Issue 10
2009
ÂŁ12 â‚Ź18 $25 Rs.300
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Mega Mergers Are they turning pharma companies into zombies?
New Patents for Old Drugs Label-based strategies in the United States
Preclinical Research in Big Biotech Vertical integration is the key
Accelerating Central Nervous System Trials Neurophysiological approaches
Foreword Personalised 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
hile mergers and acquisitions, partnerships and collaborations still offer avenues for growth for the pharma industry, many feel that the concept of personalised medicine, if used intelligently, will set the industry on the right path. By enabling highly-customised therapies to treat diseases based on the patients’ genetic makeup, personalised medicine offers companies alternative avenues for growth in terms of niche markets often left unexplored because of feasibility issues. It also provides an opportunity to eliminate unfavourable products much earlier in the development stages, save investment by testing medicines on targeted sub-populations and avoid failures by eliminating inappropriate patients whose genetic makeup does not suit the medicines. Right drug for the right patient and benefits without toxicity offers a viable business model to the industry. Personalised medicine effectively tackles the issues of toxicity, side effects and medical errors due to wrong dosages or incompatibility while offering patients effective therapies. The industry has a lot to benefit by leveraging the rapid developments in biomarker usage strategies for personalised healthcare. Experts opine that the biomarkers used to optimise clinical study designs could be eventually used to conduct smaller trials and allow a combination of medicine to be prescribed based on the outcome of a specific diagnostic test for the patient. Additionally, personalised medicine can help create and enhance product differentiation and potentially extend the life cycle of drugs.
Though the benefits are immense, challenges abound. Optimising the drug development for target patient populations—usually small—at low cost while satisfying the tough regulatory guidelines and reimbursement procedures is a daunting task. Many healthcare payers now demand evidence-based medicine to avoid unnecessary costs and low-yield interventions for patients. However, most reimbursement procedures tend to fix a ceiling for tests. Developing the tests, an important element of the personalised medicines concept, is a costly and unfeasible affair with the ceilings. Enough support from healthcare insurers is paramount for the growth of personalised medicine. Experts, however, hope that realising the long-term savings in treating a disease or preventing it will offer enough incentive to payers to support personalised medicine on a greater scale. At the moment, its greatest advantage lies in its capability to maximise the effectiveness of medicines used to treat diseases affecting a specific population with documented cases of toxicity and side effects. The cover story “Future of Medicine - Personalised” discusses some important issues: how targeted therapies can offer a sustainable business model, the changing business models and how biomarkers are leading the way in the development of personalised medicine.
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
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Targeted Therapies A sustainable business model? Erik Tambuyzer, Genzyme Corporation
Research & Development 36 Biosimilar Medicines Understanding the challenges Cecil Nick, PAREXEL International
40 Drug Discovery in Academia An evolving model Edward Holson, NovoNordisk A/S
30
Personalised Medicine Changing business models Bruce Quinn, Foley Hoag LLP
34
Personalised Medicine and Drug Development Biomarkers leading the way Michael Lutz, PGxHealth
44 Preclinical Research in Big Biotech Vertical integration is the key David R Webb, Celgene Corporation
46 Computerised Cognitive Function Assessment Coming of age Keith A Wesnes, Steve Satek, Andrew C Embleton, Rianne E Stacey Cognitive Drug Research Ltd.
36
44
60
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
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Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy
Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA
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Pharma Focus Asia is published by
Neil J Campbell CEO, Mosaigen Inc. and Partner, Endeavour Capital Asia Ltd., USA
Phil Kaminsky Founder, Center for Biopharmaceutical Operations, University of California, Berkeley, USA
Rustom Mody Director, Quality and Strategic Research, Intas Biopharmaceuticals Limited, India
Sanjoy Ray Director, Technology Innovation, Merck Research Laboratories, USA
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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 India is on the cusp of a great opportunity—the opportunity to innovate and create novel medicines to meet unmet medical needs of today and the future, thus making a positive impact on global health. It is imperative to capitalise on the enormous wealth of creative and scientific resources that our country has been blessed with for the benefit of the patient by discovering medicines for unmet medical needs. As we go forward, India is tipped to become a pivotal player in the global economy and the country’s pharmaceutical industry stands on firm ground both as a provider of authorised generic drugs as well as the seat of pharmaceutical research. This position however is only attainable if India aggressively nurtures innovation and is seen as a country that respects intellectual property rights while tackling the twin issues of health and education.
Newer, more effective products at lower costs
The pharmaceutical industry is under growing pressure from multiple stakeholders to keep delivering blockbuster products providing fair return to investors while at the same time ensuring that prices are affordable. Currently, it takes at least eight to ten years to bring a compound from an idea to a usable medicine. During that time, pharmaceutical companies spend up to US$ 1 to 1.7 billion in researching, developing and testing to create a single drug. Sources show that while US$ 100 billion worth of drugs will be going off patent by 2010, clinical development time has actually doubled since 1982 to an average high of 68 months. Boxed in as it is from all corners, pharmaceutical companies have to rely on their innate skills to deliver products that meet not only the medical needs of today but also that of the future. While doing so, pharmaceutical companies
need to keep a keen eye on research costs and look at the various avenues to partner with others so as to deliver newer and more effective products at lower costs. India on its way to become a pharmaceutical powerhouse
Looking back at history, much of the progress of civilisation in various fields including mathematics, physics, chemistry, astronomy, medical science and the arts can be attributed to India. There is ample evidence to show that various kinds of surgeries including plastic surgery, ophthalmic surgery and dental surgery were being done in India long before they were even known in other parts of the world. The world has long since changed and India has lost ground relative to some other economies in the area of pharmaceutical innovation. However, today the world has moved to become a knowledge economy and India with
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Strategy
its vast intellectual capital has an advanthe 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 leaderrecognise incremental innovation or innotime 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 delivin the pharmaceutical field. In addiincremental 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 manuthe 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 manufacin 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 breakproduct 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 findUS 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 productivand 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 costof medicines on the market competitive throughout the today are the result of increThe pharmaceutical industry is under value chain. Above all, India mental improvements on a base growing pressure from multiple has the third largest Englishmolecule. 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 recogentrepreneurial spirit. The nised and failing to do so would time ensuring that prices are affordable. 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 Need for world-class IPR steam engine offered transport an alteronly encourage national pharmaceutical 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 pharmaceutichanging the way people and goods were innovation is not “evergreening” which cal industry. transported. is an attempt to extend patent protecWith 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 pharmadid 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 evergreenshift toward research and development. innovator did do was build on the existing ing purposes do not represent medical Leading research-based Indian pharknowledge 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 clinias compared to what the large pharmaand 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 beneficilaw 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
Innovation nurtures creativity and productivity
Investments to grow our capacity for research and to create intellectual capital in the pharmaceutical space will not help if we as a country refuse to respect intellectual property rights. Indian pharmaceutical companies must be geared to nurture innovation as it leads to greater productivity, higher economic growth and better standards of living. There are various ways to achieve this including public funding of research, collaboration with academia, funding via surpluses of large corporations involved in traditional businesses, venture capital funding and the like. Our country has a glorious past and there is every reason to believe we can achieve in pharma what we have managed to achieve in IT. A strong patent regime will instill confidence in innovation, research and creativity in
global and national companies operating in India and encourage them to increase investments in the country, especially in pharmaceutical research and enter into partnerships where appropriate. As eminent scientist and Director General of the Council of Scientific and Industrial Research (CSIR), India, Dr. R A Mashelkar said not long ago, “the process of globalisation, corporatisation and privatisation of research has shifted the dynamics of knowledge production and dissemination dramatically just as issues of Intellectual Property Rights (IPR) and proprietary information and knowledge have begun to open up new dialogues on public good versus private profit. New models of the innovation chain and new paradigms of the science-society contracts have begun to emerge.” It is heartening to know that India actually has the highest intellectual capital available per dollar anywhere in the world. In fact a publication of the standing of The Far Eastern Economic Review had remarked that India ranked number one as the source of knowledge workers—ahead of all other countries in Asia including China, Japan and Singapore. CSIR to date has 302 patents in the field of medicine alone. In chemistry it has 1799 patents, 221 in biological science, 90 patents in analytical techniques. Estimates indicate that it costs over US$ 1.2 billion to get a single New Chemical Entity (NCE) into the market. Multinationals can outsource much of their R&D clinical activity to India lowering their overall costs. Conducting preclinical and clinical trials in India has three-fold advantages. Firstly, the cost of such trials in India would be in the range of 30 to 50 per cent of costs
Author
development. An important part of the research and development jigsaw is data gathering on the safety and effectiveness of drugs. Lack of data protection, an integral part of intellectual property rights, acts as a barrier to research. Pharmaceutical companies generate significant amounts of data while conducting research and this data goes to government by way of a dossier while seeking marketing approval for a new drug. Unfortunately, this data is used by makers of generic drugs in India to get regulatory approval for their medicines without conducting clinical trials. There is a fear, unsubstantiated I might add, that protecting this data will lead to higher drug prices. There is no reason to believe this as history shows that there is no correlation between data protection and the pricing of drugs. Data protection exists in many countries including China, Egypt, Mexico, Columbia, Korea, Brazil and Taiwan for a period ranging from 5 to 6 years. Market forces including limitations of purchasing power help keep prices down.
in the US and EU. Secondly, India has huge genetically diverse patient pools who are “drug naïve”, not having taken any drugs for their condition. Thirdly, the country has a significant number of qualified doctors who have the expertise to conduct and supervise clinical trials as per global standards. And it is not just in the area of clinical trials that India has fair opportunity to be a strategic partner but also in the areas of contract manufacturing, custom synthesis, biostatistics, bioinformatics and technical services among others. Partnering to win
Collaborations will be the way forward and are a win-win situation offering Indian companies an opportunity to tap into the world’s largest global research networks and providing access to new technologies. The industry also serves as a platform for Big Pharma to tap into the huge scientific talent available in India. India has the potential of becoming a hub for drug discovery programmes. While there are some concerns with regard to IPR particularly with regard to enforcement and these clearly continue, the framework is in place. An environment where innovation and research are encouraged will only serve to raise the level of interest in the country as an investment destination. There is therefore little doubt that as time moves on, India will quickly emerge as a leader in the world pharmaceutical market. Will the 21st century belong to India? Will India, the land of milk and honey, go back to realising as in ancient times that “Prajnam Brahma” or Knowledge is God? Why not? I have every reason to believe it will.
Ranjit Shahani is a strong proponent of IPR and a thought leader in the pharmaceutical industry. He was President of the Organisation of Pharmaceutical Producers of India (for an unprecedented three terms).
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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 pharma has strived to achieve revenue growth and pipeline stocking through M&A. In 2007, the pharma industry mainly targeted latestage biotechnology acquisitions to consolidate some drug development platforms, namely those with disease franchises and drug class expansion. Then came the ever-worsening financial crisis during 2008 that rapidly spread to become a global recession. This has put many big pharma companies into a holding pattern exacerbated by difficulties of accessing finance and the need to satisfy investors for the short-term. One interesting observation is that at the time of writing this article, more than 40 per cent of the biotech companies in the US had less than a year of cash on hand. Does this serve as a once-ina-lifetime-opportunity to build value by rapid M&A of biotech companies that could stock various stages of development for big pharma? The latest pharma rage – Mega mergers
The forcible merger of two big companies that lack innovation doesn’t necessarily result in forming a good company. There have been academic and industry studies that have shown that this strategy had failed time and again to create any value for shareholders, drug pipelines and ultimately patients beyond a few years. The past 12 months have witnessed many such deals in the pharma industry. (Table 1). The mega merger of Pfizer and Pharmacia in 2000 illustrates how a merger, which lacks long-term value, has huge dilution and which is not properly integrated, fails. The Pfizer CEO, Jeffrey Kindler, was on the airwaves touting the
great value that this upcoming PfizerWyeth mega merger would provide. What is interesting here is that in all his interviews Jeffrey Kindler was overtly promising that the past failures to integrate value into the past M&A would not be repeated. As a result, many large pharma companies are still going for mega mergers. The latest being PfizerWyeth mega merger for about US$ 68 billion in stock and cash. The Pfizer-Wyeth deal, if consummated, would be the fourth largest M&A deal ever and would give Pfizer the distinction of having made the first, fourth and fifth largest pharmaceutical deals in history. Pfizer is still trying to integrate the Pharmacia acquisition of 2000 which was the fourth and now is the fifth largest deal ever (Table 2). The deal will merge two major pipelines with patent expiry falling in the period 2011-2013. Lipitor alone constitutes 35 per cent of Pfizer’s annual sales according to the latest IMS studies and Pfizer press reports. Putting two anaemic pipelines together with no innovative system in place doesn’t make one great pipeline for future growth. In fact, Jeffrey Kindler repeatedly stated on news interviews that this deal would unlock value for both companies and solve the short-term problems facing Pfizer. He repeatedly stated that past M&A mistakes that destroyed value will this time provide value. Time alone will reveal the truth, but the analysis of the combined pipelines seems to be making a bigger issue and is expected to affect investors and value. It can take years to integrate the R&D and corporate cultures following these mega mergers—business development groups can be taken off task for up to two years while trying to manage the integration. Big pharma companies
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Strategy
Biggest health care buys – The last 12 months Buyer
Buyer Home City
Acquiree
Acquiree Home City
Deal Size (US$ 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.
Largest pharma M&A deals Target
Acquirer
Deal Value (US$ bn)
Warner-Lambert
Pfizer
111.8
SmithKline Beecham
Glaxo Wellcome
79.6
Aventis
Sanofi-Synthelabo
71.3
Wyeth
Pfizer
68.3 (Pending)
Pharmacia
Pfizer
59.8
Genentech
Roche
42.6 (44.1% Stake)
Astra
Zeneca
39.9
Hoechst
Rhone-Poulenc
33.8
Pharmacia & Upjohn
Monsanto
31.9
Ciba-Geigy
Sandoz
27.0
Schering
Bayer
19.3 (92.4% Stake)
Table 2
Pharma Focus AsiA
ISSUE - 10 2009
Table 1
are scared and have started reacting to the industry woes. These woes are being driven by a slowdown in growth as revenues come under threat from expiry of patents of blockbuster drugs, shrinking pipelines from original science programmes and the ever-increasing reach and breadth of generic drug competition. Are there alternatives to this mega merger mania? Well, you have Astellas, the Japanese Pharma (Fugisawa and Yamanouchi consolidation) moving towards acquiring Small to Mid-size Biotech (SMBs); could this be a better place to put money, time and longerterm focus? (Table 1). Global financial credit crisis – A silver lining for the big pharma?
Sources: Dealogic, Company News
10
Deal Announced
With so many biotech companies short of cash and in mid to later stages of clinical development, does this provide a buying opportunity for low-cost drug pipeline stocking? It sure seems that way.
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11
Strategy
If big pharma can muster a strong business development and licensing effort, they can merge or acquire a succession of smaller biotech companies and fill the gaps in drug pipelines from late preclinical / pre-IND to phase III / NDA. This thought is probably causing big pharma heartburn, but what are the alternatives: mega mergers? There are many problems that mega mergers won’t address (Table 3). Three interesting deals at the moment are the GSK-Attack Strategy, the continuing saga of Roche’s attempt to buy the remaining shares in Genentech and the Astellas-CV Therapeutics replay from the fall of 2008. There are many benefits to an aggressive biotech M&A roll-up approach. Let’s look at the three scenarios in reverse order.
Industry trends driving the mega mergers bandwagon Industry Trends Driving Mega-Mergers Big Pharma focus is on sales and marketing
No drug pipeline development, push limited life to secure sales at longer term benefits of building sustainable businesses
Big Pharma spending more on marketing than R&D for new drugs
Misaligned priorities to innovation, reward now, not later, bad trend to start
Consolidate with like-minded large companies
Mind-set to find other Big Pharma, Stunt long-term growth potential, missed opportunities with smaller biotechs
Blockbuster legacy drug patent expiry in next several years
Short-term stocking M&A at risk of finding medium and longer term synergies
Cost to development increasing-failure rates increasing
Regulatory shift since Vioxx to safety over efficacy, need better balance reviews
Generic drug growth / biogenerics coming Other drug strategies such as Nutriceuticals, Cosmeceuticals, Therapeutic medical devices
For smart companies, this is portfolio management; for myopic ones, knee-jerk reactions to save businesses, currently mega merger mania Table 3
Astellas and CV Therapeutics – Hostile takeover attempt
Astellas is moving in on a hostile takeover with a second attempt at CV Therapeutics. The first attempt was in the fall of 2008 with CV Therapeutics turning away from any deal. As the market has moved downwards and cash reserves dwindled, Astellas feels that the addition of CV Therapeutics would provide growth into new areas and potential revenue paths for the medium future. Being a Japanese pharma company and concerned with long-term growth prospects along with a willingness to build out new franchises in both diseases and drug classes and shouldering some of the risk, Astellas is bucking the trend of Wall Street pressures, quarter-to-quarter financial performance and western big pharma. The deal that formed Astellas—putting together Yamanouchi and Fujisawa—built a sustainable foundation to grow from. It is predicted that Astellas will make more smart acquisitions in the next couple of years and take advantage of the current financial crisis. Table 4 presents a summary of drivers providing advantages to larger pharmaceutical companies with their biotech brethren.
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Pharma Focus AsiA
ISSUE - 10 2009
Effect on Growth Strategies
Potential benefits that biotech M&A provide Aspects of Biotech M&A
Potential Benefits to Big Pharma
Short of cash, less than year
Could pull M&A together quicker for impact to short to medium term
Lowest company valuations in 25 years
Ability to "shop" and buy many ones
Biotechs, historically, have science platforms that built their drug portfolios
Build medium to longer term value for drug portfolio, have potential revenues, but platforms for innovative development
Some biotechs could provide new franchises
Big Pharma add-ons could be diseases, drug classes, or operational capabilities
More biotechs have Big Pharma partnershipsdrive interesting options
If selected properly, big pharmas could stock pipelines and force big pharma to big pharma collaborations / M&A with the biotechs who have big pharma partnerships
Provides many more variables for deal-making and out-licensing monetisation strategies
Financial crisis has tightened up credit, this could allow for more original deal-making Table 4
Roche and Genentech – Remaining share buyout
Another interesting potential trendsetting deal involves the buyout of remaining Genentech shares by Roche. Roche is driving hard to purchase the remaining stake of Genentech to form the largest biopharmaceutical company with broad research platforms, core capabilities, preclinical and clinical
drug pipelines. The first deal acquired a 44.1 per cent stake in Genentech at a cost of US$ 42.6 billion making it the sixth largest deal to date (Table 2). This time around, it could cost Roche double that sum. Genentech, one of the two largest biotechs in the world, could very well rebuff the Roche deal and start its own biotech M&A strategy. An approach that can be more
Strategy
Strategies for drug development
Drug Development & Approval Process Postmarketing - Phase IV
“Co-Promote” Approaches
Preregistration - FDA/EMEA
“Co-Development” Approaches
File NDA at FDA
“PDC” Development Approaches Clinical Trial - Phase III Clinical Trial - Phase II
“Foster” Development Approaches
Clinical Trial - Phase I
“Sponsored” Research Approaches
File IDA at FDA Preclincal Testing
Figure 1
The pharma innovation gap – Increased R&D spending yielding lesser drug approvals
50
$50
40 Pharma Innovation Gap
$40 $30
20
$20
10
$10 $0
30
New Drug Approvals
Pharma R&D ($Billions)
$60
1992 ‘96
2000 ‘01
Pharma R&D Investment
‘02
‘03
‘04
BioPharm R&D Investment
‘05
‘06
‘07
New Drug Approvals by US FDA
Sources: Pharmaceutical Research and Manufacturers (PhRMA) Annual Report 2007; Burill & Company Report 2003; PhRMA Annual Member Survey, 2007: US Food & Drug Administration Databases.
accretive for Genentech shareholders and a better fit with the corporate culture in California. A Roche takeover could kill the remaining innovative juices that Genentech has. One thing is probably for sure, the co-founder and current CEO, Levinson may leave his position if the deal goes through; not necessar-
0
Figure 2
ily a bad thing. We would like to see him in a more expansive role helping more biotechs grow to become future Genentechs. Aggressive M&A strategies of GSK
The global financial crisis has provided an opportunity for big pharma to really
make a difference in how they build value into their drug pipelines. The crisis has plummeted company valuations to their lowest level in 25 years (the life of the biotech industry is almost that old) and it is estimated that more than a third of the over 3,500 biotech companies that exist in the US have less than a year of cash on hand. With most pundits predicting that financial problems would continue till mid2010, you have a lot of companies with potentially great science and pipelines in clinical development on the verge of extinction. Enter GSK. Although some are predicting the Pfizer-Wyeth deal could help Pfizer with short-term revenues and give a little breadth from the Wyeth pipeline, most are pointing towards GSK as the company and M&A trend to watch more closely. To date, GSK has avoided any mega merger in favour of mobilising its cash on smaller, more asset-building type of deals. The goal is an obvious one: to address long-term problems instead of adopting a myopic blockbuster-drug-only strategy and build both drug classes and drug portfolios in focussed disease franchises. Over the past 24 months, GSK has aggressively bought an accretive, sustainable and potentially expansive diverse set of drug assets—such as UCB’s late-stage drug assets and Biotene’s dry mouth drug treatment—in both established and emerging markets. It is also rumoured that GSK is looking at more targeted diversified healthcare companies and this approach could provide for more portfolio management across healthcare systems. Adopting new development strategies
Johnson & Johnson, Abbott Laboratories and Novartis are just a few to deploy this approach with repeated success. Companies like OSI Pharma, Celgene, Amylin are just a few who are still independent and could provide great buys for big pharma. Combine one of these
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Author
companies with smaller biotechs and you could build a strategy around developing some drugs yourself, co-developing with other partners (possible future acquisition targets), co-promoting late-stage assets to free up resources for creative development strategies like fostering drug programmes. AstraZeneca is very good at this. License a drug to a company, have that company develop the asset in close ties with it and at some pre-determined point in the future, it gets the rights back if requested. If not, the biotech / pharma partner has rights to development or share a range of business development options. Another approach is the Pharmaceutical Development Company (PDC) option. One of the best companies to create and lead with great success using the PDC model is DeBiopharm, S.A in Lausanne, Switzerland. In the PDC model, a company acquires the drug asset which is generally at a PreIND or phase I stage and takes ownership. It then develops it through phase II, phase III or NDA. In return, the PDC gives milestone payment, royalties and / or sales kickers to the original source of the drug asset. Most PDCs don’t promote the products, they usually sell or out-license the asset to a larger company. The PDC and fostering models are great strategies for sharing resources, risk and allowing larger companies to leverage a stockpile of drug candidates on their shelves that may never be developed. Figure 2 depicts the overall strategic approach to drug portfolio development and management.
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Predictions for 2009 and 2010
GSK, Roche and Novartis represent some of the best possible examples of building a diversified and scientificallyrich big pharma and could very well use the multiple biotech M&A model. As Roche eventually acquires the remaining shares of Genentech it will have a fairly balanced small molecule portfolio / pipeline with advanced biopharma capabilities. Genentech, one of the two largest biotech leaders worldwide, has both short-term goals combined with long-term visions. Amgen should be seeking targets for M&A, not being acquired. Astellas might lose out on this bid with CV Therapeutics, but they can have a short list for M&A. Companies like Abbott Labs and Celgene provide great add-on revenues, deep pipelines and sound scientific platforms. Those companies seeking growth only through the mega merger approach will have limited success, take themselves out of contention during one of the most opportunistic times we’ve seen in decades and could spell potential disaster for the big pharma seeking to grow revenues in the medium to long term. Pfizer-Wyeth in the end won’t be any better than its previous mega merger deals and hopefully they will see this and push along with vetting and closing a few biotech M&A deals before the good ones are gone. In the end, these purge cycles are good because they force the crème de la crème to the top and this is what we need to bridge the gap in innovation among the Big Pharma companies.
Neil J Campbell is currently Chairman & CEO for Mosaigen®, Inc., a global Life Science development corporation, and Partner with Endeavour Capital Ltd., An Asian Venture Capital Fund. During his career, he has successfully developed and introduced over 200 products in healthcare, life sciences and information technologies. He earned his MBA and MA in Management Systems from Webster University, MO and his BS-BA from Norwich University. He is also Adjunct Professor at Carey Graduate School of Business – Johns Hopkins University.
ISSUE - 10 2009
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, joint actions of two or more parties to achieve a common goal. This is a straightforward concept in principle, but often more complex in the real world. Within the pharmaceutical and biotechnology sectors, one can easily identify at least six major classes of stakeholders, viz. private industry, academia, regulatory agencies, governments (policy and legislation), patient advocacy groups, and payers (public / private). Each of them can be involved in collaborative activities with one or more organisations in their own or other stakeholder categories. On a purely numeric basis, a single stakeholder could be involved in as many as 32 different kinds of collaborative interactions with organisations from their own or other stakeholder categories. When discussing collaborations as a class of business transactions, it may be useful to consider why a corporation should engage in collaborations at all—after all, the typical outcome of any collaboration involves the sharing of the upside with an outside party.
Begin at the beginning… and go on till you come to the end: then stop. Lewis Carroll
Alice’s Adventures in Wonderland
However, within that outcome lie the two fundamental reasons for engaging in collaborations. First, the belief that the apportioned, and anticipated return on investment from the shared outcome will exceed that which might be achieved independently. The second, and equally important driver for collaborations, is the recognition, by each party, that they have insufficient internal resources, e.g. cash, expertise, time, infrastructure or intellectual property, to independently achieve the desired outcome. Within the pharmaceutical and biotechnology sector, two fundamental objectives underlie much of what we do: First is the need to get effective therapies and service to patients with unmet medical needs; and second is the necessity to create and maintain sustainable economic models which allow for the continuous creation of needed products and services. Collaborations are, in the broadest sense, tools which can be used to achieve these objectives. In this context collaborations are classified into three categories—noncompetitive, pre-competitive and competitive.
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of collaboration, and consider their discussion / negotiation between the two match (or mismatch) with some essenThe first group, non-competitive parties. Such differences in valuation are tial aspects of the business model of collaborations, is best exemplified by to be expected. Each party is striving the sector. The essential hallmark of private industry-academia collaborato maximise their return on investment pre-competitive collaborations is the tions. Within the US, this model of (money, personnel and infrastructure), focus on the development of tools and industry-academia collaboration, with while simultaneously working to reasonstandards, and not the development its concomitant flow of innovation from ably reduce / limit their costs. of products and services. This aspect academia to industry has its basis in the of pre-competitive collaborations is Patent and Trademark Act Amendments Pre-competitive collaborations exemplified by one of the earliest and of 1980 (University and Small Business The second major class of collaborations, most often cited NCRA collaborations, Patent Procedures Act), more commonly pre-competitive collaborations, also have Sematech. It was initially established as known as the Bayh-Dole Act. Under the a legislative underpinning within the US, an industry / government collaboraprovisions of this act, universities, nonin this case, The National Cooperative tion for the development of advanced profit organisations and small businesses Research Act of 1984 (NCRA), and manufacturing methods for the US can obtain and retain ownership of, and the National Cooperative Research and semiconductor manufacturing sector, patents on, inventions funded by the Production Act of 1993. These laws were and was created in direct response to federal government. Additionally, the enacted to enhance the competitivethe perceived domination of this manuact requires that the universities actively ness of the US-based industries in an facturing sector by Japan. engage in the commercialisation of these increasingly competitive international patented assets. With this legal foundamarketplace. 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-operative collaborations in the pharmaceutipast 28 years, become increascal and biotechnology sectors. ingly important and currently Several points are notable. First, essential sources of innovation as mentioned above, all of these for the pharmaceutical and collaborations are focussed on The essential hallmark of pre-competitive biotechnology sector. the development of information, collaborations is the focus on the In non-competitive collabotools and standards, putting development of tools and standards, and not rations, such as those of industhem clearly in the pre-competithe 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 opporthe 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 collaboitself, 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 develand 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 comparanew 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 pharEnlight, are also focussed on problems the academic laboratory. maceutical and biotechnology sectors whose solutions are likely to provide Although the qualitative distriburepresent substantially less than 5 per significant competitive advantages only tion of outcomes, e.g. de-risked prodcent of the total. when combined with additional propriuct / service opportunity, scientific To begin to probe why this collaboetary, drug-specific information. This publication(s), is relatively straightforrative model is apparently not favoured synergistic linkage of commonly held ward, the quantitative prediction of the by the pharmaceutical and biotechnoland 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. Non-competitive collaborations
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Strategy
Sampling of pre-competitive collaborations in pharmaceutical and biotechnology sectors Group Name
Activity
Participants
Start Year
Pharmaceutical Aerosol Consortium
Identification of CFC-free propellant gases for aerosol delivery of drugs
Private Industry
1990
Dundee Kinase Consortium
Research on kinases and phosphatases for drug discovery
Private Industry, Academia, Government
1998
SNP Consortium / HapMap Project
Identification of Single Nucleotide Polymorphisms (SNP) and haplotypes associated with human disease states
Private Industry, Non-profit organisations, Governments, Academia
1999
Predictive Safety Testing Consortium
Identification of biomarkers to predict preclinical safety of drugs
Private Industry, Academia, Regulatory Agencies
2006
Biomarkers Consortium
Identification of biomarkers for risk assessment, diagnosis and treatment of human diseases
Government, Private Industry, Not-profit organisations
2006
SAE Consortium
Identification of SNP’s associated with drug-related Serious Adverse Events (SAE)
Private Industry, Academia
2007
Enlight Biosciences
Enabling technology incubation – first program: non-invasive imaging
Private Industry, Venture Capital Fund
2008 Table 1
To return to the possible reasons for the relative paucity of pre-competitive collaborations within the pharmaceutical and biotechnology sectors; although information / tools can be the subject of pre-competitive collaborations, they can also provide a competitive advantage to their owner. If an individual corporation has the resources and infrastructure to create a proprietary data set, extract useful information from that data set, and protect that information as trade secrets or patents, they will certainly do so. As noted earlier, a corporation is only going to collaborate in this effort when they have insufficient internal resources to complete the task on their own. Until recently, the complexity of problems, and size and complexity of the resultant data sets which were tackled by pharmaceutical or biotechnology companies were generally manageable as intramural projects, providing little impetus for pre-collaborative collaborations. However, with the arrival of “omes”, genome, transcriptome, proteome, metabolome, lipidome etc., some projects at this scale have become
too massive and “drug-relevant” data too sparse to be cost-effective as intramural projects, and consequently, albeit slowly, are becoming the foci of pre-competitive collaborations. Two additional factors may be contributing to the historically low numbers of pre-competitive collaborations. Until relatively recently, the standard pharmaceutical drug development model was inward focussed, with the belief that internal research and development could provide a sufficient number of commercially successful drug to sustain the growth of the corporation. Under that model, pre-competitive collaborations would have been unnecessary and perhaps unwanted. In recent years a more externally focussed drug development model has emerged, in which pharmaceutical companies have engaged in increasing numbers of non-competitive collaborations with academia. It remains to be seen if this trend towards utilisation of external resources will extend to the pre-collaborative space. An additional factor working against pre-competitive
collaborations may be related to the extraordinarily long product development life cycle which is unique to the pharmaceutical and biotechnology sectors. Any strategic initiative in the pre-competitive space is unlikely to have a significant impact on a corporation until 8 to 10 years in the future. Given the shorter-term revenue and expense pressures which the pharmaceutical and biotechnology sectors currently face, the allocation of scarce resources to highly speculative, pre-discovery activities may not be viewed in a favourable light. A final factor in this matter may be simply one of cultural inertia. The sector as a whole has much more experience and familiarity with other kinds of transactions, e.g. mergers and acquisitions, product in-licensing and joint ventures. Even if pre-competitive collaborations offer some theoretical advantages, in the absence of clearly documented examples of strategic or financial benefit deriving from participation in pre-competitive collaborations, there may be a degree of reluctance to be an early adopter of this strategy.
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Competitive collaborations
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Competitive collaboration landscape
Minimal overlap
In / Outlicensing Joint venture / Merger
Strategic alliance Acquisition
Skill sets / IP / Market Co-marketing Anti-competitive Anti-trust
Strong overlap
Equal
Valuation / Size
Not equal Figure 1
lack of overlap in market to avoid antitrust / anti-competitive issues. Finally, the “buy your competition” business strategy, in which a large entity may wish to acquire a smaller party operating within the same market segment, may run afoul of anti-trust / competition laws. Refinements of this schema are clearly possible. Nevertheless, this approach, even in its current form, may provide some clarification or rationalisation of the type of collaborative transaction chosen to achieve a desired outcome. In summary, collaborations involving the pharmaceutical and biotechnology sector, non-competitive, pre-competitive and competitive, may differ in their legal underpinnings, structure, complexity and value. However, all of these interactions are driven by: 1) the mutual recognition that some objectives can
Author
Collaborations between competitors are also regulated by large bodies of antitrust or competition law in all jurisdictions. Within the US, the Sherman Ant-Trust Act of 1890 briefly states, “Every contract, combination in the form of trust or otherwise, or conspiracy, in restraint of trade or commerce among the several States, or with foreign nations, is declared to be illegal”. Within this legal framework, the underlying need for competitive collaborations is the same as that of other collaborative types, i.e. the need to achieve an outcome which cannot be accomplished alone. To solve this need, a wide spectrum of collaborative activities between competitors (business-to-business transactions) has evolved. One way to structure and view the relationships between these different types of collaborations is to consider them in the context of a two-dimensional space as described in Figure 1. The first axis is the relative valuation and size of the two entities with respect to each other and the second axis is the degree of overlap of skill sets, or intellectual property or infrastructure between the participating entities. Utilising these axes, it is possible to place most competitive transactions within this space. For example, joint ventures and mergers are usually formed between entities of roughly comparable size and complementary skill sets or intellectual property. Licensing deals and strategic alliances are characterised by a minimal overlap in skills or IP (depending on the subject of the transaction) and are not particularly dependent on the relative size of the two parties. Co-marketing arrangements tend to be done between partners of roughly equal size, with a strong overlap in market, but some moderate degree of separation in call point or geographic coverage. Acquisitions are typically asymmetric transactions where the larger partner takes control of the smaller party and there is sufficient
only be achieved by the combination of resources from two or more parties, and 2) the mutual expectation that the joint outcome will provide a positive benefit to each party that exceeds what might be achieved by proceeding independently. Disclaimer: The opinions expressed in this article are personal opinions of the author and do not necessarily represent the opinions or positions of Genzyme Corporation or its senior management. Likewise, the identification of specific products, or organisations does not constitute an endorsement of those entities by Genzyme Corporation or its senior management. The commentary on, and summaries of, laws of the United States do not represent legal opinions on these laws. Full references are available at www.pharmafocusasia.com/magazine/
Bruce M Pratt works for Genzyme Corporation on identification and evaluation of early stage product opportunities, proactive outreach to academic and biotechnology sectors, and works with Corporate Development on issues related to product development.
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Strategy
New Patents for Old Drugs
Label-based strategies
in the United States
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Strategy
I
n recent years, particularly since the Dot-com stock market crash in 2000-2001, venture capitalists have been increasingly reluctant to fund US companies engaging in drug development. Such investments are often considered to be too risky, too capital-intensive, and to take too long to fit the new, more conservative venture capital model. Indeed, it has been estimated that only 1 in 100 preclinical drug candidates and only 1 in 10 drugs that enter US FDA clinical trials ultimately receive FDA approval. The average cost of developing a drug through FDA approval is approximately US$ 1 billion, and it takes up to 15 years from discovery to product launch. This
drugs. By starting with a drug that has already been in the clinic, risk is reduced in each category of concern. Approval time is shortened for drugs that have already been proven safe. The cost of the clinical trials is less, because pre-existing ADME and safety data can substitute for expensive research and trials. The risk of failure is also reduced for drugs having known safety and pharmacology. For all of these reasons, repurposed drugs are attracting more and more early-stage investment dollars.
not available for previously-approved repurposed drugs. Finally, the period of data exclusivity in the US FDA (during which a generic application will not be approved) is five years for NCEs, but only three years for repurposed drugs that are not NCEs (See exclusivity chart). Because a three-year exclusivity period is generally insufficient, development of repurposed drugs hinges on the availability of adequate patent protection.
The exclusivity problem
Generic drug approvals in the US are subject to a detailed regulatory scheme set up by the Hatch-Waxman Act in 1984. Applicants seeking approval of
A major drawback to the development of repurposed drugs is lack of exclusivity. These drugs simply will not be developed
The FDA, drug patents, and generic drug approval
Patent and regulatory exclusivities should both be considered when evaluating a repurposed drug
Repurposed pharmaceuticals are attractive candidates for clinical development, but only with sufficient marketing exclusivity. Patents that focus on the uses and compositions in the product label can provide up to 20 years of exclusive marketing rights.
Exclusivities applicable to US drug products
Ned Israelsen, Managing Partner, Knobbe Martens Olson & Bear LLP, USA
Patent term: 20 years from original filing date • Runs concurrently with regulatory exclusivity • NCE and original method patents often have little life left upon FDA approval • New 20 year term for label patents
combination of time, money, and risk has sent venture money fleeing for safer, quicker investments, albeit with a lower upside potential. Growing investments
One bright spot for start-up pharma companies and venture investors has been speciality pharmaceuticals (or repurposed drugs). Such products include drugs that previously fell out of clinical trials and new uses for old
without sufficient exclusivity to allow a reasonable return on investment. For New Chemical Entities (NCEs), this is usually not a problem, because the typical 20-year patent term (measured from filing) is sufficient. However, for repurposed drugs, the NCE patents often have little or no term left. Moreover, US patent term extension and European Supplementary Protection Certificates apply to the first approval or marketing authorisation of a drug, and so are
FDA gives regulatory exclusivity • 3 years for new indication • 5 years for first approval of NCE • 7 years for orphan drug • 6 months additional for paediatric data • Paediatric exclusivity attaches to end of all other exclusivities, patent or data
a generic drug typically do so with an Abbreviated New Drug Application, or ANDA. The primary scientific data required in an ANDA is the demonstration that the generic product is bioequivalent to the originally-approved drug. Expensive clinical trials are not required, because ANDAs rely on the safety and efficacy data generated under the original New Drug Application, or NDA, of the original innovator. However, if the original drug product or its use is covered
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by patents listed in the FDA’s Orange Book, generic marketing approval is effective only after the patents expire. The exception is when the ANDA-filer certifies that the relevant patents are invalid or not infringed. Such certification opens the generic drug company to patent litigation, and an automatic 30month 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.
Patent strategies for repurposed drugs often overlap significantly with those used for life cycle management of name brand pharmaceuticals
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 interactions and use in specific populations. With minor exceptions, the ANDA-filer must adopt the approved label. The Orange Book also focusses on the label, listing only patents for approved NCEs, drug formulations, and methods of use that appear in the label. Close coordination between regulatory and patent professionals can enhance correspondence between patent claims and the label. Extending exclusivity through label patents
A “label patent” is any patent that covers a method or product recited in the FDAapproved label. Because the ANDA-filer must adopt the product label, careful attention should be given to patenting new, non-obvious methods disclosed in the label. Repurposed drugs typically target a new patient population, new indication, or include a new dosage form, dosing regimen or route of administration. Corresponding methods of use in the label are all potentially patentable. Unlike the rule in most countries, methods of medical treatment are patentable
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Drug Life Cycle Management – Common patent types Enantiomer patents • Pro: NCE claims; Orange Book listable • Con: Current obviousness standard makes patenting more difficult Composition / formulation patents • Pro: Can cover ideal product or most stable formulation; Orange Book listable • Con: Generics can usually design around; obviousness Crystal form (polymorphs, amorphous) • Pro: Cover stable or desirable product; Orange Book listable • Con: Generics often design around or invalidate Synthesis or manufacturing method patents • Pro: Cover actual production process • Con: Not Orange Book listable; often designed around Key intermediates • Pro: May represent a chokepoint in synthesis • Con: Not Orange Book listable; often designed around
in the US. In short, any time the label instructs the patient or physician to do something, consider whether that method is patentable. The patent term for such new patents is 20 years from date of filing, which can significantly extend the period of exclusivity for the repurposed drug. Those developing repurposed drugs should not overlook the possibility of obtaining patents on seemingly minor
improvements or innovations that are reflected in the label. Unlike traditional patent strategies, which focus on obtaining broad patents to cover potential modifications, label patents only need to cover the exact method disclosed in the label. This, in turn, can improve patentability by allowing inclusion of very specific details in the patent claims that are not obvious in light of the prior art. Obtaining several such
Strategy
Label patents are not necessarily easy to obtain
In the US, patents can only be obtained for inventions that are both novel (new) and non-obvious. In the pharmaceutical area, novelty problems often arise when trying to patent a newly-recognised property of a drug. A result that inherently occurred in the prior art is not considered novel, even if that result was unrecognised. In dealing with inherency issues, is it helpful to ask whether something different is done as a result of the discovery. If the answer is in the affirmative, then including those new actions in the claim can usually overcome the inherent novelty rejection. Obviousness can be a major issue for label patent claims. In 2007, the US Supreme Court decided KSR vs. Teleflex, which overturned the requirement that the prior art must contain a teaching, suggestion, or motivation to make the new invention. This case makes patents harder to get and easier to invalidate.
Examples of label patent claims • Administering a different dose to the elderly • Titration of dosage over X days • Titration pack with escalation dosages • Administer drug without food • Administer a dosage form that achieves plasma level of X, measured Y hours after dosing • Administer with an anticonvulsant in patients at risk of seizure • Informing the caregiver or patient to avoid taking the approved drug with drug • Drug in combination with unique packaging • Drug in combination with delivery device, e.g. inhaler • Unit dosage of drug with particular dissolution values or resulting pK values.
Although some subsequent cases suggest that inventions made through routine experimentation may well be obvious, such a rule may not apply to unpredictable technologies, such as pharmacology. The very simplicity (and to some, triviality) of some label patent claims may result in obviousness rejections. Good strategies for overcoming those rejections include emphasising the unpredictability of the new discovery, presentation of comparative data (usually available from the clinical trials), long felt need, clinical importance, and lack of suggestion in the prior art. The ability to write very narrow claims (as narrow as the label language) can also help overcome an obviousness rejection, because it is more
Author
patents enhances the odds of having a patent that is held valid and infringed at the conclusion of ANDA litigation. It is desirable to identify potential label patent opportunities prior to public disclosure. When reviewing new clinical data, one should look carefully for unexpected or unpredictable results. In addition, it is helpful to ask what changes will be made in the label or the use of the drug as a result of the new data. Each of these areas represents fruitful ground for obtaining label patents. A word of caution: in case of public companies, clinical trial results are often disclosed very quickly, leaving little time to prepare patent applications on new observations. In this situation, close coordination with highly-responsive patent counsel is important. Although there is a one-year grace period for filing patents in the US, most non-US countries have an absolute novelty requirement. Thus, filing the US application before any public disclosure can preserve foreign patent opportunities.
difficult to show obviousness of all the details of such a claim. In addition to overcoming these bona fide legal issues, applicants may face less tangible psychological issues in obtaining and defending label patents. Pharmaceutical inventions in general and follow-on patents in particular may be reviewed more closely in both the Patent Office and the courts. Although the original NCE and method of use patents are often well respected, the same does not always hold true for follow-on patents. The latter are often filed as part of a drug life cycle management strategy with the objective of delaying or preventing generic competition. In light of the negative image of pharmaceutical companies and the public interest in the availability of lowpriced generic drugs, exclusivity-extending patents receive enhanced scrutiny. Patents for repurposed drugs have a very different purpose from Big Pharma’s life cycle management patents. They often serve a gating function; in other words, without the patent, the repurposed drug will never be developed or available to the public. However, because of the overlap between patent strategies for protecting repurposed drugs and those for product life extension, repurposed drug patents may suffer from the same negative perceptions in the Patent Office and the courts. Despite these perception issues, in the end, the Patent Office and the courts are bound to follow the same rules of patentability in all cases. Label patent applications do make it through the Patent Office, and the resulting patents provide major value to innovators, drug developers, investors, and the public who receive the benefits of new and otherwise unavailable therapies.
Ned Israelsen is a lawyer and Managing Partner of the San Diego office of Knobbe, Martens, Olson & Bear, LLP, California, USA. He is registered before the US Patent and Trademark Office, and advises clients in the area of pharmaceutical and life science patent law, including worldwide protection of new and repurposed drugs.
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Strategy
Innovation
The key growth mantra
Sasikant Misra Deputy Director, Confederation of Indian Industry, India
I
ndian life sciences industry is undergoing rapid transformation. New and emerging business models are changing the way business will be done over the years. With the advent of the Product Patent regime Indian life sciences industry is beginning to realise that Innovation is the key to growth and in achieving global scale in the long-term. Innovation which is expected to be the leading growth driver, has made the Indian life sciences industry focus on building their portfolios of speciality and niche drugs or entering into alliances with the innovator companies to tap this key business opportunity. Indian life sciences industry is making constant efforts to have a thrust on innovation as the key value creator in all the aspects of the business through technology, services, manufacturing and excellent quality initiatives to come out with innovative products matching global standards. The industry is embracing innovation and the latest technology to bring to the market novel drugs for treatment of unmet medical needs innovation is being imbibed in scaling up expertise in advanced research areas, building high value intellectual property, creating optimal funding mechanisms and the entrepreneurial environment to take
ideas from lab to market, strengthen and ensure consistent supply of capacity to encourage research and foster a favourable policy and incentive framework. The Indian life sciences industry has been innovating within its means right from its early days by mastering the art of process re-engineering during the process patent regime. With the onset of the product patent regime, the industry felt the need to build expertise in formulation research and discovery research in order to achieve global competitiveness. The Industry today, strives to create a sustainable system of innovation that consistently ensures medicines for all, profitability and global market leadership. Some of the key focussed areas for the industry are Industry-Academia linkages, public-private partnerships and key organisational initiatives. Innovation requires cutting-edge technologies and has a long incubation period. A Cooperate and Collaborate strategy has proven to be successful in this scenario. Indian companies have adopted this strategy which is reflected in the number of strategic R&D collaborations across the drug discovery and development value chain making the transition from a service-based to a partnership-led relationship. Further collaborative alliances in which both the stakeholders pursue a high-risk and high-reward strategy are increasingly appearing on the alliance landscape. The focus of the Indian life sciences industry is on Profitability—to ensure sustained growth in all the key pharma markets of the world, through innovation in research and development while maintaining high standards of quality and ethics. The industry aspires to emulate the success of the global pharma industry
The feedback on this article can be sent to sasikant.misra@cii.in or sasikant_in@yahoo.co.in.
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and is striving to create a balance between earning healthy profits and realising their responsibilities towards society. In order to acquire a global status, the Indian life sciences industry places its foremost priority on well-established and robust regulatory system. The industry is looking at innovation in the regulatory standards, which play a key role in the progress. The industry is looking at a strong, well-equipped, empowered, independent and professionallymanaged body which can address the key regulatory issues and build faith in Made in India brand by establishing a robust regulatory system on the lines of US FDA. Innovation can play a vital role in providing access to improved healthcare to patients. Public health objectives will be realised if innovation is fostered. Healthcare benefits both the individuals and the economy as well. Most of innovations today are patient-centric. The Indian life sciences industry is inculcating innovation as the mantra across different functional departments in key areas of the organisation such as quality, sales, marketing and creating differentiation through innovative platforms to enhance effectiveness and improve business performance. Life sciences industry, which is knowledge-based, is undoubtedly one of the most innovative sectors of the Indian economy. The industry is looking at innovation in all aspects of the business and its strategy in tapping key opportunities in the current and emerging business segments and key emerging markets to achieve the required growth and scale in the short and long term.
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Targeted
Therapies A Sustainable Business Model?
F
or many rare diseases, there is as yet no satisfactory treatment. Rare diseases are defined as lifethreatening and / or serious and chronic diseases, according to the European Orphan Medicinal Products regulation. These diseases represent a high unmet medical need. Rare diseases, with their genetic origin and because of small number of patients to be treated, require effective diagnosis linked to treatment.
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So, orphan drugs, with their targeted nature, are of immense use and could pave the way for future developments in healthcare Since 70 to 80 per cent of rare diseases are genetic in origin, the right diagnosis before treatment is of high importance to ensure that the patient not only gets the right treatment but also does not suffer from side effects. The rarity and severity of the diseases not only mean lesser patients are treated but also result in a high compliance because the medicines work. Rarity also leads to higher costs, but orphan drugs also have a higher innovative nature and a higher benefit
Strategy
Personalised medicine breaks the cycle of trial and error medicine and helps ineffectiveness rates of medicines to decrease dramatically. Orphan drugs, targeted therapies for rare diseases, with their innovative nature and improved efficacy, make it a precursor for personalised medicine therapies and can offer a viable business model to expand from. Society should develop consensus for such new models in multi-stakeholder partnerships which will also make it sustainable. Erik Tambuyzer, Senior Vice President, Corporate Affairs, Europe and International, Genzyme Corporation, Belgium
than average drugs through their better clinical efficacy and effectiveness. In the European definition, orphan drugs are unique treatments, meaning there are no alternatives available. This is the case for about one-third of the orphan drugs approved in Europe) or make a better therapy over (an) existing one(s), which is the case for the other two-thirds of approved orphan drugs in Europe. Not only economic factors but social benefits also need to be taken into account as well: many patients affected by rare diseases had no therapy available before and such therapy is often a first in human history. Innovation, rarity and complexities caused
The current debate in society is about the value of innovation in healthcare: our society supports such beneficial or
valuable innovation to the benefit of patients, including those in the case of orphan drugs. Even in difficult economic times, such beneficial innovation must be encouraged and the resulting products must be reimbursed when they have measurable and demonstrable value. However, given the rarity of the diseases studied, sufficient time to gather data to show such value must be granted.
In order to understand the concept of rarity, Figures 1 and 2 provide the number of patients treated in the US in 2006 for a number of non-rare disease and, from Gleevec (Glivec TM) downwards, for rare diseases. The application of models used in health economics introduces further challenges to the development of orphan medicines and to the discussion about their reimbursement. Cost-Effectiveness = Cost / Effectiveness, where cost is raised by rarity, but data to calculate effectiveness are limited by rarity. Therefore, rarity is affecting both the factors of the equation making the outcome much more uncertain as it grows. Based on this, it has to be clear that cost-effectiveness cannot be the only decisive factor. Current definitions of health technology assessment, therefore, include other factors such as equity, fairness, ethics and social values. Politicians need to take responsibility to reward innovations in this field to allow them to happen and to continue. As shown by the consultancy company Alcimed in a report for the European commission in 2004, pricing is a function of the rarity of the treated disease. Therefore, the prices of orphan drugs, given that their development cost is not necessarily lower than the cost to develop a medicine for a common disease, will be higher than the prices of drugs for treating
Rarity visualised – Commonly used medicines Patients ('000) Treated (US 2006)
Nexium Lipitor Singulair Fosamax Zoloft Plavix Advair-Diskus Celebrex Aranesp Epogen Gleevec
Orphan Drug (<200,000 prevalence in US, < 250,000 in EU)
Figure 1
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The future of personalised medicine
Diagnostic and therapy combinations which are being marketed today Enzyme replacement therapies with genetic confirmatory tests to treat lysosomal storage diseases such as • Gaucher’s disease with Cerezyme • Fabry’s disease with Fabrazyme and Replagal • Pompe disease with Myozyme • Hunter’s disease with Elaprase • Hurler-Scheie disease with Aldurazyme • MPS VI with Naglazyme Oncology drugs such as • Her2 and Herceptin (in breast cancer) • BCR-ABL and Glee(i)vec (in leukemia) • UGT1A1 and Camptosar dosing • ER/PR tests with drugs like Tamoxifen (in breast cancer) FDA recently approved a label change to recommend a test with two mutations to help with Warfarin dosing in cardiovascular field
Rarity visualised – Medicines for rare diseases
Patients treated (US 2006)
Soliris based on 2007 estimates
a (more) common disease. As such, prices largely depend on the patient population to be treated. As a consequence, the application of the same rules of costeffectiveness for orphan drugs, and especially for drugs for very rare diseases, will
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Figure 2
not be appropriate, as this would result in orphan drugs and even more clearly the so-called ultra-orphan drugs being excluded from reimbursement since they often do not reach the required Quality Adjusted Life Year (QALY) limit.
Further, drawing the analogy with personalised medicine, a future with more compliance and far less side effects would be the goal. This will ultimately result in costs going down, as only the right medicine would reach the right patient and minimise side effects. In order to do that, the following series of questions need to be answered: • Which medicine should I use? • How much of the medicine do I need? • Is the medicine working? • Is my disease controlled or gone? The old paradigm of trial and error medicine, based on the sequence of an observation with an action followed by an observable response is only successful when it leads to innovation and improved standard of care. But it fails when we settle for “trial and error” medicine as the standard of care. The new paradigm of personalised medicine links diagnostic tests to action and therapy. This happens by having an observation confirmed by a test and have it followed by appropriate physician actions which will result in a predictable response, that breaks the cycle of trial and error medicine and helps the patient. Personalised medicine leads to the right drug for the right patient. It results in providing benefits without toxicity. It saves patients from the 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 ranging from 40 to 75 per cent, but this percentage will dramatically decrease with the venue of personalised medicine. No future without challenges
The current evolution in evidence-based medicine also comes with challenges: • Physicians are being overwhelmed
Strategy
Balancing fears versus hope • Patients want better treatment but need information • Physicians want better products but are being pressured for economic effectiveness • Industry wants a fair return on high and risky investments • Payers are afraid of the impact of targeted therapies and personalised medicine on health care budgets. They look at the experience with orphan drugs and fear a tsunami of personalised medicines at orphan drug prices.
Test to increase drug efficacy / Quality of care Therapeutic Area
Ineffective Rate (%)
75%
Spears et al. TRENDS in Molecular Medicine Vol. 7 No. 5 May 2001
parts of the healthcare community. • Payers face difficulties to follow the rapid evolution of the diagnostics / genetics field, but, demand evidencebased medicine. They also want to make payment conditional on drug effectiveness, but face challenges as we have discussed above. Payers fund their own databases on patient outcomes, which they usually don’t share with other stakeholders. In demanding tests for evidence-based medicine,
Author
by the volume of the available data, so, they need more tools to identify and track test / drug combinations, as well as need more education on diagnostics and genomics. They also need more treatment guidelines and are organising themselves into expert centres. They may carry an increased liability risk confronted with patients who are more vocal, informed and organised. • Diagnostic testing laboratories perform intense data acquisition, with high manipulation and storage requirements, while they face complex reimbursement challenges with new technologies coming into routine practice. They also face issues based on expanded intellectual property portfolios and enjoy an increased focus and scrutiny from all
Figure 3
they require the providers to prove the relevance of such tests to the patient and the physician. • Regulators face increased concerns about safety of medicines, and need to remain up-to-date on the new technologies. Such new technologies may bring along the need for adaptive clinical trials as many new insights are gained while the trials progress. • Industry is facing vastly increasing costs driven by the increased demand for data and ever more complex clinical trials, while at the same time facing downward pressure on prices and a more complex reimbursement negotiation 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 treatments coming onto the market. Clearly, having a market for personalised medicines is in the society’s best interest. We must all work on making it happen! As the public image of the pharmaceutical industry is challenging, better and clearer communication is needed to explain the contributions it makes to society. And while no company on its own can change the sector’s image, industry must work together. Personalised medicine represents a great opportunity to change public image of the industry for the better!
Erik Tambuyzer is Senior Vice President of Corporate Affairs Europe and International at Genzyme Corporation. He is a founding Board member and past Chairman of EuropaBio, the European Association for Bioindustries, and founder of its Ethics Working Group, as well as the Chair of the EBE / EuropaBio Rare Diseases and Orphan Drugs Task Force.
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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 pharmaceutical development in the first decades of this century will be dominated by the “personalised medicine” concept. Personalised medicine encompasses the development and marketing of molecular tests which help to target the use of pharmaceuticals and biologicals in ways that maximise their effectiveness. Of course, lab tests have always guided diagnostics: for high glucose, a physician will diagnose diabetes and prescribe insulin, and so a lab test was paired with a drug. But personalised medicine, as the term is used, almost always involves carving out new subsets of patients with a particular form of disease, such as Herceptin-sensitive breast cancer. The interactions between the development of complex tests, drug trials, regulatory approval, and drug marketing will cause substantial shifts in the way healthcare is delivered. One obvious business issue (a smaller market for a more specific drug) has dominated thinking about how personalised medicine will develop, how it will impact the pharmaceutical industry, and indeed, whether it is “good” or “bad” for pharma. Because that topic has been discussed so
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frequently, the present article will focus on other ways in which a new era of interactions between lab tests and drugs will stress existing business models or require the development of new ones. We emphasise that there is no single model for clinical trials which incorporates genetic or other complex molecular information. There are at least three basic clinical models (combinations of these models are also possible) and they are as follows: Evidence-based medicine and diagnostic tests
Throughout the developed countries, government-based and private insurance systems are showing rising interest in the rigorous application of evidence-based medicine to control costs, by reducing unnecessary or low-yield interventions. Clinical trial experts and payer decision-makers are quite familiar with outcomes analysis of therapeutic trials. In general, control and treatment groups are matched and randomised. To the degree possible, subjects and evaluators are masked to the interventions offered. Outcomes and adverse events are statistically compared. Controversies over the
choice of clinical endpoints, or the use of clinical versus surrogate endpoints, are debated but gradually move towards a consensus. For example, is a negative Prostate Serum Antigen (PSA) at two years an adequate marker of effective radiation treatment for prostate cancer, or should the therapy be considered experimental until ten-year data are in hand? Even when regulators in different countries differ in their decisions, the basic issues for therapeutic trails, such as the choice of endpoints and the weighing of risks and benefits, are familiar. The tools for assessment of diagnostic tests are very different, and the usual terms of art like sensitivity and specificity, familiar from college statistics, fall far short when the actual decision point for regulators and payers rests on the clinical utility of a test. For example, “sensitivity” can mean the chemical threshold of a test—does it measure down to 0.1 ng/ml of PSA? Sensitivity and specificity are usually used in statistical sense, describing the performance of the test in known populations of cases and controls. The clinical accuracy of the test depends on the base rate of positive and negative cases in the
Strategy
Clinical models 1. Drug targeted by clinical trial The already-classic example of this approach is the identification of Her-2/neu as marker for breast cancer patients who are likely to respond to trastuzumab (Herceptin). Alternately, we could classify Her-2 / neu-negative patients as ruled out for trastuzumab therapy. There are already several examples of this model in oncology, some of which emerged only after the drug’s regulatory approval. For example, increasing evidence suggests that cancer monoclonals which target the EGFR receptor are ineffective in patients whose tumour has a mutation downstream of EGFR which tonically activates the KRAS gene regardless of whether the monoclonal neutralises the surface receptor for EGFR.
2. Drug rescue by identification of adverse events Many drugs cause distinctive adverse events only in a minority of patients. To some extent, this is a truism: otherwise the drug candidate would not reach the market. A molecular cause for the uncommon adverse events might now be identified either before launch or during post-marketing surveillance. An example is identification of the HLA B*5701 genotype, which is associated with serious adverse events in response to abacavir (Ziagen). This test became a recommended diagnostic only several years after the drug’s launch, and improved the acceptance of the drug. It also
population at hand, which allows prediction of true and false positives and negatives. Sometimes, other already known characteristics of the patient will be calculated together with test results to give a more sophisticated prediction for the test in the patient at hand (Bayesian statistics). All of these statistics become much more complicated for diagnostic tests that have a spectrum of results, rather than just positive or negative results. Meanwhile, specificity and sensitivity lose much of their meaning for genetic tests that answer whether the patient does or doesn’t have the gene in question; the accuracy of the test is essentially 100 per cent. But even here, because of untested mutations or interactions with other untested genes with superimposed functions, the clinical variance accounted for by the gene may be much less than 100 per cent. When the results of the test are proposed for clinical practice, differ-
helped in avoiding the prescription of the drug in the subgroup of patients at risk.
3. Third-party innovator differentiates members of a drug class A third-party innovator (or academic laboratory) identifies genes which allow choice of the drug in a drug category which is best suited to individual patients. For example, genes which optimise choice of statins could be identified and commercialised. Such a test, if developed, would allow the genetic profile of patients to be assessed so that a physician can prescribe the statin which is most likely to be effective. So far, we lack clinical examples of this model. The most likely reason is limited motive for this clinical trial investment by any single pharma or diagnostics company, since a pharma may lose market share and a diagnostics company may be unable to set a price high enough to repay the trial. Alternately, the a priori development risk may seem too high, since there is no certainty that a small gene panel could be found and commercialized that would classify statin patients effectively. We can use three categories to highlight the diversity of gene types that may contribute to personalised medicine. Like the three clinical models just discussed, the three gene categories shown here are not absolute, but they do illustrate the diverse biologies which are being studied to support personalised medicine.
ent evaluators will differ as to whether the test is well-enough established for clinical use. Often, evaluators will differ sharply on whether enough is known about the test in practice to recommend the test to be used routinely. Paradoxes of clinical trial ethics
A distinctive problem with diagnostic tests, as opposed to therapies, occurs when retrospective data analysis suggests that a clinical use of the test is likely but not certain to be valid—say, 70, 80 or 90 per cent likely. An example occurred when retrospective studies of clinical trials with EGFR-blocking monoclonals found them to be ineffective if a downstream gene, KRAS, was constitutively activated due to a mutation. Because the results of the retrospective study are incompatible with clinical equipoise, it is impossible to conduct a clinical trial where cancer patients with KRASactivated tumours are randomised to
receive EGFR therapy, a therapy which is very likely to be ineffective for such tumours. However, the state of information at this point may be criticised due to the fact that retrospective trials are fraught with confounding variables and a critic can quickly cite many retrospective conclusions that were invalidated by prospective controlled trials. Payers may question whether the cost of the molecular test should be covered, if its clinical use is uncertain. Although the resulting debate over levels of evidence may seem arcane, this scenario is fairly common with diagnostic tests. Development risk for complex diagnostics
At present, relatively few pharmaceutical or biotechnology firms have the in-house capabilities to develop innovative molecular diagnostics de novo and carry them through commercialisation. Therefore, when tests are used as early as clinical
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trials, an outsourcing contract or a more sophisticated contractual partnership exists between a test developer and the drug developer. Contractual issues can become very complex and go beyond the scope of this article. But as one example, the freestanding test developer must develop a commercialisation-ready test by the beginning of Phase II. This is because regulators will be very sensitive to technical variations between the test used in clinical trials and the test that will be commercially available after drug launch. Therefore, most of the developer’s sunk costs occur early, although the drug candidate has 90 per cent risk of failure that any drug has at the beginning of Phase II trials. The drug manufacturer will be concerned about lock-in to a contractual relationship with the test manufacturer, while the test manufac-
turer will worry about a competitor who could produce a rival test after the risky and costly proof-of-concept stage has been passed. Intellectual property on the diagnostic test alone may be more difficult to defend, even in the short term, than the pharma’s core patents on the molecular structure of the companion drug or biological. Regulatory challenges for complex diagnostics
Complex diagnostics raise a number of regulatory challenges. For example, several tests at the forefront of personalised medicine are too complex to be packaged as kits. An early example is the Trofile test (Monogram Biosciences), a gateway test to the use of a newgeneration HIV anti-viral, maraviroc (Selzentry). The test requires gene-splic-
ing steps and is currently run at one centralised and standardised laboratory. In the United States, this category of test is called a “laboratory-developed test” or LDT. In other cases, the lack of a “gold standard” test or variability of testing between laboratories has raised questions about the accuracy of diagnostics even for the prototypic personalised medicine test, the Her-2neu test (See Fitzgibbons PL et al., Arch Pathol Lab Med 2006, 130:1440-5, and references therein). Another regulatory challenge which may have seemed like science fiction only a few years ago is the prospect of prescribing cancer drugs based on oncogene characteristics rather than gross tumour type. Today, clinical trials for cancer drugs are categorised by the type of cancer: small cell lung cancer,
Molecular models 1. Enzymes of metabolism and transport Across many different drug classes, human beings are remarkably diverse in their metabolism and transport of drugs. For a given drug, a patient may be a typical metaboliser, slow metaboliser, or ultrametaboliser. In the United States, the FDA has remarked on pharmacogenetic information (usually related to metabolism) of over 100 drug labels (Frueh FW et al., Pharmacotherapy, 2008, 28:992-8). However, very few of those drugs have clear labelled instructions for changes in dosage or carry a direct recommendation that testing should be undertaken before prescription. Genes related to tamoxifen metabolism, warfarin metabolism and pharmacodynamics are currently being investigated for clinical utility.
2. Drug target Molecular analysis of drug targets has found the quickest clinical application in chemotherapy. Examples include expression of Her-2/neu as a marker of response to trastuzumab (Herceptin), expression of the EGFR receptor or related downstream mutations as markers of response to cetuximab (Erbitux), and expression of the bcr-abl rearrangement with respect to imatinib’s (Gleevec’s) effectiveness in individual patients.
3. Markers of adverse events (other than metabolism) Examples in this group include hypersensitivity reactions (the HLA B*5701 variant and reaction to abacavir) and idiosyn-
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cratic adverse events such as myopathy (an infrequent adverse event caused by statins) or rhabdomyolysis (a life-threatening but extremely uncommon event caused by statins). Ideally, early identification of vulnerable patients could allow clinical trials to proceed and the drug to be marketed, if always paired with a genetic test. On the other hand, for highly toxic but extremely rare genotypes, there are unwelcome economic issues such as number-needed-to-test to obtain a better outcome. For example, it is impractical to give a US$ 200 genetic test on 10,000 patients to identify one rare patient who would be vulnerable to a severe adverse event. The design and analysis of therapeutic trials is costly and complicated, and so is the conduct of diagnostic test development, but for different reasons. The business dynamics and regulatory requirements of both therapeutic trials and diagnostic test trials must be satisfied to bring a combination test and drug to market, while meeting prospective estimates for development risk and likely economic return. Putting all of these factors together may mean that the net risk and complexity is actually squared or cubed relative to a more routine therapeutic trial. Six ways in which potential difficulties manifest themselves include: • Evidence-based medicine • Paradoxes of clinical trial ethics • Development risk for complex diagnostics • Regulatory challenges for complex diagnostics • Economic hurdles for complex diagnostics • Challenges in marketing.
Strategy
adenocarcinoma of the pancreas, renal cell carcinoma, and so on. However, we are already seeing targeted cancer drugs which are effective in ways that are completely unforeseen by legacy histologic classifications of tumours (Both chronic myelogenous leukemia and gastrointestinal stromal cell tumours respond to imatinib, if they express the bcr-abl oncogene translocation). Although there are some highly effective cancer / chemotherapy regimens, the impact of chemotherapy on many cancers is notoriously limited (e.g. 5-10 per cent of patients benefit, or alternatively, the number-needed-to-treat is 10 to 20 or more.) Therefore, the hurdle rate for results matching tumours to chemotherapy based on molecular expression panels (e.g. tumour X in a case that also carries the bcr-abl mutation) should be equivalent efficacy. But all regulatory conventions, and payer guidelines for chemotherapy coverage, are based on the legacy approach to classifying tumours histologically and studying them in drug-specific trials.
wise and pound foolish. For example, a hypothetical new test which could save the healthcare system US$ 100 million over a few years costs US$ 10 million in clinical trials to develop and needs to be sold at US$ 300 to cover risk, investment, and marginal cost; but the test will never exist if the reimbursement is locked at US$ 20 and the US$ 100 million will never be saved. New regulatory schemes for payer systems will need to adapt to some form of valuebased reimbursement at least where the net outcome is to encourage cost-saving forms of investment. One bright spot in the economic logic does occur if the healthcare system bundles a spectrum of interlocking costs together, such as the costs of cancer chemotherapy and chemotherapy diagnostics. Here, the test manufacturer could command value-based market prices in its direct transactions with chemotherapy centres, if the net outcome of test usage was ultimately cost-saving for the chemotherapy centre.
Economic hurdles for complex diagnostics
Historically, there has been relatively little advertising or detailing of laboratory tests, probably because there were undifferentiated commodity products with low margins. Therefore, there is little apparatus in place to educate physicians about new molecular diagnostics, and older physicians may find the topic of molecular diagnostics quite confusing. One solution could be integration of electronic medical records and e-prescribing programmes with pop-up information on relevant diagnostic tests, or flags in the healthcare system that hold a prescription until a relevant diagnostic test has been performed.
Author
Laboratory tests have traditionally been treated as commodities in the medical marketplace. In most countries, costs of laboratory tests are either bundled with episodes of care or paid at fixed rates based on the chemistry of the test (e.g. nucleic acid amplification, US$ 20; serum immunoassay, US$ 25; flow cytometry, US$ 50). These fixed fee schedules appear to be adequate for the development of new tests of the same type when the main parameter of the test is accuracy. Fixed fee schedules also encourage technological change to produce the same types of tests faster and less expensively. However, laboratory test reimbursement that is administratively locked to the marginal cost of the test’s chemistry is incompatible with significant clinical trials to develop and launch a novel type of test. In economic terms, this can be very inefficient, penny
Challenges in marketing
In addition, diagnostic tests have a rare reverse-supply chain configuration. Instead of manufacturing a drug or device in a factory, shipping to a regional warehouse, and then a retail location (pharmacy or hospital), a diagnostic test requires shipping of the test from thousands of doctors’ offices or clinics backwards to a central laboratory. The logistics become quite formidable for very complex diagnostics that are only performed at one or a very few locations, and especially if the samples must be chilled or frozen at the point of collection and during shipping. Moving forward
Speculation on the slow growth rate for personalised medicine focusses too much on the supposed reluctance of the pharmaceutical industry to investigate diagnostics which could carve down the market size of new drugs. When discussion stops there, the analysis has fallen into a mental trap, in which one credible answer is found quickly and this halts the search for alternative and perhaps more important explanations. In fact, in the past year, several CEOs at leading pharmaceutical firms have stated that personalised medicine—the pairing of diagnostics and drugs—has to be a core competence of their development strategy. Numerous additional barriers to development and commercialisation were described in this article, but they can be dealt with by good policy and appropriate innovation in the regulatory process. Only by elevating the addition problems into view will they become part of the dialogue on personalised medicine and part of our solution kit in moving the healthcare industry forward for more effective and accurate patient care.
Bruce Quinn is US physician executive in the law firm Foley Hoag LLP. A former medical school professor and strategy consultant with Accenture, from 2004-2008 he was the regional medical director for the Medicare program in California.
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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 pharmaceutical industry had followed a trial-and-error approach to medicine by applying a drug to an entire patient population when treating a given disease. As a result, the overall drug efficacy in selected diseases was only around 50 per cent. Moreover, adverse drug reactions were among the leading causes for hospitalisation and mortality in the US. Given the associated cost burden with this approach and the vastly improved understanding about the important role of biomarkers in the light of disease biology and drug interactions, a significant change towards more targeted drugs was initiated by the pharmaceutical industry since then. During drug research, biomarker activities are aimed at validating drug targets or to further the understanding of drug-related pathway biology and the underlying disease mechanism. In this regard, a significant number of whole genome association studies have
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been performed with a focus on gene selection. During drug development, the current focus is clearly on applying biomarker strategies to optimise clinical study designs to facilitate a faster path to proof-of concept and a go / no go decision with respect to clinical outcome. Eventually, this approach may even lead to companies conducting smaller clinical trials through patient stratification with the potential to market a drug based on a respective diagnostic outcome to guide treatment decisions. In addition, using genetic biomarkers may help pharmaceutical companies enhance product differentiation and potentially extend product life cycles by targeting therapies earlier on in the treatment of disease, or even in disease prevention. To date, significant biomarker activities are focussed on the field of oncology where more targeted drugs have demonstrated improved efficacy and, therefore, often command a higher price. Some of
the most recently marketed cancer drugs have found their niche with the aid of biomarker-related molecular assays. For example, Roche’s Herceptin and GSK’s Tykerb both treat breast cancer patients whose tumours contain multiple copies of a gene called HER2. In addition, Roche’s Tarceva, Imclone’s Erbitux and Amgen’s Vectibix all target EGFR which is activated in various ways in many forms of cancer. Novartis’ Gleevec was followed by newer ABL inhibitors including BMS’ Sprycel and Novartis’ Tasigna which address patients with BCR-ABL mutations resulting from Gleevec treatment. All drugs mentioned are supported by diagnostic assays that have been specifically developed for the respective biomarker / drug. In addition to oncology, strong efforts are on in other disease areas with large patient populations with a high clinical need. Such disease areas include Central Nervous System, Inflammation and Metabolic Disorders.
Strategy
Response rates for vilazodone and placebo in biomarker-positive and - negative subgroups
Mean MADAS +/-SEM
35 Placebo with biomarker
Vilazodone with out biomarker
Placebo with out biomarker
Vilazodone with biomarker
25
15
6.9 Biomarker patients had 2x response at week 8 30% of patients are biomarker positive
5 1
Clinical Data Inc. is a global biotech company with over a decade of experience in discovering and applying biomarkers to drug development. It is developing vilazodone, a targeted therapeutic for the treatment of major depressive disorder. Vilazodone is a geneticallyguided serotonergic antidepressant with a dual mechanism of action: a Selective Serotonin Reuptake Inhibitor (SSRI) and a 5HT1A partial agonist. In late 2007, the company announced positive results from its first Phase III registration trial which compared vilazodone to placebo in 410 patients. This trial also helped to identify proprietary candidate biomarkers for a potential companion pharmacogenetic test for assessing a patient’s likelihood of response to Vilazodone. As depicted in Figure 1, a biomarker -positive treatment group showed a two-fold increase in terms of efficacy after eight weeks compared to the biomarker -negative subgroup but also compared to placebo. Interestingly, this biomarker subgroup represents about 30 per cent of the total depression in patient population. Clinical Data has almost completed its second Phase III registration trial, which is designed to confirm these findings from the first Phase III study and to validate the biomarkers that were identified. Results of the second study are expected in the first half of 2009,
2
3
4 Week of treatment
5
and the company anticipates filing a new drug application (NDA) with the US FDA for vilazodone for the treatment of major depression by the end of 2009. Biomarkers represent an attractive, and arguably more efficient, approach to developing targeted therapies with improved efficacy and safety, as well as predictive diagnostics that can be used to guide treatment decisions. At the same time, biomarkers offer the opportunity to reduce both the technical risks associated with drug development and the related R&D costs. Regulatory authorities, such as the FDA, are clearly supportive of biomarker approaches as witnessed by the FDA’s guidance in 2005 with respect to the submission of pharmacogenetic data as part of NDA filings. The FDA also recently drove label changes to marketed drugs such as irinotecan and warfarin by incorporating biomarker-related information into the label in an effort to increase
Author
0
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7
8
Figure 1
patient safety when using certain drugs, which in turn could reduce the healthcare costs associated with the treatment of adverse events. Pharmaceutical companies are also beginning to advocate for label changes as new biomarker information on their drugs emerges. For example, Amgen reanalysed their clinical trial data for their colon cancer drug Vectibix following concerns from the EMEA that the drug did not provide enough benefit to patients. The drug was finally approved for patients only whose tumours did not have a mutation in a gene called KRAS. And these are just some of the recent examples which demonstrate the power of biomarkers for improving the development and marketing of targeted therapeutics and diagnostics. This trend is likely to continue and the ‘promise of personalised medicine’ may be fully realised as biomarkers become a more integral part of future drug development and commercialisation.
Michael Lutz came to Clinical Data Inc., a NASDAQ-listed biotech company in August 2007 following the acquisition of Epidauros where he served as Chief Executive Officer since April 2006. Lutz became Global General Manager of Cogenics, the service division of Clinical Data, in November 2007 and was also appointed as Senior Vice President Pharmacogenetic Partnerships of PGxHealth,USA, the product division of Clinical Data.
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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
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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;
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Research & Developement
Biosimilar Medicines
Understanding the challenges but for the more complex proteins such as monoclonals, the jury is still to come out. The problem is that like any jury, every member has their own view, and this does not bode well for establishing a global programme for the development of a biosimilar. The complexity and uncertainty is exacerbated by the fact that regulations for market approval of biosimilars are still evolving around the world and at different rates. The European Union (EU) has led the way in establishing regulations for follow-on proteins and several biosimilar products have already been approved in the EU; these include somatropin, filgrastim and epoetin. Elsewhere, the regulatory landscape varies dramatically. In parts of Asia, such as India, although biosimilar products have been on the market for many years regulatory thinking is still evolving. In the United States, Congress has yet to establish regulations for followon proteins. Other major markets, such as Canada and Japan, have issued draft guidelines. In this maelstrom of views, industry has the opportunity to guide rational thinking with cogent scientifically robust arguments through comments to guidelines, participating at international meetings, regulatory scientific advice submissions and other such forums.
Even as regulations begin to appear, new questions are being raised: How should follow‑on products for monoclonals and other complex proteins be handled? How much clinical data should be required to demonstrate equivalence? How similar does a biosimilar product need to be? The challenge for both regulators and the biopharmaceutical industry in this constantly changing environment is to maintain a reasoned approach and resolve the issues in a way that keeps the science of biosimilars moving forward for the benefit of patients around the world. How “similar” is biosimilar?
One of the most basic issues surrounding follow-on proteins is determining what types of proteins can be considered biosimilar. One viewpoint is that only proteins that can be fully characterised, with no discernible differences in either the structure or impurity profile, can be considered biosimilar. However, this narrow view is not shared within the EU, where guidelines and precedence allow a degree of difference—provided this can be justified. For example, one approved biosimilar product is expressed from yeast, whereas its reference product is expressed from E coli. Although this variation in
production method creates differences in the follow-on protein’s impurity profile, those differences have been demonstrated not to impact safety or efficacy and the product has been accepted as biosimilar. Similarly differences in glycosylation profile have been justified and accepted by the EU regulators. If lower-cost therapeutic proteins are to reach the market, more innovative and efficient production technologies, including transgenic production, must be introduced. Although these technologies may create differences in impurities or post-translational modifications, it should still be scientifically possible to demonstrate that the biosimilar product provides equivalent safety and efficacy to the reference product. While, there is no regulatory precedent for this approach today, this seems scientifically sound and hopefully common sense science will prevail. On the other hand, if differences in primary structure or profound posttranslational modifications are detected, then, according to current views such a product would need to be treated as a novel compound. Yet, such a clearcut position may not be necessary or scientifically justified. As experience with biosimilars grows, regulators may become
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more comfortable in allowing greater flexibility and may approve less similar follow-on proteins based on an abridged “Biosimilar” approach. This approach can even be taken where significant differences from the reference product exist, although always equivalent safety and efficacy will need to be proven. However, we have not yet reached this point. Can the biosimilar concept be applied to complex proteins?
The biosimilars approved under the current EU process represent just the beginning of a global biosimilar revolution. A host of other products, including follow-on monoclonal antibodies, exist or are in development and will probably be submitted to regulatory agencies in the years ahead. The EU’s “Guideline on Similar Biological Medical Products” (CHMP / 437 / 04) states that, in principle, the biosimilar concept applies to any biological medicine. However, the guideline notes that this will depend on a number of factors—including the ability to characterise the product. Clearly technology is moving forward apace and the power to characterise complex proteins down to the last atom is now a reality whereas a decade ago it was a dream. Methods such as MS-MS, 2D-NMR, and chemi-luminescence are but a few of the powerful tools available today that enable resolution to atomic levels, generation of high fidelity information on protein folding and detection of impurities even to picogram levels. Science allows full understanding as to how the protein binds to its ligand and the type of bonds involved. Biological testing using methods such as surface plasmon resonance, FluorescenceActivated Cell Sorting (FACS) and other cell-based assays can provide a thorough insight into biological effects compared with the reference product. Thus, strong evidence of similar therapeutic effect can be available well before the biosimilar ever enters a patient. These technologies should make it possible to demonstrate biosimilarity
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at the physico-chemical and biological level for virtually any highly purified protein. The next step in demonstrating biosimilarity requires leveraging current knowledge and filling the gaps by conducting appropriate non-clinical and clinical studies. Even for small molecule generics, bioequivalence in terms of absorption needs to be demonstrated in clinical studies and so it is no surprise that this applies to biosimilars as well. However, for biosimilars, the EU regulators require more data to be convinced of similarity; for example, they will want evidence for equivalent efficacy and adequate safety, which will require clinical trials. The requisite clinical programme will vary and will require detailed thought and justification from the sponsor, who is well advised to work with external expertise and seek scientific advice from the regulatory agencies. In the EU it is incumbent on the sponsor to submit a scientifically robust justification in support of their programme and such submissions will play a significant role in shaping future thinking. The size and complexity of the clinical programme will depend on the level of understanding and interactions of the protein structure, the impurity profile, and other characteristics, as well as the relative difficulty of demonstrating therapeutic equivalence. In some cases, a biosimilar development programme may require the study of more patients than were included in the innovator programme! Can biosimilar development be globalised?
Key to the success of a biosimilar programme is accessing markets throughout the world, but regulations and experience around the globe differ dramatically. The adoption of a biosimilar approval pathway in the US and other major markets will certainly ignite new thinking that will influence current strategies for development of biosimilars and set new precedents for their approval.
For now, fundamental challenges confront the establishment of a global biosimilar programme. Foremost, there is currently no way of confirming that the reference product sold in one region is identical to that in another region even when they are sold under the same brand name, which indeed is not always the case. Until this problem is resolved, a worldwide biosimilar development programme cannot be a reality. Currently to achieve EU approval, the reference product must be sourced from within the EU. If similar demands are set in other regions, then development programmes will need to be replicated in each region, resulting in duplication of effort and unsustainable costs. There is obviously an urgent need to establish some level of international harmonisation to allow mutual recognition of reference products and data for approved biosimilars. Yet another challenge is regulatory concern about the impact of ethnicity. In reality, this should not be an issue for biosimilars where the reference product will have already been approved and marketed in the target region, and there would seem to be no rational reason why a biosimilar product would display a different ethnicity profile; however regulators may not always share this view. Even if the above barriers are crossed, regional differences in data requirements may still dictate the need to replicate certain aspects of a biosimilar development programme, tailored to the requirements of specific regions. This is another area where global harmonisation of biosimilar guidelines would greatly benefit the development of global biosimilar products. Can the obstacles be overcome?
Despite the progress in the EU, much uncertainty remains as to which products will qualify as biosimilars, and what degree of similarity will be required for follow-on and subsequent-entry proteins. Furthermore, the level of supporting clinical data that will be required for
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reference biological entity. Extension of the biosimilar concept to “biosuperiors” does not align with current regulatory views but its future adoption could serve to nurture innovations such as novel and more efficient manufacturing technologies that will enable the generation of more affordable protein-based medicines. The ability of biosimilars to access global markets based on a single development programme that meets the requirement of all markets is clearly an important factor driving the success of biosimilars. Although, World Health Organization
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the more complex proteins has yet to be fully defined—which is not surprising, given that it is a multidimensional issue, influenced by the complexity of the protein, the potential for differences between the reference product and the biosimilar, and the challenges of demonstrating therapeutic equivalence. The uncertainty and variability of the biosimilar environment increase in proportion to the complexity of protein. The level of clinical and nonclinical data required to bridge the gap between the reference protein and the follow-on protein needs to be based on risk analysis, with the amount of data being proportionate to the level of uncertainty and risk. In fact, the idea of a risk-based approach could be applied even to improved intentionally modified proteins or “biosuperiors” where receptor interactions, pharmacokinetics, and pharmacodynamics mirror those of the
has issued guidelines which establish a base standard, the regulatory framework for the approval of biosimilars in major markets is very much still in flux and relies on the generic and biotechnology industry to guide regulatory thinking towards a harmonised approach. Biosimilarity is still in its early stage of evolution and the industry and regulators together now need to drive the concept so that it becomes a powerful vehicle for delivering affordable and better biological medicines to patients throughout the world.
Cecil Nick, Vice President – Biotechnology at PAREXEL Consulting, is a trained biochemist and has over twenty years of experience in the development of biological medicinal products. He now provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. He has been involved in the development and regulatory approval of a number of innovative and biosimilar medicinal products in Europe.
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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
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ver the past decade there has been increasing pressure on the pharmaceutical industry to increase economic efficiencies in drug discovery. This has been driven by several factors including the increased costs of R&D, lower productivity, patent expiration, generic competition and the increasing difficulty in bringing new chemical entities to market. The extraordinary investment requirements have also led the industry to focus on only those disease areas which have high commercial potential and are deemed prosecutable. Many feel that this has led to a risk-averse behaviour which has hindered innovation in the field and created a focus on what are considered “druggable” targets. This has created a narrow view of biological space and has left major “third world” diseases orphaned. While there has always been synergy between industry and academia in drug discovery, there is growing momentum within the ranks of academic and non-profit organisations to fill this
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innovation and therapeutic development gap through adoption of more conventional drug discovery and development approaches. Incorporation of disciplines and infrastructures that were the domain of industry is at the leading edge of this new paradigm in academia. The Stanley Center for Psychiatric Research within the Broad Institute of MIT and Harvard is providing a forum to explore such a model. The Stanley Center was founded to discover the human genes that confer risk for bipolar disorder and schizophrenia and to use
this information to develop new diagnostic tests and treatments for these illnesses. Consistent with this mission and key to this emerging ‘academic drug discovery’ model are industry veterans, who are making a transition from industry back into this new academic environment. Integrated role of medicinal chemistry
The Stanley Center medicinal chemistry group is a small focussed group of four computational and medicinal chemists with both Big Pharma and
Embedded biotech model Historically, the later stage development of small molecules into drugs was more the province of industry with few exceptions. Now, however, a model is evolving in academia of front-loading the academic experience with more of an eye towards drug discovery and development. The Broad Institute of MIT and Harvard and the Stanley Center for Psychiatric Research provides an ideal environment to explore and refine this new model of drug discovery in academia. The Stanley Center medicinal chemistry group has adopted an “embedded” biotech model to leverage the strengths and practices of both academia and industry in this new context of drug discovery. http://www.broad.mh.edu/nodi/638
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Integrated model of drug discovery utilising internal and external resources PK, ADME Tox (in vivo, study design)
Chemistry scaleup, analoging Computational chemistry
Efficacy, Behavioural models
Design / Synthesis Structural biology (X-ray)
Medicinal chemistry
Chemical screens (HTS)
PK, ADME Tox (in vitro)
Biological Assays in vitro, cellular In-house / Outsourced
Analytical / QC Compound mgmt.
Formulation
Target indentification / Probe development
biotech experience. The primary goal of this group was to implement a fully functional medicinal chemistry group mirrored on the capabilities of industry with limited permanent staff to allow for fiscal and staffing flexibility as projects evolved. Rather than following a fully integrated model supported by fulltime staff, we adopted a hybrid virtual biotech model wherein we formed a core competency internally and outsourced the majority of analogue and bulk chemical synthesis. The medicinal chemistry group functions to collaborate with multiple academic groups at various stages of the discovery process, including high throughput screening, probe compound development, lead optimisation, formulation, PK / ADME and in vivo efficacy experiments. Shown in Figure 1 is a â&#x20AC;&#x2DC;chemocentricâ&#x20AC;&#x2122; view of the various disciplines integrated within the Stanley Center. The medicinal chemistry group focuses on hypothesis-driven compound design, synthesis, data analysis and the development of new approaches to drug discovery. Resources are augmented through the use of several Contract Research Organisations (CROs) for analogue and bulk chemical synthesis.
Outsourced
Figure 1
Academic collaborators constitute core biology and in vivo efficacy (behavioural models). External vendors are used for more traditional drug development disciplines such as PK / ADME for both in vitro and in vivo studies. The majority of our biological studies including in vitro binding, enzyme and cellular assays are done in collaboration with academic groups at local institutions (MIT, Harvard and Massachusetts General Hospital). The majority of our target identification, high throughput screening and compound management activities are conducted in collaboration with established core facilities at the Broad Institute. The goal was to develop an infrastructure which would allow a group of two internal medicinal chemists and four to six external chemists to efficiently process 200 to 300 compounds per year across multiple projects. By careful selection of CROs, we hoped that over time we would have a push back of ideas from our contractors and active participation in design and data evaluation. Ultimately, we hoped to establish our external contractors in chemistry as an extension of our team and leverage their capabilities as deep into our process as possible making them indistinguishable from internal resources.
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Stanley center's medicinal chemistry development cycle
SAR (Compound database) Structural biology In silico / In vitro ADME multiparametric optimisation software homology models / Docking / Scoring
Medicinal chemistry group Multiple academic collaborators Multiple CROs
Data analysis, Model refinement, Design
In vitro assays, cell-based assays, In vivo efficacy, In vivo PK / ADME
Testing
Lead optimisation cycle
Synthesis
Analogue, Scale-up tool compounds
Multiple academic collaborators Multiple CROs
Compound management analytical chemistry Quality control, Sample repository dissolution, Plating and distribution of compounds
Courtesy: Mike Moyer
Medicinal chemistry development cycle
Our approach is similar to an industrial template in the overall flow but differs in the organisational arrangements of the different disciplines. Our design and development cycle is shown in Figure 2 and mirrors the cycle found in an industrial setting. Key functions include: 1. Compound design and synthesis 2. Compound management—notebooks, QA / QC, tracking of compounds, information capture from CROs, registration, plating and distribution of compounds 3. Compound testing (in vitro and in vivo) 4. Data analysis and storage 5. Repeat. While our cycle mirrors industry, the various stages of the development cycle are performed outside the traditional organisational format. Unlike a typical company, where project team members specialising in various disciplines are unified as part of a single organisation, in an academic setting disparate disciplines from distinct organisations (universities, principal investigators, etc.) are involved.
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A model that lacks a clear organisational structure is highly reliant on communication and collaboration across groups. From a medicinal chemistry viewpoint, a key goal was to establish a highly efficient chemistry group by identifying “best-in-class” contract research organisations, leveraging the capabilities of the Broad Institute and establishing an efficient process to manage hundreds of compounds through the development cycle. Lessons learnt
We began our chemistry programme by examining several different chemistry CROs. We chose to compare vendors by assigning similar chemistries to assess not only their core chemistry competency but also their communication skills, problem solving, creativity and informatics capabilities. Working on an FTE basis for a period of three months with two to four FTEs per site, we began a rolling evaluation across several companies. We conducted weekly or biweekly teleconferences along with site visits to get hands-on experience with the chemists as well as evaluate their resources and capabilities. We found a wide variation from vendor to vendor across all areas.
Broad Institute
Figure 2
Moreover, we found that small inefficiencies in the process (communication, problem solving, and record keeping) were amplified in our small group and created large time drains internally. To streamline the flow of information and to centralise the capture of chemical information from all vendors, we adopted an electronic notebook (e-notebook) system established by the Chemical Biology Platform at the Broad. Originally, we transcribed varying report formats and data into the Stanley Center’s enotebooks. We quickly found that this administrative task required a prohibitive amount of time. Ultimately, synchronisation with our vendor’s records by providing remote login (to the Broad’s e-notebook system) allowed each vendor to download experimental details and analytical data in real time. This provided several advantages: 1. A permanent record of experiment details with associated analytical data on an internal server 2. A searchable chemistry database within the Stanley Center and Broad Institute 3. A source for real-time evaluation of ongoing chemistries 4. A cornerstone for leveraging existing
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How will we measure? • Success • Shortening of the typical development time for new discoveries emerging from academia • More refined chemical and/or biological leads from non-profit organisations • The discovery of new biological targets with an approach toward a novel therapeutic • The development of new chemical entities through phase I or phase II clinical trials Certainly, achievement of any one of these goals would be considered a success and help to refine the approaches implemented in drug discovery.
the first steps of the drug discovery cycle has been established. We hope with time to extend these efficiencies deeper into the drug discovery process and continue to refine this model. Future
With the implementation of an efficient chemistry infrastructure based on an industrial model we are poised to engage and refine more of the discovery cycle in this new environment. What remains to be seen is whether this model is sustainable and how it will impact industry and academia. Implementing a drug discovery programme creates a large burden on resources. Thus, sustaining drug discovery and development in academia will require both a shift in funding initiatives to foster this type of research as well as successful partnering between academic institutions and industry. The landscape does indeed appear to be shifting in this direction. Government funding agencies have initiated programmes geared
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capabilities of the Broad Institute (compound registration, analytical (QA / QC), compound management) 5. An expansion of CROs’ capabilities and responsibilities By integrating our compound flow into the existing informatics structure of the Broad Institute via e-notebook we were able to adopt already established protocols. Compound registration (Broad ID) assigns a unique alpha-numeric code for each compound which contains purity, batch and salt information. In addition, compound registration provides access to the Broad’s analytical capabilities. Once registered, integration of an open-source web-based image viewer (“aView”) allowed rapid annotation of analytical results and streamlined the process of compound purity assessment and re-analysis and / or re-synthesis. Moreover, this allowed us to work with the Broad’s compound management group to plate compounds efficiently for in vitro and cell-based assays. The E-notebook system facilitated complete coordination among our chemistry contract partners and chemists working internally, thereby fully integrating them with our informatics environment. Contract chemists synthesise, document and register each compound remotely. Compounds are received pre-registered in bar-coded vials and forwarded to compound management for dissolution, preparation of stock solutions, and plating for biological assays as well as LC / MS analysis. Review and annotation of analytical data via aView prior to assaying provides a filter to remove compounds from the system that do not meet our purity requirements. What had taken hours (document, register, and collate data from various vendor sources) for each compound has now been reduced to minutes by extending our process into the hands of our chemistry CROs. Through careful evaluation and utilisation of external CROs and by integrating into existing infrastructures at the Broad Institute, an efficient process for
specifically toward IND-enabling studies (NIH’s National Cooperative Drug Discovery and Development Groups Program) and towards funding for drug development activities (NIHRAID, Rapid Access to Interventional Development). Charitable organisations and philanthropic foundations are also having an enormous impact on funding this research (The Broad Institute and the Stanley Center are just two examples). In addition, private resources are funding the earliest stages of discovery in psychiatric disease through a special outreach initiative (‘PsychHTS’) for primary high-throughput screens. Finally, academic centres focussed on specific disease areas have had major upfront investments from industry which should allow sufficient opportunity to test this new model (e.g. Vanderbilt and Johnson & Johnson). The next 5 to 10 years will define how much this new model will impact our traditional models of drug discovery and development.
Edward Holson is Medicinal Chemist III, Stanley Center for Psychiatric Research at The Broad Institute of MIT and Harvard. In February 2008, he joined the medicinal chemistry group at the Stanley Center to design and implement strategies towards developing novel therapies in CNS related disorders including schizophrenia, bipolar and cognitive functional impairment. Prior to joining the Broad Institute he worked with Merck & Co. and Infinity Pharmaceuticals in medicinal chemistry and pharmaceutical development across multiple therapeutic areas.
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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 longterm 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
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n the biotechnology world, starting a new venture is fraught with a mixture of excitement and anxiety. Using a new technology or drugs platform that has yet to prove itself in the clinic and the marketplace can be one of lifeâ&#x20AC;&#x2122;s greatest adventures for scientists and entrepreneurs. As companies transition from that initial phase and with some success, move on to a more mature organisation, the need to carefully manage growth and product commercialisation becomes the paramount objective. The primacy of place for the preclinical organisation is supplanted by the need for growth in other parts of the organisationâ&#x20AC;&#x201D;clinical, regulatory, CMC (Chemistry, Manufacturing and Control) and commercial groups. As the needs
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of the organisation change, Research must change as well. It no longer needs to prove the worth of an approach or platform, rather it must now provide a sustainable flow of new drugs to meet commercial expectations (e.g. in the US this means Wall Street). How the company approaches this challenge ultimately determines the success of the enterprise. Without a flow of competitive new products, the companyâ&#x20AC;&#x2122;s commercial value diminishes and a likely merger or acquisition will be, most often, the only exit strategy. Thus, building an organisation that can be self-sustaining is of paramount importance and never more so than at the level of preclinical discovery. Achieving vertical integration
Over most of the last century, the response
was for Research to grow apace with all other areas of the company. This often led to large and expensive research organisations, which often experienced a paralysing disruption to research programmes due to constant mergers and acquisitions. The result today is that biotechnology companies are seen as far more nimble, original and creative than their much larger competitors. Knowing this, what should a big biotechnology company do? Big here refers to companies with market capitalisations greater than US$ 10 billion and are fully integrated. Fully integrated implies a vertical integration that allows all the activities from drug discovery and development through to registration to take place within the company.
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Model of a big biotechnology company with vertical integration Informatics and information technology
CROs
Vertical Integration
University based alliances CROs
Company-based alliances
R core comptencies 2 TA's ~ 200 scientists
Translational medicine
CROs
CROs Virtual discovery platform
Company-based alliances
D Organisation
Optimising through vertical integration
Thus, a fully vertically integrated big biotechnology company has its preclinical discovery research take full advantage of a variety of approaches and tools to advance drug candidates. It is linked to its clinical development research group via its translational science and medicine team. Integrating all of this requires the highest level of competence in bioinformatics and information technology (Figure 1). The IT group is the glue that allows the best integration of information and the greatest capacity for data mining.
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Each of the big biotechnology companies has taken a slightly different approach to this challenge and in some cases has eliminated preclinical discovery entirely. The remainder tend towards highly focussed preclinical research teams that take calculated risks, use academic centres (i.e. Universities and Research Institutes) to bolster their understanding of fundamental biological and disease processes as well as take advantage of the growing expertise of Contract Research Organisations (CROs) to help carry out research programmes. The half dozen or so of the large biotechs which have large market capitalisations also engage in company to company based collaborations to fill gaps in their discovery and development pipelines; similar to what is done by Big Pharma. A recent development has been the increased role of translational science and medicine, which can bridge the gap between the laboratory bench and the clinic by providing essential information concerning biomarkers, defining cohorts of potentially responsive patients, and providing early clinical feedback on the effectiveness of drugs or biologics against their molecular target. One approach to expand the reach of the preclinical research organisation is to use outside CROs in such a way as to constitute a virtual discovery platform that takes advantage of their various scientific platforms to perform much of the work needed to advance a programme to lead optimisation. Adjunctive to this approach are alliances with universities and private research institutes that provide fundamental information on potential new targets or new research directions. Both approaches allow the internal organisation to focus its attention on the critical late stage of lead optimisation and drug candidate selection without having to use its precious resources on multiple early programmes. Rather, it can pick and choose among these for the programme that is judged to have the best chance of success in moving into clinical evaluation.
Figure 1
The maintenance of a culture of originality and risk-taking at the level of discovery research requires a continued commitment not only by the research scientists but also by the management team that supports it. It also requires a vigilance on the part of supervisors and managers at all levels to encourage individual initiative within the framework of the goals and visions of the company. At the end of the day, proof of success is most easily measured by the productivity of the research organisation in terms of NCEs that move forward through the pipeline to ultimate approval.
David R Webb joined Celgene in 2003 as Vice President of Research. Between 1987-2003 he held senior research positions in several biotechnology companies and in big Pharma. He was a member of the Department of Cell Biology at the Roche Institute of Molecular Biology from 1973 to 1987 and Adjunct Professor of Human Genetics at Columbia University College of Physicians and Surgeons. David Webb received his PhD from Rutgers University and was a Dernham Junior Fellow in Cancer Research at UCSF.
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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
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ognitive function testing was first introduced into drug development to assess the unwanted side effects of many medicines to produce impairments to mental functioning, and is still widely utilised to establish whether newer medicines are relatively free from such effects. However, the opportunities for medicines to improve cognitive function in the dementias and other disorders have led to the widespread incorporation of such testing into efficacy trials, sometimes as the primary outcome. Cognitive function refers to mental processes which are crucial for the conduct of the activities of daily living. These processes include attention (concentration, vigilance), the ability to hold information temporarily â&#x20AC;&#x2DC;on lineâ&#x20AC;&#x2122; (working memory), the ability to store, retain and retrieve information over hours, days and years (episodic secondary memory) and the coordina-
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tion of movement. While there are many other facets of cognitive function, these are particularly important because they can be influenced by a wide variety of factors, including trauma, fatigue, stress, nutrition, ageing, disease (both physical and mental), and, of course, medicines and drugs. The efficiency with which these processes operate has a direct influence on how effectively everyday activities are conducted; essentially, the quality of everyday behaviour is underpinned by cognitive function. Our appreciation of the importance of cognitive function depends on the appropriateness and also the quality of the measurements. The only direct way to assess aspects of cognitive function is to require an individual to perform mental tasks whose successful performance is dependent upon those aspects. Thus, if a researcher wished to assess memory, the test would involve the subject remembering some kind of
information with the outcome measure reflecting how successfully this information was memorised and subsequently retrieved. Equally, if the object of study was to assess the ability to maintain attention, the test would involve sustaining attention to a set of pre-defined stimuli and the outcome measures would reflect both the accuracy and speed of the responses. Ultimately, the quality of the measurement of cognitive processes depends on how well the tasks have been designed and implemented. In the past, many aspects of cognitive dysfunction have been difficult to assess, not because they are subtle or have little relevance to everyday behaviour, but generally because they have not been subject to the diligent application of appropriate tests. Even when testing has shown cognitive dysfunction to be present, its clinical relevance can be questioned; sometimes because the tests have not been demonstrated to
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have relevance to everyday activities, or because the psychologists who have developed them have failed to convince physicians of either the importance of the construct they are measuring, and / or the ability of the test to measure the particular construct. Thus, while it has long been demonstrated that Alzheimer’s patients perform poorly on tests of attention, the importance of attention deficits in the profile of dementia has only become widely accepted in recent years. Even when there is widespread agreement, for example, that pronounced memory loss is a major characteristic of Alzheimer’s disease, and this memory loss can be observed non-clinically and without the need to quantify it; such observation is not sufficient if we are to chart the progression of the disease or identify improvements which may be conferred by medication, and thus precise tests of memory are essential.
which a test is administered will have a consequence on how it is performed. It must also be acknowledged that different test administrators, no matter how professional, will adopt varying manners of test administration. Automation can go a long way towards minimising the influence of these factors; standardised instructions can be administered via the computer screen and the test stimuli (pictures, words and other information) can be presented for precisely controlled durations and at specific rates. Further, test administrators being human, make mistakes and, in some procedures, there are also judgements to be made. These judgements, by their nature, can be subjective and will always be a potential source of variability. Such problems can be largely overcome with the proper automation of tests.
Most of the advantages described above serve to reduce the variability associated with test administration, which improves the precision of the assessment and thus the sensitivity of the test. The ability to measure, to the nearest millisecond, the time, as well as the accuracy, of each response, is one of the most significant advances to the sensitivity and quality of cognitive assessment which automation has brought to the field. This comprehensive measurement confers huge advantages; not only can trade-offs between speed and accuracy be identified (and thus changes in response style can be differentiated from changes to mental ability), but also improvements to both accuracy and speed can be unequivocally interpreted as reflecting enhanced performance. The security and integrity of cognitive data can also be guaranteed by automated tests, responses being stored in encrypted files which can only be accessed by authorised A further advantage is that automation Automation – Rationale personnel. 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 cognithe advantages have been repeatprocedures cannot unequivocally assess. tive function. One is to edly identified. In 1996, researchimprove 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 nonwhile also automatically collecting and Automation of testing can also automated tests including the Miniprocessing 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-autotest 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 definion subsequent occasions, computerdifferentiate 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 tradiappropriate 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 pharmost 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
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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 cognico-development programmes with larger procedures sometimes called biomarktive 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 justificamedicine 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 medidevelopment process. likelihood of wasted resources due to cations like oxybutynin. This absence candidate drugs failing later in the cliniof 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 cognihas identified a range of compounds that been slow. In part, this has been due to tive impairment. Although phase I studcan potentially treat the symptoms of the unofficial acceptance of the ADASies 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 intetrials, 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 of cognitive tests are employed. numerous and have been described millisecond, the time, as well as the In most phase I Units, volunwidely elsewhere; many relating accuracy, of each response, is one of the teers are housed in wards and to the problems inherent in nonmost 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 attenas auditory instructions or tion, now established to be a core responses are not required and a cognitive deficit in Alzheimer’s single administrator can simuldisease. 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 antiand / 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 shiftevidence 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 environtrials 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 procenow 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
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Research & Developement
in Alzheimer’s disease can be profound in magnitude, representing up to 40 per cent reversals of these attentional deficits. The improvements to attention were also favourably reflected in Clinicians’ Global Clinical Impressions, and had implications for everyday behaviour and also for carer burden. The treatable cognitive deficits in other major forms of dementia are also being profiled and recent consensus criteria for Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) have established that the profound attention deficits identified in both dementias using the CDR System are central to the symptomatology of the both diseases and of greater significance potential than the memory deficits. The criteria recommend that automated attention measures should be part of assessments of therapeutic outcomes in the disorders. The first randomised clinical trials in DLB and PDD have identified that rivastigmine can produce large and clinically meaningful reversals of attention deficits of up to 50 per cent in DLB and 68 per cent in PDD. Furthermore, work in PDD has shown that CDR attention tests predict the capabilities of conducting the activities of daily living far more strongly than does the ADAS-cog. The European Medicines Agency (EMEA) 2008 Guidelines for Development of Medicines for Alzheimer’s disease and Parkinson’s Disease have stressed that attention should be one of the domains assessed in the dementias, and has also provided a green light for properly validated alternatives to the ADAS-cog to be incorporated into future trials. Therefore, automated tests such as the CDR System which have satisfied the various validation requirements stipulated by the guidelines can now be introduced into pivotal Alzheimer’s trials, if not immediately to replace the ADAS-cog, but at least to supplement it. In the case of other dementias such as PDD and DLB as well as Huntington’s and Vascular dementia,
there is or never has been any rationale for using the ADAS-cog and future trials can proceed with alternative methodologies more suitable to the deficit profiles in these dementias. Schizophrenia
The growing recognition that cognitive dysfunction in schizophrenia plays a major role in the poor rehabilitation rates of otherwise successfully treated psychotic patients into functional roles in society, has led to the development of the MATRICS Consensus Cognitive Battery (MCCB). The initiative identified seven target domains covering core aspects of cognitive function including attention,
Other clinical conditions in which cognitive disorder is present
Coronary Artery Bypass Graft (CABG) surgery has long been associated with residual cognitive dysfunction. Recently, a worldwide pivotal trial sponsored by Neuren used the CDR System as one of the two primary outcome variables to test Glypromate. The FDA approved trial was terminated early due to the lower than expected variability in the cognitive data resulting from the use of computerised testing. The sponsors argued that the reduction in variability meant that the study objectives could be adequately tested with 320 patients as opposed to the originally planned 600.
The case for Internet-based cognitive testing – The potential value for phase IV Cognitive testing can now be delivered via the Internet which will enable cognitive testing to be introduced in phase IV programmes. Such trials will enable the benefits of medicines on cognitive function to be captured in large post-marketing studies, patients either logging on at home to perform testing, or having testing conducted while making visits to the clinic. It will also enable medical practitioners to test patients prior to recommending medications, and then to conduct follow up testing at regular intervals. This will enable clinicians to determine for themselves whether cognition enhancers are having their desired positive cognitive effects, or conversely, that other compounds are indeed free from unwanted cognitive effects. Evidence-based prescribing will thus be feasible in clinical settings, which would enhance the credibility of many potential treatments for cognitive disorders.
speed of processing, working memory and verbal and visual learning. Unfortunately the developers included mainly traditional pencil and paper neuropsychological tests and not surprisingly, the first trial to be published using the MCCB, identified training effects on the various tasks which obscured the potential treatment effects the study was designed to identify. However, the positive contribution the MATRICS initiative has brought to the field is the establishment of the core cognitive domains which should be targeted in schizophrenia research, which has opened the door for properly validated automated test systems such as the CDR System to be used in such research.
Sadly, the initial reports are that the study compound did not provide a protective cognitive effect to the patents, but this trial does provide the rationale for other trials to address this topic with markedly smaller sample sizes than would be required with traditional neuropsychological tests. Cognitive dysfunction is widely recognised to occur in a variety of clinical conditions. A core benefit cognitive testing can bring to such work is to establish the benefits which can accrue from therapies which alleviate the symptoms in the conditions and / or enhance cognitive function. Benefits with the CDR System have been identified in depression with reboxetine;
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Research & Developement
cancer with fentanyl, epoetin alpha, and modafinil; sleep apnea with armodafinil; narcolepsy with armodafinil; fibromyalgia with galantamine; hypertension with candesartan; epilepsy with remacemide; ispronicline in Age-Associated Memory Impairment; and ABT-089 and NS2359 in adult ADHD. The application to herbal medicines
As herbal medicines become more widely available and get subjected to regulatory scrutiny, the requirement to properly assess their purported benefits becomes overwhelming. Many have been traditionally believed to enhance cognitive function and the CDR System was used in one of the first randomised trials of ginkgo biloba in elderly patients with mild cognitive impairment. Over the last 20 years, clinical trials using the CDR System have been able to confirm many of these purported cognitive benefits in the young and elderly for a variety of substances including gingko biloba, panax ginseng, Sage, guarana, Bacopa Monniera, Melissa and rosemary. Such work has been used to support product claims, advertising and patents.
CNS, such as EEG, PET and fMRI. While these hugely sensitive measures reveal vast amounts about CNS function and activity, it must be remembered that they are not in themselves direct measures of cognitive function. Instead, they identify patterns of activity, which may be the neural substrates for various aspects of function, and these measures are thus indirect assessments. However, when such assessments are directly integrated with tests of cognitive function, these co-joint evaluations of performance and CNS activity become extremely powerful instruments which are, for example, capable of functionally linking druginduced changes in cognitive function with activation of various brain areas, or in the case of SPECT, with receptor occupancy. It is time to act
The importance of cognitive function assessments in contemporary drug development makes a strong case for the
Imaging trials
Interest is growing in combining cognitive testing with other techniques in phase I trials which measure various aspects of activity in the
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Full references are available at www.pharmafocusasia.com/magazine/
Keith Wesnes is the owner and Chief Executive of Cognitive Drug Research (CDR) Ltd., which he founded in 1986. He trained at Reading University, Indiana University and Guy’s Hospital Medical School, has published over 200 peer reviewed papers and holds Professorships at Northumbria University, Newcastle, UK and Swinburne University, Melbourne, Australia.
Authors
Paediatric clinical trials
Children as young as six can be tested using the CDR System and a variety of trials have been conducted including the cognitive effects of breakfast cereals, classroom ventilation and mobile phones, as well as clinical trials including one assessing the effects of anti-epileptic medications in adolescents with epilepsy. The worldwide moves to increase the regulatory requirement to establish safety data in children for medicines they are likely to receive will provide the opportunity to assess the cognitive risks or benefits children may experience from a range of novel and existing drugs.
proper automation of test procedures. Much of the benefits of automated testing in translational medicine and many other areas of drug development which have been discussed have been based on the extensive experience gained with an automated cognitive test system which has been used in clinical trials worldwide since the 1980s. The ability to definitively assess changes in cognitive function in clinical trials opens up possibilities in numerous areas, including paediatric studies, studies of herbal medicines, imaging studies, as well as more mainstream areas of drug development including dementia, schizophrenia and numerous other neurological, psychiatric or clinical conditions. Computerised assessment of cognitive function has now come of age in drug development, and the pharmaceutical industry has a range of systems and technologies available to better characterise and develop its products.
Rianne Stacey has been working for CDR for just over a year as a member of the Research and Development Team. She has a strong academic background gaining a masters degree from the University of Cambridge in 2002 before embarking on a PhD at the University of Manchester, which she completed in 2007.
Andrew Embleton is a recent graduate of the University of Reading having studied Applied Statistics before joining CDR’s Research and Development Team. As part of his BSc he worked on a year’s placement in the pharmaceutical industry. He is also in his second year as a member of the Royal Statistical Society.
Steve Satek has spent nearly 20 years in the clinical research industry before joining Cognitive Drug Research as Vice President of North American Operations. Steve graduated from University of Wisconsin-Madison in 1988 with a double Bachelor’s Degree in Biochemistry and Molecular Biology, before earning his Master’s Degree in Business Administration from Lake Forest Graduate School of Management in 1999.
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 pharmaceutical industry for years. It’s a way to protect sensitive molecules from degradation, allowing their shelf life to be extended from days or months to years. Moreover, the technology is perfectly integrated inside industrial GMP (Good Manufacturing Practice) production giving a high degree of confidence in product sterility. However, the process has some drawbacks: it incurs huge costs and is very complex. Other techniques exist to stabilise molecules, but they are not so well accepted in the pharmaceutical industry. Freeze-drying may be seen as the relationship between the following three parts: • The freeze-dryer: a complex mechanical high performance apparatus • The product: vaccines in our case, but it can be whole cells, yeast, bacteria, protein or other molecules of interest • The process: The freeze-drying cycle is the link between the freeze-dryer and the product. It allows to obtain a quality product inside a specific equipment. The advancements in science now allow us to produce more and more complex molecules to target specific diseases. The complexity of these mole-
cules makes it very difficult to stabilise them. In this context, freeze-drying appears as a method of choice to stabilise the molecules. Consequently, there’s a need to rationalise the way process development is done. The development process
The product development process consists of different steps. First, cryoprotective molecules such as sugars, salts and polymers are chosen to protect the targeted active ingredients at the liquid state before and during freeze-drying. Then,
a freeze-drying cycle is designed to process the formulation. Finally, the process is scaled-up for clinical production and is later transferred to industrial production facilities. In the past, freeze-drying process development consisted of finding a dedicated process for each product. As there were no technological tools to follow the process, the release criteria were mainly used. Generally, a satisfying cycle was reached by the trial and error method. With the advances in the scientific knowledge of new molecules, various
A freeze-drying cycle may be divided into three parts The product is first frozen at a low temperature to reach a vitreous state. The nature and structure of the frozen plug allows a good protection Then, it undergoes sublimation under vacuum maintaining the product temperature below its glass transition temperature or collapse temperature. That specific temperature is determined by the stabilisers chosen and is measured with specific tools such as the cryomicroscope. This value is of paramount importance for the product elegance. If the product is sublimated at too high a temperature it ends up to be a melted product that will be rejected, creating burden (write-off) at industrial scale After primary drying, 10 to 20 per cent water is still inside the formulation adsorbed by the active ingredient. Secondary drying, often called desorption, removes that bound water from the product. This step is carried out at a higher temperature to remove the absorbed water. Removal of water is done by diffusion and not anymore by sublimation. Since diffusion kinetics is slower, it explains why secondary drying can take one-third of process length to remove only 10 to 20 per cent of the total water. The maximum temperature is defined in function of the product, but usually stays below 40°C for biopharmaceutical molecules.
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Selection of stabilisers
The following example illustrates how stabilisers are selected from various options keeping in mind the business interests. The first screening shows equivalence between two different stabilisers for biological activity. One of the two stabilisers has a higher collapse temperature. If chosen, this stabiliser will allow developing a more robust and quick (as the allowed temperature is higher, the product can be dried faster) freeze-drying cycle. It is better to run a three freezedrying cycles a week than two freezedrying cycles a week as it increases the capacity by 33 per cent. On the other hand if the right stabiliser is chosen at the beginning of the development it allows you to obtain the desired result. The development of process is generally well defined and involves several steps. If the stabiliser is a well-known substance, former development and some modelisation will help to quickly define the safety margin of the process and necessary trials are planned accordingly. For branding new kind of products, the available tools will be reviewed and applied. In this category some new equipment have appeared during the last years. Previously, developers only had two online tools to monitor the process, an invasive temperature probe placed in a vial and the view port, through which they could have a look at their product during drying. Now, micro balance can follow the loss of weight of the product during the whole cycle allowing easy optimisation. Cold plasma system can measure the water vapour flux inside the freeze-drying chamber during development phase of the stabiliser. Another step of process development is to make the cycle robust with Design Space study. The input and output parameters of the process are reviewed. Input parameters for freeze-drying are: shelf temperature, pressure in the system
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and time. The output parameters can be: residual moisture, potency, content, drying kinetics. The goal is to obtain the same range for output (i.e. good potency) at all times by varying on a wide range the input parameters (i.e. pressure 10 and 100 microbars). If one can reach this target they end up with a robust product where they are confident about the scale-up. The freeze-drying cycle development directly integrates safety margin to assure a smooth transfer to larger scale. For regulatory purpose itâ&#x20AC;&#x2122;s far easier when freeze-drying cycle is not modified between different clinical phases. Those studies are not performed on a trial and error basis anymore, but use the power of DOE (Design of Experiment). This approach is perfectly suitable for freeze-drying since there are only a few well-characterised input parameters for this closed system process. Clinical development
A further step is clinical development. All the development trials are performed at small scale (below 5,000 units) to avoid wastage of raw materials. Once clinical consistency is established, the trials are performed at larger scale.. This is the first scale-up of the product towards larger scale. At least three batches are produced with the target value of the developed cycle. They are deeply analysed for visual appearance, moisture content and moisture distribution. Statistical analysis is done on the result to underline any deviation compared to early development results. Transferring for large-scale production
The last step is the transfer to production unit. It requires people with a good
Author
online and offline tools have been used to improve the process to meet the requirements of the industry.
knowledge of clinical and industrial freeze-dryers. The engineering department should receive guidance before buying new freeze-dryers. An exotic industrial freeze-dryer may require upgrade of some technical part, since it will run out of the defined range. The transfer involves a multidisciplinary team in terms of department and competencies. Freeze-drying is not a stand-alone technology; the formulation, filling and some specific tests are equally transferred. For example, with each product a kit of known visual defects is provided to the manufacturing department. Summary of the process evaluation and process validation is set up for transfer. Commercial consistency batches are produced in the targeted factory. Specific sampling procedure is developed to assure homogeneity inside the load for specific attributes of the new product. Like at clinical step, statistical analysis is realised on each batch and a comparison between batches of different freeze-dryers is done. After transfer a support of the product is kept. It allows detecting any unexpected behaviour of the product at industrial scale. These learnings act as feedback during the development of other new products in order to continually improve the scaling-up model. Freeze-drying process development is a robust, well-defined way to assure the success of new products. Even if it can be seen as time-consuming, the knowledge of the product and process acquired in the first step of development will avoid a lot of costly burden at production scale with better product understanding. Full references are available at www.pharmafocusasia.com/magazine/
Yves Mayeresse is senior freeze-drying manager at GlaxoSmithKline Biologicals. He has more than fifteen years of experience in the pharmaceutical sector and has managed activities such as parenterals production, set-up of new freezedrying facilities, design of freeze-drying cycle and development of new stabilisers for freeze-dried products.
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 manufacturers encounter unique demands in their endeavour to manage improvement with operational excellence. In the past it was easier for pharmaceutical manufacturers to achieve the desired margins. But in the current scenario of competition, price pressure, stringent FDA regulations and the ongoing economic crisis, pharmaceutical manufacturers world over are under pressure with operational performance being a major concern. Pharmaceutical companies lose around US$ 15 billion every year due to disorganisation in the manufacturing lines. Efficiency, availability and performance of the packaging line affect the entire manufacturing process and, therefore, the company’s bottom line. Most of the manufacturers are striving for reduction in downtime and manufacturing cost, improved time-to-market and compliance to regulations. Making the best use of the equipment and reducing costs are two of the key challenges among many that manufacturers in general and pharmaceutical companies in particular strive to overcome. Overall Equipment Effectiveness (OEE) software is a boon
in addressing the said challenges and aids in enhancement of overall operational efficiency. What is OEE?
OEE is a calculation that permits managers and operators measure process efficiency. Based on the outcome of the calculation, organisations can understand the performance efficiency, identify areas of improvement and targets and align the identified targets with the overall business strategy. OEE considers the common sources of manufacturing productivity losses
and classifies them into three groups listed below: 1. Availability (A) – is a measure of productivity losses from downtime 2. Performance (P) – is a measure of losses from slow cycles 3. Quality (Q) – is a measure of losses from manufactured products / parts that do not meet quality specification OEE = A × P × Q OEE filters production data into understandable metrics that provide a means for measuring true manufacturing efficiency. It also forms the basis
Factors affecting production efficiency Equipment Breakdown 20%
Table 1 Parameters
Percentage
Yield Loss
02%
Speed Loss
05%
Preventive Maintenance
12%
Setup and Change over
19%
Equipment Breakdown
20%
OEE
42% Source: OEEsystems
19% Setup and Change over
12% Preventive Maintenance
42% OEE
5% Speed Loss
2% Yield Loss
Figure 1
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Manufacturing
for tools that facilitate enhancement in productivity. OEE score provides a complete measure of manufacturing effectiveness.
Production data Item
Data
Shift Length
8 hours = 480 min.
Tea Breaks
2 × 10 min. = 20 min.
Lunch / Dinner Breaks
1 × 40 min. = 40 min.
Down Time
50 minutes
Ideal Run Rate
60 tablets per minute
Total tablets
18,800
Rejected tablets
400
Why OEE?
Table 2
OEE Availability
Operating Time / Planned Production Time 370 minutes / 420 minutes 0.8809 (88.09%)
Performance
(Total tablets / Operating Time) / Ideal Run Rate (18,800 tablets / 370 minutes) / 60 tablets per minute 0.8468 (84.68%)
Quality
OEE
Good tablets / Total tablets
Loss in yields, stoppages due to equipment breakdown, delays in setting up the production line and maintenance activity are key factors that affect the overall production efficiency. These factors reduce the production capacity by 40 to 60 per cent. Lack of understanding of the true performance of the manufacturing units by the Plant Managers, is the cause for encountering challenges in improving the overall operational efficiency. OEE measurement tools and techniques provide a much clearer understanding of where improvements can be made.
18,400 / 18,800 tablets
How to calculate OEE?
0.9787 (97.87%)
Table 2 contains shift data of formulation unit, to be used for a complete OEE calculation, starting with the calculation of the OEE Factors of Availability, Performance, and Quality.
Availability × Performance × Quality 0.8809 × 0.8468 × 0.9787 0.7300 (73.00%) Table 3
OEE – Systems and Software The following companies are some of the leading suppliers of OEE systems for calculating, tracking and reporting of OEE. OEEsystems – Having its international headquarters at Ireland, OEE Systems works with manufacturing companies to improve competitiveness, increase capacity, reduce costs and deliver business performance excellence. In partnership with global manufacturing customers OEE Systems has refined PerformOEE™ to meet their specific business requirements. PerformOEE™ - Bulk Manufacturing – Although OEE has traditionally been applied only to discrete manufacturing processes, PerformOEE™ uses an adaptation of the traditional OEE model to fully accommodate the requirements of bulkmanufacturing and process-based manufacturing businesses and provide the process industry with a practical Manufacturing Intelligence and Performance Management software solution based on the OEE model. Vorne Industries – Having its corporate office at Il, USA, Vorne Industries develops tools that enable customers to improve their manufacturing productivity: quickly, efficiently
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and effectively. Vorne strives for excellence in all aspects of the company—people, products, and service. Vorne’s XL800 Production Monitor is a product for performance management, productivity improvement and lean manufacturing. XL800 is a “six-in-one” product that combines a large-area visual display, a high-performance production monitor, expandable I/O, a multiple channel communication hub, a program executioner and a data warehouse—all in one package. Gemba Solutions / OEE Impact – Specialists in delivering tangible results quickly. They help manufacturing units to slash production costs, increase capacity eliminate waste, save energy and optimise labour. Idhammar Systems Ltd. – Idhammar is a leading provider of total productive maintenance and manufacturing software. Idhammar has its Headquarters in the UK and has expert teams of OEE and maintenance specialists, software developers, customer support, and help desk staff who work together to develop, support and promote systems that are improving industrial operations worldwide.
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process. Efficiency, aids in generation of extensive reports easily and enables production managers to perform additional long-term analysis on the trends that matter.
OEE – A translatable business metric CEO
Improved Return on Total Capital (ROTC) Reduced capital needs
Finance & Operations
Enhanced profit
Less capital investment
Fewer assets
Reduced cost
Predictability
Manufacturing & Maintenance
OEE for enhancement of operational excellence
Improved revenue
Less Waste
More output
OEE OEE enables to identify root causes for loss of efficiency and helps to make the decisionsthat can improve the process and the bottom line of companies.
Courtesy: GE Fanuc
Figure 2
Variables
Planned Production Time = [Shift Length - Breaks] = [480 - 60] = 420 minutes Operating Time = [Planned Production Time - Down Time = [420 - 50] = 370 minutes Good Tablets = [Total tablets - Rejected tablets] = [18,800 - 400] = 18,400 tablets
OEE and automation companies
Rockwell Automation’s new line monitoring and OEE solution has helped a pharmaceutical manufacturer to capitalise on line information and improve effectiveness throughout its packaging process. Rockwell Automation was able to integrate raw data into a single information interface presenting OEE calculations by output, throughput and by each machine across process and product.
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World Class (%)
Availability
90.0
Performance
95.0
Quality
99.9
OEE
85.0 Table 4
Management suite, Efficiency is designed to calculate OEE quickly and easily. Efficiency helps to track downtime, waste, production counts, and user-defined events specific to the
Author
The accepted average OEE score in manufacturing plants ranges from 45 to 60 per cent. A world-class OEE score is greater than or equal to 85 per cent in batch manufacturing and as high as 95% in continuous processes . The accepted world-class goals for each factor are as shown in Table 4.
Pharma Focus AsiA
World-class OEE OEE Factor
World-class OEE
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GE Fanuc’s Plant Applications Efficiency solution is a powerful software module that lets plant managers make sense of the plant data and evaluate efficiency in real time. Part of the larger Proficy Plant Applications Collaborative Production
OEE data – • provides one version of truth • is comprehensive • can impact wide range of issues from shop floor to board room • aids in analysis of who, what, why, where and when • ensures ROI. OEE is a metric that can be embraced at every level of the organisation. It is meaningful to the operator on the shop floor, yet translates all the way up to the board room. If companies can produce more with less equipment / machinery, it means growth and increased revenue with less capital investment. Higher efficiency drives down the cost. By reducing capital needs and increasing profit, a business will improve its Return on Total Capital, the primary metric of the company / CEO performance. Acknowledgement: The author acknowledges with gratitude the support extended by OEEsystems, GE Fanuc and Rockwell Automation in providing facts & figures for the article. The author also acknowledges with thanks the details from the websites of Systech International, Vorne Industries, Gemba Solutions / OEE Impact and Idhammar Systems Ltd. Full references are available at www.pharmafocusasia.com/magazine/
Pala Bushanam Janardhan is a Senior Business Consultant (Manufacturing & Plant Automation Services) in the Life Sciences and Healthcare Practice at HCL Technologies Ltd., since April 2006. Prior to joining HCL, he has served the Pharmaceutical industry in various capacities—handled process technology development, technology transfers regulatory compliance, supply chain management, outsourcing and business development for more than 18 years.
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 health problem is underscored by its increasing incidence. With better understanding of the biologic processes underlying the causes and progression of cancer, great strides have been taken in inducing incremental improvements in survival. Indeed the face of oncology has changed in the last decade from a paradigm where a diagnosis of cancer and treatment decisions were based primarily on morphology and histology, to one where treatment decisions are now tailored based on molecular profiling of tumours. However, these new avenues of molecular approaches come at a price: Cancer has become a highly segmented disease with over hundreds of biologically distinctive diseases that require differential therapeutic approaches. In an environment, where pharmaceutical companies are facing a difficult future with higher hurdles of regulatory approvals, sustained costs to research and development, patient segmentation, restricted reimbursement, patent expiry, or decreased growth revenues, oncology no longer remained sacrosanct. Increasingly restricted reimbursement can ultimately affect the patient outcome. Recent examples are drawn from The National Institute for Clinical Excellence (NICE) in United Kingdom, which has a stringent approach to cost-effectiveness
evaluation and has resulted in negative guidance for several oncology agents, although “end-of-life” appraisal has begun to address this issue. Stricter definition of innovation is required, which aims at the provision of clear patient benefit and more individualised therapy. With more than 500 anti-cancer compounds in various phases of clinical development, there is lesser and lesser access to
With more than 500 anti-cancer compounds in various phases of clinical development, there is lesser and lesser access to patients for enrollment in clinical trials, which presses the need for “smarter” and “simpler” clinical development strategies.
patients for enrolment in clinical trials, which presses the need for ‘smarter’ and ‘simpler’ clinical development strategies. The question posed here is: What would make sense to achieve personalised medicine for cancer?
In the last decade, there has been a major shift towards the use of rationally-designed, tumour-targeted therapies. Indeed, targeted drugs such as rituximab, trastuzumab, imatinib, erlotinib, lapatinib, bevacizumab, and cetuximab have revolutionised the treatment of a variety of cancers. With the increasing number of targeted agents in clinical development, several unique issues are identified. The article sheds some light on these issues, addresses some lessons from the past, and the implications for late phase clinical trials. Although the advances made in cancer management are based on the results of the hundreds of clinical trials that assess the benefit of the new therapeutics on patient survival and quality of life, there is an increasing need to change the paradigm of demonstrating anti-tumour activity of newly developed agents. There is a need to do more work upfront in order to conduct smaller, less resource intensive mechanistic clinical trials that provide a deeper understanding of the biological consequences of the targeted agent on signalling networks involved in the regulation of tumour cell growth and survival. Indeed, the “bench-to-bed and back again” concept has now become the new model for developing new anti-cancer agents (Figure 1). In this model, arsenals of drugs are being developed that are based on our
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Clinical Trials
Discovery
Target selection
Gene to function to target
Gen
Development
Target to lead
Target
Lead optimisation
Lead
Safety developability
Candidate
Marketing
FTIM to PoC
PoC phase II
FTIH
Pivotal
Phase III
File launch
File approval and launch
Life cycle mgmt.
Life cycle
“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
understanding of the transcriptomic, proteomic, and the genetic and epigenetic changes that occur in cancer cells. More emphasis has therefore been laid on the use of the diagnostic, prognostic and predictive biomarkers in all phases of drug development. Easy as it sounds, the reality is that there are few markers of response that are validated and are acceptable to regulators. Despite the shortcomings of pharmacodynamic biomarkers, its applicability in clinical trial setting has demonstrated tangible benefits. One of the successful strategies in rationally designed clinical trials is testing of new agents in ‘window of opportunity’ phase II setting. Typically, these studies are designed as single arm small studies (approximately 50 patients), where the study drug is administered for a short duration, usually between 2-3 weeks, in the neo-adjuvant setting. The main premise of these trials is based on measuring pharmacodynamic effect(s) of the tested drug in paired preand post-treatment tumour biopsies, e.g. changes in receptor expression and / or the activation state, downstream signalling pathways, anti-tumour proliferative activity as detected by Ki-67, and / or ability to increase the rate of apoptosis. Further information is obtained by
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utilising PET, or DCE-MRI, and / or proteomics and transcriptomics of serum samples. There is a plethora of such studies in the literature. Conceptually, such an exploratory approach is very useful, as it provides a direct in vivo assessment of the biological activity of a new chemical entity; understand the potential mechanism of action in inhibiting the intended target; and correlating the biological and clinical activities.
Despite the shortcomings of pharmacodynamic biomarkers, its applicability in clinical trial setting has demonstrated tangible benefits.
Identification of putative predictive markers of response could be utilised as surrogate endpoints for clinical activity in subsequent confirmatory studies for validation. Moreover, with carefully designed trials, this approach could provide an understanding of the patient population who would potentially benefit from a given treatment and therefore insight into the patient selection in further phase II and phase III trials. Despite their increasingly widespread use, the utility of biomarkers in clini-
Figure 1
cal setting is hampered by methodology issues, by the lack of consistent results in multiple testing for the same and across tumour types, and by trial design issues. For instance, various studies demonstrated conflicting results on the value of decreased proliferation as detected by changes in Ki-67, in predicting for response of breast tumours to aromatase inhibitors, tamoxifen, or chemotherapy. To put this all in context, it is important to remember that the role of biomarkers remain largely exploratory. To limit the diluting effects of methodology deficiencies in measuring these biomarkers, the following is recommended for consideration in trial designs. First, careful selection of homogeneous patient population will limit the variability in detecting or measuring a biological effect. With shortterm administration of a tested drug up to three weeks, it is possible to design studies in earlier disease settings, which are considered ethical and would not have an adverse effect on the delivery of standard treatment in most tumour types, such as breast, colorectal, or head and neck cancers. The timing of the biopsies, the standardisation of the assays, and the scoring systems should be carefully considered in order to maximise the
Clinical Trials
Author
ability to detect a pharmacodynamic effect. More importantly, these studies should be designed as randomised trials. The control arm could be a standard treatment, or placebo, or even a different dosing schedule of the tested drug. Multiple dynamic biomarkers should be examined to provide a more global understanding of the drugâ&#x20AC;&#x2122;s biological effects. With adequately powered clinical trials, it is possible to gain information that would dramatically help tailor and accelerate drug development strategies. Some success stories can be drawn from the lapatinib development in advanced stage breast cancer. Lapatinib is a dual tyrosine kinase inhibitor of both EGFR and HER2 receptors. In a recent study in refractory inflammatory breast cancer (IBC), the co-expression of the activated, phosphorylated forms of HER-2 and HER-3 seemed to predict for a favourable response to lapatinib. More recently, short-term administration of lapatinib up to six weeks was assessed in patients with locally advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). Compared to placebo, there was a significant reduction in proliferation, but no difference in inducing apoptosis. Well-conducted clinical trials are essential for successful oncology drug development, and consequent improvement in patient outcomes. Although single arm small phase II studies have been extensively utilised for an early read out of activity of new cytotoxic or cytostatic agents alike, it is argued that their true value in advancing medical research may be limited, in light of false positive results that are often obtained, and the lack of efficacy when the drug is tested in confirmatory randomised
clinical trials. For phase II screening studies to have a useful role in oncology drug development, it is important that homogeneous-enriched patient population are selected; that randomised design be considered, even if not statistically powered. Alternatively, the use of innovative trial designs, such as adaptive or sequential designs, have gained traction as strategies in the development of oncology drugs, particularly as these designs have become increasingly accepted by regulatory authorities as the basis for examining the efficacy of a tested drug in phase III setting. With such designs, smaller patient sample size is generally required, and the studies can be stopped earlier in the absence of patient benefit. In conclusion, there has been a major leap in oncology drug development, with multiple success stories of drugs that truly and effectively improved the patient outcomes and quality of life. Some of major lessons from these new targeted agents are the importance of target selection; and the changing goals of phase I and phase II trials, including not only traditional endpoints such as pharmcokinetics, assessment of toxicity, clinical efficacy, but also insight into mechanisms of anti-tumour activity, identification of surrogates of activity and panels of biomarkers that predict for response. These tools will hopefully facilitate the drug development process through rational rather than empiric drug development strategies, clinical trial design, patient selection, and approach to combining therapies to overcome or prevent the development of therapeutic resistance. Full references are available at www.pharmafocusasia.com/magazine/
Iman El-hariry is a clinical oncolgist, who did her training in Alexandria Medical School, Egypt, and gained her PhD at the Imperial College, London. Currently, she is leading globally the clinical development in head and neck cancer of lapatinib at GSK
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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
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Clinical Trials
T
he incidence of Central Nervous System (CNS) illness is on the upswing and exacts a heavy human and economic toll. According to the World Health Organization, more than 120 million people worldwide suffer from depression, and the number is expected to rise. The occurrence of Alzheimer’s disease is slated to grow by more than 100 per cent in developed countries by 2040 and by 300 per cent in China, India, South Asia and Western Pacific countries over the same time period. In the United States, the National Mental Health Association estimates the annual cost of direct treatment of mental illnesses, the social costs of leaving it untreated and lost productivity at US$ 205 billion. With these statistics as a backdrop, it is worth noting that hundreds of CNS therapies are in development, more than 300 in the United States alone, yet they lag behind in the development of therapies for non-CNS disorders in terms of the time needed to bring them to market. Data suggest that it takes 12.6 years on average for CNS agents to obtain regulatory approval, twice as long as cardiovascular agents. In addition, a mere 7 per cent of investigational CNS drugs that start in clinical development are eventually marketed as compared to 15 per cent for non-CNS candidates. The reasons are many as to why CNS drugs are more difficult to develop successfully, namely the sheer complexity of the brain; the presence of CNS-mediated side effects such as nausea, dizziness and seizures; the need for agents to pass the blood-brain barrier; and the lack of validated biomarkers. Yet, with the implementation of targeted strategies, it may be possible to identify more quickly and with greater accuracy those therapeutics agents with the most promise, leading to better GO / NO-GO decisions. This article focusses on selected techniques that can be used early on, following preclinical work, to launch Phase I studies that determine if compounds are entering the brain, and how this
action may be impacted by dose ranging. These techniques are the routine Electroencephalogram (EEG), the Quantitative Electroencephalogram (QEEG) and Evoked Potential (EP). They can be used as tools for translating preclinical findings into first-in-human studies. They may also play a role in later phase studies when compounds shift from being studied in healthy volunteers to CNS patients. Additional translational techniques employed in Phase I programmes include cerebral spinal fluid sampling, brain imaging methodologies, and cognitive and behavioural assessments. These are beyond the scope of this paper.
It is worth noting that hundreds of CNS therapies are in development, more than 300 in the United States alone, yet they lag behind in the development of therapies for non-CNS disorders in terms of the time needed to bring them to market. The techniques
The EEG, QEEG and EP are non-invasive techniques with results recorded from electrodes attached to the surface of the scalp according to an internationally standardised arrangement, the so called 10-20 system (Figure 1). The promise for these methods is to be able to predict, early on in the clinical development of novel therapies that an antidepressant or analgesic will be safe and efficacious at various doses as compared to placebo. Moreover, the EEG or EP signature observed, including dose versus response relationships observed, in animals can be translated and validated against healthy human volunteers and in subjects with CNS disorders. The EEG, QEEG and EP are wellestablished measures of electrical patterns
in the brain, but their power as tools for translating preclinical findings into Phase I trials is just beginning to be applied. Depending upon the therapeutic area— Alzheimer’s disease, Schizophrenia, pain, Major Depression, Parkinson’s disease, or sleep disorders—all or some of the three techniques might prove useful in characterising compounds starting into Phase I clinical trials. Routine EEGs, for example, can be used for monitoring CNS toxicity and for detecting increased seizure likelihood. They provide a continuous measure of cortical function with excellent time resolution, measurable in milliseconds. Unlike relatively new functional imaging procedures, such as Single-Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), and functional MRI (fMRI), EEG has the advantage of being well tolerated, easy to administer, and relatively inexpensive. Quantitative EEGs are more sophisticated as they can monitor the time course of CNS effects of compounds, detail typical profiles of drugs in proof of concept studies and monitor vigilance effects, which refers to the brain’s state of receptivity to external stimuli associated with alertness. Both types of EEGs can be used in conjunction with fMRI, which, while slower to react, in the range of seconds, offers better spatial resolution and could corroborate EEG findings. Together, they can offer a higher degree of confidence that there is a useful signal to go forward. Evoked potential refers to an electrical potential recorded from a subject following presentation of an acoustic or visual stimulus, and can be a surrogate biomarker for cognitive information processing and for neurotransmitter systems such as serotonin. The ability to monitor serotoninergic function is valuable because of its putative role in the pathophysiology and in therapeutic interventions for CNS disorders. An EP method known as the Loudness Dependence Auditory Evoked Potential (LDAEP) can serve as an indicator of central serotonin function
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on the neurophysiological differences between patients and healthy volunteers. MMN response is a tool that can be used to explore the potential differences in treatment effect between patient populations and volunteers. If there is a normalisation response among the schizophrenic patients, this would be indicative of drug action, i.e. normalising the observed mismatch negativity. This electrophysiological endpoint might serve as a surrogate marker, convergent with the cognitive and information deficit symptoms observed in the disorder. Even if surrogate marker validation is preliminary, the observed effect demonstrates that the compound is crossing the blood-brain barrier and is showing evidence of efficacy. Using the techniques
A number of studies have been conducted that demonstrate the value of using the described methods to translate preclinical findings into Phase I trials. This section is not intended as a review of all of the studies in this area, but rather, it is meant to highlight a few examples of how the electrophysiological techniques have been applied. Parker et al. (2001) report using the quantitative EEG approach in an animal study to define the pharmacokinetic / pharmacodynamic (PK / PD) profile
of two investigational antipsychotic compounds, known as S18327 and S16924. Clozapine, also an anti-psychotic, served as an active control. Qualitative EEG changes in this animal model were similar for clozapine, but different for the investigational compounds potentially indicating a different multi-receptor activity and a clinical relevance since EEG changes had been strongly related to positive clinical outcome in schizophrenic patients. This was a small study, using only eight animals. According to the author, however, a limited number of samples can be used when applying the QEEG technique to characterise the PK / PD profiles of early compounds. Importantly, this work highlights the value of using the QEEG approach in preclinical and early phase investigation as it provides proof that a compound passes the blood-brain barrier; it allows translational approaches by comparing animal model results with human results; and provides data in the form of EEG profiles, comparing an existing compound to investigational ones. These are useful tools that help pharmaceutical sponsors make better GO / NO-GO decisions for CNS drug candidates. Baldeweg et al. (2006) used evoked potential, specifically impaired mismatch negativity, as a biomarker of Schizophrenia
Electrode Placement
in animals and humans and may show promise as a predictor of selective serotonin reuptake inhibitor antidepressant treatment response. With the LDAEP method, various techniques, such as dipole source analysis and scalp topography analysis, may detect the effect of enhanced serotonin availability. One component of EP, known as Mismatch Negativity (MMN) is particularly useful as a biomarker for schizophrenia. MMN is a response that a subject has a variation within a sequence of regular stimuli and is a reflection of sensory memory. For example, if there is repetitive auditory stimulation, such as “bb-b-b-b”, interspersed with an occasional “r”, the subject elicits an MMN response. Furthermore, the MMN response grows in correlation with the number of repetitions of the standard stimulation. Subjects with chronic schizophrenia, however, tend to generate impaired MMN, indicating that they recognise the change within the sequence in a less robust manner than healthy volunteers and the impaired response may grow as the disease progresses. Although, schizophrenia therapies in development can be tested in healthy volunteers, frequently the sensitivity to detect a relevant therapeutic surrogate for the drug effect expected in the disorder can be either enhanced or reduced based
Source: Handbook from Charite EEG Lab
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Figure 1
Clinical Trials
in a study of the effects of acute administration of nicotine on auditory sensory memory. The study was conducted in 20 healthy smokers who were randomised to either nicotine gum or placebo. Evoked potential responses to deviations in tones (deviants) were recorded using constantly changing standard stimuli in order to measure the effect of stimulus repetitions on the encoding of new stimuli. Results showed that there was a marked effect of stimulus repetition on the standard EP. Acute nicotine administration increased MMN amplitude significantly in the treatment group as compared to the baseline recording, whereas no changes in MMN were seen in the placebo group. Although schizophrenics were not included in this small study, the results support validating this approach as a possible surrogate marker for the treatment of cognitive deficits in Schizophrenia and with the observed functional impairment observed in patients. MMN might therefore be possible. Schizophrenia biomarkers with benchmarking of ‘novel therapies’ assessed not only against placebo but against nicotine mediated improvement in the patients’ MMN impairment (enhancing stimulus encoding and sensory memory). Moving beyond small, single-site studies
For the most part, the EEG, QEEG and EP methodologies are used in small preclinical and Phase I studies in the hope of gathering and comparing data in animals, healthy volunteers and CNS patients to identify promising drug candidates. As those therapies move forward, the tools have application for Phase II studies and eventually into multicentre studies. This section discusses two clinical trials in which neurophysiological approaches were incorporated into later phase testing. In one study, routine EEGs were performed as part of a multiple dose Phase I trial of a compound with a glutamatergic mode of action, meaning that it impacts the neurotransmitter system linked to
EEG Changes in Phase I Study
Source: PAREXEL 2008
Figure 2
memory formation and information processing, and to excitatory CNS effects, up to and including seizures. The therapeutic indication studied was a degenerative disorder (Alzheimer’s disease), although this neurotransmitter system is also implicated in Schizophrenia, Major Depression and other CNS disorders. The study enrolled 12 healthy male volunteers, who were randomised to a low, mid, or high dose of the drug. The EEG changes shown in Figure 2 reflect the high dose arm two hours after drug intake in 50 per cent of the subjects. The changes show electrical discharges with high amplitudes indicating an increased likelihood of seizure. The low
and midrange dosage groups did not show any changes known as epileptiform discharges, suggesting that they are safer with respect to seizure likelihood. In a follow-up study in healthy male volunteers, a first tonic-clonic seizure appeared as a serious adverse effect. The observed EEG data led to an adjustment in dosage in consecutive Phase II studies and to the implementation of routine EEG monitoring in a central EEG reading unit. One of the first larger studies to use QEEG as a predictive tool is known as Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD). It is being conducted in 10 locations throughout the United States (Chart 1) and sought to recruit 375 subjects with a diagnosis of major depressive disorder. The goal is to evaluate the potential of early EEGs as a predictor of an individual’s response to treatment with specific antidepressant medications. Enrollment was completed in March 2007, with 220 subjects analysed for 7-week endpoints. The BRITE-MD trial tests two antidepressants—escitalopram (Selective Serotonin Reuptake Inhibitor (SSRI)) and bupropion XL—studying them as single-drug therapy and in combination. It also introduces a dose escalation phase. The intent of the study is prospective
Sites participating in BRITE-MD Study • Baylor College of Medicine, Houston, Texas • Cedars-Sinai Medical Center, Los Angeles, California • Massachusetts General Hospital, Boston, Massachusetts • Northwestern University, Chicago, Illinois • R/D Clinical Research, Lake Jackson, Texas • University of California, Los Angeles, Harbor • University of California (Neuropsychiatric Institute & Hospital), Los Angeles, Westwood • University of California, San Diego • University of Pittsburgh, Pittsburgh, Pennsylvania • University of Texas Southwestern, Dallas, Texas Source: Clinicaltrials.gov
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Going forward
Reducing the timelines and cost of investigational therapies are keys to expanding the number of treatment options for the growing number of people suffering from a range of CNS disorders. One
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promising approach for speeding the clinical development process is to use established neurophysiological tools, such as the routine EEG, quantitative EEG and EP, in a search for biomarkers that allow researchers to integrate preclinical results in the design of Phase I studies. How do results of first-in-human studies compare to what was seen in animal studies? Using these methods allows researchers to characterise the PK / PD profile of compounds early on and to compare results to preclinical data in an effort to determine whether a compound crosses the blood-brain barrier or produces CNS-mediated side effects in humans. Frequently, there is a platform of compounds with similar properties under developmentâ&#x20AC;&#x201D;differentiating these, one from the other, and selecting the best drug for development is critical. These electrophysiological techniques, along with imaging and cerebral spinal fluid sampling can provide invaluable information and accelerate drug development. With EEG, QEEG and EP, small studies can be conducted in which healthy volunteers are exposed to varying doses of a compound. This approach can bring into Phase I the kinds of dose-ranging studies that traditionally occur in Phase II. Pushing early dose-ranging into Phase I and matching results to preclinical work holds promise for improving the GO / NO-GO decision-making process. In addition, these tools enable the use of surrogate biomarkers, such as whether an EEG indicates central action. Later on, if the biomarkers become validated
Authors
validation of an Antidepressant Treatment Response (ATR) indicator as a biomarker of clinical response to an SSRI, and to determine the best treatment option for patients who are predicted to be non-responders to an SSRI. The study is designed to use EEG, starting on Day 0, to determine the association between drug treatment outcome and brain function in patients with Major Depressive Disorder. Electrodes are placed on a patientâ&#x20AC;&#x2122;s forehead and earlobes to measure brain responses that appear within seven days, and sometimes as early as 48 hours, after beginning antidepressant treatment. On Day 7, there is an ATR assessment, clinician prediction of response, and randomisation. Interim results indicated that the ATR index reached statistical significance in predicting seven-week clinical response as measured by the standard Hamilton Depression Rating Scale after just one week on treatment with an SSRI. Results presented in December 2007 showed ATR-predicted responders to escitalopram are significantly more likely (67 per cent) to respond to seven weeks of escitalopram treatment than are ATR-predicted nonresponders (28 per cent). Findings also showed that ATR-predicted responders are significantly more likely (50 per cent vs. 21 per cent) to achieve remission with seven weeks of escitalopram treatment, and ATR predicted non-responders to escitalopram are significantly more likely to respond if switched to bupropion XL at one week (53 per cent) versus staying on escitalopram for seven weeks (28 per cent). These findings suggest that early EEG testing can detect an early brain signal of response, which can help clinicians determine treatment response much faster and effectively than a trial and error approach that can take weeks.
surrogate endpoints, their use could reduce years from the overall clinical development path. By increasing detection sensitivity and reliability, samples sizes required to demonstrate efficacy would be substantially reduced. CNS drugs typically require large multi-centre global trials to achieve adequate response data against placebo, and take years to conduct. Clinical trials would benefit from the incorporation of potential bio / surrogate markers as a corroborative signal converging on the currently employed clinical endpoints, especially when the diminished placebo versus the drug effect size difference is small. A variety of neurophysiologic techniques are being employed to study compounds early on in clinical development, in the target diagnostic CNS patient population. By bridging animal findings to humans, and then from volunteers to patients, these techniques contribute to our ability to translate preclinical disease and toxicity models to patients, and inform drug developers of possibly effective doses. Currently, these methods are being validated in small Phase I trials, but they hold promise for use in later stage studies. The infrastructure to conduct QEEG or EP in large-scale clinical trials is becoming a possibility, as equipment becomes more portable and affordable, and central reading of data is readily achieved by electronic data transmission. Full references are available at www.pharmafocusasia.com/magazine/
Larry Ereshefsky is Chief Scientific Officer, Vice President, and Principal Pharmacologist in Early Development at PAREXEL International. He serves as Clinical Professor of Psychiatric at the University of Texas Health Science Center in San Antonio, Texas in the United States.
Malek Bajbouj is a Principal Consultant in Early Development at PAREXEL International and has in-depth expertise in the Central Nervous System (CNS) therapeutic area. He serves as Professor for Psychiatry and Affective Neuroscience at the CharitĂŠ University Hospital and the Freie Universitaet in Berlin, Germany.
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 to 30 per cent of Investigators participating in a trial may recruit no patients. When considering this statistic, it is important to remember that every site—also those that have not recruited to target—has been through a process of selection. Whilst this process may determine whether a site can provide suitable staff and facilities in accordance with regulatory guidelines, it is evident that the site selection process is not foolproof in assessing whether or not a site will in fact recruit patients as anticipated, or at all. This article evaluates a number of pragmatic approaches to more effectively identify suitable sites by proactively weeding out the types of surprises that—with the 20 / 20 vision of hindsight—were not so very surprising. We move beyond the basics of the site selection visit and consider the process as both a strategic and tactical challenge focussing on three key factors: • The impact of company processes in setting the tone for success or failure
• Identifying the less obvious but crucial characteristics of successful sites • The importance of investigator motivation. The golden site profile
Looking to the investigators, prior experience and personal relationships often form the basis for selection. Given the increasing volume of competing trials, experienced investigators are in great demand. However, they may not offer the certainty of delivery they once did. Data also suggests that the number of investigators active for only one year in clinical trials is increasing. Taken together, the necessity to work with new investigators becomes apparent. In such circumstances, it is important to extrapolate from previous experience to identify the indirect and less obvious characteristics associated with good sites—characteristics that may not be apparent at the individual site selection visit. For instance, an analysis of stroke studies conducted at over 400 sites globally for over a five-year period showed that the top decile of investigators (in terms of recruitment) displayed
the following characteristics: • Located in countries / cities with an older population • Practicing in a large or general hospital • Located in more densely populated cities / countries • Specialising in neurology with an emphasis on geriatrics. Whilst perhaps not surprising, these findings allow the conclusion that the successful recruitment of patients in such studies is linked to the ability to identify investigators who fulfill this specific set of criteria. Assessing investigator motivation
There is, of course, only so much that can be predicted from an investigator survey process and analysis of past data. Assuming the investigators are located in the same country, have access to similar patient populations, similar facilities and staff, why do we continue to see a broad range in recruitment performance across sites that appear similar or at least equivalent? To help explain this, we turn to two of the less tangible
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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.
• How often does a site selection visit result in the investigator not participating in the study? With up to 30 per cent of site not recruiting any patients, should we not also expect 30 per cent of the sites we visit to not go forward? Naturally, it is not this simple, but with relatively few sites dropping out at this stage it should be considered whether the balance is in the right place.
the number of sites. This can create a disconnect between site selection and the actual trial conduct, which may be exacerbated when the team managing the sites throughout the study receives such a list of investigators they did not select themselves. If not appropriately and proactively managed, this process allows for a lack of ownership and responsibility for site performance.
• How often are investigators re-selected who have previously taken part in trials but not recruited any patients? Again, this is not straightforward given the various reasons why an investigator may not have recruited patients to a previous trial, or why the investigator may be selected for continued trial participation. However, we should at least have a realistic view of the investigator’s likely contribution and account for this in study planning.
• Do the individuals responsible to select the investigators have the required experience to assess some of the more complex factors, for instance investigator motivation? CRAs may be trained to select investigators in line with ICH and the protocol. However, is the site selection staff trained to effectively assess the less tangible aspects of what makes for a successful site? Moreover, is the staff in a position to reject investigators they do not consider suitable?
• Are the individuals who select investigators accountable for the subsequent performance of the investigators? One team of people may be responsible solely to select a set number of investigators from a limited pool, and may be facing considerable time pressure to do so. As such, their chief concern will be to meet the immediate commitment in terms of
• There simply may not be sufficient sites that meet all the criteria. This is an increasing problem in many therapeutic areas, notably oncology. Consider whether we are being too conservative in terms of investing in new investigators in emerging markets and facilitating their trial participation. Are we actually taking greater risk by not being more inclusive in this regard?
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—investigator interest and motivation. For most investigators clinical research is only a small part of their practice, compared to the dominant obligation of patient care. Moreover, the investigators continually face time constraints and have to prioritise their time. In this context the importance of investigator motivation is evident. When considering motivation we should first address why investigators make the decision to take part in clinical trials? Reasons vary and are specific to each individual investigator,
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but generally include potential benefits to patient, scientific or medical interest and financial benefit. In today’s world of health economics, trials may also be a conduit not only to the test drug, but also the comparator drug that may already be on the market but cost-prohibitive to many patients. Regardless of what drives their motivation, it is necessary to confirm that investigators participating in a trial possess this key ingredient if the current cycle of delayed studies is to be broken. With experience, it is possible for the site selection staff to get a
general impression of how motivated an investigator is. To more accurately assess investigator motivation, consideration should be given to the following practical approaches: Strategic partnering – Depending on the healthcare system, institutions may have a Research & Development office that has worked with investigators over a number of years. By meeting only with the individual investigator and maintaining a transactional relationship, instead of collaborating also with centralised R&D functions, we may continue to select
Clinical Trials
entation followed by an invitation for the investigator to ask questions in fact veil how much time the investigator spent reading the protocol in advance of the visit. Instead, starting the visit by simply asking the investigator their opinion of the protocol is a good indication of their level of interest and motivation. In summary, a site selection visit that ensures facilities and qualified staff are in place is a relatively straightforward process. However, determining if a site will actually recruit patients into the trial is another matter
Author
investigators in a relatively blinded fashion. However, developing shared objectives and working collaboratively with such central functions can add great value and prevent inappropriate investigators from being approached. Asking the right people â&#x20AC;&#x201C; Itâ&#x20AC;&#x2122;s no surprise that the research nurse or other members of the team running trials dayto-day will be able to give a more accurate view of the practical implementation of a trial than the investigators themselves. Similarly, an investigator may not be aware whether support functions, such as the radiography department, can provide the volume and frequency of scans required. Such logistical challenges often are the hidden reason for study delays and should always be assessed directly and proactively with the individuals responsible. Asking the right questions â&#x20AC;&#x201C; Site selection visits that start with a protocol pres-
entirely. In order to make the process more effective and successful, we need to start by creating a culture and company processes that engender ownership and encourage the selection of the right sites. On a day-to-day basis, application of the assessment approaches explored in this article provides a greater probability of selecting investigators that will recruit as anticipated. Full references are available at www.pharmafocusasia.com/magazine/
Benjamin Quartley started his career working as a CRA in the Pharmaceutical Industry. Recognising the challenges presented in patient recruitment he joined a company established to support Investigators in the delivery of clinical trials, where he gained an insight into the Investigators world across eight years. Ben has now taken this experience back to the Industry and works for Covance in Feasibility and Patient Recruitment.
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Glenn Saldanha, Managing Director and CEO, Glenmark Pharmaceuticals, India Glenn Saldanha who has steered the organization for the last nine years holds a Bachelorâ&#x20AC;&#x2122;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.
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Innovation for Growth
Where does the company stand today with respect to its motto “To emerge as a leading integrated research-based global pharmaceutical company.”? When we began the process of discovery research in 2000, very few believed that we could do it. We were clear at that time and even now that innovation was the only way for sustained growth and for that one had to venture into highend discovery research. Today, we are leaders in the drug discovery sphere in India and have a rich pipeline of 13 molecules (NCEs and NBEs) of which eight molecules are in clinics (including Crofelemer for HIV associated diarrhoea in-licensed from Napo). To have eight molecules in clinics is a significant achievement. All the molecules which are in clinics are either first-in-class or best-in-class targeting chronic diseases ailing the world. In the next financial year, we will have two of these eight molecules entering phase III trials, and three more starting phase II trials. Each of the molecules is a potential blockbuster with peak sales opportunity of US$ 1 billion to US$ 3 billion. We have always believed, even in the area of discovery research to do cutting-edge work and the peak sales opportunity for each molecule validates that fact. For instance our latest molecule which is filed for Phase I trials in the UK i.e. GRC 15300 for Osteoarthritic pain, Neuropathic pain, and other Inflammatory pain conditions globally, will be the first TRPV3 molecule to enter clinical trials. We have made significant progress regarding our vision, but we still have a long way to go. What has been the role of international partnerships in Glenmark’s success over the last few years? Discovering a new chemical entity and seeing the molecule all the way till the end requires a sizeable investment. A single new chemical entity which runs through preclinical and clinical development can cost companies millions of dollars. Also it’s a zero-sum investment if the molecule fails. Thus one has to look at various options when venturing into
discovery research. Though we are doing pioneering work in the area of discovery research we must keep the risk factor in mind and partner with global pharmaceuticals organisations to share the risks and benefits. In the last five odd years, we have struck four out-licensing deals collecting around Rs. 500 crore in cash as milestone payments. One must note that unless your research is world-class the Big Pharma will not be willing to participate in the process. These partnerships have not only boosted our research efforts but also helped sustain our investment in the area of discovery.
With eight molecules under clinical trials, we have clearly demonstrated that we have one of the best pipelines in the area of drug discovery. The molecules that are in the clinics are potential blockbusters with sales opportunity for each molecule being in the range of US$ 1 to 3 billion. We will continue to step up the pace of our discovery programme and look to push molecules ahead in clinical development. At the same time, we will actively pursue out-licensing opportunities for few of our molecules which are in clinical development.
What went into building the drug discovery capability and the product pipeline at Glenmark? Excellent scientific talent along with focussed selection of targets and therapeutic areas have been the key differentiators in building the pipeline. In addition to this, well-planned schedules and advice from an excellent scientific advisory board and key opinion leaders have backed the target identification process from time to time.
What has been Glenmark’s experience with innovation? Innovation has to start at the top. A considerable amount of time needs to be spent on developing and sustaining innovation, and making it clear that it is fundamental to the company’s success. A second thing is bringing people together who share a common vision, providing them with the resources to pursue that vision, and giving them the autonomy and responsibility for executing against that vision. Most innovators thrive on empowerment, so you need to make sure the structure and the decision-making in your organisation genuinely have that quality. The third thing is having access to the capital needed to support innovation. This has always been an issue for smaller and mid-sized companies, and, in the current environment, is even an issue for large companies. Now more than ever, you need to be selective about the ideas you pursue. At Glenmark, innovation has been the defining factor in our success. We have managed to do what very few pharma companies have done in the world. We have continuously developed new molecules, cut out-licensing deals, expanded our presence in new markets and built a strong generics business, all within a short span of a few years. When we look ahead, sustaining this growth is going to be the single biggest challenge and I have no doubt that innovation will continue to be the differentiator.
How do you hedge the risks while improving the success rate of your drug discovery programmes? We have considered the route of outlicensing our molecules to Big Pharma once the molecule reaches Phase I / Phase II trials as part of our strategy to hedge our risks. While partnering with Big Pharma, we look to close deals that will give them the rights for that molecule for three regions in the world—North America, Europe and Japan. The rights for the molecule in other parts of the world remain with us. So if a molecule reaches the market place, the partner (Big Pharma) will have rights to sell the newly approved drug in these three regions. They will pay Glenmark royalties on sales. In other parts of the world, Glenmark will directly sell the newly approved drug. What are the current priorities for the company in its drug discovery programme?
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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 interrelationships among all key stakeholders is the critical aspect in risk management planning in today’s rapidly changing, complex global healthcare environment. These can include payers, providers, patients, care givers, patient advocacy groups, regulators and other government agencies. All these stakeholders should be considered when planning and communicating benefit and risk. In the US and Europe there have been significant updates in safety and risk management regulations. Many other countries are actively revising drug regulations such as India and China among others. In the face of these rapid and global regulatory changes one must constantly evaluate their readiness in responding with timely and compliant benefit-risk management systems. This readiness assessment will encompass several key areas but must also be comprehensive and open. The organisation must understand the principles of the culture of safety and put in place systems and processes to support this concept as a core characteristic of the company. One must identify gaps in knowledge
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of both risks and benefits for example, special populations both of those with identified risks and those that have not been evaluated such as the seniors and children. Given today’s advances one should also consider the implication of pharmacogenomics on the risk management programme. Is the company ready to manage a marketed product? Are there sufficient systems, processes, procedures and finally sufficient personnel both in quality and quantity? Four key components of the comprehensive benefit-risk management programme
When considering comprehensive and cross-functional benefit-risk management programmes, it is possible to organise the efforts into four key areas. They are • Protocol review and approval • Active surveillance • Provider and patient education and intervention and • Appropriate use management. These categories are used to help assure that the programme will be comprehensive and effectively designed based on all available information and utilising crossfunctional capabilities (Figure 1).
Protocol review
During the investigation phase, the sponsor has complete control over product distribution and use. However, he loses the control substantially as product receives marketing authorisation. With market authorisation and distribution, the product is available to licensed medical practitioners in accordance with local laws and regulations. Also, physicians could often approach the sponsor with a request to provide the medicinal product free of charge for the expressed purpose of conducting independent clinical research. In addition, a sponsor can have a programme of investigation on the medicinal product that has been designed internally to provide additional information as determined by the gap analysis noted above. These investigations could be both internal and external. The sponsor should put in place a mechanism to assure adequate design; inclusion and exclusion criteria; and adequate subject protections for each of these protocols. To focus on science and ensure that at-risk populations are protected, the sponsor can constitute a protocol review committee with adequate committee structure and document procedures. Commercial
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Clinical Trials
interests cannot outweigh patient protection. Key stakeholders who can be included in this committee may be from the areas of Research & Development, Medical Affairs, Regulatory, Law, and Commerce. Other groups such as public affairs may also be included. The sponsor must be inclusive and open and avoid silo behaviour. Active surveillance
Active surveillance programmes include a variety of methods: Consider monitoring commercial databases and insurance databases for retrospective and prospective analyses. The sponsor may also consider utilising more modern methodologies that take advantage of advanced web-based tools. One unique design taking advantage of these Internet capabilities is to create a web-based patient community. In this example a sponsor would offer access to a unique product or disease portal where the patient could enroll and opt for receiving information and also be available to participate in both prospective and retrospective research programmes. Again, the patients could be offered the opportunity to opt for the research programme on a voluntary basis. This community should then provide a platform for the sponsor to readily recruit patients for epidemiologic hypothesis generating and hypothesis testing programmes. In addition, the sponsor could consider signal detection and an evaluation programme which includes actively reviewing single case reports, case series, claims data, data warehouses, and public databases such as the World Health Organizationâ&#x20AC;&#x2122;s Uppsala Monitoring Center, and the United States Food and Drug Associationâ&#x20AC;&#x2122;s Adverse Event Reporting System. Sponsors need to evaluate and understand the appropriate measures to utilise, in the active surveillance programme understanding the key domains, data sources and appropriate methods to apply at each intersection. The purpose of these programmes is to aggressively monitor and investigate events of interest, develop targeted
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Proactive benefit-risk management
1
2 Protocol design and review
3
Active safety surveillance and measures of harm
Provider and patient education and intervention
4 Appropriate use management
Continuous quality improvement programme Programme project management Figure 1
follow-up questionnaires, establish special reporting agreements with regulators (if needed) and effectively communicate the findings to all interested parties in an open and timely manner. Appropriate use programmes
Appropriate use programmes provide a thorough assessment of marketed product usage. These programmes monitor all uses, approved and unapproved indications. They are especially useful for monitoring known high-risk unapproved exposures. When inappropriate use is detected, a sponsor may consider holding provider and patient education programmes that would reinforce appropriate use. There are many tools available to sponsors in developing appropriate use programmes. One can develop drug and disease registries, sample use through market research, utilise publicly available databases, and commercial resources. Ultimately, the sponsor must continuously monitor usage and put appropriate measures in place when aggressive management of the medicinal product distribution is needed. The most restricted method of distribution is used in risk management programmes utilising a performancelinked access system. These programmes ensure that only those patients who understand the specific risks are exposed to products. Notable examples of this restricted distribution in the US include the programmes for isotretinoin and natalizumab both of which have well characterised serious risk profiles.
Provider and patient education
The cornerstone of any risk management programme is the education component. It is critical that the sponsor adequately and continuously educates healthcare professionals, patients, caregivers, and patient advocacy groups with the best and latest information related to the product use. The education programme could be developed along with the entire product development programme. The sponsor can again utilise the online patient community to both provide them with education materials directly and assess their level of comprehension of the critical elements of the programme. Patientdirected online programmes could be expanded to the level of disease communities. These programmes can provide patients access to proactive and interactive educational programmes. The online community can also be used for patient-directed physician communication wherein the patient provides permission to contact their healthcare provider for verification of specific medical information. Programme management
These complex multiple-component programmes require professional project managers to oversee the design, implementation, maintenance, reporting and communications. The project manager assures that the various service components are effectively implemented and anticipates programme problems and addresses them.
Clinical Trials
The final element of the comprehensive benefit-risk management programme should be that of quality management. For each component of the programme, metrics should be established to assess the effectiveness of the service delivery and the effectiveness of the programme to reduce the specific risk elements defined. If the programme is designed to reduce the incidence of events of interest then that will be a key efficacy parameter for measurement and analysis. This ongoing quality analysis will lead to a continuous improvement model. Progress should be tracked over time to identify areas for improvement; define and implement best practices; create process maps to find potential efficiencies and establish Corrective and Preventive Programs (CAPA) as needed. An often-overlooked element
of the quality management system is the inclusion of key stakeholders such as prescribers, pharmacists, and patients in the evaluation process. Summary
Utilisation of modern technologies and effective communication with consistent and audience-appropriate messages is critical for an effective product benefit-risk programme management. Full characterisation of events of interest and validated mechanisms to mitigate risk prior to market authorisation and
Author
Quality systems
active product defense throughout a product life cycle is the backbone of a successful medicinal product. The benefit of which will be the optimal public health outcome assuring that the right patients have the most effective medications for their unique circumstances. And prescribers are provided clear accurate communication to best advise their patients for their course of treatment. Full references are available at www.pharmafocusasia.com/magazine/
Axel K Olsen currently provides leadership and guidance to the development and execution of pharmaceutical safety programs at Quintiles. Prior to his experience as an independent consultant in 2002 and 2003, He was a Vice President in the Global Medical Affairs Department at Wyeth Pharmaceuticals. From 1989 to 1997 he was the head of Worldwide Safety Surveillance at Wyeth.
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Clinical Trials
Clinical Trials in China&Japan Dynamic opportunities for sponsors and CROs
T
he historical approach to clinical drug development, and one that served drug companies well for the past thirty years, was to initiate testing in humans at clinical research units, typically located in the UK and the US and to proceed further to Phase II testing and beyond to patients with clinical evidence of the disease with investigators mostly located in the US, Canada and Western European countries. An increasingly intense competitive environment and the shrinking pools of treatment populations in the traditional North American and Western European markets, however, have led sponsors and CROs to ‘discover’ emerging markets to source high quality research and secure timely enrollment of patients. This article focusses on two of the most dynamic emerging markets, both Asian: China and Japan. China The advantages of being in China for an international CRO
The importance of China to get miracles to market is absolutely indisputable. China represents the fourth biggest economy on the planet and its own drug market is growing at a pace that
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is enviable to any western market, at 28 per cent CAGR. Presence of regional affiliates of global CROs in important locations such as Beijing and Shanghai makes it possible for global pharmaceutical companies to offer easy access to leverage the tremendous potential of this key Asian market. They can also help pharmaceutical companies to extend their reach into a large and important source of patients, investigators and sites. With good local understanding, experienced monitoring, project management and other staff, including regulatory experts, it can provide seamless support to sponsors with regards to high quality clinical development services or assistance with regional registration. Naturally, not only international CROs but also international pharmaceutical companies have ‘discovered’ China as their destination. This, in fact, is a benefit to the CROs. The increasing footprint of a growing number of global pharmaceutical companies in China is vital and has an unequivocal benefit in that it helps escalate the understanding and adoption of fundamental international clinical trial requirements such as ICH and GCP amongst an ever increas-
ing number of investigators and sites. Equally, the commitment by sponsors to engage China first-hand opens up even more opportunities for CROs to work with global sponsors and their local affiliate offices to provide global, regional and local clinical development services. The Chinese regulatory environment
The Chinese regulatory environment is highly dynamic and is maintaining open lines of communication which is absolutely crucial to ensure success. Acknowledging the paramount importance of local regulatory understanding, it is important to build a strong, local team of Chinese regulatory experts who understand the current requirements and work with the clients to understand their needs. Similarly, sponsors and CROs alike need to invest considerable time and effort to understand the evolving Chinese regulatory requirements. Challenges in clinical development
The demand for access to patients and high-quality clinical development delivered on time and to budget, is rapidly increasing. This growth in demand is pushing the limits of local supply, meaning it can be a challenge to staff
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. Short- and long-term goals
Many international companies have long recognised China’s potential as a source of patients for clinical trials and as a growing market for new medicines. Investment in internal infrastructure in China is set to continue, to meet the increasing needs of current and future clients. Specifically, the investment includes significantly increasing monitoring capabilities, growing in-country project management and expanding regulatory capabilities. Basically, both short
and long-term strategies are centered on the key capabilities to help clients effectively leverage China for high-quality clinical development. Japan A “Closed Country” – No more
Two overriding trends drive the majority of events influencing the clinical research potential in Japan. First, Japan has taken a number of steps to make it easier to include the country in global trials. Second, Japan is encouraging its
own drug companies to reach out to neighbouring Asian countries such as South Korea and China, to help make the clinical trial process more effective and efficient. These developments bode well both for Japan and the region at large. This being said, certain regulations and restrictions in Japan (e.g. limiting the length of time a CRA is permitted to spend at an investigative site) appear more burdensome than those in other countries. This means trial conduct can be very costly in
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Clinical Trials
More international clinical trials
In the not too distant past, Japan would have rarely come up for inclusion into clinical trials, considering past hurdles to trial conduct. This picture is changing fast, however Japan still requires very careful consideration, for instance, with regards to cost impact and start-up and enrollment timelines. To overcome frustrations and disappointments in future, a very clear analysis of benefits versus challenges needs to be done before including Japan into trials. Covance has run clinical trials where Japan was included on the same timeline as all other countries in the trial, and indeed Japan did not ‘finish last’—the sites in Japan performed along standard expectations. This type of solid, predictable performance will help draw more trials to Japan which, in turn, helps Japanese investigators and research staff build more experience—it’s a positive spiral. The obstacles to simultaneous drug development
The obstacles to simultaneous drug development in Japan are well known. Interestingly, the Japanese Ministry of Health, Labour and Welfare has signalled that the so-called bridging studies are at best a tactical solution to a strategic problem and at worst have helped delay the necessary globalisation of Japanese trials. Instead, the long-term focus is on reaching out to countries such as China and South Korea for sharing clinical data as the populations of these countries are considered sufficiently close to the native Japanese population. Also of note is that Japan plans to network their major clinical trial sites into ‘hubs’ and nodes— this is a five-year plan which started in 2007, to promote better coordination,
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efficiencies and sharing of experience. These initiatives amongst others will help Japanese investigators and research staff build more experience and help close gaps versus the global market. What’s ahead?
Local Japanese CROs increasingly contribute to global trials and this exposure has helped the CRO industry in Japan mature. To grow internationally, the Japanese CROs will likely need to engage in strategic transactions with other CROs or grow organically by establishing a presence in key markets. As the Japanese CRO industry enters this phase, a new set of challenges will present itself—similar ones that CROs face elsewhere, and it will be interesting to see the developments as the Japanese CRO industry matures further. It’s crucial to keep in mind that Japan is an established, experienced market when it comes to clinical trials, ICH and GCP. In Japan, the clinical trial industry does not start from a small or less developed base—rather, the task at hand is to finally start leveraging the established strengths resident in what is in fact the world’s second largest pharmaceutical market. These strengths have not historically been easily accessible, just as circumstances have not permitted for the industry to effectively and efficiently leverage them. In closing
The composition of markets that contribute to international clinical trials clearly has changed and will continue to change. One requirement of clinical trials will, however, be emphasised consistently: the focus on quality in clinical trials. Here, quality is defined in terms of trial design, the validity of the results, the protection
Author
Japan, even in comparison to traditional markets such as the US and Western Europe, as well as the emerging markets across the globe. Even today, efficient trial management faces an additional set of hurdles in Japan—hurdles not found in other countries looking to claim a stake in global clinical trials.
of subject rights and well-being, and of course regulatory compliance. Most of outsourcing’s focus is on time, cost and scope, but a major challenge is in the quality of the process and the major deliverables. Though it must be conceded that many current practices were reactively triggered in response to quality problems, the future will require that quality management be more proactively and comprehensively integrated into study planning and execution regardless of where the trial takes place. When performing trials in markets such as China and Japan, the number of potential pitfalls, site idiosyncrasies and country-specific regulatory, ethical and administrative requirements increases exponentially. Any challenges which plagued trial performance in ‘traditional’ western markets previously tend to multiply, and no single adjustment can be counted on to remedy those challenges. Instead, an integrative, quantitative, proactive trial management is required and it needs to be geared towards handling not only current day site performance variability, but also the variability in the underlying patient population which can dramatically impact trial outcomes, especially in the complex long-term studies that are increasingly common. A key component in successfully leveraging the potential of emerging markets is a proactive and predictive operational approach. The approach should focus more on risk prevention rather than remediation of investigator errors, and also deliver improved productivity, lower operational risk, and improved scientific robustness— not to mention increased investigator satisfaction.
Nick Wright is Vice President and General Manager for Clinical Development for Asia-Pacific at Covance, a global full service CRO. Nick brings extensive international experience of working in China, Taiwan, Japan and across South-East Asia.
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