Mega-Mergers: Are Pharma Turning into Zombies?

Issue 10 2009 £12 €18 $25 Rs.300 www.pharmafocusasia.com Published by Verticaltalk The B2B Division of Ochre Media A member of CII Mega Mergers New Patents for Old Drugs Preclinical Research Accelerating in Big Biotech Central Nervous System Trials Are they turning pharma Label-based strategies in the companies into zombies? United States Vertical integration is the key Neurophysiological approaches

Foreword Personalised Medicine What next? 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. W Though the benefits are immense, challenges hile mergers and acquisitions, partnerships abound. Optimising the drug development for target and collaborations still offer avenues for patient populations—usually small—at low cost while growth for the pharma industry, many feel satisfying the tough regulatory guidelines and reim- that the concept of personalised medicine, if used bursement procedures is a daunting task. Many health- intelligently, will set the industry on the right path. care payers now demand evidence-based medicine By enabling highly-customised therapies to treat to avoid unnecessary costs and low-yield interven- diseases based on the patients’ genetic makeup, tions for patients. However, most reimbursement personalised medicine offers companies alternative procedures tend to fix a ceiling for tests. Developing avenues for growth in terms of niche markets often the tests, an important element of the personalised left unexplored because of feasibility issues. It also medicines concept, is a costly and unfeasible affair provides an opportunity to eliminate unfavourable with the ceilings. products much earlier in the development stages, save investment by testing medicines on targeted Enough support from healthcare insurers is sub-populations and avoid failures by eliminating paramount for the growth of personalised medicine. inappropriate patients whose genetic makeup does Experts, however, hope that realising the long-term not suit the medicines. savings in treating a disease or preventing it will offer enough incentive to payers to support personalised Right drug for the right patient and benefits with- medicine on a greater scale. out toxicity offers a viable business model to the industry. Personalised medicine effectively tackles At the moment, its greatest advantage lies in its the issues of toxicity, side effects and medical errors capability to maximise the effectiveness of medicines due to wrong dosages or incompatibility while offering used to treat diseases affecting a specific population patients effective therapies. The industry has a lot with documented cases of toxicity and side effects. to benefit by leveraging the rapid developments in The cover story “Future of Medicine - Personalised” biomarker usage strategies for personalised healthcare. discusses some important issues: how targeted thera- Experts opine that the biomarkers used to optimise pies can offer a sustainable business model, the clinical study designs could be eventually used to changing business models and how biomarkers are conduct smaller trials and allow a combination of leading the way in the development of personalised medicine to be prescribed based on the outcome of medicine. 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 Reddy Editor

Contents Strategy 05 Indian Pharmaceutical Industry On the cusp of a great opportunity Ranjit Shahani, Novartis India Limited 08 Mega Mergers Are they turning pharma companies into zombies? Neil Campbell, Mosaigen, Inc. 15 Pharma and Biotech Collaborative models Bruce Pratt, Genzyme Corporation 20 New Patents for Old Drugs Label-based strategies in the United States Ned Israelsen, Knobbe Martens Olson & Bear LLP 24 Innovation The key growth mantra Sasikant Misra, Confederation of Indian Industry reSearch & Development 26 36 Biosimilar Medicines Understanding the challenges Targeted Therapies Cecil Nick, PAREXEL International A sustainable business model? 40 Drug Discovery in Academia Erik Tambuyzer, Genzyme Corporation An evolving model Edward Holson, NovoNordisk A/S 44 Preclinical Research in Big Biotech 30 Vertical integration is the key David R Webb, Celgene Corporation Personalised Medicine 46 Computerised Cognitive Function Assessment Changing business models Coming of age Bruce Quinn, Foley Hoag LLP Keith A Wesnes, Steve Satek, Andrew C Embleton, Rianne E Stacey Cognitive Drug Research Ltd. 34 36 44 60 Personalised Medicine and Drug Development Biomarkers leading the way Michael Lutz, PGxHealth

manufacturing 51 Lyophilisation Process Development Yves Mayeresse, GSK Biologicals Industrialisation 53 OEE Systems and Software Enhancing operational efficiency Pala Bhushanam Janardhan, HCL Technologies Ltd. clinical trialS 57 Clinical Trials in Oncology Some sense and simplicity Iman El-Hariry, GlaxoSmithKline 60 Accelerating Central Nervous System Trials Neurophysiological approaches Larry Ereshefsky, Malek Bajbouj PAREXEL International 65 Optimising the Site Selection Process Assessment of investigator motivation Benjamin Quartley, Clinical Development Services, Covance 70 Developing Benefit-Risk management programmes Best practices Axel K Olsen, Quintiles, Inc. 74 Clinical Trials in China and Japan Dynamic opportunities for sponsors and CROs Nick Wright, Tufts University 68 Innovation for Growth Glenn Saldanha, Glenmark Pharmaceuticals 74 26 www.pharmafocusasia.com

Advisory Board Senior Product Manager and editor Aala Santhosh Reddy alan S louie aSSiStant Product Manager Research Director, Health Industry Insights, Bhamoti Basu an IDC Company, USA editorial aSSociate and coPy editor Prity Jaiswal christopher-Paul Milne art director Associate Director, Tufts Center for the Study of M A Hannan Drug Development, Tufts University, USA Senior deSigner Ayodhya Pendem SaleS Manager Rajkiran Boda douglas Meyer Senior Director, Aptuit Informatics Inc., USA SaleS aSSociateS Kunal Ahuja Murali Manohar John Milton Kirtana John frank a Jaeger Director, New Business Development, aSSiStant Manager – coMPliance Solvay Pharmaceuticals, Inc., USA P Bhavani Prasad crM Yahiya Sultan SubScriPtionS incharge georg c terstappen Vijay Gaddam Chief Scientific Officer, Siena Biotech S.p.A., Italy it teaM Ifthakhar Mohammed Azeemuddin Mohammed Sankar Kodali Kenneth i Kaitin Thirupathi Botla N Saritha Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA chief executive officer Vijay Chintamaneni Managing director Ashok Nair laurence flint Associate Director, Clinical Research, Schering-Plough Research Institute, USA Pharma Focus Asia is published by A member of neil J campbell CEO, Mosaigen Inc. and Partner, Endeavour Capital Asia Ltd., USA Confederation of Indian Industry Ochre Media Private Limited, Media Resource Centre, 6-3-1219/1/6, Street No. 1, Uma Nagar, Begumpet, Hyderabad - 500016, Andhra Pradesh, India Phil Kaminsky Tel: +91 (0) 40 44855000 Founder, Center for Biopharmaceutical Operations, Fax: +91 (0) 40 44855140 / 41 University of California, Berkeley, USA Email: pharmafocusasia@ochre-media.com www.pharmafocusasia.com|www.verticaltalk.com|www.ochre-media.com rustom Mody Director, Quality and Strategic Research, Intas Biopharmaceuticals Limited, India © Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright Sanjoy ray owner. Whilst every effort has been made to ensure the accuracy of the information in this Director, Technology Innovation, publication, the publisher accepts no responsibility for errors or omissions. Merck Research Laboratories, USA The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates. Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA. Sasikant Misra Printed at Kala Jyothi Process Private Limited. City Office: 1-1-60/5, RTC X Roads, Deputy Director, Hyderabad - 500 020, Andhra Pradesh, India. Confederation of Indian Industry, India

Strategy indian pharmaceutical industry on the cusp of a great opportunity leading 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 T he pharmaceutical industry in need to keep a keen eye on research Newer, more effective products at lower costs India is on the cusp of a great costs and look at the various avenues opportunity—the opportunity The pharmaceutical industry is under to partner with others so as to deliver to innovate and create novel medi- growing pressure from multiple stake- newer and more effective products at cines to meet unmet medical needs of holders to keep delivering blockbuster lower costs. today and the future, thus making a products providing fair return to inves- positive impact on global health. It is tors while at the same time ensuring India on its way to become a pharmaceutical powerhouse imperative to capitalise on the enor- that prices are affordable. Currently, mous wealth of creative and scientific it takes at least eight to ten years to Looking back at history, much of the resources that our country has been bring a compound from an idea to a progress of civilisation in various fields blessed with for the benefit of the usable medicine. During that time, including mathematics, physics, chemis- patient by discovering medicines for pharmaceutical companies spend up try, astronomy, medical science and the unmet medical needs. to US$ 1 to 1.7 billion in researching, arts can be attributed to India. There As we go forward, India is tipped to developing and testing to create a single is ample evidence to show that vari- become a pivotal player in the global drug. Sources show that while US$ 100 ous kinds of surgeries including plastic economy and the country’s pharmaceuti- billion worth of drugs will be going off surgery, ophthalmic surgery and dental cal industry stands on firm ground both patent by 2010, clinical development surgery were being done in India long as a provider of authorised generic drugs time has actually doubled since 1982 before they were even known in other as well as the seat of pharmaceutical to an average high of 68 months. parts of the world. research. This position however is only Boxed in as it is from all corners, The world has long since changed attainable if India aggressively nurtures pharmaceutical companies have to rely and India has lost ground relative to innovation and is seen as a country that on their innate skills to deliver products some other economies in the area of respects intellectual property rights while that meet not only the medical needs of pharmaceutical innovation. However, tackling the twin issues of health and today but also that of the future. While today the world has moved to become education. doing so, pharmaceutical companies a knowledge economy and India with www.pharmafocusasia.com

Strategy its vast intellectual capital has an advan- the Indian pharmaceutical industry can If drug discovery is perforce required tage over many other nations. With a be called truly world-class. to go back to the drawing board in its prodigious knowledge pool, expertise The law as it stands today does not quest for new medicines, the kind of in process chemistry and proven leader- recognise incremental innovation or inno- time and money that would be required ship in IT, India has all the ingredients vation in sequential steps. It is important would not only be mind-boggling but necessary to become a developed country to recognise the tremendous value that would also significantly delay the deliv- in the pharmaceutical field. In addi- incremental innovation has made to ery of new medicines to patients. As tion, the pharmaceutical industry is a the progress of modern science. It is in a global pandemic becomes a reality, mature industry with a strong manu- the interest of overall public health for biological weapons become a threat facturing base. It is also well developed India to allow patents for incremental and preventable diseases continue to as an ancillary industry and has the innovation. Breakthrough innovations take lives, we should work to shorten technological capability to manufac- in all fields are rarer than we imagine. the amount of time it takes to bring a ture Active Pharmaceutical Ingredients The invention of the wheel was a break- product to market, not unnecessarily (APIs). India has the largest number of through innovation in transportation. lengthen it. US FDA approved plants outside the What came later by way of the bicycle From improving a medicine’s US and the recent development of the where two wheels, pedals and gears were safety and side-effect profile to find- US FDA setting up a base in India is put together, completely revolutionised ing a solution for unmet medical needs of great significance for the country the way people travelled over land and and increasing a country’s productiv- and her capabilities. Besides being a practically did away with horse-drawn ity, incremental innovation provides net foreign exchange earner, exceptional value for patients the pharmaceutical industry and society. Over 70 per cent has shown skills in being cost- of medicines on the market The pharmaceutical industry is under competitive throughout the today are the result of incre- value chain. Above all, India mental improvements on a base growing pressure from multiple has the third largest English- molecule. stakeholders to keep delivering speaking scientific and technical The central role played blockbuster products providing fair manpower in the world and its by incremental innovation in return to investors while at the same people have shown significant medical progress must be recog- time ensuring that prices are affordable. entrepreneurial spirit. The nised and failing to do so would industry has a well-deserved mean a disregard for the way in reputation for producing low which healthcare has progressed. cost / high quality medicines. Granting patents to incremental transportation. The discovery of the innovations is critical for India to not steam engine offered transport an alter- only encourage national pharmaceutical Need for world-class IPR As the world ushered in the New Year native source of power. Once a suitable companies to increase their research on January 01, 2005, India ushered in gas-powered engine was perfected, this focus but also to ultimately bring better product patents. However, there were innovation replaced the earlier steam medicines to the people of India no fireworks to mark the defining engine, creating the first automobile and It must be stated that incremental moment of the Indian pharmaceuti- changing the way people and goods were innovation is not “evergreening” which cal industry. transported. is an attempt to extend patent protec- With the advent of a new era in At no time in this process of invention tion for a product by making minute product patent law, the Indian pharma- did an innovator go back to the drawing changes to a drug just before patent ceutical industry began the important board to reinvent the wheel. What an expiry. Changes made for evergreen- shift toward research and development. innovator did do was build on the existing ing purposes do not represent medical Leading research-based Indian phar- knowledge base and by using additional advancement and often do not bring maceutical companies spend less than creative thinking and going through a additional therapeutic benefits while 10 per cent of their sales on research. process of further research and trials so changes made to convert a compound While this figure seems abysmally low that he could come up with a better into a better medicine provide clini- as compared to what the large pharma- and more efficient means of transport. cal efficacy and exceptional value for ceuticals companies of the world spend, One base technology—the wheel—has patients and society. it is a good beginning. However, the been continuously modified to make Patients are the ultimate benefici- law needs to see some changes before transportation as we know it today. aries of pharmaceutical research and P h A r mA F o c u s A s i A issuE - 10 2009

Strategy development. An important part of global and national companies operating in the US and EU. Secondly, India has the research and development jigsaw in India and encourage them to increase huge genetically diverse patient pools is data gathering on the safety and investments in the country, especially in who are “drug naïve”, not having taken effectiveness of drugs. Lack of data pharmaceutical research and enter into any drugs for their condition. Thirdly, protection, an integral part of intel- partnerships where appropriate. the country has a significant number of lectual property rights, acts as a barrier As eminent scientist and Director qualified doctors who have the exper- to research. Pharmaceutical companies General of the Council of Scientific and tise to conduct and supervise clinical generate significant amounts of data Industrial Research (CSIR), India, Dr. trials as per global standards. And it while conducting research and this data R A Mashelkar said not long ago, “the is not just in the area of clinical trials goes to government by way of a dossier process of globalisation, corporatisation that India has fair opportunity to be a while seeking marketing approval for and privatisation of research has shifted strategic partner but also in the areas a new drug. Unfortunately, this data the dynamics of knowledge production of contract manufacturing, custom is used by makers of generic drugs in and dissemination dramatically just as synthesis, biostatistics, bioinformatics India to get regulatory approval for their issues of Intellectual Property Rights and technical services among others. medicines without conducting clinical (IPR) and proprietary information and trials. There is a fear, unsubstantiated knowledge have begun to open up new Partnering to win I might add, that protecting this data dialogues on public good versus private Collaborations will be the way forward will lead to higher drug prices. There profit. New models of the innova- and are a win-win situation offering is no reason to believe this as history tion chain and new paradigms of the Indian companies an opportunity to tap shows that there is no correlation science-society contracts have begun into the world’s largest global research between data protection and the pric- to emerge.” networks and providing access to new ing of drugs. Data protection exists in It is heartening to know that India technologies. The industry also serves many countries including China, Egypt, actually has the highest intellectual capi- as a platform for Big Pharma to tap Mexico, Columbia, Korea, Brazil and tal available per dollar anywhere in the into the huge scientific talent available Taiwan for a period ranging from 5 to world. In fact a publication of the stand- in India. 6 years. Market forces including limi- ing of The Far Eastern Economic Review India has the potential of becoming tations of purchasing power help keep had remarked that India ranked number a hub for drug discovery programmes. prices down. one as the source of knowledge work- While there are some concerns with ers—ahead of all other countries in Asia regard to IPR particularly with regard to including China, Japan and Singapore. enforcement and these clearly continue, Innovation nurtures creativity and productivity CSIR to date has 302 patents in the field the framework is in place. An environ- Investments to grow our capacity for of medicine alone. In chemistry it has ment where innovation and research research and to create intellectual capital 1799 patents, 221 in biological science, are encouraged will only serve to raise in the pharmaceutical space will not 90 patents in analytical techniques. the level of interest in the country as help if we as a country refuse to respect Estimates indicate that it costs over an investment destination. intellectual property rights. US$ 1.2 billion to get a single New There is therefore little doubt that as Indian pharmaceutical companies Chemical Entity (NCE) into the market. time moves on, India will quickly emerge must be geared to nurture innovation as Multinationals can outsource much of as a leader in the world pharmaceutical it leads to greater productivity, higher their R&D clinical activity to India market. Will the 21st century belong economic growth and better standards lowering their overall costs. Conducting to India? Will India, the land of milk of living. There are various ways to preclinical and clinical trials in India and honey, go back to realising as in achieve this including public funding has three-fold advantages. Firstly, the ancient times that “Prajnam Brahma” of research, collaboration with academia, cost of such trials in India would be in or Knowledge is God? Why not? I have funding via surpluses of large corpora- the range of 30 to 50 per cent of costs every reason to believe it will. tions involved in traditional businesses, venture capital funding and the like. Our country has a glorious past Ranjit Shahani is a strong proponent of ipr and a thought author and there is every reason to believe we leader in the pharmaceutical industry. he was president of the organisation of pharmaceutical producers of india (for an can achieve in pharma what we have unprecedented three terms). managed to achieve in IT. A strong patent regime will instill confidence in innovation, research and creativity in www.pharmafocusasia.com

Strategy mega mergerS ARe 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. and Partner, Endeavour Capital Asia Ltd. USA P h A r mA F o c u s A s i A issuE - 10 2009

Strategy O ver the past two years, big great value that this upcoming Pfizer- pharma has strived to achieve Wyeth mega merger would provide. revenue growth and pipeline What is interesting here is that in all stocking through M&A. In 2007, the his interviews Jeffrey Kindler was overtly pharma industry mainly targeted late- promising that the past failures to inte- stage biotechnology acquisitions to grate value into the past M&A would consolidate some drug development not be repeated. As a result, many large platforms, namely those with disease pharma companies are still going for franchises and drug class expansion. mega mergers. The latest being Pfizer- Then came the ever-worsening financial Wyeth mega merger for about US$ 68 crisis during 2008 that rapidly spread billion in stock and cash. to become a global recession. This has The Pfizer-Wyeth deal, if consum- put many big pharma companies into a mated, would be the fourth largest holding pattern exacerbated by difficul- M&A deal ever and would give Pfizer ties of accessing finance and the need to the distinction of having made the first, satisfy investors for the short-term. fourth and fifth largest pharmaceutical One interesting observation is that at deals in history. Pfizer is still trying to the time of writing this article, more than integrate the Pharmacia acquisition of 40 per cent of the biotech companies 2000 which was the fourth and now in the US had less than a year of cash is the fifth largest deal ever (Table 2). on hand. Does this serve as a once-in- The deal will merge two major pipelines a-lifetime-opportunity to build value by with patent expiry falling in the period rapid M&A of biotech companies that 2011-2013. Lipitor alone constitutes 35 could stock various stages of develop- per cent of Pfizer’s annual sales accord- ment for big pharma? ing to the latest IMS studies and Pfizer press reports. Putting two anaemic pipelines The latest pharma rage – Mega mergers together with no innovative system in The forcible merger of two big compa- place doesn’t make one great pipeline for nies that lack innovation doesn’t future growth. In fact, Jeffrey Kindler necessarily result in forming a good repeatedly stated on news interviews that company. There have been academic this deal would unlock value for both and industry studies that have shown companies and solve the short-term prob- that this strategy had failed time lems facing Pfizer. He repeatedly stated and again to create any value for that past M&A mistakes that destroyed shareholders, drug pipelines and ulti- value will this time provide value. Time mately patients beyond a few years. The alone will reveal the truth, but the analy- past 12 months have witnessed many sis of the combined pipelines seems to such deals in the pharma industry. be making a bigger issue and is expected (Table 1). to affect investors and value. The mega merger of Pfizer and It can take years to integrate the Pharmacia in 2000 illustrates how a R&D and corporate cultures following merger, which lacks long-term value, has these mega mergers—business develop- huge dilution and which is not properly ment groups can be taken off task for integrated, fails. The Pfizer CEO, Jeffrey up to two years while trying to manage Kindler, was on the airwaves touting the the integration. Big pharma companies www.pharmafocusasia.com

Strategy Biggest health care buys – The last 12 months Deal Size (US$ Buyer Buyer Home City Acquiree Acquiree Home City Deal Announced bn) 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 Largest pharma M&A deals driven by a slowdown in growth as reve- Target Acquirer Deal Value (US$ bn) nues come under threat from expiry of patents of blockbuster drugs, shrinking Warner-Lambert Pfizer 111.8 pipelines from original science programmes and the ever-increasing SmithKline Beecham Glaxo Wellcome 79.6 reach and breadth of generic drug Aventis Sanofi-Synthelabo 71.3 competition. Are there alternatives to this mega merger mania? Well, you have Wyeth Pfizer 68.3 (Pending) Astellas, the Japanese Pharma (Fugisawa and Yamanouchi consolidation) moving Pharmacia Pfizer 59.8 towards acquiring Small to Mid-size Genentech Roche 42.6 (44.1% Stake) Biotech (SMBs); could this be a better place to put money, time and longer- Astra Zeneca 39.9 term focus? (Table 1). Hoechst Rhone-Poulenc 33.8 Global financial credit crisis – Pharmacia & Upjohn Monsanto 31.9 A silver lining for the big pharma? With so many biotech companies short Ciba-Geigy Sandoz 27.0 of cash and in mid to later stages of clinical development, does this provide Schering Bayer 19.3 (92.4% Stake) a buying opportunity for low-cost drug Sources: Dealogic, Company News pipeline stocking? It sure seems that way. Table 2 P hA r m A F o c u s A s i A issuE - 10 2009 10

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Strategy If big pharma can muster a strong busi- Industry trends driving the mega mergers bandwagon ness development and licensing effort, they can merge or acquire a succession Industry Trends Driving Mega-Mergers Effect on Growth Strategies of smaller biotech companies and fill the Big Pharma focus is on sales and marketing No drug pipeline development, push limited life gaps in drug pipelines from late preclini- to secure sales at longer term benefits of building cal / pre-IND to phase III / NDA. This sustainable businesses thought is probably causing big pharma Big Pharma spending more on marketing than Misaligned priorities to innovation, reward now, not heartburn, but what are the alternatives: R&D for new drugs later, bad trend to start mega mergers? There are many problems that mega mergers won’t address Consolidate with like-minded large companies Mind-set to find other Big Pharma, Stunt long-term growth potential, missed opportunities with smaller (Table 3). Three interesting deals at the biotechs moment are the GSK-Attack Strategy, the continuing saga of Roche’s attempt to Blockbuster legacy drug patent expiry in next Short-term stocking M&A at risk of finding medium several years and longer term synergies buy the remaining shares in Genentech and the Astellas-CV Therapeutics replay Cost to development increasing-failure rates Regulatory shift since Vioxx to safety over efficacy, from the fall of 2008. increasing need better balance reviews There are many benefits to an aggres- Generic drug growth / biogenerics coming For smart companies, this is portfolio sive biotech M&A roll-up approach. Let’s Other drug strategies such as Nutriceuticals, management; for myopic ones, knee-jerk reactions look at the three scenarios in reverse Cosmeceuticals, Therapeutic medical devices to save businesses, currently mega merger mania order. Table 3 Astellas and CV Therapeutics – Potential benefits that biotech M&A provide Hostile takeover attempt Astellas is moving in on a hostile take- Aspects of Biotech M&A Potential Benefits to Big Pharma over with a second attempt at CV Could pull M&A together quicker for impact to Short of cash, less than year Therapeutics. The first attempt was in the short to medium term fall of 2008 with CV Therapeutics turn- Lowest company valuations in 25 years Ability to \"shop\" and buy many ones ing away from any deal. As the market has moved downwards and cash reserves Build medium to longer term value for drug portfolio, Biotechs, historically, have science platforms dwindled, Astellas feels that the addi- have potential revenues, but platforms for innovative that built their drug portfolios development tion of CV Therapeutics would provide growth into new areas and potential Big Pharma add-ons could be diseases, drug Some biotechs could provide new franchises revenue paths for the medium future. classes, or operational capabilities Being a Japanese pharma company and If selected properly, big pharmas could stock concerned with long-term growth pros- More biotechs have Big Pharma partnerships- pipelines and force big pharma to big pharma pects along with a willingness to build drive interesting options collaborations / M&A with the biotechs who have out new franchises in both diseases and big pharma partnerships drug classes and shouldering some of Provides many more variables for deal-making Financial crisis has tightened up credit, this could the risk, Astellas is bucking the trend of and out-licensing monetisation strategies allow for more original deal-making Wall Street pressures, quarter-to-quarter financial performance and western Table 4 big pharma. The deal that formed Astellas—putting together Yamanouchi drug pipelines. The first deal acquired Roche and Genentech – Remaining share buyout and Fujisawa—built a sustainable foun- a 44.1 per cent stake in Genentech at dation to grow from. It is predicted that Another interesting potential trend- a cost of US$ 42.6 billion making it Astellas will make more smart acquisi- setting deal involves the buyout of the sixth largest deal to date (Table 2). tions in the next couple of years and remaining Genentech shares by Roche. This time around, it could cost Roche take advantage of the current financial Roche is driving hard to purchase the double that sum. Genentech, one of crisis. Table 4 presents a summary of remaining stake of Genentech to form the two largest biotechs in the world, drivers providing advantages to larger the largest biopharmaceutical company could very well rebuff the Roche deal pharmaceutical companies with their with broad research platforms, core and start its own biotech M&A strat- biotech brethren. capabilities, preclinical and clinical egy. An approach that can be more P hA r m A F o c u s A s i A issuE - 10 2009 12

Strategy make a difference in how they build Strategies for drug development value into their drug pipelines. The crisis has plummeted company valuations to their lowest level in 25 years Drug Development & Approval Process (the life of the biotech industry is almost that old) and it is estimated that more Postmarketing - Phase IV “Co-Promote” Approaches than a third of the over 3,500 biotech companies that exist in the US have Preregistration - FDA/EMEA “Co-Development” Approaches less than a year of cash on hand. With File NDA at FDA most pundits predicting that financial “PDC” Development Approaches problems would continue till mid- Clinical Trial - Phase III 2010, you have a lot of companies with Clinical Trial - Phase II potentially great science and pipelines “Foster” Development Approaches in clinical development on the verge Clinical Trial - Phase I of extinction. “Sponsored” Research Approaches File IDA at FDA Enter GSK. Although some are predicting the Pfizer-Wyeth deal could Preclincal Testing help Pfizer with short-term revenues and give a little breadth from the Wyeth pipeline, most are pointing towards Figure 1 GSK as the company and M&A trend to watch more closely. To date, GSK The pharma innovation gap – has avoided any mega merger in favour Increased R&D spending yielding lesser drug approvals of mobilising its cash on smaller, more asset-building type of deals. The goal is an obvious one: to address long-term $60 50 problems instead of adopting a myopic blockbuster-drug-only strategy and build $50 Pharma R&D ($Billions) New Drug Approvals 40 both drug classes and drug portfolios Pharma $40 in focussed disease franchises. Over the Innovation 30 past 24 months, GSK has aggressively Gap $30 bought an accretive, sustainable and 20 potentially expansive diverse set of drug $20 assets—such as UCB’s late-stage drug 10 assets and Biotene’s dry mouth drug $10 treatment—in both established and 0 $0 emerging markets. It is also rumoured 1992 ‘96 2000 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 that GSK is looking at more targeted diversified healthcare companies and Pharma R&D Investment BioPharm R&D Investment New Drug Approvals by US FDA this approach could provide for more portfolio management across healthcare Sources: Pharmaceutical Research and Manufacturers (PhRMA) Annual Report 2007; Burill & Company Figure 2 systems. Report 2003; PhRMA Annual Member Survey, 2007: US Food & Drug Administration Databases. Adopting new development strategies accretive for Genentech shareholders and ily a bad thing. We would like to see a better fit with the corporate culture him in a more expansive role helping Johnson & Johnson, Abbott Laboratories in California. A Roche takeover could more biotechs grow to become future and Novartis are just a few to deploy kill the remaining innovative juices that Genentechs. this approach with repeated success. Genentech has. One thing is probably Companies like OSI Pharma, Celgene, for sure, the co-founder and current Amylin are just a few who are still inde- Aggressive M&A strategies of GSK CEO, Levinson may leave his position The global financial crisis has provided pendent and could provide great buys if the deal goes through; not necessar- an opportunity for big pharma to really for big pharma. Combine one of these www.pharmafocusasia.com 1

Strategy companies with smaller biotechs and you Predictions for 2009 and 2010 could build a strategy around developing GSK, Roche and Novartis represent some drugs yourself, co-developing with some of the best possible examples of other partners (possible future acquisi- building a diversified and scientifically- tion targets), co-promoting late-stage rich big pharma and could very well use assets to free up resources for creative the multiple biotech M&A model. As development strategies like fostering Roche eventually acquires the remain- drug programmes. AstraZeneca is ing shares of Genentech it will have a very good at this. License a drug to a fairly balanced small molecule portfolio company, have that company develop / pipeline with advanced biopharma the asset in close ties with it and at some capabilities. Genentech, one of the two pre-determined point in the future, it largest biotech leaders worldwide, has gets the rights back if requested. If not, both short-term goals combined with the biotech / pharma partner has rights long-term visions. Amgen should be to development or share a range of busi- seeking targets for M&A, not being ness development options. acquired. Astellas might lose out on this Another approach is the bid with CV Therapeutics, but they can Pharmaceutical Development Company have a short list for M&A. Companies (PDC) option. One of the best compa- like Abbott Labs and Celgene provide nies to create and lead with great success great add-on revenues, deep pipelines using the PDC model is DeBiopharm, and sound scientific platforms. S.A in Lausanne, Switzerland. In the Those companies seeking growth PDC model, a company acquires the only through the mega merger approach drug asset which is generally at a Pre- will have limited success, take them- IND or phase I stage and takes owner- selves out of contention during one of ship. It then develops it through phase the most opportunistic times we’ve seen II, phase III or NDA. In return, the in decades and could spell potential PDC gives milestone payment, royalties disaster for the big pharma seeking to and / or sales kickers to the original grow revenues in the medium to long source of the drug asset. Most PDCs term. don’t promote the products, they usually Pfizer-Wyeth in the end won’t be any sell or out-license the asset to a larger better than its previous mega merger company. The PDC and fostering deals and hopefully they will see this models are great strategies for shar- and push along with vetting and closing ing resources, risk and allowing larger a few biotech M&A deals before the companies to leverage a stockpile of good ones are gone. In the end, these drug candidates on their shelves that purge cycles are good because they force may never be developed. Figure 2 the crème de la crème to the top and depicts the overall strategic approach this is what we need to bridge the gap to drug portfolio development and in innovation among the Big Pharma management. companies. 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. author 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. P hA r m A F o c u s A s i A issuE - 10 2009 14

Strategy pharma and Biotech collaborative models collaborations 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 C ollaborations are the voluntary, However, within that outcome lie the joint actions of two or more two fundamental reasons for engag- parties to achieve a common ing in collaborations. First, the belief goal. This is a straightforward concept that the apportioned, and anticipated in principle, but often more complex return on investment from the shared in the real world. outcome will exceed that which might Within the pharmaceutical and be achieved independently. The second, biotechnology sectors, one can easily and equally important driver for identify at least six major classes collaborations, is the recognition, by of stakeholders, viz. private indus- each party, that they have insufficient try, academia, regulatory agencies, internal resources, e.g. cash, expertise, governments (policy and legislation), time, infrastructure or intellectual patient advocacy groups, and payers property, to independently achieve the (public / private). Each of them can desired outcome. Within the pharma- be involved in collaborative activities ceutical and biotechnology sector, two with one or more organisations in their fundamental objectives underlie much own or other stakeholder categories. of what we do: First is the need to On a purely numeric basis, a single get effective therapies and service to stakeholder could be involved in as patients with unmet medical needs; and many as 32 different kinds of collabo- second is the necessity to create and rative interactions with organisations maintain sustainable economic models from their own or other stakeholder which allow for the continuous crea- categories. tion of needed products and services. Begin at the beginning… When discussing collaborations as Collaborations are, in the broadest sense, and go on till you come to a class of business transactions, it may tools which can be used to achieve these the end: then stop. be useful to consider why a corpora- objectives. tion should engage in collaborations at In this context collaborations are Lewis Carroll all—after all, the typical outcome of classified into three categories—non- Alice’s Adventures in Wonderland any collaboration involves the sharing competitive, pre-competitive and of the upside with an outside party. competitive. www.pharmafocusasia.com 1

Strategy discussion / negotiation between the two of collaboration, and consider their Non-competitive collaborations The first group, non-competitive parties. Such differences in valuation are match (or mismatch) with some essen- collaborations, is best exemplified by to be expected. Each party is striving tial aspects of the business model of private industry-academia collabora- to maximise their return on investment the sector. The essential hallmark of tions. Within the US, this model of (money, personnel and infrastructure), pre-competitive collaborations is the industry-academia collaboration, with while simultaneously working to reason- focus on the development of tools and its concomitant flow of innovation from ably reduce / limit their costs. standards, and not the development academia to industry has its basis in the of products and services. This aspect Patent and Trademark Act Amendments of pre-competitive collaborations is Pre-competitive collaborations of 1980 (University and Small Business The second major class of collaborations, exemplified by one of the earliest and Patent Procedures Act), more commonly pre-competitive collaborations, also have most often cited NCRA collaborations, known as the Bayh-Dole Act. Under the a legislative underpinning within the US, Sematech. It was initially established as provisions of this act, universities, non- in this case, The National Cooperative an industry / government collabora- profit organisations and small businesses Research Act of 1984 (NCRA), and tion for the development of advanced can obtain and retain ownership of, and the National Cooperative Research and manufacturing methods for the US patents on, inventions funded by the Production Act of 1993. These laws were semiconductor manufacturing sector, federal government. Additionally, the enacted to enhance the competitive- and was created in direct response to act requires that the universities actively ness of the US-based industries in an the perceived domination of this manu- engage in the commercialisation of these increasingly competitive international facturing sector by Japan. patented assets. With this legal founda- marketplace. The 1984 law clarified the Table 1 is a sampling of pre-competition, American universities have, over the application of anti-trust law to co-opera- tive collaborations in the pharmaceuti- past 28 years, become increas- cal and biotechnology sectors. ingly important and currently Several points are notable. First, essential sources of innovation as mentioned above, all of these The essential hallmark of pre-competitive for the pharmaceutical and collaborations are focussed on collaborations is the focus on the biotechnology sector. the development of information, In non-competitive collabo- tools and standards, putting development of tools and standards, and not rations, such as those of indus- them clearly in the pre-competi- the development of products and services. try and academia, the desired tive space. Second, five of the outcomes by each party are seven are dedicated to generating generally non-overlapping. For massive data sets from various example, the industrial partner may be tive research ventures, and eliminated “omes”, genome, proteome, kinome seeking novel product / service oppor- the treble damage awards associated etc. and analysing these data sets for tunities to develop within their own with anti-trust violations. These benefits relatively sparse information which, by pipeline, or access to the specialised accrue to the members of a collabo- itself, may have minimal competitive analytical or preclinical expertise of an rative research consortium, provided value. This general information, however academic laboratory. In a complementary that the consortium complies with the when combined with proprietary and fashion, the academic partner may be mandated disclosure of all participants drug-specific information belonging to seeking to commercialise an asset devel- and the purpose of the collaboration. the individual participating companies, oped within the university or to generate The 1993 amendment extended similar will be expected to provide a compara- new scientific observations (publications) provisions to joint production activities. ble, but unique competitive advantage by evaluating the activity of a novel Although more than 900 groups have to each participating corporation. The pharmaceutical agent in a preclinical registered under NCRA since 1984, remaining two consortia, Aerosol and model which is well established within registered collaborations in the phar- Enlight, are also focussed on problems the academic laboratory. maceutical and biotechnology sectors whose solutions are likely to provide Although the qualitative distribu- represent substantially less than 5 per significant competitive advantages only tion of outcomes, e.g. de-risked prod- cent of the total. when combined with additional propri- uct / service opportunity, scientific To begin to probe why this collabo- etary, drug-specific information. This publication(s), is relatively straightfor- rative model is apparently not favoured synergistic linkage of commonly held ward, the quantitative prediction of the by the pharmaceutical and biotechnol- and proprietary information is a second value of these outcomes can sometimes ogy sector, we can examine some of defining criterion of pre-competitive be a critical point of disagreement / the main characteristics of this type collaborations. P hA r m A F o c u s A s i A issuE - 10 2009 1

Strategy Sampling of pre-competitive collaborations in pharmaceutical and biotechnology sectors Group Name Activity Participants Start Year Pharmaceutical Aerosol Identification of CFC-free propellant gases for Private Industry 1990 Consortium aerosol delivery of drugs Research on kinases and phosphatases for drug Private Industry, Academia, Dundee Kinase Consortium 1998 discovery Government Identification of Single Nucleotide Polymorphisms Private Industry, Non-profit SNP Consortium / HapMap (SNP) and haplotypes associated with human organisations, Governments, 1999 Project disease states Academia Predictive Safety Testing Identification of biomarkers to predict preclinical Private Industry, Academia, 2006 Consortium safety of drugs Regulatory Agencies Identification of biomarkers for risk assessment, Government, Private Industry, Biomarkers Consortium 2006 diagnosis and treatment of human diseases Not-profit organisations Identification of SNP’s associated with drug-related SAE Consortium Private Industry, Academia 2007 Serious Adverse Events (SAE) Enabling technology incubation – first program: Private Industry, Venture Capital Enlight Biosciences 2008 non-invasive imaging Fund Table 1 To return to the possible reasons for too massive and “drug-relevant” data too collaborations may be related to the the relative paucity of pre-competitive sparse to be cost-effective as intramural extraordinarily long product develop- collaborations within the pharmaceuti- projects, and consequently, albeit slowly, ment life cycle which is unique to the cal and biotechnology sectors; although are becoming the foci of pre-competi- pharmaceutical and biotechnology information / tools can be the subject of tive collaborations. sectors. Any strategic initiative in the pre-competitive collaborations, they can Two additional factors may be pre-competitive space is unlikely to have also provide a competitive advantage to contributing to the historically low a significant impact on a corporation their owner. If an individual corporation numbers of pre-competitive collabo- until 8 to 10 years in the future. Given has the resources and infrastructure to rations. Until relatively recently, the the shorter-term revenue and expense create a proprietary data set, extract standard pharmaceutical drug devel- pressures which the pharmaceutical and useful information from that data set, opment model was inward focussed, biotechnology sectors currently face, the and protect that information as trade with the belief that internal research allocation of scarce resources to highly secrets or patents, they will certainly and development could provide a speculative, pre-discovery activities may do so. As noted earlier, a corporation is sufficient number of commercially not be viewed in a favourable light. A only going to collaborate in this effort successful drug to sustain the growth final factor in this matter may be simply when they have insufficient internal of the corporation. Under that model, one of cultural inertia. The sector as a resources to complete the task on their pre-competitive collaborations would whole has much more experience and own. Until recently, the complexity of have been unnecessary and perhaps familiarity with other kinds of trans- problems, and size and complexity of the unwanted. In recent years a more exter- actions, e.g. mergers and acquisitions, resultant data sets which were tackled nally focussed drug development model product in-licensing and joint ventures. by pharmaceutical or biotechnology has emerged, in which pharmaceutical Even if pre-competitive collaborations companies were generally manageable companies have engaged in increasing offer some theoretical advantages, in the as intramural projects, providing little numbers of non-competitive collabora- absence of clearly documented examples impetus for pre-collaborative collabo- tions with academia. It remains to be of strategic or financial benefit deriving rations. However, with the arrival seen if this trend towards utilisation from participation in pre-competitive of “omes”, genome, transcriptome, of external resources will extend to the collaborations, there may be a degree proteome, metabolome, lipidome etc., pre-collaborative space. An additional of reluctance to be an early adopter of some projects at this scale have become factor working against pre-competitive this strategy. www.pharmafocusasia.com 1

Strategy Competitive collaborations Competitive collaboration landscape Collaborations between competitors are also regulated by large bodies of antitrust or competition law in all juris- dictions. Within the US, the Sherman Minimal In / Out- overlap Ant-Trust Act of 1890 briefly states, licensing Joint “Every contract, combination in the Strategic venture / form of trust or otherwise, or conspir- alliance Merger acy, in restraint of trade or commerce Acquisition among the several States, or with foreign Skill sets / IP nations, is declared to be illegal”. Within / Market this legal framework, the underlying need for competitive collaborations is Co-marketing the same as that of other collaborative types, i.e. the need to achieve an Anti-competitive outcome which cannot be accomplished Strong Anti-trust overlap alone. To solve this need, a wide spectrum of collaborative activities between competitors (business-to-business trans- Equal Not equal actions) has evolved. Valuation / Size One way to structure and view the Figure 1 relationships between these different types of collaborations is to consider lack of overlap in market to avoid anti- only be achieved by the combination them in the context of a two-dimen- trust / anti-competitive issues. Finally, of resources from two or more parties, sional space as described in Figure 1. the “buy your competition” business and 2) the mutual expectation that the The first axis is the relative valuation strategy, in which a large entity may joint outcome will provide a positive and size of the two entities with respect wish to acquire a smaller party operat- benefit to each party that exceeds what to each other and the second axis is ing within the same market segment, might be achieved by proceeding inde- the degree of overlap of skill sets, or may run afoul of anti-trust / competi- pendently. intellectual property or infrastructure tion laws. Refinements of this schema Disclaimer: The opinions expressed in this between the participating entities. are clearly possible. Nevertheless, this article are personal opinions of the author Utilising these axes, it is possible to approach, even in its current form, may and do not necessarily represent the opin- place most competitive transactions provide some clarification or ration- ions or positions of Genzyme Corporation within this space. For example, joint alisation of the type of collaborative or its senior management. Likewise, ventures and mergers are usually formed transaction chosen to achieve a desired the identification of specific products, between entities of roughly comparable outcome. or organisations does not constitute an size and complementary skill sets or In summary, collaborations involving endorsement of those entities by Genzyme intellectual property. Licensing deals the pharmaceutical and biotechnology Corporation or its senior management. and strategic alliances are character- sector, non-competitive, pre-competitive The commentary on, and summaries of, ised by a minimal overlap in skills or and competitive, may differ in their legal laws of the United States do not represent IP (depending on the subject of the underpinnings, structure, complexity legal opinions on these laws. transaction) and are not particularly and value. However, all of these inter- dependent on the relative size of the actions are driven by: 1) the mutual full references are available at two parties. Co-marketing arrange- recognition that some objectives can www.pharmafocusasia.com/magazine/ ments tend to be done between partners of roughly equal size, with a strong overlap in market, but some moderate Bruce m pratt works for Genzyme Corporation on identification author degree of separation in call point or and evaluation of early stage product opportunities, proactive outreach to academic and biotechnology sectors, and works geographic coverage. Acquisitions are with corporate Development on issues related to product devel- typically asymmetric transactions where opment. the larger partner takes control of the smaller party and there is sufficient P hA r m A F o c u s A s i A issuE - 10 2009 1

Strategy new patents for old Drugs LABeL-BASeD StRAtegieS in the uniteD StAteS P hA r m A F o c u s A s i A issuE - 10 2009 20

Strategy I n recent years, particularly since drugs. By starting with a drug that has not available for previously-approved the Dot-com stock market crash in already been in the clinic, risk is reduced repurposed drugs. Finally, the period of 2000-2001, venture capitalists have in each category of concern. Approval data exclusivity in the US FDA (during been increasingly reluctant to fund US time is shortened for drugs that have which a generic application will not be companies engaging in drug devel- already been proven safe. The cost of the approved) is five years for NCEs, but opment. Such investments are often clinical trials is less, because pre-existing only three years for repurposed drugs considered to be too risky, too capi- ADME and safety data can substitute for that are not NCEs (See exclusivity chart). tal-intensive, and to take too long to expensive research and trials. The risk of Because a three-year exclusivity period fit the new, more conservative venture failure is also reduced for drugs having is generally insufficient, development of capital model. Indeed, it has been esti- known safety and pharmacology. For all repurposed drugs hinges on the avail- mated that only 1 in 100 preclinical of these reasons, repurposed drugs are ability of adequate patent protection. drug candidates and only 1 in 10 drugs attracting more and more early-stage that enter US FDA clinical trials ulti- investment dollars. The FDA, drug patents, and generic drug approval mately receive FDA approval. The average cost of developing a drug through Generic drug approvals in the US are The exclusivity problem FDA approval is approximately US$ A major drawback to the development subject to a detailed regulatory scheme 1 billion, and it takes up to 15 years of repurposed drugs is lack of exclusivity. set up by the Hatch-Waxman Act in from discovery to product launch. This These drugs simply will not be developed 1984. Applicants seeking approval of Patent and regulatory exclusivities should both be considered when evaluating a repurposed drug Exclusivities applicable to repurposed pharmaceuticals are attractive US drug products candidates for clinical development, but only FDA gives regulatory exclusivity with sufficient marketing exclusivity. Patents • 3 years for new indication that focus on the uses and compositions • 5 years for first approval of NCE in the product label can provide up to 20 • 7 years for orphan drug • 6 months additional for paediatric data years of exclusive marketing rights. • Paediatric exclusivity attaches to end of all other exclusivities, patent or data ned israelsen, Managing Partner, Patent term: 20 years from original Knobbe Martens Olson & Bear LLP, USA 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 combination of time, money, and risk without sufficient exclusivity to allow a generic drug typically do so with an has sent venture money fleeing for safer, a reasonable return on investment. For Abbreviated New Drug Application, quicker investments, albeit with a lower New Chemical Entities (NCEs), this or ANDA. The primary scientific data upside potential. is usually not a problem, because the required in an ANDA is the demonstra- typical 20-year patent term (measured tion that the generic product is bioequiv- from filing) is sufficient. However, for alent to the originally-approved drug. Growing investments One bright spot for start-up pharma repurposed drugs, the NCE patents often Expensive clinical trials are not required, companies and venture investors has have little or no term left. Moreover, US because ANDAs rely on the safety and been speciality pharmaceuticals (or patent term extension and European efficacy data generated under the origi- repurposed drugs). Such products Supplementary Protection Certificates nal New Drug Application, or NDA, of include drugs that previously fell out apply to the first approval or market- the original innovator. However, if the of clinical trials and new uses for old ing authorisation of a drug, and so are original drug product or its use is covered www.pharmafocusasia.com 21

Strategy by patents listed in the FDA’s Orange Patent strategies for repurposed drugs often overlap significantly with those Book, generic marketing approval is used for life cycle management of name brand pharmaceuticals 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 label In 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 Life Cycle Management – Common patent types drug interactions and use in specific Enantiomer patents populations. With minor exceptions, • Pro: NCE claims; Orange Book listable the ANDA-filer must adopt the approved • Con: Current obviousness standard makes patenting more difficult label. The Orange Book also focusses Composition / formulation patents on the label, listing only patents for • Pro: Can cover ideal product or most stable formulation; Orange Book listable approved NCEs, drug formulations, and • Con: Generics can usually design around; obviousness methods of use that appear in the label. Crystal form (polymorphs, amorphous) Close coordination between regulatory • Pro: Cover stable or desirable product; Orange Book listable • Con: Generics often design around or invalidate and patent professionals can enhance correspondence between patent claims Synthesis or manufacturing method patents and the label. • Pro: Cover actual production process • Con: Not Orange Book listable; often designed around Extending exclusivity through label Key intermediates • Pro: May represent a chokepoint in synthesis patents • Con: Not Orange Book listable; often designed around A “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 in the US. In short, any time the label improvements or innovations that are attention should be given to patenting instructs the patient or physician to reflected in the label. Unlike tradi- new, non-obvious methods disclosed in do something, consider whether that tional patent strategies, which focus the label. Repurposed drugs typically method is patentable. The patent term on obtaining broad patents to cover target a new patient population, new for such new patents is 20 years from potential modifications, label patents indication, or include a new dosage form, date of filing, which can significantly only need to cover the exact method dosing regimen or route of administra- extend the period of exclusivity for the disclosed in the label. This, in turn, can tion. Corresponding methods of use in repurposed drug. improve patentability by allowing inclu- the label are all potentially patentable. Those developing repurposed drugs sion of very specific details in the patent Unlike the rule in most countries, meth- should not overlook the possibility of claims that are not obvious in light of ods of medical treatment are patentable obtaining patents on seemingly minor the prior art. Obtaining several such P hA r m A F o c u s A s i A issuE - 10 2009 22

Strategy patents enhances the odds of having a difficult to show obviousness of all the Examples of label patent that is held valid and infringed details of such a claim. patent claims at the conclusion of ANDA litigation. In addition to overcoming these It is desirable to identify potential bona fide legal issues, applicants may label patent opportunities prior to public face less tangible psychological issues in • Administering a different dose to disclosure. When reviewing new clini- obtaining and defending label patents. the elderly cal data, one should look carefully for Pharmaceutical inventions in general and • Titration of dosage over X days unexpected or unpredictable results. In follow-on patents in particular may be • Titration pack with escalation addition, it is helpful to ask what changes reviewed more closely in both the Patent dosages • Administer drug without food will be made in the label or the use of Office and the courts. Although the origi- • Administer a dosage form that the drug as a result of the new data. Each nal NCE and method of use patents are achieves plasma level of X, of these areas represents fruitful ground often well respected, the same does not measured Y hours after dosing for obtaining label patents. always hold true for follow-on patents. • Administer with an A word of caution: in case of public The latter are often filed as part of a drug anticonvulsant in patients at risk companies, clinical trial results are often life cycle management strategy with the of seizure disclosed very quickly, leaving little time objective of delaying or preventing generic • Informing the caregiver or patient to prepare patent applications on new competition. In light of the negative image to avoid taking the approved observations. In this situation, close of pharmaceutical companies and the drug with drug • Drug in combination with unique coordination with highly-responsive public interest in the availability of low- packaging patent counsel is important. Although priced generic drugs, exclusivity-extending • Drug in combination with there is a one-year grace period for filing patents receive enhanced scrutiny. delivery device, e.g. inhaler patents in the US, most non-US coun- Patents for repurposed drugs have a • Unit dosage of drug with tries have an absolute novelty require- very different purpose from Big Pharma’s particular dissolution values or ment. Thus, filing the US application life cycle management patents. They often resulting pK values. before any public disclosure can preserve serve a gating function; in other words, foreign patent opportunities. without the patent, the repurposed drug Although some subsequent cases suggest will never be developed or available to that inventions made through routine the public. However, because of the Label patents are not necessarily easy to obtain experimentation may well be obvious, overlap between patent strategies for In the US, patents can only be obtained such a rule may not apply to unpredict- protecting repurposed drugs and those for inventions that are both novel (new) able technologies, such as pharmacology. for product life extension, repurposed and non-obvious. In the pharmaceuti- The very simplicity (and to some, trivi- drug patents may suffer from the same cal area, novelty problems often arise ality) of some label patent claims may negative perceptions in the Patent Office when trying to patent a newly-recog- result in obviousness rejections. Good and the courts. nised property of a drug. A result that strategies for overcoming those rejections Despite these perception issues, in inherently occurred in the prior art is include emphasising the unpredictability the end, the Patent Office and the courts not considered novel, even if that result of the new discovery, presentation of are bound to follow the same rules of was unrecognised. In dealing with inher- comparative data (usually available from patentability in all cases. Label patent ency issues, is it helpful to ask whether the clinical trials), long felt need, clinical applications do make it through the something different is done as a result importance, and lack of suggestion in Patent Office, and the resulting patents of the discovery. If the answer is in the the prior art. The ability to write very provide major value to innovators, drug affirmative, then including those new narrow claims (as narrow as the label developers, investors, and the public who actions in the claim can usually overcome language) can also help overcome an receive the benefits of new and otherwise the inherent novelty rejection. obviousness rejection, because it is more unavailable therapies. Obviousness can be a major issue for label patent claims. In 2007, the US Supreme Court decided KSR vs. Teleflex, ned israelsen is a lawyer and managing partner of the San author which overturned the requirement that Diego office of Knobbe, Martens, Olson & Bear, LLP, California, uSa. he is registered before the uS patent and trademark the prior art must contain a teaching, Office, and advises clients in the area of pharmaceutical and life suggestion, or motivation to make the science patent law, including worldwide protection of new and new invention. This case makes patents repurposed drugs. harder to get and easier to invalidate. www.pharmafocusasia.com 2

Strategy innovation the key growth mantra ideas from lab to market, strengthen and and is striving to create a balance between ensure consistent supply of capacity to earning healthy profits and realising their encourage research and foster a favourable responsibilities towards society. policy and incentive framework. In order to acquire a global status, The Indian life sciences industry has the Indian life sciences industry places its been innovating within its means right foremost priority on well-established and from its early days by mastering the art of robust regulatory system. The industry Sasikant misra Deputy Director, process re-engineering during the proc- is looking at innovation in the regula- Confederation of Indian Industry, India ess patent regime. With the onset of the tory standards, which play a key role product patent regime, the industry felt in the progress. The industry is look- I ndian life sciences industry is under- the need to build expertise in formulation ing at a strong, well-equipped, empow- going rapid transformation. New research and discovery research in order ered, independent and professionally- and emerging business models to achieve global competitiveness. managed body which can address the are changing the way business will be The Industry today, strives to create key regulatory issues and build faith in done over the years. With the advent of a sustainable system of innovation that Made in India brand by establishing a the Product Patent regime Indian life consistently ensures medicines for all, robust regulatory system on the lines of sciences industry is beginning to real- profitability and global market leader- US FDA. ise that Innovation is the key to growth ship. Some of the key focussed areas for Innovation can play a vital role in and in achieving global scale in the the industry are Industry-Academia link- providing access to improved healthcare long-term. ages, public-private partnerships and key to patients. Public health objectives will Innovation which is expected to be organisational initiatives. be realised if innovation is fostered. the leading growth driver, has made the Innovation requires cutting-edge tech- Healthcare benefits both the individu- Indian life sciences industry focus on nologies and has a long incubation period. als and the economy as well. Most of building their portfolios of speciality and A Cooperate and Collaborate strategy has innovations today are patient-centric. niche drugs or entering into alliances with proven to be successful in this scenario. The Indian life sciences industry is incul- the innovator companies to tap this key Indian companies have adopted this strat- cating innovation as the mantra across business opportunity. Indian life sciences egy which is reflected in the number of different functional departments in key industry is making constant efforts to have strategic R&D collaborations across the areas of the organisation such as quality, a thrust on innovation as the key value drug discovery and development value sales, marketing and creating differen- creator in all the aspects of the business chain making the transition from a serv- tiation through innovative platforms to through technology, services, manufac- ice-based to a partnership-led relationship. enhance effectiveness and improve busi- turing and excellent quality initiatives Further collaborative alliances in which ness performance. to come out with innovative products both the stakeholders pursue a high-risk Life sciences industry, which is matching global standards. and high-reward strategy are increasingly knowledge-based, is undoubtedly one The industry is embracing innova- appearing on the alliance landscape. of the most innovative sectors of the tion and the latest technology to bring The focus of the Indian life sciences Indian economy. The industry is look- to the market novel drugs for treatment industry is on Profitability—to ensure ing at innovation in all aspects of the of unmet medical needs innovation is sustained growth in all the key pharma business and its strategy in tapping being imbibed in scaling up expertise markets of the world, through innova- key opportunities in the current and in advanced research areas, building tion in research and development while emerging business segments and high value intellectual property, creat- maintaining high standards of quality and key emerging markets to achieve the ing optimal funding mechanisms and ethics. The industry aspires to emulate required growth and scale in the short the entrepreneurial environment to take the success of the global pharma industry and long term. the feedback on this article can be sent to sasikant.misra@cii.in or sasikant_in@yahoo.co.in. P hA r m A F o c u s A s i A issuE - 10 2009 24

tArgeted therApieS A SuStAinAble buSineSS Model? 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 F or many rare diseases, there is are genetic in origin, the right diagnosis as yet no satisfactory treatment. before treatment is of high importance Rare diseases are defined as life- to ensure that the patient not only gets threatening and / or serious and chronic the right treatment but also does not diseases, according to the European suffer from side effects. The rarity and Orphan Medicinal Products regulation. severity of the diseases not only mean These diseases represent a high unmet lesser patients are treated but also result medical need. Rare diseases, with their in a high compliance because the medi- genetic origin and because of small cines work. Rarity also leads to higher number of patients to be treated, require costs, but orphan drugs also have a higher effective diagnosis linked to treatment. innovative nature and a higher benefit P hA r m A F o c u s A s i A issuE - 10 2009 2

Strategy In order to understand the concept personalised medicine breaks the cycle of trial and error of rarity, Figures 1 and 2 provide the medicine and helps ineffectiveness rates of medicines to number of patients treated in the US in decrease dramatically. orphan drugs, targeted therapies 2006 for a number of non-rare disease for rare diseases, with their innovative nature and improved and, from Gleevec (Glivec TM) downwards, efficacy, make it a precursor for personalised medicine for rare diseases. The application of models used in therapies and can offer a viable business model to health economics introduces further expand from. Society should develop consensus challenges to the development of orphan for such new models in multi-stakeholder medicines and to the discussion about partnerships which will also make it sustainable. their reimbursement. Cost-Effectiveness = Cost / Effectiveness, where cost is raised by erik tambuyzer, rarity, but data to calculate effectiveness Senior Vice President, are limited by rarity. Therefore, rarity is Corporate Affairs, Europe and International, affecting both the factors of the equa- Genzyme Corporation, tion making the outcome much more Belgium 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 valuable innovation to the benefit of to happen and to continue. patients, including those in the case of As shown by the consultancy company orphan drugs. Even in difficult economic Alcimed in a report for the European times, such beneficial innovation must be commission in 2004, pricing is a func- than average drugs through their better encouraged and the resulting products tion of the rarity of the treated disease. clinical efficacy and effectiveness. In the must be reimbursed when they have meas- Therefore, the prices of orphan drugs, European definition, orphan drugs are urable and demonstrable value. However, given that their development cost is not unique treatments, meaning there are given the rarity of the diseases studied, necessarily lower than the cost to develop no alternatives available. This is the case sufficient time to gather data to show a medicine for a common disease, will be for about one-third of the orphan drugs such value must be granted. higher than the prices of drugs for treating approved in Europe) or make a better therapy over (an) existing one(s), which Rarity visualised – Commonly used medicines is the case for the other two-thirds of Patients ('000) Treated (US 2006) approved orphan drugs in Europe. Not only economic factors but social benefits also need to be taken into account as well: Nexium Lipitor many patients affected by rare diseases Singulair had no therapy available before and Fosamax such therapy is often a first in human Zoloft history. Plavix Advair-Diskus Innovation, rarity and complexities Celebrex caused Aranesp The current debate in society is about Epogen the value of innovation in healthcare: Gleevec our society supports such beneficial or Orphan Drug (<200,000 prevalence in US, < 250,000 in EU) Figure 1 www.pharmafocusasia.com 2

The future of personalised Diagnostic and therapy combinations medicine which are being marketed today Further, drawing the analogy with personalised medicine, a future with more compliance and far less side effects would Enzyme replacement therapies with genetic confirmatory tests to treat lysosomal storage diseases such as be the goal. This will ultimately result in costs going down, as only the right • Gaucher’s disease with Cerezyme medicine would reach the right patient • Fabry’s disease with Fabrazyme and Replagal and minimise side effects. In order to do that, the following series of questions • Pompe disease with Myozyme need to be answered: • Hunter’s disease with Elaprase • Which medicine should I use? • Hurler-Scheie disease with Aldurazyme • How much of the medicine do I need? • MPS VI with Naglazyme • Is the medicine working? Oncology drugs such as • Is my disease controlled or gone? • Her2 and Herceptin (in breast cancer) The old paradigm of trial and error medicine, based on the sequence of an • BCR-ABL and Glee(i)vec (in leukemia) observation with an action followed by • UGT1A1 and Camptosar dosing an observable response is only successful when it leads to innovation and improved • ER/PR tests with drugs like Tamoxifen (in breast cancer) standard of care. But it fails when we FDA recently approved a label change to recommend a test with two settle for “trial and error” medicine as mutations to help with Warfarin dosing in cardiovascular field 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 Rarity visualised – Medicines for rare diseases test and have it followed by appropriate physician actions which will result in a predictable response, that breaks the cycle Patients treated (US 2006) 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 treatment that would have the benefits but with the toxicity of the medicine if any. Also, it excludes them from the treatments 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- Soliris based on 2007 estimates ing from 40 to 75 per cent, but this Figure 2 percentage will dramatically decrease with a (more) common disease. As such, prices not be appropriate, as this would result the venue of personalised medicine. largely depend on the patient popula- in orphan drugs and even more clearly tion to be treated. As a consequence, the so-called ultra-orphan drugs being No future without challenges the application of the same rules of cost- excluded from reimbursement since they The current evolution in evidence-based effectiveness for orphan drugs, and espe- often do not reach the required Quality medicine also comes with challenges: cially for drugs for very rare diseases, will Adjusted Life Year (QALY) limit. • Physicians are being overwhelmed P hA r m A F o c u s A s i A issuE - 10 2009 2

Strategy they require the providers to prove the Balancing fears versus hope relevance of such tests to the patient and the physician. • Regulators face increased concerns • Patients want better treatment but need information about safety of medicines, and need • Physicians want better products but are being pressured for economic effectiveness to remain up-to-date on the new • Industry wants a fair return on high and risky investments technologies. Such new technologies may bring along the need for adaptive • Payers are afraid of the impact of targeted therapies and personalised medicine on clinical trials as many new insights are health care budgets. They look at the experience with orphan drugs and fear a tsunami gained while the trials progress. of personalised medicines at orphan drug prices. • Industry is facing vastly increasing costs driven by the increased demand for data and ever more complex clinical Test to increase drug efficacy / Quality of care trials, while at the same time facing downward pressure on prices and a Therapeutic Area Ineffective Rate (%) more complex reimbursement nego- 75% 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-stakeholder partnerships to develop consensus on the way forward. This should result in a wheel of sustainability: life-saving treatments 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- Spears et al. TRENDS in Molecular Medicine Vol. 7 No. 5 May 2001 Figure 3 ments coming onto the market. Clearly, having a market for personalised medi- by the volume of the available data, parts of the healthcare community. cines is in the society’s best interest. We so, they need more tools to identify • Payers face difficulties to follow the must all work on making it happen! and track test / drug combinations, rapid evolution of the diagnostics / As the public image of the pharma- as well as need more education on genetics field, but, demand evidence- ceutical industry is challenging, better diagnostics and genomics. They also based medicine. They also want to and clearer communication is needed need more treatment guidelines and make payment conditional on drug to explain the contributions it makes are organising themselves into expert effectiveness, but face challenges as we to society. And while no company on centres. They may carry an increased have discussed above. Payers fund their its own can change the sector’s image, liability risk confronted with patients own databases on patient outcomes, industry must work together. Personalised who are more vocal, informed and which they usually don’t share with medicine represents a great opportunity organised. other stakeholders. In demanding to change public image of the industry • Diagnostic testing laboratories perform tests for evidence-based medicine, for the better! intense data acquisition, with high manipulation and storage requirements, while they face complex reimburse- erik tambuyzer is Senior vice president of corporate affairs author ment challenges with new technologies europe and international at genzyme corporation. he is a founding Board member and past chairman of europaBio, the coming into routine practice. They also european association for Bioindustries, and founder of its ethics face issues based on expanded intellec- Working group, as well as the chair of the eBe / europaBio rare tual property portfolios and enjoy an Diseases and orphan Drugs task force. increased focus and scrutiny from all www.pharmafocusasia.com 2

personalised medicine Changing business models personalised 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 I t has become clear that pharmaceuti- frequently, the present article will focus choice of clinical endpoints, or the use cal development in the first decades on other ways in which a new era of of clinical versus surrogate endpoints, of this century will be dominated interactions between lab tests and drugs are debated but gradually move towards by the “personalised medicine” concept. will stress existing business models or a consensus. For example, is a negative Personalised medicine encompasses the require the development of new ones. Prostate Serum Antigen (PSA) at two development and marketing of molec- We emphasise that there is no single years an adequate marker of effective ular tests which help to target the use model for clinical trials which incorpo- radiation treatment for prostate cancer, of pharmaceuticals and biologicals in rates genetic or other complex molecular or should the therapy be considered ways that maximise their effectiveness. information. There are at least three basic experimental until ten-year data are in Of course, lab tests have always guided clinical models (combinations of these hand? Even when regulators in different diagnostics: for high glucose, a physi- models are also possible) and they are countries differ in their decisions, the cian will diagnose diabetes and prescribe as follows: basic issues for therapeutic trails, such as insulin, and so a lab test was paired with the choice of endpoints and the weighing a drug. But personalised medicine, as of risks and benefits, are familiar. Evidence-based medicine and diagnostic tests the term is used, almost always involves The tools for assessment of diag- carving out new subsets of patients with Throughout the developed countries, nostic tests are very different, and the a particular form of disease, such as government-based and private insurance usual terms of art like sensitivity and Herceptin-sensitive breast cancer. systems are showing rising interest in the specificity, familiar from college statistics, The interactions between the devel- rigorous application of evidence-based fall far short when the actual decision opment of complex tests, drug trials, medicine to control costs, by reducing point for regulators and payers rests regulatory approval, and drug market- unnecessary or low-yield interventions. on the clinical utility of a test. For ing will cause substantial shifts in the Clinical trial experts and payer deci- example, “sensitivity” can mean the way healthcare is delivered. One obvious sion-makers are quite familiar with chemical threshold of a test—does it business issue (a smaller market for a outcomes analysis of therapeutic trials. measure down to 0.1 ng/ml of PSA? more specific drug) has dominated think- In general, control and treatment groups Sensitivity and specificity are usually ing about how personalised medicine are matched and randomised. To the used in statistical sense, describing the will develop, how it will impact the degree possible, subjects and evaluators performance of the test in known popu- pharmaceutical industry, and indeed, are masked to the interventions offered. lations of cases and controls. The clinical whether it is “good” or “bad” for pharma. Outcomes and adverse events are statisti- accuracy of the test depends on the base Because that topic has been discussed so cally compared. Controversies over the rate of positive and negative cases in the P hA r m A F o c u s A s i A issuE - 10 2009 30

Strategy Clinical models helped in avoiding the prescription of the drug in the subgroup 1. Drug targeted by clinical trial of patients at risk. The already-classic example of this approach is the identifi- 3. Third-party innovator differentiates members of a cation of Her-2/neu as marker for breast cancer patients who drug class are likely to respond to trastuzumab (Herceptin). Alternately, we could classify Her-2 / neu-negative patients as ruled out A third-party innovator (or academic laboratory) identifies genes for trastuzumab therapy. There are already several examples which allow choice of the drug in a drug category which is best of this model in oncology, some of which emerged only suited to individual patients. For example, genes which optimise after the drug’s regulatory approval. For example, increasing choice of statins could be identified and commercialised. Such evidence suggests that cancer monoclonals which target the a test, if developed, would allow the genetic profile of patients to EGFR receptor are ineffective in patients whose tumour has a be assessed so that a physician can prescribe the statin which mutation downstream of EGFR which tonically activates the is most likely to be effective. So far, we lack clinical examples KRAS gene regardless of whether the monoclonal neutral- of this model. The most likely reason is limited motive for this ises the surface receptor for EGFR. clinical trial investment by any single pharma or diagnostics 2. Drug rescue by identification of adverse events company, since a pharma may lose market share and a diagnostics company may be unable to set a price high enough to repay Many drugs cause distinctive adverse events only in a the trial. Alternately, the a priori development risk may seem too minority of patients. To some extent, this is a truism: other- high, since there is no certainty that a small gene panel could wise the drug candidate would not reach the market. A be found and commercialized that would classify statin patients molecular cause for the uncommon adverse events might effectively. now be identified either before launch or during post-market- We can use three categories to highlight the diversity of gene ing surveillance. An example is identification of the HLA types that may contribute to personalised medicine. Like the three B*5701 genotype, which is associated with serious adverse clinical models just discussed, the three gene categories shown events in response to abacavir (Ziagen). This test became a here are not absolute, but they do illustrate the diverse biologies recommended diagnostic only several years after the drug’s which are being studied to support personalised medicine. launch, and improved the acceptance of the drug. It also population at hand, which allows ent evaluators will differ as to whether receive EGFR therapy, a therapy which prediction of true and false positives the test is well-enough established for is very likely to be ineffective for such and negatives. Sometimes, other already clinical use. Often, evaluators will differ tumours. However, the state of informa- known characteristics of the patient will sharply on whether enough is known tion at this point may be criticised due be calculated together with test results to about the test in practice to recommend to the fact that retrospective trials are give a more sophisticated prediction for the test to be used routinely. fraught with confounding variables and the test in the patient at hand (Bayesian a critic can quickly cite many retrospec- statistics). All of these statistics become tive conclusions that were invalidated Paradoxes of clinical trial ethics much more complicated for diagnostic A distinctive problem with diagnostic by prospective controlled trials. Payers tests that have a spectrum of results, tests, as opposed to therapies, occurs may question whether the cost of the rather than just positive or negative when retrospective data analysis suggests molecular test should be covered, if its results. Meanwhile, specificity and that a clinical use of the test is likely but clinical use is uncertain. Although the sensitivity lose much of their meaning not certain to be valid—say, 70, 80 or resulting debate over levels of evidence for genetic tests that answer whether the 90 per cent likely. An example occurred may seem arcane, this scenario is fairly patient does or doesn’t have the gene when retrospective studies of clinical common with diagnostic tests. in question; the accuracy of the test trials with EGFR-blocking monoclonals is essentially 100 per cent. But even found them to be ineffective if a down- Development risk for complex diagnostics here, because of untested mutations or stream gene, KRAS, was constitutively interactions with other untested genes activated due to a mutation. Because At present, relatively few pharmaceutical with superimposed functions, the clinical the results of the retrospective study are or biotechnology firms have the in-house variance accounted for by the gene may incompatible with clinical equipoise, capabilities to develop innovative molec- be much less than 100 per cent. it is impossible to conduct a clinical ular diagnostics de novo and carry them When the results of the test are trial where cancer patients with KRAS- through commercialisation. Therefore, proposed for clinical practice, differ- activated tumours are randomised to when tests are used as early as clinical www.pharmafocusasia.com 1

trials, an outsourcing contract or a more turer will worry about a competitor who ing steps and is currently run at one sophisticated contractual partnership could produce a rival test after the risky centralised and standardised laboratory. exists between a test developer and the and costly proof-of-concept stage has In the United States, this category of drug developer. Contractual issues can been passed. Intellectual property on test is called a “laboratory-developed become very complex and go beyond the the diagnostic test alone may be more test” or LDT. In other cases, the lack scope of this article. But as one exam- difficult to defend, even in the short of a “gold standard” test or variabil- ple, the freestanding test developer must term, than the pharma’s core patents on ity of testing between laboratories has develop a commercialisation-ready test the molecular structure of the companion raised questions about the accuracy by the beginning of Phase II. This is drug or biological. of diagnostics even for the prototypic because regulators will be very sensitive personalised medicine test, the Her-2- to technical variations between the test neu test (See Fitzgibbons PL et al., Arch Regulatory challenges for complex diagnostics used in clinical trials and the test that Pathol Lab Med 2006, 130:1440-5, and will be commercially available after drug Complex diagnostics raise a number references therein). launch. Therefore, most of the developer’s of regulatory challenges. For example, Another regulatory challenge which sunk costs occur early, although the drug several tests at the forefront of person- may have seemed like science fiction candidate has 90 per cent risk of failure alised medicine are too complex to be only a few years ago is the prospect that any drug has at the beginning of packaged as kits. An early example is of prescribing cancer drugs based on Phase II trials. The drug manufacturer the Trofile test (Monogram Biosciences), oncogene characteristics rather than will be concerned about lock-in to a a gateway test to the use of a new- gross tumour type. Today, clinical trials contractual relationship with the test generation HIV anti-viral, maraviroc for cancer drugs are categorised by the manufacturer, while the test manufac- (Selzentry). The test requires gene-splic- type of cancer: small cell lung cancer, Molecular models cratic adverse events such as myopathy (an infrequent adverse 1. Enzymes of metabolism and transport event caused by statins) or rhabdomyolysis (a life-threatening Across many different drug classes, human beings are but extremely uncommon event caused by statins). Ideally, early remarkably diverse in their metabolism and transport of identification of vulnerable patients could allow clinical trials to drugs. For a given drug, a patient may be a typical metabo- proceed and the drug to be marketed, if always paired with a liser, slow metaboliser, or ultrametaboliser. In the United genetic test. On the other hand, for highly toxic but extremely States, the FDA has remarked on pharmacogenetic infor- rare genotypes, there are unwelcome economic issues such as mation (usually related to metabolism) of over 100 drug number-needed-to-test to obtain a better outcome. For example, labels (Frueh FW et al., Pharmacotherapy, 2008, 28:992-8). it is impractical to give a US$ 200 genetic test on 10,000 patients However, very few of those drugs have clear labelled instruc- to identify one rare patient who would be vulnerable to a severe tions for changes in dosage or carry a direct recommenda- adverse event. tion that testing should be undertaken before prescription. The design and analysis of therapeutic trials is costly and Genes related to tamoxifen metabolism, warfarin metabolism complicated, and so is the conduct of diagnostic test develop- and pharmacodynamics are currently being investigated for ment, but for different reasons. The business dynamics and clinical utility. regulatory requirements of both therapeutic trials and diagnos- 2. Drug target tic test trials must be satisfied to bring a combination test and drug to market, while meeting prospective estimates for develop- Molecular analysis of drug targets has found the quick- ment risk and likely economic return. Putting all of these factors est clinical application in chemotherapy. Examples include together may mean that the net risk and complexity is actually expression of Her-2/neu as a marker of response to trastuzu- squared or cubed relative to a more routine therapeutic trial. Six mab (Herceptin), expression of the EGFR receptor or related ways in which potential difficulties manifest themselves include: downstream mutations as markers of response to cetuximab (Erbitux), and expression of the bcr-abl rearrangement with • Evidence-based medicine respect to imatinib’s (Gleevec’s) effectiveness in individual • Paradoxes of clinical trial ethics patients. • Development risk for complex diagnostics 3. Markers of adverse events (other than • Regulatory challenges for complex diagnostics metabolism) • Economic hurdles for complex diagnostics Examples in this group include hypersensitivity reactions (the • Challenges in marketing. HLA B*5701 variant and reaction to abacavir) and idiosyn- P hA r m A F o c u s A s i A issuE - 10 2009 32

Strategy adenocarcinoma of the pancreas, renal wise and pound foolish. For example, a In addition, diagnostic tests have cell carcinoma, and so on. However, hypothetical new test which could save a rare reverse-supply chain configura- we are already seeing targeted cancer the healthcare system US$ 100 million tion. Instead of manufacturing a drug or drugs which are effective in ways that over a few years costs US$ 10 million device in a factory, shipping to a regional are completely unforeseen by legacy in clinical trials to develop and needs warehouse, and then a retail location histologic classifications of tumours to be sold at US$ 300 to cover risk, (pharmacy or hospital), a diagnostic (Both chronic myelogenous leukemia investment, and marginal cost; but the test requires shipping of the test from and gastrointestinal stromal cell tumours test will never exist if the reimburse- thousands of doctors’ offices or clin- respond to imatinib, if they express ment is locked at US$ 20 and the US$ ics backwards to a central laboratory. the bcr-abl oncogene translocation). 100 million will never be saved. New The logistics become quite formidable Although there are some highly effec- regulatory schemes for payer systems will for very complex diagnostics that are tive cancer / chemotherapy regimens, need to adapt to some form of value- only performed at one or a very few the impact of chemotherapy on many based reimbursement at least where the locations, and especially if the samples cancers is notoriously limited (e.g. 5-10 net outcome is to encourage cost-saving must be chilled or frozen at the point of per cent of patients benefit, or alterna- forms of investment. collection and during shipping. tively, the number-needed-to-treat is 10 One bright spot in the economic to 20 or more.) Therefore, the hurdle rate logic does occur if the healthcare system Moving forward for results matching tumours to chemo- bundles a spectrum of interlocking costs Speculation on the slow growth rate therapy based on molecular expression together, such as the costs of cancer for personalised medicine focusses too panels (e.g. tumour X in a case that also chemotherapy and chemotherapy diag- much on the supposed reluctance of the carries the bcr-abl mutation) should be nostics. Here, the test manufacturer pharmaceutical industry to investigate equivalent efficacy. But all regulatory could command value-based market diagnostics which could carve down the conventions, and payer guidelines for prices in its direct transactions with market size of new drugs. When discus- chemotherapy coverage, are based on the chemotherapy centres, if the net outcome sion stops there, the analysis has fallen legacy approach to classifying tumours of test usage was ultimately cost-saving into a mental trap, in which one credible histologically and studying them in for the chemotherapy centre. answer is found quickly and this halts the drug-specific trials. search for alternative and perhaps more important explanations. In fact, in the Challenges in marketing Historically, there has been relatively past year, several CEOs at leading phar- Economic hurdles for complex diagnostics little advertising or detailing of labora- maceutical firms have stated that personal- Laboratory tests have traditionally been tory tests, probably because there were ised medicine—the pairing of diagnostics treated as commodities in the medical undifferentiated commodity products and drugs—has to be a core competence marketplace. In most countries, costs with low margins. Therefore, there is of their development strategy. Numerous of laboratory tests are either bundled little apparatus in place to educate physi- additional barriers to development and with episodes of care or paid at fixed cians about new molecular diagnostics, commercialisation were described in rates based on the chemistry of the test and older physicians may find the topic this article, but they can be dealt with (e.g. nucleic acid amplification, US$ of molecular diagnostics quite confus- by good policy and appropriate innova- 20; serum immunoassay, US$ 25; flow ing. One solution could be integration in the regulatory process. Only by cytometry, US$ 50). These fixed fee tion of electronic medical records and elevating the addition problems into view schedules appear to be adequate for e-prescribing programmes with pop-up will they become part of the dialogue on the development of new tests of the information on relevant diagnostic tests, personalised medicine and part of our same type when the main parameter of or flags in the healthcare system that hold solution kit in moving the healthcare the test is accuracy. Fixed fee schedules a prescription until a relevant diagnostic industry forward for more effective and also encourage technological change to test has been performed. accurate patient care. produce the same types of tests faster and less expensively. However, laboratory test reimbursement that is administra- Bruce Quinn is US physician executive in the law firm Foley author tively locked to the marginal cost of hoag llp. a former medical school professor and strategy consultant with accenture, from 2004-2008 he was the regional the test’s chemistry is incompatible with medical director for the medicare program in california. significant clinical trials to develop and launch a novel type of test. In economic terms, this can be very inefficient, penny www.pharmafocusasia.com

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 U p to the last decade, the been performed with a focus on gene the most recently marketed cancer drugs pharmaceutical industry had selection. have found their niche with the aid of followed a trial-and-error During drug development, the biomarker-related molecular assays. For approach to medicine by applying a drug current focus is clearly on applying example, Roche’s Herceptin and GSK’s to an entire patient population when biomarker strategies to optimise clinical Tykerb both treat breast cancer patients treating a given disease. As a result, the study designs to facilitate a faster path whose tumours contain multiple copies overall drug efficacy in selected diseases to proof-of concept and a go / no go of a gene called HER2. In addition, was only around 50 per cent. Moreover, decision with respect to clinical outcome. Roche’s Tarceva, Imclone’s Erbitux adverse drug reactions were among the Eventually, this approach may even lead and Amgen’s Vectibix all target EGFR leading causes for hospitalisation and to companies conducting smaller clinical which is activated in various ways in mortality in the US. trials through patient stratification with many forms of cancer. Novartis’ Gleevec Given the associated cost burden with the potential to market a drug based was followed by newer ABL inhibitors this approach and the vastly improved on a respective diagnostic outcome to including BMS’ Sprycel and Novartis’ understanding about the important role guide treatment decisions. In addition, Tasigna which address patients with of biomarkers in the light of disease biol- using genetic biomarkers may help phar- BCR-ABL mutations resulting from ogy and drug interactions, a significant maceutical companies enhance product Gleevec treatment. All drugs mentioned change towards more targeted drugs was differentiation and potentially extend are supported by diagnostic assays that initiated by the pharmaceutical indus- product life cycles by targeting therapies have been specifically developed for the try since then. During drug research, earlier on in the treatment of disease, respective biomarker / drug. biomarker activities are aimed at validat- or even in disease prevention. In addition to oncology, strong ing drug targets or to further the under- To date, significant biomarker activi- efforts are on in other disease areas with standing of drug-related pathway biology ties are focussed on the field of oncology large patient populations with a high and the underlying disease mechanism. where more targeted drugs have demon- clinical need. Such disease areas include In this regard, a significant number of strated improved efficacy and, therefore, Central Nervous System, Inflammation whole genome association studies have often command a higher price. Some of and Metabolic Disorders. P hA r m A F o c u s A s i A issuE - 10 2009 34

Strategy Response rates for vilazodone and placebo in biomarker-positive and - negative subgroups 35 Vilazodone with out biomarker Placebo with biomarker Vilazodone with biomarker Placebo with out biomarker Mean MADAS +/-SEM 25 15 6.9 Biomarker patients had 2x response at week 8 30% of patients are biomarker positive 5 0 1 2 3 4 5 6 7 8 Figure 1 Week of treatment Clinical Data Inc. is a global biotech and the company anticipates filing a patient safety when using certain drugs, company with over a decade of experience new drug application (NDA) with the which in turn could reduce the health- in discovering and applying biomark- US FDA for vilazodone for the treat- care costs associated with the treatment ers to drug development. It is development of major depression by the end of adverse events. ing vilazodone, a targeted therapeutic of 2009. Pharmaceutical companies are also for the treatment of major depressive Biomarkers represent an attractive, beginning to advocate for label changes disorder. Vilazodone is a genetically- and arguably more efficient, approach as new biomarker information on their guided serotonergic antidepressant with to developing targeted therapies with drugs emerges. For example, Amgen a dual mechanism of action: a Selective improved efficacy and safety, as well reanalysed their clinical trial data for Serotonin Reuptake Inhibitor (SSRI) and as predictive diagnostics that can be their colon cancer drug Vectibix follow- a 5HT1A partial agonist. In late 2007, the used to guide treatment decisions. At ing concerns from the EMEA that the company announced positive results from the same time, biomarkers offer the drug did not provide enough benefit to its first Phase III registration trial which opportunity to reduce both the technical patients. The drug was finally approved compared vilazodone to placebo in 410 risks associated with drug development for patients only whose tumours did patients. This trial also helped to identify and the related R&D costs. Regulatory not have a mutation in a gene called proprietary candidate biomarkers for a authorities, such as the FDA, are clearly KRAS. And these are just some of the potential companion pharmacogenetic supportive of biomarker approaches recent examples which demonstrate the test for assessing a patient’s likelihood of as witnessed by the FDA’s guidance in power of biomarkers for improving the response to Vilazodone. As depicted in 2005 with respect to the submission of development and marketing of targeted Figure 1, a biomarker -positive treatment pharmacogenetic data as part of NDA therapeutics and diagnostics. This trend group showed a two-fold increase in terms filings. The FDA also recently drove is likely to continue and the ‘promise of efficacy after eight weeks compared label changes to marketed drugs such of personalised medicine’ may be fully to the biomarker -negative subgroup but as irinotecan and warfarin by incorpo- realised as biomarkers become a more also compared to placebo. Interestingly, rating biomarker-related information integral part of future drug development this biomarker subgroup represents about into the label in an effort to increase and commercialisation. 30 per cent of the total depression in patient population. michael Lutz came to clinical Data inc., a naSDaQ-listed Clinical Data has almost completed biotech company in august 2007 following the acquisition of its second Phase III registration trial, author Epidauros where he served as Chief Executive Officer since which is designed to confirm these find- april 2006. lutz became global general manager of cogenics, the service division of clinical Data, in november 2007 and ings from the first Phase III study and was also appointed as Senior vice president pharmacogenetic to validate the biomarkers that were Partnerships of PGxHealth,USA, the product division of Clinical identified. Results of the second study Data. are expected in the first half of 2009, www.pharmafocusasia.com

reSearch & Developement “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 M any of the blockbuster biological products that currently dominate the markets are coming to the end of their patent protection. The opportunity 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 “biosimilars” 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 opportunities 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; P hA r m A F o c u s A s i A issuE - 10 2009 3

reSearch & Developement Biosimilar medicines unDeRStAnDing the ChALLengeS but for the more complex proteins such Even as regulations begin to appear, production method creates differences in as monoclonals, the jury is still to come new questions are being raised: How the follow-on protein’s impurity profile, out. The problem is that like any jury, should follow-on products for mono- those differences have been demonstrated every member has their own view, and clonals and other complex proteins be not to impact safety or efficacy and the this does not bode well for establishing handled? How much clinical data should product has been accepted as biosimi- a global programme for the develop- be required to demonstrate equivalence? lar. Similarly differences in glycosylation ment of a biosimilar. The complexity How similar does a biosimilar product profile have been justified and accepted and uncertainty is exacerbated by the need to be? The challenge for both regula- by the EU regulators. fact that regulations for market approval tors and the biopharmaceutical industry If lower-cost therapeutic proteins are of biosimilars are still evolving around in this constantly changing environment to reach the market, more innovative the world and at different rates. The is to maintain a reasoned approach and and efficient production technologies, European Union (EU) has led the way resolve the issues in a way that keeps the including transgenic production, must in establishing regulations for follow-on science of biosimilars moving forward be introduced. Although these technolo- proteins and several biosimilar products for the benefit of patients around the gies may create differences in impurities have already been approved in the EU; world. or post-translational modifications, it these include somatropin, filgrastim should still be scientifically possible to and epoetin. Elsewhere, the regulatory demonstrate that the biosimilar product How “similar” is biosimilar? landscape varies dramatically. In parts of One of the most basic issues surround- provides equivalent safety and efficacy to Asia, such as India, although biosimilar ing follow-on proteins is determining the reference product. While, there is no products have been on the market for what types of proteins can be considered regulatory precedent for this approach many years regulatory thinking is still biosimilar. One viewpoint is that only today, this seems scientifically sound evolving. In the United States, Congress proteins that can be fully characterised, and hopefully common sense science has yet to establish regulations for follow- with no discernible differences in either will prevail. on proteins. Other major markets, such the structure or impurity profile, can On the other hand, if differences as Canada and Japan, have issued draft be considered biosimilar. However, this in primary structure or profound post- guidelines. In this maelstrom of views, narrow view is not shared within the EU, translational modifications are detected, industry has the opportunity to guide where guidelines and precedence allow a then, according to current views such rational thinking with cogent scientifically degree of difference—provided this can a product would need to be treated as robust arguments through comments to be justified. For example, one approved a novel compound. Yet, such a clear- guidelines, participating at international biosimilar product is expressed from yeast, cut position may not be necessary or meetings, regulatory scientific advice whereas its reference product is expressed scientifically justified. As experience with submissions and other such forums. from E coli. Although this variation in biosimilars grows, regulators may become www.pharmafocusasia.com

reSearch & Developement more comfortable in allowing greater at the physico-chemical and biological For now, fundamental challenges flexibility and may approve less similar level for virtually any highly purified confront the establishment of a global follow-on proteins based on an abridged protein. The next step in demonstrat- biosimilar programme. Foremost, there “Biosimilar” approach. This approach can ing biosimilarity requires leveraging is currently no way of confirming that even be taken where significant differ- current knowledge and filling the gaps the reference product sold in one region ences from the reference product exist, by conducting appropriate non-clinical is identical to that in another region although always equivalent safety and and clinical studies. even when they are sold under the efficacy will need to be proven. However, Even for small molecule generics, same brand name, which indeed is not we have not yet reached this point. bioequivalence in terms of absorption always the case. Until this problem is needs to be demonstrated in clinical resolved, a worldwide biosimilar devel- studies and so it is no surprise that this opment programme cannot be a reality. Can the biosimilar concept be applied to complex proteins? applies to biosimilars as well. However, Currently to achieve EU approval, the The biosimilars approved under the for biosimilars, the EU regulators require reference product must be sourced from current EU process represent just the more data to be convinced of similarity; within the EU. If similar demands are beginning of a global biosimilar revolu- for example, they will want evidence for set in other regions, then development tion. A host of other products, including equivalent efficacy and adequate safety, programmes will need to be replicated follow-on monoclonal antibodies, exist which will require clinical trials. The in each region, resulting in duplication or are in development and will probably requisite clinical programme will vary of effort and unsustainable costs. be submitted to regulatory agencies in and will require detailed thought and There is obviously an urgent need the years ahead. justification from the sponsor, who is well to establish some level of international The EU’s “Guideline on Similar advised to work with external expertise harmonisation to allow mutual recogni- Biological Medical Products” (CHMP and seek scientific advice from the regulation of reference products and data for / 437 / 04) states that, in principle, the tory agencies. In the EU it is incumbent approved biosimilars. biosimilar concept applies to any biologi- on the sponsor to submit a scientifically Yet another challenge is regulatory cal medicine. However, the guideline robust justification in support of their concern about the impact of ethnicity. notes that this will depend on a number programme and such submissions will In reality, this should not be an issue for of factors—including the ability to char- play a significant role in shaping future biosimilars where the reference prod- acterise the product. Clearly technology thinking. uct will have already been approved is moving forward apace and the power The size and complexity of the clinical and marketed in the target region, and to characterise complex proteins down to programme will depend on the level of there would seem to be no rational reason the last atom is now a reality whereas a understanding and interactions of the why a biosimilar product would display decade ago it was a dream. Methods such protein structure, the impurity profile, a different ethnicity profile; however regu- as MS-MS, 2D-NMR, and chemi-lumi- and other characteristics, as well as the lators may not always share this view. nescence are but a few of the powerful relative difficulty of demonstrating Even if the above barriers are crossed, tools available today that enable resolu- therapeutic equivalence. In some cases, regional differences in data requirements tion to atomic levels, generation of high a biosimilar development programme may still dictate the need to replicate fidelity information on protein folding may require the study of more patients certain aspects of a biosimilar devel- and detection of impurities even to pico- than were included in the innovator opment programme, tailored to the gram levels. Science allows full under- programme! requirements of specific regions. This standing as to how the protein binds to is another area where global harmoni- its ligand and the type of bonds involved. sation of biosimilar guidelines would Can biosimilar development be globalised? Biological testing using methods such as greatly benefit the development of global surface plasmon resonance, Fluorescence- Key to the success of a biosimilar biosimilar products. Activated Cell Sorting (FACS) and other programme is accessing markets through- cell-based assays can provide a thorough out the world, but regulations and experi- Can the obstacles be overcome? insight into biological effects compared ence around the globe differ dramatically. Despite the progress in the EU, much with the reference product. Thus, strong The adoption of a biosimilar approval uncertainty remains as to which prod- evidence of similar therapeutic effect can pathway in the US and other major ucts will qualify as biosimilars, and what be available well before the biosimilar markets will certainly ignite new thinking degree of similarity will be required for ever enters a patient. that will influence current strategies for follow-on and subsequent-entry proteins. These technologies should make it development of biosimilars and set new Furthermore, the level of supporting possible to demonstrate biosimilarity precedents for their approval. clinical data that will be required for P hA r m A F o c u s A s i A issuE - 10 2009 3

reSearch & Developement the more complex proteins has yet to reference biological entity. Extension of has issued guidelines which establish a be fully defined—which is not surpris- the biosimilar concept to “biosuperiors” base standard, the regulatory framework ing, given that it is a multidimensional does not align with current regulatory for the approval of biosimilars in major issue, influenced by the complexity of views but its future adoption could serve markets is very much still in flux and the protein, the potential for differences to nurture innovations such as novel and relies on the generic and biotechnology between the reference product and the more efficient manufacturing technologies industry to guide regulatory thinking biosimilar, and the challenges of demon- that will enable the generation of more towards a harmonised approach. strating therapeutic equivalence. affordable protein-based medicines. Biosimilarity is still in its early stage The uncertainty and variability of The ability of biosimilars to access of evolution and the industry and regu- the biosimilar environment increase global markets based on a single develop- lators together now need to drive the in proportion to the complexity of ment programme that meets the require- concept so that it becomes a powerful protein. The level of clinical and non- ment of all markets is clearly an important vehicle for delivering affordable and clinical data required to bridge the gap factor driving the success of biosimilars. better biological medicines to patients between the reference protein and the Although, World Health Organization throughout the world. follow-on protein needs to be based on risk analysis, with the amount of data Cecil nick, vice president – Biotechnology at pareXel consulting, being proportionate to the level of uncer- is a trained biochemist and has over twenty years of experience tainty and risk. In fact, the idea of a author in the development of biological medicinal products. he now risk-based approach could be applied provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological even to improved intentionally modified products. he has been involved in the development and regula- proteins or “biosuperiors” where recep- tory approval of a number of innovative and biosimilar medicinal tor interactions, pharmacokinetics, and products in europe. pharmacodynamics mirror those of the www.pharmafocusasia.com

reSearch & Developement Drug Discovery in Academia an evolving model as 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 O ver the past decade there has innovation and therapeutic development this information to develop new diagnos- been increasing pressure on gap through adoption of more conven- tic tests and treatments for these illnesses. the pharmaceutical industry tional drug discovery and development Consistent with this mission and key to to increase economic efficiencies in approaches. Incorporation of disciplines this emerging ‘academic drug discovery’ drug discovery. This has been driven by and infrastructures that were the domain model are industry veterans, who are several factors including the increased of industry is at the leading edge of this making a transition from industry back costs of R&D, lower productivity, new paradigm in academia. into this new academic environment. patent expiration, generic competition The Stanley Center for Psychiatric and the increasing difficulty in bringing Research within the Broad Institute of Integrated role of medicinal chemistry new chemical entities to market. MIT and Harvard is providing a forum The extraordinary investment require- to explore such a model. The Stanley The Stanley Center medicinal chem- ments have also led the industry to focus Center was founded to discover the istry group is a small focussed group on only those disease areas which have human genes that confer risk for bipolar of four computational and medicinal high commercial potential and are disorder and schizophrenia and to use chemists with both Big Pharma and deemed prosecutable. Many feel that this has led to a risk-averse behaviour Embedded biotech model which has hindered innovation in the field and created a focus on what are considered “druggable” targets. This 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 has created a narrow view of biological academia of front-loading the academic experience with more of an eye towards space and has left major “third world” drug discovery and development. The Broad Institute of MIT and Harvard and the diseases orphaned. Stanley Center for Psychiatric Research provides an ideal environment to explore and While there has always been synergy refine this new model of drug discovery in academia. The Stanley Center medicinal between industry and academia in drug chemistry group has adopted an “embedded” biotech model to leverage the strengths discovery, there is growing momen- and practices of both academia and industry in this new context of drug discovery. tum within the ranks of academic and http://www.broad.mh.edu/nodi/638 non-profit organisations to fill this P hA r m A F o c u s A s i A issuE - 10 2009 40

reSearch & Developement Integrated model of drug discovery utilising internal and external resources PK, ADME Tox (in vivo, Chemistry scale- study design) up, analoging Computational Efficacy, chemistry Behavioural models Design / Synthesis Structural Medicinal biology (X-ray) Analytical / QC chemistry Compound mgmt. Chemical PK, ADME screens (HTS) Tox (in vitro) Biological Assays in Formulation vitro, cellular Target indentification / Probe development Outsourced In-house / Outsourced Figure 1 biotech experience. The primary goal Academic collaborators constitute core of this group was to implement a fully biology and in vivo efficacy (behavioural functional medicinal chemistry group models). External vendors are used for mirrored on the capabilities of industry more traditional drug development disci- with limited permanent staff to allow for plines such as PK / ADME for both in fiscal and staffing flexibility as projects vitro and in vivo studies. evolved. Rather than following a fully The majority of our biological studies integrated model supported by full- including in vitro binding, enzyme and time staff, we adopted a hybrid virtual cellular assays are done in collaboration biotech model wherein we formed a core with academic groups at local institu- competency internally and outsourced tions (MIT, Harvard and Massachusetts the majority of analogue and bulk General Hospital). The majority of our chemical synthesis. target identification, high throughput The medicinal chemistry group screening and compound management functions to collaborate with multiple activities are conducted in collaboration academic groups at various stages of with established core facilities at the the discovery process, including high Broad Institute. The goal was to develop throughput screening, probe compound an infrastructure which would allow a development, lead optimisation, formu- group of two internal medicinal chem- lation, PK / ADME and in vivo efficacy ists and four to six external chemists to experiments. efficiently process 200 to 300 compounds Shown in Figure 1 is a ‘chemo- per year across multiple projects. By care- centric’ view of the various disciplines ful selection of CROs, we hoped that integrated within the Stanley Center. over time we would have a push back The medicinal chemistry group focuses of ideas from our contractors and active on hypothesis-driven compound design, participation in design and data evalua- synthesis, data analysis and the devel- tion. Ultimately, we hoped to establish opment of new approaches to drug our external contractors in chemistry as discovery. Resources are augmented an extension of our team and leverage through the use of several Contract their capabilities as deep into our process Research Organisations (CROs) for as possible making them indistinguish- analogue and bulk chemical synthesis. able from internal resources. www.pharmafocusasia.com 41

reSearch & Developement Stanley center's medicinal chemistry development cycle SAR (Compound database) Structural biology In silico / In vitro ADME multiparametric Medicinal chemistry group Multiple academic collaborators optimisation software homology models / Docking / Scoring Multiple CROs Data analysis, Model refinement, Design Lead In vitro assays, cell-based assays, Analogue, Scale-up Testing optimisation Synthesis In vivo efficacy, In vivo PK / ADME tool compounds cycle Multiple academic collaborators Multiple CROs Compound management analytical chemistry Quality control, Sample repository dissolution, Plating and distribution of compounds Figure 2 Courtesy: Mike Moyer Broad Institute A model that lacks a clear organi- Moreover, we found that small ineffi- Medicinal chemistry development cycle sational structure is highly reliant on ciencies in the process (communication, Our approach is similar to an industrial communication and collaboration across problem solving, and record keeping) template in the overall flow but differs groups. From a medicinal chemistry were amplified in our small group and in the organisational arrangements of viewpoint, a key goal was to establish a created large time drains internally. the different disciplines. Our design and highly efficient chemistry group by iden- To streamline the flow of information development cycle is shown in Figure tifying “best-in-class” contract research and to centralise the capture of chemi- 2 and mirrors the cycle found in an organisations, leveraging the capabilities cal information from all vendors, we industrial setting. of the Broad Institute and establishing adopted an electronic notebook (e-note- Key functions include: an efficient process to manage hundreds book) system established by the Chemical 1. Compound design and synthesis of compounds through the development Biology Platform at the Broad. Originally, 2. Compound management—notebooks, cycle. we transcribed varying report formats QA / QC, tracking of compounds, and data into the Stanley Center’s e- information capture from CROs, regis- notebooks. We quickly found that this Lessons learnt tration, plating and distribution of We began our chemistry programme by administrative task required a prohibitive compounds examining several different chemistry amount of time. Ultimately, synchro- 3. Compound testing (in vitro and in CROs. We chose to compare vendors by nisation with our vendor’s records by vivo) assigning similar chemistries to assess not providing remote login (to the Broad’s 4. Data analysis and storage only their core chemistry competency e-notebook system) allowed each vendor 5. Repeat. but also their communication skills, to download experimental details and While our cycle mirrors industry, the problem solving, creativity and infor- analytical data in real time. This provided various stages of the development cycle matics capabilities. Working on an FTE several advantages: are performed outside the traditional basis for a period of three months with 1. A permanent record of experiment organisational format. Unlike a typical two to four FTEs per site, we began a details with associated analytical data company, where project team members rolling evaluation across several compa- on an internal server specialising in various disciplines are nies. We conducted weekly or biweekly 2. A searchable chemistry database unified as part of a single organisa- teleconferences along with site visits to within the Stanley Center and Broad tion, in an academic setting disparate get hands-on experience with the chem- Institute disciplines from distinct organisations ists as well as evaluate their resources and 3. A source for real-time evaluation of (universities, principal investigators, etc.) capabilities. We found a wide variation ongoing chemistries are involved. from vendor to vendor across all areas. 4. A cornerstone for leveraging existing P hA r m A F o c u s A s i A issuE - 10 2009 42

reSearch & Developement capabilities of the Broad Institute How will we measure? (compound registration, analytical (QA / QC), compound management) • Success 5. An expansion of CROs’ capabilities • Shortening of the typical development time for new discoveries emerging from and responsibilities academia By integrating our compound flow • More refined chemical and/or biological leads from non-profit organisations into the existing informatics structure • The discovery of new biological targets with an approach toward a novel of the Broad Institute via e-notebook we therapeutic were able to adopt already established • The development of new chemical entities through phase I or phase II clinical protocols. Compound registration (Broad trials ID) assigns a unique alpha-numeric code Certainly, achievement of any one of these goals would be considered a for each compound which contains success and help to refine the approaches implemented in drug discovery. purity, batch and salt information. In addition, compound registration provides access to the Broad’s analytical capabilities. Once registered, integration of an the first steps of the drug discovery cycle specifically toward IND-enabling stud- open-source web-based image viewer has been established. We hope with time ies (NIH’s National Cooperative Drug (“aView”) allowed rapid annotation of to extend these efficiencies deeper into Discovery and Development Groups analytical results and streamlined the the drug discovery process and continue Program) and towards funding for process of compound purity assessment to refine this model. drug development activities (NIH- and re-analysis and / or re-synthesis. RAID, Rapid Access to Interventional Moreover, this allowed us to work with Development). Charitable organisations Future the Broad’s compound management With the implementation of an efficient and philanthropic foundations are also group to plate compounds efficiently chemistry infrastructure based on an having an enormous impact on fund- for in vitro and cell-based assays. industrial model we are poised to engage ing this research (The Broad Institute The E-notebook system facili- and refine more of the discovery cycle in and the Stanley Center are just two tated complete coordination among this new environment. What remains to examples). In addition, private our chemistry contract partners and be seen is whether this model is sustain- resources are funding the earliest stages chemists working internally, thereby able and how it will impact industry of discovery in psychiatric disease fully integrating them with our infor- and academia. through a special outreach initiative matics environment. Contract chemists Implementing a drug discovery (‘PsychHTS’) for primary high-through- synthesise, document and register each programme creates a large burden on put screens. Finally, academic centres compound remotely. Compounds are resources. Thus, sustaining drug discov- focussed on specific disease areas have received pre-registered in bar-coded vials ery and development in academia will had major upfront investments from and forwarded to compound manage- require both a shift in funding initiatives industry which should allow sufficient ment for dissolution, preparation of to foster this type of research as well as opportunity to test this new model (e.g. stock solutions, and plating for biologi- successful partnering between academic Vanderbilt and Johnson & Johnson). cal assays as well as LC / MS analysis. institutions and industry. The landscape The next 5 to 10 years will define how Review and annotation of analytical data does indeed appear to be shifting in this much this new model will impact our via aView prior to assaying provides a direction. Government funding agen- traditional models of drug discovery and filter to remove compounds from the cies have initiated programmes geared development. system that do not meet our purity requirements. What had taken hours (document, register, and collate data from various vendor sources) for each edward holson is medicinal chemist iii, Stanley center for compound has now been reduced to psychiatric research at the Broad institute of mit and harvard. author in february 2008, he joined the medicinal chemistry group at minutes by extending our process into the Stanley center to design and implement strategies towards the hands of our chemistry CROs. developing novel therapies in cnS related disorders including Through careful evaluation and utili- schizophrenia, bipolar and cognitive functional impairment. prior to joining the Broad institute he worked with merck & co. and sation of external CROs and by integrat- Infinity Pharmaceuticals in medicinal chemistry and pharmaceu- ing into existing infrastructures at the tical development across multiple therapeutic areas. Broad Institute, an efficient process for www.pharmafocusasia.com 4

reSearch & Developement preclinical research in Big Biotech Vertical integration is the key as 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 I n the biotechnology world, start- of the organisation change, Research was for Research to grow apace with all ing a new venture is fraught with a must change as well. It no longer needs other areas of the company. This often led mixture of excitement and anxiety. to prove the worth of an approach or to large and expensive research organisa- Using a new technology or drugs plat- platform, rather it must now provide a tions, which often experienced a paralys- form that has yet to prove itself in the sustainable flow of new drugs to meet ing disruption to research programmes clinic and the marketplace can be one of commercial expectations (e.g. in the US due to constant mergers and acquisitions. life’s greatest adventures for scientists and this means Wall Street). How the company The result today is that biotechnology entrepreneurs. approaches this challenge ultimately deter- companies are seen as far more nimble, As companies transition from that mines the success of the enterprise. original and creative than their much initial phase and with some success, move Without a flow of competitive new larger competitors. Knowing this, what on to a more mature organisation, the products, the company’s commercial value should a big biotechnology company need to carefully manage growth and diminishes and a likely merger or acqui- do? product commercialisation becomes the sition will be, most often, the only exit Big here refers to companies with paramount objective. strategy. Thus, building an organisation market capitalisations greater than The primacy of place for the preclini- that can be self-sustaining is of paramount US$ 10 billion and are fully integrated. cal organisation is supplanted by the importance and never more so than at Fully integrated implies a vertical inte- need for growth in other parts of the the level of preclinical discovery. gration that allows all the activities from organisation—clinical, regulatory, CMC drug discovery and development through (Chemistry, Manufacturing and Control) to registration to take place within the Achieving vertical integration and commercial groups. As the needs Over most of the last century, the response company. P hA r m A F o c u s A s i A issuE - 10 2009 44

reSearch & Developement Each of the big biotechnology companies has taken a slightly different Model of a big biotechnology company with vertical integration approach to this challenge and in some cases has eliminated preclinical discovery entirely. The remainder tend towards Informatics and information technology highly focussed preclinical research teams that take calculated risks, use academic centres (i.e. Universities and Research CROs CROs University Institutes) to bolster their understanding CROs R based of fundamental biological and disease core alliances comptencies processes as well as take advantage of the Virtual discovery 2 TA's VERTICAL INTEGRATION growing expertise of Contract Research platform CROs ~ 200 scientists Organisations (CROs) to help carry out research programmes. The half dozen or so of the large Company-based Translational Company-based biotechs which have large market capi- alliances medicine alliances 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. D A recent development has been the Organisation Figure 1 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 The maintenance of a culture of Optimising through vertical integration of potentially responsive patients, and originality and risk-taking at the level of providing early clinical feedback on the Thus, a fully vertically integrated big discovery research requires a continued effectiveness of drugs or biologics against biotechnology company has its preclini- commitment not only by the research their molecular target. cal discovery research take full advantage scientists but also by the management One approach to expand the reach of a variety of approaches and tools to team that supports it. It also requires of the preclinical research organisation is advance drug candidates. a vigilance on the part of supervisors to use outside CROs in such a way as to It is linked to its clinical development and managers at all levels to encour- constitute a virtual discovery platform that research group via its translational science age individual initiative within the takes advantage of their various scientific and medicine team. Integrating all of this framework of the goals and visions of platforms to perform much of the work requires the highest level of competence the company. At the end of the day, needed to advance a programme to lead in bioinformatics and information tech- proof of success is most easily meas- optimisation. Adjunctive to this approach nology (Figure 1). The IT group is the ured by the productivity of the research are alliances with universities and private glue that allows the best integration of organisation in terms of NCEs that research institutes that provide fundamen- information and the greatest capacity for move forward through the pipeline to tal information on potential new targets or data mining. ultimate approval. new research directions. Both approaches allow the internal organisation to focus its attention on the critical late stage of lead David R Webb joined celgene in 2003 as vice president of optimisation and drug candidate selec- research. Between 1987-2003 he held senior research positions in several biotechnology companies and in big pharma. he author tion without having to use its precious was a member of the Department of cell Biology at the roche resources on multiple early programmes. institute of molecular Biology from 1973 to 1987 and adjunct Rather, it can pick and choose among professor of human genetics at columbia university college of physicians and Surgeons. David Webb received his phD from these for the programme that is judged to rutgers university and was a Dernham Junior fellow in cancer have the best chance of success in moving research at ucSf. into clinical evaluation. www.pharmafocusasia.com 4

reSearch & Developement computerised cognitive function assessment coming of age the 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 Executive Rianne e Stacey, Report Writer Andrew C embleton, R&D Statistician Steve Satek, Vice President Cognitive Drug Research Ltd, UK C ognitive function testing was tion of movement. While there are many information with the outcome measure first introduced into drug other facets of cognitive function, these reflecting how successfully this informa- development to assess the are particularly important because they tion was memorised and subsequently unwanted side effects of many medi- can be influenced by a wide variety of retrieved. Equally, if the object of study cines to produce impairments to mental factors, including trauma, fatigue, stress, was to assess the ability to maintain functioning, and is still widely utilised nutrition, ageing, disease (both physical attention, the test would involve sustain- to establish whether newer medicines and mental), and, of course, medicines ing attention to a set of pre-defined are relatively free from such effects. and drugs. The efficiency with which stimuli and the outcome measures would However, the opportunities for medi- these processes operate has a direct reflect both the accuracy and speed of cines to improve cognitive function in influence on how effectively everyday the responses. Ultimately, the quality of the dementias and other disorders have activities are conducted; essentially, the the measurement of cognitive processes led to the widespread incorporation of quality of everyday behaviour is under- depends on how well the tasks have been such testing into efficacy trials, some- pinned by cognitive function. designed and implemented. times as the primary outcome. Our appreciation of the importance In the past, many aspects of cogni- Cognitive function refers to of cognitive function depends on the tive dysfunction have been difficult to mental processes which are crucial for appropriateness and also the quality of assess, not because they are subtle or the conduct of the activities of daily the measurements. The only direct way have little relevance to everyday behav- living. These processes include attention to assess aspects of cognitive function iour, but generally because they have not (concentration, vigilance), the ability is to require an individual to perform been subject to the diligent application to hold information temporarily ‘on mental tasks whose successful perform- of appropriate tests. Even when test- line’ (working memory), the ability to ance is dependent upon those aspects. ing has shown cognitive dysfunction store, retain and retrieve information Thus, if a researcher wished to assess to be present, its clinical relevance can over hours, days and years (episodic memory, the test would involve the be questioned; sometimes because the secondary memory) and the coordina- subject remembering some kind of tests have not been demonstrated to P hA r m A F o c u s A s i A issuE - 10 2009 4

reSearch & Developement have relevance to everyday activities, which a test is administered will have a Most of the advantages described or because the psychologists who have consequence on how it is performed. It above serve to reduce the variability developed them have failed to convince must also be acknowledged that differ- associated with test administration, physicians of either the importance of ent test administrators, no matter how which improves the precision of the the construct they are measuring, and / professional, will adopt varying manners assessment and thus the sensitivity of or the ability of the test to measure the of test administration. Automation can the test. The ability to measure, to the particular construct. Thus, while it has go a long way towards minimising the nearest millisecond, the time, as well long been demonstrated that Alzheimer’s influence of these factors; standardised as the accuracy, of each response, is patients perform poorly on tests of atten- instructions can be administered via the one of the most significant advances tion, the importance of attention defi- computer screen and the test stimuli to the sensitivity and quality of cogni- cits in the profile of dementia has only (pictures, words and other information) tive assessment which automation has become widely accepted in recent years. can be presented for precisely controlled brought to the field. This comprehensive Even when there is widespread agree- durations and at specific rates. Further, measurement confers huge advantages; ment, for example, that pronounced test administrators being human, make not only can trade-offs between speed and memory loss is a major characteristic mistakes and, in some procedures, there accuracy be identified (and thus changes of Alzheimer’s disease, and this memory are also judgements to be made. These in response style can be differentiated loss can be observed non-clinically and judgements, by their nature, can be from changes to mental ability), but without the need to quantify it; such subjective and will always be a poten- also improvements to both accuracy and observation is not sufficient if we are to tial source of variability. Such problems speed can be unequivocally interpreted chart the progression of the disease or can be largely overcome with the proper as reflecting enhanced performance. identify improvements which may be automation of tests. The security and integrity of cognitive conferred by medication, and data can also be guaranteed by thus precise tests of memory automated tests, responses being are essential. stored in encrypted files which can A further advantage is that automation only be accessed by authorised personnel. Automation – Rationale can enable tests to definitively and and benefits Some automated systems have objectively measure particular aspects There are a number of reasons been in use since the 1980s and of cognitive function that traditional for automating tests of cogni- the advantages have been repeat- procedures cannot unequivocally assess. tive function. One is to edly identified. In 1996, research- improve the overall quality of ers from the Canadian Institute testing by standardising and of Mental Health compared the facilitating test administration CDR System to a range of non- while also automatically collecting and Automation of testing can also automated tests including the Mini- processing the responses in an unbiased provide the opportunity to facilitate Mental State Examination (MMSE), manner. Another is to precisely capture the process of test administration in the Alzheimer’s Disease Assessment the speed of each response, something various ways. For example, automated Scale—cognitive subscale (ADAS-cog) which cannot be done with non-auto- test systems can cue both experimenter and the Wechsler Memory Scale. They mated tests and, therefore, limits the and subject for the various stages of found that the CDR System was not sensitivity of such pencil and paper tests and introduce the next test in only superior in detecting dementia methods. A further advantage is that sequence. When testing is repeated but was the only test that could reliably automation can enable tests to defini- on subsequent occasions, computer- differentiate patients with Alzheimer’s tively and objectively measure particular ised tests can automatically select the disease from those with Huntington’s aspects of cognitive function that tradi- appropriate parallel (or alternate) forms. dementia. tional procedures cannot unequivocally A further benefit in volunteer trials is assess. that groups can be tested simultaneously Translational Medicine – The value in phase I and II drug development The diverse range of cognitive tests using multiple computer set-ups, often available makes it hard to generalise administered by a single experimenter. Traditional drug development simply findings from one study to another, and Widely used systems like the Cognitive assessed the safety, tolerability of phar- most researchers would agree that the Drug Research (CDR) System have the macokinetics of novel compounds in standardisation of tests is desirable. It further benefit that non-specialists can phase I and sought evidence of efficacy is well established that the manner in administer the tests. in large phase II, or in some cases phase www.pharmafocusasia.com 4

reSearch & Developement III, trials. A widespread trend over recent in a number of conditions including demonstrate potential efficacy as soon years has been to seek evidence of the adult ADHD, Alzheimer’s disease and as possible in the development process desired effects of a compound as early of schizophrenia. Other work in phase I to enable them to establish licensing or possible in the development process using has established the absence of cogni- co-development programmes with larger procedures sometimes called biomark- tive impairment for compounds such as companies. With these considerations ers. This work is termed translational darifenacin, a selective M3 antagonist in mind, there is now little justifica- medicine and permits the early selection targeted to treat urge incontinent in the tion or excuse for not properly assessing of compounds that show more potential elderly without the cognitive impairment cognitive function throughout the drug for further development and reduces the known to result from traditional medi- development process. likelihood of wasted resources due to cations like oxybutynin. This absence candidate drugs failing later in the clini- of impairment was followed up in Alzheimer’s disease and other dementias cal development cycle. Cognitive testing larger phase I trails and has since been can serve drug development by either confirmed in clinical practice. The search for drugs to treat the cognitive identifying the ability of a compound Computerised testing has also been dysfunction associated with Alzheimer’s to enhance cognitive function, or by used in phase I models, for example the disease and other dementias is now well ensuring that a compound is relatively scopolamine model of dementia which into its third decade, yet progress has free of the unwanted side-effect of cogni- has identified a range of compounds that been slow. In part, this has been due to tive impairment. Although phase I stud- can potentially treat the symptoms of the unofficial acceptance of the ADAS- ies are by their nature busy, intensive Alzheimer’s disease, including Debio cog as the gold-standard for measuring and often invasive, cognitive cognition in pivotal Alzheimer’s function testing can be inte- trials, despite there being no grated into the study design, regulatory mandate for this. The The ability to measure, to the nearest provided the appropriate types limitations of the ADAS-cog are millisecond, the time, as well as the of cognitive tests are employed. numerous and have been described In most phase I Units, volun- widely elsewhere; many relating accuracy, of each response, is one of the teers are housed in wards and to the problems inherent in non- most significant advances to the sensitivity the majority of study procedures automated tests, but a particularly and quality of cognitive assessment which are performed there. Properly serious limitation is the failure automation has brought to the field. computerised tests are ideal, of the ADAS-cog to assess atten- as auditory instructions or tion, now established to be a core responses are not required and a cognitive deficit in Alzheimer’s single administrator can simul- disease. The highly controversial taneously test several volunteers, whereas 9902 a third - generation anti-Alzheimer’s decision by the UK’s National Institute many pencil and paper techniques by compound now in phase II trials. Sleep of Clinical Excellence (NICE) in 2005 to their interactive nature are inappropriate deprivation models in volunteers have recommend that currently available anti- and / or impractical. Brief but sensitive also been used to identify the wake dementia drugs (the anticholinesterases) tests are the ideal, measuring a range of promoting properties of compounds, not be given to patients with mild to cognitive domains within 15-20 minutes. for example armodafinil, which was moderate Alzheimer’s disease was based These tests can be repeated a number of subsequently approved by the FDA for on their judgement that the available times over the study day to assess any the treatment of narcolepsy and shift- evidence of efficacy was limited. As time profile of effects and can be done work sleep disorder. the ADAS-cog was the sole cognitive by the bedside if necessary. There are cognitive assessment systems outcome assessment in the regulatory Evidence of cognition enhancement that can be used in virtually any environ- trials of the anticholinesterases, the has been identified in routine phase I ment with any population. The benefits potential of the compounds to also safety and tolerability trials by simply of identifying wanted or unwanted effects improve attention went unaddressed. introducing appropriately sensitive as soon as possible in development are Had attention tests been included in computerised tests into the study proce- now widely recognised and accepted. such work and improvements been dure, without compromising the primary Many companies have many compounds identified, this extra evidence may have safety objectives of the trials or requiring to choose from and they can stop the helped address NICE’s reservations. More larger sample sizes. These findings have development of inferior compounds as recent work using computerised tests, subsequently been confirmed using the soon as possible. Smaller companies has shown that the attention benefits of same procedures in small phase II trials developing cognition enhancers need to anticholinesterases such as galantamine P hA r m A F o c u s A s i A issuE - 10 2009 4

reSearch & Developement in Alzheimer’s disease can be profound there is or never has been any rationale Other clinical conditions in which cognitive disorder is present in magnitude, representing up to 40 per for using the ADAS-cog and future trials cent reversals of these attentional deficits. can proceed with alternative methodolo- Coronary Artery Bypass Graft (CABG) The improvements to attention were also gies more suitable to the deficit profiles surgery has long been associated with favourably reflected in Clinicians’ Global in these dementias. residual cognitive dysfunction. Recently, Clinical Impressions, and had implica- a worldwide pivotal trial sponsored by tions for everyday behaviour and also Neuren used the CDR System as one Schizophrenia for carer burden. The growing recognition that cogni- of the two primary outcome variables The treatable cognitive deficits in tive dysfunction in schizophrenia plays to test Glypromate. The FDA approved other major forms of dementia are also a major role in the poor rehabilitation trial was terminated early due to the being profiled and recent consensus rates of otherwise successfully treated lower than expected variability in the criteria for Parkinson’s Disease Dementia psychotic patients into functional roles in cognitive data resulting from the use (PDD) and Dementia with Lewy Bodies society, has led to the development of the of computerised testing. The sponsors (DLB) have established that the profound MATRICS Consensus Cognitive Battery argued that the reduction in variability attention deficits identified in both (MCCB). The initiative identified seven meant that the study objectives could be dementias using the CDR System are target domains covering core aspects of adequately tested with 320 patients as central to the symptomatology of the cognitive function including attention, opposed to the originally planned 600. both diseases and of greater significance potential than the memory deficits. The The case for Internet-based cognitive testing – criteria recommend that automated The potential value for phase IV attention measures should be part of assessments of therapeutic outcomes in the disorders. The first randomised Cognitive testing can now be delivered via the Internet which will enable cognitive clinical trials in DLB and PDD have 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, identified that rivastigmine can produce patients either logging on at home to perform testing, or having testing conducted large and clinically meaningful revers- while making visits to the clinic. It will also enable medical practitioners to test patients als of attention deficits of up to 50 per prior to recommending medications, and then to conduct follow up testing at regular cent in DLB and 68 per cent in PDD. intervals. This will enable clinicians to determine for themselves whether cognition Furthermore, work in PDD has shown enhancers are having their desired positive cognitive effects, or conversely, that other that CDR attention tests predict the compounds are indeed free from unwanted cognitive effects. Evidence-based prescrib- capabilities of conducting the activities ing will thus be feasible in clinical settings, which would enhance the credibility of of daily living far more strongly than many potential treatments for cognitive disorders. does the ADAS-cog. The European Medicines Agency (EMEA) 2008 Guidelines speed of processing, working memory and Sadly, the initial reports are that the study for Development of Medicines for verbal and visual learning. Unfortunately compound did not provide a protective Alzheimer’s disease and Parkinson’s the developers included mainly traditional cognitive effect to the patents, but this Disease have stressed that attention pencil and paper neuropsychological tests trial does provide the rationale for other should be one of the domains assessed and not surprisingly, the first trial to trials to address this topic with mark- in the dementias, and has also provided a be published using the MCCB, identi- edly smaller sample sizes than would be green light for properly validated alterna- fied training effects on the various tasks required with traditional neuropsycho- tives to the ADAS-cog to be incorporated which obscured the potential treatment logical tests. into future trials. Therefore, automated effects the study was designed to iden- Cognitive dysfunction is widely tests such as the CDR System which tify. However, the positive contribution recognised to occur in a variety of clin- have satisfied the various validation the MATRICS initiative has brought ical conditions. A core benefit cogni- requirements stipulated by the guide- to the field is the establishment of the tive testing can bring to such work lines can now be introduced into pivotal core cognitive domains which should is to establish the benefits which can Alzheimer’s trials, if not immediately be targeted in schizophrenia research, accrue from therapies which alleviate to replace the ADAS-cog, but at least which has opened the door for properly the symptoms in the conditions and / to supplement it. In the case of other validated automated test systems such or enhance cognitive function. Benefits dementias such as PDD and DLB as well as the CDR System to be used in such with the CDR System have been iden- as Huntington’s and Vascular dementia, research. tified in depression with reboxetine; www.pharmafocusasia.com 4

reSearch & Developement cancer with fentanyl, epoetin alpha, and CNS, such as EEG, PET and proper automation of test procedures. modafinil; sleep apnea with armodafinil; fMRI. While these hugely sensitive Much of the benefits of automated narcolepsy with armodafinil; fibromyal- measures reveal vast amounts about testing in translational medicine and gia with galantamine; hypertension with CNS function and activity, it must be many other areas of drug development candesartan; epilepsy with remacemide; remembered that they are not in which have been discussed have been ispronicline in Age-Associated Memory themselves direct measures of based on the extensive experience gained Impairment; and ABT-089 and NS2359 cognitive function. Instead, they iden- with an automated cognitive test system in adult ADHD. tify patterns of activity, which may which has been used in clinical trials be the neural substrates for various worldwide since the 1980s. The ability aspects of function, and these meas- to definitively assess changes in cogni- The application to herbal medicines As herbal medicines become more widely ures are thus indirect assessments. tive function in clinical trials opens up available and get subjected to regulatory However, when such assessments possibilities in numerous areas, including scrutiny, the requirement to properly are directly integrated with tests of paediatric studies, studies of herbal medi- assess their purported benefits becomes cognitive function, these co-joint cines, imaging studies, as well as more overwhelming. Many have been tradi- evaluations of performance and CNS mainstream areas of drug development tionally believed to enhance cognitive activity become extremely powerful including dementia, schizophrenia and function and the CDR System was used instruments which are, for example, numerous other neurological, psychiat- in one of the first randomised trials of capable of functionally linking drug- ric or clinical conditions. Computerised ginkgo biloba in elderly patients with induced changes in cognitive function assessment of cognitive function has mild cognitive impairment. Over the last with activation of various brain areas, now come of age in drug development, 20 years, clinical trials using the CDR or in the case of SPECT, with receptor and the pharmaceutical industry has a System have been able to confirm many occupancy. range of systems and technologies avail- of these purported cognitive benefits in able to better characterise and develop the young and elderly for a variety of its products. It is time to act substances including gingko biloba, The importance of cognitive function panax ginseng, Sage, guarana, Bacopa assessments in contemporary drug full references are available at Monniera, Melissa and rosemary. Such development makes a strong case for the www.pharmafocusasia.com/magazine/ work has been used to support product claims, advertising and patents. Keith Wesnes is the owner and Chief Executive of Cognitive Paediatric clinical trials Drug research (cDr) ltd., which he founded in 1986. he trained at reading university, indiana university and guy’s hospital Children as young as six can be tested medical School, has published over 200 peer reviewed papers using the CDR System and a variety and holds professorships at northumbria university, newcastle, of trials have been conducted including UK and Swinburne University, Melbourne, Australia. the cognitive effects of breakfast cere- Rianne Stacey has been working for cDr for just over a year as als, classroom ventilation and mobile a member of the research and Development team. She has a phones, as well as clinical trials including strong academic background gaining a masters degree from the one assessing the effects of anti-epileptic university of cambridge in 2002 before embarking on a phD at the university of manchester, which she completed in 2007. medications in adolescents with epilepsy. authorS The worldwide moves to increase the regulatory requirement to establish safety Andrew embleton is a recent graduate of the university of data in children for medicines they are reading having studied applied Statistics before joining cDr’s research and Development team. as part of his BSc he worked likely to receive will provide the oppor- on a year’s placement in the pharmaceutical industry. he is also tunity to assess the cognitive risks or in his second year as a member of the royal Statistical Society. benefits children may experience from a range of novel and existing drugs. Steve Satek has spent nearly 20 years in the clinical research industry before joining cognitive Drug research as vice president Imaging trials of north american operations. Steve graduated from university Interest is growing in combining of Wisconsin-madison in 1988 with a double Bachelor’s Degree in Biochemistry and molecular Biology, before earning his cognitive testing with other tech- master’s Degree in Business administration from lake forest niques in phase I trials which measure graduate School of management in 1999. various aspects of activity in the P hA r m A F o c u s A s i A issuE - 10 2009 50

manufacturing 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 F reeze-drying is used by the phar- cules makes it very difficult to stabilise a freeze-drying cycle is designed to proc- maceutical industry for years. It’s a them. In this context, freeze-drying ess the formulation. Finally, the process way to protect sensitive molecules appears as a method of choice to stabilise is scaled-up for clinical production and from degradation, allowing their shelf the molecules. Consequently, there’s a is later transferred to industrial produc- life to be extended from days or months need to rationalise the way process devel- tion facilities. to years. Moreover, the technology is opment is done. In the past, freeze-drying process perfectly integrated inside industrial development consisted of finding a dedi- GMP (Good Manufacturing Practice) cated process for each product. As there The development process production giving a high degree of confi- The product development process consists were no technological tools to follow the dence in product sterility. However, the of different steps. First, cryoprotective process, the release criteria were mainly process has some drawbacks: it incurs molecules such as sugars, salts and poly- used. Generally, a satisfying cycle was huge costs and is very complex. Other mers are chosen to protect the targeted reached by the trial and error method. techniques exist to stabilise molecules, active ingredients at the liquid state With the advances in the scientific but they are not so well accepted in the before and during freeze-drying. Then, knowledge of new molecules, various pharmaceutical industry. Freeze-drying may be seen as the A freeze-drying cycle may be divided into three parts relationship between the following three parts: The product is first frozen at a low temperature to reach a vitreous state. The nature and • The freeze-dryer: a complex mechanical structure of the frozen plug allows a good protection Then, it undergoes sublimation high performance apparatus under vacuum maintaining the product temperature below its glass transition tempera- • The product: vaccines in our case, ture or collapse temperature. That specific temperature is determined by the stabilisers but it can be whole cells, yeast, chosen and is measured with specific tools such as the cryomicroscope. This value bacteria, protein or other molecules of is of paramount importance for the product elegance. If the product is sublimated at interest too high a temperature it ends up to be a melted product that will be rejected, creating burden (write-off) at industrial scale • The process: The freeze-drying cycle is the link between the freeze-dryer After primary drying, 10 to 20 per cent water is still inside the formulation adsorbed and the product. It allows to obtain a 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 quality product inside a specific equip- absorbed water. Removal of water is done by diffusion and not anymore by subli- ment. mation. Since diffusion kinetics is slower, it explains why secondary drying can take The advancements in science now one-third of process length to remove only 10 to 20 per cent of the total water. The allow us to produce more and more maximum temperature is defined in function of the product, but usually stays below complex molecules to target specific 40°C for biopharmaceutical molecules. diseases. The complexity of these mole- www.pharmafocusasia.com 1

manufacturing online and offline tools have been used to and time. The output parameters can knowledge of clinical and industrial improve the process to meet the require- be: residual moisture, potency, content, freeze-dryers. The engineering departments of the industry. drying kinetics. The goal is to obtain the ment should receive guidance before same range for output (i.e. good potency) buying new freeze-dryers. An exotic at all times by varying on a wide range industrial freeze-dryer may require Selection of stabilisers The following example illustrates how the input parameters (i.e. pressure 10 upgrade of some technical part, since stabilisers are selected from various and 100 microbars). If one can reach it will run out of the defined range. The options keeping in mind the business this target they end up with a robust transfer involves a multidisciplinary team interests. The first screening shows equiva- product where they are confident about in terms of department and competen- lence between two different stabilisers the scale-up. The freeze-drying cycle cies. Freeze-drying is not a stand-alone for biological activity. One of the two development directly integrates safety technology; the formulation, filling and stabilisers has a higher collapse tempera- margin to assure a smooth transfer to some specific tests are equally transferred. ture. If chosen, this stabiliser will allow larger scale. For regulatory purpose it’s For example, with each product a kit of developing a more robust and quick (as far easier when freeze-drying cycle is not known visual defects is provided to the the allowed temperature is higher, the modified between different clinical phases. manufacturing department. Summary product can be dried faster) freeze-drying Those studies are not performed on a of the process evaluation and proc- cycle. It is better to run a three freeze- trial and error basis anymore, but use the ess validation is set up for transfer. drying cycles a week than two freeze- power of DOE (Design of Experiment). Commercial consistency batches are drying cycles a week as it increases the This approach is perfectly suitable for produced in the targeted factory. capacity by 33 per cent. On the other freeze-drying since there are only a few Specific sampling procedure is devel- hand if the right stabiliser is chosen at the well-characterised input parameters for oped to assure homogeneity inside the beginning of the development it allows this closed system process. load for specific attributes of the new you to obtain the desired result. product. Like at clinical step, statistical The development of process is gener- analysis is realised on each batch and a Clinical development ally well defined and involves several steps. A further step is clinical development. All comparison between batches of different If the stabiliser is a well-known substance, the development trials are performed at freeze-dryers is done. After transfer a former development and some modelisa- small scale (below 5,000 units) to avoid support of the product is kept. It allows tion will help to quickly define the safety wastage of raw materials. Once clinical detecting any unexpected behaviour of margin of the process and necessary trials consistency is established, the trials are the product at industrial scale. These are planned accordingly. For branding performed at larger scale.. This is the first learnings act as feedback during the new kind of products, the available tools scale-up of the product towards larger development of other new products in will be reviewed and applied. scale. At least three batches are produced order to continually improve the scal- In this category some new equip- with the target value of the developed ing-up model. ment have appeared during the last cycle. They are deeply analysed for visual Freeze-drying process development is years. Previously, developers only had appearance, moisture content and mois- a robust, well-defined way to assure the two online tools to monitor the process, ture distribution. Statistical analysis is success of new products. Even if it can be an invasive temperature probe placed in done on the result to underline any seen as time-consuming, the knowledge a vial and the view port, through which deviation compared to early develop- of the product and process acquired in they could have a look at their product ment results. the first step of development will avoid a during drying. Now, micro balance can lot of costly burden at production scale follow the loss of weight of the product with better product understanding. Transferring for large-scale production during the whole cycle allowing easy optimisation. Cold plasma system can The last step is the transfer to produc- full references are available at measure the water vapour flux inside the tion unit. It requires people with a good www.pharmafocusasia.com/magazine/ freeze-drying chamber during development phase of the stabiliser. Another step of process develop- yves mayeresse is senior freeze-drying manager at author ment is to make the cycle robust with GlaxoSmithKline Biologicals. He has more than fifteen years of experience in the pharmaceutical sector and has managed Design Space study. The input and output activities such as parenterals production, set-up of new freeze- parameters of the process are reviewed. drying facilities, design of freeze-drying cycle and development Input parameters for freeze-drying are: of new stabilisers for freeze-dried products. shelf temperature, pressure in the system P hA r m A F o c u s A s i A issuE - 10 2009 52

manufacturing oee Systems and Software Enhancing operational efficiency making 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 P harmaceutical manufactur- in addressing the said challenges and and classifies them into three groups ers encounter unique demands aids in enhancement of overall opera- listed below: in their endeavour to manage tional efficiency. 1. Availability (A) – is a measure of improvement with operational excel- productivity losses from downtime lence. In the past it was easier for phar- 2. Performance (P) – is a measure of What is OEE? maceutical manufacturers to achieve OEE is a calculation that permits losses from slow cycles the desired margins. But in the current managers and operators measure process 3. Quality (Q) – is a measure of scenario of competition, price pressure, efficiency. Based on the outcome of the losses from manufactured products stringent FDA regulations and the calculation, organisations can under- / parts that do not meet quality ongoing economic crisis, pharmaceuti- stand the performance efficiency, iden- specification cal manufacturers world over are under tify areas of improvement and targets OEE = A × P × Q pressure with operational performance and align the identified targets with OEE filters production data into being a major concern. Pharmaceutical the overall business strategy. understandable metrics that provide a companies lose around US$ 15 billion OEE considers the common sources means for measuring true manufactur- every year due to disorganisation in the of manufacturing productivity losses ing efficiency. It also forms the basis manufacturing lines. Efficiency, availability and performance of the packag- Factors affecting production efficiency ing line affect the entire manufacturing Equipment Table 1 process and, therefore, the company’s Breakdown bottom line. Most of the manufac- 20% Parameters Percentage turers are striving for reduction in Yield Loss 02% downtime and manufacturing cost, Speed Loss 05% improved time-to-market and compli- 19% Preventive 12% ance to regulations. Setup and 42% Maintenance Making the best use of the equip- Change over OEE Setup and 19% ment and reducing costs are two of Change over the key challenges among many that Equipment 20% manufacturers in general and phar- Breakdown 12% maceutical companies in particular Preventive OEE 42% strive to overcome. Overall Equipment 2% Maintenance 5% Yield Speed Effectiveness (OEE) software is a boon Loss Loss Figure 1 Source: OEEsystems www.pharmafocusasia.com

manufacturing for tools that facilitate enhancement Production data in productivity. OEE score provides a complete measure of manufacturing Item Data effectiveness. Shift Length 8 hours = 480 min. 2 × 10 min. = 20 min. Tea Breaks Why OEE? 1 × 40 min. = 40 min. Lunch / Dinner Breaks Loss in yields, stoppages due to equip- Down Time 50 minutes ment breakdown, delays in setting up the production line and maintenance Ideal Run Rate 60 tablets per minute activity are key factors that affect the Total tablets 18,800 overall production efficiency. These Rejected tablets 400 factors reduce the production capac- Table 2 ity by 40 to 60 per cent. OEE Lack of understanding of the true Availability Operating Time / Planned Production Time performance of the manufacturing units by the Plant Managers, is the cause 370 minutes / 420 minutes for encountering challenges in improv- 0.8809 (88.09%) ing the overall operational efficiency. Performance (Total tablets / Operating Time) / Ideal Run Rate OEE measurement tools and techniques (18,800 tablets / 370 minutes) / 60 tablets per minute provide a much clearer understanding of 0.8468 (84.68%) where improvements can be made. Quality Good tablets / Total tablets How to calculate OEE? 18,400 / 18,800 tablets Table 2 contains shift data of formula- 0.9787 (97.87%) tion unit, to be used for a complete OEE Availability × Performance × Quality OEE calculation, starting with the calcula- 0.8809 × 0.8468 × 0.9787 tion of the OEE Factors of Availability, Performance, and Quality. 0.7300 (73.00%) Table 3 OEE – Systems and Software The following companies are some of the leading suppliers of and effectively. Vorne strives for excellence in all aspects of OEE systems for calculating, tracking and reporting of OEE. the company—people, products, and service. Vorne’s XL800 Production Monitor is a product for performance management, OEEsystems – Having its international headquarters at productivity improvement and lean manufacturing. XL800 is a Ireland, OEE Systems works with manufacturing companies “six-in-one” product that combines a large-area visual display, to improve competitiveness, increase capacity, reduce costs a high-performance production monitor, expandable I/O, a and deliver business performance excellence. In partnership multiple channel communication hub, a program executioner with global manufacturing customers OEE Systems has refined and a data warehouse—all in one package. PerformOEE™ to meet their specific business requirements. Gemba Solutions / OEE Impact – Specialists in delivering PerformOEE™ - Bulk Manufacturing – Although OEE has tangible results quickly. They help manufacturing units to slash traditionally been applied only to discrete manufacturing production costs, increase capacity eliminate waste, save processes, PerformOEE™ uses an adaptation of the traditional energy and optimise labour. OEE model to fully accommodate the requirements of bulk- manufacturing and process-based manufacturing businesses Idhammar Systems Ltd. – Idhammar is a leading provider and provide the process industry with a practical Manufacturing of total productive maintenance and manufacturing software. Intelligence and Performance Management software solution Idhammar has its Headquarters in the UK and has expert teams based on the OEE model. of OEE and maintenance specialists, software developers, customer support, and help desk staff who work together to Vorne Industries – Having its corporate office at Il, USA, develop, support and promote systems that are improving Vorne Industries develops tools that enable customers to industrial operations worldwide. improve their manufacturing productivity: quickly, efficiently P hA r m A F o c u s A s i A issuE - 10 2009 54

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manufacturing process. Efficiency, aids in generation OEE – A translatable business metric of extensive reports easily and enables production managers to perform additional long-term analysis on the trends CEO Improved Return on Total Capital (ROTC) that matter. Reduced capital needs Enhanced profit OEE for enhancement of operational excellence OEE data – Finance & Less capital investment Reduced cost Improved revenue Operations • provides one version of truth • is comprehensive • can impact wide range of issues from Fewer assets Predictability Less Waste More output shop floor to board room • aids in analysis of who, what, why, where and when Manufacturing & • ensures ROI. OEE Maintenance OEE is a metric that can be OEE enables to identify root causes for loss of efficiency and helps to make embraced at every level of the organi- the decisionsthat can improve the process and the bottom line of companies. sation. It is meaningful to the operator Courtesy: GE Fanuc on the shop floor, yet translates all Figure 2 the way up to the board room. If GE Fanuc’s Plant Applications companies can produce more with Variables Planned Production Time = [Shift Length Efficiency solution is a powerful soft- less equipment / machinery, it means - Breaks] = [480 - 60] = 420 minutes ware module that lets plant manag- growth and increased revenue with Operating Time = [Planned Production ers make sense of the plant data less capital investment. Higher Time - Down Time = [420 - 50] = 370 and evaluate efficiency in real time. efficiency drives down the cost. By minutes Part of the larger Proficy Plant reducing capital needs and increasing Good Tablets = [Total tablets - Rejected Applications Collaborative Production profit, a business will improve tablets] = [18,800 - 400] = 18,400 its Return on Total Capital, the World-class OEE tablets primary metric of the company / CEO performance. OEE Factor World Class (%) Acknowledgement: The author acknowl- World-class OEE Availability 90.0 The accepted average OEE score in manu- edges with gratitude the support extended facturing plants ranges from 45 to 60 by OEEsystems, GE Fanuc and Rockwell Performance 95.0 per cent. A world-class OEE score is Automation in providing facts & figures for Quality 99.9 greater than or equal to 85 per cent in the article. The author also acknowledges batch manufacturing and as high as 95% with thanks the details from the websites OEE 85.0 in continuous processes . The accepted of Systech International, Vorne Industries, Table 4 world-class goals for each factor are as Management suite, Efficiency is Gemba Solutions / OEE Impact and shown in Table 4. designed to calculate OEE quickly Idhammar Systems Ltd. and easily. Efficiency helps to track downtime, waste, production counts, OEE and automation companies full references are available at Rockwell Automation’s new line and user-defined events specific to the www.pharmafocusasia.com/magazine/ monitoring and OEE solution has helped a pharmaceutical manufacturer to capitalise on line information and improve pala Bushanam Janardhan is a Senior Business consultant (manufacturing & plant automation Services) in the life Sciences effectiveness throughout its packaging author and healthcare practice at hcl technologies ltd., since april process. Rockwell Automation was able 2006. prior to joining hcl, he has served the pharmaceutical to integrate raw data into a single infor- industry in various capacities—handled process technology development, technology transfers regulatory compliance, mation interface presenting OEE calcula- supply chain management, outsourcing and business develop- tions by output, throughput and by each ment for more than 18 years. machine across process and product. P hA r m A F o c u s A s i A issuE - 10 2009 5

clinical trialS clinical trials in oncology Some sense and simplicity With 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 T he burden of cancer as a global evaluation and has resulted in negative In the last decade, there has been a health problem is underscored guidance for several oncology agents, major shift towards the use of ration- by its increasing incidence. although “end-of-life” appraisal has begun ally-designed, tumour-targeted therapies. With better understanding of the to address this issue. Stricter definition Indeed, targeted drugs such as rituxi- biologic processes underlying the causes of innovation is required, which aims mab, trastuzumab, imatinib, erlotinib, and progression of cancer, great strides at the provision of clear patient benefit lapatinib, bevacizumab, and cetuximab have been taken in inducing incremen- and more individualised therapy. With have revolutionised the treatment of a tal improvements in survival. Indeed more than 500 anti-cancer compounds variety of cancers. With the increasing the face of oncology has changed in the in various phases of clinical develop- number of targeted agents in clinical last decade from a paradigm where a ment, there is lesser and lesser access to development, several unique issues are diagnosis of cancer and treatment deci- identified. The article sheds some light sions were based primarily on morphol- on these issues, addresses some lessons ogy and histology, to one where treat- from the past, and the implications for ment decisions are now tailored based late phase clinical trials. With more than 500 on molecular profiling of tumours. Although the advances made in anti-cancer compounds in However, these new avenues of molecu- cancer management are based on the various phases of clinical lar approaches come at a price: Cancer results of the hundreds of clinical trials development, there is has become a highly segmented disease that assess the benefit of the new thera- lesser and lesser access with over hundreds of biologically peutics on patient survival and quality distinctive diseases that require differen- of life, there is an increasing need to to patients for enrollment tial therapeutic approaches. In an envi- change the paradigm of demonstrating in clinical trials, which ronment, where pharmaceutical compa- anti-tumour activity of newly developed presses the need for nies are facing a difficult future with agents. There is a need to do more work “smarter” and “simpler” higher hurdles of regulatory approvals, upfront in order to conduct smaller, less clinical development sustained costs to research and develop- resource intensive mechanistic clinical ment, patient segmentation, restricted trials that provide a deeper understand- strategies. reimbursement, patent expiry, or ing of the biological consequences of the decreased growth revenues, oncology no targeted agent on signalling networks longer remained sacrosanct. involved in the regulation of tumour Increasingly restricted reimbursement patients for enrolment in clinical trials, cell growth and survival. Indeed, the can ultimately affect the patient outcome. which presses the need for ‘smarter’ and “bench-to-bed and back again” concept Recent examples are drawn from The ‘simpler’ clinical development strategies. has now become the new model for devel- National Institute for Clinical Excellence The question posed here is: What would oping new anti-cancer agents (Figure (NICE) in United Kingdom, which has make sense to achieve personalised medi- 1). In this model, arsenals of drugs are a stringent approach to cost-effectiveness cine for cancer? being developed that are based on our www.pharmafocusasia.com

clinical trialS Discovery Development Marketing Gene to Target Target to Lead Safety FTIM to PoC Life cycle function Phase III File launch selection lead optimisation developability PoC phase II mgmt. to target File approval Gen Target Lead Candidate FTIH Pivotal Life cycle and launch “Bench / Bed / Bench” loop 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 understanding of the transcriptomic, utilising PET, or DCE-MRI, and / or cal setting is hampered by methodology proteomic, and the genetic and epige- proteomics and transcriptomics of serum issues, by the lack of consistent results in netic changes that occur in cancer cells. samples. There is a plethora of such stud- multiple testing for the same and across More emphasis has therefore been laid ies in the literature. Conceptually, such tumour types, and by trial design issues. on the use of the diagnostic, prognostic an exploratory approach is very useful, as For instance, various studies demon- and predictive biomarkers in all phases it provides a direct in vivo assessment of strated conflicting results on the value of drug development. Easy as it sounds, the biological activity of a new chemical of decreased proliferation as detected the reality is that there are few markers entity; understand the potential mecha- by changes in Ki-67, in predicting for of response that are validated and are nism of action in inhibiting the intended response of breast tumours to aromatase acceptable to regulators. target; and correlating the biological and inhibitors, tamoxifen, or chemotherapy. Despite the shortcomings of pharma- clinical activities. To put this all in context, it is impor- codynamic biomarkers, its appli- tant to remember that the role cability in clinical trial setting has of biomarkers remain largely demonstrated tangible benefits. exploratory. Despite the shortcomings of One of the successful strategies To limit the diluting effects pharmacodynamic biomarkers, its in rationally designed clinical of methodology deficiencies in applicability in clinical trial setting has trials is testing of new agents in measuring these biomarkers, the ‘window of opportunity’ phase following is recommended for demonstrated tangible benefits. II setting. Typically, these stud- consideration in trial designs. ies are designed as single arm First, careful selection of homo- small studies (approximately geneous patient population will 50 patients), where the study drug is Identification of putative predictive limit the variability in detecting or meas- administered for a short duration, usually markers of response could be utilised as uring a biological effect. With short- between 2-3 weeks, in the neo-adjuvant surrogate endpoints for clinical activity in term administration of a tested drug up setting. The main premise of these trials subsequent confirmatory studies for vali- to three weeks, it is possible to design is based on measuring pharmacodynamic dation. Moreover, with carefully designed studies in earlier disease settings, which effect(s) of the tested drug in paired pre- trials, this approach could provide an are considered ethical and would not and post-treatment tumour biopsies, e.g. understanding of the patient population have an adverse effect on the delivery of changes in receptor expression and / or who would potentially benefit from a standard treatment in most tumour types, the activation state, downstream signal- given treatment and therefore insight into such as breast, colorectal, or head and ling pathways, anti-tumour proliferative the patient selection in further phase II neck cancers. The timing of the biopsies, activity as detected by Ki-67, and / or and phase III trials. the standardisation of the assays, and ability to increase the rate of apopto- Despite their increasingly widespread the scoring systems should be carefully sis. Further information is obtained by use, the utility of biomarkers in clini- considered in order to maximise the P hA r m A F o c u s A s i A issuE - 10 2009 5

clinical trialS ability to detect a pharmacodynamic clinical trials. For phase II screening effect. More importantly, these studies studies to have a useful role in oncology should be designed as randomised trials. drug development, it is important that The control arm could be a standard homogeneous-enriched patient popula- treatment, or placebo, or even a differ- tion are selected; that randomised design ent dosing schedule of the tested drug. be considered, even if not statistically Multiple dynamic biomarkers should be powered. Alternatively, the use of inno- examined to provide a more global under- vative trial designs, such as adaptive or standing of the drug’s biological effects. sequential designs, have gained traction as With adequately powered clinical trials, it strategies in the development of oncology is possible to gain information that would drugs, particularly as these designs have dramatically help tailor and accelerate become increasingly accepted by regula- drug development strategies. tory authorities as the basis for examining Some success stories can be drawn the efficacy of a tested drug in phase from the lapatinib development in III setting. With such designs, smaller advanced stage breast cancer. Lapatinib patient sample size is generally required, is a dual tyrosine kinase inhibitor of and the studies can be stopped earlier in both EGFR and HER2 receptors. In a the absence of patient benefit. recent study in refractory inflammatory In conclusion, there has been a major breast cancer (IBC), the co-expression of leap in oncology drug development, the activated, phosphorylated forms of with multiple success stories of drugs HER-2 and HER-3 seemed to predict that truly and effectively improved the for a favourable response to lapatinib. patient outcomes and quality of life. More recently, short-term administra- Some of major lessons from these new tion of lapatinib up to six weeks was targeted agents are the importance of assessed in patients with locally advanced target selection; and the changing goals Squamous Cell Carcinoma of the Head of phase I and phase II trials, including and Neck (SCCHN). Compared to not only traditional endpoints such as placebo, there was a significant reduc- pharmcokinetics, assessment of toxicity, tion in proliferation, but no difference clinical efficacy, but also insight into in inducing apoptosis. mechanisms of anti-tumour activity, Well-conducted clinical trials are identification of surrogates of activity essential for successful oncology drug and panels of biomarkers that predict development, and consequent improve- for response. These tools will hopefully ment in patient outcomes. Although facilitate the drug development proc- single arm small phase II studies have ess through rational rather than empiric been extensively utilised for an early drug development strategies, clinical trial read out of activity of new cytotoxic or design, patient selection, and approach cytostatic agents alike, it is argued that to combining therapies to overcome or their true value in advancing medical prevent the development of therapeutic research may be limited, in light of false resistance. positive results that are often obtained, and the lack of efficacy when the drug full references are available at is tested in confirmatory randomised www.pharmafocusasia.com/magazine/ iman el-hariry is a clinical oncolgist, who did her training in author 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 www.pharmafocusasia.com

clinical trialS Accelerating Central nervous System trials neurophysiological approaches 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 P hA r m A F o c u s A s i A issuE - 10 2009 0

clinical trialS T he incidence of Central Nervous action may be impacted by dose rang- in the brain, but their power as tools for System (CNS) illness is on the ing. These techniques are the routine translating preclinical findings into Phase upswing and exacts a heavy Electroencephalogram (EEG), the I trials is just beginning to be applied. human and economic toll. According Quantitative Electroencephalogram Depending upon the therapeutic area— to the World Health Organization, (QEEG) and Evoked Potential (EP). They Alzheimer’s disease, Schizophrenia, pain, more than 120 million people world- can be used as tools for translating preclin- Major Depression, Parkinson’s disease, wide suffer from depression, and the ical findings into first-in-human studies. or sleep disorders—all or some of the number is expected to rise. The occur- They may also play a role in later phase three techniques might prove useful in rence of Alzheimer’s disease is slated studies when compounds shift from being characterising compounds starting into to grow by more than 100 per cent in studied in healthy volunteers to CNS Phase I clinical trials. developed countries by 2040 and by patients. Additional translational tech- Routine EEGs, for example, can be 300 per cent in China, India, South Asia niques employed in Phase I programmes used for monitoring CNS toxicity and and Western Pacific countries over the include cerebral spinal fluid sampling, for detecting increased seizure likelihood. same time period. In the United States, brain imaging methodologies, and cogni- They provide a continuous measure of the National Mental Health Association tive and behavioural assessments. These cortical function with excellent time reso- estimates the annual cost of direct treat- are beyond the scope of this paper. lution, measurable in milliseconds. Unlike ment of mental illnesses, the social costs relatively new functional imaging proce- of leaving it untreated and lost produc- dures, such as Single-Photon Emission tivity at US$ 205 billion. Computed Tomography (SPECT), It is worth noting that With these statistics as a backdrop, it Positron Emission Tomography (PET), hundreds of CNS therapies is worth noting that hundreds of CNS and functional MRI (fMRI), EEG has the are in development, more therapies are in development, more than advantage of being well tolerated, easy to than 300 in the United 300 in the United States alone, yet they administer, and relatively inexpensive. States alone, yet they lag lag behind in the development of therapies Quantitative EEGs are more sophis- for non-CNS disorders in terms of the ticated as they can monitor the time behind in the development time needed to bring them to market. course of CNS effects of compounds, of therapies for non-CNS Data suggest that it takes 12.6 years on detail typical profiles of drugs in proof disorders in terms of the average for CNS agents to obtain regula- of concept studies and monitor vigilance time needed to bring them tory approval, twice as long as cardiovas- effects, which refers to the brain’s state of to market. cular agents. In addition, a mere 7 per receptivity to external stimuli associated cent of investigational CNS drugs that with alertness. Both types of EEGs can be start in clinical development are eventu- used in conjunction with fMRI, which, ally marketed as compared to 15 per cent while slower to react, in the range of The techniques for non-CNS candidates. The EEG, QEEG and EP are non-invasive seconds, offers better spatial resolution The reasons are many as to why techniques with results recorded from and could corroborate EEG findings. CNS drugs are more difficult to develop electrodes attached to the surface of the Together, they can offer a higher degree successfully, namely the sheer complexity scalp according to an internationally of confidence that there is a useful signal of the brain; the presence of CNS-medi- standardised arrangement, the so called to go forward. ated side effects such as nausea, dizziness 10-20 system (Figure 1). The promise for Evoked potential refers to an electrical and seizures; the need for agents to pass these methods is to be able to predict, potential recorded from a subject follow- the blood-brain barrier; and the lack of early on in the clinical development of ing presentation of an acoustic or visual validated biomarkers. Yet, with the imple- novel therapies that an antidepressant stimulus, and can be a surrogate biomar- mentation of targeted strategies, it may or analgesic will be safe and efficacious ker for cognitive information processing be possible to identify more quickly and at various doses as compared to placebo. and for neurotransmitter systems such as with greater accuracy those therapeutics Moreover, the EEG or EP signature serotonin. The ability to monitor sero- agents with the most promise, leading to observed, including dose versus response toninergic function is valuable because better GO / NO-GO decisions. relationships observed, in animals can be of its putative role in the pathophysiol- This article focusses on selected tech- translated and validated against healthy ogy and in therapeutic interventions for niques that can be used early on, follow- human volunteers and in subjects with CNS disorders. An EP method known ing preclinical work, to launch Phase I CNS disorders. as the Loudness Dependence Auditory studies that determine if compounds The EEG, QEEG and EP are well- Evoked Potential (LDAEP) can serve as are entering the brain, and how this established measures of electrical patterns an indicator of central serotonin function www.pharmafocusasia.com 61

clinical trialS in animals and humans and may show on the neurophysiological differences of two investigational antipsychotic promise as a predictor of selective sero- between patients and healthy volun- compounds, known as S18327 and tonin reuptake inhibitor antidepressant teers. MMN response is a tool that can S16924. Clozapine, also an anti-psychotic, treatment response. With the LDAEP be used to explore the potential differ- served as an active control. Qualitative method, various techniques, such as ences in treatment effect between patient EEG changes in this animal model were dipole source analysis and scalp topog- populations and volunteers. If there is similar for clozapine, but different for the raphy analysis, may detect the effect of a normalisation response among the investigational compounds potentially enhanced serotonin availability. schizophrenic patients, this would be indicating a different multi-receptor One component of EP, known indicative of drug action, i.e. normalis- activity and a clinical relevance since as Mismatch Negativity (MMN) is ing the observed mismatch negativity. EEG changes had been strongly related particularly useful as a biomarker for This electrophysiological endpoint might to positive clinical outcome in schizo- schizophrenia. MMN is a response that serve as a surrogate marker, convergent phrenic patients. a subject has a variation within a sequence with the cognitive and information defi- This was a small study, using only of regular stimuli and is a reflection of cit symptoms observed in the disorder. eight animals. According to the author, sensory memory. For example, if there is Even if surrogate marker validation is however, a limited number of samples repetitive auditory stimulation, such as “b- preliminary, the observed effect demon- can be used when applying the QEEG b-b-b-b”, interspersed with an occasional strates that the compound is crossing technique to characterise the PK / PD “r”, the subject elicits an MMN response. the blood-brain barrier and is showing profiles of early compounds. Furthermore, the MMN response evidence of efficacy. Importantly, this work highlights the grows in correlation with the number value of using the QEEG approach in of repetitions of the standard stimula- preclinical and early phase investigation Using the techniques tion. Subjects with chronic schizophre- A number of studies have been conducted as it provides proof that a compound nia, however, tend to generate impaired that demonstrate the value of using the passes the blood-brain barrier; it allows MMN, indicating that they recognise described methods to translate preclinical translational approaches by comparing the change within the sequence in a less findings into Phase I trials. This section animal model results with human results; robust manner than healthy volunteers is not intended as a review of all of the and provides data in the form of EEG and the impaired response may grow as studies in this area, but rather, it is meant profiles, comparing an existing compound the disease progresses. to highlight a few examples of how the to investigational ones. These are useful Although, schizophrenia therapies electrophysiological techniques have been tools that help pharmaceutical sponsors in development can be tested in healthy applied. make better GO / NO-GO decisions for volunteers, frequently the sensitivity to Parker et al. (2001) report using the CNS drug candidates. detect a relevant therapeutic surrogate for quantitative EEG approach in an animal Baldeweg et al. (2006) used evoked the drug effect expected in the disorder study to define the pharmacokinetic / potential, specifically impaired mismatch can be either enhanced or reduced based pharmacodynamic (PK / PD) profile negativity, as a biomarker of Schizophrenia ELECTRODE PLACEMENT Figure 1 Source: Handbook from Charite EEG Lab P hA r m A F o c u s A s i A issuE - 10 2009 2

clinical trialS in a study of the effects of acute admin- and midrange dosage groups did not EEG CHANGES IN istration of nicotine on auditory sensory show any changes known as epileptiform PHASE I STUDy memory. The study was conducted in 20 discharges, suggesting that they are safer healthy smokers who were randomised to with respect to seizure likelihood. either nicotine gum or placebo. Evoked In a follow-up study in healthy male potential responses to deviations in tones volunteers, a first tonic-clonic seizure (deviants) were recorded using constantly appeared as a serious adverse effect. The changing standard stimuli in order to observed EEG data led to an adjustment measure the effect of stimulus repetitions in dosage in consecutive Phase II studies on the encoding of new stimuli. Results and to the implementation of routine showed that there was a marked effect of EEG monitoring in a central EEG read- stimulus repetition on the standard EP. ing unit. Acute nicotine administration increased One of the first larger studies to use MMN amplitude significantly in the treat- QEEG as a predictive tool is known as ment group as compared to the baseline Biomarkers for Rapid Identification recording, whereas no changes in MMN of Treatment Effectiveness in Major Source: PAREXEL 2008 Figure 2 were seen in the placebo group. Depression (BRITE-MD). It is being Although schizophrenics were not memory formation and information conducted in 10 locations throughout included in this small study, the results processing, and to excitatory CNS effects, the United States (Chart 1) and sought support validating this approach as a up to and including seizures. The thera- to recruit 375 subjects with a diagnosis possible surrogate marker for the treat- peutic indication studied was a degen- of major depressive disorder. The goal is ment of cognitive deficits in Schizophrenia erative disorder (Alzheimer’s disease), to evaluate the potential of early EEGs and with the observed functional impair- although this neurotransmitter system as a predictor of an individual’s response ment observed in patients. MMN might is also implicated in Schizophrenia, Major to treatment with specific antidepressant therefore be possible. Schizophrenia Depression and other CNS disorders. medications. Enrollment was completed in biomarkers with benchmarking of ‘novel The study enrolled 12 healthy male March 2007, with 220 subjects analysed therapies’ assessed not only against placebo volunteers, who were randomised to a for 7-week endpoints. but against nicotine mediated improve- low, mid, or high dose of the drug. The The BRITE-MD trial tests two anti- ment in the patients’ MMN impairment EEG changes shown in Figure 2 reflect depressants—escitalopram (Selective (enhancing stimulus encoding and sensory the high dose arm two hours after drug Serotonin Reuptake Inhibitor (SSRI)) memory). intake in 50 per cent of the subjects. and bupropion XL—studying them as The changes show electrical discharges single-drug therapy and in combination. with high amplitudes indicating an It also introduces a dose escalation phase. Moving beyond small, single-site studies increased likelihood of seizure. The low The intent of the study is prospective For the most part, the EEG, QEEG and EP methodologies are used in Sites participating in BRITE-MD Study small preclinical and Phase I studies in the hope of gathering and compar- • Baylor College of Medicine, Houston, Texas ing data in animals, healthy volunteers and CNS patients to identify promising • Cedars-Sinai Medical Center, Los Angeles, California drug candidates. As those therapies move • Massachusetts General Hospital, Boston, Massachusetts forward, the tools have application for • Northwestern University, Chicago, Illinois Phase II studies and eventually into multi- centre studies. This section discusses two • R/D Clinical Research, Lake Jackson, Texas clinical trials in which neurophysiological • University of California, Los Angeles, Harbor approaches were incorporated into later phase testing. • University of California (Neuropsychiatric Institute & Hospital), Los Angeles, Westwood In one study, routine EEGs were • University of California, San Diego performed as part of a multiple dose Phase • University of Pittsburgh, Pittsburgh, Pennsylvania I trial of a compound with a glutamatergic mode of action, meaning that it impacts • University of Texas Southwestern, Dallas, Texas the neurotransmitter system linked to Source: Clinicaltrials.gov www.pharmafocusasia.com 6

clinical trialS validation of an Antidepressant Treatment promising approach for speeding the surrogate endpoints, their use could Response (ATR) indicator as a biomar- clinical development process is to use reduce years from the overall clinical ker of clinical response to an SSRI, and established neurophysiological tools, such development path. By increasing detec- to determine the best treatment option as the routine EEG, quantitative EEG tion sensitivity and reliability, samples for patients who are predicted to be and EP, in a search for biomarkers that sizes required to demonstrate efficacy non-responders to an SSRI. The study allow researchers to integrate preclinical would be substantially reduced. CNS is designed to use EEG, starting on Day results in the design of Phase I stud- drugs typically require large multi-centre 0, to determine the association between ies. How do results of first-in-human global trials to achieve adequate response drug treatment outcome and brain func- studies compare to what was seen in data against placebo, and take years to tion in patients with Major Depressive animal studies? Using these methods conduct. Clinical trials would benefit Disorder. Electrodes are placed on a allows researchers to characterise the from the incorporation of potential bio / patient’s forehead and earlobes to measure PK / PD profile of compounds early surrogate markers as a corroborative signal brain responses that appear within seven on and to compare results to preclinical converging on the currently employed days, and sometimes as early as 48 hours, data in an effort to determine whether a clinical endpoints, especially when the after beginning antidepressant treatment. compound crosses the blood-brain barrier diminished placebo versus the drug effect On Day 7, there is an ATR assessment, or produces CNS-mediated side effects in size difference is small. clinician prediction of response, and humans. Frequently, there is a platform of A variety of neurophysiologic tech- randomisation. compounds with similar properties under niques are being employed to study Interim results indicated that the ATR development—differentiating these, one compounds early on in clinical devel- index reached statistical significance in from the other, and selecting the best opment, in the target diagnostic CNS predicting seven-week clinical response drug for development is critical. These patient population. By bridging animal as measured by the standard Hamilton electrophysiological techniques, along findings to humans, and then from volun- Depression Rating Scale after just one with imaging and cerebral spinal fluid teers to patients, these techniques contrib- week on treatment with an SSRI. Results sampling can provide invaluable informa- ute to our ability to translate preclinical presented in December 2007 showed tion and accelerate drug development. disease and toxicity models to patients, ATR-predicted responders to escitalopram With EEG, QEEG and EP, small and inform drug developers of possibly are significantly more likely (67 per cent) studies can be conducted in which healthy effective doses. Currently, these meth- to respond to seven weeks of escitalopram volunteers are exposed to varying doses ods are being validated in small Phase treatment than are ATR-predicted non- of a compound. This approach can bring I trials, but they hold promise for use responders (28 per cent). Findings also into Phase I the kinds of dose-ranging in later stage studies. The infrastructure showed that ATR-predicted responders studies that traditionally occur in Phase to conduct QEEG or EP in large-scale are significantly more likely (50 per cent II. Pushing early dose-ranging into Phase clinical trials is becoming a possibility, vs. 21 per cent) to achieve remission with I and matching results to preclinical work as equipment becomes more portable seven weeks of escitalopram treatment, holds promise for improving the GO and affordable, and central reading of and ATR predicted non-responders to / NO-GO decision-making process. In data is readily achieved by electronic data escitalopram are significantly more likely addition, these tools enable the use of transmission. to respond if switched to bupropion XL surrogate biomarkers, such as whether full references are available at at one week (53 per cent) versus staying an EEG indicates central action. Later www.pharmafocusasia.com/magazine/ on escitalopram for seven weeks (28 per on, if the biomarkers become validated cent). These findings suggest that early EEG testing can detect an early brain signal of response, which can help clini- Larry ereshefsky is Chief Scientific Officer, Vice President, and principal pharmacologist in early Development at pareXel cians determine treatment response much international. he serves as clinical professor of psychiatric at the faster and effectively than a trial and error University of Texas Health Science Center in San Antonio, Texas authorS approach that can take weeks. in the united States. Going forward malek Bajbouj is a principal consultant in early Development Reducing the timelines and cost of inves- at PAREXEL International and has in-depth expertise in the tigational therapies are keys to expand- central nervous System (cnS) therapeutic area. he serves as professor for psychiatry and affective neuroscience at the ing the number of treatment options for charité university hospital and the freie universitaet in Berlin, the growing number of people suffering germany. from a range of CNS disorders. One P hA r m A F o c u s A s i A issuE - 10 2009 4

clinical trialS optimiSing the Site Selection process assessment of investigator motivation Identifying 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 A ccording to some estimates, up • Identifying the less obvious but crucial the following characteristics: to 30 per cent of Investigators characteristics of successful sites • Located in countries / cities with an participating in a trial may • The importance of investigator older population recruit no patients. When considering motivation. • Practicing in a large or general this statistic, it is important to remember hospital that every site—also those that have not • Located in more densely populated The golden site profile recruited to target—has been through Looking to the investigators, prior expe- cities / countries a process of selection. Whilst this proc- rience and personal relationships often • Specialising in neurology with an ess may determine whether a site can form the basis for selection. Given the emphasis on geriatrics. provide suitable staff and facilities in increasing volume of competing trials, Whilst perhaps not surprising, these accordance with regulatory guidelines, experienced investigators are in great findings allow the conclusion that the it is evident that the site selection proc- demand. However, they may not offer the successful recruitment of patients in such ess is not foolproof in assessing whether certainty of delivery they once did. Data studies is linked to the ability to identify or not a site will in fact recruit patients also suggests that the number of investi- investigators who fulfill this specific set as anticipated, or at all. gators active for only one year in clinical of criteria. This article evaluates a number of trials is increasing. Taken together, the pragmatic approaches to more effectively necessity to work with new investigators Assessing investigator motivation identify suitable sites by proactively weed- becomes apparent. In such circumstances, There is, of course, only so much that ing out the types of surprises that—with it is important to extrapolate from previ- can be predicted from an investigator the 20 / 20 vision of hindsight—were ous experience to identify the indirect survey process and analysis of past data. not so very surprising. We move beyond and less obvious characteristics associated Assuming the investigators are located the basics of the site selection visit and with good sites—characteristics that may in the same country, have access to simi- consider the process as both a strategic not be apparent at the individual site lar patient populations, similar facilities and tactical challenge focussing on three selection visit. For instance, an analysis and staff, why do we continue to see key factors: of stroke studies conducted at over 400 a broad range in recruitment perform- • The impact of company processes sites globally for over a five-year period ance across sites that appear similar in setting the tone for success or showed that the top decile of investiga- or at least equivalent? To help explain failure tors (in terms of recruitment) displayed this, we turn to two of the less tangible www.pharmafocusasia.com 6

clinical trialS 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. the number of sites. This can create a disconnect • How often does a site selection visit result in the between site selection and the actual trial conduct, investigator not participating in the study? With up to which may be exacerbated when the team managing 30 per cent of site not recruiting any patients, should the sites throughout the study receives such a list of we not also expect 30 per cent of the sites we visit investigators they did not select themselves. If not to not go forward? Naturally, it is not this simple, but appropriately and proactively managed, this process with relatively few sites dropping out at this stage it allows for a lack of ownership and responsibility for should be considered whether the balance is in the site performance. right place. • Do the individuals responsible to select the investiga- • How often are investigators re-selected who have tors have the required experience to assess some of previously taken part in trials but not recruited any the more complex factors, for instance investigator patients? Again, this is not straightforward given the motivation? CRAs may be trained to select investiga- various reasons why an investigator may not have tors in line with ICH and the protocol. However, is the recruited patients to a previous trial, or why the inves- site selection staff trained to effectively assess the tigator may be selected for continued trial participa- less tangible aspects of what makes for a success- tion. However, we should at least have a realistic view ful site? Moreover, is the staff in a position to reject of the investigator’s likely contribution and account for investigators they do not consider suitable? this in study planning. • There simply may not be sufficient sites that meet all • Are the individuals who select investigators account- the criteria. This is an increasing problem in many able for the subsequent performance of the inves- therapeutic areas, notably oncology. Consider whether tigators? One team of people may be responsible we are being too conservative in terms of investing in solely to select a set number of investigators from new investigators in emerging markets and facilitating a limited pool, and may be facing considerable time their trial participation. Are we actually taking greater pressure to do so. As such, their chief concern will risk by not being more inclusive in this regard? be to meet the immediate commitment in terms of 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. aspects of successful sites—investiga- but generally include potential benefits general impression of how motivated an tor interest and motivation. For most to patient, scientific or medical interest investigator is. To more accurately assess investigators clinical research is only a and financial benefit. In today’s world investigator motivation, consideration small part of their practice, compared of health economics, trials may also be a should be given to the following practi- to the dominant obligation of patient conduit not only to the test drug, but also cal approaches: care. Moreover, the investigators continu- the comparator drug that may already Strategic partnering – Depending on ally face time constraints and have to be on the market but cost-prohibitive the healthcare system, institutions may prioritise their time. In this context the to many patients. Regardless of what have a Research & Development office importance of investigator motivation drives their motivation, it is necessary that has worked with investigators over is evident. When considering motiva- to confirm that investigators participat- a number of years. By meeting only with tion we should first address why inves- ing in a trial possess this key ingredient the individual investigator and maintain- tigators make the decision to take part if the current cycle of delayed studies ing a transactional relationship, instead of in clinical trials? Reasons vary and are is to be broken. With experience, it is collaborating also with centralised R&D specific to each individual investigator, possible for the site selection staff to get a functions, we may continue to select P hA r m A F o c u s A s i A issuE - 10 2009

clinical trialS investigators in a relatively blinded fash- entation followed by an invitation for the entirely. In order to make the proc- ion. However, developing shared objec- investigator to ask questions in fact veil ess more effective and successful, tives and working collaboratively with how much time the investigator spent we need to start by creating a culture such central functions can add great value reading the protocol in advance of the and company processes that engender and prevent inappropriate investigators visit. Instead, starting the visit by simply ownership and encourage the selec- from being approached. asking the investigator their opinion of tion of the right sites. On a day-to-day Asking the right people – It’s no the protocol is a good indication of their basis, application of the assessment surprise that the research nurse or other level of interest and motivation. approaches explored in this article members of the team running trials day- In summary, a site selection visit provides a greater probability of select- to-day will be able to give a more accurate that ensures facilities and qualified staff ing investigators that will recruit as view of the practical implementation of are in place is a relatively straightfor- anticipated. a trial than the investigators themselves. ward process. However, determining Similarly, an investigator may not be if a site will actually recruit patients full references are available at www.pharmafocusasia.com/magazine/ aware whether support functions, such into the trial is another matter as the radiography department, can provide the volume and frequency of scans required. Such logistical challenges Benjamin Quartley started his career working as a cra in the often are the hidden reason for study pharmaceutical industry. recognising the challenges presented author delays and should always be assessed in patient recruitment he joined a company established to directly and proactively with the indi- support investigators in the delivery of clinical trials, where he gained an insight into the investigators world across eight years. viduals responsible. Ben has now taken this experience back to the Industry and Asking the right questions – Site selec- works for covance in feasibility and patient recruitment. tion visits that start with a protocol pres- www.pharmafocusasia.com 6

innovation glenn Saldanha, Managing Director and CEO, Glenmark Pharmaceuticals, India 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. P hA r m A F o c u s A s i A issuE - 10 2009

discovery research. Though we are doing With eight molecules under clinical Where does the company stand today pioneering work in the area of discovery trials, we have clearly demonstrated with respect to its motto “To emerge research we must keep the risk factor in that we have one of the best pipe- as a leading integrated research-based mind and partner with global pharma- lines in the area of drug discovery. global pharmaceutical company.”? When we began the process of discovery ceuticals organisations to share the risks The molecules that are in the clinics research in 2000, very few believed that and benefits. In the last five odd years, are potential blockbusters with sales we could do it. We were clear at that we have struck four out-licensing deals opportunity for each molecule being time and even now that innovation was collecting around Rs. 500 crore in cash as in the range of US$ 1 to 3 billion. the only way for sustained growth and milestone payments. One must note that We will continue to step up the pace for that one had to venture into high- unless your research is world-class the Big of our discovery programme and look end discovery research. Today, we are Pharma will not be willing to participate to push molecules ahead in clinical leaders in the drug discovery sphere in in the process. These partnerships have development. At the same time, we will India and have a rich pipeline of 13 not only boosted our research efforts actively pursue out-licensing opportu- molecules (NCEs and NBEs) of which but also helped sustain our investment nities for few of our molecules which eight molecules are in clinics (including in the area of discovery. are in clinical development. Crofelemer for HIV associated diarrhoea in-licensed from Napo). What has been Glenmark’s experience What went into building the drug To have eight molecules in clinics is a with innovation? discovery capability and the product significant achievement. All the molecules Innovation has to start at the top. A pipeline at Glenmark? which are in clinics are either first-in-class Excellent scientific talent along with considerable amount of time needs to or best-in-class targeting chronic diseases focussed selection of targets and thera- be spent on developing and sustaining ailing the world. In the next financial peutic areas have been the key differ- innovation, and making it clear that it is year, we will have two of these eight entiators in building the pipeline. In fundamental to the company’s success. A molecules entering phase III trials, and addition to this, well-planned schedules second thing is bringing people together three more starting phase II trials. Each and advice from an excellent scientific who share a common vision, providing of the molecules is a potential blockbuster advisory board and key opinion lead- them with the resources to pursue that with peak sales opportunity of US$ 1 ers have backed the target identification vision, and giving them the autonomy billion to US$ 3 billion. We have always process from time to time. and responsibility for executing against believed, even in the area of discovery that vision. Most innovators thrive on research to do cutting-edge work and the How do you hedge the risks while empowerment, so you need to make sure peak sales opportunity for each mole- improving the success rate of your drug the structure and the decision-making cule validates that fact. For instance our discovery programmes? in your organisation genuinely have that latest molecule which is filed for Phase We have considered the route of out- quality. The third thing is having access I trials in the UK i.e. GRC 15300 for licensing our molecules to Big Pharma to the capital needed to support innova- Osteoarthritic pain, Neuropathic pain, once the molecule reaches Phase I / Phase tion. This has always been an issue for and other Inflammatory pain conditions II trials as part of our strategy to hedge smaller and mid-sized companies, and, globally, will be the first TRPV3 molecule our risks. While partnering with Big in the current environment, is even an to enter clinical trials. We have made Pharma, we look to close deals that will issue for large companies. Now more significant progress regarding our vision, give them the rights for that molecule than ever, you need to be selective about but we still have a long way to go. for three regions in the world—North the ideas you pursue. America, Europe and Japan. The rights At Glenmark, innovation has been for the molecule in other parts of the the defining factor in our success. We What has been the role of international world remain with us. So if a molecule have managed to do what very few partnerships in Glenmark’s success over reaches the market place, the partner (Big pharma companies have done in the the last few years? Discovering a new chemical entity and Pharma) will have rights to sell the newly world. We have continuously developed seeing the molecule all the way till the approved drug in these three regions. They new molecules, cut out-licensing deals, end requires a sizeable investment. A will pay Glenmark royalties on sales. In expanded our presence in new markets single new chemical entity which runs other parts of the world, Glenmark will and built a strong generics business, all through preclinical and clinical devel- directly sell the newly approved drug. within a short span of a few years. When opment can cost companies millions of we look ahead, sustaining this growth is dollars. Also it’s a zero-sum investment if going to be the single biggest challenge What are the current priorities for the molecule fails. Thus one has to look and I have no doubt that innovation will the company in its drug discovery at various options when venturing into continue to be the differentiator. programme? www.pharmafocusasia.com 6

clinical trialS Developing Benefit-Risk management programmes Best practices There 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 U nderstanding the interrelation- of both risks and benefits for example, Protocol review ships among all key stakehold- special populations both of those with During the investigation phase, the spon- ers is the critical aspect in risk identified risks and those that have not sor has complete control over product management planning in today’s rapidly been evaluated such as the seniors and distribution and use. However, he loses changing, complex global healthcare children. Given today’s advances one the control substantially as product environment. These can include payers, should also consider the implication of receives marketing authorisation. With providers, patients, care givers, patient pharmacogenomics on the risk manage- market authorisation and distribution, the advocacy groups, regulators and other ment programme. Is the company ready product is available to licensed medical government agencies. All these stake- to manage a marketed product? Are there practitioners in accordance with local holders should be considered when sufficient systems, processes, procedures laws and regulations. Also, physicians planning and communicating benefit and finally sufficient personnel both in could often approach the sponsor with and risk. quality and quantity? a request to provide the medicinal In the US and Europe there have product free of charge for the expressed been significant updates in safety and purpose of conducting independent Four key components of the comprehensive benefit-risk risk management regulations. Many other clinical research. In addition, a sponsor management programme countries are actively revising drug regu- can have a programme of investigation lations such as India and China among When considering comprehensive and on the medicinal product that has been others. In the face of these rapid and cross-functional benefit-risk management designed internally to provide additional global regulatory changes one must programmes, it is possible to organise the information as determined by the gap constantly evaluate their readiness in efforts into four key areas. They are analysis noted above. These investigations responding with timely and compli- • Protocol review and approval could be both internal and external. The ant benefit-risk management systems. • Active surveillance sponsor should put in place a mechanism This readiness assessment will encom- • Provider and patient education and to assure adequate design; inclusion and pass several key areas but must also be intervention and exclusion criteria; and adequate subject comprehensive and open. The organisa- • Appropriate use management. protections for each of these protocols. To tion must understand the principles of the These categories are used to help assure focus on science and ensure that at-risk culture of safety and put in place systems that the programme will be comprehen- populations are protected, the sponsor and processes to support this concept sive and effectively designed based on all can constitute a protocol review commit- as a core characteristic of the company. available information and utilising cross- tee with adequate committee structure One must identify gaps in knowledge functional capabilities (Figure 1). and document procedures. Commercial P hA r m A F o c u s A s i A issuE - 10 2009 70

clinical trialS interests cannot outweigh patient protec- Proactive benefit-risk management tion. Key stakeholders who can be included in this committee may be from 1 2 3 4 the areas of Research & Development, Medical Affairs, Regulatory, Law, and Protocol design Active safety Provider and Appropriate use and review surveillance and patient education management Commerce. Other groups such as public measures of harm and intervention affairs may also be included. The sponsor must be inclusive and open and avoid silo behaviour. Continuous quality improvement programme Active surveillance Programme project management Active surveillance programmes include Figure 1 a variety of methods: Consider monitoring commercial databases and insurance follow-up questionnaires, establish special Provider and patient education databases for retrospective and prospective reporting agreements with regulators (if The cornerstone of any risk management analyses. The sponsor may also consider needed) and effectively communicate the programme is the education component. utilising more modern methodologies that findings to all interested parties in an It is critical that the sponsor adequately take advantage of advanced web-based open and timely manner. and continuously educates healthcare tools. One unique design taking advan- professionals, patients, caregivers, and tage of these Internet capabilities is to patient advocacy groups with the best Appropriate use programmes create a web-based patient community. In Appropriate use programmes provide a and latest information related to the this example a sponsor would offer access thorough assessment of marketed product product use. The education programme to a unique product or disease portal usage. These programmes monitor all uses, could be developed along with the entire where the patient could enroll and opt for approved and unapproved indications. product development programme. receiving information and also be avail- They are especially useful for monitoring The sponsor can again utilise the able to participate in both prospective and known high-risk unapproved exposures. online patient community to both retrospective research programmes. Again, When inappropriate use is detected, a provide them with education mate- the patients could be offered the oppor- sponsor may consider holding provider rials directly and assess their level tunity to opt for the research programme and patient education programmes that of comprehension of the critical on a voluntary basis. This community would reinforce appropriate use. There elements of the programme. Patient- should then provide a platform for the are many tools available to sponsors in directed online programmes could sponsor to readily recruit patients for developing appropriate use programmes. be expanded to the level of disease epidemiologic hypothesis generating and One can develop drug and disease regis- communities. These programmes can hypothesis testing programmes. In addi- tries, sample use through market research, provide patients access to proactive and tion, the sponsor could consider signal utilise publicly available databases, and interactive educational programmes. detection and an evaluation programme commercial resources. Ultimately, the The online community can also be which includes actively reviewing single sponsor must continuously monitor used for patient-directed physician case reports, case series, claims data, data usage and put appropriate measures in communication wherein the patient warehouses, and public databases such as place when aggressive management of provides permission to contact their the World Health Organization’s Uppsala the medicinal product distribution is healthcare provider for verification of Monitoring Center, and the United States needed. The most restricted method of specific medical information. Food and Drug Association’s Adverse distribution is used in risk management Event Reporting System. Sponsors need programmes utilising a performance- Programme management to evaluate and understand the appro- linked access system. These complex multiple-component priate measures to utilise, in the active These programmes ensure that only programmes require professional project surveillance programme understand- those patients who understand the specific managers to oversee the design, imple- ing the key domains, data sources and risks are exposed to products. Notable mentation, maintenance, reporting and appropriate methods to apply at each examples of this restricted distribution communications. The project manager intersection. in the US include the programmes for assures that the various service compo- The purpose of these programmes isotretinoin and natalizumab both of nents are effectively implemented and is to aggressively monitor and investi- which have well characterised serious anticipates programme problems and gate events of interest, develop targeted risk profiles. addresses them. P hA r m A F o c u s A s i A issuE - 10 2009 72

clinical trialS of the quality management system is active product defense throughout a Quality systems The final element of the comprehensive the inclusion of key stakeholders such product life cycle is the backbone of benefit-risk management programme as prescribers, pharmacists, and patients a successful medicinal product. The should be that of quality management. in the evaluation process. benefit of which will be the optimal For each component of the programme, public health outcome assuring that the metrics should be established to right patients have the most effective Summary assess the effectiveness of the service Utilisation of modern technologies and medications for their unique circum- delivery and the effectiveness of the effective communication with consistent stances. And prescribers are provided programme to reduce the specific risk and audience-appropriate messages is clear accurate communication to best elements defined. If the programme critical for an effective product bene- advise their patients for their course is designed to reduce the inci- fit-risk programme management. Full of treatment. dence of events of interest then that characterisation of events of interest will be a key efficacy parameter for and validated mechanisms to mitigate full references are available at measurement and analysis. This risk prior to market authorisation and www.pharmafocusasia.com/magazine/ ongoing quality analysis will lead to a continuous improvement model. Progress should be tracked over time Axel K olsen currently provides leadership and guidance to the to identify areas for improvement; development and execution of pharmaceutical safety programs author define and implement best practices; at Quintiles. Prior to his experience as an independent consultant in 2002 and 2003, he was a vice president in the global create process maps to find potential medical affairs Department at Wyeth pharmaceuticals. from efficiencies and establish Corrective 1989 to 1997 he was the head of Worldwide Safety Surveillance and Preventive Programs (CAPA) as at Wyeth. needed. An often-overlooked element www.pharmafocusasia.com

clinical trialS CLiniCAL tRiALS in ChinA&JApAn Dynamic opportunities for sponsors and cros T he historical approach to clinical is enviable to any western market, at 28 ing number of investigators and sites. drug development, and one that per cent CAGR. Presence of regional Equally, the commitment by sponsors served drug companies well for affiliates of global CROs in important to engage China first-hand opens up the past thirty years, was to initiate test- locations such as Beijing and Shanghai even more opportunities for CROs to ing in humans at clinical research units, makes it possible for global pharmaceu- work with global sponsors and their typically located in the UK and the US tical companies to offer easy access to local affiliate offices to provide global, and to proceed further to Phase II test- leverage the tremendous potential of this regional and local clinical development ing and beyond to patients with clinical key Asian market. They can also help services. evidence of the disease with investiga- pharmaceutical companies to extend The Chinese regulatory environment tors mostly located in the US, Canada their reach into a large and important The Chinese regulatory environment and Western European countries. source of patients, investigators and is highly dynamic and is maintaining An increasingly intense competitive sites. With good local understand- open lines of communication which environment and the shrinking pools of ing, experienced monitoring, project is absolutely crucial to ensure success. treatment populations in the traditional management and other staff, including Acknowledging the paramount North American and Western European regulatory experts, it can provide seam- importance of local regulatory markets, however, have led sponsors and less support to sponsors with regards understanding, it is important to CROs to ‘discover’ emerging markets to to high quality clinical development build a strong, local team of Chinese source high quality research and secure services or assistance with regional regulatory experts who understand the timely enrollment of patients. This article registration. current requirements and work with focusses on two of the most dynamic Naturally, not only international the clients to understand their needs. emerging markets, both Asian: China CROs but also international pharmaceu- Similarly, sponsors and CROs alike need and Japan. tical companies have ‘discovered’ China to invest considerable time and effort as their destination. This, in fact, is a to understand the evolving Chinese benefit to the CROs. The increasing regulatory requirements. China footprint of a growing number of global The advantages of being in China for an Challenges in clinical development pharmaceutical companies in China is The demand for access to patients and international CRO The importance of China to get miracles vital and has an unequivocal benefit in high-quality clinical development deliv- to market is absolutely indisputable. that it helps escalate the understanding ered on time and to budget, is rapidly China represents the fourth biggest and adoption of fundamental interna- increasing. This growth in demand economy on the planet and its own tional clinical trial requirements such as is pushing the limits of local supply, drug market is growing at a pace that ICH and GCP amongst an ever increas- meaning it can be a challenge to staff P hA r m A F o c u s A s i A issuE - 10 2009 74

clinical trialS 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 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. and long-term strategies are centered own drug companies to reach out to Short- and long-term goals Many international companies have on the key capabilities to help clients neighbouring Asian countries such as long recognised China’s potential as a effectively leverage China for high-quality South Korea and China, to help make source of patients for clinical trials and clinical development. the clinical trial process more effective as a growing market for new medicines. and efficient. Investment in internal infrastructure in These developments bode well both Japan China is set to continue, to meet the for Japan and the region at large. This A “Closed Country” – No more increasing needs of current and future Two overriding trends drive the major- being said, certain regulations and restric- clients. Specifically, the investment ity of events influencing the clinical tions in Japan (e.g. limiting the length of includes significantly increasing moni- research potential in Japan. First, Japan time a CRA is permitted to spend at an toring capabilities, growing in-country has taken a number of steps to make it investigative site) appear more burden- project management and expanding regu- easier to include the country in global some than those in other countries. This latory capabilities. Basically, both short trials. Second, Japan is encouraging its means trial conduct can be very costly in www.pharmafocusasia.com

clinical trialS Japan, even in comparison to traditional efficiencies and sharing of experience. of subject rights and well-being, and markets such as the US and Western These initiatives amongst others will help of course regulatory compliance. Most Europe, as well as the emerging markets Japanese investigators and research staff of outsourcing’s focus is on time, cost across the globe. Even today, efficient build more experience and help close and scope, but a major challenge is in trial management faces an additional set gaps versus the global market. the quality of the process and the major of hurdles in Japan—hurdles not found deliverables. Though it must be conceded What’s ahead? in other countries looking to claim a Local Japanese CROs increasingly that many current practices were reac- stake in global clinical trials. contribute to global trials and this expo- tively triggered in response to quality sure has helped the CRO industry in problems, the future will require that More international clinical trials In the not too distant past, Japan would Japan mature. To grow internationally, quality management be more proactively have rarely come up for inclusion into the Japanese CROs will likely need to and comprehensively integrated into clinical trials, considering past hurdles engage in strategic transactions with study planning and execution regard- to trial conduct. This picture is changing other CROs or grow organically by less of where the trial takes place. fast, however Japan still requires very establishing a presence in key markets. When performing trials in markets careful consideration, for instance, with As the Japanese CRO industry enters such as China and Japan, the number of regards to cost impact and start-up and this phase, a new set of challenges will potential pitfalls, site idiosyncrasies and enrollment timelines. To overcome frus- present itself—similar ones that CROs country-specific regulatory, ethical and trations and disappointments in future, face elsewhere, and it will be interesting administrative requirements increases a very clear analysis of benefits versus to see the developments as the Japanese exponentially. Any challenges which challenges needs to be done before CRO industry matures further. plagued trial performance in ‘tradi- including Japan into trials. It’s crucial to keep in mind that tional’ western markets previously tend Covance has run clinical trials where Japan is an established, experienced to multiply, and no single adjustment Japan was included on the same timeline market when it comes to clinical trials, can be counted on to remedy those as all other countries in the trial, and ICH and GCP. In Japan, the clinical challenges. indeed Japan did not ‘finish last’—the trial industry does not start from a small Instead, an integrative, quantitative, sites in Japan performed along standard or less developed base—rather, the task proactive trial management is required expectations. This type of solid, predict- at hand is to finally start leveraging the and it needs to be geared towards able performance will help draw more established strengths resident in what is handling not only current day site trials to Japan which, in turn, helps in fact the world’s second largest phar- performance variability, but also the vari- Japanese investigators and research staff maceutical market. These strengths have ability in the underlying patient popu- build more experience—it’s a positive not historically been easily accessible, lation which can dramatically impact spiral. just as circumstances have not permit- trial outcomes, especially in the complex ted for the industry to effectively and long-term studies that are increasingly The obstacles to simultaneous drug efficiently leverage them. common. A key component in success- development The obstacles to simultaneous drug fully leveraging the potential of emerging development in Japan are well known. markets is a proactive and predictive In closing Interestingly, the Japanese Ministry of The composition of markets that contrib- operational approach. The approach Health, Labour and Welfare has signalled ute to international clinical trials clearly should focus more on risk prevention that the so-called bridging studies are has changed and will continue to change. rather than remediation of investiga- at best a tactical solution to a strategic One requirement of clinical trials will, tor errors, and also deliver improved problem and at worst have helped delay however, be emphasised consistently: the productivity, lower operational risk, the necessary globalisation of Japanese focus on quality in clinical trials. Here, and improved scientific robustness— trials. Instead, the long-term focus is on quality is defined in terms of trial design, not to mention increased investigator reaching out to countries such as China the validity of the results, the protection satisfaction. and South Korea for sharing clinical data as the populations of these countries are considered sufficiently close to the nick Wright is vice president and general manager for clinical author native Japanese population. Also of note Development for Asia-Pacific at Covance, a global full service CRO. Nick brings extensive international experience of working is that Japan plans to network their major in china, taiwan, Japan and across South-east asia. clinical trial sites into ‘hubs’ and nodes— this is a five-year plan which started in 2007, to promote better coordination, P hA r m A F o c u s A s i A issuE - 10 2009 7

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