The EMEA has also issued guidelines on risk management systems, a template for a European Union Risk Management Plan (EU-RMP), and new regulations governing pharmacovigilance. The EMEA accentuates the importance of having pharmacovigilance systems in place, and mandates the creation of the position of Qualified Person for Pharmacovigilance (QPPV) to be responsible for a company’s pharmacovigilance efforts for marketed products. Much of the emphasis is placed on databases and reporting systems, especially for post-marketing.

Unfortunately, in spite of having all these pan-European guidelines before them, different EU Member States have taken varying approaches to the collection and reporting of safety data.

For biopharmaceutical companies developing products for the global market, these varying standards mean that risk management planning in the near term remains a complex undertaking that must be discussed in close consultation with individual regulatory agencies for every product—making the current process more costly and cumbersome. Although the International Conference on Harmonisation (ICH) has also issued a guidance on pharmacovigilance, more work needs to be done between the industry and regulatory agencies to make the risk management process more transparent and predictable on a global scale.

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Given these numerous challenges, what steps should biopharmaceutical companies take to improve global risk management?

• Emphasise risk management and safety planning throughout the product development process – Effective risk management goes far beyond the development of the formal risk management plans that are now becoming standard for regulatory submissions. The evaluation of safety and risk should begin at the earliest stages of development and carry through the entire product lifecycle.

Understanding product risks early in the development process would facilitate better management of risk of product for an appropriate target indication and population—without impeding innovation.

• Create a company-wide, proactive “safety culture” – Establish improved safety and risk management as corporate priorities that are integrated into every decision and every part of the company values for which all levels of the company are held responsible. Invest in the people, processes, and technology needed to improve risk management and protect the company’s most important assets: its products.

• Use peri-approval trials to gain safety data – Make greater use of clinical trials conducted during the preapproval periods to gain additional information on product safety and risk in potential target populations, and to refine the product’s risk profile.

• Work closely with regulatory agencies on safety issues – With the evolving regulatory landscape, companies should discuss risk management issues with the appropriate agency officials during the pre-submission period to foster greater understanding about a product’s risk factors and gain the agency’s insight into potential requirements for safety data or formal risk management plans.

• Continue to promote regulatory harmonisation – The biopharmaceutical industry needs to continue to work with global regulatory agencies and the ICH to bring greater consistency and predictability to risk management planning at a global level.

• Support awareness programmes for appropriate prescribing and usage – Although a product’s labelling spells out the approved indication and usage guidelines, the statistics concerning inappropriate use of prescriptions drugs show that more needs to be done to educate healthcare professionals and the public about the proper use of each new drug that reaches the

A company with a proactive approach to safety and risk management will reap competitive benefits.

market. Such programmes help avoid undue risk, while maintaining access to new therapies for those who need them.

Particularly for stakeholders in the prescription drug arena—pharmaceutical companies, regulatory agencies, healthcare providers, and patients—the most important goal is to bring safe, efficacious medicines to market with the

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Meeting the challenges

appropriate benefit / risk ratio as quickly as possible, and to keep those products available to help those who need them.

Achieving that goal, however, means that risk management must be viewed as a continual process of understanding and reducing risk.

Within the biopharmaceutical industry, the key to responsible risk management is to understand the risks of a product as much as possible before it reaches the market, and manage those risks once the product is launched in the market. That means investing in and promoting safety and risk management throughout the product development process. While that investment can be costly, it pales in comparison to the cost of taking a product through development, only to have it fail to be approved or be withdrawn from the market because of safety issues.

Whether it is through better education of physicians and patients about appropriate product use, a reduction in adverse events, elimination of product withdrawals, or other safety improvements, a company with a proactive approach to safety and risk management will reap competitive benefits.

Additionally, the company will enhance its reputation among patients, regulators, lawmakers, physicians, insurers, and the many other important constituencies. And, this brand image ultimately determines the success of a company in the healthcare field. But, most importantly, companies that have a proactive approach to safety and risk management will be able to more positively contribute to bringing safe and effective treatments to patients worldwide, and keeping these products in the market.

Nayan Nanavati serves as Vice President, Peri Approval Clinical Excellence (PACE™), Americas in the Clinical Research Services business of PAREXEL International. He has more than 20 years of experience in the clinical product development industry and has worked extensively in peri- and post-approval clinical research.

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Getting from Challenge to Change How far, how fast?

Metrics for cost, time and success rates show that the current level of investment is challenging industry's viability. Success rates are an attractive target for effecting overall change. Getting from challenge to change, however, will demand migration from primary care market to speciality market, process redesign, outsourcing of clinical trials to emerging economies, and offshoring of ancillary pharma business segments. what FDA terms the Critical Path, a period when compounds attain proofof-concept and “go / no-go” decisions are made. In this view, the failure of the regulatory scheme and applied sciences to keep pace with the output from the discovery end of the R&D continuum have thus caused a productivity bottleneck in the development phase.

Yet another perspective on what ails the clinical research enterprise calls the current system “fragmented, outdated and ailing,” and chronically vulnerable to funding uncertainty. Whether the

Christopher-Paul Milne, Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

T

he biopharmaceutical industry is currently experiencing a very challenging environment.

There are many indicators: lower number of product approvals; consolidation among companies; fewer Big Pharma companies among the top 100 companies; decrease in the relative profitability of drug manufacturers; decline in the rate of increase of pharmaceutical sales; the variability of venture capital available to biotech; and, the increasing proportion of sales volume occupied by generic drugs in major markets.

How did this happen? According to some industry executives and analysts, production of new drugs is cyclical and the 2000s is merely a downswing after a very productive period throughout most of the 1990s. This slow down has caused a bubble in the flow of new products through the pipeline into the marketplace, exacerbated by increasing unpredictability of the longevity of products reaching the marketplace.

Although a recent Tufts Center for the Study Drug Development (Tufts CSDD) study revealed a 52 per cent increase in the number of investiga-

tional compounds entering clinical development in 2003-2005 compared to the 1999-2002 period for the top 10 pharmaceutical companies, basic development obstacles such as time and cost of development as well as low success rates remain formidable challenges to the industry’s ROI. Another view is that there is a disconnect in the R&D continuum that occurs during

R&D metrics 3.5 3.0 2.5 2.0 1.5

2.15

3.00

1.0 0.5 0.0

0.75

0.81

Time

(In Decades)

1.32

1.24

Cost

(In Billions)

Traditional Pharmaceutical

Success Rate (Out of 10)

Biopharmaceutical

Source: Tufts CSDD, IR Nov/Dec 2006 (based on paper in press Dimasi & Grabowski, Management & Decision Economics, 2007) Figure 1

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problem is margins, markets, or myths, at one end of the pipeline or the other, the real question that confronts industry, policy makers, regulators, and stakeholders is how we progress from challenge to change.

Industry metrics – What they tell us about how far, how fast

The cost of development of a new pharmaceutical was estimated at US$ 802 million by a 2003 Tufts CSDD publication, based on a study of drugs with approvals from 1992 to 2001. This figure included the cost of failure as well as opportunity costs (i.e. what the investment would have garnered in the decade or so that it took to go from “lead to launch”). The study showed a 2.5-fold increase in the overall cost of drug development from the 1980s to the 1990s. An updated study on a more recent cohort (by approximately five years) of new approvals with broader representation of products from both biotech and pharmaceutical firms demonstrated that the overall cost had again risen, this time by 60 per cent, with less than expected differences in the costs of small versus large molecule development programmes.

Time is money

Another factor contributing to the escalation in the cost of drug development is that the time it takes to bring a drug through the clinical development.

Average time taken for a regulatory approval process has not changed significantly in several decades and remains at about 7-8 years. While there were some gains in terms of clinical time during 1990s and 2000s, pre-clinical time increased considerably. One could attribute this to the 10-fold increase in potential drug targets due to the elucidation of the human genome, and the difficulties in validating these biological targets and identifying investigational compounds that affect them in useful ways. FDA review time has more or less stagnated after some dramatic

improvements in the mid and late 1990s compared to the 1980s.

Success Rates – Obstacle to productivity

Success rates are another challenge that remains an obstacle to productivity.

Success rates for new small molecule drugs hover between 10 per cent and 20 per cent, with an even wider range for large molecule drugs, depending on the therapeutic areas and types of compounds studied, the time frame, as well as the study methodology.

The impact of the cost of failures has been estimated to be as high as 75 per cent of the cost of drug development.

Failure rates for later phases in the drug development timeline are increasing, and have surged from around 30 per cent to 50 per cent in phase III. These late-stage failures are not only more costly in terms of time and money, but also in terms of resources diverted that could have been expended elsewhere.

This level of investment, in both absolute and relative terms, is considered “unsustainable” by regulators as well as industry executives and analysts.

Modelling by Tufts CSDD indicates that success rates are the most attractive target in terms of impacting the overall cost of drug development. Increasing success rates by just 5 per cent and 10 per cent could reduce the cost of drug development by 14 per cent and 33 per cent, respectively. By comparison, reduction in pre-clinical costs would have to be on the order of 30-60 per cent, and decreases in clinical development time would have to reach 20-40 per cent to achieve the same effect.

The way forward – Process, products and paradigm

Process of development is in critical need of repairs. Recent work by the Tufts CSDD on the efficiency of innovation reviewed several dozen innovation initiatives worldwide (e.g. FDA’s Critical Path Initiative, the EU’s Innovative

Tufts’ ‘Short List’

Process bottlenecks at each stage of R&D

Basic research What’s druggable?

Discovery

Validation of targets and biomarkers

Pre-clinical

Animal models versus in silico modelling

Clinical

Reducing attrition and improved dosing through new trial design (e.g. adaptive clinical trials, microdosing, electronic data capture, biomarkers, pharmacogenomics)

Manufacturing

Technology turnover

Regulatory review

Pre versus post-approval safety

Medicines Initiative, the HapMap project, involving the UK, US, Japan, China, Canada and Nigeria).

The clinical phase is the lynchpin of the R&D process. Much attention has been devoted recently on how to break bottlenecks at this phase. Biomarkers are key to assessing safety and efficacy of investigational compounds early in development to decide which ones should proceed to later stage trials, and confirming the utility of drugs in pivotal trials by predicting the ultimate clinical benefit of a drug without having to wait for long-term outcomes such as survival time. FDA has initiated a programme of Voluntary Exploratory Data Submission (VXDS) together with the European Medicines Agency (EMEA) in order to expand the science base, instill public

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Technology – How fast, how far to future

EDC

40-50%

Biomarker

40%

Adaptive Design

15%

Microdosing

Pharmacogenomics

3-15% 25-90%

Source: Mucke & Goldman, Pharm. Exec. Supplement, June 2006: CenterWatch, Lehman Brothers Figure 2

confidence and improve regulatory decision-making on pharmacogenomic data and its uses. Adaptive clinical trials and EDC are methodological and operational processes that are expected to improve the efficiency of clinical trials. Microdosing is one of several exploratory IND approaches that should promote earlier “go / nogo” decisions, reducing the number of compounds brought forward into the clinic as well as better characterising the ones that are targeted for further testing. This could reduce costs, but the initial impact is likely to be in the form of increased success rates.

How fast the technological fix for the clinical phase is progressing can be seen in Figure 2 based on recent surveys of utilisation of new approaches in trials currently in progress. However, anec-

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dotally drug developers have reported that rates for trials just getting underway approach 90 per cent for incorporating EDC and pharmacogenomic testing.

Meanwhile, on the regulatory side, FDA is emphasising its openness to adaptive designs, has also published a list of genomic biomarkers that have been used successfully to support approval, and together with the EMEA and MHLW, is working on a proposal for harmonising the qualification of pharmacogenomic biomarkers.

While improved process will address some of the challenges, others are related to the products themselves. The FDA points out that even a commonly used drug, such as warfarin, has been found to have a 7-fold inter-individual variability for dose. For this reason, the FDA wishes to move from a population-based model of product development in which one-size-fits-all, to a more targeted approach based on pharmacogenomics, i.e. personalised medicines. While these medicines will not be individually tailored per se, they will be increasingly limited to smaller subpopulations of patients evidencing certain genetically identifiable responses to drugs. This will increase the current momentum within the industry to move away from the highly competitive primary care market model based on blockbusters to speciality care markets (typically characterised as being biotechderived, requiring special conditions of administration, and having high-costper-treatment cycle).

Identifying and developing plans to manage product safety prophylactically through risk management plans may increase the cost of drug development in the short run, but in the long run will hopefully decrease time of development, while laying the groundwork for a return to confidence among practitioners, patients and investors. Some regulatory process initiatives, however, have proven successful already. For example, under the FDA’s fast track programme, products intended to treat serious and

life-threatening conditions with unmet medical needs are given special attention by the FDA through intensive scientific interaction. Other such programmes target products for rare diseases or illnesses for which the benefit-risk balance indicates that the need to make treatments available surmounts the regulatory requirement for completing the dossier until after approval (i.e. accelerated approval). Japan and the EU have similar programmes. Review of FDA approvals for the last decade indicates that the number of new approvals for such special populations has increased from 20 to 40 per cent, yet the subsequent safety history of these products in terms of safety withdrawals has been better than new approvals overall.

This changeover in product focus could serve three major goals: increasing industry’s economic health by decreasing its reliance on blockbusters; increasing its attention towards emerging markets; and, better serving public health by directing more R&D resources towards unmet medical needs. There are signals that this is indeed happening. A 2007 IMS report indicated that emerging markets contributed 27 per cent of the growth in world sales, double the rate in 2001. Also, of the 105 global blockbusters, almost half were specialist-driven, up from just 14 in 2000. Yet, there is much room for growth in these emerging and specialised markets. As of 2002, WHO estimates that there are some 2,000 diseases worldwide considered to have unmet medical needs.

While changes in the process and product realms will help address some of the challenges facing the industry, the paradigm itself will have to evolve before sustainability and profitability become the mainstays of a healthier and health-creating biopharmaceutical industry. Regardless of which way biotech is going, it is difficult to separate the fate of biotech from Big Pharma. Wealth Daily reports that in 2007 nearly US$ 100 billion was spent in Europe and the US on biotech mergers and acquisi-

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Challenge to change

In response to evolutionary stress, the R&D paradigm itself is undergoing metamorphosis, albeit a circular one. The biotech revolution was made

possible by a revolutionary business model, spin-offs from academia funded by venture capitalists. The scientists that formed the core of the movement were highly innovative, but also highly specialised, and thus vulnerable to economic extinction events. This left the door open for Big Pharma to survive, both competitively through horizontal integration and adaptively through vertical integration. The tableau has come full circle. Now markets are becoming specialised with the prospect of further movement in this direction under pressure from personalised medi-

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tions, much of it by Big Pharma, which may be strapped for products, but not cash. While Big Pharma is absorbing biotech products, companies, and platforms at an increasing rate, and shapeshifting into a new industry, it will also have to economise to sustain itself.

This will demand rapid reapportionment of R&D resources from highlycompetitive therapeutic areas in primary care to more specialised therapeutic areas, utilising process redesign to shorten clinical development time, decreasing costs and increasing patient recruitment by outsourcing clinical trials to sites in emerging economies, and offshoring of ancillary pharma business segments.

cine. The R&D niches of the public and private sectors increasingly intersect. Biotech spin-offs often rotate back within the sphere of Big Pharma or coalesce into big biotechs. This has given rise to the emergence of an all-encompassing biopharmaceutical sector highly charged to innovate technologically, organisationally, and commercially. Yet in order to thrive, it must first survive the rough road from challenge to change.

Full references are available at www.pharmafocusasia.com/magazine/

Christopher Milne is the Associate Director of The Tufts Center for the Study of Drug Development. Milne received his master’s degree in public health from the Johns Hopkins University.

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Sustainable Drug Discovery Galapagos’ alliance strategy

Andre Hoekema Senior Vice President, Corporate Development, Galapagos, The Netherlands

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CaseStudy

Alliances can capitalise on the synergies between biotech’s innovations in drug discovery on the one hand and the pharma expertise in moving novel candidate drugs from the clinic to registration and product launch on the other.

I

n the past few years we have seen the announcement of many drug discovery alliances between biotechnology and major pharma companies. Pharma companies have started to outsource increasing parts of their drug discovery R&D to biotechs, signalling a trend in a changing industry. The alliances seek to capitalise on the synergies between biotech’s innovations in drug discovery on the one hand and the pharma expertise in moving novel candidate drugs from the clinic to registration and product launch on the other. The drug discovery alliances signed by Galapagos over the past two years is reviewed and the risk-sharing model that forms the basis of these pharma-biotech partnerships, from both the biotech and the pharma perspective is analysed here.

Rapid changes in the pharma industry

There is an overall consensus that the pharma industry is at a pivotal point in its evolution and is seeing the beginning of a lot of changes. The evolving patent landscape, with multiple patents on drugs launched in the 1990s expiring over the next few years, is one of the main drivers of these changes. Furthermore, the number of new medicines reaching the market is decreasing every year despite a rapid increase in the pharma industry’s investments in both R&D, and sales marketing over the past decade. The business model

Overview of the drug discovery process and roles of partners Target to optimised lead

Pre-clinical

Phase I

Development Registration

Phase IIA

Galápagos

Marketing and sales

Partner Figure 1

Handover

of creating and marketing blockbuster drugs is no longer sustainable as pharma companies have moved away from innovative new-mode-of-action-products to less risky me-too (molecules that act on a target for which drugs are already approved). This strategy has led to pipelines that lack innovative products and therefore will not be able to compensate for current medicines coming off patent.

The current high-cost R&D pharma model needs to be replaced and pharmaceutical companies need to find ways to improve their R&D productivity, increase success rates, and cut R&D costs.

One of the ways in which the pharmaceutical industry seeks to address the challenges mentioned above, is by focussing on their core competencies: late stage development, registration, and sales and marketing of drugs. Furthermore, pharmaceutical companies are aiming to gain access to novel technologies or products and are looking for opportunities to expand their development pipelines through M&A, in-licensing of clinical drug candidates as well as through partnerships with biotechnology companies.

It has become critical for pharmaceutical companies to establishing alliances with biotech patents to secure innovation to fill their product pipelines.

The biotech perspective

The evident strengths of biotech companies are the innovative power in early drug discovery, the spirit of entrepreneurship and the willingness to take early technological risks. An inherent weakness of many biotech companies, however, is the lack of sufficient funding to support their R&D efforts; the costs for drug discovery research continue to increase, and the access to capital is becoming increasingly

difficult. Alliances with the pharmaceutical industry can serve to balance these costs and thereby effectively reduce the financial risks by sharing it with the partner. The essential element that defines the structure of such partnerships is the sharing of risks as well as rewards between the two companies.

With both pharma and biotech companies having incentives to pursue alliances, it should come as no surprise that deal-making is vigorous today. Over the last five years, more than 700 collaborative agreements were signed between pharma and biotech companies.

Risk sharing in drug discovery

The drug discovery process can be divided into several phases, starting from the search for drug targets through to launching and marketing a novel medicine. Figure 1 shows an overview of these phases including the main activities; each phase has its own profile in terms of requirements for technology and expertise, as well in terms of risk and funding needs.

Galapagos’ role in the alliances is to execute the early discovery and development phases of this process. This includes Summary of financial milestones Date Jul ’07

Therapeutic area Osteoarthritis

Partner

Milestone

(in millions)

GSK

€4.4*

Oct ’07 Rheumatoid Arthritis

Janssen

€2.0

Dec ’07 Osteoarthritis

GSK

€7.5

Jan ’08 Rheumatoid Arthritis

Janseen

€3.4

Jun ’08 Osteoarthritis

GSK

€0.6

Jul ’08

Lilly

€1.0

Osteoporosis

* Equity investment

Table 1

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Galapagos’ therapeutic alliance programmes Galapagos R&D has ongoing pre-clinical programmes in bone and joint diseases and in infectious diseases

Osteoarthritis (OA)

Rheumatoid arthritis (RA)

The most common form of arthritis, affecting people of age 45 and older. The disease is characterised by the destruction of joint tissue and a loss of articular cartilage. There are currently no treatments to prevent OA or even to reverse or block the disease process.

Treatment of OA involves pain control, weight control, and exercise. It is expected that with the ageing of the population, more individuals will be prone to develop OA. The market potential of a disease-modifying drug for OA could exceed US$ 8 billion annually, based on the current market and the absence of disease-modifying treatment.

The Galapagos focus in OA research is on human primary chondrocytes, which are the main cell types in cartilage. Galapagos has identified and validated novel OA targets and has progressed these into drug discovery. Modulation of these targets in human chondrocytes should lead to a net production of stable cartilage and should therefore be able to prevent and repair damage to this cartilage in patients. Galapagos showed Proof of Principle (reduction of disease markers) and Proof of Concept (reduction of targeted symptoms) in pre-clinical models. The Company expects to nominate a pre-clinical candidate in its osteoarthritis programme in 2008.

Osteoporosis

Rheumatoid arthritis (RA) is a chronic disease, mainly affecting the joints. The disease is characterised by inflammation of joints, which can be the cause of pain, swelling of the joints and stiffness. In later stages it can result in joint destruction and even disability.

RA is the most debilitating form of arthritis and the most common inflammatory joint disease. It is estimated that 1 to 2 per cent of the population in the Western world has RA, and although it can occur at any age, onset usually begins between the ages of 25 and 50. Current market for RA medicines is estimated at €7 billion annually; this is expected to approach €9 billion by 2011.

In the Galapagos RA programme, lead compounds have shown significant disease-modifying properties and good pharmacokinetic properties in relevant animal models of the disease. These molecules also show substantial protection against bone loss in the industry standard RA animal models. The compounds target proprietary kinase proteins. Preparation for IND filings and initiation of Phase I trials for rheumatoid arthritis will take place in early 2009.

Infectious diseases Osteoporosis is a disease that affects people of middle age during which the hormone levels that are essential to maintain bone density start to decline. The development of this disease is characterised by a significant loss in bone density as a result of an increase in bone resorption.

The disease is four times as common in women as in men. The major healthcare costs for osteoporosis, estimated at €10 billion in the USA, can mainly be attributed to the increased incidence of fractures in osteoporosis patients.

Currently available medicines aim to reduce bone resorption, while the novel molecules that Galapagos develops aim to build new bone tissue, thus contributing to overall bone strength.

the discovery and validation of novel disease targets, conducting compound screening on these targets, identifying tractable chemical hits, pursuing hitto-lead programmes, and developing resulting leads into candidate selection compounds through to a successful Proof of Concept in clinical research Phase IIa. At that stage the hand-over to the pharma partner takes place for all execution from Phase IIb onwards. The pharma partner

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Infectious diseases are caused by pathogenic micro-organisms such as bacteria, viruses, parasites or fungi. Infectious diseases are a leading cause of death worldwide. Existing therapies against infectious diseases currently account for an estimated €45 billion in annual global sales.

The need for new therapies is on the rise due to increasing resistance of micro-organisms to available therapies.

Natural products are a significant source of new medicines: nearly half of all new drugs devloped in the last two decades are derived from compounds of natural origin. Natural products allow the exploration of novel chemical spaces and targets that offer new prospects for treatments across a range of infectious diseases.

has exclusive options to further develop and commercialise these compounds.

Overview of the Galapagos’ alliances

The agreements that Galapagos signed thus far provide the partner access to a number of Galapagos’ novel proprietary targets that play a role in a specific disease.

In each alliance, Galapagos is responsible for developing candidate drugs and

take these through to Phase IIa clinical Proof of Concept. At that point in the development, the partner gets the option to exclusively develop, manufacture and commercialise these candidates. In addition to receiving an upfront payment as technology access fee, Galapagos stands to receive discovery, development and regulatory milestones for each discovery program plus sales milestones and up to doubledigit royalties on worldwide product sales.

CaseStudy

Milestone payments Disease area

Partner

Total deal value

Osteoarthritis

GSK

€186 mn. + royalties

Rheumatoid Arthritis

Janssen Pharma

up to €1 bn. + royalties

Osteoporosis

Lilly

€275 mn. + royalties

Infectious diseases

GSK

€219 mn. + royalties Table 2

The revenues received from the alliance partners allow Galapagos to expand its drug discovery portfolio, from target validation to lead discovery, and to develop the resulting leads into candidate selection compounds. Since the first alliance was signed in June of 2006, Galapagos received €18.3 million in financial milestones; the main events are summarised in Table 1. Galapagos drug discovery teams now handle over 30 novel targets in partnered R&D programmes.

Rationale for the alliances

Each party brought capabilities to the alliance that the other party valued; Galapagos was looking for a collaborator with deep pockets and vast experience in late stage clinical development, registration and commercialisation.

The pharma partners needed a collaborator that would bring an innovative approach and expertise in early drug discovery.

The alliances have transformed Galapagos into a more mature drug discovery entity, through the expansion of Galapagos’ drug discovery activities to ‘pharma scale development’, and by reducing the portfolio risk while preserving long-term value of the pipeline.

In structuring the deals, the alliance partners were able to define a creative funding structure that avoided the need for direct funding of Galapagos staff by the partners while securing milestone-based payments to cover Galapagos’ costs. The milestones in the alliances cover a wide variety of pre-agreed events, all the way from the identification of novel target sets through to regulatory approval of a new therapeutic. During the period that Galapagos is performing the drug discovery activities for the alliances, the milestone payments from the alliance partners compensate more or less the costs for Galapagos. That way, these large research programmes that in total have about 80 Galapagos researchers assigned, have a very limited impact on the cash burn of the company, assuming that the milestones are reached within the budgeted timeframe. After the handover of the product to the partner, further milestones and royalty payments will be pure profit for Galapagos as it no further incurs costs for that product.

Advancing through partnerships

Risk-sharing alliances provide a novel way for biotechnology and pharmaceutical companies to capitalise on the

Through the alliance strategy described here, Galapagos is eligible to receive in excess of €1.7 billion in success-dependent milestone payments, up to double-digit royalties on sales of medicines that result from these programmes.

A uthor

Financial aspects

complementary strengths of the partner, and to effectively de-risk the process of drug discovery. For the biotech partner the alliance provides the funding required to progress its product pipeline, and brings the late stage pharma development expertise and experience. For the major pharma partners the alliances secure access to novel technologies and options to product candidates that will help fill their product pipelines.

About Galapagos Galapagos is a drug discovery company with pre-clinical programmes in bone and joint diseases and bone metastasis. Its division BioFocus DPI offers a full suite of target-to-drug discovery products and services to pharmaceutical and biotech companies, encompassing target discovery and validation, screening and drug discovery through to delivery of pre-clinical candidates.

Galapagos currently employs 500 people and operates facilities in six countries, with global headquarters in Mechelen, Belgium.

Andre Hoekema has a PhD degree from Leiden University in Holland and is the inventor of over 20 series of patents. He has over 20 years of experience in the biotech industry.

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Indian Patent Law Relevance to global pharmaceutical industry

The Section 3 of Indian Patent Act is considered as a roadblock for patenting invention by many global pharmaceutical industries. Here is the brief analysis of this section and its impact on the global pharmaceutical industry, with some recent case illustrations.

Vijay Soni , Executive Vice President - IP, Glenmark Generics Inc., USA

I

n India the agreement on Trade Related Intellectual Property Rights (TRIPS) was brought about through an amendment to the Patent Act of 1970 and became active as on January 1, 2005 and was obliged from that day to grant patents for pharmaceuticals.

In 2005 the Indian Patents Act, 1970, which provides patent protection for pharmaceutical products or drugs, was amended However this amendment was only applicable for patentability of pharmaceutical substances to new chemical entities. Section 3(d) of the Patents Act, 1970 explains that the new form of a known substance, new property / new use for a known substance and the mere use of a known process are not patentable and is not different from the known substance and is, therefore, not an invention, unless there is a significant increase in efficacy. Though, there were several outcries from the both the generic companies and the innovator companies, the fact of the day is that the section still exists.

There are still several patents that are being granted for salts, ethers, esters, polymorphs and other “derivatives of known substance� as mentioned in the

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clause. This is due to the fact that the Indian law provides a provision for patenting such derivatives, if there is an enhancement of efficacy.

Pharmaceutical patents a. Patentability of various forms of substances

There have been instances of patents being granted for polymorphs, e.g. certain polymorphs of sertraline when mixed with certain excipients demonstrated increased bioavailability and improved pharmacokinetic profiles and were considered patentable.

Similarly, a new polymorphic form of celecoxib, wherein bioavailability was increased from 40 to 95 per cent has been patented.

Nevertheless, certain isomers, both stereo and enantiomers have been considered as obvious over the racemic mixture and non-patentable. For example, esomeprazole was considered as non patentable over omeprazole. Similarly, due to the lack of unexpected properties over that of the parent compounds, metabolites are also considered as non-patentable. Pro-drugs is still an unexplored domain and the merit of pro-drugs being patentable have to be

still considered case by case. If the prodrug has better properties than the drug by itself, it may be considered patentable. Hydrates, acid addition salts and other derivatives, which are routinely prepared prima facie, lack inventive step and hence in many cases, they are non-patentable, before the question of 3(d) arises. The practice may also evolve to consider the long standing issues such as stability and absorption as efficacy.

However, Section 3(d) and its interpretation by the Patent office, and its ultimate practice are still evolving. Decisions by the Controller and courts of India on the several pending pre-grant, post-grant oppositions and revocations may provide the much needed direction. b. Oppositions – Pre-grant, post-grant and revocation

India had agreed to oppositions as a founding member of World Trade Organisation (WTO), ten years ago.

The oppositions are mainly pre-grant, wherein an opposition can be filed till the date of grant of application; postgrant, wherein the opposition can be filed till one year from the date of grant; and revocation that is filed after one year of grant.

Nevertheless, effective use of this provision is not being made by many

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companies and only a small percentage of the granted patents are being opposed. It must be admitted that the oppositions are also tiresome at some instances, as here in India, a pre-grant opposition does not prevent the same or a different party from applying for post-grant opposition, and later a revocation. This leads to delay in the execution of the Patents and such delays are of course, a big cause of worry, for the MNCs, as the patent’s term starts from the date of filing of the application. In most cases, the Indian Patent Office is really much faster in making decisions of oppositions than many developed countries.

The opposition filed against Glivec riveted the attention of the world to the Indian Patent system. Novartis could not seek protection of Imatinib Free base in 1993 which discloses the salt Imatinib mesylate, as one amongst the various salts, decided in 1998 to file its application (without any support regarding the enhanced efficacy) before three critical amendments were made in 1999, 2002 and 2005.

The Chennai Patent Office rejected the application in January 2006 under Section 3(d). Novartis appealed the decision in Chennai High Court and the case was later shifted to Intellectual Property Appellate Board (IPAB). The Supreme Court also suggested having an expert member on the Intellectual Property Appellate Board (IPAB) that reviews decisions of the Indian patent office.

In the TRIPS Agreement the vital constituents of patentability i.e. “novelty”, “inventive step” and “industrial application” were left undefined. It was almost certain that member countries of the WTO would take liberties in defining them. When the standard of patentability advocated by the TRIPS is unclear, the question of domestic laws confirming to that standard has to be viewed more critically. Thus, while the

interesting issue of whether Section 3(d) complies with the TRIPS Agreement still remains unanswered, the questions that remain to be debated are: 1. Is there a really any need for a national law to be more stringent than TRIPs agreement?

2. Is it proper to question the constitutional validity of a provision of the Indian Patents Act merely because it could not achieve what it intended?

Several other oppositions mainly involving the issue of Selection Patents are in progress. For instance, Ranbaxy had filed an opposition questioning the validity of the Valcyte patent here as the drug was not proved for enhanced efficacy in comparison to what is already known. Sun Pharma filed an opposi-

While on the one hand MNCs are using all tactics to get the so-called ever greening patents granted, on the other hand, Section 3(d) is protecting poor people paying from higher money for their medications.

tion against a granted patent to Janssen Pharmaceuticals, related to sustainedrelease particles of Risperidone, which Sun Pharma had considered as a Selection Patent.

Roche India received the first product patent in 2006 in India for its biotech drug Pegasys (pegylated interferon alpha 2a), a recombinant DNA technology drug. Pegasys product patent is under post-grant opposition

by Wockhardt and an NGO Sankalp on various grounds, but mainly on Sections 3 (e) and 3(d). It was alleged that “mere admixture” of known substances is not patentable under Section 3(e) of the Patents Act 1970, and hence Roche’s “invention” was not patentable. It is to be seen how long the patent office will

continue to decide patent oppositions based on Section 3(d).

The Indian Patent Office rejected Boehringer Ingelheim’s patent application for the syrup form of Nevirapine.

Another patent application, this time for a combination hypertension drug—Telmisartan, has been filed by Boehringer Ingelheim. Indian companies are planning to oppose the drug on the grounds that the individual drugs and the combination, both, existed prior to 1995 and hence are not patentable under Indian Patent Law. Boehringer Ingelheim will most likely have to prove increased efficacy when compared to pre-1995 drug for its combination drug. The patent application is being examined by the Mumbai Patent Office.

One of the other highprofile case is that of Tarceva.

The Indian patent application on Tarceva was filed in 1996

by Roche and was granted in 2007 and Roche, intermittently obtained a market approval from the Drug Controller General of India to market Tarceva, in 2005. Cipla launched a generic version of Tarceva in 2008.

Immediately, Roche filed a suit for infringement against Cipla. A division bench of the Delhi High Court upheld an earlier ruling that allowed Cipla to manufacture and market a copy of patented drug Tarceva in the Indian market citing that there is a price difference between the drug sold by Roche and its generic version by Cipla. The court did not want patients to be deprived of a low-cost alternative by allowing sales of the generic product as there was substantial price difference.

For the first time in India, court recognised the need to consider public interest in allowing or rejecting an order of injunction. However, many innovator companies feel cheated as they are unable to recover the cost of “drug discovery”.

It also brought to light the fact that there is no link between the drug approval

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authority and the Patent divisions of India. Legal system in India will have many more such cases in coming years.

There will be a need for having specialised court / legal experts’ pool to hear these legal cases.

While on the one hand MNCs are using all tactics to get the so-called ever greening patents granted, on the other hand, Section 3(d) is protecting poor people paying from higher money for their medications. Indian government should continue to ensure that the best interests of the population are kept in mind without coming under the international pressures. c. Proposal to link generic approvals with patents

Currently, the Indian Patent Office grants the patent and Drug Controller General of India (DCGI) provides marketing approvals without crosschecking with the other division. Hence, a generic manufacturer has to launch the drug in Indian market at his own risk. There are proposals to link the approvals with patents. However, there are still some major roadblocks for this proposal. For instance, the complete database detailing the legal status of the patents is still unavailable. Currently, as a temporary solution, DCGI has asked the industry to provide details of granted patent for new medicine, with an intention to pass patent details to the Indian Patent Office and obtain an opinion before approving generic drugs.

Biological products

A uthor

The law on biotechnological products is still evolving and still comprises a lot of grey areas. Many biotechnological firms believe that the law is not clear

20

on patentability of biomolecules, i.e. nucleic acids and polypeptides, and hence the grant of patent is still subjective. The allowability of the products under the section and the requirements for disclosure of geographical origin and source of biological materials used for invention are still areas of concern for many biotechnological firms. Many firms are of the opinion that by revealing the source and origin, they are opening a ground for opposition.

The patents ahead

The products in the countries where the laws are in transition become the first casualties as they face the risk of testing them for the first time. More litigation would come as some of the products gain value by then and there will be many more attempts by big MNCs to stop launching of major products.

It will be very unfair to compare IP / legal systems of developed countries, where all these systems are in place since last 25-30 years, with the developing countries like India which are in the initial phase of developing the systems.

Many pharmaceutical giants have recently announced expansions of their Indian operations. However, even with such expansions, companies are still cautious until the enforcement of the new patent bill has shown to be effective at preventing infringement. There is, however, a longer-term issue. The lingering doubt in many a mind if patent rights will be allowed for ever greening patents in developing countries, where the extra costs MNCs impose may be at the expense of the necessities of life for poor people.

Vijay Soni is the Executive Vice President of IP of Glenmark Generics Inc. based in New Jersey, and is responsible for Global IP for the company. He was Senior Director IP of Dr Reddys Laboratories and has also worked for Ranbaxy Laboratories as Senior Scientist.

He has completed his PhD in organic chemistry and has over 18 years of experience in the areas of R&D of synthetic molecules, regulatory affairs and Intellectual Property.

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Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices Authors: John J Tobin, Gary Walsh Year of Publication: 2008 Pages: 297 Published by: Wiley-VCH ISBN-10: 3527318771 ISBN-13: 978-3527318773 Description: Written in a clear and concise style by an experienced author, this attractivelypriced book covers regulatory affairs in all major global markets for pharmaceuticals and medical devices, making it the most comprehensive in its field.

Following a look at drug development, complete sections are devoted to national and EU regulatory issues, manufacturing license application and retention, and regulation in the USA. Other topics dealt with include CDER, CBER and marketing and manufacturing licenses, the ICH process and Good Laboratory/Clinical/ Manufacturing Practices.

Everything pharmacologists, bioengineers, pharma engineers, students in pharmacy and those working in the pharmaceutical industry need to know about medical regulatory affairs.

For more books, visit Knowledge Bank section of www.pharmafocusasia.com

In-depth articles on innovations and discoveries. Information and insights on the future of the industry. Discussions and debates between names who matter. Relevant and original content, to help decide your future course of action.

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The drug development model today is under increasing pressure as the number of drugs approved for marketing has dwindled to an all time low. Drug developers must acknowledge this trend before initiating the development process. However, for a developing biotechnology or pharmaceutical company, where resources are usually limited, it is critical to have an absolute appreciation of the industry trends.

Compound Success Rates Pharma 2004 R&D expenditure*

US$ 9.6 Billion

Years

5,00010,000 compounds

Safety focus

Drug Discovery

Modify compound to reduce side effects

Pre-clinical

Lab and animal testing performed to test for potential adverse effects

250 compounds IND Application Submitted

Clinical Trials Phase I 20-100 Volunteers

Phase II 100-500 Volunteers Phase III 1,000-5,000 Volunteers

06 Phase I and II: Find safe dose and side effects

5 compounds

US$ 15.9 Billion

09 Phase III: Check for adverse effects and efficacy 12

HDA Submitted US$ 3.4 Billion

US$ 4.9** Billion

FDA Review

Large-scale manufacturing/ Phase IV

Strong evidence of safety needed for approval 1 FDA Approved Drug

* Adapted from appendix Table 4, uncategorised: US$ 3.2 billion ** This figure includes Phase IV testing only 22

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15 FDA inspects manufacturing safety ongoing studies of approved drugs’ safety Source: PhRMA, 2006 Industry Profile

T

he year 2004 marked a 20-year low in the introduction of new medical treatments into the global market. Over the last two-and-ahalf decades the pharmaceutical industry has been under increasing pressure to constrain its costs and expenditure whilst the pressures for replenishing the dwindling drug development pipeline have remained unabated.

Though cost is usually cited as the main reason to explain this trend, one must also consider other factors like increasing regulations, generic competition, reimbursement challenges, development models, recruitment and retention.

In the past, the pharmaceutical industry has witnessed consolidation through mergers and acquisitions which has led to the formation of mega giants, e.g.

Pfizer and AstraZeneca. This period of consolidation may have initially led to some cost efficiencies and economies of scale, nevertheless it has failed to address the underlying reasons for the lack of organic growth of the drug development pipeline.

More recently, Big Pharma has concentrated its efforts on biotechnology companies which offer the promise of new discovery and development platforms. The increasing trend of mergers and acquisitions of biotechnology companies has spawned a new term for the industry “Biopharmaceuticals”.

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Harjit Singh Senior Development Consultant, Clinical Research, UK

Probability of technical success for biopharma recombinant proteins, NCEs and mAbs Clinical approval success rate

19.5%

Recombinant

NCE

18.6%

mAb

Source: DiMasi, Tufts CSDD Databases

Figure 1

Trends in fully allocated capitalised cost per approved drug

Drug development process

802

900 800 700

466

600 500

300

0

54

Preclinical

Approvals:

138

104

200 100

318

336

400

214

The overall development approval process is complex and involves lot of time as per the requirements of US FDA guidelines. The process for a new compound from synthesis to obtaining marketing approval can take from anywhere between 10 to 20 years, with an estimated average of 9 to 12 years.

Over the last two-and-a-half decades the length and cost of this process has increased considerably. It is important to understand at what stage of development expenses occur. Figure 2 illustrates the cost of this process for the period of three decades 1970s-1990s and the following points can be deduced from it:

39.8%

84

The success of Biotechs can be illustrated if one was to compare the clinical approval success rates of biologics (recombinant proteins and monoclonal antibodies) against new chemical entities (Figure 1).

Although the success factors for biologics appear to be more favourable as a whole, the challenges listed earlier still pose a formidable obstacle for developing biotechnology and pharmaceutical companies. Prior to embarking on a development programme one should therefore investigate these challenges further in order to fully appreciate the complexities of the development process.

1970s

Clinical 1980s

Total 1990s

Source: DiMasi et al, J Health Economics 2003

• Total drug development costs have risen almost six times • Clinical costs have risen at a faster rate at almost nine times over the last three decades The development process of a new compound is initiated at the pre-clinical stage where a compound undergoes trials in vitro and then in vivo in laboratory animals to evaluate the pharmacological and toxic effects. The drugs genotoxicity is also investigated at this stage.

At this point if the compound under investigation is worth pursuing, an Investigational New Drug (IND) application will be filed with the US FDA. The IND will document the results of short-term toxicity testing in at least two animal species and also describes the compound’s pharmacological profile.

The FDA has 30 days to review the submitted IND application. If the FDA does not place a hold on the application, the drug developer can begin “first in man” Phase I clinical trials in humans.

Clinical (human) testing usually proceeds through three successive clinical phases prior to a marketing application followed by post-marketing Phase IV trials.

The costs associated with each clinical phase increases progressively from Phase I through to Phase III.

Figure 3

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The largest single investment throughout development will be at Phase III due to the clinical trial sample size which usually ranges in the thousands but also due to the design of the study as it must include a comparator arm(s).

Sourcing of the comparator drug(s) is usually an expense which is paid for by the developer. However, this is not always necessary as in some countries the comparator(s) may be the standard of care and as such may be provided by the healthcare provider.

Challenges

Phases of clinical trials Phase I

Clinical trials are conducted on a small number of normal healthy volunteers to establish safe dosages. Information is also gathered on the Absorption, Distribution, Metabolism, Excretion (ADME) and toxicity of the compound. If the compound is still promising, it will progress to Phase II testing.

Phase II

Trials are conducted on volunteers who have the specific medical condition and are designed to obtain evidence on initial efficacy data and safety. A greater sample of volunteers are tested than in Phase I, usually in the hundreds, which is large enough to support “proof of concept” but small enough to be a measured step before Phase III.

Phase III

Consists of a number of large scale multicentre trials that demonstrate efficacy and to uncover side effects that occur infrequently. The number of subjects can total in the thousands however, to approve a new compound the FDA generally requires evidence from at least two well designed, randomised, double-blind placebo controlled clinical trials.

Once drug developers believe that they have enough evidence of safety, efficacy and a positive risk-benefit profile, they will submit a New Drug Application (NDA) to the FDA.

Phase IV

Also known as post-marketing safety surveillance trial, may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons (for example, on certain population groups such as pregnant women). Any rare or long-term adverse effects are detected by safety surveillance conducted over a much longer period of time and larger patient population than the Phase I-III clinical trials.

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Regulatory requirements and commitments have increased progressively over time and this has led to an increase in both the trial size and the length and hence a rise in the overall cost of the development process. More subjects are needed as many of the treatments under development require greater numbers to achieve FDA statistical standards for demonstrating safety and efficacy.

Clinical trial sample sizes increased at an average rate of 7.47 per cent per annum, from the 1970s to 2001, as reported by DiMasi et al.

As a result of the increasing clinical trial sample sizes, it has become necessary to conduct trials in many countries, each with their own unique regulations.

One must also consider the number of existing guidelines which have been introduced progressively over the years, e.g. approximately • Thirty ICH guidelines relevant to global drug development • Seventy FDA guidelines relevant to clinical research • Six guidelines that support the EU clinical trial directive.

More recently there has been an increase in the number of safety recalls of previously approved drugs, e.g. cox inhibitor / Vioxx. This has led to an emphasis by regulators on the development of risk profiles for pharmaceutical products and also closer scrutiny of clinical trials combined with post-marketing commitments.

S trateg y

Clinical research outsourcing – The pitfalls Complete outsourcing of trials leads to a lack of ownership and may be problematic especially when the developing company is on a steep learning curve.

Some CROs have a high turnover rate in their staff and this leads to a lack of continuity.

Large CROs may involve “high maintenance”, often requiring careful management which for a developing company will be problematic as they lack the experience and expertise to manage CROs.

Final costs are almost always higher than the original quote.

Large CROs often appear to operate as two distinct different businesses—winning new business but without having the personnel to deliver.

Exposure to liability may not be apparent in new markets where requirements / obligations differ. This may be due to lack of experience.

Large CROs are usually based in various countries globally and operate in a virtual setup with very limited face-to-face interaction.

Once on board, the CRO becomes almost indispensable.

Other requirements include the electronic submission to the regulatory authorities which is mandatory in some key countries like the US. In the EU, the Electronic Common Technical Document (eCTD) will soon be the mandatory format for EMEA submissions and is already compulsory for some national authorities. The transition to

eCTD has many benefits including better lifecycle management of regulatory submissions and easier review of documents which should reduce the review time. Developing companies must quickly adopt this approach as they need to be eCTD-ready in order to actively manage the product lifecycle during the development process.

Reimbursement

Obtaining approval to market a compound is sometimes only half the battle won especially in Europe where additional health economic data is usually required in order to ensure reimbursement from health authorities. Tools (i.e. Patient Reported Outcomes or PROs) should be utilised and planned into clinical trials early on in the development process so as to ensure maximum reimbursement.

Innovative target oncology treatments (i.e. Bevacizumab, sorafenib, sunitinib and temsirolimus) have not been granted approval for reimbursement by the UK National Institute for Health and Clinical Excellence (NICE). Following a preliminary review, NICE ruled that although these drugs are clinically effective, they do not provide good value for money (the cost of these treatments are approximately US$ 5,000-10,000 per month).

Generic competition

It is no longer acceptable for drug developers to commence efforts to extend a product’s lifecycle as patent expiry approaches. When a drug’s market exclusivity is lost, a meltdown in sales may be experienced within one business quarter. Companies need to be developing a strategy to protect against patent expiry even before a product is launched. There are numerous potential strategies and the choice depends on the particular circumstances of the product. For example, second-generation versions with improved safety or efficacy, new formulations, combination products, licensed generics, and Over-

The-Counter (OTC) switching, are all the potential choices.

Recruitment and retention

Competition from similar studies run by rival companies combined with increasing clinical trial sample sizes has led to expanding recruitment efforts to more exotic countries. This in itself brings its own complications due to the uncertainty associated with unfamiliar regulations but sometimes it is worth the extra risk as recruitment rates tend to be higher than the more established countries.

As clinical trial designs become lengthier and complex, the burden on subjects increases and hence the retention rate decreases. Overcoming this problem is the key in keeping the costs down as subjects who withdraw from the study will usually need to be replaced. Recruitment can be further compounded by regulatory requirements to include certain patient populations (i.e. children).

Development models

In-house development is usually the preserve of large and medium-sized pharmaceutical companies that have the money to build large research teams.

The advantage of this model is that you are not always reinventing the wheel and it results in continuity, leading to expertise and cost-efficiency. The industry has moved away from this trend mainly to streamline existing teams and save costs. However, this is not an option for developing biotechnology and pharmaceutical companies as it is hugely expensive.

Outsourcing to a large Clinical Research Organisation (CRO) has many advantages and is usually the option that developing companies opt for, but at the same time this model does have some disadvantages which must be thoroughly considered before this option is selected. Any wrong decision for a company with limited resources can potentially be catastrophic.

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Opportunities to use new science to modernise drug development Innovative clinical trial designs may make it possible to develop accepted protocols for smaller but more intelligent trials. For example, new statistical techniques used in adaptive trials.

Development of improved pre-clinical models; the uptake of new genetic technologies may make it possible to develop animal models that are more predictive of human responses thereby reducing the risk of failure in the clinical phase.

Computer modelling and utilisation of data mining to provide better designed trials and help predict safety outcomes, through advances in IT and accumulation of data on the safety and efficacy of both approved and failed compounds.

Development of new biomarkers that is more predictive of clinical risks or benefits than single markers for a given condition. Recent innovations in imaging technologies may contribute to the development of influential new biomarkers for drug distribution, metabolism, and pharmacodynamics and to be used as outcome measures.

Solutions

The advantages of this type of model are: • The consultancy only utilises specialist niche service providers which helps focus on time critical components without sacrificing quality whilst keeping cost to a minimum • Smaller teams, sometimes limited to 2-3 people, ensure continuity through lower turnover • Ongoing training and mentoring may be provided enabling the company to establish or strengthen its own R&D team where experience may be limited • Implementing or updating Standard Operating Procedures (SOPs) in synergy with ongoing development efforts • Mentoring the inexperienced development team from the inception of a compound right through to marketing approval equipping the R&D team with the appropriate knowledge and skill set • Managing interactions with potential alliance partners (i.e. Big Pharma) is an option that is not usually offered by large CROs but can quite easily be performed by a consultancy as their experience is more comprehensive.

Innovation

From a scientific perspective, many of the tools used today to predict and evaluate product safety and efficacy are outdated. There has been a lack of investment in less common (unprofitable) diseases or risky innovative approaches and to apply new scientific knowledge in areas such as gene expression, analytic methods and bioinformatics to medical product development. There exists opportunities to create more effective tests

An alternative development model that is more cost and time efficient may be to partner with a consultancy service which can assist the project by managing the whole development process or just a small portion of it.

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Alternative development model

and tools however, this will entail an initial investment of resources before these innovations are turned into reliable applied sciences. Although this may not yet be an option for developing biotechnology and pharmaceutical companies, they should still be considered for future consideration once revenue streams begin to flow.

Overcoming the challenges

Drug development is much more than designing a clinical trial. However as we have seen, this is by far the most lengthy and costly stage of the overall process. It is therefore imperative that developing biotechnology and pharmaceutical companies consider the causes and trends responsible for the burgeoning cost of pharmaceutical innovation before embarking on their own development programme.

Rising cost of drug development together with the continuing high clinical failure rate, increased regulation, competition and reimbursement efforts are on a collision course with societal demand for more cost effective accessible treatments.

A new development model or paradigm is needed, however this must delivered by Big Pharma as due to limited resources the only real options available to developing biotechnology and pharmaceutical companies are outsourcing alternatives.

For a developing biotechnology or pharmaceutical company, the prospect of embarking on the complex drug development process seems to be daunting and may even appear unaffordable. Employing the services of specialist niche service providers can help mitigate this hurdle.

Harjit Singh is a Clinical Research Professional currently based in London. He has international expertise in drug development with several global players and providing strategic planning and execution of global clinical development plans.

R esearch & development

Antibacterial Research

Bright future?

New antibacterial drugs have been few and far between due to a slump in the R&D activities and also due to many unique challenges in this area. However, of late, there is renewed interest in this field and many innovative concepts and targets are being looked into.

Uma Ramachandran Vice President - Medicinal Chemistry Mrinalkanti Kundu Associate Director - Medicinal Chemistry Orchid Research Laboratories Ltd., India

T

he accidental discovery of Penicillin by Sir Alexander Fleming in 1928 followed by its development for use as a medicine

by Australian Nobel Laureate Howard Walter Florey ushered in the era of antibiotics; the antibacterial drug discovery peaked after the middle of 20th century.

However, after the introduction of streptogramin and quinolones in 1962 (Table 1), no novel class of anti-bacterial drug was discovered until the year 2000 when Linezolid (Zyvox®) was launched followed by the introduction of Daptomycin in 2003.

During the last thirty years major pharma companies downplayed this area as they considered that infectious diseases was “not a serious problem” of the developed countries and that it was the bane of the underdeveloped nations. They took their investments to other “glamorous” therapeutic areas like cardiovascular and other life-style diseases where they probed new druggable targets and came up with “blockbuster” drugs.

Thus, today there is a huge unmet medical need for new antibacterial drugs

due to fast multiplication of drug resistant bacterial strains and also new, emerging pathogens. While in 1975 just 3 per cent of resistance isolates were registered, by 2003 it had grown to 59.5 per cent; especially Methicillin Resistance Streptococcus aureus (MRSA). More people have died of the bacterial infection caused by microbes than HIV disease alone.

Resistance is a complex problem and associated with multiple mechanisms in the bugs such as, existence of over 500 discrete beta-lactamases (enzymes which hydrolyse most of the −lactam based drugs such as Penicillins and Cephalosporins); operation of efflux pumps through which the bacteria bale Introduction of new drug classes by the pharmaceutical industry till 1960s Antibiotic class

Year of launch

Sulphonamides

1936

Penicillins

1940

Tetracyclines

1949

Chloramphenicol

1949

Aminoglycosides

1950

Macrolides

1952

Glycopeptides

1958

Streptogramins

1962

Quinolones

1962

out the drugs even before they have a chance to act; occurrence of changes in the cell wall of the pathogens, especially in the Gram negative organisms, which have an additional outer membrane, affects the permeability of drugs.

Big Pharma’s disillusionment

One of the reasons big pharmaceutical companies moved out of the antibacterial R&D was their disillusionment with the lack of results using high-end technologies in this area. They had embraced genomics and High-Throughput Screening (HTS) methodologies all through the 1990s.

Though these technologies yielded valuable scientific insights, they failed to produce many leads for antibacterial drugs. GlaxoSmithKline embarked on antibacterial drug discovery programme and searched the bacterial genome for new targets. Spanning seven years, they conducted 17 HTS campaigns on antibacterial new targets using several thousands of compounds. They were able to get just few hits, out of which only five leads were obtained. The reasons for this dismal result were many—some of the compounds turned out to be nonspecific membrane-active agents; there was a lack of compound diversity in the compound libraries and most of them turned out to have high liphophilicity and for some others no mechanism of action could be ascertained.

Table 1

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Gradual decrease in approval of antibacterial drugs in the US Antibacterial drug approvals 20 15 10 5 0

1983-87

1988-92

1993-97

1998-2002

2003-07

Source: Infectious Diseases Society of America

Even considering that a novel antibacterial lead was found, its optimisation phase was very challenging especially in nosocomial and community acquired infections. The compound must inhibit the growth of many different Gram-positive and Gram–negative bacterial species.

A better understanding of the physicochemical parameter is one of multiple parameters that are essential to improve the future success rate for identifying clinical candidates. Not only the well-known Lipinski “rule of five” guideline failed to apply to this class of drugs, but also the physicochemical values favourable to the two strains seem to differ. Precisely, the compounds with only Gram-positive activity have much less restriction in MW and permeation through inner lipid membrane. On the other hand, Gram–negative antibacterial agents in order to function, must penetrate the porin channels and for this, high polarity plays a significant role; but not at the cost of good oral bioavailability which requires reasonable level of lipophilicity in the molecule!

Another interesting feature is that the natural products have been tapped much more effectively in the field of antibacterial drugs. This could be because microorganisms have made use of antibacterial xenobiotics extensively as their defense mechanism. We see that around 70 per cent of compounds are either natural prod-

Figure 1

ucts or semi-synthetic derivatives thereof.

Only 3 out of the 20 represented classes of antibacterial drugs are synthetic in origin, those being sulfonamides, fluroquinolones and oxazolidinones. Some of the natural products have very high molecular weights and generally most of these compounds are very polar, making their oral delivery products a challenge for R&D. Promising developments

The two small molecule class of compounds namely fluroquinolones and oxazolidinones (Figure 2) have been a subject of extensive Structure Activity Structural representation of Fluoroquinolones and Oxazolidinones Fluoroquinolone

Oxazolidinone

Filling the gap

As mentioned previously, smaller players have filled the gap left in the area of antibacterial R&D by the MNCs, to some Figure 2

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Relationship (SAR) studies for quite some time. Fluoroquinolones target the DNA gyrase enzyme and act by blocking the DNA replication. Starting with Ciprofloxacin, many new compounds have been commercialised including Gatifloxacin and the third-generation quinolone namely, Moxifloxacin.

These classes of drugs have proven to be very promising broad spectral antibacterial agents covering both Gramnegative and Gram-positive bacteria. In terms of physicochemical properties, they possess higher polarity as compared to other drugs. However, this seems to be ideal for touching broad spectral activity and moreover, they exhibit high level of oral bioavailability too.

On the other hand, the oxazolidinone class exerts its antibacterial action by disrupting initiation of bacterial protein synthesis by a novel mechanism that would possibly lead to checking cross-resistance.

Linezolid, which belongs to this class, was approved by FDA in 2000 for treating a wide range of Gram-positive bacteria including MRSA, Vancomycin-Resistant Enterococci (VRE) and PenicillinResistant Pneumococci (PRSP), but not against Gram-negative pathogens. It has filled a niche market and it is heading to becoming a blockbuster. However, the most vexing issue of this compound is that of toxicology—85 per cent of the adverse events had mild to moderate toxicity including reversible myelosuppression along with contraindication especially when used together with an anti-depressant and / or tyramine containing foods such as cheese. Soon after the success of Linezolid, many groups, both in industry and in academics have worked for nearly a decade trying to get a secondgeneration molecule in this class but with limited success. Extensive SAR on A to D rings (Figure 2) has been done on the oxazolidinone scaffold thus far.

R esearch & development

extent. Among them, few have focussed on established classes of drugs and have made improvements on the existing molecules and as a result, several important antibacterial agents have emerged from these efforts. For instance, now we are into the fifth generation of cephalosporins (Ceftobiprole, FDA approved-about to be launched), third generation of macrolides (Telithromycin), second generation of carbapenams (Ertapenems), and third generation of tetracyclins (Tegecyclin).

Yet others have come up with very innovative methods to address the issue of poor productivity of discovery progress for new classes of antibacterials. Companies like Mpex and Protez have very successful programmmes in developing effective efflux pump inhibitors for Gram–negative and Gram-positive strains respectively.

Inhibition of efflux is a promising strategy to preserve activity of the existing antibiotics and expand the spectrum of new and established classes.

Other companies like Basilea have potentiated the existing -lactam antibiotics by using them along with -Lactamase Inhibitors (BLI). Besides the existing three BLIs in market today namely, Clavulanic acid, Sulbactam and Tazobactam, which act only on class A of lactamases, there are many −lactambased BLIs which are in clinical trials with extended spectrum of activity against chromosomally encoded class C lactamases that are expressed by some Enterobacteria and Pseudomonas. Indeed, it has been demonstrated that in the presence of −lactam-based inhibitor, some

pathogens up-regulate the expression of the −lactamases. Accordingly, the need had motivated a search for novel inhibitors structurally unrelated to −lactams, keeping in mind that, these non−lactam based inhibitors might be able to evade pre-evolved bacterial resistance.

As a result today, the first non- −lactam based BLI, NXL-104, from Novexel, a spin-off company from Sanofi-Aventis, is undergoing clinical trials.

Antibacterials – Bright future

The continuous development of antibiotic resistance has not only spurred the discovery of broad-spectral antibiotics but also search for newer targets in the coming years. In this context, researchers have been engaged using the vast knowledge about the bacterial cell-division pathway to identify novel inhibitors of the cell-division proteins that are mainly conserved in prokaryotes. Targeting unique proteins like these should reduce the likelihood of side effects in human and the very low level of bacterial resistance would probably be expected because of the novel mechanism of action governed by this new class of molecules. Accordingly, these agents would create new clinical opportunities and may be aimed at multiple segments of the antibacterial market, including hospital-acquired, community-associated and prophylactic therapies for the treatment of bacterial infections.

Full references are available at www.pharmafocusasia.com/magazine/

Uma Ramachandran has rich experience in the area of pharmaceutical sciences both in academics as well as in industry. For the last few years she has worked in new drug discovery in anti-infectives.

A uthors

BOOK Shelf

High-Throughput Analysis in the Pharmaceutical Industry Editor: Perry G Wang Year of Publication: 2008 Pages: 432 Published by: CRC Press ISBN-10: 142005953X ISBN-13: 978-1420059533 Description: High-throughput analysis plays a critical role in the pharmaceutical industry. The ever-shortening timelines and high costs of drug discovery and development have brought about the need for high-throughput approaches to methods that are currently used in the industry. Written and edited by well-known contributors who remain active in this line of research, this book systematically describes high-throughput analysis for the pharmaceutical industry, including advanced instrumentation and automated sample preparation. The text discusses various techniques, including HPLC, MALDI-MS, and LC-MS/MS methods, with an emphasis on the later stage of drug development, including pharmacokinetics.

Mrinalkanti Kundu graduated from IIT. Following his postdoctoral research abroad, he has been working for last five years in NDDR, in the area of metabolic disorders, and anti-infectives.

For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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R esearch & development

Targeted Delivery

Photosensitiser conjugated gold nanoparticles Biocompatible gold nanoparticles have been explored as a new vehicle to deliver photosensitiser to tumour cells. The use of gold nanoparticles can significantly increase the accumulation of photosensitiser in tumour cells and lead to a high efficiency in destroying the tumour cells.

Maung Kyaw Khaing Oo, Doctoral Candidate in Materials Science Hongjun Wang, Assistant Professor, Biomedical Engineering Henry Du, Professor and Director of Chemical Engineering and Materials Science Stevens Institute of Technology, USA

P

hotodynamic Therapy (PDT), a minimal invasive cancer treatment approach, holds tremendous promise in particularly treating the local tumours. It is based on the administration of a photosensitising compound (also called photosensitiser) and subsequent irradiation with light of an appropriate wavelength to produce Reactive Oxygen Species (ROS). The elevated formation of ROS can lead to the destruction of tumour tissues.

Several photosensitisers have been developed and evaluated for PDT application. Photofrin® (PF) and 5-aminolevulinic acid (5-ALA) are the most active photosensitisers in clinical application.

In contrast to 5-ALA, PF has some inherent disadvantages, including prolonged skin sensitivity that requires to avoid sunlight for many weeks, sub-optimal tumour selectivity, poor light penetration into the tumour constrained by the use of relatively short light wavelength (630 nm) for irradiation, and the fact that it is a complex mixture of the uncertain structures. 5-ALA, a well-known biochemical precursor of the Photosensitiser Protoporphyrin IX (PpIX), has several unique characteris-

tics determining its popularity in PDT application: 1. ALA is the only PDT agent that can naturally form PpIX by the body, and alone shows low dark toxicity to cells.

2. Topical application of 5-ALA does not cause any prolonged skin photosensitivity, allowing the selective delivery of 5-ALA in the areas to be treated.

3. PpIX endogenously produced can be rapidly cleared from the body within 24 to 48 hours through a natural clearance mechanism.

4. A short time interval (1–8 hours, depending on the mode of administration) is needed between the administration of 5-ALA and the maximal accumulation of PpIX in the target tissues, which makes 5-ALA practically attractive for the patients.

However, 5-ALA itself is hydrophilic and as a result it has poor penetration through the natural barriers such as the intact skin, the nodular skin lesions, the stomach and the intestinal walls, as well as through the cell membranes.

The limited cellular uptake of 5-ALA has motivated diverse explorations for effective delivery of 5-ALA to cells. Among various delivery carriers, nanoparticles represent a great promise with respect to their large surface to

Schematic illustration of the synthesis of gold nanoparticles and 5-ALA conjugation

–OOC –OOC

–OOC –OOC

Positively charged gold nanoparticles

–OOC

Net negative charge of 5-ALA at the physiological pH

Figure 1

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Materials and methods

Gold nanoparticles were synthesised using a polyelectrolyte reduction method assisted by UV radiation (Figure 1).

During the preparation, 40 mL of the branched polyethyleneimine (BPEI) (0.2 mg/mL, molecular weight = 10,000) and 40 mL of 0.01 wt% HAuCl4 were first mixed under stirring. To avoid the immediate start of the reaction, the mixing step was performed in an ice bath. Then, the solution was placed under a 400 W metal halide UV lamp (Cure Zone 2) for one hour until the solution turned to dark red, indicating the completion of the reduction reaction. The gold particles formed in the solution were examined with a Scanning Electron Microscope (SEM) for their shape and with a Nano Z Zetasizer for their size and surface charge.

The conjugation of 5-ALA onto the gold nanoparticles was achieved through an electrostatic interaction between 5-ALA and the positive GNPs. 5-ALA dissolved in Dulbecco’s Modified Eagle Medium (DMEM) was sterilised by filtering through a 0.2

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UV-Vis absorption spectra of gold nanoparticles conjugated with 5-ALA of different concentrations. Insets are the SEM micrographs of the morphology of conjugated nanoparticles.

1.2

100 mM ALA

1.1

10 mM ALA

1.0

Absorbance (a.u.)

volume ratio and the cell permeable size. The application of novel biocompatible gold nanoparticles to specifically deliver 5-ALA to the tumour cells allows for an efficient PDT treatment.

5-ALA was successfully conjugated onto the Gold Nanoparticles (GNP) with a positive surface charge. The incubation of tumour cells (fibrosarcoma, a malignant cancer of connective tissues) with 5-ALA-GNP showed a significant accumulation of PpIX in the tumour cells and resulted in a substantial increase in the destruction of tumour cells after the PDT treatment. The 5-ALA-GNPs also showed a preferred uptake by fibrosarcoma cells in the presence of normal fibroblasts, which led to the selective destruction of fibrosarcoma cells with minimal damage to the normal fibroblasts.

1 mM ALA

0.9

0 mM ALA

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

300

400

500

600

700

800

900

Wavelength (nm)

Figure 2

µm filter. Colloidal solution of GNPs was also sterilised with a 0.2 µm filter.

One mL of 5-ALA solution was then mixed with 20 µL of the GNP solution. The pH of the solution mixture was adjusted to between pH 7.2 and 7.6 with 1N NaOH solution. The conjugation was characterised by UV-Vis absorption spectroscopy and SEM. To compare the differential effect of 5-ALA-GNPs on tumour cells and normal cells, especially in the PDT treatment, Normal Human Neonatal Dermal Fibroblasts (NHDF) and human fibrosarcoma (WT) cells were used in this study. Cells seeded in 96-well plates were treated with DMEM containing GNPs, 1 mM 5-ALA or 5-ALA-GNPs. After incubation for four hours, the well plates were carefully washed with PBS in the dark and then replaced with Hank’s Balanced Salt Solutions (HBSS). For the PDT treatment, the cells were irradiated with a broadband light source using a 150W halogen lamp for one minute.

After irradiation, the cells were further incubated for 24 hours. Survived cells were determined by a standard colori-

metric MTT [3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide] assay.

The selective uptake of 5-ALAGNPs by tumour cells and the selective destruction of tumour cells, especially in the presence of normal cells were studied by incubating the cocultured WT cells and NHDF with 5-ALA-GNPs for the PDT treatment.

To better distinguish the WT cells from NHDF, WT cells were first labelled with a CellTrackerTM Green CMFDA (5-chloromethylfluorescein diacetate) and then the same amount of NHDF and WT cell were mixed and co-cultured in a Petri dish. The co-culture was incubated with 5-ALA-GNPs for four hours, and then followed by the PDT treatment. After the PDT treatment, cells were further cultured in DMEM containing 10 per cent fetal bovine serum. After culture for 24 hours, the cells were examined under a Nikon Eclipse TE 300 fluorescence microscope and images of randomly selected area were taken to quantify the treatment efficiency by counting the green labelled cells.

R esearch & development

Results and discussion

GNPs with a positive charge were synthesised following a UV assisted reduction approach (Figure 1). Majority of the obtained GNPs were sphere-like with an average diameter of 30 nm (Figure 2 inset) and had an average zeta potential ( ) of +33 mV. BPEI is considered as the major contributor to the positive charge of GNPs. 5-ALA, a zwitterionic compound can have either an end group of COO− or NH3+, depending on the solution pH. At the physiological pH (pH 7.2 ~ 7.6), its net negative charge enables its conjugation to the positive GNPs (Figure 1). The conjugation of 5-ALA to GNPs surface was confirmed by a decreased of the GNPs. To determine the optimal conjugation ratio between 5-ALA and GNPs, various concentrations of 5-ALA were mixed with GNPs and the corresponding absorption spectrum was obtained. Compared to other concentration, the conjugation of GNPs with 1 mM ALA showed unnoticeable shift in the absorption band (Figure 2).

The gold colloid itself had an absorbance wavelength at 520 nm (Figure 2).

With the increase of ALA, the absorption intensity of gold colloid at ~ 520 nm decreased and a new absorption band appeared in the long wavelength region. Moreover, this new band showed a “red” shift with the increase of ALA (Figure 2), which is closely related to the particle size of the conjugates. SEM examination of the conjugates revealed that large aggregates were formed at higher ALA concentrations (Figure 2 inset), but not at 1 mM. It is critical for the agents used in the PDT treatment to have a minimal toxicity to the cells, which is important to prevent the unwanted damage to the normal cells. The cytotoxicity of synthesised GNPs, 1 mM 5-ALA, and 5-ALA conjugated GNPs were respectively tested on NHDF and WT cells by incubating for 24 hours under dark conditions. The MTT assay result revealed that no signifi-

Merged bright field and fluorescent microscopy images of the co-cultured NHDF (non-labelled) and WT (green) before and 24 hours after the PDT treatment with 5-ALA-GNP and 1 min irradiation. Scale: 200 μm.

Before PDT

After PDT

Figure 3

cant cytotoxicity was measured for all of them, suggesting their biocompatibility. In the PDT study, the treatment of WT cells with 5-ALA-GNPs and 1-minute irradiation resulted in a very low cell survival rate, only 28.7± 0.8 per cent of the non-treated control. In contrast, WT cells treated with 5-ALA and irradiation yielded a cell survival rate of 59±10 per cent, as high as two times of the 5-ALA-GNP group. A more interesting result was obtained in the PDT treatment of NHDF. A survival rate of 54±8 per cent (relative to the non-treated control) was obtained in the NHDF cells treated with 5-ALA and irradiation, and this survival rate remained similar in those treated with 5-ALA-GNPs and irradiation (50±7 per cent). Necessary to mention, both NHDF and WT cells treated with only GNPs and light irradiation did not show cell destruction, with an identical number of viable cells as the non-treated control. These findings suggest that the discerning effect of the 5-ALA-GNP on NHDF and WT cells can result from a differential uptake of 5-ALA-GNPs by the cells of different type. To confirm this, a study on the uptake of 5-ALAGNPs by NHDF and WT cells was performed. The result showed that the accumulation of 5-ALA-GNPs in WT cells was about two-fold higher than that in NHDF. The uptake of 5-ALA-GNPs by cells occurs in two steps: binding to the cell

membrane and then internalisation.

The binding of 5-ALA-GNP to the cell membrane is the most critical step and it is mainly mediated by the potentials of both cell membrane and GNPs surface.

The positive of the GNPs prepared in this study would favour their binding to the negative cell membrane. In general, the membrane potential of tumour cells is more negative than the normal cells, which can facilitate the binding of 5ALA-GNP and lead to a significant uptake. Therefore, the use of GNPs can significantly improve the delivery of 5-ALA into WT cells. Although 5ALA itself is not a photosensitiser, it can induce the intracellular formation of PpIX, a very efficient photosensitiser.

It was observed that the WT cells incubated with 5-ALA-GNP showed a high amount of PpIX, about five times higher than that in the NHDF. More importantly, a selective destruction of tumour cells by 5-ALA-GNPs was observed in the co-culture experiment with the normal fibroblasts (Figure 3).

Based on this observation, we hypothesised that minimal damage to the healthy cells (i.e. NHDF) and maximal destruction of tumour cells (i.e. WT) can be achieved by using 5-ALA-GNPs. The selective destruction of WT cells is a synergy among the preferred uptake of 5-ALA-GNPs, enhanced PpIX formation in WT, and the subsequent elevation of ROS formation by GNPs. This selectivity has an important implication in clinical

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application to minimise the undesirable cytotoxicity to the surrounding healthy cells.

imaging of the intracellular activities during the PDT treatment.

Golden days ahead

Maung Kyaw Khaing Oo is a PhD student in Materials Science at Stevens Institute of Technology, USA. His current research is “Gold nanoparticles for drug delivery and imaging”. He earned his MSc in Materials Science and Engineering from National University of Singapore, Singapore.

A uthors

In this study, 5-ALA was successfully conjugated onto the positively charged GNPs through electrostatic interaction.

The use of positive gold nanoparticles to deliver 5-ALA not only enhanced the uptake of 5-ALA by tumour cells, but also improved the delivery specificity.

As a result, an effective and specific destruction of tumour cells but with a minimal damage to the healthy cells was achieved in the PDT treatment of cocultured fibrosarcoma cells and normal fibroblasts. The current approach holds an important potential in the cancer treatment using PDT. The intrinsic activity of gold nanoparticles in Surface Enhanced Raman Scattering (SERS) will also allow a concurrent Raman

Full references are available at www.pharmafocusasia.com/magazine/

Hongjun Wang is an Assistant Professor in Biomedical Engineering at Stevens Institute of Technology. His research interests include tissue engineering, nanomedicine and cell-material interaction. He did his postdoctoral training at the Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School.

Henry Du is a Professor and Director of Chemical Engineering and Materials Science at Stevens Institute of Technology, USA. His primary research interests are surface chemical processes and surface modification, processing and measurements of electronic and photonic materials for integrated devices, surface-enhanced Raman spectroscopy for chemical and biological sensing and biomedical imaging.

BOOK Shelf

Quality Systems and Controls for Pharmaceuticals Description: Quality Systems and Control for Pharmaceuticals is an accessible overview of the highly-regulated area of pharmaceutical manufacture, the production of biomedical materials, and biomedical devices. Introducing the subject in a clear and logical manner it enables the reader to grasp the key concepts of the multidisciplinary area of control science and specifically quality control using industrial and theoretical models.

Taking a multidisciplinary approach to the subject the reader is guided through key topics such as product safety which takes into account aspects of analytical science, statistics, microbiology, biotechnology, engineering, business practice and optimising models, the law and safeguarding public health, innovation and inventiveness and contemporary best practice.

Author: Dipak Kumar Sarker Year of Publication: 2008 Pages: 204 Published by: Wiley ISBN-13: 978-0-470-05693-6

The author has both industry and academic experience and many ‘best practice’ examples are included throughout the text based on his own industry experience and current practicing industrial pharmacists. This is an invaluable reference for all students of pharmacy who may have little or no familiarity with industrial practice and for those studying BSc chemistry, biomedical sciences, process analytical chemistry and MSc in Industrial Practice.

For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Adjuvant Systems

Next stage of rational vaccine design Although vaccines helped in improving healthcare globally, significant disease challenges still remain. As such, new solutions are required where classical vaccine approaches are insufficient to provide optimal protection for specific populations and against certain diseases.

Nathalie Garçon, Vice President, Head of Global Adjuvant Center for Vaccine Development, Global Vaccine Development, GlaxoSmithKline Biologicals, Belgium

V

accine adjuvants, compounds used to enhance a vaccine antigen’s ability to elicit a desired immune response, have been known and used for over 80 years to increase the immune response against a given antigen. With the continued emergence of new diseases and the need to find ways to address remaining disease challenges, new breakthroughs in immunol-

ogy offer vaccine developers a way to design more tailored vaccine adjuvant / antigen formulations.

A tailored approach to vaccine design may help accomplish several goals: i. To elicit the most effective immune response (humoral and / or cellular) against a given disease; ii. To induce long-term protection with a higher level of immune

response as well as improved immune memory; iii. To overcome weakened immunity, as seen in the case of immunosuppression or immunosenescence, a deterioration of the immune system that is associated with ageing; and iv. To allow for immunomodulation, activation, suppression or redirection of specific immune response.

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vaccine—antigen and adjuvant(s)—works together to produce an appropriate and lasting immune response.

Adjuvanted vaccines licensed for human use Adjuvant

Description

Selected examples

Aluminium compounds

Aluminium salts (e.g. aluminium hydroxide or phosphate). These are the most widely used adjuvants in human vaccines today

Diphtheria, pertussis, tetanus, and HBV, HAV vaccines etc

AS04

An Adjuvant System consisting of aluminium salt and MPL, a purified, detoxified derivative of bacterial lipopolysaccharide

An HBV vaccine for pre-hemodialysis and haemodialysis patients in the EU and an HPV cervical cancer vaccine approved in 60 countries

Exotoxins

Bacterial ADP-ribosylating exotoxins (bAREs)

The only licensed bARE adjuvanted vaccine was an intranasal virosome-based influenza vaccine (since withdrawn)

MF-59

Microfluidised oil / water emulsion, including squalene and surfactants Tween 80 and Span 85

An influenza vaccine for elderly licensed in parts of Europe

Immunopotentiating reconstituted influenza virosomes (IRIV)—influenza H1N1 surface glycoproteins intercalated in natural and synthetic phospholipids

Two examples include an hepatitis A vaccine registered in several countries around the world, and an influenza vaccine

Virosomes

Table 1

Classical adjuvants such as aluminium salts, have shown to be safe and effective in humans for decades. As a result, roughly 90 per cent of all approved human vaccines contain aluminium salts as an adjuvant. To a lesser extent, additional classical adjuvants such as emulsions, liposomes and virosomes have also been licensed for use in human vaccines.

Combining adjuvants – The next step in vaccine design

Thanks to improvements in immunological and biochemical tools that have allowed a better understanding of immune mechanisms, vaccine developers can make use of a variety of classical and novel “immunomodulator” molecules to improve antigen-specific protection in a given population or against a specific disease. At present dozens of new adjuvants are being evaluated in vaccines intended for human use. A few examples of novel immunomodulators include CpG-containing oligodinucle-

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otides (CpG), monophosphoryl lipid A (MPL), and QS-21.

While adjuvants may be incorporated into vaccines individually, combining both classical adjuvants and novel immunomodulators presents yet another option for vaccine developers looking to optimise the immune response to a given disease, or in the case of a sub-population of individuals. One such adjuvant combination is the immunostimulating complex ISCOM. Considered to be a single adjuvant but possessing multiple properties, ISCOM is made up of cholesterol, lipid, immunogen, and saponins.

An even more nuanced understanding of immunogenicity pathways, such as the interactions between innate and adaptive immune responses, allows scientists to achieve synergistic effects through certain combinations. With a growing number of novel adjuvants to choose from, one of the greatest challenges now is finding the best-suited combination to achieve an optimally effective and safe formulation in which each part of the

GSK Biologicals’ experience with Adjuvant Systems

GlaxoSmithKline Biologicals (GSK) is a pioneer in the development of adjuvant combinations, and has devoted more than18 years to the study of what it terms as “Adjuvant Systems”. The company currently maintains a portfolio of proprietary Adjuvant Systems. The following examples illustrate the benefit they have shown in vaccines and vaccine candidates designed with a specific pathogen or subpopulation in mind.

AS04 – Formulated vaccines

The Adjuvant System AS04 consists of the immunomodulator MPL, a stimulant of the immune system, adsorbed on different aluminium salts. AS04 has already been evaluated in various vaccines and vaccine candidates intended to protect against viral infections / diseases including herpes simplex viruses, hepatitis B, the EpsteinBarr virus and Human Papillomaviruses (HPV).

The first AS04-formulated vaccine approved for use in humans is hepatitis B surface antigen (trade name: FENDrix™), developed specifically for patients with end stage renal diseases with a high risk of hepatitis B infection. This tailored hepatitis B vaccine, adjuvanted with AS04, allows the induction of higher specific antibody titers, enhanced cell-mediated responses, and increased seroprotection rates. Clinical data also suggest that protective antibody levels persist longer with the AS04-adjuvanted vaccine, so individuals require fewer boosters.

Now approved for use in more than 60 countries worldwide, GSK’s AS04-formulated cervical cancer vaccine Cervarix™ was designed to target the two most common cervical cancer-causing types, HPV 16 and 18. The vaccine is indicated to prevent persistent oncogenic HPV infection and cytological abnormalities that could lead to cervical cancer. The AS04-containing vaccine induces a stronger and more

R esearch & development

AS02 – Formulated vaccines

The AS02 Adjuvant System is the combination of an oil-in-water emulsion with MPL and QS-21. The latter is an immunomodulator extracted from the bark of a South American tree, Quillaria saponaria.

AS02 was originally developed for use in a malaria vaccine candidate, and it has since been used in a number of other vaccine candidates, where a strong T-cell response is needed to obtain effective protection, including HIV and tuberculosis.

Development is ongoing on an AS02-formulated malaria vaccine. Malaria, a major health problem in endemic areas, is caused by multi-stage protozoan parasites of the genus Plasmodium. P. falciparum which is responsible for the most severe disease and accounts for the highest mortality rate (1 child dies every 30 seconds from malaria infection). AS02 was selected for the candidate malaria vaccine as it had shown to generate an effective antibody response and to elicit a cell-mediated immune response capable of interfering with the intra-hepatic stage of the parasite. This is the only vaccine candidate to date that has been shown to protect against P. falciparum infection, and to prevent disease in children and infants living in malaria endemic regions.

A number of additional studies are being performed in various African countries to evaluate a number of vaccine parameters.

A large multi-centre phase III clinical trial is planned to start in late 2008, in 8 to 10 sites across sub-Saharan Africa.

In clinical studies performed to date, AS02-adjuvanted vaccines have been welltolerated, with the most frequent solicited local adverse events being mild to moderate swelling and pain at the injection sites and the most common general solicited adverse events being mild to moderate headache, fatigue and myalgia.

AS01 – Formulated vaccines

Other vaccines for specific diseases or subpopulations may require different immunostimulations in order to induce effects other than those provided by the AS02 or AS04 formulations. The AS01 Adjuvant System was developed using an alternative formulation based on the combination of liposomes, MPL and QS21.

The current AS02-adjuvanted candidate malaria vaccine has provided unprecedented protection against P. falciparum infection and malaria clinical disease. To further increase the immune response and protect a higher percentage of people, the AS01 Adjuvant System has also been evaluated in the malaria candidate vaccine. A comparative challenge study in humans has demonstrated the superiority of AS01-adjuvanted candidate malaria vaccine when compared with the AS02adjuvanted candidate vaccine in terms of antibody titers, T cell-mediated immunity, and protection level. Based on these results, the AS01 formulation is now also being evaluated in field studies, both in adult and paediatric populations.

Pre-clinical safety evaluations of AS01 have shown a safety pattern similar to that observed with other Adjuvant Systems.

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sustained immune response than the same virus antigens formulated with aluminium hydroxide alone. This translates into a fast and strong onset of the humoral response through antibody production that persists at a high level over time. These antibodies are not only produced at a high level but are functional as observed by their long lasting neutralisation ability.

The AS04 formulation has been evaluated over 15 years, involving over 43,000 subjects. AS04-based vaccines are generally well-tolerated, although solicited local symptoms are usually reported at somewhat higher rates than vaccines adjuvanted with aluminium salts. This, however, may reflect a stronger immunological stimulation, with higher involvement of innate and adaptive immunity than that induced

by AS04 adjuvantation.

To date, AS01 has been administered to a limited number of clinical trial volunteers, including young children, and the overall safety profile appears similar to the profile of AS02 containing vaccines. Further clinical evaluation will be needed to confirm the safety and tolerability profile of this Adjuvant System.

Adjuvants – Leading the way

The use of adjuvants in vaccines has progressed from a primarily empiricalbased approach to an increasingly rational design, as scientists become better able to measure and analyse diverse aspects of the immune system. It is now possible to combine a tailored Adjuvant System with the most appropriate antigen in order to create vaccines that may provide a more effective immune response against a specific pathogen or for a sub-population. Persistent unmet medical needs in immunisation demand increasingly sophisticated vaccine design. While challenging diseases have been discussed, one area for improvement in the case of a sub-population is vaccines for the elderly, whose immune systems are frequently less responsive than younger individuals. The emerging area of therapeutic vaccines, designed to treat rather than prevent disease, is another place where novel adjuvants and / or combinations of adjuvants may be required to elicit an antigen-specific immune response that would be capable of halting the disease process. Advancements in vaccine adjuvant science may one day help scientists and medical professionals find immunological solutions to these and many other areas of unmet medical needs.

Full references are available at www.pharmafocusasia.com/magazine/

Nathalie Garçon is Vice President, Head of Research and North America R&D at GlaxoSmithKline Biologicals, and has been involved in the adjuvant work since its inception.

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Early Formulation

Shortening the development timelines Formulators are faced with an increasingly competitive industrial environment and very challenging compound properties. Smart development strategies, like frontloading are needed in order to increase the R&D productivity and to bring new chemical entities earlier onto the market. Key factor for success is the intensified cooperation between research and development.

Jan Möschwitzer, Senior Pharmaceutical Scientist, CPD-PSA Han Op’t Land, Head of the Biopharmaceutical Platform Solvay Pharmaceuticals B.V., NCE Development Center, The Netherlands

Flower Model

It represents mixed team structures of dedicated task teams with a core team in the centre.

Synthesis drug substance (small/large scale

Tox supplies Clinical supplies

CMC Core Team • Strategy • Planning • Specification sheets • Critical issues

Solid state characterisation

Pharmaceutical development

Chemical development Analytical development

Figure 1

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Regulatory (IMPD/IND, MAA/NDA)

ISSUE - 8 2008

T

he duration of drug development cycles is continuously being challenged by an increasingly competitive industrial environment. The number of drug candidates intended for pre-clinical and clinical development has dramatically increased by using modern high-throughput technologies, such as combinatorial chemistry and pharmacological screening. However, in most of the new compound selection processes an increasing number of new chemical entities were found to be showing poor aqueous solubility and poor membrane permeability. This is due to the fact that the compounds are getting more and more difficult to formulate and at the same time, the time available to develop these drug candidates is continuously reduced.

This presents a major contradiction: In a consistently decreasing process time, an increasing number of complex drug candidates have to be formulated in order to support pre-clinical programmes as well as human clinical studies.

In order to overcome this contradiction, smart development strategies are needed to maintain or even shorten the overall development timelines and to address the compound related issues adequately and in a timely manner.

Moreover, in early development, aspects such as upscalability and cost of goods, which are of primary importance in commercial manufacturing, need to

R esearch & development

be considered. The common goal of the pharmaceutical industry is to bring new chemical entities earlier onto the market and to be able to reap the benefits of the patent protection of a new drug.

At Solvay Pharmaceuticals, this need is approached through an integrated analytical, chemical and pharmaceutical development. All disciplines contribute to the success equally. An insight into the implementation of the frontloading strategy with a special focus on the implementation of new formulation development strategy is discussed here.

General requirements for an accelerated development process

One of the most important requirements to increase the R&D effectiveness is an improvement of the intra- and interdisciplinary communication. A strategy change can only be successfully implemented when the walls between the “silos” (i.e. the different disciplines) are successfully broken down. At Solvay Pharmaceuticals, this is achieved by having mixed team structures. A core team of scientists from various disciplines is responsible for the chemical and pharmaceutical development activities of a compound. The tasks are performed by interdisciplinary task teams. That enables a very good knowledge sharing among and inputs from all disciplines. Representatives of the task teams form the core team and it is mainly responsible for the strategy, planning and interaction between the task teams (Figure 1).

The implementation of a biopharmaceutical platform has improved the communication between different departments and disciplines even further.

The platform helps to bring the right people together and to coordinate the data sharing among Research, Chemical & Pharmaceutical Development and Clinical Pharmacology departments. The data sharing aims at making available of all the data related to the compound to the team members so that the efficient evaluation of the compound character-

Issues of current drug candidates

requires a smarter chemical development, as well as an improved analytical and formulation development.

Frontloading – From a serial approach towards a parallel approach

Insufficient exposures after oral dosing Food effects Non-linearity Poor permeability Efflux effects Risk of late failures Formulation change requires bridging studies Figure 2

istics can be done based on all relevant in vitro and in vivo data. This is a key requirement for enabling right decisions at the right time.

It is very important that all disciplines contribute to the success equally.

A shortening of development timelines

In the past, a serial approach was followed from the lead candidates towards the market formulation. In general, the good water-soluble and good permeable compounds (defined as BCS class 1 compounds according to the wellknown Biopharmaceutics Classification System) did not require intensive formulation efforts to become bioavailable.

Therefore, the formulations for these compounds used in pre-clinical and clinical programmes were relatively simple, like suspensions of micronised API—in capsules or even just plain solutions. The real formulation development including process development was started after a proof-of-principle study in patients was successfully completed (i.e. clinical phase IIa).

As long as the compounds belong to BCS class 1, the conventional approach is very effective and also reduces costs.

However, this approach does not work very well for more challenging compounds from the BCS classes 2, 3 and 4.

A scheme of a frontloaded development process Preclin

Clin I

Clin IIa

Clin IIb

Clin III

PLE/LCM

Approach 1 Approach 2

Lead form

Market form

Backup

PLE/LCM

Approach 3 Approach 4 Approach 5 Approach 6 Selection of appropriate formulation approach

Formulation optimisation/ confirmation

Scale up / process development

Scale up / process development

POP

Drug product manufacturing

Launch Figure 3

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The administration of such compounds is connected with a lot of different issues as shown in Figure 2.

If such complex compounds are administered as standard formulations, often enormous API loadings are required to reach sufficient blood levels. Normally, the formulators are then asked to come up with enabling formulations to decrease the doses or to make the formulations more attractive for marketing. The formulation changes require bridging studies. There is a high risk of late failure when no suitable formulation approaches can be found to solve the issues. All the above-mentioned facts necessitate the implementation of a new strategy.

It is therefore clear that only by putting more efforts into the processes would one be able to minimise the risk of inadequate exposure when formulating problematic compounds. The key question to answer while formulating complex compounds is which of them has the potential to be the most promising drug candidate that can be taken further into the full development programmes. Therefore, it is necessary to develop different formulation approaches in parallel and to test the different formulations in suitable in vitro and in vivo test systems. The aim of all these efforts is the identification of the optimal formulation principle for the specific API as early as possible. This lead formulation principle can then be maintained for this specific API throughout all pre-clinical and clinical phases. In some cases it will be even possible to identify two almost equally suitable formulation approaches. In this case it would be possible to select the lead formulation approach and to keep a potential backup formulation for the life cycle management of the drug. The earlier the lead formulation principle can be identified, the more time will be available for the optimisation of the formulation including, for instance, the Quality by Design activities and process optimisation. This is of particular interest if a relatively new formulation approach has to be applied in an industrial scale setting.

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The formulation development route from the compound selection up to the formulation choice for the first clinical trials

Determine solubility, permeability and metabolic characteristics

Conventional approach

Frontloading approach

Liquid or solid dosage form

Oral solution or suspension

Simple capsule formulation

Preparation of several prototypes for in vitro and in vivo testing

Micro

Nano

Solubilised

Amorphous

Iv-ref.

Dissolution and stability testing, comparative bioavailability

Appropriate formulation approach for Phase I clinical trial materials (SRDT and MRDT) Figure 4

There is also another big advantage of using this strategy. If it is not possible to find a suitable formulation approach during the early stages, then there is very little chance that this formulation approach can be found later. Hence, the development of such compounds could be discontinued as early as possible. Resources thus saved could be used for more promising drug candidates.

Furthermore, the medicinal chemists could try to improve the compound characteristics, if the underlying reasons for the low bioavailability are elucidated.

When comparing both the strategies, it becomes obvious that in the new approach many development activities are shifted towards a very early stage

of the process. Hence, this approach is termed as frontloading (Figure 3).

Implementation of the strategy

The implementation of the strategy in Solvay Pharmaceuticals started with considerations as to how the most appropriate formulation approach can be selected in an effective manner. It should not be forgotten, that the goal of this strategy is to shorten the overall development timelines. When a new compound arises it is first classified with regard to its aqueous solubility and its permeability.

If the compound can be regarded as BCS class 1 compound the formulation should be as simple as possible, comparable to the conventional approaches. However,

R esearch & development

Bioavailability influencing factors; the parameters that can be influenced by the formulation choice are highlighted in red

Bioavailability

First pass clearance

Intestinal

Absorption

Hepatic

Biliary

Solubility

Permeability

Hepatic Figure 5

if a compound shows solubility in aqueous media of lower than 40Âľg per mL and/or a very low permeability or a high metabolism rate, determined through in vitro tests, then it is a candidate for the full blown formulation approach. That means that different formulation types are developed in parallel. This multi-tier approach comprises many vitro tests, like discriminating dissolution tests, short-term stability test of prototype formulations (Figure 4).

The low bioavailability of a compound can be in general either due to low solubility, dissolution or permeability rates.

In some cases it can also be a combination of the different factors leading to a very low bioavailability. A very high first

pass clearance could be another reason for low blood concentrations. In this case the tools of formulation developers to improve the bioavailability are relatively limited. Normally, the influence of the formulation ends with the intestinal absorption. A hepatic first pass effect is therefore out of the range of formulation improvement. However, solubility related issues, and to a minor extent even permeability related issues, can be addressed and improved with suitable formulations.

Particle size reduction, solid state manipulation, solubilisation and permeation enhancement are the main techniques to improve the bioavailability of problematic drug candidates within

Universal formulation approaches The nanonisation principle can be applied in liquid form as well as solid dosage forms.

Clin Ia: SRDT Liquid

Nano-suspension

Clin Ib: MRDT Powder in capsule

Nano-Powder

Clin IIa

PoP

Tablet

Nano-Tablet

Solvay Pharmaceuticals. A comparison of the influence of the first three approaches can elucidate solubility rate and dissolution rate limited bioavailabilities. The permeation enhancing strategies are of particular interest for BCS class III compounds, but can also be used for BCS class 4 compounds.

The approaches should be as universal as possible, meaning that one should be able to apply this formulation principle for liquid formulations as well as solid dosage forms. An example of a universal formulation approach is given in Figure 6. For instance, the formulation approach particle size reduction can be applied as nanosuspension when a flexible dosing or a special administration route is required.

However, the nanosuspension can also be transferred into solid dosage forms, like capsules or tablets. The formulation principle in this case would be particle size reduction or nanonisation.

This part of the development ends normally with a comparative PK study of different optimised prototype formulations in a suitable species. Normally, this comparative bioavailability study enables the formulators to select the most promising formulation approach with regard to predefined parameters like developability, patentability, scalability, cost of goods, stability and bioavailability improvement.

Experimental design and miniaturisation of the processes

The limited availability of API of sufficient quality is one major obstacle for the development of different formulations in parallel. It is clear that formulation development especially during the early drug discovery and lead optimisation phase is always a balance between rapid screening and commercially viable formulation development. Frontloading certainly requires more API at earlier stages. This needs to be addressed by the chemists.

However, the formulation scientists are also asked to improve their experiments in such a way that less API is

Figure 6

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toxicity study reflect the properties of the lead formulation approach considered for the clinical trial material.

The importance of the inteference between research and development HIT

LEAD Optimisation / Clinical candidate selection

LEAD Suspension

Solution

Clinical candidate

la

Clinical Phase l b / ll a

Frontloading – Accelerating drug development

Micro-susp.

Micro-susp./caps Micro-susp./caps Micro-caps*

Nano-susp.

Nano-susp./caps Nano-susp./caps Nano-caps*

Micellar sol.

Solub./LFC

Solub./LFC

LFC*

Solution

Solution

Solution

IR caps*

Amorphous

Amorph. caps

Amorph. caps

Amorph. caps*

intr-PK rodent SD-PK rodent

SD PK sec spec.

comp. PK

FIM/SRDT

MRDT

IV/PO rodent In vitro

In vitro disease

In vitro disease

DRF Tox

Tox

long term Tox

Research

Development

* Instead of capsule formulations tablet formulations can also be developed

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Figure 7

formulation approach and a potential backup formulation approach are chosen, it is no longer necessary to develop the unsuccessful approaches further. The parallel approach is also beneficial for the biological testing.

Suitable formulations can be chosen from the portfolio with respect to the kind of the in vivo study, for instance the requirements for long-term toxicity studies are different from that of explorative PK studies. However, it is necessary that formulations used within the enabling

A uthors

needed in order to save costs. Therefore, the miniaturisation of the experiments is an important requirement to start more activities earlier. Furthermore, it is important to avoid an unnecessary replication of experiments. All formulation activities from the lead candidate phase until the clinical phases have to be linked with one another. Figure 7 shows the ideal situation for a poorly soluble compound in which the formulation selection and optimisation process starts during the lead phase, when normally only very tiny amounts of API are available. For that reason, only two different approaches are tested in vivo at this stage.

The comparison of the bioavailability obtained from, e.g. a suspension or a solubilised system, can give important guidance for the subsequent development steps. During the lead optimisation phase when more API is available, the number of different formulation approaches to be tested can be increased.

The figure also shows that it is possible to transform liquid formulations into solid dosage forms while maintaining the formulation principle. Once the lead

POP

The strategy change described in this article requires a change in the mindsets of the people involved in the drug development process. Every member of the organisation has to be involved in the process. Frontloading can lead to an accelerated development process, if smarter techniques are applied consistently from all disciplines. Furthermore it is important to miniaturise the experiments in order to reduce the required drug amounts. An integrated development approach including the right in vivo studies can enable the formulator to decide on suitable formulation approaches very early on. The frontloading strategy facilitates that within shorter time periods. Even very challenging compounds can be formulated adequately to support pre-clinical programmes as well as human clinical studies. Compounds with issues that cannot be solved can be identified and discarded early in the beginning.

The capacities can then be focussed on the most promising compounds. All these activities can enable the pharmaceutical industry to reach the overall goal—to launch new drugs onto the market earlier.

Full references are available at www.pharmafocusasia.com/magazine/

Jan Möschwitzer is a Senior Pharmaceutical Scientist at the NCE Development Center of Solvay Pharmaceuticals in Weesp, The Netherlands. Jan is Pharmacist and holds a PhD in Pharmaceutical Technology from the Freie Universitaet Berlin, Germany. His main research activities are focussed on the implementation of an integrated formulation approach using enabling formulations for poorly soluble and poorly permeable compounds.

Han Op’t Land is a pharmacist. He held positions in Analytical development, QA/QC related to API manufacturing and early Formulation Development. His current responsibilities as Head of the BioPharmaceutical Platform include optimising the information flow between research and development and redesigning development processes to shorten the time to market.

R esearch & development

Enhancing Antibody-based

Cancer Therapy Monoclonal antibodies are becoming an important class of antitumour agents, as they have been shown to enhance the efficacy of various therapeutic regimens without significantly increasing systemic toxicity. Combination of antibody-based therapeutics may be more efficacious than each individual antibody alone. Antibody combinations and dual-targeting bispecific antibodies represent promising approaches to more efficacious antitumour therapy.

Zhenping Zhu, Vice President, Antibody Technology, ImClone Systems Incorporated, USA

T

he additive and synergistic therapeutic effects derived from combinations of cytotoxic agents support the notion that cancer, a disease of multiple genetic alterations, must be attacked on multiple fronts. In the past decades, a number of chemotherapy regimens have been developed. These regimens are usually cocktails that comprise several cytotoxic agents that act on different cellular targets and / or processes critical for cancer development, growth and metastasis. Because most cytotoxic agents lack selectivity towards tumour cells, the increased antitumour efficacy of these regimens unfortunately also cause severe systemic toxicity To this end, Monoclonal Antibodies (mAb) with high specificity and affinity have been developed. These mAb are being used either as unmodified

(or “naked�) or as targeting devices to deliver toxic molecules to tumour cells that overexpress the defined antigens, and have shown considerable success for the treatment of certain type of cancers. The unmodified mAb

An obvious approach to overcome cancer cell escape from monotherapy is to simultaneously attack multiple cellular proliferative / survival mechanisms of the malignant cells by a combination of chemotherapeutics, radiation, and antibody-based drugs.

exert their antitumour activity via one or more mechanisms, including direct inhibition of a specific aberrant signal transduction pathway in cancer cells by blocking growth factor /

receptor interaction, down-regulation of oncogene expression, induction of cell apoptosis, and mediation of effector mechanisms such as AntibodyDependent Cellular Cytotoxicity (ADCC) and Complement-Mediated Cytotoxicity (CMC).

Unfortunately, due to the low intrinsic cytotoxicity of the unmodified mAb drugs, many cancers escape from antibody monotherapy by exploiting redundant signal transduction pathways and by compensating for the inhibition of one survival / proliferation pathway with upregulation of another.

An obvious approach to overcome cancer cell escape from monotherapy is to simultaneously attack multiple cellular proliferative / survival mechanisms of the malignant cells by a combination of chemotherapeutics, radiation, and antibody-based drugs. It has been well-established in the clinic in several cancers that the addition of a specific mAb to chemotherapy or radiation regimens led to increased antitumour efficacy without concomitantly

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increasing systemic toxicity, which is usually dictated by the chemo or radiotherapy agent. In addition, accumulating evidence suggests that the use of two or more antibodies targeting different mechanisms of tumour growth / survival may be more efficacious.

However, the costs on research, development, manufacturing, and regulatory approval of therapeutic mAb are already extraordinarily high, and the addition of a second, or even the third, mAb to a treatment regimen could make such approach prohibitively expensive. To this end, a promising alternative to antibody combinations is the development of dual-targeting Bispecific Antibodies (BsAb) that simultaneously act on two or more cellular pathways critical to tumour growth and metastasis.

Antibody combination therapies

While combination treatment with antibodies and chemo / radiotherapy is clearly effective, improvements must still be made. Since the toxicity of these regimens is attributable primarily to the cytotoxic agents, which are frequently used at their maximum tolerant doses, fine tuning of the dosage / scheduling of these components is unlikely to yield dramatic results. To this end, combinations of mAb directed against multiple proteins associated with tumour growth and survival may represent a better strategy for increasing efficacy while limiting systemic toxicity.

The most obvious approach to antibody-based combination therapy is to simultaneously administer two or more approved antibodies to a patient.

Unfortunately, because only nine antibodies have been approved so far by the US FDA for cancer applications, and because the approved indications of these mAb are usually non-overlapping, the clinical utility and efficacy

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of antibody combination therapy has not been pursued systematically and significantly to this date. Since this field is still in its infancy, most of the evidence supporting antibody combination therapy comes from preclinical studies. For example, combinations of antibodies targeting Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR), or EGFR and Insulin-like Growth Factor Receptor (IGFR), or EGFR and Her2 / neu, have all been demonstrated to produce synergistic / additive antitumour activity in animal models. Further, combination of antibodies to different epitopes on the same target, e.g. Herceptin and Omnitarg® to Her2 / neu, has been shown to synergistically inhibit the survival

Combinations of mAb directed against multiple proteins associated with tumour growth and survival may represent a better strategy for increasing efficacy while limiting systemic toxicity.

of breast cancer cells in vitro and the growth of xenografted tumours in vivo.

On clinical development front, the combination of Erbitux®, an anti-EGFR antibody, and Avastin®, an anti-VEGF antibody, which have been approved for treatment of patients with Colorectal Cancer (CRC), is particularly noteworthy. A Phase II study (81 patients) has been performed to test the effect of the combination of both antibodies with or without irinotecan for irinotecanrefractory CRC. Of those receiving Erbitux®, Avastin®, and irinotecan, 37 per cent achieved a partial response and had a median time to progression of 7.9 months, while 20 per cent of those receiving just Erbitux® and Avastin® had

a partial response, with a median time to progression of 5.6 months. Although not all the drug permutations are included, and inter-study comparisons are not statistically valid, the relatively high response rate of Erbitux® / Avastin® / irinotecan combination (37 per cent) compared to Erbitux® / irinotecan alone (23 per cent, historical rate) suggests that antibody combination therapy warrants further study. Phase III trials with this combination for CRC are underway.

Similarly, multiple late stage clinical trials using a combination of Herceptin® and Avastin® are being conducted in breast cancer patients.

Bispecific antibodies (BsAb)

Although there are many potential benefits of using approved mAb in combination therapy, there are many drawbacks as well.

The characterisation and development of a mAb-based therapeutic can be a very timeconsuming process. Developing antibodies individually in clinical trials and then repeating this process with combinations of antibodies would present an unacceptable cost and delay to pharmaceutical and biotech companies. Further, developing an antibody in combination with one made by another company poses a serious risk to the investment due to the lack of control of the development plan. From the consumers’ perspective (and insurance companies), the cost of mAb therapy is staggering—a typical mAb-containing regimen cost tens of thousands of dollars while a combination therapy can easily exceed US$ 100,000.

An attractive alternative to mAb cocktails is the use of dual-targeting BsAb. BsAb have the potential to alleviate the aforementioned issues by combining two treatment modalities in one molecule. While the concept of BsAb as potential therapeutics for cancer treatment has been around for

R esearch & development

more than 20 years, no BsAb has so far been approved for clinical therapy.

Most BsAb research has been on the creation of bispecific fragments, and centred on developing BsAb as retargeting agents that simultaneously bind tumour antigens on one arm, and effector cell antigens such as CD3 and CD16, radioisotopes, or chemotoxins on the other. Recently there has been an increased focus on IgG-like BsAb. These molecules contain an intact Fc domain, which endows them with the effector functions, such as ADCC and CMC, and the long half-life of normal IgG. As with antibody fragments, most applications of IgG-like BsAb have been for re-targeted therapy. However, the use of IgG-like BsAb as integrated dualtargeting agents that simultaneously block two tumour-associated targets is becoming an increasingly attractive approach in further enhancing anticancer therapy.

BsAb Case Study – Anti-EGFR x antiIGFR BsAb

It has recently been shown that in some cancer cells, upregulation of IGFR compensates for inhibition of EGFR, and renders the cells insensitive to anti-EGFR therapy. It is, therefore, plausible that a BsAb inhibiting both the receptors would have increased efficacy over each mAb alone. With this in mind, we have constructed and tested pre-clinically both in vitro and in vivo two bispecific IgG-like molecules targeting both EGFR and IGFR, using the variable domains of two fully human antibodies directly against EGFR and IGFR, respectively.

In one format, the single chain Fv (scFv) are fused to the constant domains of an IgG (scFv EGFR-CL and scFvIGFR-CH1-CH2-CH3), and bispecificity is achieved through CL-CH1 dimerisation. This construct, called (scFv)4-IgG, blocks ligand binding to both receptors, and inhibits EGF and IGF induced activation of EGFR, IGFR, and their downstream signal-

ling pathways. In a pancreatic tumour cell line that expresses high levels of both EGFR and IGFR, treatment with anti-EGFR or anti-IGFR alone inhibited growth of only 25 to 35 per cent, while treatment with the combination of both monospecific antibodies or the bispecific construct inhibited growth by ~80 per cent and ~60 per cent, respectively. In the another format, a bispecific IgG-like antibody is made by substitution of the CL and CH1 domains with VL and VH domains conferring secondary specificity, resulting in a diabody-Fc fusion, called a “di-diabody”. The two chains (VLIGFRVHEGFR and VLEGFR-VHIGFR-CH2-CH3) associate by the natural affinity of VL and VH domains. This BsAb binds both receptors simultaneously and blocks the signalling pathways stimulated

The di-diabody inhibited the growth of two tumour xenografts in vivo as effectively as the combination of the two parent mAb.

by EGF and IGF. Furthermore, the di-diabody triggers internalisation and degradation of IGFR, and also mediates ADCC activity on tumour cells that express EGFR and / or IGFR. Most importantly, the di-diabody inhibited the growth of two tumour xenografts in vivo as effectively as the combination of the two parent mAb. Other approaches to antibody combinations – Oligoclonal and polyclonal antibodies

If combinations of mAb of different specificities could provide multiple mechanisms for tumour inhibition, then in theory, more is better. To this end, oligoclonal antibodies (defined mixtures of mAb) and polyclonal antibodies could represent good candidates as potentially effective cancer thera-

peutic agents. Recently, recombinant methods for production of polyclonal antibodies have been developed.

Basically, phage display of a Fab library is used in conjunction with negative selection to isolate many antibodies that specifically bind cancer cells. The DNA encoding these Fabs is recloned en masse into a mammalian IgG expression vector and polyclonal IgG produced.

In one study, a polyclonal IgG raised against a tumour cell line was shown to be more effective than a mAb at inhibiting the growth of the same tumour cells. Alternatively, cell lines expressing the mAb of interest can be generated, banked and maintained individually, and then combined just before the final production process. While the concept of oligoclonal and polyclonal antibodies is appealing, they are likely to be met with skepticism by the FDA regarding their safety and efficacy, as well as batch consistency in the manufacturing process.

Future prospective

We are fortunate to have a variety of arsenal available for treating cancer, including conventional cytotoxic agents, radiation, targeted toxins / conjugates, and signal transduction inhibitors. While cytotoxics and radiation are very effective at cellkilling, the lack of selectivity towards tumour cells severely limits their potential, thus they are unlikely to provide a “cure” for cancer. The challenge in developing better treatments for cancer thus may lie in increasing the efficacy of more tumour-specific therapies and targeted toxins / conjugates without concomitantly increasing systemic toxicity.

The therapeutic efficacy and manufacturing capacity to produce the materials in sufficient quality and quantity are two of the most important factors in determining our success in developing the BsAb into powerful anticancer agents. It has long been known

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with conventional chemo and radiotherapy regimens for further enhanced efficacy.

On the manufacturing front, as with many protein-based therapeutics, the most limiting factors to BsAb production are practical and technical in nature. Ideally, a BsAb would be homogenous, stable, and well expressed, like normal IgG. BsAb have historically been produced by co-expression of two antibodies in one cell, via the hybrid hybridoma technique or DNA co-transfection. Because there are many possible pairings of light and heavy chains (16 permutations), the A uthor

that not every single combination of cytotoxic agents, e.g. chemo or radiotherapeutics, would necessarily lead to additive or synergistic antitumour activity—inappropriate combinations may result in unwanted drug-drug interaction, even inter-drug antagonism, due to difference in their mechanisms of action. To this end, developing BsAb that are highly effective dual-modality therapeutics will require good understanding of the molecular basis in the aberrant signalling pathways that lead to cancer growth and development. With this information, appropriate combinations of targets, such as EGFR and IGFR, can be chosen for simultaneous targeting in order to maximise the antitumour effects and / or minimise the potential inter-target antagonism.

Finally, it is pertinent to note that, BsAb, like the monospecific mAb therapeutics, can be used both as standalone therapies and in combination

desired bispecific product is only a small fraction, in theory an eighth, of the total protein produced. In the past years, there have been a number of new IgG-like BsAb created through recombinant techniques for the production of high quality, homogenous proteins, including the (scFv)4-IgG, di-diabody, IgG-scFv fusion and dual-variabledomain IgG (DVD-IgG), but still more work must be done to bring production yields up to the levels obtained with conventional mAb. Full references are available at www.pharmafocusasia.com/magazine/

Zhenping Zhu has been working in the field of antibody therapeutics for over 23 years, and has authored over 160 peer-reviewed scientific publications. He leads the antibody discovery and protein engineering efforts at ImClone, and has produced more than a half dozen of antibodies that are currently in clinical development, including phase III trials.

CoverStory

Unleashing the Industry’s True Potential Closed loop clinical trial supply chain

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Closed-loop supply chain is an imperative first step in the process of clinical supply chain performance improvement, leading to reductions in time to launch a new product in the market.

Clinical Supplies Adapting to trial demand

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By increasing the efficiency in which the supply chain can respond to change, a window of time is opened up in which real-time data can be collected from a trial to adjust forecasts and adapt to trial changes.

Clinical Trial Supply Chain Streamlining information management

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Business intelligence tools allow for improved inventory decision making and flexibility to respond to changes in protocol.

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Unleashing the Industry’s True Potential Closed loop clinical trial supply chain

Clinical trial supply chain will play a significant role in launch of new products in a globalised environment of clinical trials and clinical supplies manufacturing.

RS Kumar, Senior Manager, Life Sciences Practice, BearingPoint, USA

T

he lead time for conducting clinical trials is one of the critical paths in the launch of a new product for life sciences companies, while providing clinical supplies at the right time at the right site is the most daunting challenge faced by the clinical operations team. Changes in the trial design and uncertainty in the demand of clinical supplies due to unpredictable patient retention have been the traditional challenges faced by the clinical team, which typically lacked a formal process or cross-functional collaboration. Over the years, complexity of

launching a new product has increased exponentially thanks to the heightened competition, increased pricing pressure and globalisation of clinical trials, as well as sourcing of clinical supplies.

Adding to the challenge, clinical trials have grown larger in size and longer in duration (Figure 1). However, heightened regulatory compliance requirements (e.g., quality and global trade) and consumer awareness of multiple drug therapy options have reduced the margin of error during clinical trials.

Last but not the least, the success of bio-pharmaceutical companies has put Challenges in clinical trials

Decreased Trials Subjects

Budgets

Costs

Scope for errors

Complexity

Resources

Duration

Increased

Figure 1

Source : BearingPoint

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• Right kit at the right time • Forecast complexity • Limited shelf life of drugs • Blinding and repackaging • Drug accountability • Pooled supplies • Global regulatory compliance • Adaptive clinical trials • On-demand supplies • Demand & supply networks

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enormous pressure on the traditional blockbuster model of large pharma companies, which is reflected in the reduced budget allocation for clinical trials and stringent metrics for the successful launch of new product into the market. One solution for achieving this is to incorporate a closed-loop supply chain that connects the various functions in a real-time fashion. This is an imperative first step in the process of clinical supply chain performance improvement, leading to reductions in time to launch a new product in the market—the ultimate goal for any pharmaceutical organisation.

Clinical trial supply chain benchmarking study

A recent study by AMR Research, in conjunction with BearingPoint, surveyed executives working for mid-size to large companies in life sciences or medical device industries from North America to Europe that are directly involved in supply chain-related activities. The results of the study illustrate the criticality of Clinical Trial Supply Chain (CTSC) performance in reducing the lead time of launching new products in the market.

Only 36 per cent of the companies surveyed admitted having conducted planning meetings to translate their demand to operational plan. Just 23 per cent of the companies confirmed that their current supply chain proc-

Most significant clinical trial supply chain challenge Which one is the most significant challenge to date?

13%

Getting the right kit at the right time & site Regulatory compliance Overcome org. challenges moving to more antic/collab environ Source : AMR Research and BearingPoint

esses are effective, which explained why more than two-thirds of the companies outsourced their supply chain to meet their objectives of agility, cost and expertise. Additionally, nearly half of the companies confirmed the difficulty in establishing global operational procedures. This explains the slow response by the research and development organisations to deal with challenges around clinical supply chain management. Instead of trying to reinvent the wheel, there is an opportunity to leverage lessons learned by other industries in improving their supply chain, identify the area of similarities, and selectively apply them to the clinical environment.

The first safe step would be to look at closing the supply chain loop to ensure tighter integration across functions to collectively respond to the challenge, rather than treating this as a supply chain problem.

Current industry response to meet the challenge

Several companies have taken the lead in making significant changes to their CTSC capability. These organisations have taken different approaches to dealing with the issue and have tasted varying degrees of success. These approaches entail adjusting the process, organisation, strategy and technology.

Process – Be collaborative

Realising the significance of improved demand forecasting, some companies have implemented Sales and Operations Planning (S&OP) type of models with a formal collaborative process between

11% 10%

Some companies are applying innovative strategies to leverage key elements of commercial supply chain organisations and outsourcing to manage the sourcing, packaging, labelling and distribution of supplies to deal with the complexities of global demand and supply networks.

Technology – Invest and integrate

Figure 2

clinical research and supply chain teams.

There are weekly meetings conducted between the teams sharing demand and supply data on a more frequent basis, leading to effective planning and utilisation of resources in the downstream processes. This is where decisions related to changes in trial design / logistics are made jointly, keeping in mind the financial implications, as well as the increase in supply chain lead times that has helped manage the clinical trial within budget.

As observed in Figure 2, regulatory compliance and collaborative environment are the other key challenges in a globalised world, where documentation requirements are becoming very stringent to avoid delays in shipment or hold-ups in customs clearance. R&D organisations have started implementing formal processes to deal with the above as they have been recognised as major risk areas from a supply chain perspective.

Organisation – Provide dedicated support

The role and definition of CTSC organisations have evolved over time.

Recognising the need for cleaner upstream processes, certified supply chain professionals are leading some of the transformation programmes to implement formal planning and forecasting processes. Supply chain coordinators support various protocols by therapeutic area and work collaboratively in a matrix organisation of plant supervisors who are responsible for scheduling and managing manufacturing capacities of clinical supplies.

Technology is one area where R&D organisations have not made much investment. The CTSC functions are mainly supported by use of Microsoft® Excel spreadsheets to homegrown applications loosely interfaced with data inputs from Interactive Voice Response Systems (IVRS) and back-end manufacturing and sourcing systems. With this, much of the business communication happens over phone and e-mail.

Thanks to their dedicated effort, clinical operations teams have been able to maintain a high level of performance to get the supplies on-time to their clinical sites.

Despite these attempts to use technology to provide scalability, companies have not achieved a high level of integration across the following packaged applications: Clinical Trial Management Systems, IVRS, third-party service providers systems. This has increased the risk exposure in the areas of inventory visibility, traceability, returns and reconciliation at sites.

Strategy – Find the right one

Multiple strategies exist for approaching the CTSC. These include the selective or complete outsourcing of clinical operations—fostering extensive collaboration between the supply chain and clinical research teams early on in the trial design phase to factor in their feedback to mitigate key supply chain risks / constraints during the process, all the way up to using delivery postponement strategies and implementing concepts of pooled supplies and on-demand labelling.

As can be observed in Figure 3 and Figure 4, which highlight additional findings of the AMR Research study,

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CoverStory The companies with a higher perfect order rate have a more mature CTSC organisation How long has your clinical trial supply chain team been functioning?

37%

48%

4 Years or more

68%

Less than 3 years

37%

32%

19%

3 Years

23%

2%

All Countries

We don't have a CTSC team 22% 1%

5%

<60%

3%

60%+

Perfect Order Rate Source : AMR Research and BearingPoint

Figure 3

The companies better at sensing demand have a higher perfect order rate How long does it take your organisation to sense real or actual changes in clinical trial demand?

2%

11%

12%

39%

47%

5% 14% 24%

32% 33%

4 to less than 5 weeks 3 to less than 4 weeks 2 to less than 3 weeks 1 to less than 2 weeks Daily

33% 25%

13%

7%

All Countries

<60%

60%+

Perfect Order Rate Source : AMR Research and BearingPoint

these strategies have yielded encouraging results in the form of a mature CTSC organisation leading to a higher perfect order rate.

So, why do life sciences companies need to implement a future state clinical supply chain that is agile, robust, reliable, scalable and efficient?

What are the key elements of such an organisation?

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Figure 4

The recommended solution – Closed loop clinical supply chain

As the name suggests, the key aspect of this model is “closed loop,” which means effective real-time communication across all functions to factor each other’s constraints and operate on a single version of truth at all times. In simple terms, this requires the following key elements to be implemented (Figure 5).

Sales and operations planning: Again, this is a key element to improve the upstream process in clinical supply chain. When combined with a creative requirements planning strategy (Materials Requirement Planning / Consumption Based Planning), these processes can save significant amount of time and effort for the clinical supply chain coordinators to focus on key tasks of efficient planning and timely communication to help optimise resources and costs at all levels.

Manufacturing integration (MI): A tighter integration between manufacturing, planning and clinical research teams would enable real-time information exchange on delays due to capacity or resource constraints between shop supervisors and planning coordinators.

This will help the clinical research teams to take appropriate action at their end in a proactive manner and eliminate waste or redundancy in the process. For example, patient visits can be rescheduled well in advance or alternative plans can be made to ensure timely supplies to sites.

Supplier collaboration (SC): This helps in streamlining the procurement process and making it more efficient by allowing communication of variability in supply and demand in a timely manner. Additionally, this helps in minimising various issues around documentation and compliance requirements by ensuring exchange of accurate and complete information about the products (clinical supplies) across all parties, such as Contract Manufacturers and Contract Research Organisations (CROs) involved in the process. This is particularly important in the context of globalisation or outsourcing, where the number of parties involved in the process is increasing.

The Rubik’s cube of CTSC

For large companies conducting multiple global trials at any given point of time, the list of challenges keep growing with the advent of globalisation

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CoverStory (culture, language and infrastructure), outsourcing (additional process steps and IP concerns), and above all, changes to the concepts of trial design—with adaptive trials leading to even lower response times. It is important for these companies to take a serious look at options beyond just the closed loop clinical supply chain.

Agile clinical enterprise

For those companies that run large complex clinical programmes, a robust and Agile Clinical Enterprise (ACE) is a potential solution. Tracking key metrics (Figure 6) to make prioritised, continuous improvement enhances the ability to sense and respond to demand and supply situations through the supply chain, while optimising the key resources.

As can be seen from the hierarchy diagram, there are several key factors both upstream (e.g. Clinical Trial Demand Forecast) and downstream (e.g. Inventory) in the process that finally contribute to the performance, such as the time from concept to launch of a new product. This is not just within the clinical supply chain, but also within the R&D function as a whole. The other components of ACE are described below.

Demand forecast accuracy

There are attempts to focus on whatif simulation using Monte Carlo-type techniques to predict patient retention rates (kit demand) and communicate it real-time to downstream functions.

Using the Bill of Material (BOM) explosion, companies are attempting to improve the forecast accuracy of all items critical to ensure on-time availability of clinical supplies. For example, knowing the demands of a “comparator drug” accurately and well ahead of time can save the last-minute rush by sourcing teams and help mitigate risks due to availability of key supplies critical for the success of trials. This can also help drive understanding of the requirements of labels and accessories

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well ahead of time to give supply chain professionals the ability to determine important make or buy decisions that factors capacity and resource constraints, while ensuring timely availability of these supplies.

Clinical supply chain strategy

Some of the key proven concepts from Consumer Products, Hi-Tech and Automotive can help streamline the clinical supply chain process: First on the list would be a consumer or patient-centric CTSC strategy. This is a paradigm shift from the traditional concept of “inventory overages” and “build to stock” to ensure high serviceability of continuously changing clinical trial needs. Not only does this help save precious resource capacity in the supply chain, but it helps maintain just adequate inventory, which will minimise the challenges in storage, packaging, labelling, distribution and accountability.

The second concept would be “selective outsourcing” of some of the repetitive tasks or high volume items that do not add much value in the process through internal manufacturing. Some of the potential candidates for this could be sourcing of APIs (with a consolidating and maturing pool of suppliers) or labels.

Third would be the concept of “pooled supplies,” “on-demand labelling” or “delivery postponement,” which is quite similar in objective to

Sales & Operation Planning

Supplier Collaboration

Source : BearingPoint

Manufacturing Integration

Figure 5

the famous Just-In-Time concepts that helped the automotive and high-tech manufacturers remain competitive and profitable.

Global trade management

Taking into consideration that globalisation of trials (demand) and sourcing (supplies) is the future of the industry, it is extremely important for R&D organisations to have a Global Trade Management (GTM) programme in place that can help mitigate the compliance risks and also save millions in taxes and duties. A typical trade management programme would include customs environment optimisation, GTM operations support, GTM data management and performance visibility, trade security and risk management, and a comprehensive global trade governance framework that supports corporate risk and escalation management.

Leverage commercial infrastructure

Mergers, acquisitions and outsourcing are driving companies to consolidate their capacities, including the R&D space. Concepts such as co-development and Quality by Design (QbD) to address scale-up issues are changing the way traditionally technology transfers have been handled. R&D organisations have been asked to consolidate the demand in clinical supplies and use some of the commercial infrastructure in core manufacturing, as well as lab capacities.

Supplier consolidation is another area where R&D can leverage a smaller set of approved suppliers for commercial manufacturing to make it manageable and help lower procurement costs.

Making best use of the well-oiled distribution networks by experienced supply chain professionals is one of the optimal ways to mitigate the challenges arising from the highly complex demand and supply networks described earlier.

With a combination of training, formalisation of processes, innovation and smart strategies, companies have tasted success in overcoming the mental block of “we are different, since we oper-

Hierarchy of clinical supply chain metrics

ate in a regulated environment.” By overcoming this challenge, companies are able to take advantage of this huge internal asset for driving improvements.

One of the ancillary benefits of this approach has been the ability to provide a collaborative virtual organisation for R&D to support key functions, such as global trade logistics, global trade compliance, and key finance functions for budgeting, which were not available early on, due to the perceived cost and value benefits of having a dedicated organisation for R&D.

CT Demand Forecast CT Perfect Order

CT Scan Cost

New Product Time-to-Market

Concept to Pototype Supplier Quality

Supply chain risk assessment

Gathering continuous data on the key supply chain parameters—demand visibility, demand variability, transportation lead times, lead times for internal and external processes like sourcing, documentation, workflow approvals, cold chain supply chain, etc.—to sense and proactively take corrective action not only mitigates the risks but also helps save significant amount spent on taxes, duties and transportation costs. Some of the large pharmaceutical companies have achieved tremendous success in having the global logistics compliance team provide direct oversight and advice to the clinical supply chain experts. By closely tracking the cross-border shipment times, these companies have started planning the shipments from the less busy and more actively supportive ports, leading to significant reduction in lead times and costs.

Similarly, data has been gathered on the maturity and consistency level of vendors, such as contract manufacturers, freight forwarders, customs brokers and clearing agents. This supports the clinical supply chain to take proactive measures in providing training and direct documentation support to mitigate the risks, such as delays or hold-ups in customs clearing due to incomplete documentation or movement of banned substances in those countries.

Armed in advance with the information of the total demand of movement of clinical supplies, logistics compliance

Assess

Cost Detail

Production Schedule Variance

Prototype to first production Supplier on-Time Plant Utilisation

Source : AMR Research and BearingPoint

teams have been able to work with the agencies of different governments to adequately classify goods. This includes addressing questions on the intended use of the clinical supplies, or even going to the extent of advising the S&OP teams to make intelligent decisions in trial design around, for example, the selection of sites and countries upfront in the clinical trial process. This has helped companies avoid situations where clinical trials have been seriously affected, due to lack of knowledge about the local regulations (e.g. import / export of investigational drug or devices, depot requirements, bio-terrorism laws) in countries like Brazil, Russia, India, China and Japan.

Vaccine manufacturing companies have been the hardest hit due to lack of poor infrastructure in some of the developing countries to support cold chain supply chain needs in shipping the clinical supplies across tropical locations.

Automation

Technology is an enabler to automate some of the complex processes described above. This is critical not only to provide single version of truth, scalability and savings in costs, but also to enable a healthy work environment, providing much needed relief to the highly stressed supply chain specialists who are working

First production to launch

Return Cost Inventory Inventory RM+WIP +FG

Return %

Diagnose

Correct

Order Cycle Perfect Order Detail Time Figure 6

to ensure on-time delivery of supplies to sites.

Emerging new technology vendors helped in addressing the key needs of clinical supply chain, while the existing Manufacturing Enterprise Systems (MES) and Enterprise Resource Planning (ERP) vendors have recognised the need to provide enhanced solutions to address the specific demands of R&D in the life sciences industry. Leaders in the life sciences industry have recognised this by initiating technology implementation projects, breaking the myth of whether new product development—especially clinical trials with hosts of uncertainties from product definition to demand—can ever be supported by these packaged solutions available in the market. One of the major benefits from technology has been seen in the area of automating labelling as a collaborative process from design, approval to print. Companies have initiated “eLabelling” projects that not only address the complex needs of clinical labelling, but also build a common repository and smooth transition to commercial labelling in a global environment.

Last but not least, with the emergence of Service Oriented Architecture (SOA) supported by most of the solutions

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Training

None of the above can be realised if the clinical supply teams are not provided with adequate and continuous training around key technologies, modern supply chain concepts, global regulations and infrastructure constraints in developing countries and also in different cultures.

This is an area where companies in the life sciences industry can improve by investing in training programmes. A combination of internal and external trainings can result in much higher return on investment, which is extremely critical to develop the CTSC into an agile and

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mature organisation responding to the dynamically changing environment in the clinical space.

Unleash the potential

To all those leaders and practitioners in the R&D organisations within the life sciences industry, in companies both small and large across the globe: it is time for you to recognise that you have an “ACE” up your sleeve and to take the first step towards a closed-loop clinical supply chain to meet the growing complex needs of this industry in a highly competitive

A uthor

listed above, key challenges and risks in systems integration, both internally across geographical locations or with external vendors like contract manufacturers, third-party packaging, labelling and distribution vendors or CROs across time zones and diverse locations, would be addressed.

environment. It is time to unleash the potential you have in making a drastic reduction to the ever rising lead time and costs of launching a new product in the market. This will not only revitalise the industry as a whole by facilitating the launch of more research projects that can deliver more therapeutic solutions, but also help keep the costs of healthcare— which is having a domino effect on other industries—under control.

Full references are available at www.pharmafocusasia.com/magazine/

Sivakumar Rajagopalan is a Senior Manager in BearingPoint’s Life Sciences practice. Over the last 25 years, he is acknowledged as an industry thought leader offering pioneering solutions in the area of Clinical Trial Supply Chain Management.

Clinical Supplies Adapting to trial demand

In todayâ&#x20AC;&#x2122;s clinical trial environment, change is at the front lines acting as an obstacle to the success of a clinical supply plan. How many times has the clinical trial design changed after supplies are already packed and labelled? Preparing clinical supplies in this environment is challenging supply chains to create adaptive supplies that can easily respond to the changes in todayâ&#x20AC;&#x2122;s clinical trials.

Catherine Hall, Supply Chain Coordinator, Pfizer Global Research and Development Supply Chain Management, USA

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hether it is adding new sites in an existing study or adding new doses, clinical customers look to the supply chain to be agile with supplies and respond in turn with flexibility while maintaining timely delivery. There are many challenges facing clinical supplies and how the supply chain can be prepared to meet the demand changes.

Challenges facing clinical supplies

In the past decade clinical trials have evolved to adopt a global approach. Trials today are commonly engaged in multiple countries than ever before and are venturing into new and expanding markets like Asia. This movement has had an impact on clinical supply chain organisations demanding that a common platform of supplies appeal to the needs of a wide scope of countries.

The effects of this demand are several-fold. First is the need to gather translations for clinical labels and incorporate regulatory statements for each country involved in a trial. Secondly, there is the need to source compara-

tors from multiple countries in order to supply the trial worldwide. This process can get complicated by differences in approved sources of material, treatment options, or packaging requirements in each country. Another effect is in the distribution of clinical supplies.

As trials reach multiple countries, import and export regulations, inspec-

A clinical supply chain must be prepared to meet the needs of a trial while facing the challenges of global distribution.

tions and costs impose the need for companies to dedicate significant resources (internal or external) just to manage these logistics. A factor across all of these elements is the impact of growth and competition in the industry to reach patients in these countries. As new markets gain experience with clinical trials, they adopt new regulations or translation standards, and heighten scrutiny over trial applications and

imports. Countries with limited infrastructure can struggle to keep up with all the materials being imported into their country.

As a result of all these effects, there can be a heavy influence on the timelines required to prepare and deliver clinical supplies to sites around the world. A clinical supply chain must be prepared to meet the needs of a trial while facing these challenges of global distribution.

As clinical trials have evolved, there is more emphasis on and deliberation over trial design. It has become a common custom for protocols to be amended several times prior to even the start of the study start and then again during the course of the trial. These changes can range from minor ones, including updates in language or laboratory procedures, to major changes in number of subjects, visit schedules or treatment arms. As a result, clinical supplies are planned based on a theoretical demand of the most likely scenario rather than on a realistic expectation of the needs of a trial. This demands that clinical supplies be agile to adapt to the changes in a trial prior to the start of the study and then again be ready to adapt to changes that occur throughout the trial. One of the most difficult challenges of an ongoing trial is to predict and adapt to enrollment rates.

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Sourcing

Drug Product Manufacturing

Packaging and Labelling

Shipping and Distribution

IVR Load

Expiry Date

Manufacture Date

Optimising a supply chain

Drug Product Manufacturing

Batch record preparation begins ahead of drug delivery

Packaging and Labelling QP Release

Package at Risk Ship at Risk

Shipping and Distribution IVR Load

Introducing strategic risks based on the strengths in the supply chain increased time in the field opening a window of adaptability in a supply plan.

Inclusion and exclusion criteria play a large part in determining how quickly a trial may enroll, but it is also subject to investigator engagement, competition with other ongoing trials, and the overall willingness of the patient population that is required for the study. As a result of poor enrollment, a clinical trial may have to add additional sites or further expand into more countries in order to reach the desired patient population.

These changes, if not anticipated, can negatively impact supply stocks.

Recognising that clinical trial design is critical and often varies, growing trends in clinical trials are to utilise flexible dosing paradigms or adopt an adaptive trial design in order to maximise the success of a trial. These designs challenge supply chains to prepare for trials where everything from treatment options to the number of subjects can change at points during a trial. Therefore, clinical supply chains must plan for a supply platform that can adapt to major design changes. To be successful, all variables in a trial must be constantly monitored in order to adapt to trial changes and ensure that demand can be met throughout the trial.

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42 Weeks

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QP Release

To meet ever changing demands, clinical supply chain organisations have to provide: 1. a common supply platform that meets a variety of global needs; 2. a strategic and flexible forecast that is based on a theoretical demand of the most likely scenario; and 3. a supply that continually adjusts to ongoing study variables to ensure that clinical supplies are delivered at the right rime to the right place in the right amount and in the right presentation and still has robust expiry.

Unfortunately there is no secret formula in the industrial vault that always delivers against this expectation.

Supply chain project managers can only forecast based on a limited number of variables before the cost of the supply chain overshadows the risk of excluded variables impacting supplies. However, there are many approaches that can be considered to position clinical supplies for success.

Approaches to meet changing demands

The first approach is to understand and optimise the supply chain. Optimisation

Window of adaptability Figure 1

requires that a supply chain maximises strengths, provides alternatives for its weaknesses and mitigates its constraints.

Optimisation further requires a forecast to minimise assumptions and set clear decision points around key milestones in the trial to evaluate the variables and adjust the forecast accordingly. By increasing the efficiency in which the supply chain can respond to change, a window of time is opened up in which real-time data can be collected from a trial to adjust forecasts and adapt to trial changes. This â&#x20AC;&#x153;Window of Adaptabilityâ&#x20AC;? is created by reducing cycle times in the supply chain and ensures that clinical supplies always meet the trial demand.

The second approach is to create a common supply platform. This starts in development with formulation. The most valuable tool in a supply platform is to have a single appearance across all dosage forms in a trial. This provides maximum flexibility to meet the demand of a variety of trial designs.

This single appearance applies not only to the investigational drug product but also to potential comparator agents. By adopting a common packaging design,

supplies can be fit into multiple clinical needed to forecast supplies effectively trial designs, and the supply chain can are identified. Through partnership, therefore be positioned to adjust to the the supply chain can contribute to an changes that may occur. In particular, effective trial design. Working together these strategies are essential for flexclinical teams and the supply chain can ible dosing paradigms or adaptive trial optimise a packaging platform, fit visit design. By having dosage forms with a schedules to supplies effectively and single appearance in a common packidentify countries that will perform aging design, these materials can be well for both clinical needs and supply mixed and matched together in a variety needs.. of combinations to satisfy a variety of By selecting preferred distribution designs without risking the blind of points and expanding a trial within a a study. regional label pool rather than across Part of developing a common packlabel pools, clinical supplies are posiaging platform is developing a global tioned for success and the usage is labelling platform. By developing maximised. Through partnership, regulatory templates for each country clinical supplies become a part of the and establishing a library of approved trial design. There is a new sense of phrases and translations, the supply chain can develop a label that fits with a packagPartnership with clinical teams is most ing design for any country important to determine which variables ahead of the study demand.

By further grouping countries will be included in the forecasting plans into regional booklet labels, and which will be excluded. the supply chain is prepared to expand into new countries within any region when enrollment demands it. By combinvisibility of the supply chain which is ing packaging and labelling platforms a key to further developing trust in the together, a single global supply can be partnership. Risks in the supply plan generated that is pooled across multiple must be disclosed and limitations and trials. From a single flexible inventory, constraints highlighted so that the clinimultiple protocols can be managed such cal partner understands how changes in that when one trial struggles for enrollclinical design or adoption of certain ment, supplies are diverted to another enrollment strategies will impact clinitrial that is moving quickly. Managing cal supplies. one inventory helps to reduce the burden By offering strengths and Windows on the supply chain to track multiple of Adaptability to clinical partners, in packaging platforms and study demands return the supply chain will be tied into so that more attention can be given decisions which change the key trial varito monitoring variables and adjusting ables. It is important to establish mileforecasts for additional supply needs. stones within a Window of Adaptability

to discuss enrollment targets and any plans to upgrade enrollment with your clinical partners so that any changes in assumptions fit with the forecasting strategy. When a window is short and the data input is limited, partnership with clinical teams is most important to determine which variables will be included in the forecasting plans and which will be excluded at their own risk. Even when the supply strategy is to provide a bolus supply, partnership is still important to validate that the assumptions and variables used in the initial forecast have not changed and supplies will not expire before the end of the trial. Thus, it is important to communicate with clinical partners during the course of a trial to evaluate assumptions and make decisions that involve clinical supplies.

Adapting to change

Adapting to change is a must in clinical trials. It also places a high demand on supplies to be flexible and be able to respond to multiple variables. By optimising the supply chain, Windows of Adaptability are created which then allow supply forecasts to adjust to realtime trial demand. By adopting common packaging and labelling platforms, maximum flexibility to meet a variety of trial demands could be achieved. The most powerful asset is a good partnership with clinical customers. By changing supplies from an ordering process to become apart of clinical trial design, co-ownership is established and supply plans succeed to meet the demand of a trial.

The most important approach is to create a partnership with your clinical customers. By transforming your customer into a partner, clinical supplies responsibilities are adopted and there is a new sense of co-ownership. Through partnership, key variables which are

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Introducing clinical partnership Catherine Hall has worked as a Supply Chain Coordinator with Pfizer Global Research and Development for the past seven years. In this role she has managed the clinical supply chain for over 30 compounds through all phases of development and across six different therapeutic disciplines. She has an MS from Baylor College of Medicine in Molecular Biology, and an MBA from University of Houston.

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CoverStory

Clinical Trial Supply Chain Streamlining information management

Consolidating and integrating data across systems and relationships can help manage some of the challenges associated with supplying investigational and comparator drugs for clinical trials.

The current landscape in clinical trial supply information management

FORECASTING

Raw Materials

Inventory Management

Bulk Materials

Packed Materials

Manufacturing Excellence

Shipping Materials

LABELLING

MRP

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IVRS

Douglas Meyer, Senior Director, Aptuit Informatics Inc., USA

E

nsuring the efficiency and validity of clinical trials requires that several factors come together, not the least of which is the investigational material. The supply chain underlying a clinical trial is a complex entity, with product passing through numerous hands before reaching the clinic and, ultimately, the patient.

Understanding the challenges

Clinical trial supply managers face several challenges in tracking drugs through this journey, including finding ways of managing supply data. For instance, to make sure

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that all necessary tracking data is captured, trials have information systems in place at every point along the supply chain, such as forecasting, inventory management, labelling, and distribution (Figure 1). These systems are not necessarily interoperable; there are no industry standards for clinical trial supply chain management akin to Clinical Data Interchange Standards Consortium (CDISC) standards which are widely used for Electronic Data Capture (EDC). Thus, to centralise such information, sponsors generally have to write proprietary code that allows disparate systems to exchange data.

CTMS

Investigator

EDC

Drug Accounting

Figure 1

Keeping in mind that we use the term “information systems” as an overall descriptor, one should not necessarily assume that all of these systems are automated or electronic. Many trials still rely on hand-entered data in spreadsheets or even paper-based systems. These practices can be particularly problematic in the event of a regulatory audit, as they force sponsors—who are ultimately responsible for all data from all aspects of a trial, including supply management—to spend significant time and resources reconciling data.

The practice of outsourcing complicates the picture. A recent survey in Contract Pharma revealed that of 175 Roth G. (2008.) 4th Annual Outsourcing Survey. Contract Pharma. Vol. 10. Issue 4.

biotechnology and pharmaceutical companies, 48 per cent engaged six or more preferred outsourcing vendors in their clinical trials. The path that a drug may take through the series of vendors can differ from protocol to protocol. As noted above, the trial sponsor is ultimately responsible for gathering all relevant information generated by the trial, including data from outsourcing vendors.

Trial design is also evolving, with adaptive trials becoming more prevalent.

The dosage of an investigational drug, or the number of trial participants, can change dramatically following an adaptive trial’s interim analysis, which can significantly impact supply forecasting and management. Also, trials are crossing international borders, reaching out to include patients in multiple countries so as to achieve greater power.

Thus, supply plans (and as a result, the infrastructure for information management) must account for the regulations of each participating country, including packaging and labelling rules, and ensure that an appropriate amount of investigational drug and comparator drug (which may differ depending on which drugs are approved in a particular market, adding additional complexity) reaches the patients in each country.

Bringing data together

The software industry has responded to these challenges with a number of IT solutions, some based on adaptations of data management systems developed for commercial manufacturing and supply.

Such solutions, however, do not meet the particular environment of the clinical trial, where lot sizes are small, packaging and labelling requirements are unique to the protocol, and doses must be blinded to ensure the integrity of the trial’s clinical / biological data and conclusions. There are a variety of other solutions employed in the supply chain including integrated, “purpose-built” systems, more evolved forecasting and simulation tools and data warehousing and business intelligence tools.

Of these solutions, those based on data warehousing and business intelligence are starting to play a more critical role.

Before going into these, some definitions are in order. Briefly, a data warehouse is a repository of an organisation’s electronically stored data. Business intelligence tools are applications designed to report, analyse, and present data, providing the analytical and presentation (dashboard) functions that allows data to be used in decision making. A third concept that should be included in this discussion is the data mart, an organisational data subset (a room within the warehouse, if you will) that is usually oriented toward a specific task, purpose, or data subject.

The idealised supply chain management scenario centres on the data mart, containing all that subsets of organisational data (from the data warehouse) having to do with clinical trial inventory and supply. The data mart serves as a data repository, as an engine for consolidating and transforming / adapting data from vendors or suppliers to common formats, and as a means of receiving, storing, and routing inventory requests. Information from all of the varied supply management systems noted earlier in this article would pass through and be stored in the data mart. Business intelligence tools serve as means to access (ideally, via Web-based portals), share, query, and act upon data within the mart so as to respond to the needs of the trial sponsor and trial locations (Figure 2).

There are numerous benefits to solutions that combine data marts with business intelligence tools. For instance, such a combination of tools allows all members of the trial, including the clinical team, to access supply data and adjust their own planning accordingly. Business intelligence tools allow for improved inventory decision making and flexibility to respond to changes in protocol (a boon for supply chain managers taking part in adaptive trials). By consolidating and presenting all supply-related data in one location, the data mart-business intelligence combination allows for more effi-

cient reporting of inventory at the end of a study. Lastly, business intelligence tools can serve as a dashboard for senior management, facilitating a top-down view of product supply and distribution and the Key Performance Indicators (KPIs) that are used to measure the health of the organisation’s internal and external supply chain operations.

Considerations when designing a solution

Implementation of such solutions is not without its own challenges. For instance, as noted above, the industry has not agreed upon standards for formatting, storing, and exchanging supply chain data.

For now, most organisations overcome this challenge by creating proprietary transformation and exchange tools that bridge disparate systems. This is not, however, an ideal solution, as the process for developing, validating, deploying, and maintaining such bridge tools is onerous and time consuming. Such solutions also do not provide adequate flexibility to accommodate various system upgrades or easy replacement of one or more of the component systems in the supply chain. For this reason alone, a concerted industry-wide effort towards development of standards would bring new efficiency to supply chain management, just as it has for data capture and trial management.

If a combination data mart-business intelligence system were to be used in GMP-related decision making or study reporting, it would have to undergo system verification. This is a time-consuming process, but one that would give assurance of the reliability and fidelity of the storage solution and accuracy of the analyses generated using the business intelligence component—an important consideration when looking forward to regulatory submission.

Data contained within a data mart is only useful if it can be queried and accessed in ways that fit an organisation’s reporting and analysis needs. Thus,

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CoverStory Schematic representation of a clinical trial supply IT solution based on a data mart and business intelligence model

Web Portal ta Da Data

Data Mart Data Transformation Data Repository Request Storage & Routing Adapter

Adapter

ta

Re q

Da

ta

IVRS Vendor 2

Manufacturing Vendor 3

Contractor Environments

The ten-year view

Whether this kind of data consolidation and storage can in practice provide

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the benefits noted above remains to be seen, as it has not yet been deployed in a widespread fashion. However, this model feeds directly into a vision of how the clinical trial supply chain would look 10 years from now. In this forward-looking scenario: • Manufacturing and packaging processes will be increasingly automated, if not entirely • A standardised data dictionary will be applied to all clinical supply services • The hosted “software-as-a-service” model will come to predominate as a means of controlling costs, thereby necessitating interoperability • Label information will increasingly be published electronically, rather than in print • Real-time patient enrollment data will be utilised to influence strategies

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systems built on this combined model must be constructed with intuitive and flexible reporting in mind. The data mart must be understandable in order to allow the inclusion of ad hoc reporting. KPIs, which can be of great help in pointing out areas for improvement that would increase overall organisational efficiency, can be difficult to extract from supply chain and inventory data unless the system is built with the foresight to allow for measurement of the proper metrics.

Information systems have evolved such that decision making in near realtime is possible. But how real-time will a data mart system be? Or need to be?

Because of the limited availability of industry experience with such solutions, the first question is difficult to answer.

The second can only be addressed by a thorough examination of trial protocol’s information needs, with particular consideration of decision timeframes and the temporal resolution needed to support them.

sts

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Packaging & Distribution Vendor 1

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• Inv. Systems • Doc Systems • IVRS • CTMS • LIMS

q Re

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Business Intelligence

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Figure 2

and workflows for packaging and labelling • Planning, simulation and measurement capabilities will become more sophisticated • Integration of sponsor and vendor data systems will achieve seamlessness.

This kind of automated, standardsdriven paradigm of trial supply management will bring the same efficiency and integration now being seen in trial data collection. The development and adoption of information system models like data mart-business intelligence will accelerate the evolution of this paradigm.

At the same time, it will offer significant advantages in trial efficiency now, enabling companies to more rapidly enroll and execute clinical trials and reduce the time to market for new innovative products.

Douglas Meyer received a BS in Pharmacy and an MBA from the University of Connecticut and is a member of the Investigation Products Steering Committee of ISPE. A senior director at Aptuit Informatics, he currently leads the Client Services division at Aptuit Informatics with responsibilities for the implementation of software at the customer site as well as training and validation support for clients.

C linical trials

Personalised Healthcare Hitting the mark

The concept of Personalised Healthcare (PHC) is being driven by the idea of improved patient outcomes and also to contain soaring healthcare costs. It is only when the right patients receive the right treatment that the true value of PHC is realised. To achieve this, biomarkers that are quantifiable need to be identified to select the right patient populations.

The challenges of implementing this new research strategy are complex and would require a multifaceted approach.

Shannon A Graver, Global Studies Operations Manager, PDOC Stefan J Scherer, Senior Biomarker Program Leader Angiogenesis, PDEO F Hoffmann-La Roche, Switzerland

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ersonalised Healthcare is not a novel concept, but has undergone a continual evolution.

More than 1000 years ago diagnosis and treatments were based on what could be seen, smelt, tasted, palpated or intuited. About 100 years ago, diagnosis and treatment started to be based on a greater understanding of surgery, biochemistry and cellular processes.

Today, the focus is getting sharper and rapidly growing insights into molecular processes and variations in our genes, is changing the path of medicine.

The aims of Personalised Healthcare (PHC) initiatives are simple: only treat those patients who are likely to respond to a given treatment. By achieving this, the efficacy and safety for every patient can be greatly improved. However, the reality is, that science and medical advancements have been sluggish to capitalise.

The term “Biomarker” is all encompassing; it requires our understanding of drug metabolism, action, efficacy and / or safety; facilitates prediction of the response to therapies; can expand the molecular definition of disease; and can

recognise the stage of diseases. According to this broad definition, biomarkers include all diagnostic tests, imaging technologies and any other objective measure of a person’s health status and all pharmacodiagnostic tests. Genetics, genomics, proteomics, modern imaging techniques and other technologies enable this detection and quantification of many more markers than ever before which leads to an improvement in our understanding of targets, signaling pathways, metabolism and mechanisms of toxicity.

Today molecular technologies are available to better target treatments, but discovering and developing novel medicines and diagnostic markers (biomarkers) is a very complex and timeconsuming undertaking. By evaluating the individual characteristics of patients and their diseases (e.g. cancer subtypes) into account, PHC could 1. improve medical outcomes and the quality of care; 2. predict which patients will most likely benefit—helping avoid treatment without benefit; 3. aid in the development of safer and

more effective treatments by reducing the risk of side effects; and 4. save patients’ lives and improve their quality of life.

By increasing efficacy and safety, PHC could 1. make therapies more cost-effective; 2. create diagnostic products that can help save costs by targeting therapies to the patients who are most likely to respond; 3. create diagnostic products may also help avoid severe side effects 4. make more efficient use of healthcare budgets.

“Omics”

The Human Genome Project (HGP) took 13 years to be completed (2003).

The project identified the human DNA was made up of approximately 3 billion chemical base pairs and 25,000-30,000 genes. As a result, genetic strategies were the first to adopt the concept of personalised healthcare, and the pharmacogenomics era was born. Pharmacogenomics is an example of revolutionary technologies and evolutionary practices coming together to determine an individual response to drugs that is based on the affects of genetic inheritance as opposed to the traditional means of a “one size fits all” approach. The benefits of a diagnosis based on genotypic and integrated phenotypic data could result in significant

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improvements in earlier treatments and extending not only the life of patient populations but also the quality. However, the limitations of pharmacogenomics soon became apparent as it failed to account for individual environmental factors.

As a consequence, and as an alternative approach to pharmacogenomics, research into the metabolic profile, the so called pharmacometabonomics, was undertaken.

This technique could demonstrate for example that pre-dose urinary profiles carried information about the degree of toxicity post-dosing and, in the case of paracetamol, information that is predictive of the drug’s in vivo biotransformation. Furthermore, a responder / nonresponder pattern of liver damage at 24 hour post-dosing was reflected in the pre-dose metabolic profile of the urine, as described by Nicholson JK, Molecular Systems Biology 2:52. These studies show that there is a realistic and valuable approach to screen human populations with plasma metabolic profiles which result in indicative measures.

Given the reality that therapeutics appear to be effective for only 20 to 60 per cent of patients prescribed, and, nearly 200,000 people die from adverse drug reactions each year, researchers and physicians need new tools to be able to combat the variability of diseases. Within the next decade, the development of molecular diagnostic products will most likely give researchers the tools to predict a patient’s therapeutic response that is based on either the patient’s inherited genetics, or the genetic makeup of a tumour or the viral genotype.

If it were not for the great variability among individuals, medicine might as well be a science and not an art.

– Sir William Osler A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to therapeutic intervention, as defined by the biomarker definition working group, Clinical Pharmacology & Therapeutics (2001) 69, 89–95. Some

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unanswered questions where the solution could hide in the discovery of novel markers include, the prevalence of diabetes that is highest among Alaskan Natives and American Indians; and that men are more likely to die from congestive heart disease than women.

Biomarkers may or may not be dynamically modulated (e.g. DNA, which generally does not change, versus metabolites or proteins, which do change). Medicine and science are moving in this direction, as some of the following examples might tell: We measure blood glucose to tailor insulin treatment to patients’ needs. In the case of Osteoporosis, a broad range of tests is available to assess bone integrity and to monitor the effects of antiresorptive therapy. Patients suffering from HIV are being tested in order to measure viral levels in HIV patients before and during treatment with an antiretroviral drug, this allows physicians to monitor success as well as evolving resistance to the therapy.

In the large area of oncology, breast cancer is a perfect example. It is globally accepted to measure the presence / expression of a growth factor (HER2)

in breast cancer with specific tests such as IHC, FISH or CISH, identifying patients who are likely to respond to Herceptin, a therapy that specifically targets this growth factor. Another important case for patients with Chronic Myelogenous Leukaemia (CML) is Gleevec where patients being tested for the presence of mutations in BCR-ABL are also used to monitor drug resistance to the treatment.

However, for predicting individual drug response, the gene-chip technology, AmpliChip CYP450 test, the world’s first commercial pharmacogenetic product, analyses variations in two genes that play a major role in the metabolism of many widely prescribed drugs. Another example of current advances in molecular diagnostics is a myocardial infarction diagnostic tool, developed by deCODE genetics and Affymetrix which is a prognostic test that gives insight into the probability of patients developing a myocardial infarction.

There are many areas where progress is being made by developing a sound biomarker strategy. It has been shown recently that biomarkers are unlocking

Elements that contribute to worthwhile PHC strategy Clinical sample

Theranostics

Genetic Profiling

Personalised Healthcare

Creative trials

in vivo / in vitro models

Biomarker

Figure 1

C linical trials

some indicative mechanisms such as the inhibition of tyrosine kinase in tumours with EGFR somatic mutations; the influences on the response to Gefitinib, Irinotecan with UGT1A1 mutations; Warfarin with CYP2C9, and VKORC1 and DPD polymorphisms and ability to metabolise 5FU Novel molecular and imaging technologies, such as genetics, genomics, proteomics and PET / DCE-MRI imaging are increasingly used in early drug development to try and identify biomarkers which may enable advancements in PHC. PHC is a complex process, but often underestimated, which requires the use of various diagnostic and imaging technologies (see Figure 1) in order to be successful. Its true value may not be realised if part of the tasks (identifying the concerned marker) remains unfinished Men are only so good as their technical developments allow them to be.

– George Orwell Discovering the marker that has the potential to stratify patients is only half the mystery—the way to measure markers that can be implemented into routine clinical practice, is the real challenge.

The current discovery and validation of biomarkers is still based on an outdated research model that assumes a given treatment will react on a disease regardless of individual variability. Because of this approach, the burden of this breakthrough technology is placed in the later stage of drug development, rather than synchronised detection during pre-clinical and early stage drug development, with an emphasis on validation during the later phases. This alternative methodology could allow us to make considerably better decisions in late research and early development—essentially an evolution of the current discovery paradigm.

To reap the benefits of biomarker discovery in trial design, validated surrogate markers need to be identified to run shorter trials whereby response is measured based on the changes of these markers; and also smaller trials should

When is a biomarker not a biomarker?

There are different utilities of biomarkers which facilitate their differentiation as defined by the National Institute of Health (NIH), see Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework, Biomarkers Definitions Working Group • Pharmacodynamic markers confirm biological activity of drugs: Enable earlier go / no go decisions, and make optimisation of dosing and schedule more efficient.

• Prognostic markers (e.g. CRP in rheumatoid arthritis) correlate with disease outcome: Improve the ability to design informative trials and to interpret them confidently.

• Disease specific markers (e.g. PSA in Prostate Cancer) correlate well with the presence or absence of the disease. In some cases, these can be used to identify disease subtypes that are more amenable to one therapeutic intervention than another—or can be used to enrich trials for those most likely to respond.

• Predictive markers (e.g. HER2 over-expression in breast cancer) correlate with the activity of drugs: They help match the drugs with appropriate patient populations.

Source: Biomarkers Definition Working Group and Office of Biotechnology Activities, National Institutes of Health.

be the aim, where potential responders can be determined through the detection and quantification of “response” markers. However, the rapidly growing understanding of the molecular basis of disease pathology, aided by progress in genomics, genetics and basic cell biology provides us with new insights into inherited differences among patients and disease states. This understanding enables the development of new diagnostics and more targeted medicines that are more effective and safer to be developed—the ultimate goal of “personalised healthcare”.

Diagnostics plays a decisive role in personalised healthcare. Research-use assays are able to quantify biomarkers to support decision making during drug development and to better understand disease pathways and mechanisms.

Further, diagnostic tests would allow identification of patients who are most likely to respond to a specific treatment, helping physicians better diagnose and manage diseases at a patient level.

The development of any diagnostic technology involves challenges like identifying the right biomarker early enough, developing pharmacodiagnostics within

drug timelines and ensuring sufficient collection of the right samples types, which bring into play countless regulatory and operational issues that can not be simply overcome when working across the globe. But, as Albert Einstein once said, “In the middle of difficulty lies great opportunity.”

The cost advantage of biomarkers in routine practice

The value of biomarkers is rarely in question, for example when one looks at the efficacy of widely used drugs of selected classes: ACE inhibitors (1030%), beta blockers (15-35%), SSRIs (10-25%), TCA (20-50%) and statins (10-60%), a personalised concept is warranted. The value and cost of treatment is put into context when you consider if 65 previously well middleaged men with high LDL, will take over 200,000 prescribed statin pills over the course of five years, when the likelihood that only one of those men would develop a stroke or transient ischemic attack without treatment. It’s probable that a biomarker measure could address the question of whether or not every patient should take a statin for high

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LDL (Low-density lipoprotein) levels.

However, when the benefit risk ratio is evaluated for such an indication it may no longer warrant such a concentrated effort when the incidence of cardiovascular disease has dropped considerably in the last decades. There is also value with regards to costs and patient safety, with a recent meta-analysis of the incidence of serious (6.7%) and fatal (0.3%) ADRs in hospitalised patients claiming that 100,000 Americans die each year from drugs and 2.2 million Americans experience serious ADRs that act as an economic burden to the healthcare system.

There are obvious financial benefits of Personalised Medicines from the point of view of ever soaring healthcare costs, as the non-responders or poor responders are removed from the pool of users, the costs (both monetary and negative utility) for adverse events are avoided.

Moreover, more precise targeting can lead to a greater volume of adoption by good responders who tend to have improved compliance and therefore additional net benefits, especially for long-term chronic therapies. Importantly, the ability to predict improvements or outcomes creates additional value for patients as they face less uncertainty when confronted with their disease prognosis.

Realising the true value

Biomarker discovery and validation is essentially the driver for many PHC treatments, however the return on investment when there is no guarantee of success, puts into question the â&#x20AC;&#x153;economic valueâ&#x20AC;? of such an approach. There is no real measure of the value of a new diagnostic test or targeted therapy but could be based on factors such as cost savings for both governments and patients, years

of life gained, improvements in quality of life or morbidity and the decreased doubt on the potential outcome. There remains a fundamental question on how fast the progress of the science behind biomarkers can be translated into useful applications in drug development and clinical use. To help answer the scientific question of biomarkers, it is important for regulatory systems to be able to adopt a flexible approach and see the long-term benefits of patient related goals as well as cost savings. There is a need to encourage the basic science and information sharing for hypothesis generation in the clinical trial setting, to enable the personalised approach when assessing the overarching value of new treatments taking into account the balance of the appropriate patient safety considerations.

Full references are available at www.pharmafocusasia.com/magazine/

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C linical trials

Proteomic Biomarkers Transforming drug development

The success of many investigational drugs is dependent on matching treatments with the appropriate target populations. Such “personalised medicine” is now possible with recent advances in proteomics for the discovery and validation of biomarkers of disease and drug efficacy.

Daniel Chelsky, Chief Scientific Officer, Caprion Proteomics, Inc., Canada

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he success of many investigational drugs is dependent on matching treatments with the appropriate target populations.

Variability in response to therapy, both with regards to efficacy and to adverse events, is leading the pharmaceutical industry down the path of personalised medicine. Further pushing the process along are government and private insurance payors who are faced with very expensive treatments that can help some but provide little benefit and possible harm to others.

One promising solution to the problem is to identify predictive biomarkers of drug efficacy; circulating proteins that stratify patients into populations of likely responders and non-responders to a proposed therapy. Finding such biomarkers has been challenging due to the complexity of human plasma, the sample of choice, and the availability of technologies for detection and quantification of thousands of proteins. Based on the experience of over 30 pre-clinical and clinical proteomic studies with pharmaceutical partners, an “industrialised” and very productive approach to biomarker discovery and validation has been developed. Results from multiple studies help make the case for accelerating the move to personalised medicine.

Identification of proteins that predict drug efficacy or that stratify patients by stage and severity of disease can be accomplished through a well-controlled and “industrialised” mass spectrometry analysis of plasma samples. The process begins with uniform blood sample collection into tubes containing protease inhibitors along with EDTA. Plasma is prepared according to a standard operating procedure and depleted by antibody affinity of the high and medium abundance proteins that typically obscure

biomarkers of interest. The higher abundance proteins that are removed also show reproducible differential expression in many comparisons, but tend to be related to inflammation and other non-specific effects of disease.

Focussing on the fraction of low abundance proteins also makes it possible to be more comprehensive in terms of protein coverage. Isolated proteins from each sample are digested to peptides which are more accurately identified and quantified by a Quadrupole Time of Flight (QTOF) mass spectrometer. Peptides are matched across all samples and compared for peak intensity in each cohort of patients.

Those peptides which are differentially

Clustering of three cohorts by plasma proteomics analysis

MultiDimensional Scaling(Log Transform OFF)

Ovarian Cancer

MDS 1

MDS 3 Breast Cancer

MDS 2 Ovarian Normal

Breast

Normal Figure 1

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expressed are targeted for fragmentation to generate the amino acid sequence which is matched to the parent protein.

Peptides identifying the same protein are clustered and subjected to a consistency filter that requires all peptides from the same protein to show very similar behaviour in each patient.

Application of this process to discriminate related diseases can be very informative. In a study performed for a pharmaceutical company, plasma samples were compared between patients with ovarian cancer and breast cancer, as well as with healthy control subjects.

Of approximately 50,000 peptide ions tracked across the samples, 4,000 were found to be differentially expressed.

These peptides were used to determine the proteomic relationship between the patients by Multidimensional Scaling (MDS), as shown in Figure 1. Each cohort is found to be distinct from the perspective of plasma protein profiles.

Thus, not only can patients with disease be distinguished but those with two related diseases can be separated as well. Underlying this clustering at the patient level are specific peptides that were sequenced to identify 181 nonredundant proteins that separated the three groups on a pair-wise basis. These proteins include those involved in acute phase response, tissue damage, as well as cancer.

Ovarian and breast cancer patients were compared to healthy controls (n=8) by Liquid Chromatography-Mass Spectrometry (LC-MS). Approximately 50,000 peptide ions were tracked and compared across all samples to find 4,000 that were differentially expressed. These peptides were analysed Objective

Identify Prostate-Specific Biomarkers

Prostate: Indivumed (12) Prostate: Caprion (12) Normal(12) Figure 2

Figure 3

by Multidimensional Scaling software to show that each group was distinct from the others (each sphere represents a patient). 181 non-redundant differentially expressed proteins that separate the groups were identified by sequencing the same peptide ions by LC-MS/MS. A similar study involved the identification of circulating prostate cancer biomarkers. To determine whether markers could be found in spite of significant differences in sample acquisition, three groups of samples were compared. Healthy control samples came from a commercial supplier.

The other two sample sets came from patients with prostate cancer, but from two different suppliers. One supplier was a commercial source. The other was from collaboration between Caprion and the University of Montreal.

The three groups were analysed and compared to find peptides that distinguished the two cancer groups from the healthy control. These peptides were used to compare the patients by MDS analysis as shown in Figure 2.

The two prostate cancer sample sets were found to completely overlap at the peptide level and the combined cancer group separated well from the healthy controls. Peptides that separated each cancer group from the controls were sequenced to identify approximately 200 proteins in each comparison (Table 1). The interesting finding is that 141 of the proteins in each group were shared, demonstrating that the impact of collecting samples from different sources was relatively minor compared with the effect of the disease on the plasma proteome.

Samples of plasma from patients with prostate cancer were obtained from Indivumed (gold), and from the University of Montreal (red), along with healthy controls from Biological Specialities (n=12). Approximately 43,000 peptide ions were tracked and compared across the samples and 3,569 were found to be differentially expressed. MDS analysis of the differentially expressed peptides reveals that the two sets of prostate cancer samples cluster together and are well separated from the healthy controls.

A total of 271 non-redundant proteins were identified after sequencing the differentially expressed peptides in the prostate cancer comparisons.

Similar numbers of proteins separated the Caprion and Indivumed samples from the healthy controls. 141 of these

Comparison

Number of Proteins

Indivumed & Caprion

Healthy

141

Caprion

Healthy

191

Indivumed

Healthy

221 Table 1

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proteins are shared between the two comparisons.

Each of the prostate cancer patient sample groups contained individuals with stage T2 (n=14) and stage T3 (n=10) prostate cancer. A bioinformatics software similar to MDS, was used to compare the patients. As shown in Figure 3, most patients at the two stages could be separated based on their plasma proteomic profiles. Thus, protein expression in plasma is not limited to distinguishing disease, but can be applied to measuring the stage or severity of the disease. The implications of this finding are important to diagnosis and treatment, as well as for monitoring response to therapy.

Proteomic analysis of plasma from prostate cancer patients can be used to distinguish stage of disease. Principal Component Analysis of differentially expressed peptides (courtesy of Centocor, Inc.) shows a good separation of stage T2 (red) from stage T3 (blue) patients.

In a third example, plasma was prepared from patients with Alzheimer’s disease as well as from age-matched controls. CNS diseases are thought to be particularly challenging for plasma profiling, since Cerebrospinal Fluid (CSF) is considered to be the fluid most likely to show differential protein expression due to the higher expected concentrations of CNS related proteins. For this comparison, patients were recruited who were naïve to therapy as well as those who had been treated with donepezil. Proteomic analysis identified peptides that were

Candidate biomarker panel

Alzheimer's Patients

Donepezil Treated Patients

Healthy Controls Figure 4

able to separate the untreated patients from the healthy controls (Figure 4). As seen in the previous examples, this is often the case, as patients with disease are quite distinct from those who are healthy. A further analysis was thus performed to determine whether a relationship could be found between distance from the healthy subjects, as seen in the MDS analysis, and a standard test, the MMSE (Mini-Mental State Exam). The correlation between the two measurements was found to be high, with a Pearson correlation score of 0.75, again suggesting that the severity of disease can be measured in a quantitative manner by proteomics. Further, patients treated with donepezil were found to be significantly more similar to the healthy controls than to the untreated Alzheimer’s cohort. This apparent pharmacodynamic effect of the drug may

Target peptides from each selected biomarker

be related to its effect on disease or to some other physiological impact on the plasma. Whatever the cause, the effect appeared to be consistent across the treated patient population. A total of 100 proteins were identified that were differentially expressed in one of the three groups (healthy, Alzheimer’s untreated, and Alzheimer’s treated). Half of these proteins had a neurological association and eight of them had a direct literature link to Alzheimer’s disease.

Alzheimer’s patients treated with the acetylcholinesterase inhibitor, donepezil, (purple) show more similarity to the healthy controls than the untreated Alzheimer’s patients. A “disease axis”, drawn through the centroids (yellow) of the healthy and diseased populations, can be used to quantify the severity of disease.

Multiplexed MRM assay for biomarker validation Figure 5

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to assemble than even a single EnzymeLinked ImmunoSorbent Assay (ELISA), but they are relatively inexpensive to run and are rapidly gaining in popularity.

MRM is on track to replace the ELISA for multivariate assays, particularly when time and cost are of importance.

The best candidate biomarkers are assembled and target peptides and transitions are selected from each to construct the MRM assay as shown in Figure 5. At least 50 protein markers can be combined into the same multiplexed quantitative analysis.

Impact on healthcare

The pharmaceutical industry, driven by the regulatory agencies as well as insurance and government payors, is moving towards personalised medicine.

Such an approach will require much better diagnostic markers of disease state as well as predictive markers of drug efficacy. The convergence of a need for better diagnostic and predictive markers and the availability of the tools to identify and implement them will result in major changes to the way we develop drugs in the next few years.

Daniel Chelsky is the Chief Scientific Officer at Caprion Proteomics, a company offering biomarker discovery and validation as well as other proteomics services since 2000.

A uthor

Once proteins are identified that distinguish disease state or effect of a drug, data mining is performed.

Differentially expressed proteins are examined for supporting evidence (AUC in a ROC plot, p-value, sequence coverage, biological relevance, and specificity to target or disease of interest) and the best candidates are assembled into a candidate biomarker panel for the creation at Caprion of a multiplexed Multiple Reaction Monitoring (MRM) assay (Figure 5). These assays, made possible by improvements in QTRAP mass spectrometer technology, allow for the quantitative monitoring of 50 or more proteins simultaneously in patient plasma samples. MRM assays are very similar in nature and reliability to standard pharmacokinetic assays for small molecules and can be applied to large numbers of patient samples in a short time frame.

Not only are MRM assays much faster

BOOK Shelf

Exploitation and Developing Countries: The Ethics of Clinical Research Description: When is clinical research in developing countries exploitation? Exploitation is a concept in ordinary moral thought that has not often been analysed outside the Marxist tradition. Yet it is commonly used to describe interactions that seem morally suspect in some way. But does this, by itself, make such research exploitative?

Editor: Jennifer S Hawkins,

Ezekiel J Emanuel Year of Publication: 2008 Pages: 336 Published by: Princeton University Press ISBN-10: 0691126763 ISBN-13: 978-0691126760

Exploitation and Developing Countries is an attempt by philosophers and bioethicists to reflect on the meaning of exploitation, to ask whether and when clinical research in developing countries counts as exploitative, and to consider what can be done to minimise the possibility of exploitation in such circumstances.

Reflection on this rich and important moral concept should also interest normative moral philosophers of a non-Marxist bent.

For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Global Clinical Development Reducing Japan’s drug lag

China Korea Japan Joint Project on Ethnic Factors

Japan’s Ministry of Health, Labour and Welfare is adjusting its policies to accommodate the current trend of global clinical development to promote public health of the Japanese, especially in terms of quicker delivery of new drugs to patients.

Toshiyoshi Tominaga, Director, International Planning, Minister’s Secretariat, Ministry of Health, Labour and Welfare, Japan

T

he venues of clinical development are increasingly moving from USA and Europe to Asia Pacific, where the increase in simultaneous multinational trials has been very conspicuous. In Korea, for example, the number of such trials has more than doubled between 2004 and 2007 (67 to 147). In such trials, participating sites compete with each other in terms of their speed to recruit subjects, the quality of the data provided, the overall cost, etc. to afford an efficient development.

Japan’s drug lag

Japan accounts for about 10 per cent of the world’s pharmaceutical market, the second biggest national drug market next to USA. The Japanese public, however, lags behind in terms of access to the world’s newest drugs. According to one calculation, as of 2004, Japan’s approvals of the world’s top selling 100 drugs were, on an average, about 1,400 days after they were approved somewhere else in the world. USA’s figure by the same calculation is about 500 days, the smallest in the world. It is obvious that Japanese

Sharing Clinical Data among three countries

patients have to wait nearly 1,000 days longer than their US counterparts for using new drugs.

Since the drugs selected for the calculation were not the first-line drugs in standard therapies, but those with large sales, the significance of this figure from a public health viewpoint is not very clear.

But the situation is apparently unsavoury and Japan’s Ministry of Health, Labour, and Welfare (MHLW) has been receiving requests from doctors and patient groups that certain standard drugs unapproved in Japan but approved elsewhere should be made available for use. MHLW, with advice from its Committee on Use of Unapproved Drugs, is facilitating the delivery of such drugs to the patients by encouraging their clinical trials in Japan.

Two phases account for the drug lag.

The first phase is concerned with development; the drug development process is slower in Japan compared to other countries. The second phase is related to application review; on average New Drug application (NDA) review by

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Pharmaceuticals and Medical Device Agencies (PMDA) takes longer than its American and European counterparts.

MHLW’s countermeasures against drug lag will cover both the phases.

PMDA is MHLW’s sister agency with a status of independent administrative agency. PMDA is conducting actual reviewing of market approval applications regarding drugs and medical devices, post-marketing safety operations and relief services for Adverse Drug Reactions (ADR) sufferers for MHLW. Ethnic factors in clinical data

The variations in the drug response have been observed in patients from different ethnic backgrounds. About one-third of the drugs marketed in Japan, USA and EU have different approved doses, the Japanese doses being usually smaller.

To name a few examples, Capecitabine (anti-cancer drug) dose in Japan is 1,657 as opposed to 2,500 mg/m2/day in EU / USA, those of Telithromycin (antibiotics) is 600 mg/day in Japan and 800 mg/day in EU / USA. Ethnic factors are also found to be responsible for Adverse Drug Reactions (ADR) occurrences. Some drugs show higher incidences of ADRs in Japan than in EU / USA. Examples of such drugs and ADRs include Leflunomide (antirheumatic) for interstitial pneumonia and Irinotecan (anticancer) for diarrhoea.

The advanced research tools such as pharmacogenomics may some day enable us to predict drug actions at individual patient level, beyond ethnic groups. But currently such ethnic differences are unforeseeable without clinical trials. MHLW / PMDA therefore requires clinical data obtained in the Japanese population in application dossiers, unless there is ground for exemption. MHLW perceives, however, a room for refinement in this policy, especially in the treatment of clinical data obtained in other Asian populations. (see Section 5.

China-Korea-Japan Cooperation)

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Global Clinical Development – Reducing Japan’s drug lag

Given that global clinical development has already become the world’s norm, it is obvious that Japan’s participation in the development programmes will help it quickly address the issue of drug lag in Japan. Performing a bridging study after the drug’s development is completed elsewhere in the world is indeed another way to introduce the drugs in Japan, but the mode of development does not eliminate drug lags but preserves them.

The argument thus comes as to how Japan can improve its environment for clinical trials to attract simultaneously-run global trials. Unfortunately, the Japanese clinical trials are said to be slow in patient recruitment, high in cost, and quality (they were said to be “of low quality” in the past, but recently, probably as a reaction to the criticism, they are allegedly being performed too meticulously with excessive monitoring and auditing without any regard to cost).

Strengthening PMDA

PMDA has been in the process of increasing its reviewers from about 200 (as of 2007) to more than 440 in 2010. They not only review NDAs, but also give consultation to trial sponsors to help the clinical development. Most multinational pharmaceutical companies seem to be uncertain about how they can include Japan in their design of multinational trials and how the data will be later assessed by PMDA. With clarification and assurance from the PMDA reviewers, more global trials are expected to take place in Japan.

The measures being taken to improve PMDA’s Clinical Trial Consultation (“Chiken-Sodan”) include: a. placing consultations on global trials on the fast track with a shorter waiting period; b. increasing the total number of PMDA consultations from 300 (2006) to 1,200 (by 2007); and, c. shortening the maximum waiting period to two months (by 2009).

Moreover, MHLW published a guideline named “Basic Principles on Global Clinical Trials” in September 2007 to facilitate the understanding of its position.

5-Year plan for clinical trials activation (2007-2011)

MHLW’s 5-Year Activation Plan emphasises networking of core hospitals capable of conducting advanced global trials. Ten national centres and 30 hub hospitals have been designated and are strengthened to possess better environment for trials in terms of doctors’ incentives, infrastructure and IT systems. At such hospitals, the subjects will be given ample information on the trials and incentives including the prospect of advanced therapies.

For the new infrastructure of the hospitals, increased staffing, training thereof, betterment in patients relations, and so on, MHLW is defraying 1.75 billion yen, approximately US$ 17 million every year.

Amendments to Japan’s good clinical practice

Needless to say, Japan’s Good Clinical Practice (GCP) is based on International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). But a number of its small details were claimed to be hindering clinical trials, though they are not contrary to the ICH guidelines. Taking such claims into consideration, MHLW revised its ordinances on GCP in February 2008 to further facilitate Japanese clinical trials. The changes include: a. Relaxation of the rules on Institutional Review Board (IRB) to allow a central IRB with certain assurance of transparency (effective April 2009); b. Introduction of Periodical Safety Report (effective in one year); c. Reduction in the documents to be archived (already effective through revision of the related guidelines since 2007); and, d. Relaxation of other rules including those on trial substances (effective April 2009).

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Days

Drug lags 1,417 = about 4 years

Ca 2.5yrs

915 757 620

Japan

France

Denmark

Germany

583

Sweden

538

512

505

Switzerland

UK

USA

Period b/w approval by each country and first-approving country.

Average of the world's 100 best selling drugs.

Q&A No.11 attached to the ICH E5 Guideline “Ethnic Factors in the Acceptability of Foreign Clinical Data” states, “In general, a multi-regional study should be designed with sufficient number of subjects so that there is adequate power to have a reasonable likelihood of showing an effect in each region of interest.” Sharing of clinical data among ethnically similar populations to afford a combined sample size with sufficient power facilitates the global development and quicker delivery of drugs to the patients in the regions. There are other benefits including saving of resources and possible regional development of drugs tailored for specific regional needs.

On April 8, 2007, the Health Ministers of China, Korea and Japan met in Seoul to make a joint statement confirming the three countries’ cooperation in dealing with pandemic flu and some other issues, including clinical research. The statement indicates that the tripartite cooperation in clinical researches focusses on clarifying the role of ethnic factors.

Genetically the Chinese, the Koreans and the Japanese are close to one another.

Although extrinsic factors should be taken into consideration, the ethnic difference is expected to be small among the three populations. But there have been few studies dealing with the ethnic factors

observed in actual PK/PD, optimal doses and ADR of drugs among the three races, leading to a lack of sound scientific basis to formulate rational policies on ethnic factors in the region. The agreement above indicates the three authorities’ decision to jointly clarify the factors.

On 14 April 2008, MHLW organised the First Director-Generals’ Meeting in Tokyo. The high-ranked officials in charge of pharmaceutical affairs from China’s State Food and Drug Administration (SFDA) and Korean Food and Drug Administration (KFDA) participated in the meeting. The three Director-Generals confirmed their decision to continue the joint research project on ethnic factors as well as to enhance general information exchange among the three.

As a part of the joint research project, MHLW organised a study group already in August 2007 at its research institute, National Institute of Health Sciences.

The study group headed by a NIHS researcher includes members from the related industry associations, PMDA, and the academia. With strengthened cooperation from the study groups’ counterparts

A uthor

China-Korea-Japan cooperation

(JPMA 2006)

in Beijing and Seoul, MHLW expects tangible results from the project, which will be reported and discussed in the tripartite Working Group Meeting to be held in Tokyo in November 2008, and the Second Director-Generals’ Meeting to be held in Beijing in spring 2009.

Hopeful signs

Accordingly, MHLW’s measures have already shown results. The statistics of the last three years (2004 to 2007) show consistent increase in the number of total clinical trials and the number of products tried in Japan. This period corresponds to MHLW’s 3-Year Clinical Trial Activation Plan, the predecessor of the above-mentioned 5-Year Plan. Global trials taking place in Japan have also been increasing. Also, in a number of specific multinational trials involving Japan, the country’s sites competed favourably with those in other countries in terms of case enrollment, speed, etc.

Going ahead

MHLW has been taking strong measures to keep Japan ahead of others in simultaneous global clinical development. Japan has been already showing positive signs, indicating its increasing importance as a venue for global clinical development.

MHLW is also strengthening cooperative relationship with its Chinese and Korean counterparts for the purpose of eventually sharing clinical data among the three countries. With the measures showing positive results, MHLW expects increased availability of the world’s newest drugs in Japan and improvement in its public health.

Full references are available at www.pharmafocusasia.com/magazine/

Toshiyoshi Tominaga is a Planning Director to the Minister’s Secretariat at the Ministry of Health and Welfare, Japan since 2006. He is currently involved in MHLW’s drug-related international issues including ICH, with his experience in new drug evaluation and GCP inspection. He received his PhD degree in 1987 from the University of Tokyo and also has a MSc degree from the Harvard School of Public Health.

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Human Antibody Discovery VelocImmune - A novel platform

The direct replacement of the unrearranged genomic DNA encoding in the variable regions of the mouse heavy and kappa light chain with the equivalent human genomic sequences creates a more efficient platform for the discovery of antibody therapeutics.

Sean Stevens, Associate Director, Inflammation and Immune Diseases, Regeneron Pharmaceuticals Inc., USA

A

ntibody therapeutics are one of the fastest-growing drug classes and take advantage of the endogenous immune system for the creation of novel therapeutics. Antibodies are superior drug candidates because they are a natural constituent of the human immune response, and possess many important favourable pharmacologic qualities, such as half-life, tolerability, safety, specificity and versatility. The development of hybridoma technology

by Kohler and Milstein opened the door to the use of antibodies in the prevention and treatment of human disease.

However, the use of mouse monoclonal antibodies as drugs is limited by the immunogenicity of mouse proteins in humans, essentially allowing for only acute, single-use applications.

Immunogenicity concerns

The issue of immunogenicity spurred further improvements in antibody technologies. Initial attempts to reduce immunogenicity were accomplished by grafting murine variable regions onto human constant regions creating “chimeric” antibodies. Studies of variable region structure and function helped in further refining efforts to reduce immunogenicity by identifying those elements critical for antigen recognition and binding, termed “Complementarity Determining Regions” or “CDRs”. By transferring only the CDR residues (or even just key sub-residues within the CDR) of the mouse variable regions critical for antigen binding to similar positions with a highly-related human variable sequence, a novel antibody is

VelocImmune Technology VelocImmune technology is a major step forward in the discovery and development of fully-human antibody therapeutics. Unlike other antibody platforms, VelocImmune mice allow the efficient generation of high affinity antibodies using the normal mouse humoral response, without the need for additional engineering in vitro for optimisation of affinity or other characteristics. In contrast to other platforms for the production of fully-human antibodies in mice, VelocImmune mice have a completely normal immune system and are indistinguishable from wild-type mice in response to antigens.

Regeneron Pharmaceuticals is using VelocImmune technology to produce its next generation of drug candidates.

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created with minimal amounts of mouse sequence. These types of engineering efforts greatly reduced, but did not necessarily eliminate, the immunogenicity of antibodies and allowed their effective use as drugs. Nevertheless, ongoing concerns about immunogenicity and the expertise and resources required to engineer novel antibody molecules encouraged the further exploration of technologies for the production of fullyhuman antibodies.

Display technologies

Phage display was developed to utilise genuine human variable libraries to quickly identify fully-human antibodies for use as drugs in vitro. Ease and speed of use made display technologies attractive for drug discovery. By using fully-human sequences to generate libraries from which to identify desirable therapeutics, it would appear that many of the issues of immunogenicity are addressed. However, display technologies typically require in vitro affinity maturation, which creates the risk of introducing immunogenic sequences.

Furthermore, proteins identified in a prokaryotic system are not necessarily optimal for manufacturing and purification as full antibodies in mammalian cell lines. Issues with protein expression, aggregation, and degradation have all been noted.

Although effective fully-human antibodies have been cloned from humans, this approach requires prior exposure

CaseStudy

Generation of therapeutic antibodies in mice Mouse mAb

Chimeric

Humanised

Human mAb

human mouse

• mouse variable + constant • high immunogenicity • no repeated dosing

• all/part mouse variable-human constant • intermediate immunogenicity

(chimeric > CDR grafted) • can be time-consuming to create

• human variable + constant • low immunogenicity • repeated dosing possible • impaired generation in mice (?)

Figure 1

of the patient to the antigen of interest. Attempts to develop fully-human antibodies from mice engrafted with human hematopoietic cells, or in vitro with antigen-primer human cells, have not yielded reliable results.

Producing human antibodies in mice

Ideally, production of antibodies in response to exogenously provided antigen in a normal humoral system in vivo would have the greatest potential to generate antibodies with low immunogenicity in humans. Towards this end, several groups such as Medarex, Abgenix and Kirin, had engineered mice to produce fully-human antibodies in vivo. This was accomplished by disrupting the endogenous mouse immunoglobulin (Ig) genes and introducing either Yeast Artificial Chromosomes (YACs) bearing a portion of the unrearranged human Ig heavy and kappa light chain loci (Medarex and Abgenix), or chromosomal fragments bearing the intact human Ig loci (Kirin).

Therefore, immunisation of these mice would yield fully-human antibodies for therapeutic use.

Use of mice to generate fullyhuman antibodies addresses many of the concerns about immunogenicity and

affinity maturation. However, published data regarding the function of ‘HuMab’ mice shows that still there are issues that need to be addressed. For example, Bcell development and peripheral B-cell populations are substantially reduced in HuMab mice which exhibit reduced levels of serum Ig. Furthermore, aberrant Ig bearing murine constant regions are observed, suggesting transchromosomal rearrangements or splicing events.

Therefore, the humoral responses in HuMab mice may be less efficient than normal mice. While effective antibody therapeutics have been generated using HuMab mice, there is still room for improvement.

VelociGene technology

Regeneron has created a more efficient platform for the discovery of antibody therapeutics through the use of VelociGene technology, a proprietary, high-throughput process using automated systems to make virtually any genetic modification in mouse Embryonic Stem (ES) cells. The speed and precision of VelociGene technology permits the direct exchange of large (100-200 kilobase) genomic DNA sequences in situ, allowing the manipulation of complex genomic loci in murine ES cells.

Scientists at Regeneron recognised that antibodies are an active participant in the humoral response, which require efficient signalling through the B-cell receptor, accurate regulation by positive and negative coreceptors, and, perhaps most importantly, productive interactions with Fc receptors and similar constant region recognition elements. Therefore, use of human constant regions, as in the HuMab approaches, may yield less efficient humoral responses to some antigens.

Furthermore, the use of YAC or human chromosomal fragments in murine cells may have the added risk of inaccurate gene regulation through human enhancers or locus control regions and instability in transmission.

The Regeneron solution to these issues was the direct and precise replacement of the unrearranged genomic DNA encoding in the variable regions of the mouse heavy and kappa light chain loci with the equivalent human genomic sequences. Therefore, the resulting Ig loci encode antibodies possessing fullyhuman variable regions linked to murine constant regions utilising the genuine murine expression control mechanisms.

This approach overcomes the issues presented by HuMab mouse platforms while taking advantage of the superiority

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CaseStudy

A novel platform for production of human antibodies in mice human heavy chain Vs

human kappa chain Vs

Ds Js

Js

mouse constants and control regions

mouse constant and control regions

Introduction of human variable segments in place of mouse at Ig loci creates antibodies have human variables and mouse constants

Cloned human variables are joined to any human constant desired and produced in CHO

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Essentially the entire human Ig heavy and kappa light chain variable repertoire has been integrated into ES cells. The resulting genomic loci are stable throughout multiple generations of VelocImmune mice and have been shown to be used productively, generating antibodies of diverse fully-human variable sequences. Direct comparisons between VelocImmune mice and wildtype littermates demonstrate nearly identical responses to immunisation, regardless of the number of human variable segments the VelocImmune mice possess.

High affinity therapeutic antibodies have been generated to many different antigens utilising standard hybridoma and cloning techniques, further highlighting the speed and efficiency of VelocImmune technology.

Despite the fact that the antibodies produced by VelocImmune mice possess mouse constant regions, Regeneron scientists have developed high-throughput methods for the joining of desired

A uthor

of a natural humoral response for the production of antibody therapeutics.

VelociGene technology was employed to remove the ~3 megabase murine variable genomic sequences at the heavy and kappa light chain Ig loci in mouse ES cells, followed by the stepwise insertion of the unrearranged human heavy and kappa light chain variable genomic loci, or ~1 megabase of genomic DNA of the human heavy chain locus and 0.5 megabase of the human kappa light chain locus. This represents the largest genomic replacement ever accomplished in mouse ES cells.

At various steps in the creation of the humanised Ig loci, ES cells were microinjected and tested for their ability to generate mice and the function of the engineered Ig loci. Mice homozygous for humanised Ig heavy chain loci possessing just three variable segments (and all DH and JH segments) were observed to have completely normal immune systems, with normal B-cell populations, serum Ig, and, most importantly, normal antigenic responses. These results indicate that replacement of only the Ig variable loci in situ, while maintaining all the mouse constant regions and expression control regions (known or unknown), does indeed recreate a normal humoral response in mice.

Figure 2

variable regions to human constant regions of any type, and the subsequent insertion into mammalian production lines to create fully-human antibodies. Because of the modular nature of antibody variable domains, specificity and affinity are maintained whether on mouse or human constant regions.

Thus, the advantage of producing antibodies in vivo possessing human variable regions joined to mouse constant regions does not create any problem for the creation of fully-human antibody therapeutics.

Regeneron has used VelocImmune technology to create a broad pipeline of antibody therapeutics to a variety of targets. REGN88, directed against human interleukin 6 (IL6) receptor, is Regeneronâ&#x20AC;&#x2122;s first fully-human antibody in clinical trials for the treatment of rheumatoid arthritis.

A novel platform

VelocImmune is a novel platform for the production of fully-human therapeutic antibodies in vivo. Unlike other technological platforms, VelocImmune mice take advantage of the normal murine humoral response to create high affinity therapeutic antibodies that do not require additional engineering to drug characteristics. In contrast to HuMab mouse technologies, VelocImmune mice utilise the authentic murine loci and expression control regions for accurate regulation and antibody production, and through the use of genuine murine constant regions, reproduce a humoral immune system indistinguishable from wild-type mice. Therefore, VelocImmune mice represent a major step forward in the production of fully-human antibody therapeutics in vivo.

Sean Stevens is Associate Director of Technology Assessment at Regeneron Pharmaceuticals, where he was co-creator of the VelocImmune mouse and helped develop multiple antibody programs.

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Outsourcing CRO Services to China The staffing challenge

The ability to utilise Asia-based CRO capabilities can make it easier and more cost-effective for pharmaceutical and biotech companies to develop and market new products for the burgeoning pharmaceutical market in Asia.

D Thomas Oakley, President and CEO, Bridge Laboratories, USA

T

he business benefits of outsourcing Contract Research Organisation (CRO) services to China are compelling in todayâ&#x20AC;&#x2122;s pharmaceutical marketplace and global economy. Labour rates in China are much lower than in the West, and additionally, China offers a large pool of highly educated research talent that can be readily tapped to staff projects

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carried out in China. Also, the ability to utilise Asia-based CRO capabilities can make it easier and more cost-effective for pharmaceutical and biotech companies to develop and market new products for the burgeoning pharmaceutical market in Asia.

Experience has shown, however, that a number of staffing challenges must first be overcome in order to cost-effectively deliver Asia-based toxicology studies that meet Western standards. These challenges can be grouped into five areas: recruiting, education and experience, language and culture, training, and retention. An overview and examination of each of these challenges is discussed here.

The business benefits of outsourcing Contract Research Organisation (CRO) services to China are compelling in today’s pharmaceutical marketplace and global economy. Labour rates in China are much lower than in the West, a major incentive to outsourcing. Organisations whose research projects rely on non-human primates can procure the animals more economically in China, and because of the ready access to the animals, studies can be initiated in a timely manner. China offers a huge pool of highly educated research talent that can be readily tapped to staff projects carried out in China. In addition, the ability to utilise Asia-based CRO capabilities can make it easier and more cost-effective for pharmaceutical and biotech companies to develop and market new products for the burgeoning pharmaceutical market in Asia.

There is a great pharmaceutical research opportunity in Asia. Experience has shown, however, that a number of staffing challenges must first be overcome in order to cost-effectively deliver Asia-based toxicology studies that meet Western standards. These challenges can be grouped into five areas: recruiting, education and experience, language and culture, training, and retention.

States or anywhere else—is to know where to look, whom to talk to, and how to make the right compromises.

Specific disciplines also pose recruiting challenges of their own. For example, there is no board certification of Veterinary Pathologists in China at present, and board-certified pathologists continue to be in short supply in the West. Study Directors and experienced scientists with the required skills and desire to manage are tough to find anywhere and more so in China.

The best option would be to identify Chinese scientists with Western work experience who wish to return to China.

Alternatively, expatriates can be recruited, but that could prove to be a major cost factor. In either case, these new employees often lack specific knowledge of the local resources that they must utilise to be effective on the job, thereby requiring more time to become acclimatised to the new environment.

It is essential to strike the most costeffective and productive balance possible between expatriates and employees recruited from the local job market. Even though there is no shortage of highlytrained scientists in China, the lack of hands-on drug development experience drives a requirement to have excellent on-the-job training. A key responsibility of the expatriates and / or returnees is to mentor these scientists to build their expertise in study direction and customer interaction. Care must be taken in recruiting expatriates to achieve the greatest cost and quality benefits. In addition, every effort must be made to create healthy relationships and handle rivalries between expatriate and local employees; the pay and responsibility differentials can become problematic if not managed effectively.

With appropriate management, however, the mix of expatriates and local employees can be optimised to effectively meet the needs of the organisation.

Recruiting

Education and experience

The key to find and recruit the right talent in China—as is the case in the United

China produces 3.5 million college graduates and 32,000 doctoral gradu-

ates in science and engineering each year, with the total number of science and engineering doctorates in China expected to rise to 1 million by 2015 (versus a total of 600,000 in the US).

The availability of such large numbers of highly-educated talent in China is a major advantage for CRO vendors and clients looking to outsource their studies to China. However, this workforce is largely inexperienced, leaving most organisations no choice but to “grow their own” by making significant investments in training.

It is important to note that training investments in the Chinese workforce are well advised and can reap major benefits. This labour pool has proven to be highly trainable—bright, motivated, willing to learn, quick to understand and perform, and always ready to give their best effort.

In addition to training recruits from the local workforce, there is also an abundant supply of foreign-trained ethnic Chinese professionals motivated to “come home”, that can be tapped to meet specific staffing requirements.

Language and culture

The pool of English-proficient Chinese scientists and technicians is not large, and the shortage is likely to continue for the foreseeable future. This is a challenge that must be overcome, since excellent command of English is required for global submissions.

In the meantime, the language gap can be bridged by minimising the amount of information lost in translation. Direct instructions work best, and the use of indefinite statements (e.g. may, should, could) and Western slang should be avoided. In other words, English-speaking employees should explain clearly and not leave a lot of room for interpretation. Western managers who like to use Western slang are often met with blank stares at all-hands meetings—minimising the impact of the concepts they were so eloquently trying to explain! It’s equally important

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in all respects and should receive regular training on them.

Training

The need for a significant investment in training Chinese employees has already been mentioned. But in many ways the list of training requirements is the same as that for any GLP toxicology business anywhere in the world. It includes training in the following areas: • English conversation and writing • GLP regulations and procedures • SOPs • Technical operations • Certified animal treatment by local government • Validation policies and procedures • Equipment operation and maintenance • Safety – biosafety, radiation, chemical, non-human primate (NHP) behaviour and work safety • Study Director practices and procedures • Continuing education programmes • Finance and legal issues • Business policies and practices In the case of Chinese employees, however, English language training programmes should receive the highest priority and be conducted on an ongoing basis.

Retention

Once employees have been thoroughly trained, they become a valuable and much sought-after resource both inside and outside the organisation. The competition for good employees is significant and growing, with both clients and competitors increasingly recruiting from within the organisation’s ranks to meet their own staffing demands.

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to minimise the need for translators in meetings, so the staff does not develop a dependency.

Cultural differences are much more pervasive. It has been observed that Chinese employees generally are more hesitant to challenge authority, show a lack of knowledge, ask questions or admit errors than their Western counterparts. They also demonstrate a preference for acting based on consensus, rather than on individual initiative, and they generally eschew direct confrontation. There are exceptions, of course, but these behavioural patterns have been well documented.

Western business expectations are also very different from those encountered in China. Western management is based on meritocracy, not autocracy or democracy.

They value individual performance over that of the group, and reward performance with differential pay that inevitably raises fairness issues (equitable vs. equal compensation) in the minds of Chinese employees.

All of these differences in language and culture can directly impact the quality of CRO services delivered in China.

In the Good Laboratory Practice (GLP) world, little things do matter a lot. Plus, GLP are concepts and principles, not just written regulations. Management must, therefore, be on constant watch for subtle differences in interpretation that may arise due to language considerations.

It must also work hard to ensure that all errors are recorded by every employee— fostering the corporate philosophy that mistakes are natural and there is nothing to hide (obviously, while endeavouring to keep errors to a minimum), and pursuing a policy of correction and prevention (vs. punishment).

The best defense against the effects of these language and cultural differences is Standard Operating Procedures (SOPs) of the highest possible quality.

SOPs must be written in a way that is absolutely clear and unambiguous.

What’s more, all employees must be told to strictly adhere to the company’s SOPs

In this competitive environment, managing the employee’s expectations is a key to retention. Management must paint a clear picture of duties and expectations at hiring, emphasise the importance of career over job, and be careful to create realistic career expectations for each employee. Compensation is important, but recognition is the key to career growth and employee satisfaction.

Management should resist the tendency to hire overqualified people; advanced degrees are probably not required for some jobs. At the same time, companies should also avoid over-reliance on a few key people, as job burnout is real and always presents danger.

Key to success

Workers in China have a strong work ethic and are eager to learn. The potential is great—especially when training programmes in key areas like English language, GLP and animal care are conducted continuously throughout the organisation. Business success is dependent upon mutual appreciation of cultural differences and patience, on the part of both western managers and local employees, in negotiating those differences.

Finally, CRO management must monitor all aspects of compliance closely on a day-to-day basis. It should hire appropriately and work hard to manage employee expectations. And above all, it must make constant and consistent communication with employees its top priority. By focussing on clear, open and honest communication, management can greatly enhance the chances of business success and build great relationships with their employees.

Thomas Oakley is President and CEO of Bridge Laboratories and has over 25 years of leadership experience in major contract research organisations, industrial products and consumer products businesses. Oakley received his MBA from the J L Kellogg Graduate School of Management, Northwestern University.

M anu f acturing

Moving from R&D to Manufacturing Excellence Relative separation of manufacturing and R&D (siloed thinking) continues to characterise the pharmaceutical industry. Managing operations in a holistic manner by investing on a common platform that meets the existing standards and integrates innovative technologies across plants and different functional departments can help the pharma industry keep ahead of future trends.

Bart Moors, Business Consultant, Pharmaceutical Industry SEA, Siemens AG, Belgium

D

espite the innovations and advances in science, the pharmaceutical industry has been more used to incremental change in manufacturing than quantum leaps that anticipate the future. Initiatives like Lean manufacturing, Six Sigma and other operational excellence programmes attracted the attention of the pharmaceutical industry a few decades later than in other industries.

The pharmaceutical industry is facing many challenges in order to compete in the market and to remain profitable in a sustainable manner. However, a wide range of commercial, regulatory and competitive pressures are accelerating the changes. For this reason, the drug industry has to embrace the principles of the Toyota Management System.

Sigma Pharma

Semicon

More pharma companies are slow in implementing a systematic approach to improve there processes for research and development, manufacturing and the supply chain of a drug. Still many companies remain wary of the drastic changes, especially when it comes to introducing new technologies or changing processes.

Pharmaceutical industry – Current status

At present, the pharmaceutical industry is characterised by a fragmented and siloed organisations. R&D, manufacturing, sales & marketing and other support functions are considered as independent activities, which miss a collaborative and synchronised approach. Barriers between these activities are high and it

Ppm defects

Yield

Cost of quality

2σ

308,537.0

69.20%

25-35%

3σ

66,807.0

93.30%

20-25%

4σ

6,210.0

99.40%

12-18%

5σ

233.0

99.98%

4-8%

6σ

3.4

99.99%

1-3% Table 1

is not easy to bring them down. The same fragmentation even exists in the broader landscape which is surrounding the pharmaceutical industry. Huge discrepancies exist between pharmaceutical companies, healthcare organisations, regulatory authorities and patients. This environment fails to take customers’ (and other stakeholders’) needs into account.

One of the reasons for the success of other industries has been their ability to close the gap between suppliers, companies and the customer allied with a focus on advanced technological processes resulting in big improvements in the production quality, time to market and product innovation.

Industries such as semiconductors, food and beverages, chemicals and petrochemicals are more advanced in breaking down the barriers between stakeholders, aligning processes throughout the entire value chain and introducing innovative technologies and concepts like Process Analytical Technologies, Six Sigma, Lean Manufacturing etc.

Part of the reason for this was that the regulatory context of pharmaceutical manufacturing did not facilitate the introduction of change. Now, however, the situation is changing with the US Food and Drug Administration (FDA) recognising that stringent regulatory regulations have generated high

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barriers for pharmaceutical manufacturers to adopt state-of-the-art manufacturing process within the pharmaceutical industry.

Trends, challenges and opportunities

The pharmaceutical manufacturing sector has been inherently conservative in its approach to change. Historically, the regulatory framework, with its reliance on batch inspection has deterred innovation and maintained the silo-behaviour. Closing gaps between R&D and manufacturing will be a key strategy in responding to a range of drug development and quality concerns and for the ability to achieve manufacturing excellence. Closing the gaps between patient and heathcare systems will also be increasingly important for pharmaceutical companies in order to be more responsive to patient needs and demands. This will need a more flexible manufacturing concept to stay competitive. Coming from the times where the profit was high and where the pharmaceutical industry could relay on a wealthy portfolio of patents we determine today a lot of pressure on this industry by healthcare, by generic drugs manufacturing companies and by a lack of new developed drugs. This means that comparing the KPI’s of the pharma industry with the others there is an enormous bridge to gap.

An investigation shows the following average values for the pharmaceutical industry; Scrap rework – plan for 5 – 10% Utilisation level 15% Cycle times 720 hours Concepts like Lean Manufacturing, Total Performance Manufacturing (TPM) and Six Sigma are indispensible tools to achieve these goals.

Technologies and concepts to close the gap between R&D and Manufacturing

We see companies moving away from batch manufacturing with off-line prod-

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uct testing to continuous manufacturing with an integrated quality design into the process. Disposable manufacturing technologies will also hasten time to market, reduce or eliminate cleaning in place or Steaming in Place activities and reduce lead time, which are still very high in the pharmaceutical industry compared to other industries.

Such technologies provide a greater degree of flexibility, both in terms of scale and location and ease of use for operations. Cell chips are enabling the study of the reaction of an individual cell through the miniaturisation of different kinds of analytics and detectors. Micro reaction technology permits the synthesis of active pharmaceutical ingredients on a small-footprint, labbench scale. Because of continuous mode of production, the same annual product volume can be produced as when using larger-scale batch methods. An additional advantage of this technology is the elimination of the up-scaling effort and technology transfer.

Adopting productivity tools such as Knowledge Management, Product Lifecycle Management and Master Data Management tools, (MDM can also serve as a data portal), the organisations could facilitate better coordination between their R&D and manufacturing processes.

It is important for information to flow not only from R&D to manufacturing but the other way round as well. The collection of knowledge through manufacturing will help the R&D organisation to accelerate the development of new processes when new products have to be designed. For example, the characteristics and behaviour of production equipment and machines in the manufacturing process can be inputs for the development process.

The Product Lifecycle Management software defines, collects and keeps track securely of all product and compliance relevant information . By providing common access to a single repository of all product-related knowledge, data and processes, PLM can speed up the

innovation and launch of successful products. In the future PLM will enable companies to deliver automatically the information to support the (e-) regulatory submission and approval processes to the authorities.

Shared PLM and KM tools can work together with other solutions to help pharmaceutical companies move away from R&D and manufacturing as separate silos to deliver a more integrated and interactive manufacturing and development process, speeding the time of development. At the heart of this is the Workflow Management System and Electronic Lab Notebook (ELN)—the R&D suite that links to the production suite used in manufacturing and the PLM software. Thus, R&D dovetails into the Manufacturing Execution System (MES).

This is further facilitated by the ability to use the same sample management and Laboratory Information Management System (LIMS) in both development and manufacturing.

A range of other innovative technologies complete the picture. Process Control Systems allow automation in laboratories, even for small process equipment or pilot equipment. Micro process technology introduces this technology more quickly for broad application in the laboratory and successful transfer to industrial production levels.

Finally, Process Analytical Technology (PAT) and “ The Critical Path Initiative” of the FDA will move the pharma industry towards a science-based manufacturing industry. With PAT, the pharmaceutical manufacturing environment will move towards scientific understanding of pharmaceutical materials and processes.

PAT will play an important roll in supporting companies moving from offline quality inspections to on-line and finally towards a full real-time product release capability. The connection with Process Analytical Technologies enables companies to link all their analysers and other process measurement tools to one single system architecture. It forms a

M anu f acturing

Lean, leaner, leanest!

Innovative solutions, on the one hand, close the gap between R&D and manufacturing and on the other hand, eliminate the barriers within the entire value chain, to transform the pharmaceutical industry into a more efficient business model.

Manufacturing flexibility entails supply chain visibility, production capacity and dynamic decision making, each of them being supported by the innovative technologies. Incorporating these concepts and innovative technologies into an overall strategy can be categorised as continuous improvement and Lean Manufacturing.

Determining value based on what is valuable to the customer forms the basis of Lean Manufacturing. Hence,

it focusses on the silos that need to be bypassed within the pharmaceutical companies and around them.

Furthermore, it keeps every activity in motion and eliminates the waste.

Floorspace, work-in-progress and lead time are all interrelated. Reducing testing times is another aspect that would allow

Shiegeo Shingo’s “Non-Stock Production” If we study machine set-up time for waste maybe we can eliminate the reason for not doing one at a time.

Ohno’s “Just-In-Time method” If we pull things through the system rather than push them maybe we can eliminate the bottlenecks and the rest of the waste.

Dennis Pawley, Former Chrysler Executive “The way people think is far more important than the tools they use.”

Toyota Lean thinking Strategy “Brilliant process management is our strategy. We get brilliant results from average people managing brilliant processes. We observe that our competitors often get average (or worse) results from brilliant people managing broken processes.”

manufacturers to release products faster and reduce inventory levels.

Lean principles are very easy to understand but they are very hard to implement, especially in a regulated environment like the pharmaceutical industry where the validation and proof

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part of the process control system tightly integrated with Electronic Batch Records functions.

Knowledge management systems, data portals, totally integrated component based automation and master data systems become even more important in handling flexible, complex and dynamic interrelationships.

With this component based architecture, the requirements of the original equipment manufacturers can live up to supply their own working components and have the ability to integrate with the overall plant process system.

This requires a modular concept, based on standards, stands like OMAC and ISA S88, but also standards in the field of operation with SCADA and in the field of megatronics (Motion control).

Profinet with the supporting CBA software makes a plug and play connection possible. In this concept, the integration of Q (quality), S (supply chain) and M (asset management; OEE) aspects starting already on the lowest level, makes it easy to make this information available over the whole system and use these data to improve the manufacturing performance.

is required to introduce any change or new system to maintain or improve quality.

However, the present regulatory context, with its introduction of Quality

by Design (FDA Guidance on Process Analytical Technology and Quality by Design) facilitates the introduction of innovative technologies (as discussed above) and concepts in order to achieve the goals of Lean Manufacturing and Six Sigma methodologies.

What is essential, is connecting Innovation, TPM, Lean and Six Sigma to business objectives directly and getting the support of management by integrating these improvement programs in a pragmatic manner. Often Lean processes can get too methodical, by which efforts can become mechanical. Further, tools and systems must be in place to support people and secure the modifications.

Conclusion

The pharmaceutical environment is characterised by disconnected processes and siloed approaches throughout the entire value chain. The key is standardising and improving the processes. This enables the flawless execution of the processes.

A standardised approach doesn’t stifle creativity. It changes the way creativity is used. To stay competitive and to achieve the goals of TPM, Six Sigma and Lean Manufacturing, Pharma manufacturers must move away from the traditional approach and manage operations in a holistic manner by investing on a common platform that meets the existing standards and integrates innovative technologies across plants and different functional departments.

Bart Moors is Business Consultant for the Pharma industry of South East Asia. He works for the headquarters of Siemens AG in the Competence Center Pharma department. He has more than 10 year pharma experience. He started his profession in the chemical industry and secondly built up experience in the automotive industry before he joined Siemens. Bart has a Masters degree in Electrical-Mechanical Engineering, a specialism in Polymers and a Masters degree in Applied Economics.

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Controlling Production Process Incorporating analytical methods

Taking new regulative guidance into account, the motivation for increasing process analytical technology systems from a scientific and administrative point of view is addressed here.

Based on freeze-dried macromolecular systems, the current gains and challenges of NIR and Raman spectroscopy are discussed. The potential of spectroscopic techniques is described in more detail using the common excipient mannitol as an example.

Holger Grohganz, Assistant Professor, Pharmaceutical Technology Jukka Rantanen, Professor, Pharmaceutical Technology University of Copenhagen, Denmark

T

here is an increasing interest on drug delivery systems based on macromolecules. Peptides and proteins of pharmaceutical interest constitute a growing share of the new drugs coming into the market.

Traditionally, solid state properties were not the first issue when it came to formulation of these products. It has to be considered, however, that many therapeutic macromolecules are prone to various physical and chemical degradation reactions in solution and therefore have to be transferred to a solid state. Though the stability of the product is usually increased by such a transfer, the transformation process itself may damage the molecule.

Another area with an obvious need for more research activities is the processing of macromolecular systems.

The current quality systems in the pharmaceutical field are focussing on the testing of end-product. Achieving relevant real-time information from multicomponent systems, such as macromolecular formulations, is not a straightforward task. Consider a typical product with numerous sequential processing steps. There are many possible pitfalls

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during processing that may critically affect the final product performance. For example, during processing, an active protein may be stressed in an environment that is aqueous or changing in temperature. Focussing analysis on the end-product will not enable the early detection of problems or the complex interactions. Recently, the US Food and Drug Administration (FDA) introduced a guidance to address this issue.

Process Analytical Technology (PAT) is a system for developing and implementing new efficient tools for use during pharmaceutical development, manufacturing, and quality assurance. Final goal is to maintain or improve the current level of product quality assurance. All this work is aimed at enhancing and modernising the pharmaceutical manufacturing and quality control environment according to the Current Good Manufacturing Practices (CGMPs) for the 21st century.

The principles of this framework are being incorporated into the ICH quality guidance. Future challenge will be the implementation of the right process analytical approach into each specific situation.

Advances in process analysis

We have a wide variety of tools available for sophisticated process analysis.

Non-invasive spectroscopic approaches, such as Near Infrared (NIR) and Raman spectroscopy, provide an insight into solid state properties during processing and they are extremely useful in collecting information related to the role of water during processing. These techniques can be applied for probing the relationship between structure, dynamics and function of macromolecules and further, the role of excipients in the formulation. If one would first look at the monitoring of the macromolecules, NIR and Raman have shown to be versatile methods for the characterisation of macromolecules.

There are several reports of their use for quantification of water (NIR) and further, examples of monitoring the state of water in the system (Raman). This is a reason for a wide use of NIR for monitoring several drying processes.

As NIR radiation passes through most glass types without difficulty, a measurement through the wall of the vial is usually possible. Measurement through the side wall usually results in more reproducible results and the use of a spinning device in order to avoid local deviations can be recommended. Considering the importance of the three-dimensional structure for the activity of the molecule, NIR can be used to detect both ι-helix and β-sheet structures thereby identify-

M anu f acturing

Detecting mannitol hemihydrate

A very common excipient for freezedrying is mannitol as it forms lyophilisates with a good cake structure. Mannitol can crystallise in three polymorphic forms (α, β and δ). Furthermore, it can also form a hemihydrate, whose occurrence is partly due to chance and partly due to the freeze-drying conditions (Yu et al.,

1999). The formation of the hemihydrate is undesired as one cannot be sure of the complete removal of the bound water once it is formed. The remaining mannitol hemihydrate can release the bound water during storage thereby lowering the collapse temperature of the cake leading to shrinking of the cake and an unacceptable product. In order to prevent storage problems, mannitol hemihydrate needs to be detected as soon as possible. As water is in a different environment when it is bound to mannitol, a shift in the absorption band can be observed with NIR. This shift is not very pronounced in a normal spectrum, but data pre-treatment using second derivative can reveal the formation of mannitol hemihydrate by a band shift from 1904 nm for surface water to 1936 nm for bound water (Zhou et al., 2003). Mannitol hemihydrate could not only be identified by observing changes in the water band, but also by observing several other distinct differences in its NIR adsorption pattern compared to the anhydrous crystalline α, β and δ modifications (De Beer et al., 2007).

Maintaining protein stability

However, freeze-drying with only mannitol as adjuvant cannot be recommended.

Despite the fact that a purely crystalline cake is showing a rather good thermal stability, it is seldom desired for freezedried macromolecules as it is often negatively affecting protein stability. In order to prevent this, for example, sucrose can be used as an additive. Sucrose will

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ing denaturation processes (Izutsu et al., 2006; Robert et al., 1999). In the same manner, Raman spectroscopy can help to identify the structure of a protein.

Band assignment of both α-helix and β-sheet structures as well as band shifts of various amid bands have been shown for both freeze-dried and spray-dried proteins (Elkordy et al., 2004; Hino et al., 2003). As the chemical surroundings of a bond influence its strength and therewith the energy required for interaction of molecule and incoming radiation, the precise bands, as found by the various authors, seem to vary.

Besides these direct changes in the active compound, the influence of processing and storage on excipients must not be forgotten. Basic sugars are widely used excipients and this often creates several challenges in the solid state properties.

Freeze and spray drying produce solid matter with unique characteristics, and we still lack fundamental understanding of the role of the process variables affecting critical quality attributes. In this area, the role of molecular interactions, e.g. amorphicity and approaches to control it become important. Two of the most critical factors affecting this complex interplay are the amount and the state of water in the system. Traditionally, the water content is determined by Karl Fischer titration a method which despite being generally accepted is destructive and time-consuming. As water shows a strong concentration dependent band at around 1930 nm in a NIR spectra, several approaches can be found showing a good correlation between the water content determined by NIR and Karl Fischer titration.

result in a partly amorphous product thus providing a more favourable micro-environment for proteins. Though mannitol and sucrose are relatively similar in their chemical structure, there are areas in the NIR spectral range within which mannitol can be determined without the risk of disturbance by sucrose.

Integrating into production process

In recent times the authorities are starting to favour the idea of controlling the entire production process rather than just the endpoint of the production. For this purpose, analytical methods should be feasible to be incorporated in-line in the production stream. This is leading to the final consideration of this article: is it possible to incorporate NIR and Raman directly in a freeze-drying or spray-drying process? So far in-line measurements in a spray-dryer have not been performed, but it has recently been shown that in-line Raman measurements in a freeze-dryer are possible (De Beer et al., 2007; RomeroTorres et al., 2007). It can be concluded that NIR and Raman present methods that can identify various instabilities that might occur in dried products, e.g. high water content, hemihydrate formation and polymorphic transitions. These techniques can thus be used to increase the level of process understanding through non-invasive analysis of water and solid state properties of material.

Full references are available at www.pharmafocusasia.com/magazine/

Holger Grohganz is Assistant Professor in pharmaceutical technology at the University of Copenhagen, Denmark. His research involves the use of multivariate data analysis for spectroscopic methods with a special focus on the drying processes.

Jukka Rantanen is Professor of pharmaceutical technology at the University of Copenhagen, Denmark. He is author or co-author of 80 publications and patents within the field of solid state pharmaceuticals. His research is focussed on the molecular-level process analysis of pharmaceutical unit operations, with a special emphasis on the spectroscopic techniques (near infrared, NIR, and Raman) together with multivariate data analysis tools.

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Process Analytical Technology Application in precipitation processes

Precipitation is a commonly used purification method when a pure crystalline Active Pharmaceutical Ingredient, excipient or intermediate with specific particle properties needs to be isolated from a multi-component process solution after a synthesis, extraction or bio-process.

Marjatta Louhi-Kultanen, Research Lecturer, Docent in Industrial Crystallization, Department of Chemical Technology, Lappeenranta University of Technology, Finland

Supersaturation

T

he main factors affecting precipitation processes and inline process monitoring when Process Analytical Technology (PAT) based on in-line / on-line spectroscopic methods is applied, is discussed here.

Precipitation

The main purposes of crystal engineering of pharmaceutical compounds are usually to control crystal morphology, crystal size distribution and polymorphism.

The two main precipitation methods are: 1. Reactive crystallisation and 2. Precipitation by adding a precipitant chemical which decreases the solubility of the crystallising compound.

In the case of reactive crystallisation, the reaction can be as follows: A + B → C↓+ D (1) where A, B reactants C precipitate (poorly soluble solute /solvate / hydrate) D forming solute having high solubility There are several examples in reactive crystallisation in the pharmaceutical industry of base-acid compound systems where a change in pH by adding an acid / base precipitates the drug compound.

One example of precipitation using a

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flow rate, size of the feed tube, hydrodynamic conditions at the feeding point)

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precipitant chemical is salting out of proteins by adding an inorganic salt into the aqueous protein solution.

Precipitation processes of fine chemicals are usually operated in semi-batch mode, i.e. one or more chemicals are added by pumping them into the mixing reactor continuously. In general, temperature control is required in order to control the properties of the forming crystals and / or if the processing is highly endothermic or exothermic.

The main factors affecting precipitation are as follows: The solution: • Selection of precipitants / reactants • Selection of solvents • Additives (habit modifiers, stabilisers) • In-reactive crystallisation: reaction kinetics vs. crystallisation kinetics • Reactant / precipitant concentrations The operation conditions: • Residence time (impact on supersaturation level) • Mixing system (impeller type, mixing intensity, concentration / temperature distribution in the crystalliser, which is also important in order to avoid undesired side reactions) • Reactant / precipitant feeding (mass

The driving force of crystallisation is supersaturation, which is expressed by the difference or ratio of the actual and equilibrium (saturated solution) concentrations. While chemical potential is the true driving force, in practice, in industrial crystallisation, concentration based expressions are sufficiently accurate for most applications. The amount of solute required to make a saturated solution for a given condition is called the solubility.

The solubility of organic compounds in different solvents is difficult to predict and, therefore, the solubility is usually determined experimentally. The principle used to determine supersaturation is shown in Figure 1. In the case of reactive crystallisation, the product yield can be obtained from the equilibrium concentration line (reactant A) shown in Figure 1. It should be remarked here that the solubility of the precipitate C can be dependent on the solution composition.

The solubility is not necessarily constant as plotted in Figure 1.

Supersaturation mainly determines the rate of crystal growth and nucleation.

The general rule is: the shorter the residence time, the higher the supersaturation. Proper control of the crystal growth rate is important to obtain correctly sized crystals. Nucleation dictates the

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Determining supersaturation based on the concentration difference of the actual supersaturated solution and the saturated solution.

c=

c

c*

–

In-line/in-situ/Atline concentration measurement of actual supersaturated solution

T3

T2

T1

T2 T3

T1

Concentration of precipitant wt% Reactive crystallisation Solubility of precipitate C. g/L

Equilibrium concentration from solubility data

Solubility at different temperature, g/L

Presipitation with chemical

0

0

0 Concentration of reactant B,wt% Figure 1

In-line process monitoring Reactant(s)/Precipitant TIC

QI ATR FTIR, Raman

• Concentration measurements of the chemicals with ATR FTIR • Determination of supersaturation evolution based on ATR FTIR based concentration measurement and the equilibrium concentration •Polymorphic composition analysis and highly concentrated chemicals with Raman Figure 2

final number of particles in the batch, i.e. the higher the nucleation rate, the smaller the crystals. Moreover, it is an essential factor regarding the forming of polymorphs: what is the supersaturation level when first nuclei are formed in the solution (primary nucleation). In order to obtain the required properties of a crystalline product, it is crucial that the supersaturation level be controlled effectively by the desupersaturation rate, which is mainly determined by the crystal growth rate and the avail-

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able crystal surface area. In addition, the level of supersaturation also affects the agglomeration, shape and purity of the crystals.

In-line process monitoring

ATR FTIR spectroscopy allows simultaneous monitoring of admixture concentrations and Raman spectroscopy gives information on the polymorphism of product crystals during the semi-batch process. Figure 2 shows schematically an in-line process monitoring system

when these two methods are employed.

The ATR FTIR and Raman probes are immersed directly into the solution in the crystalliser. For the spectral treatment, in many cases multivariate models must be developed for the calibration modelling in order to be able to quantify the different species in the model compound system at the used temperature range.

The strength of in-line ATR FTIR spectroscopy in monitoring solid-liquid suspensions is that it is a back-reflective analysis method, i.e. crystals present in the suspension do not disturb the analysis even in high density suspensions. In addition, it is a method which can allow monitoring of several compounds at the same time so that they can be quantified simultaneously. Furthermore, its resolution is usually sufficient for the analysis of crystallisation processes. The quantification of different compounds is very useful especially for controlling precipitation systems, which usually contain different reactants, impurities, side-products, co-solvents, etc. as well as the crystallising compound. On the other hand, relatively complex multivariate models are required for spectral treatment (Pöllänen et al.). In addition to polymorphism monitoring, Raman spectroscopy can be used for highly concentrated solutions (Qu et al.).

Raman spectroscopy is also a good tool to investigate stability of metastable polymorphs or pseudopolymorphs in different solvents (Qu et al.). The interpretation of Raman spectra is usually easier compared to ATR FTIR. The relative quantification of Raman results is generally done based on peak height / surface area ratios. The crystalliser initially contained sodium glutamate solution and sulphuric acid was pumped into the crystalliser at a constant feed rate. In addition to ATR FTIR data, concentration determination also requires the thermodynamic model (dissolution and mass balances of solutes) which is introduced in detail by Alatalo et al. L-glutamic acid has two reported polymorphs, an α (thermodynamically metastable) and a β (stable) form.

M anu f acturing

Process control of precipitation

Future expectations

Classified Ad

Precipitation processes are complex unit operations and are challenging to control. A summary of the fundamentals of precipitation is presented along with some basic aspects concerning in-line monitoring and process control of precipitation. In many pharmaceutical applications IR and Raman spectroscopy have been proven

PID controller

SC

Spectral treatment QIC ATR FTIR

Reactant(s)/Precipitant TIC

PID controller for semi-batch precipitation: Concentration control of reactant / precipitant by adjusting the feed rate.

Figure 3

to be powerful tools for real-time measurements of solid-liquid suspensions.

It can be expected that in future these spectroscopic methods will be more commonly utilised for process control purposes.

Acknowledgments

The author would like to thank the Crystallization Group and Chemometrics

A uthor

In crystallisation systems where the supersaturation levels can be determined, a feedback process control loop of the PID controller (ProportionalIntegral-Derivative) can be built based on in-line concentration measurement with ATR FTIR, as shown schematically in Figure 3. As explained in the previous two sections, the aim can be to adjust the feeding rate of the reactant / precipitant based on the obtained momentary supersaturation level drawn from the ATR FTIR and solubility data and compare it to the set value. This approach makes it possible to use different precipitation policies in a controlled manner. It should be pointed out that seeding, i.e. usage of seed crystals with a desired polymorph, or other methods to induce the crystallisation may possibly be required for trouble-free processing and to ensure good uniformity between products obtained from different batches.

In-line process monitoring

Group of Lappeenranta University of Technology for kindly providing the PAT (in-line monitoring) and multivariate data discussed in this work. The Academy of Finland (projects No. 122828 and 117155) is thanked for financial support.

Full references are available at www.pharmafocusasia.com/magazine/

Marjatta Louhi-Kultanen is a Docent in industrial Crystallization in the Department of Chemical Technology at Lappeenranta University of Technology. Her research interests include industrial crystallisation of organic and inorganic substances, mixing, filter cake washing, particle technology, solid-liquid thermodynamics and in-line process monitoring.

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in f ormation technolog y

Business Intelligence in Pharma A key enabler of industry transformation

Business intelligence solutions, proven in other industries, offer the troubled pharmaceutical industry the potential to enable both operational excellence and better technical management to support drug development for the future.

Alan S Louie, Research Director, Health Industry Insights, an IDC Company, USA

T

he pharmaceutical industry is in the midst of fundamental changes. The changes have been brought on by the increasing concerns over expiry of patents for major blockbuster drugs, weak product pipelines, heightened awareness of drug safety, globalisation, competition from generics and growing value considerations with regards to access to and reimbursement of new speciality therapeutics.

These issues, and more, have forced top pharmaceutical companies to change their current course, in search of a stable and sustainable path that can help them maintain and improve their current profitability levels.

Near-term strategic efforts in the path towards sustainability include traditional business approaches that aspire to fully address shortcomings, but are more likely to only produce incremental improvements.

More tactical changes are also being implemented in hope of better leveraging of resources within the increasingly distributed, global pharmaceutical organisation. Key among the tactical changes that are being implemented are efforts in pursuit of information transparency. Looking significantly beyond consolidated data warehouses, pharmaceutical companies are working to bring all data (from initial laboratory e-Notebooks in discovery through to Phase IV clinical trial data reporting) into a broadly accessible and usable form that fully captures knowledge accumulated during the course of R&D. This includes supporting information (i.e. metadata) that provides procedural and analytical insights surrounding experimental data, related knowledge available from a wide variety of sources (both external and internal), analytical and visualisation tools to simplify knowledge extrac-

Traditional business approaches • An aggressive Mergers and Acquisitions strategy in search of backfilling product pipelines; • Shifting of IP-insensitive operations (e.g. clinical trials, manufacturing, customer service and some administrative activities) to lower cost locations; • Consolidation of R&D sites; and • Spin-offs, reduction or elimination of non-core R&D efforts not expected to produce near-term market impact.

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tion, and real-time tools to enhance collaboration across the organisation to more effectively exploit the collective brain trust.

To establish an effective information transparency infrastructure in the nearterm, an organisation needs to improve its ability to rapidly and regularly extract real-time data that reflects the status of projects and processes ongoing within it.

Access to accurate real-time information during every phase of development can significantly improve the effectiveness of strategic decision-making, increasing the likelihood of long-term success. It can help companies to better reach project milestones with regards to experimental progress, optimise utilisation of project resources and enable comparative analysis of specific projects undertaken by the different divisions of the company.

Heavily validated in other industries, Business Intelligence (BI) is increasingly becoming an essential part of the pharmaceutical industry. Apart from establishing an effective information transparency infrastructure, BI directly enables both senior management and project line managers to make better decisions to help their companies move forward.

Methodology

Based on telephone and in-person surveys across all aspects of the health industry, Health Industry Insights analysts assessed the industry’s use, expectations, and aspirations of adopting business intelligence solutions within their organisations.

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Discussions focussed on a number of specific factors, including top business reasons for investing in BI, anticipated benefits, and future plans expected over the next five years.

Moving beyond operational excellence

With total US spending on BI in 2007 at US$ 168.7 million and a growth rate roughly double that of the overall IT spending (12.7 per cent versus 7.3 per cent, Source: Health Industry Insights, 2007), it is clear that leaders in the pharmaceutical industry have recognised the potential of BI and are speeding up the implementation of this approach across their organisations. While the opportunity for BI to pursue operational excellence is an obvious first step (e.g. more efficient utilisation of available resources and the elimination of redundant or unproductive efforts), it is interesting to note that BI is also being applied to the technical and scientific efforts within the organisation. Specifically, BI solutions are beginning to be used to improve research and clinical performance with the goal of both accelerating organisational growth as well as saving costs.

A Health Industry Insights' simplified definition of Business Intelligence: Systems and solutions that improve organisational decision making through regular access to detailed quantitative organisational data.

Generally, BI solutions are implemented in different parts of the organisation under the common direction of the CIO. Having been successful in achieving operational excellence and improving the research / clinical performance of the companies, these solutions have been increasingly adopted, albeit at a varied pace, by pharmaceutical organisations.

With many validated examples of successful implementations focussed on operational excellence from other industries (especially the financial, manufacturing, and retail industries), BI is find-

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ing a new prominent position within pharmaceutical organisations, including project resource management, sales force tracking, and regulatory compliance reporting. From a research / clinical performance perspective, however, there have been few cross-industry examples to leverage. This has led to BI solutions for pharmaceutical organisations being developed organically. Specific applications in this area include: better ability to access and use research data from across the organisation (through elimination of data silos), improved use of data analytics and visualisation tools to extract information, and more effective comparison of project and therapeutic areas on a common value scale.

While assessing industry sentiment regarding BI, some industry-wide goals were identified which benefited the organisations significantly beyond

Business Intelligence solutions are beginning to be used to improve research and clinical performance.

pilot project boundaries, often leading to opportunities for new BI applications.

In general, three key goals for BI were identified: • Gather good data • Translate data into actionable information • Use information to effect organisational change.

Driving organisational change

All of the companies interviewed had access to one or more of the commercial BI software tools and services available in the market today. Major commercial BI solution vendors used in the industry include: Business Objects (now part of SAP), Cognos (now part of IBM), Hyperion (now part of Oracle) and SAS. However, the availability of commercial BI solutions plays a minor role in the

implementation of an effective BI solution within these organisations. Successful implementation of BI in the pharmaceutical industry requires significant changes in organisational thinking across the organisation, impacting researchers at the bench, the CIO, and all levels inbetween. Failure to recognise and adopt these philosophical changes significantly reduces the potential opportunity for BI and results in the wastage of valuable company resources.

Changes to both broad organisational mindset around data and supporting IT infrastructure are needed to enable BI to be successful. To gather good data on a regular basis, everyone in the organisation, from researchers to line management to senior leadership must recognise that accurate, quality data brings value to the organisation and that isolated silos of data significantly impair an organisation’s efforts to be successful. With quality data in hand, it then becomes necessary to have easyto-use portals, analytical tools, and simple, but powerful report generators to begin to translate this data into actionable information. Finally, it must be clear and transparent to the organisation that the data and the information derived from the data, is actively being acted upon and used to drive the organisation forward. As BI implementations begin to regularly yield successful outcomes (efforts that should be highlighted regularly and often within the company), success should breed success spurring further adoption and support for new BI initiatives.

A number of collateral benefits become possible with the creation of a fluid information infrastructure. It becomes possible to benchmark key projects, processes, and programmes, laying the foundation for future process improvements which can be better quantified for effectiveness and value. Metrics supporting Return-on-Investment (ROI) become possible, even at early stages

in f ormation technolog y

Succeeding in a new global ecosystem

At the beginning of the discussion of BI adoption, interviewees were asked whether ROI was a prerequisite to initiate pilot efforts. In all cases, it was reported that an ROI justification was not required and that initial key decision makers (typically the CIO) recognised the greater opportunity and benefits that an effec-

tive BI and supporting IT infrastructure could enable. Despite this unconstrained commitment, it was often possible in many cases to produce a demonstrable ROI from pilot efforts.

A shift towards a transparent information ecosystem that effectively leverages data and information regardless of its source will be a key differentiator for pharmaceutical companies moving forward. To be successful, drug developers (and senior management) need to have timely access to key information (both internal proprietary and external data including academic discoveries, publicly

A uthor

of adoption. Efficient and routine data collection can be expected to simplify ever growing regulatory compliance and reporting requirements. And with proper analytical efforts, it becomes easier to establish enterprise-wide standardised data definitions, which enable effective comparisons of projects and processes across the organisation, including the ability to effectively transcend geographical, divisional, and cultural boundaries.

available academic research, competitive clinical data etc.) in order to minimise development risk and to ensure that all critical factors have been fully taken into consideration before advancing specific projects forward. With the amount of available data continuing to grow at exponential rates, it is becoming increasingly impossible to manually keep up with progress. Harnessing the collective organisational brain trust in conjunction with evolving bioinformatics, BI, and content resources will be the key to success in this highly dynamic environment.

Alan Louie is Research Director at Health Industry Insights. He leads HIIâ&#x20AC;&#x2122;s pharmaceutical R&D market research efforts, with an emphasis on technology and innovation in clinical development, personalised medicine, and BI. Louie brings to HII more than 24 years of experience from the diagnostics, biotechnology, and consulting industries.

BOOK Shelf

Real World Drug Discovery: A Chemistâ&#x20AC;&#x2122;s Guide to Biotech and Pharmaceutical Research Description:

Editor: Robert M Rydzewski Year of Publication: 2008 Pages: 536 Published by: Elsevier Science ISBN-10: 0080466176 ISBN-13: 978-0080466170

Drug discovery increasingly requires a common understanding by researchers of the many and diverse factors that go into the making of new medicines. The scientist entering the field will immediately face important issues for which his education may not have prepared him: project teams, patent law, consultants, target product profiles, industry trends, Gantt charts, target validation, pharmacokinetics, proteomics, phenotype assays, biomarkers, and many other unfamiliar topics for which a basic understanding must somehow be obtained. Even the more experienced scientist can find it frustratingly difficult to get an overview of the many factors involved in modern drug discovery and often only after years of exploring does a whole and integrated picture emerge in the mind of the researcher.

Real World Drug Discovery: A Chemists Guide to Biotech and Pharmaceutical Research presents this kind of map of the landscape of drug discovery. In a single, readable volume it outlines processes and explains essential concepts and terms for the recent science graduate wondering what to expect in pharma or biotech, the medicinal chemist seeking a broader and more timely understanding of the industry, or the contractor or collaborator whose understanding of the commercial drug discovery process could increase the value of his contribution to it.

For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Biopharmaceutical Manufacturing The challenges

Rustom Mody Director, Quality and Strategic Research, Intas Biopharmaceuticals Limited, India

What is your view on the current scenario in Asian biopharmaceutical manufacturing?

Asia is emerging strongly in the area of biopharmaceutical manufacturing. More and more companies are confident of offering quality products and / or services.

In the span of past two years, the perception of having an Asian manufacturing partner has been very positive, with nearly 80 per cent of small and large companies eyeing to outsource manufacturing to Asian biopharmaceutical companies.

There is also an additional pressure of cutting cost and time, something which that the Asian companies are able to offer over the Western counterparts.

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How is India placed in this market?

India has kept excellent pace when it comes to adoption of international regulatory standards, especially with respect to facility and equipments. Indian companies have the muscle to build quality plants and machinery, and this is evident from the highest number of US FDA-approved plants in India, outside of USA. An interesting observation is in the area of biogeneric space. Many companies are launching the same product, e.g. there are over 12 brands of Erythropoietin (EPO) in the Indian market. This has not dampened the spirit of Indian biopharmaceutical companies and has certainly benefited the customer.

What are the current challenges that companies face in biopharmaceutical manufacturing?

The operational sizes of many of the fillfinish plants are quite large. What is lacking is the large-scale bulk manufacturing capacities for mammalian cell-culture derived products. This is an area where Indian companies are lagging currently, and it would take at least a couple of years before such plants get into operation.

Biopharmaceutical companies in India, in spite of the abundant qualified professionals, still have a manpower resource crunch, especially at higher levels.

One reason, which could be sited, is that biopharmaceutical manufacturing began late in the 1990s and the industry has not aged as much to have ample number of high-level professionals who are specialised in this sector.

Although the regulatory agencies are facilitating the introduction of various biopharmaceuticals products by way of streamlining regulatory pathway, there is a gap between the quality of the biopharmaceuticals manufactured in regulated countries and that manufactured in India. Take the example of biogenerics.

The regulatory requirements are far less stringent for clearance of biogeneric products in India than they are in the regulated markets. The wisdom behind keeping the regulatory barriers somewhat lower, has favoured introduction of many lifesaving biotherapeutics in the Indian market, which otherwise would have been impossible. However, on the long run, this could create a negative perception of Indian biopharmaceutical products, if the bar is not raised now.

The global manufacturing capacity in the last ten years has increased multifold while the demand has decreased considerably. How is this excess capacity being utilised?

Demand and supply follow a cyclical pattern. Just a few years back there was a severe shortage of mammalian cell culture bioreactor capacities and now it is not the situation.

Biopharmaceutical manufacturing is fast moving to countries like India and China where there is considerable costsaving. In order to be cost-competitive, even the big biopharmaceutical companies are considering tie-ups with companies in India and China to offshore manufacturing of their authorised biogenerics.

Given the high cost of production and decreasing demand, is it economically feasible to implement PAT in biopharmaceutical manufacturing?

PAT is a valuable tool that is not as costly as it seems. By applying PAT, one can improve consistency of a process, thereby eliminate costly failures, and need for investigations.

For biopharmaceuticals, the cost of bulk or finished product far exceeds chemical APIs and this should justify higher investments in PAT.

Any other issues you would like to comment on.

The number of Biotechnology and Biopharmaceutical patents filed in Indian Patent Office is growing by the day. If patents granted in India are to be taken seriously, there is a need for a serious prior art study by these patent offices. Presently this is not done to the standards required, which can lead to serious legal tangles in the coming years.

profile

What according to you are the key drivers for the future growth in this industry?

The key drivers for the future of biopharmaceutical companies will be to come out of the Biogeneric mindset and look at novelty. The â&#x20AC;&#x153;me tooâ&#x20AC;? mindset must be replaced by some tactical and strategic manoeuvre. The opportunities in India are far too many and companies can leverage many options for furthering their businesses.

Rustom Mody has 11 years of experience in the pharmaceutical industry. He currently heads the Quality Management System and Strategic Research Initiative at Intas Biopharmaceuticals Limited. He has worked in various aspects of project development such as plant design and setup, process and method development, scale-up and has interfaced with various National / International regulatory agencies.

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Public Private Partnerships

Why do you think PPPs are necessary in the current scenario?

The global pharmaceutical industry is in the middle of a pipeline crisis.

The number of incidences of approved drugs being withdrawn from the market and the molecules from development is increasing. Added to this, the looming loss of revenue from a number of blockbuster drugs going off patent in the next few years has put a lot of pressure on global pharma companies to come up with novel drugs which are safe and can meet regulatory requirements.

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Indian companies which till recently were not under pressure to innovate too have been forced to go down the challenging path of drug discovery and development thanks to the TRIPS agreement. One way of overcoming these issues is through collaborations and partnerships. Partnerships with both private companies and public funded institutions i.e. PPPs is being seen as an effective strategy to reduce pipeline stress and also keep the spiralling cost of drug discovery and development under control.

What promise does the Public Private Partnership model hold for the industry today?

PPP is one of the ways in which industry can tap into the vast knowledge base that has been generated by these institutions in basic sciences. Today it is acknowledged that in order to make effective and safe drugs we need to apply basic biology knowledge to the process of drug development. This knowledge is mainly found in academia and the scientists and researchers from these institutions are well placed to apply

How does the academia, usually seen as a not-for-profit entity, gain by working with the industry?

The central theme for academic research may be not-for-profit, but if there is an invention or a discovery that has potential to generate revenues, scientists and academicians do not shy away from this additional source of revenue. This revenue is split between the individual researcher and the institute which in turn makes use of this revenue to improve facilities or fund future projects.

Also, Research Institutes around the world have been sometimes been criticised for not applying some of their scientific inventions and discoveries for the benefit of common people, this when most of the funding for such institutes comes from public money. By collaborating with private companies which have a product or service-focussed approach, academia can help translate basic research into applied products and services.

What are the prerequisites for a successful adoption and use of the Public Private Partnership model?

One of the most important prerequisites for a successful PPP is a proper due diligence process in order to confirm the mutual benefits of the cooperation. The objectives of the cooperation have to be clearly communicated between the partners. Both parties should be committed to dedicate time and resources for the project. The project for which the PPP model is being utilised has to be commer-

cially feasible. An effective mechanism has to be agreed upon by the two parties on the commercialisation of IP generated from the partnership.

Steps should be taken to maintain confidentiality of the data generated.

These steps should be worked out in consultation with both parties and has to be agreed upon before the partnership can take off.

With the focus of the industry shifting towards improving efficiencies and developing innovative drugs, can the industry and academia achieve their goals working together?

Joseph Manoj Victor Senior Research Analyst, Healthcare Practice, Frost & Sullivan, India

Public Private Partnership (PPP) in the pharmaceutical space allows companies to leverage the knowledge and capabilities present within the institutes to rekindle their product basket; for the research institute, this offers the benefit of commercialisation of novel inventions or processes that have the potential to generate additional revenues for both researcher and institute. profile

this knowledge to the drug discovery and development process. Genomics, Proteomics and Systems Biology knowledge are increasingly being used in todayâ&#x20AC;&#x2122;s drug and diagnostic development. But the expertise for this type of high-end basic research lies with academic research institutes. Scientists in private companies have the ability to apply this basic research into developing novel products and services.

Do you think the industry in the emerging markets and especially in a country like India is very conservative in working with the public institutions?

Indian industry is definitely not conservative in working with public institutions.

The number of PPPs have been increasing over the years. The PPP process got a big boost after India became signatory to TRIPs. There have been a number of government schemes that have been set up to encourage PPP. But then the number of PPPs in India is still on the low side and more efforts are needed to encourage and nurture PPPs. Is the time right for this model to be tried out in India?

The Indian pharmaceutical industry has always been geared towards producing low-cost products and services. This can be attributed to the limited resource availability which forced the government in the 1970s to encourage process innovation rather than product innovation. While such a policy has helped India gain centre stage in the global generic industry, this policy had its pitfalls: it led to a complacent attitude towards developing innovative products.

The R&D programmes of most Indian companies are funded by the money generated through the generics business of these companies. But the generics business has been facing severe pricing pressure reducing the amount of profit generated from this business and hence the business may not be sustainable over the long run. A lack of funding is restricting the drug discovery and development work of these companies. Considering the situation industry is facing right now, more collaboration with academic institutions should be the way to go.

Joseph Manoj Victor works as a Senior Research Analyst with the Pharmaceutical and Biotech practice in Frost & Sullivan India.

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Strategy Health Protection Agency . ..........................................................

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Research & Development Aseptic Projectss ............................................................................

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Clinical Trials Aseptic Projectss ............................................................................

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Robinsons Global Logistics ........................................................

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SuppliersGuide

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NK Pharma Industries ................................................................... IFC Robinsons Global Logistics ........................................................

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Siemens ....................................................................... OBC Stamfag ....................................................................... IBC WLE Technology Sdn Bhd ..........................................................

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To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link.

October 2008 Oct 20 - 22, 2008 Bioprocess International™ Asia Pacific Venue : Mumbai, India Organisers : IBC Life Sciences Email : custserv@ibcusa.com Web Link : www.ibclifesciences.com Oct 28 - 31, 2008 5th Annual Clinical Trials Summit 2008 Venue : Sheraton Towers Hotel Singapore Organisers : IBC Asia Email : register@ibcasia.com.sg Web Link : www.ibc-asia.com

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IFC: Inside Front Cover IBC: Inside Back Cover OBC: Outside Back cover

Nov 17 - 20, 2008 Biologic India 2008 Venue : Marriot Hyderabad, India Organisers : Terrapinn Email : haslinda.haniffa@terrapinn.com Web Link : www.terrapinn.com

December 2008 Dec 1 – 5, 2008 BIT’s 1st Annual World Vaccine Congress 2008 Venue : Baiyun International Convention Center, Guangzhou, China Organisers : BIT Life Sciences Email : sean@vaccinecon.com Web Link : www.bitlifesciences.com Dec 2 - 3, 2008 SFE and Market Opportunities China Venue : Hilton Hotel, Shanghai, China Organisers : First Conferences Ltd Email : iwakeling@eyeforpharma.com Web Link : www.eyeforpharma.com Dec 5 - 7, 2008 Medifest 2008 Venue : Pragati Maidan, New Delhi , India Organisers : Vantage Medifest (P) Limited Email : medifest@gmail.com Web Link : www.vantagemedifest.com

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