mega-mergers: are pharma turning into zombies?

w w w . p h a r m a f o c u s a s i a . c o m

Issue 10 2009 £12 €18 $25 Rs.300

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Mega MergersAre they turning pharma companies into zombies?

New Patents for Old DrugsLabel-based strategies in the

United States

Preclinical Research in Big Biotech

Vertical integration is the key

Accelerating Central Nervous System Trials

Neurophysiological approaches

Foreword

Personalised MedicineWhat next?

While mergers and acquisitions, partnerships and collaborations still offer avenues for growth for the pharma industry, many feel

that the concept of personalised medicine, if used intelligently, will set the industry on the right path. By enabling highly-customised therapies to treat diseases based on the patients’ genetic makeup, personalised medicine offers companies alternative avenues for growth in terms of niche markets often left unexplored because of feasibility issues. It also provides an opportunity to eliminate unfavourable products much earlier in the development stages, save investment by testing medicines on targeted sub-populations and avoid failures by eliminating inappropriate patients whose genetic makeup does not suit the medicines.

Right drug for the right patient and benefits with-out toxicity offers a viable business model to the industry. Personalised medicine effectively tackles the issues of toxicity, side effects and medical errors due to wrong dosages or incompatibility while offering patients effective therapies. The industry has a lot to benefit by leveraging the rapid developments in biomarker usage strategies for personalised healthcare. Experts opine that the biomarkers used to optimise clinical study designs could be eventually used to conduct smaller trials and allow a combination of medicine to be prescribed based on the outcome of a specific diagnostic test for the patient. Additionally, personalised medicine can help create and enhance product differentiation and potentially extend the life cycle of drugs.

Aala Santhosh ReddyEditor

Though the benefits are immense, challenges abound. Optimising the drug development for target patient populations—usually small—at low cost while satisfying the tough regulatory guidelines and reim-bursement procedures is a daunting task. Many health-care payers now demand evidence-based medicine to avoid unnecessary costs and low-yield interven-tions for patients. However, most reimbursement procedures tend to fix a ceiling for tests. Developing the tests, an important element of the personalised medicines concept, is a costly and unfeasible affair with the ceilings.

Enough support from healthcare insurers is paramount for the growth of personalised medicine. Experts, however, hope that realising the long-term savings in treating a disease or preventing it will offer enough incentive to payers to support personalised medicine on a greater scale.

At the moment, its greatest advantage lies in its capability to maximise the effectiveness of medicines used to treat diseases affecting a specific population with documented cases of toxicity and side effects. The cover story “Future of Medicine - Personalised” discusses some important issues: how targeted thera-pies can offer a sustainable business model, the changing business models and how biomarkers are leading the way in the development of personalised medicine.

An innovative approach to overcome the risk factors and stem the failure of drugs which are often developed on a trial and error basis, the concept of personalised medicine comes with its own share of benefits and challenges.

Strategy05 Indian Pharmaceutical Industry On the cusp of a great opportunityRanjit Shahani, Novartis India Limited

08 Mega MergersAre they turning pharma companies into zombies?Neil Campbell, Mosaigen, Inc.

15 Pharma and Biotech Collaborative modelsBruce Pratt, Genzyme Corporation

20 New Patents for Old DrugsLabel-based strategies in the United StatesNed Israelsen, Knobbe Martens Olson & Bear LLP

24 InnovationThe key growth mantraSasikant Misra, Confederation of Indian Industry

reSearch & Development36 Biosimilar MedicinesUnderstanding the challengesCecil Nick, PAREXEL International

40 Drug Discovery in AcademiaAn evolving modelEdward Holson, NovoNordisk A/S

44 Preclinical Research in Big BiotechVertical integration is the keyDavid R Webb, Celgene Corporation

46 Computerised Cognitive Function AssessmentComing of ageKeith A Wesnes, Steve Satek, Andrew C Embleton, Rianne E Stacey Cognitive Drug Research Ltd.

Contents

Targeted TherapiesA sustainable business model?

Erik Tambuyzer, Genzyme Corporation

Personalised MedicineChanging business models

Bruce Quinn, Foley Hoag LLP

Personalised Medicine and Drug Development

Biomarkers leading the way Michael Lutz, PGxHealth

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manufacturing51 Lyophilisation Process DevelopmentYves Mayeresse, GSK Biologicals Industrialisation

53 OEE Systems and Software Enhancing operational efficiencyPala Bhushanam Janardhan, HCL Technologies Ltd.

clinical trialS57 Clinical Trials in OncologySome sense and simplicity Iman El-Hariry, GlaxoSmithKline

60 Accelerating Central Nervous System TrialsNeurophysiological approachesLarry Ereshefsky, Malek BajboujPAREXEL International

65 Optimising the Site Selection Process Assessment of investigator motivation Benjamin Quartley, Clinical Development Services, Covance

70 Developing Benefit-Risk management programmes Best practicesAxel K Olsen, Quintiles, Inc.

74 Clinical Trials in China and Japan Dynamic opportunities for sponsors and CROs Nick Wright, Tufts University

68 Innovation for GrowthGlenn Saldanha, Glenmark Pharmaceuticals

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Senior Product Manager and editorAala Santhosh Reddy

aSSiStant Product ManagerBhamoti Basu

editorial aSSociate and coPy editorPrity Jaiswal

art directorM A Hannan

Senior deSignerAyodhya Pendem

SaleS ManagerRajkiran Boda

SaleS aSSociateSKunal AhujaMurali Manohar John Milton Kirtana John

aSSiStant Manager – coMPlianceP Bhavani Prasad

crMYahiya Sultan

SubScriPtionS inchargeVijay Gaddam

it teaMIfthakhar Mohammed Azeemuddin Mohammed Sankar Kodali Thirupathi Botla N Saritha

chief executive officerVijay Chintamaneni

Managing directorAshok Nair

Adv

isor

y B

oard

Sasikant MisraDeputy Director, Confederation of Indian Industry, India

frank a JaegerDirector, New Business Development, Solvay Pharmaceuticals, Inc., USA

douglas MeyerSenior Director, Aptuit Informatics Inc., USA

christopher-Paul MilneAssociate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

alan S louieResearch Director, Health Industry Insights, an IDC Company, USA

georg c terstappenChief Scientific Officer, Siena Biotech S.p.A., Italy

Sanjoy rayDirector, Technology Innovation, Merck Research Laboratories, USA

rustom ModyDirector, Quality and Strategic Research, Intas Biopharmaceuticals Limited, India

Phil KaminskyFounder, Center for Biopharmaceutical Operations, University of California, Berkeley, USA

neil J campbellCEO, Mosaigen Inc. and Partner, Endeavour Capital Asia Ltd., USA

laurence flintAssociate Director, Clinical Research, Schering-Plough Research Institute, USA

Kenneth i KaitinDirector and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA


indian pharmaceutical industry on the cusp of a great opportunityleading research-based indian pharmaceutical companies spend less than 10 per cent of their sales on research. in the interest of overall public health, india should allow patents for incremental innovation. incremental innovation, or innovation by sequential steps, is essential to pharmaceutical development of new and improved medicines and public health and is indeed the major way in which medical science has progressed.

Ranjit Shahani, Vice Chairman & Managing Director, Novartis India Limited, India

The pharmaceutical industry in India is on the cusp of a great opportunity—the opportunity

to innovate and create novel medi-cines to meet unmet medical needs of today and the future, thus making a positive impact on global health. It is imperative to capitalise on the enor-mous wealth of creative and scientific resources that our country has been blessed with for the benefit of the patient by discovering medicines for unmet medical needs.

As we go forward, India is tipped to become a pivotal player in the global economy and the country’s pharmaceuti-cal industry stands on firm ground both as a provider of authorised generic drugs as well as the seat of pharmaceutical research. This position however is only attainable if India aggressively nurtures innovation and is seen as a country that respects intellectual property rights while tackling the twin issues of health and education.

Newer, more effective products at lower costsThe pharmaceutical industry is under growing pressure from multiple stake-holders to keep delivering blockbuster products providing fair return to inves-tors while at the same time ensuring that prices are affordable. Currently, it takes at least eight to ten years to bring a compound from an idea to a usable medicine. During that time, pharmaceutical companies spend up to US$ 1 to 1.7 billion in researching, developing and testing to create a single drug. Sources show that while US$ 100 billion worth of drugs will be going off patent by 2010, clinical development time has actually doubled since 1982 to an average high of 68 months.

Boxed in as it is from all corners, pharmaceutical companies have to rely on their innate skills to deliver products that meet not only the medical needs of today but also that of the future. While doing so, pharmaceutical companies

need to keep a keen eye on research costs and look at the various avenues to partner with others so as to deliver newer and more effective products at lower costs.

India on its way to become a pharmaceutical powerhouseLooking back at history, much of the progress of civilisation in various fields including mathematics, physics, chemis-try, astronomy, medical science and the arts can be attributed to India. There is ample evidence to show that vari-ous kinds of surgeries including plastic surgery, ophthalmic surgery and dental surgery were being done in India long before they were even known in other parts of the world.

The world has long since changed and India has lost ground relative to some other economies in the area of pharmaceutical innovation. However, today the world has moved to become a knowledge economy and India with

Strategy

� PhArmA Focus AsiA issuE - 10 2009

its vast intellectual capital has an advan-tage over many other nations. With a prodigious knowledge pool, expertise in process chemistry and proven leader-ship in IT, India has all the ingredients necessary to become a developed country in the pharmaceutical field. In addi-tion, the pharmaceutical industry is a mature industry with a strong manu-facturing base. It is also well developed as an ancillary industry and has the technological capability to manufac-ture Active Pharmaceutical Ingredients (APIs). India has the largest number of US FDA approved plants outside the US and the recent development of the US FDA setting up a base in India is of great significance for the country and her capabilities. Besides being a net foreign exchange earner, the pharmaceutical industry has shown skills in being cost-competitive throughout the value chain. Above all, India has the third largest English-speaking scientific and technical manpower in the world and its people have shown significant entrepreneurial spirit. The industry has a well-deserved reputation for producing low cost / high quality medicines.

Need for world-class IPRAs the world ushered in the New Year on January 01, 2005, India ushered in product patents. However, there were no fireworks to mark the defining moment of the Indian pharmaceuti-cal industry.

With the advent of a new era in product patent law, the Indian pharma-ceutical industry began the important shift toward research and development. Leading research-based Indian phar-maceutical companies spend less than 10 per cent of their sales on research. While this figure seems abysmally low as compared to what the large pharma-ceuticals companies of the world spend, it is a good beginning. However, the law needs to see some changes before

the Indian pharmaceutical industry can be called truly world-class.

The law as it stands today does not recognise incremental innovation or inno-vation in sequential steps. It is important to recognise the tremendous value that incremental innovation has made to the progress of modern science. It is in the interest of overall public health for India to allow patents for incremental innovation. Breakthrough innovations in all fields are rarer than we imagine. The invention of the wheel was a break-through innovation in transportation. What came later by way of the bicycle where two wheels, pedals and gears were put together, completely revolutionised the way people travelled over land and practically did away with horse-drawn

transportation. The discovery of the steam engine offered transport an alter-native source of power. Once a suitable gas-powered engine was perfected, this innovation replaced the earlier steam engine, creating the first automobile and changing the way people and goods were transported.

At no time in this process of invention did an innovator go back to the drawing board to reinvent the wheel. What an innovator did do was build on the existing knowledge base and by using additional creative thinking and going through a process of further research and trials so that he could come up with a better and more efficient means of transport. One base technology—the wheel—has been continuously modified to make transportation as we know it today.

If drug discovery is perforce required to go back to the drawing board in its quest for new medicines, the kind of time and money that would be required would not only be mind-boggling but would also significantly delay the deliv-ery of new medicines to patients. As a global pandemic becomes a reality, biological weapons become a threat and preventable diseases continue to take lives, we should work to shorten the amount of time it takes to bring a product to market, not unnecessarily lengthen it.

From improving a medicine’s safety and side-effect profile to find-ing a solution for unmet medical needs and increasing a country’s productiv-ity, incremental innovation provides

exceptional value for patients and society. Over 70 per cent of medicines on the market today are the result of incre-mental improvements on a base molecule.

The central role played by incremental innovation in medical progress must be recog-nised and failing to do so would mean a disregard for the way in which healthcare has progressed. Granting patents to incremental

innovations is critical for India to not only encourage national pharmaceutical companies to increase their research focus but also to ultimately bring better medicines to the people of India

It must be stated that incremental innovation is not “evergreening” which is an attempt to extend patent protec-tion for a product by making minute changes to a drug just before patent expiry. Changes made for evergreen-ing purposes do not represent medical advancement and often do not bring additional therapeutic benefits while changes made to convert a compound into a better medicine provide clini-cal efficacy and exceptional value for patients and society.

Patients are the ultimate benefici-aries of pharmaceutical research and

The pharmaceutical industry is under growing pressure from multiple stakeholders to keep delivering

blockbuster products providing fair return to investors while at the same

time ensuring that prices are affordable.

Strategy


development. An important part of the research and development jigsaw is data gathering on the safety and effectiveness of drugs. Lack of data protection, an integral part of intel-lectual property rights, acts as a barrier to research. Pharmaceutical companies generate significant amounts of data while conducting research and this data goes to government by way of a dossier while seeking marketing approval for a new drug. Unfortunately, this data is used by makers of generic drugs in India to get regulatory approval for their medicines without conducting clinical trials. There is a fear, unsubstantiated I might add, that protecting this data will lead to higher drug prices. There is no reason to believe this as history shows that there is no correlation between data protection and the pric-ing of drugs. Data protection exists in many countries including China, Egypt, Mexico, Columbia, Korea, Brazil and Taiwan for a period ranging from 5 to 6 years. Market forces including limi-tations of purchasing power help keep prices down.

Innovation nurtures creativity and productivityInvestments to grow our capacity for research and to create intellectual capital in the pharmaceutical space will not help if we as a country refuse to respect intellectual property rights.

Indian pharmaceutical companies must be geared to nurture innovation as it leads to greater productivity, higher economic growth and better standards of living. There are various ways to achieve this including public funding of research, collaboration with academia, funding via surpluses of large corpora-tions involved in traditional businesses, venture capital funding and the like.

Our country has a glorious past and there is every reason to believe we can achieve in pharma what we have managed to achieve in IT. A strong patent regime will instill confidence in innovation, research and creativity in

global and national companies operating in India and encourage them to increase investments in the country, especially in pharmaceutical research and enter into partnerships where appropriate.

As eminent scientist and Director General of the Council of Scientific and Industrial Research (CSIR), India, Dr. R A Mashelkar said not long ago, “the process of globalisation, corporatisation and privatisation of research has shifted the dynamics of knowledge production and dissemination dramatically just as issues of Intellectual Property Rights (IPR) and proprietary information and knowledge have begun to open up new dialogues on public good versus private profit. New models of the innova-tion chain and new paradigms of the science-society contracts have begun to emerge.”

It is heartening to know that India actually has the highest intellectual capi-tal available per dollar anywhere in the world. In fact a publication of the stand-ing of The Far Eastern Economic Review had remarked that India ranked number one as the source of knowledge work-ers—ahead of all other countries in Asia including China, Japan and Singapore. CSIR to date has 302 patents in the field of medicine alone. In chemistry it has 1799 patents, 221 in biological science, 90 patents in analytical techniques.

Estimates indicate that it costs over US$ 1.2 billion to get a single New Chemical Entity (NCE) into the market. Multinationals can outsource much of their R&D clinical activity to India lowering their overall costs. Conducting preclinical and clinical trials in India has three-fold advantages. Firstly, the cost of such trials in India would be in the range of 30 to 50 per cent of costs

in the US and EU. Secondly, India has huge genetically diverse patient pools who are “drug naïve”, not having taken any drugs for their condition. Thirdly, the country has a significant number of qualified doctors who have the exper-tise to conduct and supervise clinical trials as per global standards. And it is not just in the area of clinical trials that India has fair opportunity to be a strategic partner but also in the areas of contract manufacturing, custom synthesis, biostatistics, bioinformatics and technical services among others.

Partnering to winCollaborations will be the way forward and are a win-win situation offering Indian companies an opportunity to tap into the world’s largest global research networks and providing access to new technologies. The industry also serves as a platform for Big Pharma to tap into the huge scientific talent available in India.

India has the potential of becoming a hub for drug discovery programmes. While there are some concerns with regard to IPR particularly with regard to enforcement and these clearly continue, the framework is in place. An environ-ment where innovation and research are encouraged will only serve to raise the level of interest in the country as an investment destination.

There is therefore little doubt that as time moves on, India will quickly emerge as a leader in the world pharmaceutical market. Will the 21st century belong to India? Will India, the land of milk and honey, go back to realising as in ancient times that “Prajnam Brahma” or Knowledge is God? Why not? I have every reason to believe it will.

Ranjit Shahani is a strong proponent of ipr and a thought leader in the pharmaceutical industry. he was president of the organisation of pharmaceutical producers of india (for an unprecedented three terms).

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mega mergerSARe they tuRning

phARmA CompAnieS into

Biotech consolidation through acquisition was the primary trend in 2007 for the big pharma and the global financial

crisis in 2008 has driven the pharmaceutical industry towards adopting a short-term myopic m&a approach. the innovation

gap for new drugs has widened to a cavern. in 2009, the industry has some interesting questions to answer. how to

close this innovation cavern and how will the pharmaceutical industry manage short-term perceived benefits at the expense

of long-term woes in building sustainable drug pipelines?

neil J Campbell, CEO, Mosaigen, Inc. andPartner, Endeavour Capital Asia Ltd. USA

Strategy



Over the past two years, big pharma has strived to achieve revenue growth and pipeline

stocking through M&A. In 2007, the pharma industry mainly targeted late-stage biotechnology acquisitions to consolidate some drug development platforms, namely those with disease franchises and drug class expansion. Then came the ever-worsening financial crisis during 2008 that rapidly spread to become a global recession. This has put many big pharma companies into a holding pattern exacerbated by difficul-ties of accessing finance and the need to satisfy investors for the short-term.

One interesting observation is that at the time of writing this article, more than 40 per cent of the biotech companies in the US had less than a year of cash on hand. Does this serve as a once-in-a-lifetime-opportunity to build value by rapid M&A of biotech companies that could stock various stages of develop-ment for big pharma?

The latest pharma rage – Mega mergersThe forcible merger of two big compa-nies that lack innovation doesn’t necessarily result in forming a good company. There have been academic and industry studies that have shown that this strategy had failed time and again to create any value for shareholders, drug pipelines and ulti-mately patients beyond a few years. The past 12 months have witnessed many such deals in the pharma industry. (Table 1).

The mega merger of Pfizer and Pharmacia in 2000 illustrates how a merger, which lacks long-term value, has huge dilution and which is not properly integrated, fails. The Pfizer CEO, Jeffrey Kindler, was on the airwaves touting the

great value that this upcoming Pfizer-Wyeth mega merger would provide. What is interesting here is that in all his interviews Jeffrey Kindler was overtly promising that the past failures to inte-grate value into the past M&A would not be repeated. As a result, many large pharma companies are still going for mega mergers. The latest being Pfizer-Wyeth mega merger for about US$ 68 billion in stock and cash.

The Pfizer-Wyeth deal, if consum-mated, would be the fourth largest M&A deal ever and would give Pfizer the distinction of having made the first, fourth and fifth largest pharmaceutical deals in history. Pfizer is still trying to integrate the Pharmacia acquisition of 2000 which was the fourth and now is the fifth largest deal ever (Table 2). The deal will merge two major pipelines with patent expiry falling in the period 2011-2013. Lipitor alone constitutes 35 per cent of Pfizer’s annual sales accord-ing to the latest IMS studies and Pfizer press reports.

Putting two anaemic pipelines together with no innovative system in place doesn’t make one great pipeline for future growth. In fact, Jeffrey Kindler repeatedly stated on news interviews that this deal would unlock value for both companies and solve the short-term prob-lems facing Pfizer. He repeatedly stated that past M&A mistakes that destroyed value will this time provide value. Time alone will reveal the truth, but the analy-sis of the combined pipelines seems to be making a bigger issue and is expected to affect investors and value.

It can take years to integrate the R&D and corporate cultures following these mega mergers—business develop-ment groups can be taken off task for up to two years while trying to manage the integration. Big pharma companies

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10 PhArmA Focus AsiA issuE - 10 2009

Largest pharma M&A deals

Target Acquirer Deal Value (US$ bn)

Warner-Lambert Pfizer 111.8

SmithKline Beecham Glaxo Wellcome 79.6

Aventis Sanofi-Synthelabo 71.3

Wyeth Pfizer 68.3 (Pending)

Pharmacia Pfizer 59.8

Genentech Roche 42.6 (44.1% Stake)

Astra Zeneca 39.9

Hoechst Rhone-Poulenc 33.8

Pharmacia & Upjohn Monsanto 31.9

Ciba-Geigy Sandoz 27.0

Schering Bayer 19.3 (92.4% Stake)

Sources: Dealogic, Company News

Table 2

Biggest health care buys – The last 12 months

Buyer Buyer Home City Acquiree Acquiree Home CityDeal Size (US$

bn)Deal Announced

AstraZeneca PLC London MedImmune Gaithersburg, Md. 13.8 April 24, 2007

Novartis AG Basel, Switzerland Alcon Vevey, Switzerland 10.5 April 8, 2008

Takeda Osaka Millennium Pharmaceuticals Cambridge, Mass. 8.8 April 10, 2008

Hologic Bedford, Mass. Cytyc Marlborough, Mass. 6.3 May 21, 2007

Siemens AG Munich Dade Behring Holdings Deerfield, Ill. 6.2 July 26, 2007

Warburg Pincus New York Bausch & Lomb Rochester, N.Y. 3.6 May 17, 2007

Eisai Co., Ltd. Tokyo MGI Pharma Bloomington, Minn. 3.3 December 11, 2007

Medtronic Minneapolis Kyphon Sunnyvale, Calif. 3.3 July 28, 2007

Roche Holding Basel, Switzerland Ventana Medical Systems Tucson, Ariz. 3.1 June 26, 2007

Celgene Summit, N.J. Pharmion Boulder, Co. 2.5 November 19, 2007

Source: Mergerstat via Factset Systems• The top 10 acquisitions of life science firms over the past 12 months came at a total purchase price of US$ 48 billion. • Five of the acquisitions were of U.S.-based companies by bigger companies in Europe or Asia. • These buyers spent US$ 35 billion, or 73% of the total. Table 1

are scared and have started reacting to the industry woes. These woes are being driven by a slowdown in growth as reve-nues come under threat from expiry of patents of blockbuster drugs, shrinking pipelines from original science programmes and the ever-increasing reach and breadth of generic drug competition. Are there alternatives to this mega merger mania? Well, you have Astellas, the Japanese Pharma (Fugisawa and Yamanouchi consolidation) moving towards acquiring Small to Mid-size Biotech (SMBs); could this be a better place to put money, time and longer-term focus? (Table 1).

Global financial credit crisis – A silver lining for the big pharma?With so many biotech companies short of cash and in mid to later stages of clinical development, does this provide a buying opportunity for low-cost drug pipeline stocking? It sure seems that way.

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Industry trends driving the mega mergers bandwagon

Industry Trends Driving Mega-Mergers Effect on Growth Strategies

Big Pharma focus is on sales and marketing No drug pipeline development, push limited life to secure sales at longer term benefits of building sustainable businesses

Big Pharma spending more on marketing than R&D for new drugs

Misaligned priorities to innovation, reward now, not later, bad trend to start

Consolidate with like-minded large companies Mind-set to find other Big Pharma, Stunt long-term growth potential, missed opportunities with smaller biotechs

Blockbuster legacy drug patent expiry in next several years

Short-term stocking M&A at risk of finding medium and longer term synergies

Cost to development increasing-failure rates increasing

Regulatory shift since Vioxx to safety over efficacy, need better balance reviews

Generic drug growth / biogenerics coming Other drug strategies such as Nutriceuticals, Cosmeceuticals, Therapeutic medical devices

For smart companies, this is portfolio management; for myopic ones, knee-jerk reactions to save businesses, currently mega merger mania

Table 3

Potential benefits that biotech M&A provide

Aspects of Biotech M&A Potential Benefits to Big Pharma

Short of cash, less than yearCould pull M&A together quicker for impact to short to medium term

Lowest company valuations in 25 years Ability to "shop" and buy many ones

Biotechs, historically, have science platforms that built their drug portfolios

Build medium to longer term value for drug portfolio, have potential revenues, but platforms for innovative development

Some biotechs could provide new franchisesBig Pharma add-ons could be diseases, drug classes, or operational capabilities

More biotechs have Big Pharma partnerships- drive interesting options

If selected properly, big pharmas could stock pipelines and force big pharma to big pharma collaborations / M&A with the biotechs who have big pharma partnerships

Provides many more variables for deal-making and out-licensing monetisation strategies

Financial crisis has tightened up credit, this could allow for more original deal-making

Table 4

If big pharma can muster a strong busi-ness development and licensing effort, they can merge or acquire a succession of smaller biotech companies and fill the gaps in drug pipelines from late preclini-cal / pre-IND to phase III / NDA. This thought is probably causing big pharma heartburn, but what are the alternatives: mega mergers? There are many prob-lems that mega mergers won’t address (Table 3). Three interesting deals at the moment are the GSK-Attack Strategy, the continuing saga of Roche’s attempt to buy the remaining shares in Genentech and the Astellas-CV Therapeutics replay from the fall of 2008.

There are many benefits to an aggres-sive biotech M&A roll-up approach. Let’s look at the three scenarios in reverse order.

Astellas and CV Therapeutics – Hostile takeover attemptAstellas is moving in on a hostile take-over with a second attempt at CV Therapeutics. The first attempt was in the fall of 2008 with CV Therapeutics turn-ing away from any deal. As the market has moved downwards and cash reserves dwindled, Astellas feels that the addi-tion of CV Therapeutics would provide growth into new areas and potential revenue paths for the medium future. Being a Japanese pharma company and concerned with long-term growth pros-pects along with a willingness to build out new franchises in both diseases and drug classes and shouldering some of the risk, Astellas is bucking the trend of Wall Street pressures, quarter-to-quar-ter financial performance and western big pharma. The deal that formed Astellas—putting together Yamanouchi and Fujisawa—built a sustainable foun-dation to grow from. It is predicted that Astellas will make more smart acquisi-tions in the next couple of years and take advantage of the current financial crisis. Table 4 presents a summary of drivers providing advantages to larger pharmaceutical companies with their biotech brethren.

drug pipelines. The first deal acquired a 44.1 per cent stake in Genentech at a cost of US$ 42.6 billion making it the sixth largest deal to date (Table 2). This time around, it could cost Roche double that sum. Genentech, one of the two largest biotechs in the world, could very well rebuff the Roche deal and start its own biotech M&A strat-egy. An approach that can be more

Roche and Genentech – Remaining share buyoutAnother interesting potential trend-setting deal involves the buyout of remaining Genentech shares by Roche. Roche is driving hard to purchase the remaining stake of Genentech to form the largest biopharmaceutical company with broad research platforms, core capabilities, preclinical and clinical

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Strategies for drug development

Drug Development & Approval Process

Postmarketing - Phase IV

Preregistration - FDA/EMEA

Clinical Trial - Phase III

Clinical Trial - Phase II

Clinical Trial - Phase I

Preclincal Testing

File NDA at FDA

File IDA at FDA“Sponsored” Research Approaches

“Co-Promote” Approaches

“Co-Development” Approaches

“PDC” Development Approaches

“Foster” Development Approaches

Figure 1

Sources: Pharmaceutical Research and Manufacturers (PhRMA) Annual Report 2007; Burill & Company Report 2003; PhRMA Annual Member Survey, 2007: US Food & Drug Administration Databases.

The pharma innovation gap – Increased R&D spending yielding lesser drug approvals

Figure 2

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accretive for Genentech shareholders and a better fit with the corporate culture in California. A Roche takeover could kill the remaining innovative juices that Genentech has. One thing is probably for sure, the co-founder and current CEO, Levinson may leave his position if the deal goes through; not necessar-

ily a bad thing. We would like to see him in a more expansive role helping more biotechs grow to become future Genentechs.

Aggressive M&A strategies of GSKThe global financial crisis has provided an opportunity for big pharma to really

make a difference in how they build value into their drug pipelines. The crisis has plummeted company valu-ations to their lowest level in 25 years (the life of the biotech industry is almost that old) and it is estimated that more than a third of the over 3,500 biotech companies that exist in the US have less than a year of cash on hand. With most pundits predicting that financial problems would continue till mid-2010, you have a lot of companies with potentially great science and pipelines in clinical development on the verge of extinction.

Enter GSK. Although some are predicting the Pfizer-Wyeth deal could help Pfizer with short-term revenues and give a little breadth from the Wyeth pipeline, most are pointing towards GSK as the company and M&A trend to watch more closely. To date, GSK has avoided any mega merger in favour of mobilising its cash on smaller, more asset-building type of deals. The goal is an obvious one: to address long-term problems instead of adopting a myopic blockbuster-drug-only strategy and build both drug classes and drug portfolios in focussed disease franchises. Over the past 24 months, GSK has aggressively bought an accretive, sustainable and potentially expansive diverse set of drug assets—such as UCB’s late-stage drug assets and Biotene’s dry mouth drug treatment—in both established and emerging markets. It is also rumoured that GSK is looking at more targeted diversified healthcare companies and this approach could provide for more portfolio management across healthcare systems.

Adopting new development strategies Johnson & Johnson, Abbott Laboratories and Novartis are just a few to deploy this approach with repeated success. Companies like OSI Pharma, Celgene, Amylin are just a few who are still inde-pendent and could provide great buys for big pharma. Combine one of these

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neil J Campbell is currently chairman & ceo for mosaigen®, inc., a global life Science development corporation, and partner with endeavour capital ltd., an asian venture capital fund. During his career, he has successfully developed and introduced over 200 products in healthcare, life sciences and information technologies. he earned his mBa and ma in management Systems from Webster university, mo and his BS-Ba from norwich university. he is also adjunct professor at carey graduate School of Business – Johns hopkins university.

Predictions for 2009 and 2010GSK, Roche and Novartis represent some of the best possible examples of building a diversified and scientifically-rich big pharma and could very well use the multiple biotech M&A model. As Roche eventually acquires the remain-ing shares of Genentech it will have a fairly balanced small molecule portfolio / pipeline with advanced biopharma capabilities. Genentech, one of the two largest biotech leaders worldwide, has both short-term goals combined with long-term visions. Amgen should be seeking targets for M&A, not being acquired. Astellas might lose out on this bid with CV Therapeutics, but they can have a short list for M&A. Companies like Abbott Labs and Celgene provide great add-on revenues, deep pipelines and sound scientific platforms.

Those companies seeking growth only through the mega merger approach will have limited success, take them-selves out of contention during one of the most opportunistic times we’ve seen in decades and could spell potential disaster for the big pharma seeking to grow revenues in the medium to long term.

Pfizer-Wyeth in the end won’t be any better than its previous mega merger deals and hopefully they will see this and push along with vetting and closing a few biotech M&A deals before the good ones are gone. In the end, these purge cycles are good because they force the crème de la crème to the top and this is what we need to bridge the gap in innovation among the Big Pharma companies.

companies with smaller biotechs and you could build a strategy around developing some drugs yourself, co-developing with other partners (possible future acquisi-tion targets), co-promoting late-stage assets to free up resources for creative development strategies like fostering drug programmes. AstraZeneca is very good at this. License a drug to a company, have that company develop the asset in close ties with it and at some pre-determined point in the future, it gets the rights back if requested. If not, the biotech / pharma partner has rights to development or share a range of busi-ness development options.

Another approach is the Pharmaceutical Development Company (PDC) option. One of the best compa-nies to create and lead with great success using the PDC model is DeBiopharm, S.A in Lausanne, Switzerland. In the PDC model, a company acquires the drug asset which is generally at a Pre-IND or phase I stage and takes owner-ship. It then develops it through phase II, phase III or NDA. In return, the PDC gives milestone payment, royalties and / or sales kickers to the original source of the drug asset. Most PDCs don’t promote the products, they usually sell or out-license the asset to a larger company. The PDC and fostering models are great strategies for shar-ing resources, risk and allowing larger companies to leverage a stockpile of drug candidates on their shelves that may never be developed. Figure 2 depicts the overall strategic approach to drug portfolio development and management.


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pharma and Biotech

collaborative modelscollaborations are a common business practice within the pharmaceutical and biotechnology industry. this article discusses both the strategic and tactical drivers for engaging in collaborations as well as some of the distinguishing features of the various types of collaborations used in this industry.

Bruce m pratt, Vice President, Science Development, Genzyme Corporation, USA

Collaborations are the voluntary, joint actions of two or more parties to achieve a common

goal. This is a straightforward concept in principle, but often more complex in the real world.

Within the pharmaceutical and biotechnology sectors, one can easily identify at least six major classes of stakeholders, viz. private indus-try, academia, regulatory agencies, governments (policy and legislation), patient advocacy groups, and payers (public / private). Each of them can be involved in collaborative activities with one or more organisations in their own or other stakeholder categories. On a purely numeric basis, a single stakeholder could be involved in as many as 32 different kinds of collabo-rative interactions with organisations from their own or other stakeholder categories.

When discussing collaborations as a class of business transactions, it may be useful to consider why a corpora-tion should engage in collaborations at all—after all, the typical outcome of any collaboration involves the sharing of the upside with an outside party.

However, within that outcome lie the two fundamental reasons for engag-ing in collaborations. First, the belief that the apportioned, and anticipated return on investment from the shared outcome will exceed that which might be achieved independently. The second, and equally important driver for collaborations, is the recognition, by each party, that they have insufficient internal resources, e.g. cash, expertise, time, infrastructure or intellectual property, to independently achieve the desired outcome. Within the pharma-ceutical and biotechnology sector, two fundamental objectives underlie much of what we do: First is the need to get effective therapies and service to patients with unmet medical needs; and second is the necessity to create and maintain sustainable economic models which allow for the continuous crea-tion of needed products and services. Collaborations are, in the broadest sense, tools which can be used to achieve these objectives.

In this context collaborations are classified into three categories—non-competitive, pre-competitive and competitive.

Begin at the beginning… and go on till you come to

the end: then stop.

Lewis CarrollAlice’s Adventures in Wonderland

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1� PhArmA Focus AsiA issuE - 10 2009

Non-competitive collaborationsThe first group, non-competitive collaborations, is best exemplified by private industry-academia collabora-tions. Within the US, this model of industry-academia collaboration, with its concomitant flow of innovation from academia to industry has its basis in the Patent and Trademark Act Amendments of 1980 (University and Small Business Patent Procedures Act), more commonly known as the Bayh-Dole Act. Under the provisions of this act, universities, non-profit organisations and small businesses can obtain and retain ownership of, and patents on, inventions funded by the federal government. Additionally, the act requires that the universities actively engage in the commercialisation of these patented assets. With this legal founda-tion, American universities have, over the past 28 years, become increas-ingly important and currently essential sources of innovation for the pharmaceutical and biotechnology sector.

In non-competitive collabo-rations, such as those of indus-try and academia, the desired outcomes by each party are generally non-overlapping. For example, the industrial partner may be seeking novel product / service oppor-tunities to develop within their own pipeline, or access to the specialised analytical or preclinical expertise of an academic laboratory. In a complementary fashion, the academic partner may be seeking to commercialise an asset devel-oped within the university or to generate new scientific observations (publications) by evaluating the activity of a novel pharmaceutical agent in a preclinical model which is well established within the academic laboratory.

Although the qualitative distribu-tion of outcomes, e.g. de-risked prod-uct / service opportunity, scientific publication(s), is relatively straightfor-ward, the quantitative prediction of the value of these outcomes can sometimes be a critical point of disagreement /

discussion / negotiation between the two parties. Such differences in valuation are to be expected. Each party is striving to maximise their return on investment (money, personnel and infrastructure), while simultaneously working to reason-ably reduce / limit their costs.

Pre-competitive collaborationsThe second major class of collaborations, pre-competitive collaborations, also have a legislative underpinning within the US, in this case, The National Cooperative Research Act of 1984 (NCRA), and the National Cooperative Research and Production Act of 1993. These laws were enacted to enhance the competitive-ness of the US-based industries in an increasingly competitive international marketplace. The 1984 law clarified the application of anti-trust law to co-opera-

tive research ventures, and eliminated the treble damage awards associated with anti-trust violations. These benefits accrue to the members of a collabo-rative research consortium, provided that the consortium complies with the mandated disclosure of all participants and the purpose of the collaboration. The 1993 amendment extended similar provisions to joint production activities. Although more than 900 groups have registered under NCRA since 1984, registered collaborations in the phar-maceutical and biotechnology sectors represent substantially less than 5 per cent of the total.

To begin to probe why this collabo-rative model is apparently not favoured by the pharmaceutical and biotechnol-ogy sector, we can examine some of the main characteristics of this type

of collaboration, and consider their match (or mismatch) with some essen-tial aspects of the business model of the sector. The essential hallmark of pre-competitive collaborations is the focus on the development of tools and standards, and not the development of products and services. This aspect of pre-competitive collaborations is exemplified by one of the earliest and most often cited NCRA collaborations, Sematech. It was initially established as an industry / government collabora-tion for the development of advanced manufacturing methods for the US semiconductor manufacturing sector, and was created in direct response to the perceived domination of this manu-facturing sector by Japan.

Table 1 is a sampling of pre-competi-tive collaborations in the pharmaceuti-

cal and biotechnology sectors. Several points are notable. First, as mentioned above, all of these collaborations are focussed on the development of information, tools and standards, putting them clearly in the pre-competi-tive space. Second, five of the seven are dedicated to generating massive data sets from various

“omes”, genome, proteome, kinome etc. and analysing these data sets for relatively sparse information which, by itself, may have minimal competitive value. This general information, however when combined with proprietary and drug-specific information belonging to the individual participating companies, will be expected to provide a compara-ble, but unique competitive advantage to each participating corporation. The remaining two consortia, Aerosol and Enlight, are also focussed on problems whose solutions are likely to provide significant competitive advantages only when combined with additional propri-etary, drug-specific information. This synergistic linkage of commonly held and proprietary information is a second defining criterion of pre-competitive collaborations.

The essential hallmark of pre-competitive collaborations is the focus on the

development of tools and standards, and not the development of products and services.

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Sampling of pre-competitive collaborations in pharmaceutical and biotechnology sectors

Group Name Activity Participants Start Year

Pharmaceutical Aerosol Consortium

Identification of CFC-free propellant gases for aerosol delivery of drugs

Private Industry 1990

Dundee Kinase ConsortiumResearch on kinases and phosphatases for drug discovery

Private Industry, Academia, Government

1998

SNP Consortium / HapMap Project

Identification of Single Nucleotide Polymorphisms (SNP) and haplotypes associated with human disease states

Private Industry, Non-profit organisations, Governments, Academia

1999

Predictive Safety Testing Consortium

Identification of biomarkers to predict preclinical safety of drugs

Private Industry, Academia, Regulatory Agencies

2006

Biomarkers ConsortiumIdentification of biomarkers for risk assessment, diagnosis and treatment of human diseases

Government, Private Industry, Not-profit organisations

2006

SAE ConsortiumIdentification of SNP’s associated with drug-related Serious Adverse Events (SAE)

Private Industry, Academia 2007

Enlight BiosciencesEnabling technology incubation – first program: non-invasive imaging

Private Industry, Venture Capital Fund

2008

To return to the possible reasons for the relative paucity of pre-competitive collaborations within the pharmaceuti-cal and biotechnology sectors; although information / tools can be the subject of pre-competitive collaborations, they can also provide a competitive advantage to their owner. If an individual corporation has the resources and infrastructure to create a proprietary data set, extract useful information from that data set, and protect that information as trade secrets or patents, they will certainly do so. As noted earlier, a corporation is only going to collaborate in this effort when they have insufficient internal resources to complete the task on their own. Until recently, the complexity of problems, and size and complexity of the resultant data sets which were tackled by pharmaceutical or biotechnology companies were generally manageable as intramural projects, providing little impetus for pre-collaborative collabo-rations. However, with the arrival of “omes”, genome, transcriptome, proteome, metabolome, lipidome etc., some projects at this scale have become

too massive and “drug-relevant” data too sparse to be cost-effective as intramural projects, and consequently, albeit slowly, are becoming the foci of pre-competi-tive collaborations.

Two additional factors may be contributing to the historically low numbers of pre-competitive collabo-rations. Until relatively recently, the standard pharmaceutical drug devel-opment model was inward focussed, with the belief that internal research and development could provide a sufficient number of commercially successful drug to sustain the growth of the corporation. Under that model, pre-competitive collaborations would have been unnecessary and perhaps unwanted. In recent years a more exter-nally focussed drug development model has emerged, in which pharmaceutical companies have engaged in increasing numbers of non-competitive collabora-tions with academia. It remains to be seen if this trend towards utilisation of external resources will extend to the pre-collaborative space. An additional factor working against pre-competitive

collaborations may be related to the extraordinarily long product develop-ment life cycle which is unique to the pharmaceutical and biotechnology sectors. Any strategic initiative in the pre-competitive space is unlikely to have a significant impact on a corporation until 8 to 10 years in the future. Given the shorter-term revenue and expense pressures which the pharmaceutical and biotechnology sectors currently face, the allocation of scarce resources to highly speculative, pre-discovery activities may not be viewed in a favourable light. A final factor in this matter may be simply one of cultural inertia. The sector as a whole has much more experience and familiarity with other kinds of trans-actions, e.g. mergers and acquisitions, product in-licensing and joint ventures. Even if pre-competitive collaborations offer some theoretical advantages, in the absence of clearly documented examples of strategic or financial benefit deriving from participation in pre-competitive collaborations, there may be a degree of reluctance to be an early adopter of this strategy.

Table 1

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Competitive collaboration landscape

Minimal overlap

Skill sets / IP / Market

Strong overlap

Equal Not equalValuation / Size

Joint venture / Merger

In / Out-licensing

Strategicalliance

Acquisition

Anti-competitiveAnti-trust

Co-marketing

Figure 1

Competitive collaborationsCollaborations between competitors are also regulated by large bodies of antitrust or competition law in all juris-dictions. Within the US, the Sherman Ant-Trust Act of 1890 briefly states, “Every contract, combination in the form of trust or otherwise, or conspir-acy, in restraint of trade or commerce among the several States, or with foreign nations, is declared to be illegal”. Within this legal framework, the underlying need for competitive collaborations is the same as that of other collabora-tive types, i.e. the need to achieve an outcome which cannot be accomplished alone. To solve this need, a wide spec-trum of collaborative activities between competitors (business-to-business trans-actions) has evolved.

One way to structure and view the relationships between these different types of collaborations is to consider them in the context of a two-dimen-sional space as described in Figure 1. The first axis is the relative valuation and size of the two entities with respect to each other and the second axis is the degree of overlap of skill sets, or intellectual property or infrastructure between the participating entities. Utilising these axes, it is possible to place most competitive transactions within this space. For example, joint ventures and mergers are usually formed between entities of roughly comparable size and complementary skill sets or intellectual property. Licensing deals and strategic alliances are character-ised by a minimal overlap in skills or IP (depending on the subject of the transaction) and are not particularly dependent on the relative size of the two parties. Co-marketing arrange-ments tend to be done between part-ners of roughly equal size, with a strong overlap in market, but some moderate degree of separation in call point or geographic coverage. Acquisitions are typically asymmetric transactions where the larger partner takes control of the smaller party and there is sufficient

lack of overlap in market to avoid anti-trust / anti-competitive issues. Finally, the “buy your competition” business strategy, in which a large entity may wish to acquire a smaller party operat-ing within the same market segment, may run afoul of anti-trust / competi-tion laws. Refinements of this schema are clearly possible. Nevertheless, this approach, even in its current form, may provide some clarification or ration-alisation of the type of collaborative transaction chosen to achieve a desired outcome.

In summary, collaborations involving the pharmaceutical and biotechnology sector, non-competitive, pre-competitive and competitive, may differ in their legal underpinnings, structure, complexity and value. However, all of these inter-actions are driven by: 1) the mutual recognition that some objectives can

only be achieved by the combination of resources from two or more parties, and 2) the mutual expectation that the joint outcome will provide a positive benefit to each party that exceeds what might be achieved by proceeding inde-pendently.Disclaimer: The opinions expressed in this article are personal opinions of the author and do not necessarily represent the opin-ions or positions of Genzyme Corporation or its senior management. Likewise, the identification of specific products, or organisations does not constitute an endorsement of those entities by Genzyme Corporation or its senior management. The commentary on, and summaries of, laws of the United States do not represent legal opinions on these laws.

Bruce m pratt works for Genzyme Corporation on identification and evaluation of early stage product opportunities, proactive outreach to academic and biotechnology sectors, and works with corporate Development on issues related to product devel-opment.

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new patents for old Drugs

LABeL-BASeD StRAtegieS

in the uniteD StAteS

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combination of time, money, and risk has sent venture money fleeing for safer, quicker investments, albeit with a lower upside potential.

Growing investmentsOne bright spot for start-up pharma companies and venture investors has been speciality pharmaceuticals (or repurposed drugs). Such products include drugs that previously fell out of clinical trials and new uses for old

not available for previously-approved repurposed drugs. Finally, the period of data exclusivity in the US FDA (during which a generic application will not be approved) is five years for NCEs, but only three years for repurposed drugs that are not NCEs (See exclusivity chart). Because a three-year exclusivity period is generally insufficient, development of repurposed drugs hinges on the avail-ability of adequate patent protection.

The FDA, drug patents, and generic drug approvalGeneric drug approvals in the US are subject to a detailed regulatory scheme set up by the Hatch-Waxman Act in 1984. Applicants seeking approval of

repurposed pharmaceuticals are attractive candidates for clinical development, but only with sufficient marketing exclusivity. Patents that focus on the uses and compositions in the product label can provide up to 20 years of exclusive marketing rights.

ned israelsen, Managing Partner, Knobbe Martens Olson & Bear LLP, USA

In recent years, particularly since the Dot-com stock market crash in 2000-2001, venture capitalists have

been increasingly reluctant to fund US companies engaging in drug devel-opment. Such investments are often considered to be too risky, too capi-tal-intensive, and to take too long to fit the new, more conservative venture capital model. Indeed, it has been esti-mated that only 1 in 100 preclinical drug candidates and only 1 in 10 drugs that enter US FDA clinical trials ulti-mately receive FDA approval. The aver-age cost of developing a drug through FDA approval is approximately US$ 1 billion, and it takes up to 15 years from discovery to product launch. This

drugs. By starting with a drug that has already been in the clinic, risk is reduced in each category of concern. Approval time is shortened for drugs that have already been proven safe. The cost of the clinical trials is less, because pre-existing ADME and safety data can substitute for expensive research and trials. The risk of failure is also reduced for drugs having known safety and pharmacology. For all of these reasons, repurposed drugs are attracting more and more early-stage investment dollars.

The exclusivity problemA major drawback to the development of repurposed drugs is lack of exclusivity. These drugs simply will not be developed

without sufficient exclusivity to allow a reasonable return on investment. For New Chemical Entities (NCEs), this is usually not a problem, because the typical 20-year patent term (measured from filing) is sufficient. However, for repurposed drugs, the NCE patents often have little or no term left. Moreover, US patent term extension and European Supplementary Protection Certificates apply to the first approval or market-ing authorisation of a drug, and so are

Exclusivities applicable to US drug products

FDA gives regulatory exclusivity

• 3 years for new indication• 5 years for first approval of NCE• 7 years for orphan drug• 6 months additional for paediatric data• Paediatric exclusivity attaches to end

of all other exclusivities, patent or data

Patent term: 20 years from original filing date• Runs concurrently with regulatory

exclusivity• NCE and original method patents often

have little life left upon FDA approval• New 20 year term for label patents

Patent and regulatory exclusivities should both be considered when

evaluating a repurposed drug

a generic drug typically do so with an Abbreviated New Drug Application, or ANDA. The primary scientific data required in an ANDA is the demonstra-tion that the generic product is bioequiv-alent to the originally-approved drug. Expensive clinical trials are not required, because ANDAs rely on the safety and efficacy data generated under the origi-nal New Drug Application, or NDA, of the original innovator. However, if the original drug product or its use is covered

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by patents listed in the FDA’s Orange Book, generic marketing approval is effective only after the patents expire. The exception is when the ANDA-filer certifies that the relevant patents are invalid or not infringed. Such certifica-tion opens the generic drug company to patent litigation, and an automatic 30-month stay of ANDA approval when the patent infringement suit is filed. Thus, having Orange Book-listable patents is a major consideration when investing in drug development.

The importance of the FDA-approved labelIn the course of approving an NDA, the FDA carefully reviews and approves a drug label (also known as the package insert). This label includes information relating to indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, special populations, drug interactions and use in specific populations. With minor exceptions, the ANDA-filer must adopt the approved label. The Orange Book also focusses on the label, listing only patents for approved NCEs, drug formulations, and methods of use that appear in the label. Close coordination between regulatory and patent professionals can enhance correspondence between patent claims and the label.

Extending exclusivity through label patentsA “label patent” is any patent that covers a method or product recited in the FDA-approved label. Because the ANDA-filer must adopt the product label, careful attention should be given to patenting new, non-obvious methods disclosed in the label. Repurposed drugs typically target a new patient population, new indication, or include a new dosage form, dosing regimen or route of administra-tion. Corresponding methods of use in the label are all potentially patentable. Unlike the rule in most countries, meth-ods of medical treatment are patentable

Drug Life Cycle Management – Common patent types

Enantiomer patents• Pro: NCE claims; Orange Book listable• Con: Current obviousness standard makes patenting more difficult

Composition / formulation patents• Pro: Can cover ideal product or most stable formulation; Orange Book listable• Con: Generics can usually design around; obviousness

Crystal form (polymorphs, amorphous)• Pro: Cover stable or desirable product; Orange Book listable• Con: Generics often design around or invalidate

Synthesis or manufacturing method patents• Pro: Cover actual production process• Con: Not Orange Book listable; often designed around

Key intermediates• Pro: May represent a chokepoint in synthesis• Con: Not Orange Book listable; often designed around

Patent strategies for repurposed drugs often overlap significantly with those used for life cycle management of name brand pharmaceuticals

in the US. In short, any time the label instructs the patient or physician to do something, consider whether that method is patentable. The patent term for such new patents is 20 years from date of filing, which can significantly extend the period of exclusivity for the repurposed drug.

Those developing repurposed drugs should not overlook the possibility of obtaining patents on seemingly minor

improvements or innovations that are reflected in the label. Unlike tradi-tional patent strategies, which focus on obtaining broad patents to cover potential modifications, label patents only need to cover the exact method disclosed in the label. This, in turn, can improve patentability by allowing inclu-sion of very specific details in the patent claims that are not obvious in light of the prior art. Obtaining several such

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patents enhances the odds of having a patent that is held valid and infringed at the conclusion of ANDA litigation.

It is desirable to identify potential label patent opportunities prior to public disclosure. When reviewing new clini-cal data, one should look carefully for unexpected or unpredictable results. In addition, it is helpful to ask what changes will be made in the label or the use of the drug as a result of the new data. Each of these areas represents fruitful ground for obtaining label patents.

A word of caution: in case of public companies, clinical trial results are often disclosed very quickly, leaving little time to prepare patent applications on new observations. In this situation, close coordination with highly-responsive patent counsel is important. Although there is a one-year grace period for filing patents in the US, most non-US coun-tries have an absolute novelty require-ment. Thus, filing the US application before any public disclosure can preserve foreign patent opportunities.

Label patents are not necessarily easy to obtainIn the US, patents can only be obtained for inventions that are both novel (new) and non-obvious. In the pharmaceuti-cal area, novelty problems often arise when trying to patent a newly-recog-nised property of a drug. A result that inherently occurred in the prior art is not considered novel, even if that result was unrecognised. In dealing with inher-ency issues, is it helpful to ask whether something different is done as a result of the discovery. If the answer is in the affirmative, then including those new actions in the claim can usually overcome the inherent novelty rejection.

Obviousness can be a major issue for label patent claims. In 2007, the US Supreme Court decided KSR vs. Teleflex, which overturned the requirement that the prior art must contain a teaching, suggestion, or motivation to make the new invention. This case makes patents harder to get and easier to invalidate.

ned israelsen is a lawyer and managing partner of the San Diego office of Knobbe, Martens, Olson & Bear, LLP, California, uSa. he is registered before the uS patent and trademark Office, and advises clients in the area of pharmaceutical and life science patent law, including worldwide protection of new and repurposed drugs.a

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Although some subsequent cases suggest that inventions made through routine experimentation may well be obvious, such a rule may not apply to unpredict-able technologies, such as pharmacology. The very simplicity (and to some, trivi-ality) of some label patent claims may result in obviousness rejections. Good strategies for overcoming those rejections include emphasising the unpredictability of the new discovery, presentation of comparative data (usually available from the clinical trials), long felt need, clinical importance, and lack of suggestion in the prior art. The ability to write very narrow claims (as narrow as the label language) can also help overcome an obviousness rejection, because it is more

difficult to show obviousness of all the details of such a claim.

In addition to overcoming these bona fide legal issues, applicants may face less tangible psychological issues in obtaining and defending label patents. Pharmaceutical inventions in general and follow-on patents in particular may be reviewed more closely in both the Patent Office and the courts. Although the origi-nal NCE and method of use patents are often well respected, the same does not always hold true for follow-on patents. The latter are often filed as part of a drug life cycle management strategy with the objective of delaying or preventing generic competition. In light of the negative image of pharmaceutical companies and the public interest in the availability of low-priced generic drugs, exclusivity-extending patents receive enhanced scrutiny.

Patents for repurposed drugs have a very different purpose from Big Pharma’s life cycle management patents. They often serve a gating function; in other words, without the patent, the repurposed drug will never be developed or available to the public. However, because of the overlap between patent strategies for protecting repurposed drugs and those for product life extension, repurposed drug patents may suffer from the same negative perceptions in the Patent Office and the courts.

Despite these perception issues, in the end, the Patent Office and the courts are bound to follow the same rules of patentability in all cases. Label patent applications do make it through the Patent Office, and the resulting patents provide major value to innovators, drug developers, investors, and the public who receive the benefits of new and otherwise unavailable therapies.

• Administering a different dose to the elderly

• Titration of dosage over X days• Titration pack with escalation

dosages• Administer drug without food• Administer a dosage form that

achieves plasma level of X, measured Y hours after dosing

• Administer with an anticonvulsant in patients at risk of seizure

• Informing the caregiver or patient to avoid taking the approved drug with drug

• Drug in combination with unique packaging

• Drug in combination with delivery device, e.g. inhaler

• Unit dosage of drug with particular dissolution values or resulting pK values.

Examples of label patent claims

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innovationthe key growth mantra

Sasikant misra Deputy Director, Confederation of Indian Industry, India

Indian life sciences industry is under-going rapid transformation. New and emerging business models

are changing the way business will be done over the years. With the advent of the Product Patent regime Indian life sciences industry is beginning to real-ise that Innovation is the key to growth and in achieving global scale in the long-term.

Innovation which is expected to be the leading growth driver, has made the Indian life sciences industry focus on building their portfolios of speciality and niche drugs or entering into alliances with the innovator companies to tap this key business opportunity. Indian life sciences industry is making constant efforts to have a thrust on innovation as the key value creator in all the aspects of the business through technology, services, manufac-turing and excellent quality initiatives to come out with innovative products matching global standards.

The industry is embracing innova-tion and the latest technology to bring to the market novel drugs for treatment of unmet medical needs innovation is being imbibed in scaling up expertise in advanced research areas, building high value intellectual property, creat-ing optimal funding mechanisms and the entrepreneurial environment to take

ideas from lab to market, strengthen and ensure consistent supply of capacity to encourage research and foster a favourable policy and incentive framework.

The Indian life sciences industry has been innovating within its means right from its early days by mastering the art of process re-engineering during the proc-ess patent regime. With the onset of the product patent regime, the industry felt the need to build expertise in formulation research and discovery research in order to achieve global competitiveness.

The Industry today, strives to create a sustainable system of innovation that consistently ensures medicines for all, profitability and global market leader-ship. Some of the key focussed areas for the industry are Industry-Academia link-ages, public-private partnerships and key organisational initiatives.

Innovation requires cutting-edge tech-nologies and has a long incubation period. A Cooperate and Collaborate strategy has proven to be successful in this scenario. Indian companies have adopted this strat-egy which is reflected in the number of strategic R&D collaborations across the drug discovery and development value chain making the transition from a serv-ice-based to a partnership-led relationship. Further collaborative alliances in which both the stakeholders pursue a high-risk and high-reward strategy are increasingly appearing on the alliance landscape.

The focus of the Indian life sciences industry is on Profitability—to ensure sustained growth in all the key pharma markets of the world, through innova-tion in research and development while maintaining high standards of quality and ethics. The industry aspires to emulate the success of the global pharma industry

and is striving to create a balance between earning healthy profits and realising their responsibilities towards society.

In order to acquire a global status, the Indian life sciences industry places its foremost priority on well-established and robust regulatory system. The industry is looking at innovation in the regula-tory standards, which play a key role in the progress. The industry is look-ing at a strong, well-equipped, empow-ered, independent and professionally-managed body which can address the key regulatory issues and build faith in Made in India brand by establishing a robust regulatory system on the lines of US FDA.

Innovation can play a vital role in providing access to improved healthcare to patients. Public health objectives will be realised if innovation is fostered. Healthcare benefits both the individu-als and the economy as well. Most of innovations today are patient-centric. The Indian life sciences industry is incul-cating innovation as the mantra across different functional departments in key areas of the organisation such as quality, sales, marketing and creating differen-tiation through innovative platforms to enhance effectiveness and improve busi-ness performance.

Life sciences industry, which is knowledge-based, is undoubtedly one of the most innovative sectors of the Indian economy. The industry is look-ing at innovation in all aspects of the business and its strategy in tapping key opportunities in the current and emerging business segments and key emerging markets to achieve the required growth and scale in the short and long term.

the feedback on this article can be sent to [email protected] or [email protected].

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For many rare diseases, there is as yet no satisfactory treatment. Rare diseases are defined as life-

threatening and / or serious and chronic diseases, according to the European Orphan Medicinal Products regulation. These diseases represent a high unmet medical need. Rare diseases, with their genetic origin and because of small number of patients to be treated, require effective diagnosis linked to treatment.

A SuStAinAble buSineSS Model?

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So, orphan drugs, with their targeted nature, are of immense use and could pave the way for future developments in healthcare

Since 70 to 80 per cent of rare diseases are genetic in origin, the right diagnosis before treatment is of high importance to ensure that the patient not only gets the right treatment but also does not suffer from side effects. The rarity and severity of the diseases not only mean lesser patients are treated but also result in a high compliance because the medi-cines work. Rarity also leads to higher costs, but orphan drugs also have a higher innovative nature and a higher benefit



valuable innovation to the benefit of patients, including those in the case of orphan drugs. Even in difficult economic times, such beneficial innovation must be encouraged and the resulting products must be reimbursed when they have meas-urable and demonstrable value. However, given the rarity of the diseases studied, sufficient time to gather data to show such value must be granted.

than average drugs through their better clinical efficacy and effectiveness. In the European definition, orphan drugs are unique treatments, meaning there are no alternatives available. This is the case for about one-third of the orphan drugs approved in Europe) or make a better therapy over (an) existing one(s), which is the case for the other two-thirds of approved orphan drugs in Europe. Not only economic factors but social benefits also need to be taken into account as well: many patients affected by rare diseases had no therapy available before and such therapy is often a first in human history.

Innovation, rarity and complexities causedThe current debate in society is about the value of innovation in healthcare: our society supports such beneficial or

Rarity visualised – Commonly used medicines

Patients ('000) Treated (US 2006)

Orphan Drug (<200,000 prevalence in US, < 250,000 in EU)

Nexium

Lipitor

Singulair

Fosamax

Zoloft

Plavix

Advair-Diskus

Celebrex

Aranesp

Epogen

Gleevec

In order to understand the concept of rarity, Figures 1 and 2 provide the number of patients treated in the US in 2006 for a number of non-rare disease and, from Gleevec (Glivec TM) downwards, for rare diseases.

The application of models used in health economics introduces further challenges to the development of orphan medicines and to the discussion about their reimbursement.

Cost-Effectiveness = Cost / Effectiveness, where cost is raised by rarity, but data to calculate effectiveness are limited by rarity. Therefore, rarity is affecting both the factors of the equa-tion making the outcome much more uncertain as it grows.

Based on this, it has to be clear that cost-effectiveness cannot be the only decisive factor. Current definitions of health technology assessment, therefore, include other factors such as equity, fair-ness, ethics and social values. Politicians need to take responsibility to reward innovations in this field to allow them to happen and to continue.

As shown by the consultancy company Alcimed in a report for the European commission in 2004, pricing is a func-tion of the rarity of the treated disease. Therefore, the prices of orphan drugs, given that their development cost is not necessarily lower than the cost to develop a medicine for a common disease, will be higher than the prices of drugs for treating

Figure 1

erik tambuyzer, Senior Vice President, Corporate Affairs, Europe and International, Genzyme Corporation, Belgium

personalised medicine breaks the cycle of trial and error medicine and helps ineffectiveness rates of medicines to decrease dramatically. orphan drugs, targeted therapies for rare diseases, with their innovative nature and improved efficacy, make it a precursor for personalised medicine therapies and can offer a viable business model to expand from. Society should develop consensus for such new models in multi-stakeholder partnerships which will also make it sustainable.

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The future of personalised medicineFurther, drawing the analogy with personalised medicine, a future with more compliance and far less side effects would be the goal. This will ultimately result in costs going down, as only the right medicine would reach the right patient and minimise side effects. In order to do that, the following series of questions need to be answered: • Which medicine should I use?• How much of the medicine do I

need?• Is the medicine working?• Is my disease controlled or gone?

The old paradigm of trial and error medicine, based on the sequence of an observation with an action followed by an observable response is only successful when it leads to innovation and improved standard of care. But it fails when we settle for “trial and error” medicine as the standard of care. The new paradigm of personalised medicine links diagnostic tests to action and therapy. This happens by having an observation confirmed by a test and have it followed by appropriate physician actions which will result in a predictable response, that breaks the cycle of trial and error medicine and helps the patient. Personalised medicine leads to the right drug for the right patient. It results in providing benefits without toxicity. It saves patients from the treat-ment that would have the benefits but with the toxicity of the medicine if any. Also, it excludes them from the treat-ments that would have no benefits and no toxicity, and, of course, also from those without any benefits but with toxicity.

As shown in Figure 3, the current ineffectiveness rate of medicines is rang-ing from 40 to 75 per cent, but this percentage will dramatically decrease with the venue of personalised medicine.

No future without challengesThe current evolution in evidence-based medicine also comes with challenges:• Physicians are being overwhelmed

Enzyme replacement therapies with genetic confirmatory tests to treat lysosomal storage diseases such as

• Gaucher’s disease with Cerezyme

• Fabry’s disease with Fabrazyme and Replagal

• Pompe disease with Myozyme

• Hunter’s disease with Elaprase

• Hurler-Scheie disease with Aldurazyme

• MPS VI with Naglazyme

Oncology drugs such as

• Her2 and Herceptin (in breast cancer)

• BCR-ABL and Glee(i)vec (in leukemia)

• UGT1A1 and Camptosar dosing

• ER/PR tests with drugs like Tamoxifen (in breast cancer)

FDA recently approved a label change to recommend a test with two mutations to help with Warfarin dosing in cardiovascular field

Diagnostic and therapy combinations which are being marketed today

Patients treated (US 2006)

Soliris based on 2007 estimates

Rarity visualised – Medicines for rare diseases

Figure 2

a (more) common disease. As such, prices largely depend on the patient popula-tion to be treated. As a consequence, the application of the same rules of cost-effectiveness for orphan drugs, and espe-cially for drugs for very rare diseases, will

not be appropriate, as this would result in orphan drugs and even more clearly the so-called ultra-orphan drugs being excluded from reimbursement since they often do not reach the required Quality Adjusted Life Year (QALY) limit.


erik tambuyzer is Senior vice president of corporate affairs europe and international at genzyme corporation. he is a founding Board member and past chairman of europaBio, the european association for Bioindustries, and founder of its ethics Working group, as well as the chair of the eBe / europaBio rare Diseases and orphan Drugs task force. a

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by the volume of the available data, so, they need more tools to identify and track test / drug combinations, as well as need more education on diagnostics and genomics. They also need more treatment guidelines and are organising themselves into expert centres. They may carry an increased liability risk confronted with patients who are more vocal, informed and organised.

• Diagnostic testing laboratories perform intense data acquisition, with high manipulation and storage requirements, while they face complex reimburse-ment challenges with new technologies coming into routine practice. They also face issues based on expanded intellec-tual property portfolios and enjoy an increased focus and scrutiny from all

parts of the healthcare community.• Payers face difficulties to follow the

rapid evolution of the diagnostics / genetics field, but, demand evidence-based medicine. They also want to make payment conditional on drug effectiveness, but face challenges as we have discussed above. Payers fund their own databases on patient outcomes, which they usually don’t share with other stakeholders. In demanding tests for evidence-based medicine,

Test to increase drug efficacy / Quality of care

Ineffective Rate (%)Therapeutic Area

Spears et al. TRENDS in Molecular Medicine Vol. 7 No. 5 May 2001

75%

Figure 3

• Patients want better treatment but need information

• Physicians want better products but are being pressured for economic effectiveness

• Industry wants a fair return on high and risky investments

• Payers are afraid of the impact of targeted therapies and personalised medicine on health care budgets. They look at the experience with orphan drugs and fear a tsunami of personalised medicines at orphan drug prices.

Balancing fears versus hopethey require the providers to prove the relevance of such tests to the patient and the physician.

• Regulators face increased concerns about safety of medicines, and need to remain up-to-date on the new technologies. Such new technologies may bring along the need for adaptive clinical trials as many new insights are gained while the trials progress.

• Industry is facing vastly increasing costs driven by the increased demand for data and ever more complex clinical trials, while at the same time facing downward pressure on prices and a more complex reimbursement nego-tiation process.

The only solution to such complex societal problems and in order to build new healthcare systems for the future is to be found by the creation of multi-stake-holder partnerships to develop consensus on the way forward. This should result in a wheel of sustainability: life-saving treat-ments provide a better patient outcome, which warrants reimbursement, and as a consequence, rewards risk-taking and provides return on investment, which in turn leads to more investment in risky projects, resulting in more effective treat-ments coming onto the market. Clearly, having a market for personalised medi-cines is in the society’s best interest. We must all work on making it happen!

As the public image of the pharma-ceutical industry is challenging, better and clearer communication is needed to explain the contributions it makes to society. And while no company on its own can change the sector’s image, industry must work together. Personalised medicine represents a great opportunity to change public image of the industry for the better!

Strategy


personalised medicine Changing business modelspersonalised medicine, in which sophisticated diagnostics guide drug choice, dosing, and patient appropriateness, challenges older business models for both pharma and diagnostic tests. in particular, the diagnostic tests are original inventions and often require substantial original clinical research, which may or may not be intermingled with development costs for the drug.

Bruce Quinn, Senior Health Policy Specialist, Foley Hoag LLP, USA

It has become clear that pharmaceuti-cal development in the first decades of this century will be dominated

by the “personalised medicine” concept. Personalised medicine encompasses the development and marketing of molec-ular tests which help to target the use of pharmaceuticals and biologicals in ways that maximise their effectiveness. Of course, lab tests have always guided diagnostics: for high glucose, a physi-cian will diagnose diabetes and prescribe insulin, and so a lab test was paired with a drug. But personalised medicine, as the term is used, almost always involves carving out new subsets of patients with a particular form of disease, such as Herceptin-sensitive breast cancer.

The interactions between the devel-opment of complex tests, drug trials, regulatory approval, and drug market-ing will cause substantial shifts in the way healthcare is delivered. One obvious business issue (a smaller market for a more specific drug) has dominated think-ing about how personalised medicine will develop, how it will impact the pharmaceutical industry, and indeed, whether it is “good” or “bad” for pharma. Because that topic has been discussed so

frequently, the present article will focus on other ways in which a new era of interactions between lab tests and drugs will stress existing business models or require the development of new ones.

We emphasise that there is no single model for clinical trials which incorpo-rates genetic or other complex molecular information. There are at least three basic clinical models (combinations of these models are also possible) and they are as follows:

Evidence-based medicine and diagnostic testsThroughout the developed countries, government-based and private insurance systems are showing rising interest in the rigorous application of evidence-based medicine to control costs, by reducing unnecessary or low-yield interventions. Clinical trial experts and payer deci-sion-makers are quite familiar with outcomes analysis of therapeutic trials. In general, control and treatment groups are matched and randomised. To the degree possible, subjects and evaluators are masked to the interventions offered. Outcomes and adverse events are statisti-cally compared. Controversies over the

choice of clinical endpoints, or the use of clinical versus surrogate endpoints, are debated but gradually move towards a consensus. For example, is a negative Prostate Serum Antigen (PSA) at two years an adequate marker of effective radiation treatment for prostate cancer, or should the therapy be considered experimental until ten-year data are in hand? Even when regulators in different countries differ in their decisions, the basic issues for therapeutic trails, such as the choice of endpoints and the weighing of risks and benefits, are familiar.

The tools for assessment of diag-nostic tests are very different, and the usual terms of art like sensitivity and specificity, familiar from college statistics, fall far short when the actual decision point for regulators and payers rests on the clinical utility of a test. For example, “sensitivity” can mean the chemical threshold of a test—does it measure down to 0.1 ng/ml of PSA? Sensitivity and specificity are usually used in statistical sense, describing the performance of the test in known popu-lations of cases and controls. The clinical accuracy of the test depends on the base rate of positive and negative cases in the

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population at hand, which allows prediction of true and false positives and negatives. Sometimes, other already known characteristics of the patient will be calculated together with test results to give a more sophisticated prediction for the test in the patient at hand (Bayesian statistics). All of these statistics become much more complicated for diagnostic tests that have a spectrum of results, rather than just positive or negative results. Meanwhile, specificity and sensitivity lose much of their meaning for genetic tests that answer whether the patient does or doesn’t have the gene in question; the accuracy of the test is essentially 100 per cent. But even here, because of untested mutations or interactions with other untested genes with superimposed functions, the clinical variance accounted for by the gene may be much less than 100 per cent.

When the results of the test are proposed for clinical practice, differ-

ent evaluators will differ as to whether the test is well-enough established for clinical use. Often, evaluators will differ sharply on whether enough is known about the test in practice to recommend the test to be used routinely.

Paradoxes of clinical trial ethicsA distinctive problem with diagnostic tests, as opposed to therapies, occurs when retrospective data analysis suggests that a clinical use of the test is likely but not certain to be valid—say, 70, 80 or 90 per cent likely. An example occurred when retrospective studies of clinical trials with EGFR-blocking monoclonals found them to be ineffective if a down-stream gene, KRAS, was constitutively activated due to a mutation. Because the results of the retrospective study are incompatible with clinical equipoise, it is impossible to conduct a clinical trial where cancer patients with KRAS-activated tumours are randomised to

receive EGFR therapy, a therapy which is very likely to be ineffective for such tumours. However, the state of informa-tion at this point may be criticised due to the fact that retrospective trials are fraught with confounding variables and a critic can quickly cite many retrospec-tive conclusions that were invalidated by prospective controlled trials. Payers may question whether the cost of the molecular test should be covered, if its clinical use is uncertain. Although the resulting debate over levels of evidence may seem arcane, this scenario is fairly common with diagnostic tests.

Development risk for complex diagnosticsAt present, relatively few pharmaceutical or biotechnology firms have the in-house capabilities to develop innovative molec-ular diagnostics de novo and carry them through commercialisation. Therefore, when tests are used as early as clinical

1. Drug targeted by clinical trialThe already-classic example of this approach is the identifi-cation of Her-2/neu as marker for breast cancer patients who are likely to respond to trastuzumab (Herceptin). Alternately, we could classify Her-2 / neu-negative patients as ruled out for trastuzumab therapy. There are already several examples of this model in oncology, some of which emerged only after the drug’s regulatory approval. For example, increasing evidence suggests that cancer monoclonals which target the EGFR receptor are ineffective in patients whose tumour has a mutation downstream of EGFR which tonically activates the KRAS gene regardless of whether the monoclonal neutral-ises the surface receptor for EGFR.

2. Drug rescue by identification of adverse eventsMany drugs cause distinctive adverse events only in a minority of patients. To some extent, this is a truism: other-wise the drug candidate would not reach the market. A molecular cause for the uncommon adverse events might now be identified either before launch or during post-market-ing surveillance. An example is identification of the HLA B*5701 genotype, which is associated with serious adverse events in response to abacavir (Ziagen). This test became a recommended diagnostic only several years after the drug’s launch, and improved the acceptance of the drug. It also

Clinical models

helped in avoiding the prescription of the drug in the subgroup of patients at risk.

3. Third-party innovator differentiates members of a drug classA third-party innovator (or academic laboratory) identifies genes which allow choice of the drug in a drug category which is best suited to individual patients. For example, genes which optimise choice of statins could be identified and commercialised. Such a test, if developed, would allow the genetic profile of patients to be assessed so that a physician can prescribe the statin which is most likely to be effective. So far, we lack clinical examples of this model. The most likely reason is limited motive for this clinical trial investment by any single pharma or diagnostics company, since a pharma may lose market share and a diagnos-tics company may be unable to set a price high enough to repay the trial. Alternately, the a priori development risk may seem too high, since there is no certainty that a small gene panel could be found and commercialized that would classify statin patients effectively.

We can use three categories to highlight the diversity of gene types that may contribute to personalised medicine. Like the three clinical models just discussed, the three gene categories shown here are not absolute, but they do illustrate the diverse biologies which are being studied to support personalised medicine.

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1. Enzymes of metabolism and transportAcross many different drug classes, human beings are remarkably diverse in their metabolism and transport of drugs. For a given drug, a patient may be a typical metabo-liser, slow metaboliser, or ultrametaboliser. In the United States, the FDA has remarked on pharmacogenetic infor-mation (usually related to metabolism) of over 100 drug labels (Frueh FW et al., Pharmacotherapy, 2008, 28:992-8). However, very few of those drugs have clear labelled instruc-tions for changes in dosage or carry a direct recommenda-tion that testing should be undertaken before prescription. Genes related to tamoxifen metabolism, warfarin metabolism and pharmacodynamics are currently being investigated for clinical utility.

2. Drug targetMolecular analysis of drug targets has found the quick-est clinical application in chemotherapy. Examples include expression of Her-2/neu as a marker of response to trastuzu-mab (Herceptin), expression of the EGFR receptor or related downstream mutations as markers of response to cetuximab (Erbitux), and expression of the bcr-abl rearrangement with respect to imatinib’s (Gleevec’s) effectiveness in individual patients.

3. Markers of adverse events (other than metabolism)Examples in this group include hypersensitivity reactions (the HLA B*5701 variant and reaction to abacavir) and idiosyn-

Molecular models

cratic adverse events such as myopathy (an infrequent adverse event caused by statins) or rhabdomyolysis (a life-threatening but extremely uncommon event caused by statins). Ideally, early identification of vulnerable patients could allow clinical trials to proceed and the drug to be marketed, if always paired with a genetic test. On the other hand, for highly toxic but extremely rare genotypes, there are unwelcome economic issues such as number-needed-to-test to obtain a better outcome. For example, it is impractical to give a US$ 200 genetic test on 10,000 patients to identify one rare patient who would be vulnerable to a severe adverse event.

The design and analysis of therapeutic trials is costly and complicated, and so is the conduct of diagnostic test develop-ment, but for different reasons. The business dynamics and regulatory requirements of both therapeutic trials and diagnos-tic test trials must be satisfied to bring a combination test and drug to market, while meeting prospective estimates for develop-ment risk and likely economic return. Putting all of these factors together may mean that the net risk and complexity is actually squared or cubed relative to a more routine therapeutic trial. Six ways in which potential difficulties manifest themselves include:

• Evidence-based medicine

• Paradoxes of clinical trial ethics

• Development risk for complex diagnostics

• Regulatory challenges for complex diagnostics

• Economic hurdles for complex diagnostics

• Challenges in marketing.

trials, an outsourcing contract or a more sophisticated contractual partnership exists between a test developer and the drug developer. Contractual issues can become very complex and go beyond the scope of this article. But as one exam-ple, the freestanding test developer must develop a commercialisation-ready test by the beginning of Phase II. This is because regulators will be very sensitive to technical variations between the test used in clinical trials and the test that will be commercially available after drug launch. Therefore, most of the developer’s sunk costs occur early, although the drug candidate has 90 per cent risk of failure that any drug has at the beginning of Phase II trials. The drug manufacturer will be concerned about lock-in to a contractual relationship with the test manufacturer, while the test manufac-

turer will worry about a competitor who could produce a rival test after the risky and costly proof-of-concept stage has been passed. Intellectual property on the diagnostic test alone may be more difficult to defend, even in the short term, than the pharma’s core patents on the molecular structure of the companion drug or biological.

Regulatory challenges for complex diagnosticsComplex diagnostics raise a number of regulatory challenges. For example, several tests at the forefront of person-alised medicine are too complex to be packaged as kits. An early example is the Trofile test (Monogram Biosciences), a gateway test to the use of a new-generation HIV anti-viral, maraviroc (Selzentry). The test requires gene-splic-

ing steps and is currently run at one centralised and standardised laboratory. In the United States, this category of test is called a “laboratory-developed test” or LDT. In other cases, the lack of a “gold standard” test or variabil-ity of testing between laboratories has raised questions about the accuracy of diagnostics even for the prototypic personalised medicine test, the Her-2-neu test (See Fitzgibbons PL et al., Arch Pathol Lab Med 2006, 130:1440-5, and references therein).

Another regulatory challenge which may have seemed like science fiction only a few years ago is the prospect of prescribing cancer drugs based on oncogene characteristics rather than gross tumour type. Today, clinical trials for cancer drugs are categorised by the type of cancer: small cell lung cancer,

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adenocarcinoma of the pancreas, renal cell carcinoma, and so on. However, we are already seeing targeted cancer drugs which are effective in ways that are completely unforeseen by legacy histologic classifications of tumours (Both chronic myelogenous leukemia and gastrointestinal stromal cell tumours respond to imatinib, if they express the bcr-abl oncogene translocation). Although there are some highly effec-tive cancer / chemotherapy regimens, the impact of chemotherapy on many cancers is notoriously limited (e.g. 5-10 per cent of patients benefit, or alterna-tively, the number-needed-to-treat is 10 to 20 or more.) Therefore, the hurdle rate for results matching tumours to chemo-therapy based on molecular expression panels (e.g. tumour X in a case that also carries the bcr-abl mutation) should be equivalent efficacy. But all regulatory conventions, and payer guidelines for chemotherapy coverage, are based on the legacy approach to classifying tumours histologically and studying them in drug-specific trials.

Economic hurdles for complex diagnosticsLaboratory tests have traditionally been treated as commodities in the medical marketplace. In most countries, costs of laboratory tests are either bundled with episodes of care or paid at fixed rates based on the chemistry of the test (e.g. nucleic acid amplification, US$ 20; serum immunoassay, US$ 25; flow cytometry, US$ 50). These fixed fee schedules appear to be adequate for the development of new tests of the same type when the main parameter of the test is accuracy. Fixed fee schedules also encourage technological change to produce the same types of tests faster and less expensively. However, laboratory test reimbursement that is administra-tively locked to the marginal cost of the test’s chemistry is incompatible with significant clinical trials to develop and launch a novel type of test. In economic terms, this can be very inefficient, penny

wise and pound foolish. For example, a hypothetical new test which could save the healthcare system US$ 100 million over a few years costs US$ 10 million in clinical trials to develop and needs to be sold at US$ 300 to cover risk, investment, and marginal cost; but the test will never exist if the reimburse-ment is locked at US$ 20 and the US$ 100 million will never be saved. New regulatory schemes for payer systems will need to adapt to some form of value-based reimbursement at least where the net outcome is to encourage cost-saving forms of investment.

One bright spot in the economic logic does occur if the healthcare system bundles a spectrum of interlocking costs together, such as the costs of cancer chemotherapy and chemotherapy diag-nostics. Here, the test manufacturer could command value-based market prices in its direct transactions with chemotherapy centres, if the net outcome of test usage was ultimately cost-saving for the chemotherapy centre.

Challenges in marketingHistorically, there has been relatively little advertising or detailing of labora-tory tests, probably because there were undifferentiated commodity products with low margins. Therefore, there is little apparatus in place to educate physi-cians about new molecular diagnostics, and older physicians may find the topic of molecular diagnostics quite confus-ing. One solution could be integra-tion of electronic medical records and e-prescribing programmes with pop-up information on relevant diagnostic tests, or flags in the healthcare system that hold a prescription until a relevant diagnostic test has been performed.

In addition, diagnostic tests have a rare reverse-supply chain configura-tion. Instead of manufacturing a drug or device in a factory, shipping to a regional warehouse, and then a retail location (pharmacy or hospital), a diagnostic test requires shipping of the test from thousands of doctors’ offices or clin-ics backwards to a central laboratory. The logistics become quite formidable for very complex diagnostics that are only performed at one or a very few locations, and especially if the samples must be chilled or frozen at the point of collection and during shipping.

Moving forwardSpeculation on the slow growth rate for personalised medicine focusses too much on the supposed reluctance of the pharmaceutical industry to investigate diagnostics which could carve down the market size of new drugs. When discus-sion stops there, the analysis has fallen into a mental trap, in which one credible answer is found quickly and this halts the search for alternative and perhaps more important explanations. In fact, in the past year, several CEOs at leading phar-maceutical firms have stated that personal-ised medicine—the pairing of diagnostics and drugs—has to be a core competence of their development strategy. Numerous additional barriers to development and commercialisation were described in this article, but they can be dealt with by good policy and appropriate innova-tion in the regulatory process. Only by elevating the addition problems into view will they become part of the dialogue on personalised medicine and part of our solution kit in moving the healthcare industry forward for more effective and accurate patient care.

Bruce Quinn is US physician executive in the law firm Foley hoag llp. a former medical school professor and strategy consultant with accenture, from 2004-2008 he was the regional medical director for the medicare program in california.

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Strategy


personalised medicine & Drug Development Biomarkers leading the way applying biomarkers as part of drug development efforts only started to materialise a few years ago. given the recent efforts by not only regulatory authorities but also pharmaceutical companies, several case studies are now available that suggest that biomarkers will become a more integral part of future drug development and commercialisation and, therefore, foster the “promise of personalised medicine” over the coming years.

michael Lutz, Senior Vice President, Pharmacogenetic Partnerships, PGxHealth, USA

Up to the last decade, the pharmaceutical industry had followed a trial-and-error

approach to medicine by applying a drug to an entire patient population when treating a given disease. As a result, the overall drug efficacy in selected diseases was only around 50 per cent. Moreover, adverse drug reactions were among the leading causes for hospitalisation and mortality in the US.

Given the associated cost burden with this approach and the vastly improved understanding about the important role of biomarkers in the light of disease biol-ogy and drug interactions, a significant change towards more targeted drugs was initiated by the pharmaceutical indus-try since then. During drug research, biomarker activities are aimed at validat-ing drug targets or to further the under-standing of drug-related pathway biology and the underlying disease mechanism. In this regard, a significant number of whole genome association studies have

been performed with a focus on gene selection.

During drug development, the current focus is clearly on applying biomarker strategies to optimise clinical study designs to facilitate a faster path to proof-of concept and a go / no go decision with respect to clinical outcome. Eventually, this approach may even lead to companies conducting smaller clinical trials through patient stratification with the potential to market a drug based on a respective diagnostic outcome to guide treatment decisions. In addition, using genetic biomarkers may help phar-maceutical companies enhance product differentiation and potentially extend product life cycles by targeting therapies earlier on in the treatment of disease, or even in disease prevention.

To date, significant biomarker activi-ties are focussed on the field of oncology where more targeted drugs have demon-strated improved efficacy and, therefore, often command a higher price. Some of

the most recently marketed cancer drugs have found their niche with the aid of biomarker-related molecular assays. For example, Roche’s Herceptin and GSK’s Tykerb both treat breast cancer patients whose tumours contain multiple copies of a gene called HER2. In addition, Roche’s Tarceva, Imclone’s Erbitux and Amgen’s Vectibix all target EGFR which is activated in various ways in many forms of cancer. Novartis’ Gleevec was followed by newer ABL inhibitors including BMS’ Sprycel and Novartis’ Tasigna which address patients with BCR-ABL mutations resulting from Gleevec treatment. All drugs mentioned are supported by diagnostic assays that have been specifically developed for the respective biomarker / drug.

In addition to oncology, strong efforts are on in other disease areas with large patient populations with a high clinical need. Such disease areas include Central Nervous System, Inflammation and Metabolic Disorders.


Clinical Data Inc. is a global biotech company with over a decade of experience in discovering and applying biomark-ers to drug development. It is develop-ing vilazodone, a targeted therapeutic for the treatment of major depressive disorder. Vilazodone is a genetically-guided serotonergic antidepressant with a dual mechanism of action: a Selective Serotonin Reuptake Inhibitor (SSRI) and a 5HT1A partial agonist. In late 2007, the company announced positive results from its first Phase III registration trial which compared vilazodone to placebo in 410 patients. This trial also helped to identify proprietary candidate biomarkers for a potential companion pharmacogenetic test for assessing a patient’s likelihood of response to Vilazodone. As depicted in Figure 1, a biomarker -positive treatment group showed a two-fold increase in terms of efficacy after eight weeks compared to the biomarker -negative subgroup but also compared to placebo. Interestingly, this biomarker subgroup represents about 30 per cent of the total depression in patient population.

Clinical Data has almost completed its second Phase III registration trial, which is designed to confirm these find-ings from the first Phase III study and to validate the biomarkers that were identified. Results of the second study are expected in the first half of 2009,

and the company anticipates filing a new drug application (NDA) with the US FDA for vilazodone for the treat-ment of major depression by the end of 2009.

Biomarkers represent an attractive, and arguably more efficient, approach to developing targeted therapies with improved efficacy and safety, as well as predictive diagnostics that can be used to guide treatment decisions. At the same time, biomarkers offer the opportunity to reduce both the technical risks associated with drug development and the related R&D costs. Regulatory authorities, such as the FDA, are clearly supportive of biomarker approaches as witnessed by the FDA’s guidance in 2005 with respect to the submission of pharmacogenetic data as part of NDA filings. The FDA also recently drove label changes to marketed drugs such as irinotecan and warfarin by incorpo-rating biomarker-related information into the label in an effort to increase

patient safety when using certain drugs, which in turn could reduce the health-care costs associated with the treatment of adverse events.

Pharmaceutical companies are also beginning to advocate for label changes as new biomarker information on their drugs emerges. For example, Amgen reanalysed their clinical trial data for their colon cancer drug Vectibix follow-ing concerns from the EMEA that the drug did not provide enough benefit to patients. The drug was finally approved for patients only whose tumours did not have a mutation in a gene called KRAS. And these are just some of the recent examples which demonstrate the power of biomarkers for improving the development and marketing of targeted therapeutics and diagnostics. This trend is likely to continue and the ‘promise of personalised medicine’ may be fully realised as biomarkers become a more integral part of future drug development and commercialisation.

michael Lutz came to clinical Data inc., a naSDaQ-listed biotech company in august 2007 following the acquisition of Epidauros where he served as Chief Executive Officer since april 2006. lutz became global general manager of cogenics, the service division of clinical Data, in november 2007 and was also appointed as Senior vice president pharmacogenetic Partnerships of PGxHealth,USA, the product division of Clinical Data.

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Response rates for vilazodone and placebo in biomarker-positive and - negative subgroups

Figure 1

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25

15

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n M

ADAS

+/-

SEM

Week of treatment0 1 2 3 4 5 6 7 8

6.9

Placebo with biomarker

Placebo with out biomarker

Biomarker patients had 2x response at week 830% of patients are biomarker positive

Vilazodone with out biomarker

Vilazodone with biomarker

Strategy


“follow-on” proteins pose complex questions for patients, biopharmaceutical companies, and regulators. understanding the challenges in the development of biosimilars by the industry and regulators and addressing them could pave the way for delivering affordable and better biological medicines to patients throughout the world.

Cecil nick, Vice President, Biotechnology, PAREXEL Consulting, A PAREXEL International company, USA

Many of the blockbuster biological products that currently dominate the markets are coming to the

end of their patent protection. The oppor-tunity to provide more affordable “generic” versions is now attracting the interest of both generic and research-based pharmaceutical companies. The development of “generic” biological medicines referred to as “biosimi-lars” in Europe and increasingly in the rest of the world and as follow-on-proteins in the US, could well expand their availability and usage creating new markets, new oppor-tunities and wider availability of life saving treatments.

However, those developing biosimilars face major challenges; first and foremost of these is that regulators do not accept that generic biological products can be the same as the innovator product, but only nearly the same or “similar.” The use of the word “similar” rather than “same” may seem pedantic, but it has major repercussions and obligates the generic manufacturer to embark on a complex development programme in order to gain regulatory approval. This programme involves generating non-clinical and clinical data to demonstrate equivalent safety and efficacy to the original product. This raises the questions as to what and how much data is required for the regulatory approval. For the simpler products regulatory precedence now exists;

reSearch & Developement


Biosimilar medicines

but for the more complex proteins such as monoclonals, the jury is still to come out. The problem is that like any jury, every member has their own view, and this does not bode well for establishing a global programme for the develop-ment of a biosimilar. The complexity and uncertainty is exacerbated by the fact that regulations for market approval of biosimilars are still evolving around the world and at different rates. The European Union (EU) has led the way in establishing regulations for follow-on proteins and several biosimilar products have already been approved in the EU; these include somatropin, filgrastim and epoetin. Elsewhere, the regulatory landscape varies dramatically. In parts of Asia, such as India, although biosimilar products have been on the market for many years regulatory thinking is still evolving. In the United States, Congress has yet to establish regulations for follow-on proteins. Other major markets, such as Canada and Japan, have issued draft guidelines. In this maelstrom of views, industry has the opportunity to guide rational thinking with cogent scientifically robust arguments through comments to guidelines, participating at international meetings, regulatory scientific advice submissions and other such forums.

Even as regulations begin to appear, new questions are being raised: How should follow-on products for mono-clonals and other complex proteins be handled? How much clinical data should be required to demonstrate equivalence? How similar does a biosimilar product need to be? The challenge for both regula-tors and the biopharmaceutical industry in this constantly changing environment is to maintain a reasoned approach and resolve the issues in a way that keeps the science of biosimilars moving forward for the benefit of patients around the world.

How “similar” is biosimilar?One of the most basic issues surround-ing follow-on proteins is determining what types of proteins can be considered biosimilar. One viewpoint is that only proteins that can be fully characterised, with no discernible differences in either the structure or impurity profile, can be considered biosimilar. However, this narrow view is not shared within the EU, where guidelines and precedence allow a degree of difference—provided this can be justified. For example, one approved biosimilar product is expressed from yeast, whereas its reference product is expressed from E coli. Although this variation in

production method creates differences in the follow-on protein’s impurity profile, those differences have been demonstrated not to impact safety or efficacy and the product has been accepted as biosimi-lar. Similarly differences in glycosylation profile have been justified and accepted by the EU regulators.

If lower-cost therapeutic proteins are to reach the market, more innovative and efficient production technologies, including transgenic production, must be introduced. Although these technolo-gies may create differences in impurities or post-translational modifications, it should still be scientifically possible to demonstrate that the biosimilar product provides equivalent safety and efficacy to the reference product. While, there is no regulatory precedent for this approach today, this seems scientifically sound and hopefully common sense science will prevail.

On the other hand, if differences in primary structure or profound post-translational modifications are detected, then, according to current views such a product would need to be treated as a novel compound. Yet, such a clear-cut position may not be necessary or scientifically justified. As experience with biosimilars grows, regulators may become

unDeRStAnDing the ChALLengeS




For now, fundamental challenges confront the establishment of a global biosimilar programme. Foremost, there is currently no way of confirming that the reference product sold in one region is identical to that in another region even when they are sold under the same brand name, which indeed is not always the case. Until this problem is resolved, a worldwide biosimilar devel-opment programme cannot be a reality. Currently to achieve EU approval, the reference product must be sourced from within the EU. If similar demands are set in other regions, then development programmes will need to be replicated in each region, resulting in duplication of effort and unsustainable costs.

There is obviously an urgent need to establish some level of international harmonisation to allow mutual recogni-tion of reference products and data for approved biosimilars.

Yet another challenge is regulatory concern about the impact of ethnicity. In reality, this should not be an issue for biosimilars where the reference prod-uct will have already been approved and marketed in the target region, and there would seem to be no rational reason why a biosimilar product would display a different ethnicity profile; however regu-lators may not always share this view.

Even if the above barriers are crossed, regional differences in data requirements may still dictate the need to replicate certain aspects of a biosimilar devel-opment programme, tailored to the requirements of specific regions. This is another area where global harmoni-sation of biosimilar guidelines would greatly benefit the development of global biosimilar products.

Can the obstacles be overcome?Despite the progress in the EU, much uncertainty remains as to which prod-ucts will qualify as biosimilars, and what degree of similarity will be required for follow-on and subsequent-entry proteins. Furthermore, the level of supporting clinical data that will be required for

at the physico-chemical and biological level for virtually any highly purified protein. The next step in demonstrat-ing biosimilarity requires leveraging current knowledge and filling the gaps by conducting appropriate non-clinical and clinical studies.

Even for small molecule generics, bioequivalence in terms of absorption needs to be demonstrated in clinical studies and so it is no surprise that this applies to biosimilars as well. However, for biosimilars, the EU regulators require more data to be convinced of similarity; for example, they will want evidence for equivalent efficacy and adequate safety, which will require clinical trials. The requisite clinical programme will vary and will require detailed thought and justification from the sponsor, who is well advised to work with external expertise and seek scientific advice from the regula-tory agencies. In the EU it is incumbent on the sponsor to submit a scientifically robust justification in support of their programme and such submissions will play a significant role in shaping future thinking.

The size and complexity of the clinical programme will depend on the level of understanding and interactions of the protein structure, the impurity profile, and other characteristics, as well as the relative difficulty of demonstrating therapeutic equivalence. In some cases, a biosimilar development programme may require the study of more patients than were included in the innovator programme!

Can biosimilar development be globalised? Key to the success of a biosimilar programme is accessing markets through-out the world, but regulations and experi-ence around the globe differ dramatically. The adoption of a biosimilar approval pathway in the US and other major markets will certainly ignite new thinking that will influence current strategies for development of biosimilars and set new precedents for their approval.

more comfortable in allowing greater flexibility and may approve less similar follow-on proteins based on an abridged “Biosimilar” approach. This approach can even be taken where significant differ-ences from the reference product exist, although always equivalent safety and efficacy will need to be proven. However, we have not yet reached this point.

Can the biosimilar concept be applied to complex proteins?The biosimilars approved under the current EU process represent just the beginning of a global biosimilar revolu-tion. A host of other products, including follow-on monoclonal antibodies, exist or are in development and will probably be submitted to regulatory agencies in the years ahead.

The EU’s “Guideline on Similar Biological Medical Products” (CHMP / 437 / 04) states that, in principle, the biosimilar concept applies to any biologi-cal medicine. However, the guideline notes that this will depend on a number of factors—including the ability to char-acterise the product. Clearly technology is moving forward apace and the power to characterise complex proteins down to the last atom is now a reality whereas a decade ago it was a dream. Methods such as MS-MS, 2D-NMR, and chemi-lumi-nescence are but a few of the powerful tools available today that enable resolu-tion to atomic levels, generation of high fidelity information on protein folding and detection of impurities even to pico-gram levels. Science allows full under-standing as to how the protein binds to its ligand and the type of bonds involved. Biological testing using methods such as surface plasmon resonance, Fluorescence-Activated Cell Sorting (FACS) and other cell-based assays can provide a thorough insight into biological effects compared with the reference product. Thus, strong evidence of similar therapeutic effect can be available well before the biosimilar ever enters a patient.

These technologies should make it possible to demonstrate biosimilarity




the more complex proteins has yet to be fully defined—which is not surpris-ing, given that it is a multidimensional issue, influenced by the complexity of the protein, the potential for differences between the reference product and the biosimilar, and the challenges of demon-strating therapeutic equivalence.

The uncertainty and variability of the biosimilar environment increase in proportion to the complexity of protein. The level of clinical and non-clinical data required to bridge the gap between the reference protein and the follow-on protein needs to be based on risk analysis, with the amount of data being proportionate to the level of uncer-tainty and risk. In fact, the idea of a risk-based approach could be applied even to improved intentionally modified proteins or “biosuperiors” where recep-tor interactions, pharmacokinetics, and pharmacodynamics mirror those of the

reference biological entity. Extension of the biosimilar concept to “biosuperiors” does not align with current regulatory views but its future adoption could serve to nurture innovations such as novel and more efficient manufacturing technologies that will enable the generation of more affordable protein-based medicines.

The ability of biosimilars to access global markets based on a single develop-ment programme that meets the require-ment of all markets is clearly an important factor driving the success of biosimilars. Although, World Health Organization

has issued guidelines which establish a base standard, the regulatory framework for the approval of biosimilars in major markets is very much still in flux and relies on the generic and biotechnology industry to guide regulatory thinking towards a harmonised approach.

Biosimilarity is still in its early stage of evolution and the industry and regu-lators together now need to drive the concept so that it becomes a powerful vehicle for delivering affordable and better biological medicines to patients throughout the world.

Cecil nick, vice president – Biotechnology at pareXel consulting, is a trained biochemist and has over twenty years of experience in the development of biological medicinal products. he now provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. he has been involved in the development and regula-tory approval of a number of innovative and biosimilar medicinal products in europe.

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Drug Discovery in Academiaan evolving modelas economic pressures mount on the current industrial model of drug discovery and development, there is growing momentum in academic institutions to enter the fray of drug discovery and development. there has always been a symbiotic relationship between academia and industry in the discovery and elucidation of new biological targets; however, the delineation of the roles of academia and industry are beginning to blur.

edward holson, Medicinal Chemist III, Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, USA

Over the past decade there has been increasing pressure on the pharmaceutical industry

to increase economic efficiencies in drug discovery. This has been driven by several factors including the increased costs of R&D, lower productivity, patent expiration, generic competition and the increasing difficulty in bringing new chemical entities to market.

The extraordinary investment require-ments have also led the industry to focus on only those disease areas which have high commercial potential and are deemed prosecutable. Many feel that this has led to a risk-averse behaviour which has hindered innovation in the field and created a focus on what are considered “druggable” targets. This has created a narrow view of biological space and has left major “third world” diseases orphaned.

While there has always been synergy between industry and academia in drug discovery, there is growing momen-tum within the ranks of academic and non-profit organisations to fill this

innovation and therapeutic development gap through adoption of more conven-tional drug discovery and development approaches. Incorporation of disciplines and infrastructures that were the domain of industry is at the leading edge of this new paradigm in academia.

The Stanley Center for Psychiatric Research within the Broad Institute of MIT and Harvard is providing a forum to explore such a model. The Stanley Center was founded to discover the human genes that confer risk for bipolar disorder and schizophrenia and to use

this information to develop new diagnos-tic tests and treatments for these illnesses. Consistent with this mission and key to this emerging ‘academic drug discovery’ model are industry veterans, who are making a transition from industry back into this new academic environment.

Integrated role of medicinal chemistryThe Stanley Center medicinal chem-istry group is a small focussed group of four computational and medicinal chemists with both Big Pharma and


Historically, the later stage development of small molecules into drugs was more the province of industry with few exceptions. Now, however, a model is evolving in academia of front-loading the academic experience with more of an eye towards drug discovery and development. The Broad Institute of MIT and Harvard and the Stanley Center for Psychiatric Research provides an ideal environment to explore and refine this new model of drug discovery in academia. The Stanley Center medicinal chemistry group has adopted an “embedded” biotech model to leverage the strengths and practices of both academia and industry in this new context of drug discovery.

Embedded biotech model

http://www.broad.mh.edu/nodi/638


biotech experience. The primary goal of this group was to implement a fully functional medicinal chemistry group mirrored on the capabilities of industry with limited permanent staff to allow for fiscal and staffing flexibility as projects evolved. Rather than following a fully integrated model supported by full-time staff, we adopted a hybrid virtual biotech model wherein we formed a core competency internally and outsourced the majority of analogue and bulk chemical synthesis.

The medicinal chemistry group functions to collaborate with multiple academic groups at various stages of the discovery process, including high throughput screening, probe compound development, lead optimisation, formu-lation, PK / ADME and in vivo efficacy experiments.

Shown in Figure 1 is a ‘chemo-centric’ view of the various disciplines integrated within the Stanley Center. The medicinal chemistry group focuses on hypothesis-driven compound design, synthesis, data analysis and the devel-opment of new approaches to drug discovery. Resources are augmented through the use of several Contract Research Organisations (CROs) for analogue and bulk chemical synthesis.

Academic collaborators constitute core biology and in vivo efficacy (behavioural models). External vendors are used for more traditional drug development disci-plines such as PK / ADME for both in vitro and in vivo studies.

The majority of our biological studies including in vitro binding, enzyme and cellular assays are done in collaboration with academic groups at local institu-tions (MIT, Harvard and Massachusetts General Hospital). The majority of our target identification, high throughput screening and compound management activities are conducted in collaboration with established core facilities at the Broad Institute. The goal was to develop an infrastructure which would allow a group of two internal medicinal chem-ists and four to six external chemists to efficiently process 200 to 300 compounds per year across multiple projects. By care-ful selection of CROs, we hoped that over time we would have a push back of ideas from our contractors and active participation in design and data evalua-tion. Ultimately, we hoped to establish our external contractors in chemistry as an extension of our team and leverage their capabilities as deep into our process as possible making them indistinguish-able from internal resources.

Integrated model of drug discovery utilising internal and external resources

Medicinal chemistry

OutsourcedIn-house / Outsourced

Chemistry scale-up, analoging

Computational chemistry

Design / Synthesis

Analytical / QC Compound mgmt.

PK, ADME Tox (in vitro)

PK, ADME Tox (in vivo, study design)

Efficacy, Behavioural models

Structural biology (X-ray)

Chemical screens (HTS)

Target indentification / Probe development

Biological Assays in vitro, cellular Formulation

Figure 1



Medicinal chemistry development cycleOur approach is similar to an industrial template in the overall flow but differs in the organisational arrangements of the different disciplines. Our design and development cycle is shown in Figure 2 and mirrors the cycle found in an industrial setting. Key functions include: 1. Compound design and synthesis2. Compound management—notebooks,

QA / QC, tracking of compounds, information capture from CROs, regis-tration, plating and distribution of compounds

3. Compound testing (in vitro and in vivo)

4. Data analysis and storage 5. Repeat.

While our cycle mirrors industry, the various stages of the development cycle are performed outside the traditional organisational format. Unlike a typical company, where project team members specialising in various disciplines are unified as part of a single organisa-tion, in an academic setting disparate disciplines from distinct organisations (universities, principal investigators, etc.) are involved.

A model that lacks a clear organi-sational structure is highly reliant on communication and collaboration across groups. From a medicinal chemistry viewpoint, a key goal was to establish a highly efficient chemistry group by iden-tifying “best-in-class” contract research organisations, leveraging the capabilities of the Broad Institute and establishing an efficient process to manage hundreds of compounds through the development cycle.

Lessons learntWe began our chemistry programme by examining several different chemistry CROs. We chose to compare vendors by assigning similar chemistries to assess not only their core chemistry competency but also their communication skills, problem solving, creativity and infor-matics capabilities. Working on an FTE basis for a period of three months with two to four FTEs per site, we began a rolling evaluation across several compa-nies. We conducted weekly or biweekly teleconferences along with site visits to get hands-on experience with the chem-ists as well as evaluate their resources and capabilities. We found a wide variation from vendor to vendor across all areas.

Moreover, we found that small ineffi-ciencies in the process (communication, problem solving, and record keeping) were amplified in our small group and created large time drains internally.

To streamline the flow of information and to centralise the capture of chemi-cal information from all vendors, we adopted an electronic notebook (e-note-book) system established by the Chemical Biology Platform at the Broad. Originally, we transcribed varying report formats and data into the Stanley Center’s e-notebooks. We quickly found that this administrative task required a prohibitive amount of time. Ultimately, synchro-nisation with our vendor’s records by providing remote login (to the Broad’s e-notebook system) allowed each vendor to download experimental details and analytical data in real time. This provided several advantages:1. A permanent record of experiment

details with associated analytical data on an internal server

2. A searchable chemistry database within the Stanley Center and Broad Institute

3. A source for real-time evaluation of ongoing chemistries

4. A cornerstone for leveraging existing

Stanley center's medicinal chemistry development cycle

Quality control, Sample repository dissolution, Plating and distribution of compounds

SAR (Compound database) Structural biology In silico / In vitro ADME multiparametric

optimisation software homology models / Docking / ScoringMedicinal chemistry groupMultiple academic collaboratorsMultiple CROs

Synthesis

Broad Institute

Compound management analytical chemistry

Data analysis, Model refinement, Design

In vitro assays, cell-based assays, In vivo efficacy, In vivo PK / ADME

Testing

Multiple academic collaboratorsMultiple CROs

Lead optimisation

cycle

Analogue, Scale-up tool compounds

Courtesy: Mike Moyer Figure 2



• Success• Shortening of the typical development time for new discoveries emerging from

academia• More refined chemical and/or biological leads from non-profit organisations• The discovery of new biological targets with an approach toward a novel

therapeutic• The development of new chemical entities through phase I or phase II clinical

trials

Certainly, achievement of any one of these goals would be considered a success and help to refine the approaches implemented in drug discovery.

How will we measure?capabilities of the Broad Institute (compound registration, analytical (QA / QC), compound management)

5. An expansion of CROs’ capabilities and responsibilities

By integrating our compound flow into the existing informatics structure of the Broad Institute via e-notebook we were able to adopt already established protocols. Compound registration (Broad ID) assigns a unique alpha-numeric code for each compound which contains purity, batch and salt information. In addition, compound registration provides access to the Broad’s analytical capabili-ties. Once registered, integration of an open-source web-based image viewer (“aView”) allowed rapid annotation of analytical results and streamlined the process of compound purity assessment and re-analysis and / or re-synthesis. Moreover, this allowed us to work with the Broad’s compound management group to plate compounds efficiently for in vitro and cell-based assays.

The E-notebook system facili-tated complete coordination among our chemistry contract partners and chemists working internally, thereby fully integrating them with our infor-matics environment. Contract chemists synthesise, document and register each compound remotely. Compounds are received pre-registered in bar-coded vials and forwarded to compound manage-ment for dissolution, preparation of stock solutions, and plating for biologi-cal assays as well as LC / MS analysis. Review and annotation of analytical data via aView prior to assaying provides a filter to remove compounds from the system that do not meet our purity requirements. What had taken hours (document, register, and collate data from various vendor sources) for each compound has now been reduced to minutes by extending our process into the hands of our chemistry CROs.

Through careful evaluation and utili-sation of external CROs and by integrat-ing into existing infrastructures at the Broad Institute, an efficient process for

the first steps of the drug discovery cycle has been established. We hope with time to extend these efficiencies deeper into the drug discovery process and continue to refine this model.

FutureWith the implementation of an efficient chemistry infrastructure based on an industrial model we are poised to engage and refine more of the discovery cycle in this new environment. What remains to be seen is whether this model is sustain-able and how it will impact industry and academia.

Implementing a drug discovery programme creates a large burden on resources. Thus, sustaining drug discov-ery and development in academia will require both a shift in funding initiatives to foster this type of research as well as successful partnering between academic institutions and industry. The landscape does indeed appear to be shifting in this direction. Government funding agen-cies have initiated programmes geared

specifically toward IND-enabling stud-ies (NIH’s National Cooperative Drug Discovery and Development Groups Program) and towards funding for drug development activities (NIH-RAID, Rapid Access to Interventional Development). Charitable organisations and philanthropic foundations are also having an enormous impact on fund-ing this research (The Broad Institute and the Stanley Center are just two examples). In addition, private resources are funding the earliest stages of discovery in psychiatric disease through a special outreach initiative (‘PsychHTS’) for primary high-through-put screens. Finally, academic centres focussed on specific disease areas have had major upfront investments from industry which should allow sufficient opportunity to test this new model (e.g. Vanderbilt and Johnson & Johnson). The next 5 to 10 years will define how much this new model will impact our traditional models of drug discovery and development.

edward holson is medicinal chemist iii, Stanley center for psychiatric research at the Broad institute of mit and harvard. in february 2008, he joined the medicinal chemistry group at the Stanley center to design and implement strategies towards developing novel therapies in cnS related disorders including schizophrenia, bipolar and cognitive functional impairment. prior to joining the Broad institute he worked with merck & co. and Infinity Pharmaceuticals in medicinal chemistry and pharmaceu-tical development across multiple therapeutic areas.

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preclinical research in Big Biotech Vertical integration is the keyas companies transition from young, start-up phase organisations to a more mature and successful stage, the needs and demands placed on the management teams from both internal and external sources change. these changes can have long-term consequences, whether they happen by strategic design or circumstance. the key element for growing companies is vertical integration.

David R Webb, Vice President, Research, San Diego Site Head, Celgene Corporation, USA

of the organisation change, Research must change as well. It no longer needs to prove the worth of an approach or platform, rather it must now provide a sustainable flow of new drugs to meet commercial expectations (e.g. in the US this means Wall Street). How the company approaches this challenge ultimately deter-mines the success of the enterprise.

Without a flow of competitive new products, the company’s commercial value diminishes and a likely merger or acqui-sition will be, most often, the only exit strategy. Thus, building an organisation that can be self-sustaining is of paramount importance and never more so than at the level of preclinical discovery.

Achieving vertical integrationOver most of the last century, the response

was for Research to grow apace with all other areas of the company. This often led to large and expensive research organisa-tions, which often experienced a paralys-ing disruption to research programmes due to constant mergers and acquisitions. The result today is that biotechnology companies are seen as far more nimble, original and creative than their much larger competitors. Knowing this, what should a big biotechnology company do?

Big here refers to companies with market capitalisations greater than US$ 10 billion and are fully integrated. Fully integrated implies a vertical inte-gration that allows all the activities from drug discovery and development through to registration to take place within the company.

In the biotechnology world, start-ing a new venture is fraught with a mixture of excitement and anxiety.

Using a new technology or drugs plat-form that has yet to prove itself in the clinic and the marketplace can be one of life’s greatest adventures for scientists and entrepreneurs.

As companies transition from that initial phase and with some success, move on to a more mature organisation, the need to carefully manage growth and product commercialisation becomes the paramount objective.

The primacy of place for the preclini-cal organisation is supplanted by the need for growth in other parts of the organisation—clinical, regulatory, CMC (Chemistry, Manufacturing and Control) and commercial groups. As the needs



Each of the big biotechnology companies has taken a slightly different approach to this challenge and in some cases has eliminated preclinical discov-ery entirely. The remainder tend towards highly focussed preclinical research teams that take calculated risks, use academic centres (i.e. Universities and Research Institutes) to bolster their understanding of fundamental biological and disease processes as well as take advantage of the growing expertise of Contract Research Organisations (CROs) to help carry out research programmes.

The half dozen or so of the large biotechs which have large market capi-talisations also engage in company to company based collaborations to fill gaps in their discovery and development pipelines; similar to what is done by Big Pharma.

A recent development has been the increased role of translational science and medicine, which can bridge the gap between the laboratory bench and the clinic by providing essential information concerning biomarkers, defining cohorts of potentially responsive patients, and providing early clinical feedback on the effectiveness of drugs or biologics against their molecular target.

One approach to expand the reach of the preclinical research organisation is to use outside CROs in such a way as to constitute a virtual discovery platform that takes advantage of their various scientific platforms to perform much of the work needed to advance a programme to lead optimisation. Adjunctive to this approach are alliances with universities and private research institutes that provide fundamen-tal information on potential new targets or new research directions. Both approaches allow the internal organisation to focus its attention on the critical late stage of lead optimisation and drug candidate selec-tion without having to use its precious resources on multiple early programmes. Rather, it can pick and choose among these for the programme that is judged to have the best chance of success in moving into clinical evaluation.

David R Webb joined celgene in 2003 as vice president of research. Between 1987-2003 he held senior research posi-tions in several biotechnology companies and in big pharma. he was a member of the Department of cell Biology at the roche institute of molecular Biology from 1973 to 1987 and adjunct professor of human genetics at columbia university college of physicians and Surgeons. David Webb received his phD from rutgers university and was a Dernham Junior fellow in cancer research at ucSf.

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Optimising through vertical integration Thus, a fully vertically integrated big biotechnology company has its preclini-cal discovery research take full advantage of a variety of approaches and tools to advance drug candidates.

It is linked to its clinical development research group via its translational science and medicine team. Integrating all of this requires the highest level of competence in bioinformatics and information tech-nology (Figure 1). The IT group is the glue that allows the best integration of information and the greatest capacity for data mining.

The maintenance of a culture of originality and risk-taking at the level of discovery research requires a continued commitment not only by the research scientists but also by the management team that supports it. It also requires a vigilance on the part of supervisors and managers at all levels to encour-age individual initiative within the framework of the goals and visions of the company. At the end of the day, proof of success is most easily meas-ured by the productivity of the research organisation in terms of NCEs that move forward through the pipeline to ultimate approval.

Model of a big biotechnology company with vertical integration

VERT

ICAL

INTE

GRAT

ION

Informatics and information technology

University based

alliances

D

Organisation

CROs

CROs CROs

Company-based alliances

Company-based alliances

Virtual discovery platform

Rcore

comptencies2 TA's

~ 200 scientistsCROs

Translational medicine

Figure 1



computerised cognitive function assessment coming of agethe role of automated cognitive function testing in contemporary drug development is assessed here, from the early stages as an aid to translational medicine, through pivotal trials of cognition enhancers to post-marketing studies. properly automated cognitive function assessments have considerable benefits over traditional pencil and paper tests, and can bring additional value to all stages of drug development.

Keith A Wesnes, Chief ExecutiveRianne e Stacey, Report WriterAndrew C embleton, R&D StatisticianSteve Satek, Vice President

Cognitive Drug Research Ltd, UK

Cognitive function testing was first introduced into drug development to assess the

unwanted side effects of many medi-cines to produce impairments to mental functioning, and is still widely utilised to establish whether newer medicines are relatively free from such effects. However, the opportunities for medi-cines to improve cognitive function in the dementias and other disorders have led to the widespread incorporation of such testing into efficacy trials, some-times as the primary outcome.

Cognitive function refers to mental processes which are crucial for the conduct of the activities of daily living. These processes include attention (concentration, vigilance), the ability to hold information temporarily ‘on line’ (working memory), the ability to store, retain and retrieve information over hours, days and years (episodic secondary memory) and the coordina-

tion of movement. While there are many other facets of cognitive function, these are particularly important because they can be influenced by a wide variety of factors, including trauma, fatigue, stress, nutrition, ageing, disease (both physical and mental), and, of course, medicines and drugs. The efficiency with which these processes operate has a direct influence on how effectively everyday activities are conducted; essentially, the quality of everyday behaviour is under-pinned by cognitive function.

Our appreciation of the importance of cognitive function depends on the appropriateness and also the quality of the measurements. The only direct way to assess aspects of cognitive function is to require an individual to perform mental tasks whose successful perform-ance is dependent upon those aspects. Thus, if a researcher wished to assess memory, the test would involve the subject remembering some kind of

information with the outcome measure reflecting how successfully this informa-tion was memorised and subsequently retrieved. Equally, if the object of study was to assess the ability to maintain attention, the test would involve sustain-ing attention to a set of pre-defined stimuli and the outcome measures would reflect both the accuracy and speed of the responses. Ultimately, the quality of the measurement of cognitive processes depends on how well the tasks have been designed and implemented.

In the past, many aspects of cogni-tive dysfunction have been difficult to assess, not because they are subtle or have little relevance to everyday behav-iour, but generally because they have not been subject to the diligent application of appropriate tests. Even when test-ing has shown cognitive dysfunction to be present, its clinical relevance can be questioned; sometimes because the tests have not been demonstrated to



have relevance to everyday activities, or because the psychologists who have developed them have failed to convince physicians of either the importance of the construct they are measuring, and / or the ability of the test to measure the particular construct. Thus, while it has long been demonstrated that Alzheimer’s patients perform poorly on tests of atten-tion, the importance of attention defi-cits in the profile of dementia has only become widely accepted in recent years. Even when there is widespread agree-ment, for example, that pronounced memory loss is a major characteristic of Alzheimer’s disease, and this memory loss can be observed non-clinically and without the need to quantify it; such observation is not sufficient if we are to chart the progression of the disease or identify improvements which may be conferred by medication, and thus precise tests of memory are essential.

Automation – Rationale and benefitsThere are a number of reasons for automating tests of cogni-tive function. One is to improve the overall quality of testing by standardising and facilitating test administration while also automatically collecting and processing the responses in an unbiased manner. Another is to precisely capture the speed of each response, something which cannot be done with non-auto-mated tests and, therefore, limits the sensitivity of such pencil and paper methods. A further advantage is that automation can enable tests to defini-tively and objectively measure particular aspects of cognitive function that tradi-tional procedures cannot unequivocally assess.

The diverse range of cognitive tests available makes it hard to generalise findings from one study to another, and most researchers would agree that the standardisation of tests is desirable. It is well established that the manner in

which a test is administered will have a consequence on how it is performed. It must also be acknowledged that differ-ent test administrators, no matter how professional, will adopt varying manners of test administration. Automation can go a long way towards minimising the influence of these factors; standardised instructions can be administered via the computer screen and the test stimuli (pictures, words and other information) can be presented for precisely controlled durations and at specific rates. Further, test administrators being human, make mistakes and, in some procedures, there are also judgements to be made. These judgements, by their nature, can be subjective and will always be a poten-tial source of variability. Such problems can be largely overcome with the proper automation of tests.

Most of the advantages described above serve to reduce the variability associated with test administration, which improves the precision of the assessment and thus the sensitivity of the test. The ability to measure, to the nearest millisecond, the time, as well as the accuracy, of each response, is one of the most significant advances to the sensitivity and quality of cogni-tive assessment which automation has brought to the field. This comprehensive measurement confers huge advantages; not only can trade-offs between speed and accuracy be identified (and thus changes in response style can be differentiated from changes to mental ability), but also improvements to both accuracy and speed can be unequivocally interpreted as reflecting enhanced performance. The security and integrity of cognitive

data can also be guaranteed by automated tests, responses being stored in encrypted files which can only be accessed by authorised personnel.

Some automated systems have been in use since the 1980s and the advantages have been repeat-edly identified. In 1996, research-ers from the Canadian Institute of Mental Health compared the CDR System to a range of non-

automated tests including the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale—cognitive subscale (ADAS-cog) and the Wechsler Memory Scale. They found that the CDR System was not only superior in detecting dementia but was the only test that could reliably differentiate patients with Alzheimer’s disease from those with Huntington’s dementia.

Translational Medicine – The value in phase I and II drug developmentTraditional drug development simply assessed the safety, tolerability of phar-macokinetics of novel compounds in phase I and sought evidence of efficacy in large phase II, or in some cases phase

A further advantage is that automation can enable tests to definitively and

objectively measure particular aspects of cognitive function that traditional

procedures cannot unequivocally assess.

Automation of testing can also provide the opportunity to facilitate the process of test administration in various ways. For example, automated test systems can cue both experimenter and subject for the various stages of tests and introduce the next test in sequence. When testing is repeated on subsequent occasions, computer-ised tests can automatically select the appropriate parallel (or alternate) forms. A further benefit in volunteer trials is that groups can be tested simultaneously using multiple computer set-ups, often administered by a single experimenter. Widely used systems like the Cognitive Drug Research (CDR) System have the further benefit that non-specialists can administer the tests.



III, trials. A widespread trend over recent years has been to seek evidence of the desired effects of a compound as early of possible in the development process using procedures sometimes called biomark-ers. This work is termed translational medicine and permits the early selection of compounds that show more potential for further development and reduces the likelihood of wasted resources due to candidate drugs failing later in the clini-cal development cycle. Cognitive testing can serve drug development by either identifying the ability of a compound to enhance cognitive function, or by ensuring that a compound is relatively free of the unwanted side-effect of cogni-tive impairment. Although phase I stud-ies are by their nature busy, intensive and often invasive, cognitive function testing can be inte-grated into the study design, provided the appropriate types of cognitive tests are employed. In most phase I Units, volun-teers are housed in wards and the majority of study procedures are performed there. Properly computerised tests are ideal, as auditory instructions or responses are not required and a single administrator can simul-taneously test several volunteers, whereas many pencil and paper techniques by their interactive nature are inappropriate and / or impractical. Brief but sensitive tests are the ideal, measuring a range of cognitive domains within 15-20 minutes. These tests can be repeated a number of times over the study day to assess any time profile of effects and can be done by the bedside if necessary.

Evidence of cognition enhancement has been identified in routine phase I safety and tolerability trials by simply introducing appropriately sensitive computerised tests into the study proce-dure, without compromising the primary safety objectives of the trials or requiring larger sample sizes. These findings have subsequently been confirmed using the same procedures in small phase II trials

in a number of conditions including adult ADHD, Alzheimer’s disease and schizophrenia. Other work in phase I has established the absence of cogni-tive impairment for compounds such as darifenacin, a selective M3 antagonist targeted to treat urge incontinent in the elderly without the cognitive impairment known to result from traditional medi-cations like oxybutynin. This absence of impairment was followed up in larger phase I trails and has since been confirmed in clinical practice.

Computerised testing has also been used in phase I models, for example the scopolamine model of dementia which has identified a range of compounds that can potentially treat the symptoms of Alzheimer’s disease, including Debio

9902 a third - generation anti-Alzheimer’s compound now in phase II trials. Sleep deprivation models in volunteers have also been used to identify the wake promoting properties of compounds, for example armodafinil, which was subsequently approved by the FDA for the treatment of narcolepsy and shift-work sleep disorder.

There are cognitive assessment systems that can be used in virtually any environ-ment with any population. The benefits of identifying wanted or unwanted effects as soon as possible in development are now widely recognised and accepted. Many companies have many compounds to choose from and they can stop the development of inferior compounds as soon as possible. Smaller companies developing cognition enhancers need to

demonstrate potential efficacy as soon as possible in the development process to enable them to establish licensing or co-development programmes with larger companies. With these considerations in mind, there is now little justifica-tion or excuse for not properly assessing cognitive function throughout the drug development process.

Alzheimer’s disease and other dementiasThe search for drugs to treat the cognitive dysfunction associated with Alzheimer’s disease and other dementias is now well into its third decade, yet progress has been slow. In part, this has been due to the unofficial acceptance of the ADAS-cog as the gold-standard for measuring

cognition in pivotal Alzheimer’s trials, despite there being no regulatory mandate for this. The limitations of the ADAS-cog are numerous and have been described widely elsewhere; many relating to the problems inherent in non-automated tests, but a particularly serious limitation is the failure of the ADAS-cog to assess atten-tion, now established to be a core cognitive deficit in Alzheimer’s disease. The highly controversial

decision by the UK’s National Institute of Clinical Excellence (NICE) in 2005 to recommend that currently available anti-dementia drugs (the anticholinesterases) not be given to patients with mild to moderate Alzheimer’s disease was based on their judgement that the available evidence of efficacy was limited. As the ADAS-cog was the sole cognitive outcome assessment in the regulatory trials of the anticholinesterases, the potential of the compounds to also improve attention went unaddressed. Had attention tests been included in such work and improvements been identified, this extra evidence may have helped address NICE’s reservations. More recent work using computerised tests, has shown that the attention benefits of anticholinesterases such as galantamine

The ability to measure, to the nearest millisecond, the time, as well as the

accuracy, of each response, is one of the most significant advances to the sensitivity and quality of cognitive assessment which

automation has brought to the field.



in Alzheimer’s disease can be profound in magnitude, representing up to 40 per cent reversals of these attentional deficits. The improvements to attention were also favourably reflected in Clinicians’ Global Clinical Impressions, and had implica-tions for everyday behaviour and also for carer burden.

The treatable cognitive deficits in other major forms of dementia are also being profiled and recent consensus criteria for Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) have established that the profound attention deficits identified in both dementias using the CDR System are central to the symptomatology of the both diseases and of greater significance potential than the memory deficits. The criteria recommend that automated attention measures should be part of assessments of therapeutic outcomes in the disorders. The first randomised clinical trials in DLB and PDD have identified that rivastigmine can produce large and clinically meaningful revers-als of attention deficits of up to 50 per cent in DLB and 68 per cent in PDD. Furthermore, work in PDD has shown that CDR attention tests predict the capabilities of conducting the activities of daily living far more strongly than does the ADAS-cog.

The European Medicines Agency (EMEA) 2008 Guidelines for Development of Medicines for Alzheimer’s disease and Parkinson’s Disease have stressed that attention should be one of the domains assessed in the dementias, and has also provided a green light for properly validated alterna-tives to the ADAS-cog to be incorporated into future trials. Therefore, automated tests such as the CDR System which have satisfied the various validation requirements stipulated by the guide-lines can now be introduced into pivotal Alzheimer’s trials, if not immediately to replace the ADAS-cog, but at least to supplement it. In the case of other dementias such as PDD and DLB as well as Huntington’s and Vascular dementia,

there is or never has been any rationale for using the ADAS-cog and future trials can proceed with alternative methodolo-gies more suitable to the deficit profiles in these dementias.

SchizophreniaThe growing recognition that cogni-tive dysfunction in schizophrenia plays a major role in the poor rehabilitation rates of otherwise successfully treated psychotic patients into functional roles in society, has led to the development of the MATRICS Consensus Cognitive Battery (MCCB). The initiative identified seven target domains covering core aspects of cognitive function including attention,

Other clinical conditions in which cognitive disorder is presentCoronary Artery Bypass Graft (CABG) surgery has long been associated with residual cognitive dysfunction. Recently, a worldwide pivotal trial sponsored by Neuren used the CDR System as one of the two primary outcome variables to test Glypromate. The FDA approved trial was terminated early due to the lower than expected variability in the cognitive data resulting from the use of computerised testing. The sponsors argued that the reduction in variability meant that the study objectives could be adequately tested with 320 patients as opposed to the originally planned 600.

Cognitive testing can now be delivered via the Internet which will enable cognitive testing to be introduced in phase IV programmes. Such trials will enable the benefits of medicines on cognitive function to be captured in large post-marketing studies, patients either logging on at home to perform testing, or having testing conducted while making visits to the clinic. It will also enable medical practitioners to test patients prior to recommending medications, and then to conduct follow up testing at regular intervals. This will enable clinicians to determine for themselves whether cognition enhancers are having their desired positive cognitive effects, or conversely, that other compounds are indeed free from unwanted cognitive effects. Evidence-based prescrib-ing will thus be feasible in clinical settings, which would enhance the credibility of many potential treatments for cognitive disorders.

The case for Internet-based cognitive testing – The potential value for phase IV

speed of processing, working memory and verbal and visual learning. Unfortunately the developers included mainly traditional pencil and paper neuropsychological tests and not surprisingly, the first trial to be published using the MCCB, identi-fied training effects on the various tasks which obscured the potential treatment effects the study was designed to iden-tify. However, the positive contribution the MATRICS initiative has brought to the field is the establishment of the core cognitive domains which should be targeted in schizophrenia research, which has opened the door for properly validated automated test systems such as the CDR System to be used in such research.

Sadly, the initial reports are that the study compound did not provide a protective cognitive effect to the patents, but this trial does provide the rationale for other trials to address this topic with mark-edly smaller sample sizes than would be required with traditional neuropsycho-logical tests.

Cognitive dysfunction is widely recognised to occur in a variety of clin-ical conditions. A core benefit cogni-tive testing can bring to such work is to establish the benefits which can accrue from therapies which alleviate the symptoms in the conditions and / or enhance cognitive function. Benefits with the CDR System have been iden-tified in depression with reboxetine;




cancer with fentanyl, epoetin alpha, and modafinil; sleep apnea with armodafinil; narcolepsy with armodafinil; fibromyal-gia with galantamine; hypertension with candesartan; epilepsy with remacemide; ispronicline in Age-Associated Memory Impairment; and ABT-089 and NS2359 in adult ADHD.

The application to herbal medicinesAs herbal medicines become more widely available and get subjected to regulatory scrutiny, the requirement to properly assess their purported benefits becomes overwhelming. Many have been tradi-tionally believed to enhance cognitive function and the CDR System was used in one of the first randomised trials of ginkgo biloba in elderly patients with mild cognitive impairment. Over the last 20 years, clinical trials using the CDR System have been able to confirm many of these purported cognitive benefits in the young and elderly for a variety of substances including gingko biloba, panax ginseng, Sage, guarana, Bacopa Monniera, Melissa and rosemary. Such work has been used to support product claims, advertising and patents.

Paediatric clinical trialsChildren as young as six can be tested using the CDR System and a variety of trials have been conducted including the cognitive effects of breakfast cere-als, classroom ventilation and mobile phones, as well as clinical trials including one assessing the effects of anti-epileptic medications in adolescents with epilepsy. The worldwide moves to increase the regulatory requirement to establish safety data in children for medicines they are likely to receive will provide the oppor-tunity to assess the cognitive risks or benefits children may experience from a range of novel and existing drugs.

Imaging trialsInterest is growing in combining cognitive testing with other tech-niques in phase I trials which measure various aspects of activity in the

CNS, such as EEG, PET and fMRI. While these hugely sensitive measures reveal vast amounts about CNS function and activity, it must be remembered that they are not in themselves direct measures of cognitive function. Instead, they iden-tify patterns of activity, which may be the neural substrates for various aspects of function, and these meas-ures are thus indirect assessments. However, when such assessments are directly integrated with tests of cognitive function, these co-joint evaluations of performance and CNS activity become extremely powerful instruments which are, for example, capable of functionally linking drug-induced changes in cognitive function with activation of various brain areas, or in the case of SPECT, with receptor occupancy.

It is time to actThe importance of cognitive function assessments in contemporary drug development makes a strong case for the

Keith Wesnes is the owner and Chief Executive of Cognitive Drug research (cDr) ltd., which he founded in 1986. he trained at reading university, indiana university and guy’s hospital medical School, has published over 200 peer reviewed papers and holds professorships at northumbria university, newcastle, UK and Swinburne University, Melbourne, Australia.

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Rianne Stacey has been working for cDr for just over a year as a member of the research and Development team. She has a strong academic background gaining a masters degree from the university of cambridge in 2002 before embarking on a phD at the university of manchester, which she completed in 2007.

Andrew embleton is a recent graduate of the university of reading having studied applied Statistics before joining cDr’s research and Development team. as part of his BSc he worked on a year’s placement in the pharmaceutical industry. he is also in his second year as a member of the royal Statistical Society.

Steve Satek has spent nearly 20 years in the clinical research industry before joining cognitive Drug research as vice president of north american operations. Steve graduated from university of Wisconsin-madison in 1988 with a double Bachelor’s Degree in Biochemistry and molecular Biology, before earning his master’s Degree in Business administration from lake forest graduate School of management in 1999.

proper automation of test procedures. Much of the benefits of automated testing in translational medicine and many other areas of drug development which have been discussed have been based on the extensive experience gained with an automated cognitive test system which has been used in clinical trials worldwide since the 1980s. The ability to definitively assess changes in cogni-tive function in clinical trials opens up possibilities in numerous areas, including paediatric studies, studies of herbal medi-cines, imaging studies, as well as more mainstream areas of drug development including dementia, schizophrenia and numerous other neurological, psychiat-ric or clinical conditions. Computerised assessment of cognitive function has now come of age in drug development, and the pharmaceutical industry has a range of systems and technologies avail-able to better characterise and develop its products.



lyophilisation process Development the development of optimised process for freeze-dried product is described. new available analytical tools are reviewed and different steps from early phase to life cycle management are covered.

yves mayeresse, Senior Freeze-Drying Manager, GSK Biologicals Industrialisation, Belgium

Freeze-drying is used by the phar-maceutical industry for years. It’s a way to protect sensitive molecules

from degradation, allowing their shelf life to be extended from days or months to years. Moreover, the technology is perfectly integrated inside industrial GMP (Good Manufacturing Practice) production giving a high degree of confi-dence in product sterility. However, the process has some drawbacks: it incurs huge costs and is very complex. Other techniques exist to stabilise molecules, but they are not so well accepted in the pharmaceutical industry.

Freeze-drying may be seen as the relationship between the following three parts:• The freeze-dryer: a complex mechanical

high performance apparatus• The product: vaccines in our case,

but it can be whole cells, yeast, bacteria, protein or other molecules of interest

• The process: The freeze-drying cycle is the link between the freeze-dryer and the product. It allows to obtain a quality product inside a specific equip-ment.

The advancements in science now allow us to produce more and more complex molecules to target specific diseases. The complexity of these mole-

cules makes it very difficult to stabilise them. In this context, freeze-drying appears as a method of choice to stabilise the molecules. Consequently, there’s a need to rationalise the way process devel-opment is done.

The development processThe product development process consists of different steps. First, cryoprotective molecules such as sugars, salts and poly-mers are chosen to protect the targeted active ingredients at the liquid state before and during freeze-drying. Then,

a freeze-drying cycle is designed to proc-ess the formulation. Finally, the process is scaled-up for clinical production and is later transferred to industrial produc-tion facilities.

In the past, freeze-drying process development consisted of finding a dedi-cated process for each product. As there were no technological tools to follow the process, the release criteria were mainly used. Generally, a satisfying cycle was reached by the trial and error method.

With the advances in the scientific knowledge of new molecules, various

The product is first frozen at a low temperature to reach a vitreous state. The nature and structure of the frozen plug allows a good protection Then, it undergoes sublimation under vacuum maintaining the product temperature below its glass transition tempera-ture or collapse temperature. That specific temperature is determined by the stabilisers chosen and is measured with specific tools such as the cryomicroscope. This value is of paramount importance for the product elegance. If the product is sublimated at too high a temperature it ends up to be a melted product that will be rejected, creating burden (write-off) at industrial scale

After primary drying, 10 to 20 per cent water is still inside the formulation adsorbed by the active ingredient. Secondary drying, often called desorption, removes that bound water from the product. This step is carried out at a higher temperature to remove the absorbed water. Removal of water is done by diffusion and not anymore by subli-mation. Since diffusion kinetics is slower, it explains why secondary drying can take one-third of process length to remove only 10 to 20 per cent of the total water. The maximum temperature is defined in function of the product, but usually stays below 40°C for biopharmaceutical molecules.

A freeze-drying cycle may be divided into three parts

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online and offline tools have been used to improve the process to meet the require-ments of the industry.

Selection of stabilisersThe following example illustrates how stabilisers are selected from various options keeping in mind the business interests. The first screening shows equiva-lence between two different stabilisers for biological activity. One of the two stabilisers has a higher collapse tempera-ture. If chosen, this stabiliser will allow developing a more robust and quick (as the allowed temperature is higher, the product can be dried faster) freeze-drying cycle. It is better to run a three freeze-drying cycles a week than two freeze-drying cycles a week as it increases the capacity by 33 per cent. On the other hand if the right stabiliser is chosen at the beginning of the development it allows you to obtain the desired result.

The development of process is gener-ally well defined and involves several steps. If the stabiliser is a well-known substance, former development and some modelisa-tion will help to quickly define the safety margin of the process and necessary trials are planned accordingly. For branding new kind of products, the available tools will be reviewed and applied.

In this category some new equip-ment have appeared during the last years. Previously, developers only had two online tools to monitor the process, an invasive temperature probe placed in a vial and the view port, through which they could have a look at their product during drying. Now, micro balance can follow the loss of weight of the product during the whole cycle allowing easy optimisation. Cold plasma system can measure the water vapour flux inside the freeze-drying chamber during develop-ment phase of the stabiliser.

Another step of process develop-ment is to make the cycle robust with Design Space study. The input and output parameters of the process are reviewed. Input parameters for freeze-drying are: shelf temperature, pressure in the system

and time. The output parameters can be: residual moisture, potency, content, drying kinetics. The goal is to obtain the same range for output (i.e. good potency) at all times by varying on a wide range the input parameters (i.e. pressure 10 and 100 microbars). If one can reach this target they end up with a robust product where they are confident about the scale-up. The freeze-drying cycle development directly integrates safety margin to assure a smooth transfer to larger scale. For regulatory purpose it’s far easier when freeze-drying cycle is not modified between different clinical phases. Those studies are not performed on a trial and error basis anymore, but use the power of DOE (Design of Experiment). This approach is perfectly suitable for freeze-drying since there are only a few well-characterised input parameters for this closed system process.

Clinical developmentA further step is clinical development. All the development trials are performed at small scale (below 5,000 units) to avoid wastage of raw materials. Once clinical consistency is established, the trials are performed at larger scale.. This is the first scale-up of the product towards larger scale. At least three batches are produced with the target value of the developed cycle. They are deeply analysed for visual appearance, moisture content and mois-ture distribution. Statistical analysis is done on the result to underline any deviation compared to early develop-ment results.

Transferring for large-scale productionThe last step is the transfer to produc-tion unit. It requires people with a good

knowledge of clinical and industrial freeze-dryers. The engineering depart-ment should receive guidance before buying new freeze-dryers. An exotic industrial freeze-dryer may require upgrade of some technical part, since it will run out of the defined range. The transfer involves a multidisciplinary team in terms of department and competen-cies. Freeze-drying is not a stand-alone technology; the formulation, filling and some specific tests are equally transferred. For example, with each product a kit of known visual defects is provided to the manufacturing department. Summary of the process evaluation and proc-ess validation is set up for transfer. Commercial consistency batches are produced in the targeted factory. Specific sampling procedure is devel-oped to assure homogeneity inside the load for specific attributes of the new product. Like at clinical step, statistical analysis is realised on each batch and a comparison between batches of different freeze-dryers is done. After transfer a support of the product is kept. It allows detecting any unexpected behaviour of the product at industrial scale. These learnings act as feedback during the development of other new products in order to continually improve the scal-ing-up model.

Freeze-drying process development is a robust, well-defined way to assure the success of new products. Even if it can be seen as time-consuming, the knowledge of the product and process acquired in the first step of development will avoid a lot of costly burden at production scale with better product understanding.

yves mayeresse is senior freeze-drying manager at GlaxoSmithKline Biologicals. He has more than fifteen years of experience in the pharmaceutical sector and has managed activities such as parenterals production, set-up of new freeze-drying facilities, design of freeze-drying cycle and development of new stabilisers for freeze-dried products.a

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oee Systems and SoftwareEnhancing operational efficiencymaking the best use of the equipment and reducing costs are two of the key challenges among many that the manufacturers in general and pharmaceutical companies in particular strive to overcome. overall equipment effectiveness software is a boon in addressing the said challenges and aids in enhancement of overall operational efficiency.

pala Bushanam Janardhan, Senior Business Consultant – Life Sciences, HCL Technologies Ltd., India

Pharmaceutical manufactur-ers encounter unique demands in their endeavour to manage

improvement with operational excel-lence. In the past it was easier for phar-maceutical manufacturers to achieve the desired margins. But in the current scenario of competition, price pressure, stringent FDA regulations and the ongoing economic crisis, pharmaceuti-cal manufacturers world over are under pressure with operational performance being a major concern. Pharmaceutical companies lose around US$ 15 billion every year due to disorganisation in the manufacturing lines. Efficiency, avail-ability and performance of the packag-ing line affect the entire manufacturing process and, therefore, the company’s bottom line. Most of the manufac-turers are striving for reduction in downtime and manufacturing cost, improved time-to-market and compli-ance to regulations.

Making the best use of the equip-ment and reducing costs are two of the key challenges among many that manufacturers in general and phar-maceutical companies in particular strive to overcome. Overall Equipment Effectiveness (OEE) software is a boon

in addressing the said challenges and aids in enhancement of overall opera-tional efficiency.

What is OEE?OEE is a calculation that permits managers and operators measure process efficiency. Based on the outcome of the calculation, organisations can under-stand the performance efficiency, iden-tify areas of improvement and targets and align the identified targets with the overall business strategy.

OEE considers the common sources of manufacturing productivity losses

and classifies them into three groups listed below: 1. Availability (A) – is a measure of

productivity losses from downtime 2. Performance (P) – is a measure of

losses from slow cycles3. Quality (Q) – is a measure of

losses from manufactured products / parts that do not meet quality specification

OEE = A × P × QOEE filters production data into

understandable metrics that provide a means for measuring true manufactur-ing efficiency. It also forms the basis

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Table 1

Factors affecting production efficiency

Figure 1Source: OEEsystems

Parameters Percentage

Yield Loss 02%

Speed Loss 05%

Preventive Maintenance

12%

Setup and Change over

19%

Equipment Breakdown

20%

OEE 42%

42% OEE

2% Yield Loss

5% Speed Loss

12% Preventive

Maintenance

19% Setup and

Change over

Equipment Breakdown20%


for tools that facilitate enhancement in productivity. OEE score provides a complete measure of manufacturing effectiveness.

Why OEE?Loss in yields, stoppages due to equip-ment breakdown, delays in setting up the production line and maintenance activity are key factors that affect the overall production efficiency. These factors reduce the production capac-ity by 40 to 60 per cent.

Lack of understanding of the true performance of the manufacturing units by the Plant Managers, is the cause for encountering challenges in improv-ing the overall operational efficiency. OEE measurement tools and techniques provide a much clearer understanding of where improvements can be made.

How to calculate OEE?Table 2 contains shift data of formula-tion unit, to be used for a complete OEE calculation, starting with the calcula-tion of the OEE Factors of Availability, Performance, and Quality.

Production data

Item Data

Shift Length 8 hours = 480 min.

Tea Breaks 2 × 10 min. = 20 min.

Lunch / Dinner Breaks 1 × 40 min. = 40 min.

Down Time 50 minutes

Ideal Run Rate 60 tablets per minute

Total tablets 18,800

Rejected tablets 400

OEE

Availability Operating Time / Planned Production Time

370 minutes / 420 minutes

0.8809 (88.09%)

Performance (Total tablets / Operating Time) / Ideal Run Rate

(18,800 tablets / 370 minutes) / 60 tablets per minute

0.8468 (84.68%)

Quality Good tablets / Total tablets

18,400 / 18,800 tablets

0.9787 (97.87%)

OEE Availability × Performance × Quality

0.8809 × 0.8468 × 0.9787

0.7300 (73.00%)

Table 2

Table 3

OEE – Systems and Software

The following companies are some of the leading suppliers of OEE systems for calculating, tracking and reporting of OEE.

OEEsystems – Having its international headquarters at Ireland, OEE Systems works with manufacturing companies to improve competitiveness, increase capacity, reduce costs and deliver business performance excellence. In partnership with global manufacturing customers OEE Systems has refined PerformOEE™ to meet their specific business requirements.

PerformOEE™ - Bulk Manufacturing – Although OEE has traditionally been applied only to discrete manufacturing processes, PerformOEE™ uses an adaptation of the traditional OEE model to fully accommodate the requirements of bulk-manufacturing and process-based manufacturing businesses and provide the process industry with a practical Manufacturing Intelligence and Performance Management software solution based on the OEE model.

Vorne Industries – Having its corporate office at Il, USA, Vorne Industries develops tools that enable customers to improve their manufacturing productivity: quickly, efficiently

and effectively. Vorne strives for excellence in all aspects of the company—people, products, and service. Vorne’s XL800 Production Monitor is a product for performance management, productivity improvement and lean manufacturing. XL800 is a “six-in-one” product that combines a large-area visual display, a high-performance production monitor, expandable I/O, a multiple channel communication hub, a program executioner and a data warehouse—all in one package.

Gemba Solutions / OEE Impact – Specialists in delivering tangible results quickly. They help manufacturing units to slash production costs, increase capacity eliminate waste, save energy and optimise labour.

Idhammar Systems Ltd. – Idhammar is a leading provider of total productive maintenance and manufacturing software. Idhammar has its Headquarters in the UK and has expert teams of OEE and maintenance specialists, software developers, customer support, and help desk staff who work together to develop, support and promote systems that are improving industrial operations worldwide.

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World-class OEE

OEE Factor World Class (%)

Availability 90.0

Performance 95.0

Quality 99.9

OEE 85.0

pala Bushanam Janardhan is a Senior Business consultant (manufacturing & plant automation Services) in the life Sciences and healthcare practice at hcl technologies ltd., since april 2006. prior to joining hcl, he has served the pharmaceutical industry in various capacities—handled process technology development, technology transfers regulatory compliance, supply chain management, outsourcing and business develop-ment for more than 18 years.

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VariablesPlanned Production Time = [Shift Length - Breaks] = [480 - 60] = 420 minutes Operating Time = [Planned Production Time - Down Time = [420 - 50] = 370 minutes Good Tablets = [Total tablets - Rejected tablets] = [18,800 - 400] = 18,400 tablets

World-class OEEThe accepted average OEE score in manu-facturing plants ranges from 45 to 60 per cent. A world-class OEE score is greater than or equal to 85 per cent in batch manufacturing and as high as 95% in continuous processes . The accepted world-class goals for each factor are as shown in Table 4.

OEE and automation companiesRockwell Automation’s new line monitoring and OEE solution has helped a pharmaceutical manufacturer to capitalise on line information and improve effectiveness throughout its packaging process. Rockwell Automation was able to integrate raw data into a single infor-mation interface presenting OEE calcula-tions by output, throughput and by each machine across process and product.

GE Fanuc’s Plant Applications Efficiency solution is a powerful soft-ware module that lets plant manag-ers make sense of the plant data and evaluate efficiency in real time. Part of the larger Proficy Plant Applications Collaborative Production

process. Efficiency, aids in generation of extensive reports easily and enables production managers to perform addi-tional long-term analysis on the trends that matter.

OEE for enhancement of operational excellenceOEE data –• provides one version of truth • is comprehensive• can impact wide range of issues from

shop floor to board room• aids in analysis of who, what, why,

where and when• ensures ROI.

OEE is a metric that can be embraced at every level of the organi-sation. It is meaningful to the operator on the shop floor, yet translates all the way up to the board room. If companies can produce more with less equipment / machinery, it means growth and increased revenue with less capital investment. Higher efficiency drives down the cost. By reducing capital needs and increasing profit, a business will improve its Return on Total Capital, the primary metric of the company / CEO performance. Acknowledgement: The author acknowl-edges with gratitude the support extended by OEEsystems, GE Fanuc and Rockwell Automation in providing facts & figures for the article. The author also acknowledges with thanks the details from the websites of Systech International, Vorne Industries, Gemba Solutions / OEE Impact and Idhammar Systems Ltd.

Management suite, Efficiency is designed to calculate OEE quickly and easily. Efficiency helps to track downtime, waste, production counts, and user-defined events specific to the

Table 4

manufacturing

Courtesy: GE Fanuc

CEO

Finance & Operations

Manufacturing & Maintenance

Fewer assets Predictability Less Waste More output

Less capital investment Reduced cost Improved revenue

Enhanced profitReduced capital needs

Improved Return on Total Capital (ROTC)

OEE – A translatable business metric

OEE

Figure 2

OEE enables to identify root causes for loss of efficiency and helps to make the decisionsthat can improve the process and the bottom line of companies.


clinical trials in oncology Some sense and simplicityWith the advancement of our understanding of pathobiology of many cancers, many biologically targeted agents have been developed. this requires a paradigm shift in clinical development, based on rational design and moving towards personalised medicine.

iman el-hariry, Senior Director, Oncology Medicines Centre, GlaxoSmithKline, UK

The burden of cancer as a global health problem is underscored by its increasing incidence.

With better understanding of the biologic processes underlying the causes and progression of cancer, great strides have been taken in inducing incremen-tal improvements in survival. Indeed the face of oncology has changed in the last decade from a paradigm where a diagnosis of cancer and treatment deci-sions were based primarily on morphol-ogy and histology, to one where treat-ment decisions are now tailored based on molecular profiling of tumours. However, these new avenues of molecu-lar approaches come at a price: Cancer has become a highly segmented disease with over hundreds of biologically distinctive diseases that require differen-tial therapeutic approaches. In an envi-ronment, where pharmaceutical compa-nies are facing a difficult future with higher hurdles of regulatory approvals, sustained costs to research and develop-ment, patient segmentation, restricted reimbursement, patent expiry, or decreased growth revenues, oncology no longer remained sacrosanct.

Increasingly restricted reimbursement can ultimately affect the patient outcome. Recent examples are drawn from The National Institute for Clinical Excellence (NICE) in United Kingdom, which has a stringent approach to cost-effectiveness

evaluation and has resulted in negative guidance for several oncology agents, although “end-of-life” appraisal has begun to address this issue. Stricter definition of innovation is required, which aims at the provision of clear patient benefit and more individualised therapy. With more than 500 anti-cancer compounds in various phases of clinical develop-ment, there is lesser and lesser access to

In the last decade, there has been a major shift towards the use of ration-ally-designed, tumour-targeted therapies. Indeed, targeted drugs such as rituxi-mab, trastuzumab, imatinib, erlotinib, lapatinib, bevacizumab, and cetuximab have revolutionised the treatment of a variety of cancers. With the increasing number of targeted agents in clinical development, several unique issues are identified. The article sheds some light on these issues, addresses some lessons from the past, and the implications for late phase clinical trials.

Although the advances made in cancer management are based on the results of the hundreds of clinical trials that assess the benefit of the new thera-peutics on patient survival and quality of life, there is an increasing need to change the paradigm of demonstrating anti-tumour activity of newly developed agents. There is a need to do more work upfront in order to conduct smaller, less resource intensive mechanistic clinical trials that provide a deeper understand-ing of the biological consequences of the targeted agent on signalling networks involved in the regulation of tumour cell growth and survival. Indeed, the “bench-to-bed and back again” concept has now become the new model for devel-oping new anti-cancer agents (Figure 1). In this model, arsenals of drugs are being developed that are based on our

With more than 500 anti-cancer compounds in various phases of clinical

development, there is lesser and lesser access to patients for enrollment

in clinical trials, which presses the need for

“smarter” and “simpler” clinical development

strategies.

patients for enrolment in clinical trials, which presses the need for ‘smarter’ and ‘simpler’ clinical development strategies. The question posed here is: What would make sense to achieve personalised medi-cine for cancer?

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understanding of the transcriptomic, proteomic, and the genetic and epige-netic changes that occur in cancer cells. More emphasis has therefore been laid on the use of the diagnostic, prognostic and predictive biomarkers in all phases of drug development. Easy as it sounds, the reality is that there are few markers of response that are validated and are acceptable to regulators.

Despite the shortcomings of pharma-codynamic biomarkers, its appli-cability in clinical trial setting has demonstrated tangible benefits. One of the successful strategies in rationally designed clinical trials is testing of new agents in ‘window of opportunity’ phase II setting. Typically, these stud-ies are designed as single arm small studies (approximately 50 patients), where the study drug is administered for a short duration, usually between 2-3 weeks, in the neo-adjuvant setting. The main premise of these trials is based on measuring pharmacodynamic effect(s) of the tested drug in paired pre- and post-treatment tumour biopsies, e.g. changes in receptor expression and / or the activation state, downstream signal-ling pathways, anti-tumour proliferative activity as detected by Ki-67, and / or ability to increase the rate of apopto-sis. Further information is obtained by

utilising PET, or DCE-MRI, and / or proteomics and transcriptomics of serum samples. There is a plethora of such stud-ies in the literature. Conceptually, such an exploratory approach is very useful, as it provides a direct in vivo assessment of the biological activity of a new chemical entity; understand the potential mecha-nism of action in inhibiting the intended target; and correlating the biological and clinical activities.

Identification of putative predictive markers of response could be utilised as surrogate endpoints for clinical activity in subsequent confirmatory studies for vali-dation. Moreover, with carefully designed trials, this approach could provide an understanding of the patient population who would potentially benefit from a given treatment and therefore insight into the patient selection in further phase II and phase III trials.

Despite their increasingly widespread use, the utility of biomarkers in clini-

cal setting is hampered by methodology issues, by the lack of consistent results in multiple testing for the same and across tumour types, and by trial design issues. For instance, various studies demon-strated conflicting results on the value of decreased proliferation as detected by changes in Ki-67, in predicting for response of breast tumours to aromatase inhibitors, tamoxifen, or chemotherapy. To put this all in context, it is impor-

tant to remember that the role of biomarkers remain largely exploratory.

To limit the diluting effects of methodology deficiencies in measuring these biomarkers, the following is recommended for consideration in trial designs. First, careful selection of homo-geneous patient population will

limit the variability in detecting or meas-uring a biological effect. With short-term administration of a tested drug up to three weeks, it is possible to design studies in earlier disease settings, which are considered ethical and would not have an adverse effect on the delivery of standard treatment in most tumour types, such as breast, colorectal, or head and neck cancers. The timing of the biopsies, the standardisation of the assays, and the scoring systems should be carefully considered in order to maximise the

Discovery Development Marketing

Target selection

Gene to function to target

Target to lead

Lead optimisation

Safety developability

FTIM to PoC

PoC phase II

Phase III File launchLife cycle

mgmt.

“Bench / Bed / Bench” loop

Gen Target Lead Candidate FTIH PivotalFile approval and launch

Life cycle

The new model of oncology drug development. In this model, there is a continuous iterative process, whereby individualised targeted agents against specific oncogenic phenotypes are developed that make their leap into the clinical testing. The evolving information from clinical

testing can be integrated and utilised for further lab testing in order to gain further insight into the inhibitory effect of the targeted agents, or improve the structural activity relationship of the agent, or even seek a different target to develop into the clinic Figure 1

Despite the shortcomings of pharmacodynamic biomarkers, its

applicability in clinical trial setting has demonstrated tangible benefits.

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ability to detect a pharmacodynamic effect. More importantly, these studies should be designed as randomised trials. The control arm could be a standard treatment, or placebo, or even a differ-ent dosing schedule of the tested drug. Multiple dynamic biomarkers should be examined to provide a more global under-standing of the drug’s biological effects. With adequately powered clinical trials, it is possible to gain information that would dramatically help tailor and accelerate drug development strategies.

Some success stories can be drawn from the lapatinib development in advanced stage breast cancer. Lapatinib is a dual tyrosine kinase inhibitor of both EGFR and HER2 receptors. In a recent study in refractory inflammatory breast cancer (IBC), the co-expression of the activated, phosphorylated forms of HER-2 and HER-3 seemed to predict for a favourable response to lapatinib. More recently, short-term administra-tion of lapatinib up to six weeks was assessed in patients with locally advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). Compared to placebo, there was a significant reduc-tion in proliferation, but no difference in inducing apoptosis.

Well-conducted clinical trials are essential for successful oncology drug development, and consequent improve-ment in patient outcomes. Although single arm small phase II studies have been extensively utilised for an early read out of activity of new cytotoxic or cytostatic agents alike, it is argued that their true value in advancing medical research may be limited, in light of false positive results that are often obtained, and the lack of efficacy when the drug is tested in confirmatory randomised

clinical trials. For phase II screening studies to have a useful role in oncology drug development, it is important that homogeneous-enriched patient popula-tion are selected; that randomised design be considered, even if not statistically powered. Alternatively, the use of inno-vative trial designs, such as adaptive or sequential designs, have gained traction as strategies in the development of oncology drugs, particularly as these designs have become increasingly accepted by regula-tory authorities as the basis for examining the efficacy of a tested drug in phase III setting. With such designs, smaller patient sample size is generally required, and the studies can be stopped earlier in the absence of patient benefit.

In conclusion, there has been a major leap in oncology drug development, with multiple success stories of drugs that truly and effectively improved the patient outcomes and quality of life. Some of major lessons from these new targeted agents are the importance of target selection; and the changing goals of phase I and phase II trials, including not only traditional endpoints such as pharmcokinetics, assessment of toxicity, clinical efficacy, but also insight into mechanisms of anti-tumour activity, identification of surrogates of activity and panels of biomarkers that predict for response. These tools will hopefully facilitate the drug development proc-ess through rational rather than empiric drug development strategies, clinical trial design, patient selection, and approach to combining therapies to overcome or prevent the development of therapeutic resistance.

iman el-hariry is a clinical oncolgist, who did her training in Alexandria Medical School, Egypt, and gained her PhD at the imperial college, london. currently, she is leading globally the clinical development in head and neck cancer of lapatinib at GSK

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AcceleratingCentral nervous System trials

Techniques such as electroencephalography and evoked potential are useful tools for translation of preclinical findings into Phase I studies. These methods can be used early on to show the presence or absence of central action and adverse effects of investigational compounds, speeding the search for biomarkers and leading to better GO / NO-GO decisions.

Larry Ereshefsky, Vice President, Principal Pharmacologist

Malek Bajbouj, Principal Consultant

Early Development, PAREXEL International, USA

neurophysiological approaches

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The incidence of Central Nervous System (CNS) illness is on the upswing and exacts a heavy

human and economic toll. According to the World Health Organization, more than 120 million people world-wide suffer from depression, and the number is expected to rise. The occur-rence of Alzheimer’s disease is slated to grow by more than 100 per cent in developed countries by 2040 and by 300 per cent in China, India, South Asia and Western Pacific countries over the same time period. In the United States, the National Mental Health Association estimates the annual cost of direct treat-ment of mental illnesses, the social costs of leaving it untreated and lost produc-tivity at US$ 205 billion.

With these statistics as a backdrop, it is worth noting that hundreds of CNS therapies are in development, more than 300 in the United States alone, yet they lag behind in the development of therapies for non-CNS disorders in terms of the time needed to bring them to market. Data suggest that it takes 12.6 years on average for CNS agents to obtain regula-tory approval, twice as long as cardiovas-cular agents. In addition, a mere 7 per cent of investigational CNS drugs that start in clinical development are eventu-ally marketed as compared to 15 per cent for non-CNS candidates.

The reasons are many as to why CNS drugs are more difficult to develop successfully, namely the sheer complexity of the brain; the presence of CNS-medi-ated side effects such as nausea, dizziness and seizures; the need for agents to pass the blood-brain barrier; and the lack of validated biomarkers. Yet, with the imple-mentation of targeted strategies, it may be possible to identify more quickly and with greater accuracy those therapeutics agents with the most promise, leading to better GO / NO-GO decisions.

This article focusses on selected tech-niques that can be used early on, follow-ing preclinical work, to launch Phase I studies that determine if compounds are entering the brain, and how this

action may be impacted by dose rang-ing. These techniques are the routine Electroencephalogram (EEG), the Quantitative Electroencephalogram (QEEG) and Evoked Potential (EP). They can be used as tools for translating preclin-ical findings into first-in-human studies. They may also play a role in later phase studies when compounds shift from being studied in healthy volunteers to CNS patients. Additional translational tech-niques employed in Phase I programmes include cerebral spinal fluid sampling, brain imaging methodologies, and cogni-tive and behavioural assessments. These are beyond the scope of this paper.

in the brain, but their power as tools for translating preclinical findings into Phase I trials is just beginning to be applied. Depending upon the therapeutic area—Alzheimer’s disease, Schizophrenia, pain, Major Depression, Parkinson’s disease, or sleep disorders—all or some of the three techniques might prove useful in characterising compounds starting into Phase I clinical trials.

Routine EEGs, for example, can be used for monitoring CNS toxicity and for detecting increased seizure likelihood. They provide a continuous measure of cortical function with excellent time reso-lution, measurable in milliseconds. Unlike relatively new functional imaging proce-dures, such as Single-Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), and functional MRI (fMRI), EEG has the advantage of being well tolerated, easy to administer, and relatively inexpensive.

Quantitative EEGs are more sophis-ticated as they can monitor the time course of CNS effects of compounds, detail typical profiles of drugs in proof of concept studies and monitor vigilance effects, which refers to the brain’s state of receptivity to external stimuli associated with alertness. Both types of EEGs can be used in conjunction with fMRI, which, while slower to react, in the range of seconds, offers better spatial resolution and could corroborate EEG findings. Together, they can offer a higher degree of confidence that there is a useful signal to go forward.

Evoked potential refers to an electrical potential recorded from a subject follow-ing presentation of an acoustic or visual stimulus, and can be a surrogate biomar-ker for cognitive information processing and for neurotransmitter systems such as serotonin. The ability to monitor sero-toninergic function is valuable because of its putative role in the pathophysiol-ogy and in therapeutic interventions for CNS disorders. An EP method known as the Loudness Dependence Auditory Evoked Potential (LDAEP) can serve as an indicator of central serotonin function

The techniquesThe EEG, QEEG and EP are non-invasive techniques with results recorded from electrodes attached to the surface of the scalp according to an internationally standardised arrangement, the so called 10-20 system (Figure 1). The promise for these methods is to be able to predict, early on in the clinical development of novel therapies that an antidepressant or analgesic will be safe and efficacious at various doses as compared to placebo. Moreover, the EEG or EP signature observed, including dose versus response relationships observed, in animals can be translated and validated against healthy human volunteers and in subjects with CNS disorders.

The EEG, QEEG and EP are well-established measures of electrical patterns

It is worth noting that hundreds of CNS therapies are in development, more

than 300 in the United States alone, yet they lag behind in the development of therapies for non-CNS disorders in terms of the

time needed to bring them to market.

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in animals and humans and may show promise as a predictor of selective sero-tonin reuptake inhibitor antidepressant treatment response. With the LDAEP method, various techniques, such as dipole source analysis and scalp topog-raphy analysis, may detect the effect of enhanced serotonin availability.

One component of EP, known as Mismatch Negativity (MMN) is particularly useful as a biomarker for schizophrenia. MMN is a response that a subject has a variation within a sequence of regular stimuli and is a reflection of sensory memory. For example, if there is repetitive auditory stimulation, such as “b-b-b-b-b”, interspersed with an occasional “r”, the subject elicits an MMN response. Furthermore, the MMN response grows in correlation with the number of repetitions of the standard stimula-tion. Subjects with chronic schizophre-nia, however, tend to generate impaired MMN, indicating that they recognise the change within the sequence in a less robust manner than healthy volunteers and the impaired response may grow as the disease progresses.

Although, schizophrenia therapies in development can be tested in healthy volunteers, frequently the sensitivity to detect a relevant therapeutic surrogate for the drug effect expected in the disorder can be either enhanced or reduced based

on the neurophysiological differences between patients and healthy volun-teers. MMN response is a tool that can be used to explore the potential differ-ences in treatment effect between patient populations and volunteers. If there is a normalisation response among the schizophrenic patients, this would be indicative of drug action, i.e. normalis-ing the observed mismatch negativity. This electrophysiological endpoint might serve as a surrogate marker, convergent with the cognitive and information defi-cit symptoms observed in the disorder. Even if surrogate marker validation is preliminary, the observed effect demon-strates that the compound is crossing the blood-brain barrier and is showing evidence of efficacy.

Using the techniquesA number of studies have been conducted that demonstrate the value of using the described methods to translate preclinical findings into Phase I trials. This section is not intended as a review of all of the studies in this area, but rather, it is meant to highlight a few examples of how the electrophysiological techniques have been applied.

Parker et al. (2001) report using the quantitative EEG approach in an animal study to define the pharmacokinetic / pharmacodynamic (PK / PD) profile

of two investigational antipsychotic compounds, known as S18327 and S16924. Clozapine, also an anti-psychotic, served as an active control. Qualitative EEG changes in this animal model were similar for clozapine, but different for the investigational compounds potentially indicating a different multi-receptor activity and a clinical relevance since EEG changes had been strongly related to positive clinical outcome in schizo-phrenic patients.

This was a small study, using only eight animals. According to the author, however, a limited number of samples can be used when applying the QEEG technique to characterise the PK / PD profiles of early compounds.

Importantly, this work highlights the value of using the QEEG approach in preclinical and early phase investigation as it provides proof that a compound passes the blood-brain barrier; it allows translational approaches by comparing animal model results with human results; and provides data in the form of EEG profiles, comparing an existing compound to investigational ones. These are useful tools that help pharmaceutical sponsors make better GO / NO-GO decisions for CNS drug candidates.

Baldeweg et al. (2006) used evoked potential, specifically impaired mismatch negativity, as a biomarker of Schizophrenia

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Figure 1Source: Handbook from Charite EEG Lab



in a study of the effects of acute admin-istration of nicotine on auditory sensory memory. The study was conducted in 20 healthy smokers who were randomised to either nicotine gum or placebo. Evoked potential responses to deviations in tones (deviants) were recorded using constantly changing standard stimuli in order to measure the effect of stimulus repetitions on the encoding of new stimuli. Results showed that there was a marked effect of stimulus repetition on the standard EP. Acute nicotine administration increased MMN amplitude significantly in the treat-ment group as compared to the baseline recording, whereas no changes in MMN were seen in the placebo group.

Although schizophrenics were not included in this small study, the results support validating this approach as a possible surrogate marker for the treat-ment of cognitive deficits in Schizophrenia and with the observed functional impair-ment observed in patients. MMN might therefore be possible. Schizophrenia biomarkers with benchmarking of ‘novel therapies’ assessed not only against placebo but against nicotine mediated improve-ment in the patients’ MMN impairment (enhancing stimulus encoding and sensory memory).

Moving beyond small, single-site studiesFor the most part, the EEG, QEEG and EP methodologies are used in small preclinical and Phase I studies in the hope of gathering and compar-ing data in animals, healthy volunteers and CNS patients to identify promising drug candidates. As those therapies move forward, the tools have application for Phase II studies and eventually into multi-centre studies. This section discusses two clinical trials in which neurophysiological approaches were incorporated into later phase testing.

In one study, routine EEGs were performed as part of a multiple dose Phase I trial of a compound with a glutamatergic mode of action, meaning that it impacts the neurotransmitter system linked to

and midrange dosage groups did not show any changes known as epileptiform discharges, suggesting that they are safer with respect to seizure likelihood.

In a follow-up study in healthy male volunteers, a first tonic-clonic seizure appeared as a serious adverse effect. The observed EEG data led to an adjustment in dosage in consecutive Phase II studies and to the implementation of routine EEG monitoring in a central EEG read-ing unit.

One of the first larger studies to use QEEG as a predictive tool is known as Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD). It is being conducted in 10 locations throughout the United States (Chart 1) and sought to recruit 375 subjects with a diagnosis of major depressive disorder. The goal is to evaluate the potential of early EEGs as a predictor of an individual’s response to treatment with specific antidepressant medications. Enrollment was completed in March 2007, with 220 subjects analysed for 7-week endpoints.

The BRITE-MD trial tests two anti-depressants—escitalopram (Selective Serotonin Reuptake Inhibitor (SSRI)) and bupropion XL—studying them as single-drug therapy and in combination. It also introduces a dose escalation phase. The intent of the study is prospective

• Baylor College of Medicine, Houston, Texas

• Cedars-Sinai Medical Center, Los Angeles, California

• Massachusetts General Hospital, Boston, Massachusetts

• Northwestern University, Chicago, Illinois

• R/D Clinical Research, Lake Jackson, Texas

• University of California, Los Angeles, Harbor

• University of California (Neuropsychiatric Institute & Hospital), Los Angeles, Westwood

• University of California, San Diego

• University of Pittsburgh, Pittsburgh, Pennsylvania

• University of Texas Southwestern, Dallas, Texas

Sites participating in BRITE-MD Study

memory formation and information processing, and to excitatory CNS effects, up to and including seizures. The thera-peutic indication studied was a degen-erative disorder (Alzheimer’s disease), although this neurotransmitter system is also implicated in Schizophrenia, Major Depression and other CNS disorders.

The study enrolled 12 healthy male volunteers, who were randomised to a low, mid, or high dose of the drug. The EEG changes shown in Figure 2 reflect the high dose arm two hours after drug intake in 50 per cent of the subjects. The changes show electrical discharges with high amplitudes indicating an increased likelihood of seizure. The low

EEG CHANGES IN PHASE I STUDy

Source: Clinicaltrials.gov

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Figure 2Source: PAREXEL 2008



Larry ereshefsky is Chief Scientific Officer, Vice President, and principal pharmacologist in early Development at pareXel international. he serves as clinical professor of psychiatric at the University of Texas Health Science Center in San Antonio, Texas in the united States.

malek Bajbouj is a principal consultant in early Development at PAREXEL International and has in-depth expertise in the central nervous System (cnS) therapeutic area. he serves as professor for psychiatry and affective neuroscience at the charité university hospital and the freie universitaet in Berlin, germany.

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validation of an Antidepressant Treatment Response (ATR) indicator as a biomar-ker of clinical response to an SSRI, and to determine the best treatment option for patients who are predicted to be non-responders to an SSRI. The study is designed to use EEG, starting on Day 0, to determine the association between drug treatment outcome and brain func-tion in patients with Major Depressive Disorder. Electrodes are placed on a patient’s forehead and earlobes to measure brain responses that appear within seven days, and sometimes as early as 48 hours, after beginning antidepressant treatment. On Day 7, there is an ATR assessment, clinician prediction of response, and randomisation.

Interim results indicated that the ATR index reached statistical significance in predicting seven-week clinical response as measured by the standard Hamilton Depression Rating Scale after just one week on treatment with an SSRI. Results presented in December 2007 showed ATR-predicted responders to escitalopram are significantly more likely (67 per cent) to respond to seven weeks of escitalopram treatment than are ATR-predicted non-responders (28 per cent). Findings also showed that ATR-predicted responders are significantly more likely (50 per cent vs. 21 per cent) to achieve remission with seven weeks of escitalopram treatment, and ATR predicted non-responders to escitalopram are significantly more likely to respond if switched to bupropion XL at one week (53 per cent) versus staying on escitalopram for seven weeks (28 per cent). These findings suggest that early EEG testing can detect an early brain signal of response, which can help clini-cians determine treatment response much faster and effectively than a trial and error approach that can take weeks.

Going forwardReducing the timelines and cost of inves-tigational therapies are keys to expand-ing the number of treatment options for the growing number of people suffering from a range of CNS disorders. One

promising approach for speeding the clinical development process is to use established neurophysiological tools, such as the routine EEG, quantitative EEG and EP, in a search for biomarkers that allow researchers to integrate preclinical results in the design of Phase I stud-ies. How do results of first-in-human studies compare to what was seen in animal studies? Using these methods allows researchers to characterise the PK / PD profile of compounds early on and to compare results to preclinical data in an effort to determine whether a compound crosses the blood-brain barrier or produces CNS-mediated side effects in humans. Frequently, there is a platform of compounds with similar properties under development—differentiating these, one from the other, and selecting the best drug for development is critical. These electrophysiological techniques, along with imaging and cerebral spinal fluid sampling can provide invaluable informa-tion and accelerate drug development.

With EEG, QEEG and EP, small studies can be conducted in which healthy volunteers are exposed to varying doses of a compound. This approach can bring into Phase I the kinds of dose-ranging studies that traditionally occur in Phase II. Pushing early dose-ranging into Phase I and matching results to preclinical work holds promise for improving the GO / NO-GO decision-making process. In addition, these tools enable the use of surrogate biomarkers, such as whether an EEG indicates central action. Later on, if the biomarkers become validated

surrogate endpoints, their use could reduce years from the overall clinical development path. By increasing detec-tion sensitivity and reliability, samples sizes required to demonstrate efficacy would be substantially reduced. CNS drugs typically require large multi-centre global trials to achieve adequate response data against placebo, and take years to conduct. Clinical trials would benefit from the incorporation of potential bio / surrogate markers as a corroborative signal converging on the currently employed clinical endpoints, especially when the diminished placebo versus the drug effect size difference is small.

A variety of neurophysiologic tech-niques are being employed to study compounds early on in clinical devel-opment, in the target diagnostic CNS patient population. By bridging animal findings to humans, and then from volun-teers to patients, these techniques contrib-ute to our ability to translate preclinical disease and toxicity models to patients, and inform drug developers of possibly effective doses. Currently, these meth-ods are being validated in small Phase I trials, but they hold promise for use in later stage studies. The infrastructure to conduct QEEG or EP in large-scale clinical trials is becoming a possibility, as equipment becomes more portable and affordable, and central reading of data is readily achieved by electronic data transmission.

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optimiSing the Site Selection process assessment of investigator motivationIdentifying sites which enroll in line with expectations represents a major challenge in clinical research. this article discusses strategies to address this challenge and explores “the golden site profile” concept.

Benjamin Quartley, Associate Director, Feasibility and Patient Recruitment,Clinical Development Services, Covance, UK

According to some estimates, up to 30 per cent of Investigators participating in a trial may

recruit no patients. When considering this statistic, it is important to remember that every site—also those that have not recruited to target—has been through a process of selection. Whilst this proc-ess may determine whether a site can provide suitable staff and facilities in accordance with regulatory guidelines, it is evident that the site selection proc-ess is not foolproof in assessing whether or not a site will in fact recruit patients as anticipated, or at all.

This article evaluates a number of pragmatic approaches to more effectively identify suitable sites by proactively weed-ing out the types of surprises that—with the 20 / 20 vision of hindsight—were not so very surprising. We move beyond the basics of the site selection visit and consider the process as both a strategic and tactical challenge focussing on three key factors:• The impact of company processes

in setting the tone for success or failure

• Identifying the less obvious but crucial characteristics of successful sites

• The importance of investigator motivation.

The golden site profile Looking to the investigators, prior expe-rience and personal relationships often form the basis for selection. Given the increasing volume of competing trials, experienced investigators are in great demand. However, they may not offer the certainty of delivery they once did. Data also suggests that the number of investi-gators active for only one year in clinical trials is increasing. Taken together, the necessity to work with new investigators becomes apparent. In such circumstances, it is important to extrapolate from previ-ous experience to identify the indirect and less obvious characteristics associated with good sites—characteristics that may not be apparent at the individual site selection visit. For instance, an analysis of stroke studies conducted at over 400 sites globally for over a five-year period showed that the top decile of investiga-tors (in terms of recruitment) displayed

the following characteristics:• Located in countries / cities with an

older population• Practicing in a large or general

hospital• Located in more densely populated

cities / countries• Specialising in neurology with an

emphasis on geriatrics.Whilst perhaps not surprising, these findings allow the conclusion that the successful recruitment of patients in such studies is linked to the ability to identify investigators who fulfill this specific set of criteria.

Assessing investigator motivation There is, of course, only so much that can be predicted from an investigator survey process and analysis of past data. Assuming the investigators are located in the same country, have access to simi-lar patient populations, similar facilities and staff, why do we continue to see a broad range in recruitment perform-ance across sites that appear similar or at least equivalent? To help explain this, we turn to two of the less tangible

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• How often does a site selection visit result in the investigator not participating in the study? With up to 30 per cent of site not recruiting any patients, should we not also expect 30 per cent of the sites we visit to not go forward? Naturally, it is not this simple, but with relatively few sites dropping out at this stage it should be considered whether the balance is in the right place.

• How often are investigators re-selected who have previously taken part in trials but not recruited any patients? Again, this is not straightforward given the various reasons why an investigator may not have recruited patients to a previous trial, or why the inves-tigator may be selected for continued trial participa-tion. However, we should at least have a realistic view of the investigator’s likely contribution and account for this in study planning.

• Are the individuals who select investigators account-able for the subsequent performance of the inves-tigators? One team of people may be responsible solely to select a set number of investigators from a limited pool, and may be facing considerable time pressure to do so. As such, their chief concern will be to meet the immediate commitment in terms of

the number of sites. This can create a disconnect between site selection and the actual trial conduct, which may be exacerbated when the team managing the sites throughout the study receives such a list of investigators they did not select themselves. If not appropriately and proactively managed, this process allows for a lack of ownership and responsibility for site performance.

• Do the individuals responsible to select the investiga-tors have the required experience to assess some of the more complex factors, for instance investigator motivation? CRAs may be trained to select investiga-tors in line with ICH and the protocol. However, is the site selection staff trained to effectively assess the less tangible aspects of what makes for a success-ful site? Moreover, is the staff in a position to reject investigators they do not consider suitable?

• There simply may not be sufficient sites that meet all the criteria. This is an increasing problem in many therapeutic areas, notably oncology. Consider whether we are being too conservative in terms of investing in new investigators in emerging markets and facilitating their trial participation. Are we actually taking greater risk by not being more inclusive in this regard?

aspects of successful sites—investiga-tor interest and motivation. For most investigators clinical research is only a small part of their practice, compared to the dominant obligation of patient care. Moreover, the investigators continu-ally face time constraints and have to prioritise their time. In this context the importance of investigator motivation is evident. When considering motiva-tion we should first address why inves-tigators make the decision to take part in clinical trials? Reasons vary and are specific to each individual investigator,

but generally include potential benefits to patient, scientific or medical interest and financial benefit. In today’s world of health economics, trials may also be a conduit not only to the test drug, but also the comparator drug that may already be on the market but cost-prohibitive to many patients. Regardless of what drives their motivation, it is necessary to confirm that investigators participat-ing in a trial possess this key ingredient if the current cycle of delayed studies is to be broken. With experience, it is possible for the site selection staff to get a

general impression of how motivated an investigator is. To more accurately assess investigator motivation, consideration should be given to the following practi-cal approaches:

Strategic partnering – Depending on the healthcare system, institutions may have a Research & Development office that has worked with investigators over a number of years. By meeting only with the individual investigator and maintain-ing a transactional relationship, instead of collaborating also with centralised R&D functions, we may continue to select

Do we as an industry set the scene for success or failure?

Before considering the investigators themselves, we should challenge ourselves as to our own role, as an industry, in building an environment that supports successful site selection.

Selecting investigators who truly deliver is an issue that goes deep into the operations of a company—and this is ultimately where it is within our own control to set the tone for success or failure.

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investigators in a relatively blinded fash-ion. However, developing shared objec-tives and working collaboratively with such central functions can add great value and prevent inappropriate investigators from being approached.

Asking the right people – It’s no surprise that the research nurse or other members of the team running trials day-to-day will be able to give a more accurate view of the practical implementation of a trial than the investigators themselves. Similarly, an investigator may not be aware whether support functions, such as the radiography department, can provide the volume and frequency of scans required. Such logistical challenges often are the hidden reason for study delays and should always be assessed directly and proactively with the indi-viduals responsible.

Asking the right questions – Site selec-tion visits that start with a protocol pres-

Benjamin Quartley started his career working as a cra in the pharmaceutical industry. recognising the challenges presented in patient recruitment he joined a company established to support investigators in the delivery of clinical trials, where he gained an insight into the investigators world across eight years. Ben has now taken this experience back to the Industry and works for covance in feasibility and patient recruitment.

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entation followed by an invitation for the investigator to ask questions in fact veil how much time the investigator spent reading the protocol in advance of the visit. Instead, starting the visit by simply asking the investigator their opinion of the protocol is a good indication of their level of interest and motivation.

In summary, a site selection visit that ensures facilities and qualified staff are in place is a relatively straightfor-ward process. However, determining if a site will actually recruit patients into the trial is another matter

entirely. In order to make the proc-ess more effective and successful, we need to start by creating a culture and company processes that engender ownership and encourage the selec-tion of the right sites. On a day-to-day basis, application of the assessment approaches explored in this article provides a greater probability of select-ing investigators that will recruit as anticipated.

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�� PhArmA Focus AsiA issuE - 10 2009

innovation for growth

glenn Saldanha who has steered the organization for the last nine years holds a Bachelor’s Degree in pharmacy from mumbai university and is an mBa from leonard Stern School of Business, new york university. prior to glenmark, Saldanha has worked with eli lily, uSa and pricewaterhousecoopers, uSa.

glenn Saldanha, Managing Director and CEO, Glenmark Pharmaceuticals, India


Where does the company stand today with respect to its motto “To emerge as a leading integrated research-based global pharmaceutical company.”?When we began the process of discovery research in 2000, very few believed that we could do it. We were clear at that time and even now that innovation was the only way for sustained growth and for that one had to venture into high-end discovery research. Today, we are leaders in the drug discovery sphere in India and have a rich pipeline of 13 molecules (NCEs and NBEs) of which eight molecules are in clinics (including Crofelemer for HIV associated diarrhoea in-licensed from Napo).

To have eight molecules in clinics is a significant achievement. All the molecules which are in clinics are either first-in-class or best-in-class targeting chronic diseases ailing the world. In the next financial year, we will have two of these eight molecules entering phase III trials, and three more starting phase II trials. Each of the molecules is a potential blockbuster with peak sales opportunity of US$ 1 billion to US$ 3 billion. We have always believed, even in the area of discovery research to do cutting-edge work and the peak sales opportunity for each mole-cule validates that fact. For instance our latest molecule which is filed for Phase I trials in the UK i.e. GRC 15300 for Osteoarthritic pain, Neuropathic pain, and other Inflammatory pain conditions globally, will be the first TRPV3 molecule to enter clinical trials. We have made significant progress regarding our vision, but we still have a long way to go.

What has been the role of international partnerships in Glenmark’s success over the last few years?Discovering a new chemical entity and seeing the molecule all the way till the end requires a sizeable investment. A single new chemical entity which runs through preclinical and clinical devel-opment can cost companies millions of dollars. Also it’s a zero-sum investment if the molecule fails. Thus one has to look at various options when venturing into

discovery research. Though we are doing pioneering work in the area of discovery research we must keep the risk factor in mind and partner with global pharma-ceuticals organisations to share the risks and benefits. In the last five odd years, we have struck four out-licensing deals collecting around Rs. 500 crore in cash as milestone payments. One must note that unless your research is world-class the Big Pharma will not be willing to participate in the process. These partnerships have not only boosted our research efforts but also helped sustain our investment in the area of discovery.

What went into building the drug discovery capability and the product pipeline at Glenmark?Excellent scientific talent along with focussed selection of targets and thera-peutic areas have been the key differ-entiators in building the pipeline. In addition to this, well-planned schedules and advice from an excellent scientific advisory board and key opinion lead-ers have backed the target identification process from time to time.

How do you hedge the risks while improving the success rate of your drug discovery programmes?We have considered the route of out-licensing our molecules to Big Pharma once the molecule reaches Phase I / Phase II trials as part of our strategy to hedge our risks. While partnering with Big Pharma, we look to close deals that will give them the rights for that molecule for three regions in the world—North America, Europe and Japan. The rights for the molecule in other parts of the world remain with us. So if a molecule reaches the market place, the partner (Big Pharma) will have rights to sell the newly approved drug in these three regions. They will pay Glenmark royalties on sales. In other parts of the world, Glenmark will directly sell the newly approved drug.

What are the current priorities for the company in its drug discovery programme?

With eight molecules under clinical trials, we have clearly demonstrated that we have one of the best pipe-lines in the area of drug discovery. The molecules that are in the clinics are potential blockbusters with sales opportunity for each molecule being in the range of US$ 1 to 3 billion. We will continue to step up the pace of our discovery programme and look to push molecules ahead in clinical development. At the same time, we will actively pursue out-licensing opportu-nities for few of our molecules which are in clinical development.

What has been Glenmark’s experience with innovation?Innovation has to start at the top. A considerable amount of time needs to be spent on developing and sustaining innovation, and making it clear that it is fundamental to the company’s success. A second thing is bringing people together who share a common vision, providing them with the resources to pursue that vision, and giving them the autonomy and responsibility for executing against that vision. Most innovators thrive on empowerment, so you need to make sure the structure and the decision-making in your organisation genuinely have that quality. The third thing is having access to the capital needed to support innova-tion. This has always been an issue for smaller and mid-sized companies, and, in the current environment, is even an issue for large companies. Now more than ever, you need to be selective about the ideas you pursue.

At Glenmark, innovation has been the defining factor in our success. We have managed to do what very few pharma companies have done in the world. We have continuously developed new molecules, cut out-licensing deals, expanded our presence in new markets and built a strong generics business, all within a short span of a few years. When we look ahead, sustaining this growth is going to be the single biggest challenge and I have no doubt that innovation will continue to be the differentiator.



Developing Benefit-Risk management programmesBest practicesThere are four distinct elements to consider in developing benefit-risk management programmes. they are: protocol design and review, active surveillance, provider and patient education and appropriate use programmes. the entire programme from design through implementation and maintenance will be overseen by programme management, quality management, continuous improvement and comprehensive communication.

Axel K olsen, Executive Director, Pharmacovigilance and Risk Management, Quintiles, Inc., USA

Understanding the interrelation-ships among all key stakehold-ers is the critical aspect in risk

management planning in today’s rapidly changing, complex global healthcare environment. These can include payers, providers, patients, care givers, patient advocacy groups, regulators and other government agencies. All these stake-holders should be considered when planning and communicating benefit and risk.

In the US and Europe there have been significant updates in safety and risk management regulations. Many other countries are actively revising drug regu-lations such as India and China among others. In the face of these rapid and global regulatory changes one must constantly evaluate their readiness in responding with timely and compli-ant benefit-risk management systems. This readiness assessment will encom-pass several key areas but must also be comprehensive and open. The organisa-tion must understand the principles of the culture of safety and put in place systems and processes to support this concept as a core characteristic of the company. One must identify gaps in knowledge

of both risks and benefits for example, special populations both of those with identified risks and those that have not been evaluated such as the seniors and children. Given today’s advances one should also consider the implication of pharmacogenomics on the risk manage-ment programme. Is the company ready to manage a marketed product? Are there sufficient systems, processes, procedures and finally sufficient personnel both in quality and quantity?

Four key components of the comprehensive benefit-risk management programme

When considering comprehensive and cross-functional benefit-risk management programmes, it is possible to organise the efforts into four key areas. They are • Protocol review and approval • Active surveillance • Provider and patient education and

intervention and • Appropriate use management.

These categories are used to help assure that the programme will be comprehen-sive and effectively designed based on all available information and utilising cross-functional capabilities (Figure 1).

Protocol review During the investigation phase, the spon-sor has complete control over product distribution and use. However, he loses the control substantially as product receives marketing authorisation. With market authorisation and distribution, the product is available to licensed medical practitioners in accordance with local laws and regulations. Also, physicians could often approach the sponsor with a request to provide the medicinal product free of charge for the expressed purpose of conducting independent clinical research. In addition, a sponsor can have a programme of investigation on the medicinal product that has been designed internally to provide additional information as determined by the gap analysis noted above. These investigations could be both internal and external. The sponsor should put in place a mechanism to assure adequate design; inclusion and exclusion criteria; and adequate subject protections for each of these protocols. To focus on science and ensure that at-risk populations are protected, the sponsor can constitute a protocol review commit-tee with adequate committee structure and document procedures. Commercial

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interests cannot outweigh patient protec-tion. Key stakeholders who can be included in this committee may be from the areas of Research & Development, Medical Affairs, Regulatory, Law, and Commerce. Other groups such as public affairs may also be included. The sponsor must be inclusive and open and avoid silo behaviour.

Active surveillanceActive surveillance programmes include a variety of methods: Consider monitor-ing commercial databases and insurance databases for retrospective and prospective analyses. The sponsor may also consider utilising more modern methodologies that take advantage of advanced web-based tools. One unique design taking advan-tage of these Internet capabilities is to create a web-based patient community. In this example a sponsor would offer access to a unique product or disease portal where the patient could enroll and opt for receiving information and also be avail-able to participate in both prospective and retrospective research programmes. Again, the patients could be offered the oppor-tunity to opt for the research programme on a voluntary basis. This community should then provide a platform for the sponsor to readily recruit patients for epidemiologic hypothesis generating and hypothesis testing programmes. In addi-tion, the sponsor could consider signal detection and an evaluation programme which includes actively reviewing single case reports, case series, claims data, data warehouses, and public databases such as the World Health Organization’s Uppsala Monitoring Center, and the United States Food and Drug Association’s Adverse Event Reporting System. Sponsors need to evaluate and understand the appro-priate measures to utilise, in the active surveillance programme understand-ing the key domains, data sources and appropriate methods to apply at each intersection.

The purpose of these programmes is to aggressively monitor and investi-gate events of interest, develop targeted

follow-up questionnaires, establish special reporting agreements with regulators (if needed) and effectively communicate the findings to all interested parties in an open and timely manner.

Appropriate use programmesAppropriate use programmes provide a thorough assessment of marketed product usage. These programmes monitor all uses, approved and unapproved indications. They are especially useful for monitoring known high-risk unapproved exposures. When inappropriate use is detected, a sponsor may consider holding provider and patient education programmes that would reinforce appropriate use. There are many tools available to sponsors in developing appropriate use programmes. One can develop drug and disease regis-tries, sample use through market research, utilise publicly available databases, and commercial resources. Ultimately, the sponsor must continuously monitor usage and put appropriate measures in place when aggressive management of the medicinal product distribution is needed. The most restricted method of distribution is used in risk management programmes utilising a performance-linked access system.

These programmes ensure that only those patients who understand the specific risks are exposed to products. Notable examples of this restricted distribution in the US include the programmes for isotretinoin and natalizumab both of which have well characterised serious risk profiles.

Provider and patient educationThe cornerstone of any risk management programme is the education component. It is critical that the sponsor adequately and continuously educates healthcare professionals, patients, caregivers, and patient advocacy groups with the best and latest information related to the product use. The education programme could be developed along with the entire product development programme.

The sponsor can again utilise the online patient community to both provide them with education mate-rials directly and assess their level of comprehension of the critical elements of the programme. Patient-directed online programmes could be expanded to the level of disease communities. These programmes can provide patients access to proactive and interactive educational programmes. The online community can also be used for patient-directed physician communication wherein the patient provides permission to contact their healthcare provider for verification of specific medical information.

Programme managementThese complex multiple-component programmes require professional project managers to oversee the design, imple-mentation, maintenance, reporting and communications. The project manager assures that the various service compo-nents are effectively implemented and anticipates programme problems and addresses them.

Proactive benefit-risk management

Protocol design and review

Active safety surveillance and

measures of harm

Provider and patient education and intervention

Appropriate use management

Continuous quality improvement programme

Programme project management

Figure 1

1 2 3 4

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Quality systemsThe final element of the comprehensive benefit-risk management programme should be that of quality management. For each component of the programme, metrics should be established to assess the effectiveness of the service delivery and the effectiveness of the programme to reduce the specific risk elements defined. If the programme is designed to reduce the inci-dence of events of interest then that will be a key efficacy parameter for measurement and analysis. This ongoing quality analysis will lead to a continuous improvement model. Progress should be tracked over time to identify areas for improvement; define and implement best practices; create process maps to find potential efficiencies and establish Corrective and Preventive Programs (CAPA) as needed. An often-overlooked element

of the quality management system is the inclusion of key stakeholders such as prescribers, pharmacists, and patients in the evaluation process.

SummaryUtilisation of modern technologies and effective communication with consistent and audience-appropriate messages is critical for an effective product bene-fit-risk programme management. Full characterisation of events of interest and validated mechanisms to mitigate risk prior to market authorisation and

active product defense throughout a product life cycle is the backbone of a successful medicinal product. The benefit of which will be the optimal public health outcome assuring that the right patients have the most effective medications for their unique circum-stances. And prescribers are provided clear accurate communication to best advise their patients for their course of treatment.

Axel K olsen currently provides leadership and guidance to the development and execution of pharmaceutical safety programs at Quintiles. Prior to his experience as an independent consult-ant in 2002 and 2003, he was a vice president in the global medical affairs Department at Wyeth pharmaceuticals. from 1989 to 1997 he was the head of Worldwide Safety Surveillance at Wyeth.

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The historical approach to clinical drug development, and one that served drug companies well for

the past thirty years, was to initiate test-ing in humans at clinical research units, typically located in the UK and the US and to proceed further to Phase II test-ing and beyond to patients with clinical evidence of the disease with investiga-tors mostly located in the US, Canada and Western European countries.

An increasingly intense competitive environment and the shrinking pools of treatment populations in the traditional North American and Western European markets, however, have led sponsors and CROs to ‘discover’ emerging markets to source high quality research and secure timely enrollment of patients. This article focusses on two of the most dynamic emerging markets, both Asian: China and Japan.

China

The advantages of being in China for an international CROThe importance of China to get miracles to market is absolutely indisputable. China represents the fourth biggest economy on the planet and its own drug market is growing at a pace that

is enviable to any western market, at 28 per cent CAGR. Presence of regional affiliates of global CROs in important locations such as Beijing and Shanghai makes it possible for global pharmaceu-tical companies to offer easy access to leverage the tremendous potential of this key Asian market. They can also help pharmaceutical companies to extend their reach into a large and important source of patients, investigators and sites. With good local understand-ing, experienced monitoring, project management and other staff, including regulatory experts, it can provide seam-less support to sponsors with regards to high quality clinical development services or assistance with regional registration.

Naturally, not only international CROs but also international pharmaceu-tical companies have ‘discovered’ China as their destination. This, in fact, is a benefit to the CROs. The increasing footprint of a growing number of global pharmaceutical companies in China is vital and has an unequivocal benefit in that it helps escalate the understanding and adoption of fundamental interna-tional clinical trial requirements such as ICH and GCP amongst an ever increas-

ing number of investigators and sites. Equally, the commitment by sponsors to engage China first-hand opens up even more opportunities for CROs to work with global sponsors and their local affiliate offices to provide global, regional and local clinical development services. The Chinese regulatory environmentThe Chinese regulatory environment is highly dynamic and is maintaining open lines of communication which is absolutely crucial to ensure success. Acknowledging the paramount importance of local regulatory understanding, it is important to build a strong, local team of Chinese regulatory experts who understand the current requirements and work with the clients to understand their needs. Similarly, sponsors and CROs alike need to invest considerable time and effort to understand the evolving Chinese regulatory requirements. Challenges in clinical development The demand for access to patients and high-quality clinical development deliv-ered on time and to budget, is rapidly increasing. This growth in demand is pushing the limits of local supply, meaning it can be a challenge to staff

Dynamic opportunities for sponsors and cros

CLiniCAL tRiALS inChinA&JApAn

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up as quickly as required. However, it is recommended to always put quality first. It is not good enough to just have the footprint and the access. The CROs and sponsors need clear assurance that they are working with qualified investigators who are capable of conducting global trials. They also need to be assured that sites and trial results stand up to any regulatory scrutiny. Insisting on quality like this of course raises the bar even further. However, it is noted that by systematically demonstrating dedication to proactive, transparent site interaction and by helping investigators develop, it is possible to attract a steady supply of highly motivated investigators and sites.Short- and long-term goalsMany international companies have long recognised China’s potential as a source of patients for clinical trials and as a growing market for new medicines. Investment in internal infrastructure in China is set to continue, to meet the increasing needs of current and future clients. Specifically, the investment includes significantly increasing moni-toring capabilities, growing in-country project management and expanding regu-latory capabilities. Basically, both short

and long-term strategies are centered on the key capabilities to help clients effectively leverage China for high-quality clinical development.

Japan

A “Closed Country” – No moreTwo overriding trends drive the major-ity of events influencing the clinical research potential in Japan. First, Japan has taken a number of steps to make it easier to include the country in global trials. Second, Japan is encouraging its

own drug companies to reach out to neighbouring Asian countries such as South Korea and China, to help make the clinical trial process more effective and efficient.

These developments bode well both for Japan and the region at large. This being said, certain regulations and restric-tions in Japan (e.g. limiting the length of time a CRA is permitted to spend at an investigative site) appear more burden-some than those in other countries. This means trial conduct can be very costly in

this article focusses on how to leverage the regional strengths of key Asia-Pacific countries such as china and Japan in clinical trials, while at the same time proactively ensuring consistency and quality.

nick Wright, Vice President and General Manager, Asia Pacific, Clinical Development Services, Covance, Australia

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Japan, even in comparison to traditional markets such as the US and Western Europe, as well as the emerging markets across the globe. Even today, efficient trial management faces an additional set of hurdles in Japan—hurdles not found in other countries looking to claim a stake in global clinical trials.More international clinical trialsIn the not too distant past, Japan would have rarely come up for inclusion into clinical trials, considering past hurdles to trial conduct. This picture is changing fast, however Japan still requires very careful consideration, for instance, with regards to cost impact and start-up and enrollment timelines. To overcome frus-trations and disappointments in future, a very clear analysis of benefits versus challenges needs to be done before including Japan into trials.

Covance has run clinical trials where Japan was included on the same timeline as all other countries in the trial, and indeed Japan did not ‘finish last’—the sites in Japan performed along standard expectations. This type of solid, predict-able performance will help draw more trials to Japan which, in turn, helps Japanese investigators and research staff build more experience—it’s a positive spiral.The obstacles to simultaneous drug developmentThe obstacles to simultaneous drug development in Japan are well known. Interestingly, the Japanese Ministry of Health, Labour and Welfare has signalled that the so-called bridging studies are at best a tactical solution to a strategic problem and at worst have helped delay the necessary globalisation of Japanese trials. Instead, the long-term focus is on reaching out to countries such as China and South Korea for sharing clinical data as the populations of these countries are considered sufficiently close to the native Japanese population. Also of note is that Japan plans to network their major clinical trial sites into ‘hubs’ and nodes—this is a five-year plan which started in 2007, to promote better coordination,

efficiencies and sharing of experience. These initiatives amongst others will help Japanese investigators and research staff build more experience and help close gaps versus the global market.What’s ahead?Local Japanese CROs increasingly contribute to global trials and this expo-sure has helped the CRO industry in Japan mature. To grow internationally, the Japanese CROs will likely need to engage in strategic transactions with other CROs or grow organically by establishing a presence in key markets. As the Japanese CRO industry enters this phase, a new set of challenges will present itself—similar ones that CROs face elsewhere, and it will be interesting to see the developments as the Japanese CRO industry matures further.

It’s crucial to keep in mind that Japan is an established, experienced market when it comes to clinical trials, ICH and GCP. In Japan, the clinical trial industry does not start from a small or less developed base—rather, the task at hand is to finally start leveraging the established strengths resident in what is in fact the world’s second largest phar-maceutical market. These strengths have not historically been easily accessible, just as circumstances have not permit-ted for the industry to effectively and efficiently leverage them.

In closingThe composition of markets that contrib-ute to international clinical trials clearly has changed and will continue to change. One requirement of clinical trials will, however, be emphasised consistently: the focus on quality in clinical trials. Here, quality is defined in terms of trial design, the validity of the results, the protection

of subject rights and well-being, and of course regulatory compliance. Most of outsourcing’s focus is on time, cost and scope, but a major challenge is in the quality of the process and the major deliverables. Though it must be conceded that many current practices were reac-tively triggered in response to quality problems, the future will require that quality management be more proactively and comprehensively integrated into study planning and execution regard-less of where the trial takes place.

When performing trials in markets such as China and Japan, the number of potential pitfalls, site idiosyncrasies and country-specific regulatory, ethical and administrative requirements increases exponentially. Any challenges which plagued trial performance in ‘tradi-tional’ western markets previously tend to multiply, and no single adjustment can be counted on to remedy those challenges.

Instead, an integrative, quantitative, proactive trial management is required and it needs to be geared towards handling not only current day site performance variability, but also the vari-ability in the underlying patient popu-lation which can dramatically impact trial outcomes, especially in the complex long-term studies that are increasingly common. A key component in success-fully leveraging the potential of emerging markets is a proactive and predictive operational approach. The approach should focus more on risk prevention rather than remediation of investiga-tor errors, and also deliver improved productivity, lower operational risk, and improved scientific robustness—not to mention increased investigator satisfaction.

nick Wright is vice president and general manager for clinical Development for Asia-Pacific at Covance, a global full service CRO. Nick brings extensive international experience of working in china, taiwan, Japan and across South-east asia.

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pareXel international ................................................. oBc


manufacturing

ace process equipment .............................................. 19

Brio pharma technologies pvt.ltd ................................ 77

halides chemicals pvt. ltd. .......................................... 39

health protection agency ............................................ iBc

hrushikesh Water Sciences pvt. ltd. ............................ 41

pratham technologies pvt. ltd. .................................... 14

precikot pharma pvt. ltd. ............................................. 55


upm raflatac ............................................................... ifc

vaya Jayanthi Drugs pvt. ltd. ...................................... 59

Wle technology Sdn Bhd ........................................... 73

youR SeARCh enDS heRe!your search for sourcing agents for bulk chemicals, active pharmaceutical ingredients (APIs) and finished dosage formulations ends here. Ace chemicals supplies and exports a comprehensive range of products that caters to the needs of pharma manufacturers. Backed by a repertoire of reputed suppliers from around the globe and a highly efficient logistics system in place, we boast of unique cost savings and time savings to our clients much to the envy of our competition.visit us at: www.indiamart.com/acechemicals or www.acechemicalsindia.com to know more of our products.

Ace Chemicals 108, K. H. Road, Bangalore - 560 001, Karnataka, India Ph: 91 80 41240325 Fax: 91 80 41240327, email: [email protected] [email protected]

Classified

ads Chlorhexidine bASe

Chlorhexidine Gluconate 20% Solution BP/EP/USP, Chlorhexidine Hydrochloride BP/EP, Chlorhexidine Acetate BP/EP,

CetriMide powder Cetrimide Strong 40% Solution BP/EP,

other produCtS Glibenclamide BP/EP/USP, Cetyl Pyridinium Chloride BP/EP, Benzalkonium Chloride 50% / 80% Solution, Niclosamide BP/EP/USP, Amlodipine Besilate BP/EP/USP, Proguanil Hydrochloride BP/EP.

Basic Pharma Life science P Ltd.A n I s O 9 0 0 1 : 2 0 0 0 c e r t i f i e d c o m p a n y

Plot No. 146/B GIDC Estate, Opp. New Fire Station, Ankleshwar – 393002, Gujarat, India.Tel.: +91-2646-645714, Fax.: +91-2646-226037, Mob.: +91-9825056886,

Email: [email protected], www.basicpharmachem.com

mega-mergers: are pharma turning into zombies?

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