Issuu

Redesigning Drugs

Issue 4

2007

Plant Automation

Orphan Drugs

IT Governance

Personalised Medicine

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“Our strategy is based on our belief that Indian scientists can become creators of intellectual property rather than be copiers.” Swati A. Piramal

Director, Strategic Alliances & Communications, Nicholas Piramal India Limited, India

a m r a h P n India

The

y r e v o c Dis S I S O H P R O M A MET

“In the next five years, Indian pharma will do

well in terms of gaining a fair understanding and being able to further evolve the drug discovery environment in India.” Glenn Saldanha CEO, Glenmark, India

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Contents Strategy

Research & Development

Cover Story

Electronic Health Records and Clinical Research 19

Paul Bleicher, Chairman and Founder, Phase Forward, USA

Pharmacogenomics and Personalised Medicine Synergy between the industry and academia

“Genetic passports”—derived from the Human Genome & HapMap Projects— help guide the choice and dosing of drugs throughout each individual’s lifetime. Paul A. Insel, Professor, Departments of Pharmacology & Medicine, University of California, USA

Indian scientists can become creators of intellectual property rather than be copiers.

Materials, Manufacturing & Packaging

Swati A. Piramal, Director, Strategic Alliances & Communications, Nicholas Piramal India Limited, India

Indian pharma will gain a fair

understanding and will further evolve the drug discovery environment in India.

Redesigning Drugs to Enhance Performance

Glenn Saldanha, CEO, Glenmark, India

Drug Discovery and Development An Indian perspective

Luigi G. Martini, Director, Process Technologies, and Patrick J. Crowley, Vice President, Pharmaceutical Development, GlaxoSmithKline, USA

Somesh Sharma, Chief Scientific Officer, Nicholas Piramal India Ltd., India

The Indian Pharmaceutical Industry Promises and perils

Utkarsh Palnitkar, National Leader, Health Sciences Industry Practice Ernst & Young, India

Fulfilling the Promise of China 04 Ray Hill, General Manager, Global Consulting, IMS Health

Victoria Hale, Founder and Chief Executive Officer, Institute for OneWorld Health, USA

Pala Bushanam Janardhan, Business Consultant, Manufacturing and Plant Automation Services, Life Sciences and Healthcare Practice, HCL Technologies Ltd., India

Single-use / Disposable Technology Considerations for biopharmaceutical facility design

Yehong Zhang, Country Manager, IMS Greater China, and

Treating Neglected Diseases The role of orphan drugs

Plant Automation in Pharma An Asian perspective

Craig Sandstrom, Principal Process Engineer, Fluor Corporation, USA

Improving Pharmaceutical Manufacturing Performance 07

Jeffrey Macher, Assistant Professor of Strategy, McDonough School of Business, Georgetown University, and Jackson Nickerson, Professor of Organization and Strategy, John M. Olin School of Business, Washington University in St. Louis, USA

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C o n t e n ts

Clinical Trials Decision Making in Drug Development Innovative designs

Issue 4

2007

Miklos Schulz, President and Chief Executive Officer, and

St. Clare Chung, Director, Bio-Statistics & CDM, SciAn Services Inc., Canada

Healthcare Editorial Team Copy Editors

Chief Editor Rajeshwer Chigullapalli Feroz Zaheer Akhil Tandulwadikar Prasanthi Potluri Kiran BV Jagadeesh N

Art Director M A Hannan Visualiser Narsingoji Raju

Project Coordinators Sunny Roger Yuvraj Sahni Project Associates Stella Powell N Sweta Madhubabu Pasulla Santosh Kumar Dasari Anthony M Hussain Khan

Emerging trends Shonagh McVean, Partner and Sara Zborovski, Partner, Gilbert’s LLP, Canada

Ethics in Clinical Trials and Drug Development

Agnes V. Klein, Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Canada

Information Technology

Kevin Smith Kranti Kalidindi Seema Singh Arun Bhol Abhishek Jain

Advertising Support Team

Manoranjan Luke Rajkiran Boda Vandana Chowdary P Venkata Nagendra Reddy

Operational Excellence IT governance, enterprise architecture and service management

Circulation Manager Gagan Kumar Vallabhaneni

Circulation Executives

Marketing Manager Ahmed Tariq

Pharma Focus Asia is published by SPG Media Limited in association with IMS

Serge Thorn, Director, IT Research and Innovation, Merck Serono, Switzerland

IT in Pharma Countering the information security risk

Pamela Campbell, Partner, Life Sciences Compliance Practice, BusinessEdge Solutions, Inc., USA

Knowledge Tools Increasing role in drug development

Alan S. Louie, Research Director, Health Industry Insights, USA

CEO, SPG Media Group Keith Sadler

Head, SPG Media, India Sanjay Manglik

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Information Technology

Right prescription for the growth of pharmaceutical companies The IT spending of companies will reflect their strategies to introduce new drugs, enter new markets, and be more competitive in the challenging Asian pharma market.

Sourabh Kankhar, Research Analyst, Life Science Practice - Asia Pacific, Frost & Sullivan, Singapore

www.pharmafocusasia.com www.imshealth.com www.spgmedia.com ISBN 1 85938 686 5 © SPG Media Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions. The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates. Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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

ISSUE - 4 2007

Foreword Kittens to Tigers

hese are tough days for world’s Big Pharma. Depleting pipelines, patent expirations, soaring R&D costs and risks etc. have all put the Big Pharma in rough weather. Against this backdrop, fast growing Asian economies - notably China and India, represent new horizons of opportunities. The silver lining to this gloomy scenario is the fast transforming Indian pharma industry. Globalisation, free trade, investment, entrepreneurial zeal are all set to metamorphose Indian pharma companies that were once labelled as the copy cat drug makers into discovery-led firms. The business leaders of top companies have understood quite early that the only way to survive and thrive in the increasingly global business world is to excel in innovation-driven R&D. In the year 2005, India became a TRIPS signatory. In a proactive move, by 2007 more than a dozen Indian companies have launched new drug discovery programmes, while some have reached the last phases of trials too. Companies like Ranbaxy, Dr. Reddy’s Laboratories (DRL), Nicholas Piramal (NPIL), Glenmark and Wockhardt are currently spending 4-7% of their revenues on R&D. Though miniscule compared to that of world’s Big Pharma, according to ASSOCHAM, this figure is likely to go up to 8-9% by the year 2010. The Indian pharmaceutical industry has a remarkable line-up of NCEs in different stages of clinical development. DRL has 9 NCEs in various stages of testing. Among these one of the molecules for diabetes is currently under the final stages i.e. in Phase III and two more molecules are in Phase II. NPIL has three of its molecules in Phase II clinical trials. Ranbaxy has one of the molecules for Malaria in Phase II. Its another NCE for urinary incontinence has successfully completed phase I single and multiple dose studies. Glenmark has 2 molecules in Phase II and one in Phase I of the total six molecules. Wockhardt has one NCE in Phase II and one in Phase I stages of development. Apart from these, companies like Torrent Pharma, Zydus Cadila, Orchid and Sun Pharma are also gradually exploring novel drug discovery. While the goal is same, interestingly, each company has adopted its own approach to achieve the goal. While some have collaborated with foreign firms as co-developers, others are outlicensing the molecules after early stages of clinical development in order to reduce the risks associated with development. DRL has

tied up with Rheosciences of Denmark and ClinTec International of UK as co-developers for two of its molecules. Glenmark focusses on promising lead candidates till early clinical development and then outlicenses them to international pharma companies. NPIL’s strategy is to research collaboratively with academic institutions and foster public-private partnerships. Ranbaxy has entered into an agreement with the Department of Science & Technology (DST), Government of India. According to the agreement, DST will provide financial support to Ranbaxy in the field of drug discovery through soft loans. Surely, it will be interesting to see how these strategies pan out for these firms. Although these are exciting times, it must be noted that these are still early days for the industry. As the articles that form a part of the cover story, and interviews with a few industry leaders reveal, a whole lot of changes need to happen at both the industry as well as the government level to facilitate the growth of industry into this area - Intellectual Property Rights, infrastructure and government policies being a few of them. Though the path to becoming discovery-led global companies is onerous, it holds the potential to bring about a lot of advantages, opportunities and recognition. During the product exclusivity period that a successful NCE is granted, companies can recover their investment many times over. The availability of a talented scientific pool, cost advantages and large patient population provide a unique competitive edge to India. The budding R&D talent and the developing regulatory environment provide the right impetus to the Indian companies. However, the industry should work closely with the academia and the government needs to provide appropriate support to encourage the growth of research talent. Indian companies getting into discovery also means that the needs of the vast patient population of the region are taken care of. It's also an opportunity for the industry to develop medicines for the poor and developing nations. The stage seems all set for transforming the kittens into tigers of tomorrow.

Rajeshwer Chigullapalli Chief Editor

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Fulfilling the

Promise of China

Yehong Zhang, Country Manager, IMS Greater China and Ray Hill, General Manager, Global Consulting, IMS Health

Sustained economic growth and tremendous unmet needs in important therapeutic areas in China are creating huge potential for the industry but the ability to adapt successful practices to the nuances of the local market will be critical.

n recent years, emerging markets have been rapidly gaining importance world wide. And this is certainly the case with pharmaceuticals. The dominance of the US and larger markets remains, but as overall growth continues to slow—reaching just 7% in 2006—emerging markets are stepping up the pace. Since 2001, their share of global pharmaceutical market growth has risen from 13% to 27%. Seven of the leading ten countries in the emerging markets group showed double-digit growth in 2006 and this group is anticipated to grow 9%-10% in 2007. The leaders among them, including China and India, are now in the top 20, with clear potential for even further growth going forward. The top, more developed pharma markets may still represent over 80% of the total world market, but the growing importance of emerging countries is undeniable.

Complex dynamics With emerging markets taking more global share each year, no multinational phar-

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ma company seeking sustainable growth can afford to ignore them. The incentives for entry or expansion are clear and many pharmaceutical companies are already turning to these bright spots outside their traditional markets, in their efforts to compensate for increasingly flat global growth. However, key to effective positioning in any emerging market—whether in the form of profitable expansion and portfolio strategies in the case of multinational companies that already have a presence, or entry strategies for companies looking to establish a local foothold—will be the ability to transfer successful practices from core markets while simultaneously understanding and adapting to the particular healthcare characteristics of each local situation. Emerging markets are notoriously dynamic. Consider the case of South Korea, where, in an effort to reduce drug abuse and misuse, the government introduced—and too quickly executed—a plan that drew a well-defined line between the roles of doctors and pharmacists. Doctors

were banned from selling drugs to outpatients, while pharmacists were prohibited from randomly dispensing drugs without prescriptions. This rapid separation of prescribing and dispensing—which occurred in the space of two years—caused a radical shift in the market and behavioural change by the major stakeholders. Companies had to rapidly and fundamentally redesign their business models as doctors dramatically changed their prescribing behaviour. The ability to forecast and keep pace with such rapid changes will be critical. Significant to the development of geographical expansion plans in these markets and monitoring of performance against them is the fact that reliable market measures are only just beginning to appear. So far these reveal a very varied picture. Although many emerging markets share similar characteristics—particularly in relation to the dominant role of generic medicines and cash-strapped public healthcare systems—all are at very different stages of evolution. As the current embryonic

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measures evolve, analogous and local expertise will be the key to informed decision-making.

China beckons… Some of the most promising opportunities for growth lie in China—positioned to overtake Germany in 2008 to become the world’s third largest economy after the US and Japan. Major drivers of this performance include exceptional economic growth—approaching 11% in 2006, the fastest rate since 1995—an increase in the average standard of living, improved health awareness, rapid expansion of social insurance programmes and significant investment by major industry players. Continued strong GDP growth exceeding that of other emerging countries such as Brazil, India, and Russia, is predicted to position China as the largest economy globally by 2040. This will not only drive the population’s ability to spend more on healthcare, but it will also, as affluence and chronic diseases increase, feed a greater need for innovative drugs. On the demand side, disease profiles in China have shifted to more expensive chronic and speciality diseases such as cancer. This trend is exacerbated by a rapidly aging population and urbanisation. Even with the fast growth of healthcare in recent years, there are still significant gaps in diagnosis, treatment and compliance in all major categories. Indeed, in some treatment areas, these gaps appear to be widening. Business activity has already started to expand outside traditional large urban areas in China. Combined with increasing diagnosis and treatment rates this is creating huge potential for the industry to secure new avenues of growth and optimise return on investment and setting up China to become the seventh largest pharma market by 2010.

…but challenges abound There is little doubt that companies which are successful in China will yield higher growth rates than those that remain focussed only on more mature markets. However, China is a prime example of the extent to which an emerging market can vary from a more developed Western one and bring its own unique challenges.

The country suffers from a particularly fragmented industry sector and huge disparity between its 650 cities and townships with varying characteristics such as physician attitudes and prescribing drivers. At the same time, fundamental issues in its healthcare system, including serious funding deficits, a poorly developed insurance market and a concentration of healthcare provision in large hospitals in major cities (when most of the population resides in rural areas), impede the delivery of quality medical care. If there is any constant in China’s healthcare environment, it is constant change and this is about to accelerate. While acknowledging the failure of past healthcare reform initiatives, the central leadership has made healthcare a central pillar in its drive to build a harmonious society. The scope and depth of its proposals demonstrate the government’s determination and commitment to providing good healthcare for China’s citizens. But these proposals have profound and game-changing implications for the pharmaceutical industry and players in the healthcare arena. The degree to which companies anticipate and successfully handle these changes will be the difference between success and failure in realising the full potential of their China business.

Market access and pricing

This question becomes even more pertinent if one takes into consideration the fact that the majority of MNC products in China today are actually generics by international standards.

Healthcare funding and distribution Another key issue is the nature of healthcare funding and how this is utilised and distributed throughout the system. As the government increases funding to provide basic healthcare services for universal coverage, how does that impact prescribing and funding for innovative medicines vis-à-vis generics? This question becomes quite complicated when the future prospect of private insurance is brought into the picture. Given the strong correlation between market growth and reimbursement funding, a likely scenario is that both will benefit although with different proportions depending on therapeutic class and geography.

Healthcare delivery and reorganisation A related issue is the continuing evolution of the healthcare delivery landscape. As the government agencies try to streamline the healthcare delivery supply chain and rationalise the allocation of limited resources (emphasis on community clinics/hospitals for example), it will have profound implications on the current engagement and selling model for pharmaceutical companies. Changing stakeholders and incentives will make some of the conventional thinking and existing practices obsolete.

At the portfolio level, there is a need to understand what kind of portfolios are profitable in the long-term given the disease burden forecast and the likelihood of favourable market access treatment in terms of listing and pricing. With increasing pressure to prove ‘value for money’, China is projected to be the 7th largest value-based arguments pharmaceutical market in the world by 2010 and analysis are anticipated to play a bigger role in 2002 RANKING 2006 RANKING 2010 RANKING the pricing and reimburseUS 1 US 1 US 1 ment framework. This has Japan 2 Japan 2 Japan 2 a profound impact on a France 3 France 3 France 3 company’s future portfoGermany 4 Germany 4 Germany 4 lio design and brand level Italy 5 Italy 5 UK 5 business model. Given the UK 6 UK 6 Italy 6 markedly different behavSpain 7 Spain 7 China 7 iour of branded generics Canada 8 Canada 8 Canada 8 in terms of their pricing Brazil 9 China 9 Spain 9 China 10 Brazil 10 Brazil 10 and sustainability, to what extent should this be part Source: IMS Health, IMS Market Prognosis International, of a multinational corpoMarch 2007 update ration’s (MNC’s) strategy?

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Getting a measure of emerging markets

Emerging markets’ contribution to world sales growth increased to 27% in 2006

-1

Japan

2001 AC = +$45.5bn

2006 AC = +$42.4bn

8 8

ROW Emerging Markets

13 16

Western Europe

-10

46 0

% Contribution to Absolute Change (AC) Source: IMS Health, IMS Market Prognosis International, March 2007

Human resource practices One of the key constraints in the industry is the dearth of talent at every level of the business. With sales force attrition level at 30% annually, it is very difficult to develop and execute a long term strategy. Investment strategies without a significant HR component are doomed to failure. But HR in China is quite different and its effectiveness drivers are different from those in the West. It is mission critical to build an HR strategy that emphasises China-specific measures which are cost-effective and implementable. Replicating global HR practices without local adaptation will be both costly and non-consequential.

Sales and marketing environment In addition, hospital channel dominance, a complex multi-tiered supply chain, proliferation of outlets and players, low levels of technology, counterfeits and corruption, all need to be understood and navigated. Identifying and focussing efforts on the key opportunities for growth will be contingent on understanding such critical issues as the shift from tier 1 to tier 2 and tier 3 cities where the population is migrating and economies are prospering; extending the reach of sales activities into new areas where drug coverage is needed;

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transforming approaches to customer segmentation; accurate hospital targeting; and the delivery of effective messaging to the right doctors and in the right format.

A new engagement model China’s healthcare—in keeping with that of many emerging markets—is at a crossroads. In such an environment, what is the role of the pharmaceutical industry as China tackles the challenge of providing affordable quality healthcare to the largest population on the globe? What can manufacturers do to successfully advocate their importance to ensure a sustainable future? Is there potential to build a broad-based, sustainable advocacy programme that will show the government that there is a better way to provide healthcare, one that will resonate with the Chinese aspiration of building an innovation driven economy? The industry is in a unique position to truly show its value, to participate in the creation of a new engagement model with the government—one that is built on partnership and the value of health. This will involve some short-term tradeoffs and investment decisions but the opportunity to create a sustainable operating environment which rewards innovation and value of medicine is one that should be grasped.

To answer the critical questions on investment and resource allocation in the emerging markets, companies need reliable information and market measures from experts on the ground; people who understand the country, the government and the systems. This type of expertise will be invaluable as an aid to forecasting, improving the tracking of market evolution, understanding the impact of policy changes and optimising resources at the global and local level. The geographic and economic diversity of countries like China makes national level market research both time-consuming and expensive, calling for smart statistical design, modern technology and adequate resources. With the renewed commitment by the government to provide universal access to basic healthcare, data capturing at the rural and community level is essential, along with prescription-level data for an understanding of disease patterns, current treatment guidelines and efficient resource allocation. Good supply chain visibility and product tracking are also essential as they not only impact the bottom line but also the safety of medicine. It is also important to recognise that Chinese data is intrinsically limited and must be combined with powerful analytics and in-depth industry knowledge to reach meaningful insights and solutions. Pioneering efforts are now underway to support the development of consistent metrics, as well as initiatives to establish treatment guidelines—increasingly seen as being crucial to cost-effective healthcare in China—and health economics data in key chronic disease areas—critical to promoting value and industry growth. For companies used to working with reliable market measures in developed markets, the nascent metrics and reliance on local expertise and consulting skills will underpin entirely new ways of understanding markets and their dynamics. There is risk, of course, but no company can overlook such a rich source of potential future growth. Those that do not move rapidly to design appropriate operations in these economies of the future will find themselves competing in an ever shrinking part of the market.

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Treating Neglected Diseases The role of orphan drugs

Source: Andy Berry, Orange Photography

The Institute for OneWorld Health has developed Paromomycin IM Injection to treat visceral leishmaniasis in India. In the future, similar models can be used to bring new drugs to the people suffering from neglected diseases in the developing countries.

Victoria Hale, Founder and Chief Executive Officer, Institute for OneWorld Health, USA

t the Institute for OneWorld Health, we are pioneering an innovative approach to developing the drugs most needed to treat neglected diseases in the newly industrialising and non-industrialised world. On August 31, 2006, the Government of India approved our first drug, Paromomycin IM Injection, to provide a new treatment for visceral leishmaniasis. Paromomycin Injection is safe, affordable, can be administered outside an urban hospital setting and most importantly, confers a lifetime cure to those suffering from this terrible disease. Visceral leishmaniasis is the second most prevalent parasitic disease in the world after malaria, and if left untreated, is almost always fatal. It’s a largely forgotten disease and is often recognised as a disease of poverty since it affects only the poorest of the rural poor. Ironically, this neglected disease afflicts almost 500,000 people around the world annually, in India, Bangladesh, Nepal and parts of Africa and Latin America. OneWorld Health was created as a non-profit pharmaceutical company because the medicines needed to treat neglected diseases were often slow in coming, or entirely absent from the pipeline of a traditional pharmaceutical company. Yet, the need for these drugs was, and

continues to be, staggering. The global disease burden associated with diarrheal diseases, is the focus of OneWorld Health’s newest area of drug research and discovery. Diarrhoeal diseases are a leading cause of death in children under the age of five worldwide taking more than 2 million children’s lives as a result of dehydration and combining with other conditions to worsen illnesses that ultimately kill 4 million more children per year. Neglected disease drug development and the recent success of Paromomycin Injection was possible due to the increase in philanthropic support, and selective and strategic partnering between the pharmaceutical industry and non-profit global health organisations combined with the incentives offered by the US and EU to neglected disease drug development efforts. OneWorld Health received Orphan Drug Designation from the US FDA and the European Agency for the Evaluation of Medicinal Products (EMEA) for Paromomycin Injection to treat visceral leishmaniasis in early 2005. Because Paromomycin Injection treats an illness that is rare in the United States and Europe, it is considered an orphan drug, essentially granting special consideration to a small disease. The policy dimensions are striking. Orphan drug status is

typically approved for the treatment of diseases that affect fewer than 200,000 people in the US or Europe. Yet, some 500,000 people around the world contract visceral leishmaniasis each year. For those of us committed to addressing global health inequities, this dichotomy can also offer opportunity, both to address other diseases and develop other medicines. Essential, life-saving treatments can offer simple and cost-effective solutions for treating many current global health problems, but existing drugs tend to be prohibitively expensive or are not available. Much has been written in the last several years about the 10/90 gap, a critical under-investment in which, on a global basis, less than 10% of health research and development (R&D) resources were being applied to 90% of the world’s health problems. Many factors are slowly helping to change the imbalance, including a resurgence of interest in and attention to global health and neglected diseases, increased resource mobilisation for research, the active management and transfer of drug development technology, and greater infrastructure and capacity development. Orphan drug designation can be an additional tool to help create and leverage commercial incentives in the United States and Europe to support the development of drugs for

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low and middle income countries with the highest burden of disease. Close to 10 million people die globally each year from diseases that are treatable with existing drugs, according to the World Health Organization. An urgent need clearly exists for new models of drug development and incentives customised to meet the growing needs and changing realities of the world’s poorest people. OneWorld Health’s work is focussed entirely on developing safe, affordable and effective health solutions to treat poor, resource-constrained populations, and we’re an important part of this rapidly expanding and influential space. With the recent approval of Paromomycin Injection for what we believe will become an additional public health tool in India’s disease control programmes, OneWorld Health is transferring technology and facilitating knowledge exchange with local Indian healthcare workers and pharmaceutical manufacturers. We are reaching out to Indian policymakers and local health officials to

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facilitate the integration and uptake of Paromomycin Injection cure in existing healthcare delivery systems. And we are building a network with local partners, including distribution and delivery implementers, to ensure that the drug reaches remote rural villages where the vast majority of visceral leishmaniasis patients live with extremely limited existing health infrastructure and public health apparatus. The implications of bringing an orphan drug to cure a neglected disease that kills communities in India, Bangladesh, Nepal and parts of Africa and Latin America are significant, but our development of Paromomycin Injection is only one small part of the renewed momentum around neglected diseases. The Bill and Melinda Gates Foundation’s work in particular has brought a hot spark of interest and hope back to the field, and a growing number of pharmaceutical companies, non-governmental organisations (NGOs) and product development partnerships (PDPs) are finding new opportunities and incentives with

financial support from private foundations, investors and governments. New and innovative partnerships are emerging to support orphan drug development, including pharmaceutical sector-PDP coalitions that champion incentives for neglected disease development. And new public initiatives also have the right spirit and intent, including the introduction of US legislation that would require parties conducting neglected disease research to grant non-exclusive licenses to generic producers who supply developing countries with medical products. At OneWorld Health, we’re excited about our part in helping to create health solutions for parts of the world where they are most needed. And essential to this effort in 2007, we will be developing customised pharmaceutical partnerships to support our access to products and compounds, manufacturing and patients. These are all important developments, with the promise of creating real social change and health impact in Asia and beyond.

With 60 NCEs in the pipeline, the Indian pharma has adopted the innovation path with enthusiastic diligence. More than a dozen Indian companies are now focussing on novel drug discovery and taking different routes viz. partnering with international pharma companies, outlicensing, researching collaboratively with government and academic institutions etc. There is little doubt that â€œdrug discoveryâ€? has become the buzzword in the Indian pharmaceutical industry. Pharma Focus Asia invited top industry leaders to give their views on the same. Swati A. Piramal, Director - Strategic Alliances & Communications, Nicholas Piramal India Limited (NPIL), Glenn Saldanha, CEO, Glenmark, Somesh Sharma, CSO, NPIL and Utkarsh Palnitkar, National Leader, Health Sciences Industry Practice, Ernst & Young, India give insights on the reasons, strategies, challenges and opportunities for Indian pharma to embark into the drug discovery era.

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Interview

A New Paradigm for the Indian Pharma Industry Where do you think the Asian pharma market stands today against the global market in terms of drug discovery? The Economist’s Pharmaceutical Survey (The Next Big Thing, June 2005) mentioned that in the year 2004 China’s and India‘s share of global drug development was only 4.6%. This share of the drug development pie is likely to rise dramatically

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from these two nations. The reasons being, better intellectual property laws, reverse brain drain and investment into drug discovery by public institutions and private industry. What are the drivers for Indian companies to transform from generic producers to drug discoverers?

In India, there has been a rise in the number of research based companies as opposed to generic companies. Like my own company, Nicholas Piramal is focussed on drug discovery. Our model is to partner rather than try and infringe patents. This concept is gathering steam and is a new paradigm. It is difficult for generic companies to be “schizophrenic”—on one side try and bust

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"Our strategy is based on our belief that Indian scientists can become creators of intellectual property rather than be copiers." Swati A. Piramal

Director, Strategic Alliances & Communications, Nicholas Piramal India Limited, India

a patent, but on the other, get your own scientists to think of inventing rather than copying. What are the reasons behind western companies collaborating with Indian companies for drug discovery? What are the pros and cons of tying up with foreign companies? Our recent research collaboration with Eli Lilly has created a new paradigm in the pharma industry. This unique drug discovery collaboration is analogous to a “relay race” where Lilly will discover a new drug, file patents and “pass the baton” to us for taking it through to Phase II clinical trials. After that they have a call back option to take it further into Phase III. NPIL gets milestone payments (potentially about US$100 million), royalties and marketing

rights for some countries. In this model the objective is to win the race by improving on time, costs and quality. It is the first agreement of its kind. It can work only when each member of the relay team is strong, has expertise and believes in the same values (in this case intellectual property protection). The model seeks to leverage the power of the network, which is a completely different approach.

India’s leading research institutions such as

What new areas of research hold promise for the Indian pharma industry? India will be strong in diseases such as diabetes, cardiovascular diseases, inflammation, cancer, infectious disease and vaccines. The day is not far when India will leverage its IT and engineering capabilities to make life saving drugs and devices.

scientists can become creators of intellec-

How is the research strategy of NPIL unique and different from the other Indian companies who are also targeting original drugs? We are leveraging the power of networks. Our motto is to “build partnerships that prosper”. Our partnerships with academia and global innovators are helping us build unique strengths and expertise. In addition, we have built a natural product library of over 50,000 microbial strains and 6000 plants from the bio-diverse regions of India. We believe this is a unique treasure house of potential new medicines. NPIL has research collaborations with academic institutions like Anna University, Indian Institute of Science, etc. How have these collaborations helped NPIL in its progress towards a new drug molecule? Indeed, our collaborations are giving us clues for developing new medicines in cancer and infectious disease research. We have a large number of collaborations with

CSIR, Anna University, Indian Institute of Science etc. NPIL aims to be the first Indian company to manufacture an original drug. How does it plan to achieve the same in the scenario where other companies' molecules are also in the final stages of testing? We have a clear and focussed strategy and decided not to be in the generics space. Our strategy is based on our belief that Indian tual property rather than be copiers. This strategy is a long term one and will take time to bear fruits, but we hope that we will be one of the first companies to take an Indian discovery into global markets and help reduce the burden of disease not just for India but the rest of the world. What are the challenges that the Indian companies face in the drug discovery process? How well equipped are they to handle these challenges on their own? The biggest challenge is government policy which tends to take a rather short sighted view and consistently reduces prices. This does not leave enough margin to invest in research. The prices of Indian medicines are perhaps the lowest in the world and the government has to be careful not to cut the wings of an industry which is making a global impact. We believe that using India’s drug discovery capability and technology we will bring affordable new patented drugs not just for India, but the rest of the world. Any other comments that you would like to make? Our goal is to make Indian drug discovery reach the global market for a price between US$ 50-100 million. It is an ambitious target but we can do this by leveraging the power of networks, effectively using Information Technology, and using the large patient base for clinical trials and betting on the creation of intellectual property and fostering global partnerships.

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Interview

Innovation - The Key Driver Where do you think the Asian pharma

100 years. Therefore, they will continue to

There are two key driversÂ: one is the gener-

market stands today against the global

lead the path. In Asia, Japan is the leader,

ics business where, given the pricing pres-

market in terms of drug discovery?

followed by countries like India and South

sure that exists and the commoditisation

From a global front, the US, Europe and

Korea who are now getting more active in

of generics, companies would increasingly

Japan are still the leaders and they will con-

drug discovery.

have to look for innovation as a key driver

tinue to dominate the drug discovery space in terms of coming out with molecules, primarily because they have been in the field of discovering new drugs for the last

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What are the drivers for Indian companies to transform from generic producers to drug discoverers?

to change their business models. The other factor driving companies to transform into drug discoverers isâ€”now that the patent laws are enforced in

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"In the next five years, Indian pharma will do well in terms of gaining a fair understanding and being able to further evolve the drug discovery environment in India."

product

Glenn Saldanha CEO, Glenmark, India

pipeline

and

then

are novel. One of the twoâ€”the asthma

outlicensing it. The advan-

molecule is novel which means there is

tage of a collaborative research

no existing drug in the market with this

model is that it gives the Indian

therapy. It is an oral drug whereas most

companies a better understand-

of asthma therapy is inhaled. The drug is

ing of how to carry out re-

given once daily, and we think it holds a

search and also help in revenue

lot of promise in terms of relief for patients.

generation. These are the two

As far as the diabetes molecule goes, there

prime reasons for collaborative

is one drug that has recently been

research.

launched by Merck & Co., Inc., US called

The disadvantages are that

Sitagliptin. The drug belongs to a novel

a lot of management, time and

class which will capture the bulk of the oral

resources would get diverted to-

diabetes market because the target itself is

wards ensuring that the collabo-

devoid of side effects of the existing thera-

ration is successful as opposed to

pies like hypoglycemia and weight gain.

generating their own intellectual property.

process? How well equipped are they to

hold promise for the Indian

handle these challenges on their own?

Biotechnology is a very promising area in addition to chemical based research. There are various new initiatives like stem cell research and very niche areas which offer a lot of promise where India could look at.

sure too has come to the fore because the

does Glenmark profit after the out-li-

pipelines are starting to diminish in the

censing?

Indian market.

Firstly, there is a huge financial gain to be

What are the reasons behind Western

made through the deal. Secondly, Glen-

Western

companies is to reduce the cost of research and they continue to at look India as a destination where they can reduce cost by

mark would keep the rights for rest of the world markets which is mainly our focus while the entire development cost responsibility is taken over by the collaborative company. Glenmark would be able to establish a pipeline in the regions where we

outsourcing certain activities of the drug

hold the rights.

discovery process.

Glenmark has two of its drug molecules

What are the pros and cons of tying up

(for asthma and diabetes) in Phase II.

with foreign companies? Though we feel Glenmark is an exception because we are developing our own

to raise sufficient capital to fund the development of new drugs. The third challenge is competing with the Western world which has been doing research for the last 100 years when compared to India which back.

tional pharmaceutical companies. How

objective

second challenge is finance i.e. being able

entered into the research field just a decade

cal stage and then outlicenses to interna-

primary

pool that exists and access to them. The

lead candidates till early cliniinvolved in innovation. The pricing pres-

The

The biggest challenge is the limited talent

Glenmark develops promising Indiaâ€”companies are forced to get

companies for drug discovery?

companies face in the drug discovery

What new areas of research pharma industry?

companies collaborating with Indian

What are the challenges that the Indian

How are these molecules different from the existing ones? Both the drug targets that are in Phase II

What are the other drug molecules in the pipeline and what are the future plans of the company? We have one more drug which is in Phase I now for pain indications and three preclinical candidates, one for obesity, the other for pain and the third for rheumatoid arthritis. We hope to move these into the clinics and pursue a similar model of outlicensing them at various stages of development. Any other comments that you would like to make... In the next five years, Indian pharma will do well in terms of gaining a fair understanding and being able to further evolve the drug discovery environment in India.

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Drug Discovery and Development An Indian perspective

India is on the threshold of drug discovery research where the next few years are going to be the most critical.

Somesh Sharma, Chief Scientific Officer, Nicholas Piramal India Ltd., India

efore embarking upon a discussion on the role of Indian pharmaceutical industry in the development of drugs for the world market, it might be beneficial to review the dilemma faced by leading pharmaceutical companies of the world. Companies like Merck were the darlings of Wall Street as well as the public at large. However, the scenario started changing in the mid 1990s and the industry has been reeling ever since. There are many forces that have contributed to the current scenario: (i) a series of product recalls (ii) continued increase in the prices of new drugs (iii) increased, perhaps unrealistic expectations regarding the safety of current and future drugs and (iv) decreased productivity despite heavy expenditure in the discovery and development of innovative drugs. Therefore, it is clear that a new strategy is required to discover and develop new drugs at a cost that allows major pharmaceutical companies to address unmet medical needs in a timely and cost-effective manner. India and China are seemingly at the forefront to offer such an opportunity. Indian companies have often been referred to as manufacturers of copycat drugs. Scores of DMF filings, highest number of FDA approved manufacturing sites (outside the US) and a not so congenial patent law; all these have not exactly given a standing of a country vying for a spot in the chase for new drug targets. With such

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a checkered background, when and how did India gain a place in the challenging business of novel drug discovery? The new millennium brought about drastic changes for the Indian pharmaceutical industry; not that the changes were unexpected. TRIPS-compliant patent regime was in the offing since India became a signatory to the WTO in 1995. The companies have quickly realised that reverse engineering alone will not provide durability, and thus, have evolved various models that could fit within their research and business scheme. Traditionally, Indian pharmaceutical companies have been investing about 2% of the turnover on R&D, which is way below the 12% mark of their Western counterparts. This paltry investment though, is bound to change in the coming years as evidenced by the emerging trend (Table 1). With robust activity at the R&D front, the Associated Chambers of Commerce and Industry of India (ASSOCHAM) has indicated that the R&D spending of the Indian pharmaceutical industry will reach about 8%-9% (of total sales volume) by the year 2010. Most of the Indian R&D has turned around and initiated drug discovery as one of the key focus areas. Taking up such a challenging path may be for many reasons, among which at least two seem to be striking: firstly, globally it is being realised that longterm success can be ensured only by inno-

vation and novel drug discovery. Secondly, patent reform has forced Indian pharma to rethink and realign its strategy, which is to innovate for long term sustenance. The high cost of drug development, a subject matter that has been discussed in many forums, is of key concern to the pharma industry. What used to be a US$ 0.5 million endeavour in the 1990s, reached a whopping US$ 800 million in the beginning of the millennium and reports put it at more than a billion as of today. There is great pressure, globally, to cut costs, eliminate redundancies and retain profit margins. The critical factors driving the global pharmaceutical industry to look for newer strategies are based on hard facts stemming from decade-long experiences. These may be one or more of the combinations as stated below: R&D Investment by Indian Pharmaceutical Companies Company

R&D Invest. in 2004*

Ranbaxy

6.0%

Cipla

4.0%

Dr. Reddy’s Labs (DRL)

4.4%

Sun Pharma

4.0%

Torrent Pharma

6.4%

Lupin

1.0%

Wockardt Nicholas Piramal *Figures represent the percentage turnover allotted to R&D Source: Market Research.com

10.5% 0.7% Table 1

• High cost of drug development in the Western countries • Drying drug pipeline • Patent expiration of blockbuster drugs • Hurdles in carrying out clinical trials In view of the increasing drug development costs, two to three different models have evolved in the past 5-10 years. In all

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these models, India along with China has shown immense promise due to its substantial pool of talent in reverse engineering and a sound base in pharma manufacturing. Following are the models: (i) Contract research and development activities, where bigger pharma outsource specific tasks (e.g. pre-clinical studies, animal studies or clinical trials) in the drug development process to smaller speciality companies. A number of Indian companies have positioned themselves to cater to such needs wherein a portion of the drug development process can be handled satisfactorily and the results achieved in a timely fashion (e.g. GVK BioSciences, TCG Life Sciences). Besides cost advantage, India scores big on ease in patient recruitment as compared to its Western counterparts where the trials stretch for years for want of patient population. (ii) Cost-effectiveness and confidence in the available skill sets have propelled many global pharmaceutical companies to set up offshore activities which should gradually result in seamless integration with the parent company. The offshore activities that merely started as manufacturing hubs in India have in due course emerged into clinical research or basic R&D units. Examples of this model include Pfizer, Novartis and AstraZeneca. There is also the future possibility of a larger multinational acquiring an Indian pharmaceutical company and developing it into a stronger R&D base. (iii) Larger Indian pharmaceuticals have taken the leap quite confidently into innovative research. Generics companies like Dr. Reddy’s Laboratories (DRL) and Ranbaxy have set their vision firmly on developing novel drugs, while Nicholas Piramal has always been a proponent of novel drug discovery approach. DRL, for example, well known for its reverse engineering and manufacturing capabilities, had redefined its motto in the early nineties as ‘discovery-led global pharmaceutical company’ and now has an impressive array of new drugs (Table 2). In addition to the above listed front-

runners, there are a number of other Drug Pipeline of Indian Pharmaceutical Companies players like Zydus Company Identifier/Molecule Stage of Disease Area Cadila, Torrent, Description Development Sun Pharma and DRL DRF 2593/ Orchid that are Diabetes Phase III Balaglitazone gradually forayDRL DRF 10945 Dislipidemia Phase II ing into the field DRL DRF 1042 Cancer Phase II of novel drug discovery. RBx 11160/Synthetic Ranbaxy Malaria Phase II variant of artemesinin There are also specific examples Nicholas Piramal CDK-4 inhibitor Oncology Phase II of how a given Nicholas Piramal TNF-α inhibitor Inflammation Phase II R&D centre, Glenmark GRC 3886/Oglemilast Asthma Phase II in totality, can Glenmark GRC 8200 Diabetes Phase II function more efWockhardt Broad Specficiently in an allWCK 771/Quinalone Phase II trum Antibiotic Indian set up. If Table 2 critically analysed, Indian pharma has circumvented some of alent in a given class of molecules is in itthe deterrents most effectively. Nicholas self a daunting chore. At the same time the Piramal’s example may be instructive here. search for a ‘me-too’ definitely has its adFirstly, the company has a state-of-the-art vantage as the family is well-researched and R&D facility, second to none built at apthe mechanism of action is known, leadproximately 1/5th of what it would cost ing to reduced risk as compared to starting in the US or Europe. Secondly, it has set with a relatively unknown molecule. its goal on novel discovery approach right It is almost certain that the immedifrom the outset and thus boasts of a roate task for the Indian companies is to bust pipeline of drugs across disease areas leverage the cost advantage in bringthat are at different stages of discovery. ing new drugs to clinical trials. Thus, the And lastly, the company has capitalised companies’ focus may not be on taking on the advantages India offers with regard the drug products themselves to the clinto clinical trials—it has been successful in ics and/or subsequently to the market. completing the duration of clinical trials For example, DRL had outlicensed some in half the estimated time in any Western of its anti-diabetic molecules to Novo country. Nordisk and an insulin sensitiser to An in depth analysis of the third modNovartis. More successful of the lot is beel described above may shed light on how lieved to be Glenmark, that has struck a Indian pharmaceutical companies are takdeal with Forest Labs (New York, USA) for ing the new challenge to the next level. The developing its GRC 3886 (PDE-4 inhibiIndian strategy, to start with, has been to tor) for pulmonary diseases. By adapting dig the pot for ‘me-too’ targets instead of this strategy, the smaller pharma could do going for an unprecedented one. It may be away with huge uncertainties associated contested that ‘me-too’ cannot be a blockwith the discovery process. Furthermore, buster as compared to its original molecule. the upfront and staggered (milestone) However, this approach has been validated payments can facilitate the licensor by the market success of drugs that have tremendously in channelling the resources followed the novel molecule in the same for allied activities. On the other hand, class, for e.g., Pfizer’s Lipitor, which has there is also this conscious effort to carry become the best selling drug in the world. on at least early clinical trials in-house Moreover, it should be clearly understood to gain expertise in clinical development here that identifying and developing a ‘mearena, which may be lacking in a basic too’ is not an ordinary feat, given the fact research set up. Added to that will be the that the innovator would have made every benefit of greater value to the discoveries effort to study and patent all the analogues. once they are licensed out at a later stage Thus, identifying a novel and active equivof development.

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It should be appreciated that drug discovery is an arduous task that could be a decade-long effort and that success is not always guaranteed. Indian pharmaceutical industry’s attempts to discover new drug entities are no exception. Reddy’s have their failure story in anti-diabetic targets while Ranbaxy’s target for prostatic hyperplasia met with stumbling blocks in the early stages of development. But isn’t early or late trial failure a part and parcel of the game? Failure of alfimeprase (Nuvelo-Bayer partnership) as recent as the end of 2006 exposes the inherent risks involved in the drug development business. Moreover, these are precious failures (though not intended) and will be tremendous learning experiences for the future drug discovery efforts. On the expertise front, the cost advantage and availability of postgraduates are repeatedly reiterated. These certainly are factors that may seem positive. However, it needs to be recognised that neither the Indian academia nor the pharma business houses have skilled personnel to lead novel drug discovery effort. A thorough under-

standing of the process from identification to having the drug in the market is absolutely essential. Even in the US and Europe, leaders who have ‘been there, done that’ are a rare find. Drug discovery is relatively new for the Indian scientific community. The search for the few leaders who could drive the crew efficiently will need a mammoth effort. While attracting trained personnel from across the shore is both feasible and a necessary option, training a whole lot of the younger generation methodically should be recognised as an urgent need. The second model of a multinational company with a proven record of drug discovery setting its own facility has a significant advantage in this respect. There is this much needed guidance from the parent company in terms of scientific inputs and business development. The only major concern in these circumstances is the challenge of bridging the distance (and time!) that may hamper the consistency to lead the discovery effort. India is on the threshold of drug discovery research where the next few years

are going to be critical in terms of delivery. Investors and pharma business owners have adopted a wait and watch attitude ruminating on whether or not to make a long term commitment. Most Indian pharmaceutical companies have spent the past decade in identifying strengths and weaknesses and shaping their business portfolios. In doing so, the companies have indulged in many appropriate but diverse activities including bulk drugs, formulations, generics, novel drug delivery systems, new chemical entities and biotechnology products. The coming decade will see these companies focussing on their strengths and leveraging opportunities in selected areas of research and development. While SWOT analyses and speculations have filled columns and discussion forums on whether or not India can produce novel drug targets, it is time to introspect, identify and fix the flaws and march forward.

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

Asia Pharmaceutical Sector – Outlook In 2005, Asia’s pharmaceutical market size was approximately US$ 106.8 billion, with Japan making up about half of the market with a domestic consumption of about US$ 58 billion. The average per capita consumption in Asia, a population of 3 billion people, stood at US$ 36 per person. In contrast with the US at US$ 839 and Europe at US$ 439, the industry in Asia offers much room for growth. Asia’s economy has been growing much faster than that of the US and Europe over the past 5 years. In 2004-2005, the Asian economy as a whole grew 4.9% compared to 3.5% in the US and a tepid growth of 1.7% in Europe. Propelled by a combination of a low per capita consumption and a rapidly growing economy, the industry is expected to sustain a double-digit growth over the next decade. Major Western pharmaceutical companies, faced with shrinking opportunities in their home markets, will thus have to focus their attention on Asia for their next phase of growth. Asia today is a net importer of pharmaceuticals mainly from Europe, with which it had a trade deficit of US$ 7 billion in 2004 but enjoyed a small trade surplus of US$ 640 million with the US. In 2004, the major net exporter of drugs in Asia was India with a total net export of about US$ 2 billion. According to preliminary data,

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India’s position as the main net exporter in Asia is being contested by Singapore, which has shown a strong track record backed by years of substantial government investment. Singapore achieved total exports of US$ 2.4 billion and imports of US$ 1.04 billion in 2005. Given Japan’s position as the world’s second largest market, it comes as no surprise that they are also Asia’s largest net importer with a deficit of US$ 3.5 billion, the majority of it with Europe. We see continued growth in the Asian pharmaceutical sector. Going forward, its size is likely to exceed that of Europe and the US within the next few decades. Asia, led by Japan and India, will also start developing a robust pipeline of novel drugs that address the needs of both Asia and the rest of the developed world such as the US and Europe. The various countries in Asia will undeniably face a multitude of challenges as they develop their industries. However, given their traditional resourcefulness and determination, it is beyond doubt that Asia’s place within the global pharmaceutical industry over the next few decades will grow in rapid prominence. Liew Kou Yew Assistant Vice President, Life Sciences - Asia, Rabobank International Full article available at: www.pharmafocusasia.com/knowledge_bank

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The Indian Pharmaceutical Industry Promises and perils

Utkarsh Palnitkar, National Leader, Health Sciences Industry Practice, Ernst & Young, India

The Indian pharmaceutical industry has evolved substantially and transformed itself from a reverse engineering led industry—focussed on the domestic market—to a research-driven, export-oriented industry with a global presence.

he pharmaceutical industry is a risky business, but in some ways the key promises of safety, integrity, transparency, compliance and corporate sustainability have not changed over time. The way promises must be delivered, however, is changing fundamentally. Pharmaceutical companies increasingly are relying on others to play key roles in this new system and deliver on their respective promises so that its reputation and footprint continue to grow. The quest for global leadership has started with the anticipation of the world becoming flatter and factoring in strategies to capture the global advantage by leveraging the benefits that accrue from operating in India. However, the area that will emerge as critical for success of Indian firms going global is maintaining the equilibrium between global and local operations along with pipeline building for the future. The impetus behind India’s fresh challenge for a greater share of the global industry is driven by last year’s introduction of product patents. For the previous 25 years, patents were largely granted on processes—a decision which made many multinational companies (MNCs) re-look their India strategy, but which resulted in India becoming a leading player in the market for generics. There was never much incentive in Indian manufacturers spending too much on drug discovery on their own, when their new product discoveries could not be patent-protected.

w w w . p h a r m a f o c u s a s i a . c o m 17

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However, with the amendment in the patent regime, the once generics oriented industry had to align its business model with the new global paradigm. Alliances and investments in basic drug discovery became the buzzwords in the industry as companies scrambled to replenish their near term product pipelines and build up a future portfolio of drugs. In addition, the attractiveness of the US market has suffered some setback in recent periods, especially for the large generics targeting exclusivity. The reasons include legal challenges by patent holders delaying and increasing the cost of launch authorised generics taking away large market share, and hence, profit from the generic patent challengers during exclusivity periods, amongst others. These factors have severely impacted the exclusivity-related profits that generic players seek from the US market. Over the years, Indian pharmaceutical companies have invested large sums of money in R&D, set up FDA approved plants and consolidated marketing activity. These companies have their strategies in place to leverage opportunities existing in formulations, bulk drugs, generics, Novel Drug Delivery Systems, New Chemical Entities, biotechnology etc.

The innovation dilemma To invest or not to invest, was the key dilemma the Indian companies were facing. Some of the companies had taken the risky approach of building up a drug discovery programme from scratch, that roughly coincided interestingly with the return of the expatriates from the regulated markets. It was a gamble and some of the companies took it head-on. At the moment, there are at least twelve Indian pharma companies that are working on developing new drugs. An estimated 60 new compounds are in various phases of development and testing. Though costs of conducting research in India are lower than the West—primarily because of more affordable scientific manpower—It is also true that most Indian companies would find it a challenge to take a new compound through all the stages on their own. This is precisely why the majority of the Indian firms are pursuing two basic strategies that help in mitigating

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their risks as well as lowering of costs. The first being a research strategy pertaining to analogue research, while the second being in the licensing arena. The out licensing strategy works in the following manner. An Indian company identifies a number of new compounds in a family that are likely to succeed, and then takes them up to the preclinical trial phase. Thereafter, they strike a deal with a commensurate Big Pharma company operating in the same area. The deal is structured this way: the multinational has the rights to market the compound in a particular market, if it clears all the tests. The Indian company gets ‘milestone payments’— a certain amount for each stage of clinical trials that its compound clears. If the compound successfully clears all tests, it also gets royalty when the drug is introduced in a market.

The co-optition model In addition to the investments in drug discovery, a quiet revolution has happened that had gone largely unnoticed. It is the acceptance of the fact that aggressive patent litigations are a thing of the past. Now, it is alliances that matter in a product patent regime. Alliances help shape best practices and leverage core competencies. Co-optition, denoting collaboration and competition at the same time, whereby companies collaborate in identifying best practices and sharing the various steps in drug discovery to competing on generics, has been identified by all the leading MNCs and their Indian counterparts. Co-optition has increasingly been adopted as a model for sustaining the growth momentum. This adoption has happened on the back of cross-border acquisitions, licensing (both inlicensing and outlicensing agreements) and by becoming preferred outsourcing partners of multinational pharma companies. Competitive pressures, new growth opportunities, diversification of risk and funding enablers are some of the key factors behind acquisitions, licensing and outsourcing partnerships happening across various segments of the industry. This has made Indian pharma companies redefine the global pharma value chain by building collaborative networks and has resulted in increasing visibility of growth.

The inorganic growth model In certain cases, the M&A route was adopted for sprinting up the growth curve. Indian companies look for pipeline acquisition, relationship building and technological competence as the major influencers in any acquisition. An enabling factor for Indian firms’ activity overseas is their increased liquidity in the market, with increasing numbers of Foreign Currency Convertible Bond listings and private equity fundings. Also, although the US is the world’s largest generics market, most of the acquisitions were in the EU. Industry sources believe that Indian firms consider European valuations to be more reasonable, and there is a wider price range of companies available. Use of generics is growing quickly in Europe, due to government price controls and other pro-generic measures, while the EU regulatory climate is proving a disincentive for some European firms to continue, creating buying opportunities for Indian firms. The three main European generics markets are Germany, France and the UK, together worth around US$ 3 billion annually.

The way to the future The way to the future lies in identifying ways and means of achieving the laudable goal of increasing access to medicines throughout the country. There has never been a more important time for India’s government and its drug producers, both multinational and domestic, to work together in partnership for the good of the industry and the nation. The interaction between the industry and government will be one of the keys in the coming years. The comparison with China is a fair one as the Chinese government’s strong commitment to pro-industry policies has created a positive environment with a strong patent regime and data protection; admittedly with issues still remaining over how these are enforced. The aims of the Indian industry—and of the government— are ambitious, but will require a strong pricing environment if the Indian people are to access the life-saving and innovative medicines they need. Industry leaders will have to work with the government on issues of affordability to point out that price controls are limited in their ability to increase access to new and effective treatments.

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Electronic Health Records and Clinical Research Despite the value of combining EHR and EDC for multicentre trials, we are many years away from a standard, usable process for this.

Paul Bleicher, Chairman and Founder, Phase Forward, USA

he past ten years have been a time of revolutionary change in both clinical research and healthcare. The clinical documentation tasks in both of these industries are undergoing a complete transition from paper to electronic data entry and processing. In healthcare, Electronic Health Records (EHR) have been extensively adopted in some healthcare settings (mostly in Europe and parts of Asia) and are on a slow, but clear, path to complete adoption, in the US and the rest of Asia. Similarly, electronic data capture (EDC) solutions for clinical data management in clinical research is also heading towards extensive adoption both in the pharmaceutical industry and in academic settings. Some of the driving forces for this change are shared between the two industries; for example, efficiency, cost, patient safety, and quality of data. However others are not. In addition to the common interests of both groups, physicians/practitioners are interested in using EHR systems if they can improve their workflow for patient encounters, coding, billing, referrals, quality of care and prescription writing. Clinical researchers, on the other hand, are interested in immediate access to data, improved data management workflow, efficient management of trial operations and cycle time reduction. Although both EHR and EDC collect patient data, the needs of the users of these systems have led to

a major divergence in features, functions and usage. These significant differences make the sharing of data and the integration of these systems quite complex. The clinical data portions of EHR systems have developed to be able to collect any information on any patient at any time, as part of a standard physician encounter. The systems are flexible, and often collect data in narrative form through dictation, large text fields and images. Data entry is designed to make an efficient workflow and allow easy recall and reading by other practitioners. The system integrations for EHR systems are typically for disease management, patient scheduling, billing, referral and other logistic aspects of patient care. EDC systems are highly structured, demanding the entry of very specific information on a defined set of patients at very specific times. Sometimes they require specific and unusual measurements that wouldn’t be recorded in an EHR system (e.g. three repetitions of standing, seated, and supine blood pressure). Data is entered into rigorously defined fields that are designed to ease programmatic statistical analysis. The system integrations of EDC systems are typically with randomisation, clinical supply, trial documents, project and budget management, and other clinical trial logistics. A good analogy for the differences between EHR and EDC systems is that of

the spreadsheet and the database. Both can be used to collect rows and columns of information and to print reports on that information. However, spreadsheets were developed to manage complex cross-cell manipulations of data whereas database programs were developed to manage large amounts of data through standard SQL queries. One can’t be substituted for the other except for some very straightforward tasks. The case of EHR and EDC systems is no different.

What can be done today Despite the disparity between these systems, there are some very powerful uses for EHR systems today (Figure 1). For example, it is easy to see that EHR systems could be examined for patients who might be eligible for inclusion in a clinical protocol. Assuming proper consent and privacy issues are dealt with, the clinician could mine the database to identify, and possibly contact, patients for entry into a trial. With some programming, it should be possible to alert physicians about the availability of a clinical trial during the patient’s visit, allowing them to enroll the patient “on the spot.” Another possible use of EHR systems is the examination of a large amount of pooled clinical data to help in generating new hypotheses for clinical trials, design of the trial, and feasibility testing of protocols. These activities and patient recruitment for clinical trials would, of course, require that the EHR systems have data in a form that could be searched and extracted. It wouldn’t require structured, field-based data but the EHR would at least have to have text fields that could be searched, and not images. Similarly, it should be possible to use these systems for epidemiologic research and some post-marketing data collection activities for safety and marketing purposes.

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R e s e arch & D e v e l o pm e n t

Uses of EHR in Clinical Research EHR Purpose

IRB/Privacy Issues

Validation Issues

Logistic Issues

Technical Issues

Possible Now?

Patient Recruitment

—

Protocol Design

—

Source data

—

+/-

—

EHR/EDC Integration

— Figure 1

Perhaps the easiest use for EHR systems is for the recording of source data in place of a paper record. There is no regulation or issue that should restrict sites from using a reasonably high quality EHR system to record clinical data for eventual transcription into a clinical trial Case Report Form (CRF).

What isn’t possible today The narrative that is driving the developing interest in EHR/EDC integration is one concerning data entry in large, multi-centre clinical trials. To most of us in the industry it absolutely makes sense that EHR systems could become the initial point of data entry for a clinical trial—whether in standard EHR screens or some purposedesigned clinical research CRF screen. The data could then be transferred to a clinical research data management system for analysis. It sounds so easy, and makes so much sense. However, it just isn’t possible today, and won’t be for a decade. There are some scenarios where EHR systems could be used today for prospective, randomised clinical trials. For example, a single office or hospital setting might have an EHR system that has been built or installed with clinical research in mind; designed to accept data in the “SAS-ready” data fields that a clinical data manager would expect. These institutions may even have specialised research data systems designed to integrate easily with the EHR system. While EHR/EDC integration for data collection could work for one, or possibly several institutions, it can’t be used for typical multi-centre clinical trials. Sites (or their institutions or governments) pick

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and deploy their own EHR systems. Even when sites share an EHR system, it may be a different version or having a different underlying data structure or data dictionary. Quite simply, the wide variety of different EHR systems (and paper systems) used at the typical collection of research sites in a clinical trial would require many different databases collected and combined (and this assumes that all the EHR systems are capable of collecting such structured information). It would require a huge and costly integration of data by the sponsor that would take a substantial toll on data quality. In many cases, EHR systems don’t even have the type of data that could be transferred to an EDC system. When they do, the process of extracting data from an EHR system to move it into an EDC system would require a whole new class of (yet) undeveloped data standards and the ability to read and write these standards by EHR and EDC software, or a painstaking mapping of the data. Some may argue that sponsors would simply pick sites with the “right” kind of EHR systems for their trials; this argument could only be made by someone unfamiliar with the difficulties in recruiting and retaining high quality, productive clinical research investigators. There simply aren’t enough around to get picky about which EHR they use. Another issue in EHR/EDC integration is the nearly impossible logistics at the site. Each site would have to allow a pharmaceutical company access to the most sensitive and valuable data an institution has. In addition, the project of mapping, implementing and testing the data transfer

would require months of work, and would likely introduce unacceptable delays and costs into the site start-up process. Certainly, data standards that link patient care and clinical research data would solve many of these problems. However, interoperability standards take years to develop and require their own cycle of consensus building, development, testing, and finally, implementation of standards adapters for the various systems. Although a standards based data transfer between systems might work, it would require much more work even when all the necessary elements were in place, than we could predict. Finally, the entire preceding argument didn’t even mention the process after data is entered into a research data management system—the data queries/clarifications and many other specific interactive (between sponsor and site) data management processes that need to occur, along with documentation of their occurrence. This is the heart of EDC systems and is not a part of the EHR process. Quite simply, this process requires a purpose-built, dedicated system, which is what an EDC system is.

Conclusion Nobody can seriously question the overwhelming value of clinical research data collection as part of clinical care. If it were possible to conduct a clinical trial through the standard workflow of clinical patient care, many investigators would be delighted. Despite this, some argue that it is important that the two activities be distinguished, because hopefully, the investigator will take special care with the quality of research data intended for analysis. Despite the value of combining EHR and EDC for multi-centre trials, we are many years away from a standard, usable process for this. It is impossible to predict what such a system might look like in the future, and what the structure of healthcare institutions would have to be to enable this. For the moment, the several pilot projects that are ongoing between major EHR and EDC vendors will generate a lot of knowledge and cross-education of issues, workflows and obstacles in combining these two worlds. As EDC took 15 to 20 years of pilots before the design and deployment of truly workable, enterprise solutions, so, too will this newest of cutting edge concepts.

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Pharmacogenomics and Personalised Medicine Synergy between the industry and academia

“Genetic passports”—derived from the Human Genome & HapMap Projects—help guide the choice and dosing of drugs throughout each individual’s lifetime.

Paul A. Insel, Professor, Departments of Pharmacology & Medicine, University of California, USA

ersonalised medicine and individualised drug therapy are terms that characterise an evolving goal of therapeutics. Although studies in the underlying science that facilitate personalised medicine were primarily initiated by investigators in government and academic laboratories, some in the pharmaceutical industry have been active participants (or interested bystanders). Regulatory agencies are also increasingly involved in such efforts. The goal of personalised medicine is to move beyond the “one-size-fits-all” approach that commonly characterises therapeutic strategies, especially in adults, to one that tailors such strategies, in terms of drugs and their doses, to individual patients. Although clinicians have often made efforts to individualise treatment regimens—therapeutic decision-making, including dosing—has generally been empiric. Progress in biomedical science, most prominently in greater understanding of

pathogenesis, has given healthcare providers the opportunity to choose therapeutic agents that more precisely target the molecular entities that cause or have impact on particular diseases in particular patients and that take into account inter-individual differences in drug handling and drug action. The key developments in this regard have been the completion of the Human Genome Project and the more recent results from the International HapMap Project. The Human Genome Project defined the number and identity of genes and gene families, based on genomic sequencing of a small number of individuals. The HapMap Project extended such studies to a larger number of ethnically diverse individuals and defined haplotype blocks, i.e., regions of individual chromosomes that are inherited together and can thus be identified/tagged by particular markers, generally Single Nucleotide Polymorphisms (SNPs), which represent changes

in individual bases that comprise DNA. Such polymorphisms occur ~1/200 bases in human genomic DNA and can alter the sequence that encodes amino acids (i.e., non-synonymous SNPs) or because of redundancy in the DNA code, substitute one base for another without changing the encoded amino acids (synonymous SNPs). Other SNPs occur outside the exonic coding region and are located in upstream 5’ and downstream 3’ non-coding regions or in introns; at those locales, such SNPs can influence gene expression and stability by altering the binding and action of regulatory proteins. Genetic variants also include deletions and insertions. Work in progress seeks to define the functional importance and influence of genetic variation on physiology, disease (propensity, phenotype, severity and progression) and drug responses. The next phase in the major initiatives related to genomic analysis is the ENCyclopedia Of DNA Elements (ENCODE) Project, which is designed to

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identify all functional elements in the human genome via computational and experimental efforts. Crawford and colleagues have stated that, “If one were to look across the human genome in the entire world population, every base compatible with life has been mutated”. This conclusion likely requires further experimental documentation, which is being sought in numerous basic and clinical research laboratories. A major driving force for the Human Genome and HapMap Projects has been the notion that information derived there from would prove essential for defining the contribution of genetics and genetic variation to human health and disease. In turn, results from these projects were expected to identify new drug targets and improve the ability to diagnose and treat patients, thus helping advance rational therapeutics. Results indicating that the overall inter-individual variability in the genome is quite small (<1%) and arranged in a blocklike manner (i.e., the haplotypes), have spawned considerable interest in terms of the identification and use of genetic mark-

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ers to characterise normal and diseased individuals. Personalised medicine is thus predicted to result from the knowledge of an individual’s genetic information that will facilitate his/her placement in a genetically determined disease “bin” and in turn, choice of therapy tailored to the nature of the underlying alterations in genes that influence disease and/or treatment. Progress related to such genomicallyenabled medicine includes efforts to: 1) reclassify diseases, e.g., various cancers and cardiovascular disorders, based on genetic/genomic “signatures”, i.e. patterns of genetic changes; 2) stratify patients so as to facilitate identification of features of diseases and outcomes in genetically uniform populations and 3) use of genetic information to guide the discovery, choice and dosing of therapeutic agents. Because we are at an early phase of the application of genomic information to human health, disease and therapeutics, one cannot predict with certainty its ultimate impact. Even so, predictions can be made based on what has been learned so far and how this informa-

tion has begun to be applied. With respect to therapeutics, the role of genetics has been recognised for several decades. The term pharmacogenetics was introduced to reflect the role of genetics on pharmacokinetics (drug absorption, distribution, metabolism, excretion) and pharmacodynamics (drug action). By contrast, pharmacogenomics is defined as the use of genetic information (identification and characterisation of genetic variants, including throughout the entire genome) that influence pharmacokinetics and pharmacodynamics. Most work in pharmacogenomics has emphasised genetic variants that influence pharmacokinetics. This is likely a consequence of several factors, including the much greater understanding of genes and proteins involved in drug absorption, distribution, metabolism and excretion. For example, the existence of genetic polymorphisms, especially SNPs, in cytochrome P450s that metabolise most drugs and environmental chemicals and the resultant inter-individual differences in such

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metabolism were known for many years prior to the Human Genome Project. There are numerous clinically relevant examples of genetic differences in drug metabolism that alter drug efficacy and toxicity: these include those in thiopurine methyltransferase that enhance 5-mercaptopurineand azathioprine (which is metabolised to 5-mercaptopurine) promoted bone marrow depression and variations in CYPD6, which metabolises >60 drugs that are commonly prescribed and in CYP2C9, which metabolises ~15 commonly used drugs. One of the drugs metabolised by CYP2C9 is the anticoagulant warfarin, which shows substantial inter-individual variation in doses required for anticoagulation through its ability to block the formation of Vitamin K-dependent clotting factors. Recent data reveal that genetic variation in the key molecular target of warfarin, Vitamin K epOxide Reductase (VKOR), which catalyses the conversion of Vitamin K 2,3-epoxide to Vitamin K, is an important source of inter-individual variation in response to warfarin. Rieder et al identified 10 common noncoding SNPs in the VKOR Complex 1 (VCORC1) that are organised into multiple haplotypes, two of which, A and B, predict, respectively, high-dose and low-dose requirements for warfarin and influence transcriptional expression of VKORC1. Asian-Americans and African-Americans more commonly express the A and B haplotypes, respectively. Genetic variation in VKORC1 contributes ~25% of the inter-individual variation in warfarin dosing while variation in warfarin metabolism by CYP2C9 contributes ~10%. Thus, genetic variation in both metabolism and action, i.e., pharmacokinetics and pharmacodynamics, contribute to inter-individual differences in warfarin dosing and response; knowledge of the key genetic contributors to such differences should help improve the clinical use of warfarin and prevent bleeding events that result from excessive administration of and response to the drug. Genetic variants in adrenergic receptors (adrenoceptors) represent another example related to pharmacodynamics. Nine adrenergic receptor genes encode each of the 3 subtypes of α1, α2 and β-adrenergic receptors that mediate response to the endogenous catecholamines norepinephrine

and epinephrine as well as to exogenous adrenergic agonists and antagonists. Many studies have assessed genetic variants in adrenergic receptor genes and their possible contribution to various diseases and responses to adrenergic agents; diseases of particular interest include asthma and other pulmonary disorders, hypertension and various cardiovascular disorders—all settings in which adrenergic agonists and/or antagonists are commonly prescribed. The precise role of genetic variants of adrenergic receptors in such disorders has not yet been fully defined. Of note is the recent demonstration of the contribution of the Gly→ Arg389 variant in the β1-adrenergic receptor in congestive heart failure patients. This variant is associated with greater agonistpromoted cardiac contractility and with greater benefit (reduced mortality) in a large clinical trial with the β-blocker bucindolol. Such data suggest that genotyping may facilitate stratification of heart failure patients and identify individuals who will benefit from treatment with bucindolol and perhaps other β-blockers. Findings such as those noted above have the potential to enhance interactions between investigators in academia and those within the pharmaceutical industry. The application of genetic information provides the opportunity to improve drug efficacy and decrease toxicity, thereby increasing the therapeutic index of particular drugs in individual patients and groups of patients. This goal may become an imperative with respect to reimbursement, quality of care and prevention of medical (i.e., therapeutic) errors by governments and third-party payers. If a therapeutic complication can be avoided by conducting a genetic test, such a test may be required as part of the standard-of-care in medical practice. The precise settings in which such genetic information will prove essential are still being defined. Testing to characterise genetic identity (termed “explicit genetic inference”) offers a means to define the contribution of genetic factors that previously were inferred through the family medical history, a subjective and often incomplete recollection of relevant medical information. As the cost of genotyping decreases and its availability increases, future extensive (or complete) genotyping will likely occur at birth or in utero, thereby

generating “genetic passports” that will help guide diagnostic, therapeutic and preventive approaches for each individual, although challenges remain in terms of implementation and availability of genetic passports. Such a scenario creates opportunities for synergy between investigators in industry and academia. Those in the pharmaceutical industry must have access to normal subjects and patients with appropriate diseases for drug testing and validation, especially since Phases 1-4 are likely to remain the sine qua non for the drug approval and monitoring processes. Such clinical testing should be aided by genetic stratification that identifies individuals who have disease-causing or disease-modifying molecular entities that also serve as drug targets. Clinical trials that utilise genetically homogeneous groups of patients have the potential to yield more cost-effective ways to obtain insights into drug efficacy and toxicity, as suggested by the results of the bucindolol trial in heart failure, noted above. Indeed, genetic information may “rescue” the latter drug since the trial was terminated because bucindolol was deemed to have no benefit, when, in fact, the drug was efficacious in patients with Gly→Arg389 β1-adrenergic receptors.

Conclusion In sum, pharmacogenomics provides the opportunity to optimise treatment for patients based on greater insight into both pharmacokinetics and pharmacodynamics. Knowledge is likely to advance most prominently regarding drug targets and underlying genetic differences in the inter-individual expression and properties of those targets. Genetic information is being rapidly generated with the use of increasingly feasible, economical methods. The ultimate utility of this information, though, will likely require partnership between academia and industry, probably together with government regulatory agencies, in their complementary and synergistic approaches to improve human health. Work in the author’s laboratory is supported by grants from the National Institutes of Health, Leukemia and Lymphoma Society and Ellison Foundation. Full references are available on www.pharmafocusasia.com/magazine/

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Redesigning Drugs to Enhance Performance

When a compound progresses to a medicinal product the complexities of disease, drug action, and the diversity of patient response can mean that nuances of drug behaviour may not be fully evident. However, new insights may emerge on more widespread use. These can provide ideas for new indications or better treatment of the existing indication. Luigi G. Martini, Director, Process Technologies, and Patrick J. Crowley, Vice President, Pharmaceutical Development, GlaxoSmithKline USA

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rograms to identify and evaluate novel therapeutic agents are expensive, take a long time and do not guarantee a successful outcome. Proving safety and efficacy is difficult, complex and slow. Furthermore, even after efficacy and safety are demonstrated and the compound becomes a medicinal product the complexities of disease and of the drug action, allied with the diversity of patient response can mean that nuances of the new drug’s behaviour may not be fully evident. Consequently, most new medications are not perfect. Recent restrictions and withdrawls of the Cox-2 Inhibitor drugs for arthritis exemplify how difficult it is to determine each and every facet of drug performance in clinical studies. Much greater patient experience may be required. As a medication becomes widely used, new insights emerge on modes of action, side effects and patient response. At the same time, advances in molecular biology, receptor pharmacology and better understanding of the clinical condition may create possibilities for new indications or for better treatment of the existing indication by altering dosage regimen or by dosage form redesign. Concurrently, technologies may emerge to enable more efficient, effective or convenient ways of delivering or even targeting the medication. Possibilities exist, therefore, to redesign established drugs—usually by reformulation—so they are more effective, safer or more convenient for the patient.

General considerations The last decade or so has seen an explosive growth in Information Technology (IT), making data and information capture, analysis and dissemination widely available. More recently there have been moves to make detailed clinical trials data available in readily accessible databases. Such knowledge, allied to creative interpretation and linkage to other emerging facets of knowledge can be a rich source of opportunities for product redesign. Information sourced in such ways may concern: • The drug • The clinical condition (“the disease”) • The patient

• New technology and diagnostic techniques

Comparison of Twice and Three Times Daily Dosage with Augmentin in Acute Otitis Media in Children Dose

The drug Development programs exploring safety and efficacy cannot possibly cover each and every permutation and combination of dose frequency and timing. Information from widespread use may suggest other more suitable regimens. The antibacterial amoxicillinclavulanate (Augmentin®) was administered three times daily when first commercialised, reflecting the rapid elimination rates of both the amoxicillin and clavulanate components. It proved to be a very effective therapy in community-acquired infections but three times daily dosage is less convenient (and may lead to reduced dosing compliance) than less frequent administration. Furthermore, diarrhoea was a frequent side effect, especially in children under two years of age. This was attributable to the clavulanate component. In vitro evidence that lower doses of clavulanate coupled with a shorter treatment period might be equally effective, prompted the development of formulations for twice daily dosage. Clinical trials in paediatrics indicated that the twice daily presentation was equally effective to that dosed three times and that the diarrhoea side effect was significantly less as illustrated in Table 1. More detailed knowledge on metabolism, pharmacokinetics of the metabolites and possible impact on clinical behaviour is also likely to accumulate on widespread usage of the medicine. This may suggest that the dosage form could be redesigned. An example concerns Niacin, utilised as a lipid lowering agent. Side effects (flushing and hepatotoxicity) are related to its metabolic pathways. Metabolism proceeds via two pathways viz. conjugation and amidation. If the amount ingested and absorbed saturates the amidation route (as would be expected from a rapidly releasing dosage form), the conjugation route dominates, resulting in a higher incidence of flushing.

Dose Frequency

(Amoxicillin/ Clavulanate mg/kg)

Efficacy % Adverse Events (% Cure)

(Diarrhoea)

40/10

Three times daily

78.8

26.7

45/6.4

Twice daily

86.5

9.6 Table 1

Slower absorption can result in enhanced amidation and a relatively higher level of the metabolites associated with hepatotoxicity (Table 2). Thus, dissolution rate from the dosage form can influence the metabolic profile and associated side effects. This knowledge allowed a formulation to be developed with drug release rate providing an appropriate metabolic balance to minimise side effects. Drug-related improvements may also be stimulated by advances in separation sciences or purification techniques to provide a medication that may be more potent, has greater specificity or evinces fewer side effects. The Proton Pump Inhibitor, omeprazole, used to treat gastric ulceration and related conditions is a racemic mixture. The single isomer esomeprazole has now largely replaced it because of better ulcer healing rates. Purity-related improvements have also been recorded for biopharm products. Recombinant human insulin reputedly has less side effects than porcine-derived material. Similar improvements have been recorded for recombinant human growth hormone. It has also been reported that a “new formulation” of ß interferon-1a is better tolerated and induces less antibody formation when treating multiple sclerosis.

The clinical condition Molecular biology

Knowledge of the aetiology of diseases is continually expanding. Two decades ago there was no evidence that gastric ulcera-

Effect of Drug Release Rate on Niacin Metabolism and Side Effects Dosage Form Performance

Metabolic Consequence

Side effect

Fast Release Rate

Conjugation Pathway Predominates

Flushing

Slow Release Rate

Clearance largely via Amidation Pathway

Hepatotoxicity Table 2

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Change in CFU

Effect of “Time >MIC” on S.pneumoniae Exposed to Amoxicillin 3 2 1 0 -1 -2 -3 -4 -5

100

T>MIC (% of 24 hrs) Figure 1

Time-related effects

Symptoms in some disease states can be manifested at different times of the day, or even seasons of the year. Seasonal effects can be environmental (e.g. Hay Fever or other allergic conditions are more acute at the height of the pollen season) but others can be more complex. Time-associated effects include: • Asthma: Airways obstruction can be most severe early in the mornings • Rheumatoid Arthritis: Joint stiffness is usually most severe in the morning. Conversely, pain from osteo-arthritis is more prominent in the evening • Cardiovascular incidents: Heart attacks occur frequently in the early morning. This may be related to the stresses to the cardiovascular system, caused by going from a prone to the upright position

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after waking up. Absorption of Amoxicillin from the GI Tract It is important, therefore, that 1.2 beta blockade or Bolus 1 other cardioproInfusion 0.8 tective effects are 0.6 optimal at this crucial time 0.4 • H y p e r t e n s i o n : 0.2 Blood pressure 0 in normotensive Duodenum Jejunum Ileum Caecum Colon subjects usually falls during sleep Regions of the GI Tract (“cardiovascular Figure 2 system rests”). ed levels of natural mediators? There is no However, in some evidence for such effects but such relationhypertensives this does not happen. The ships might merit exploration. increased incidence of nocturnal heart attacks at around 2 AM to 3 AM is asChanged disease patterns cribed to the cardiovascular system remaining under stress Infectious diseases Awareness of such circadian effects can Bacterial resistance to antibiotics stimulate ideas for timing drug delivery to is not new; it has always been a race coincide with the chronotherapeutic rebetween resistant organisms evolving quirements of the clinical condition. The better defence mechanisms and timing of the cardiovascular events listed scientists finding novel antibacterials. above has led to the development of a However, few novel antibacterials have medication of the calcium antagonist, veemerged in recent times and resistance rapamil that delays delivery of drug (the by pathogenic bacteria is a major issue. medicine being taken at bed time) until The prevalence of methicillin-resistant about 8 hours after dosing to cover the S.aureus has been well-documented. vulnerable early morning period. The drug Drug resistance by pseudomonas is thereby delivered to the receptor at the aeruginosa is also increasing. The problem time of greatest need. is not confined to hospitals or Intensive Other examples of delivering drug Care Units. Resistance in community-based “when required” concern theophylline infections is also a concern. Penicillinand salbutamol. These drugs have relaresistant Streptomyces pneumonia are tively short half lives with concomitantly now prevalent in many countries. In short durations of action. Formulation the light of all these considerations it is as delayed/sustained release formulations necessary to consider new approaches to are calculated to provide adequate plasma treating infections using existing drugs. levels to cover the vulnerable early-morning period. Sustained release theophylline New treatment paradigms The emergence of bacterial resistance also reduces its peak plasma level, thereby caused Craig W.A. and Andes.D to demitigating the effect of its low therapeutic velop the “time above MIC” concept index. for antibacterial therapy. The principle Seasonal effects, other than environis that if levels of some antibiotics are mental or climatic ones are lesser known maintained above the minimum inhibibut endorphin levels are apparently greater tory concentration for a specific time during January/February and lowest in (“T>MIC”), efficacy is enhanced. WoodJuly/August. One could speculate as to nut et al, working with resistant strains of whether this might mean that cancer Streptomyces pneumoniae confirmed this therapy would be optimal at times when thesis for the broad spectrum antibiotic the patient might be more resilient to agamoxicillin. They showed that the minigressive treatment. Could vaccination be mum “T>MIC” for amoxicillin was about more effective if aligned with season-relatAUC/Auc (Oral)

tion is caused by bacteria in the gastric mucosa. In 2005, the scientists who identified and elucidated the role of Helicobacter in gastric ulcers were awarded the Nobel Prize for Medicine. Aspirin was used as an anti inflammatory and analgesic for almost a century, before its prostaglandin inhibition mechanism was elucidated and its beneficial effects at low dose as a platelet aggregation inhibitor established. Such findings have led to the use of antibiotic preparations, possibly in conjunction with proton pump inhibitors or other anti acid agents for treating gastric ulcers and of low dose aspirin as an anti-clotting agent. Increased insight of molecular biology, whether of the disease or mechanism of drug action may also suggest a drug’s potential in related or even different clinical conditions. In such a context, the anti arthritic drug celcoxib (Celebrex) is currently being evaluated for efficacy in colon cancer.

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causing gastro-inAugmentin XR Tablets: Designed to provide prolonged T>MIC testinal side effects to maximise bacterial killing because of overSustained release growth of resistant Crystalline sodium amoxicillin 875 mg 20 bacteria. 18 The formula16 tion developed to 14 provide sustained 12 plasma levels uti10 T>MIC at 8 mg/L =35% 8 lised a novel ap6 proach, incorpoT>MIC at 4 mg/L =49% 4 rating two salts 2 of amoxicillin viz. 0 the conventional 0 2 4 6 8 10 12 trihydrate for “imTime (h) mediate release” Kaye CM, Allen A, Perry S, et al. Clin Ther 2001;23:578-584. and the sodium Figure 3 salt, co-formulated with citric acid as a release modifier to deliver a later dose. The a commercial product in the US and some plasma level profile is shown in Figure 3, European countries. with a “time above MIC” (4mcg/ml) that Prolonging drug in the biosystem for is almost 50% of the twice daily dosage the requisite time to optimise bacterial kill interval. rate is one example of changed paradigms This formulation was shown to be efproviding more effective therapy. More fective in Phase 3 clinical trials and is now recently, the concept of dosing “pulses” of Serum Concentration (mg/L)

35% of the dosage interval (Figure 1). Thus, if amoxicillin is administered twice daily, and serum levels exceed the inhibitory concentration for a minimum of 4.2 hours (35% of 12 hours) it is likely to be effective against penicillin-resistant Streptomyces pneumonia. This finding provided an opportunity for redesigning amoxicillin-containing dosage forms as findings in animal studies can be more readily translated to clinical efficacy in patients as the bacterium can be considered “the receptor” in both instances. However, the rapid clearance rate of amoxicillin (half life of about 1 hour) militates against persistence in the biosystem. This, together with its limited “absorption window”, makes it difficult to formulate as a delayed or prolonged release formulation. This is because, although it is absorbed very well in the upper regions of the duodenum absorption becomes progressively less efficient in the jejunum and ileum and is almost non-existent in the colon (Figure 2). Furthermore, “unabsorbed drug” could kill symbiotic bacteria in the colon,

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drug that provide limited time and duration in the biosystem has also been propounded. The concept has been validated in vitro with antibiotics and antifungal agents but is also being suggested for other clinical conditions including antifungal and cancer therapy. Not every drug will be suited to pulse dosing. Drugs with long half-lives will not be cleared quickly enough to get true pulse profiles. It is also likely to be difficult to deliver pulses orally; the gastro intestinal tract is too variable to facilitate such precise plasma profiling. Pulse delivery is probably best suited to parenteral administration. Variables such as the frequency and amplitude of the pulses may be critical and need to be explored and defined. It might well be that different organisms or clinical conditions require different pulse profiles. Programmable pump systems could be utilised to reliably deliver the requisite pulse profile. Knee/hip joint replacement techniques have revolutionised the treatment of joint inflammatory disease. Cardiac stents have had a similar impact in coronary bypass surgery. But they have also brought new challenges. Bacterial infections, localised at the replacement site are notoriously difficult to treat and frequently require further invasive surgery. Consequently, a need and associated opportunities exist for anti-infectives, embedded in the joint or stent material to be released slowly to evince a local antibacterial effect. Chronic low dose therapy is also being considered for treating cancer. Traditional chemotherapy usually involves giving the patient the highest dose they can tolerate to maximise tumor reduction. But such drugs are toxic, so dosing must be periodically halted for several weeks to allow the body to recover. It has been suggested that such “rest periods” can allow a tumor to rebuild the blood vessel network it needs to keep growing. So, researchers are experimenting with giving very low doses of cytotoxic drugs for extensive periods of time. Patients are spared the toxic side effects associated with high dosage, so treatment could be continuous and long term. This could help turn some cancers into chronic, manageable conditions. Promising results are being reported from clinical trials on cancers like brain tumors, non-Hodgkin’s lymphoma and breast and ovarian cancer.

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Inhalation Delivery System for Insulin*

the appropriate rate to reflect differences in clearance rates, or in other metabolic processes in the elderly, it could be enormously beneficial. A drug for insomnia might be designed to take effect quickly whereas a medication for emphysema might be released later from the dosage form. In addition to such chronotherapy-related delivery, a multi-medication unit might be designed to gradually release drug to avoid saturation of biosystems enzymes or pharmacological interactions. There are immense opportunities in geriatric medicine to provide more user-friendly and more effective medications. Pharmacogenetics and pharmacogenomics

*Reproduced with permission from Pfizer Inc. Figure 4

Prolonged administration of low doses will require more convenient, non-invasive modes of dosing than are now utilised with cytotoxic agents, again providing opportunities for developing new formulations or delivery systems.

The patient Demographics

Better diet, living conditions and healthcare programs mean that people are now living longer in many regions of the world. Consequently, diseases of old age have become more prominent. For instance, the incidence of Benign Prostatic Hyperplasia (BPH) in males at age 60 is about 50%. By age 70 it rises to 70%-80% and by age 85 incidence is in the region of 85%. Many of the elderly remain active, alert and independent because of their lifestyle, sensible dieting, and diligent use of medication, or, in many cases, several medications. Convenience can greatly affect compliance in chronic dosing scenarios. For instance, if all the medications could be incorporated in a single unit it would enhance convenience, compliance and consequently effectiveness. If such “multi-drug” medications could be designed to deliver each drug at the right time and possibly

The DNA sequence of the human genome (the “physical map”) has been elucidated. The functional aspects are also being progressively mapped and a stage may be reached where it is possible to predict many biological responses and susceptibility to particular diseases or enzyme deficiencies. Evidence is being accumulated that drug response may be influenced by individual genomic networks. This may provide greater insight on what medication might or might not be appropriate for specific individuals, leading to more focussed, more effective and safer pharmacotherapy. It might also stimulate demand for “personalised” medications, requiring greater flexibility in terms of dosage, possible rate of drug input (release rate from the dosage form) than is now thought necessary. Systems and technologies need to be developed to provide such flexibility but, when demand emerges, technologies, ideas and associated opportunities invariably follow. Paediatric medications

Medications are evaluated primarily in adults in the first instance because of ethical, regulatory and “informed consent” considerations. Traditionally, paediatric medicine has usually been an “add-on” to adult therapy. It is now accepted that the premise that plasma levels and kinetics established in adults evince the same effects (on a mg/kg basis) in paediatrics can be flawed. Children can differ from adults in metabolic and clearance capability (and such characteristics change more rapidly over time than with adults). Scaling down the dose, based on body mass considerations may be too simplistic. Paediatric-specific medications may be necessary.

M at e rials , M a n u fact u ri n g & packagi n g

Multi-Dose Inhalation Delivery System for Asthma

Figure 5

Patient convenience

Adult dosage forms (usually a tablet or capsule) are often unsuitable for dosage to young children because of size and swallowing difficulties. A liquid product is preferable but palatability then becomes critical. Taste is usually a function of the level of drug in solution. If concentration in the dissolved state exceeds the bitterness threshold there is little that can be done by simple formulation to improve matters. Sweeteners like sucrose can elevate the bitterness threshold to some extent but sucrose is now considered undesirable in medicinal products. Other techniques to mask poor taste (e.g. coating with polymeric materials) are generally of limited value. Bioavailability may be compromised and in any case coated particles (because they are likely to be larger than drug particles) can have a gritty texture and may be broken by mastication, with the drug being “released” in the mouth and evincing the bitter taste. More effective ways must, therefore, be used to improve palatability of liquid products. One approach is to utilise a form of the drug (e.g. different salt form), whose solubility is lower than the bitterness threshold. However, depression of solubility can affect absorption rate and bi-

oavailability. In very general terms it is accepted that, when solubility exceeds about 1-2mg/ml absorption may not be an issue. This suggests that, where bitterness threshold is in this region, the use of an alternative salt offers possibilities for taste masking with no impact on bioavailability.

Technological innovation Drug-device combinations

Many useful systems have been developed to facilitate parenteral administration (particularly self-injection), diagnostic testing (e.g. blood glucose monitors) and for inhalation dosage. The search for a non-invasive way of delivering insulin has lasted a long time. Indeed, many despaired that there would ever be a successful outcome. The major barriers concerned insulin’s peptide structure, making oral delivery unreliable, if not impossible. The steep dose-response relationship and need for dose to reflect blood glucose levels were also considerable constraints. Persistence has paid off, however, and a system for insulin delivery by inhalation has now been tested in clinical trials and shown to be safe and effective. The product shown in Figure 4 is now commercially available. Time will tell whether inhaled insulin

becomes widely used and whether such delivery is appropriate for patients suffering from other conditions that cause breathing problems (emphysema and asthma). At the same time, other devices for inhalation delivery of insulin are being developed. It is the nature of such competition that each new product represents an incremental improvement over existing ones. Over time, such cumulative enhancements lead to significant improvements. Incremental improvements have also featured prominently in inhalation products for treating asthma. The first systems for delivery of dry powder were effective but required manipulation of drug (which was contained in a capsule) and device prior to dosage. In young children, this could be embarrassing for dosage while at school and on social and sporting occasions. Devices are now available that do not require cumbersome pre-dosing assembly so are more convenient and acceptable to the patient (Figure 5). Drug-device combinations are likely to continue to offer great opportunities for innovative ways of drug delivery. Novel diagnostic techniques are also likely to attain greater prominence in all patient groups. The Prostate-Specific Antigen test for early diagnosis of prostate cancer is now routine but there is great hope that similar diagnostic tests for autoimmune conditions, cancer, osteoarthritis and liver disease will become available over the next decade. It is conceivable that treatment paradigms for “early disease states”, identified by such techniques may differ from those applied to well-established disease states. This too should lead to existing drugs finding new or slightly different uses that make them better medications.

Enhancing oral absorption Medicinal agents are structurally designed for optimum specificity and “potency” in most cases. They can be highly lipophilic and poorly soluble as a consequence. Yet, a material must dissolve in aqueous media to be transported to the systemic circulation (while being sufficiently lipophilic to partition from the aqueous intestinal contents across the enterocytes lining the small intestine). It may be difficult to balance such competing features in a chemical structure. Consequently absorption may be

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sub-optimal, variable or dose-constrained, leading to plasma level variations causing unreliable therapeutic response or greater incidence of side effects. Local side effects are also possible, consequent to poor absorption. Gastrointestinal side effects during treatment with broad spectrum antibiotics have been ascribed to unabsorbed antibiotic killing symbiotic bacteria and subsequent overgrowth of resistant flora. Oral absorption enhancement has the potential to make the medication more reliable, by reducing the variability in plasma levels. Other potential advantages, if absorption enhancement were to be significant might be a lower dose, smaller dosage units and lower cost of goods for the medication. Optimising absorption may involve using a different solid state form of the drug, altering the physical properties of the existing form, formulation with materials that enhance absorption, exploiting the physiology of the gastrointestinal (GI) tract or capitalising on pre-hepatic metabolic and transport systems. There is a wealth of literature to provide guidance on

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improving absorption. Hence, the topic is not reviewed in this article.

Conclusions Performance enhancement of medications is invariably driven by new biological insights that may relate to the patient, the disease condition or the drug. Generally, evidence from clinical trials is required to validate and support any claims for improvement. However, overall there is less risk of failure with such programs than with novel molecular entities. The compounds being evaluated for improvements will have been thoroughly evaluated for safety, so the risk of attrition because of toxic effects is low or maybe non-existent. Better understanding of how drugs work and increased access to such knowledge makes it likely that such opportunities will continue to become available for providing better medicines so that patients receive improved treatments to make them feel better and live longer. Full references are available on www.pharmafocusasia.com/magazine/

M at e rials , M a n u fact u ri n g & packagi n g

Plant Automation in Pharma An Asian perspective

Automation platforms that can be easily expanded to other process automation applications within the manufacturing facility would significantly reduce cost involved in ensuring regulatory compliance.

Pala Bushanam Janardhan, Business Consultant, Manufacturing and Plant Automation Services, Life Sciences and Healthcare Practice, HCL Technologies Ltd., India

he global production value of the pharmaceutical industry is expected to grow from US$ 370 billion in 2000 to about US$ 660 billion by 2010. The pharmaceutical industry is in rapid transition from a supply-driven market to a demand and service-driven market where manufacturing efficiency and responsiveness will play a critical role in future success. Manufacturing is evolving from a high margin, large volume, make-to-stock, supply-driven operation to a price sensitive, small volume, flexible, make-to-order, personalised, value-driven services operation. With limited available capital, equipment, and talented human assets, maximising asset utilisation and return on assets is becoming vital to future success and survival. Companies are building manufacturing cultures that foster innovation and teamwork while utilising common tools, technologies, and standards that deliver added value and financial benefit to their businesses.

Need for automation in Asia Ou t s o u rcing driving the need for regulatory compliance Global pharmaceutical majors are under immense pricing pressure. As a result, they are resorting to outsourcing work to Asia to ensure cost savings. They are trying to establish their presence in countries such as China and India to take advantage of the lower costs. In order to comply with stringent FDA norms and GMP, as well as, achieve global standards, maintain uniform quality, pharmaceutical manufacturers in Asia are resorting to implementing automated solutions. Manufacturers world over in general, and Asia in particular, suffer from the existence of islands of automation in their manufacturing facility. State-of-the-art automation platforms/systems that can be easily expanded to other process automation applications within the manufacturing facility would significantly reduce cost involved in ensuring regulatory compliance.

Part 11 of the Title 21 of the Code of Federal Regulations (CFR); Electronic Records: Electronic Signatures (21 CFR Part 11) stipulated by the FDA, applies to records in electronic form that are created, modified, maintained, archived, retrieved or transmitted under any records requirements set forth in the agency regulations. 21 CFR Part 11 requires pharmaceutical manufacturers to provide greater production transparency through audit trail and access control functions. It also puts forth the criterion that electronic records and signatures are equivalent to paper records and handwritten documents in the manufacturing processes. Therefore, companies are compelled to develop sophisticated means of electronic validation and batch recording. Electronic Batch Record Systems (EBRS) are a perfect solution for the pharmaceutical industry. Through a userfriendly Graphic User Interface (GUI), EBRS would provide an efficient way for automatic capturing of data, exchange of batch information, batch production management, and report generation, to increase productivity and accuracy of operators. EBRS would also provide a central storage of data to maintain data security and integrity. By providing functionality for application security, audit log generation, and e-Signature capture, EBRS would ensure that the system becomes completely compliant with the 21 CFR Part 11 regulations. Process Analytical Technology (PAT): It is a framework for innovative pharma-

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ceutical development, manufacture and quality assurance. Through this framework FDA is encouraging pharmaceutical manufacturers to adopt innovative technologies without fearing validation risks and production delays. This in turn is creating a demand for automation solutions. A desired goal of the PAT framework is to design and develop well-understood processes that will consistently ensure predefined quality at the end of the manufacturing process. Such procedures would be consistent with the basic principle of quality by design and could reduce risks to quality and regulatory concern while improving efficiency. Increasing automation to improve operator safety and reduce human errors will ensure gains in quality and efficiency. Vendors in the plant automation space illustrate how their products can help a manufacturer work towards PAT goals. A PAT environment would comprise of analysis, data mining, quality systems, documentation, implementation, validation and regulatory compliance. Some of the Manufac-

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turing Execution Systems (MES) solutions help in addressing the PAT requirements. A broad range of tools and technologies like infrared spectroscopy systems, a variety of sensors, advance process simulation tools as well as historians can be employed by pharmaceutical manufacturers to make their product features more predictable. ISA-88 standard for automation structure: Pharma manufacturers are under pressure to innovate. The competition from generics is urging companies to be flexible in manufacturing pharmaceuticals. Hence, companies are forced to manufacture potent drugs in smaller volumes. This necessitates the production of multiple products on the same equipment. Smart manufacturers leverage the primary standards ISA-88 for achieving improved quality and enhanced operational excellence. Among the 150 standards published by ISA, a non-profit organisation globally involved in writing and developing standards, ISA-88 standard is for flexible manufacturing and batch control. ISA-88 is the accepted standard for batch processes.

It enables flexible automation. ISA-88 standard defines the plant floor automation structure and is an excellent tool for definition of automation requirements. ISA-88 standard defines a common set of models and terminology that can be used to describe and define batch-manufacturing systems in accordance with GMP. Pharmaceutical manufacturers would benefit immensely from incorporation of ISA-88 methodology for its batch control systems. As per the latest US FDA list, 14 Indian companies have received 77 approvals or tentative approvals for active ingredients during January to November 2006 as compared to 60 approvals by 9 companies in the year 2005. Out of the 77 US FDA approvals for active ingredients, 31 were tentative approvals and remaining 46 were final approvals. The Indian companies are well set to obtain more approvals in the coming years and are investing in expansion of the manufacturing facilities. Similarly pharmaceutical manufacturers in other parts of Asia, China in particular, are investing in expansion and upgradation

M at e rials , M a n u fact u ri n g & packagi n g

Application spending priorities for 2007 Customer Management

15%

ERP Product Lifecycle Management Procurement and Sourcing

19% 8% 7%

Most Important Largest Dollar

6% 6% 12% 12%

Supply Chain Management Manufacturing Operations Performance Management

(n=939)

15% 14%

19%

Source: AMR Research, 2006

programmes, which will enrich their product pipeline in the coming years. This expansion and upgradation activity would necessitate implementation of Process Automation Systems (PASs), whether PASs are part of a new plant construction, an upgrade to an existing facility,

23%

10% 25% Figure 1

or a long-planned plant expansion, deciding how to choose and implement them takes time, money and plenty of control expertise. They can be implemented through a system integrator and / or in conjugation with a PAS supplier. Employing consultancy firms will help to avoid vendor bias and

aid in the right choice of the systems. A survey conducted by AMR Research indicated that applications related to manufacturing operations are the top most priority in the IT spend of manufacturers for the year 2007 (refer Figure 1). Pharmaceutical manufacturers in Asia like those in the rest of the world are feeling the economic pressure. Most of the manufacturers are striving for reduction in down time and manufacturing cost, improved time to market and compliance to regulations. The market for automation in the pharmaceutical industry in Asia has grown from US$ 700 million in the year 2000 to US$ 950 million in the year 2005. It is estimated to reach US$ 1450 million in the year 2010. This clearly reflects the strategy of the pharmaceutical manufacturers in Asia to implement plant automation systems that would ensure enhanced operational excellence. The author acknowledges the support extended by Dr. Norbert Schroeder of INTECHNO CONSULTING, Switzerland in providing facts & figures for the article.

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

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Single-use / Disposable Technology

Considerations for biopharmaceutical facility design Single-use / disposable technology offers a cost-effective and flexible process design for biopharmaceutical manufacturing facilities.

Craig Sandstrom, Principal Process Engineer, Fluor Corporation, USA

he biopharmaceutical industry is rapidly adopting single-use / disposable technology (SU / DT) for clinical, product launch, and commercial production facilities to provide cost-effective and flexible process capabilities (Langer and Ranck 2005). These recent technologies have requirements, advantages and disadvantages that differ from Traditional Reusable Technology (TRT). These differences need to be understood so that the advantages that SU / DT offers can be realised in new and renovated biopharmaceutical manufacturing facilities.

State-of-the-art SU / DT was originally applied to solution storage applications in the form of disposable bags and small scale filtration applications in the form of disposable capsule filters. SU / DT is now well established in disposable flow paths, and larger scale depth filtration, cartridge filtration and viral filtration applications. Disposable bags have also been successfully used as part of a seed bioreactor train (Morrow 2006) and intermediate and final bulk product storage (Voute et al, 2004). Current opportunities for implementing in SU / DT are summarised in Table 1.

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The technology is rapidly evolving and in the near future should include small-scale tangential flow filtration, chromatography and centrifugation applications. More recently, a number of vendors have started to develop larger scale (up to 1,000 L) production bioreactors, tangential flow filtration (up to 2.0 m2), depth filtration, cartridge filtration (up to 30 inch elements) and viral filtration. Additionally, there are a number of potential chromatography/membrane chromatography devices being developed. Table 2 summarises the current maximum size available for the different biopharmaceutical unit operations employing SU / DT and indicates applications that are currently used for GMP manufacturing.

SU / DT and TRT There are a number of fundamental differences between facilities designed for SU / DT and TRT. The primary difference is that the SU / DT-based facility will have a lower initial cost, but potentially higher operational cost, than a TRT-based facility. The overall economic evaluation is very complex, but strongly influenced by the operational frequency, system size and complexity. Studies show SU / DT to be most economical for simple systems that

are used at low frequency (Sandstrom 2003, once per week or less). Thus, simple applications such as buffer hold, media hold and intermediate product hold applications, and less frequently used seed bioreactor applications are ideal for SU / DT. An important feature of disposable bags is their relatively low initial costs. This is very attractive on projects where the candidate product is still in clinical trials, or for facilities that experience recurring modification. Disposable bags offer a great deal of flexibility for contract manufacturing, clinical trial and initial product launch facilities that require frequent reconfiguration. Traditional biopharmaceutical manufacturing facilities are piping-and-clean room-intense. Innovations developed to address these issues have driven layouts based upon equipment adjacencies to minimize piping runs, locating process equipmentâ€”to the extent possibleâ€”in non-classified manufacturing space. While this minimises cost, it results in multistory facilities with relatively inflexible designs. In contrast, single-use technology tends to involve portable equipment and flexible hose connections. These issues drive a very different type of layout based on material flows and have primarily involved extensive use of clean rooms. As the SU / DT technology has become more accepted, disposable bags used for buffer and media storage have moved from clean rooms to unclassified space, with a further reduction in capital cost. SU / DT has been developed primarily for smaller scale, portable applications. Consequently, a primary feature of facilities designed around SU / DT has to deal with portable equipment.

M at e rials , M a n u fact u ri n g & packagi n g

Proven Single-use/ Disposable Technology Applications Functional Area

Unit Operation

Traditional Design

SU/DT Option

Cell Culture Suite

Inoculum Flasks

Glass Flasks

Plastic Flasks

Seed Bioreactors

316L SS Bioreactors

Disposable Bag with Reusable Skid

Production Bioreactors

316L SS Bioreactors

Disposable Bag with Reusable Skid

Intermediate Product Hold

316L SS Vessel

Disposable Bag with Reusable Support Container

Filtration

Disposable element in reusable housing

Disposable element and housing

Solution Preparation

316L SS Vessel

Disposable Bag with Reusable Skid

Filtration

Disposable element in reusable housing

Disposable element and housing

Media & Buffer Hold

Solution Hold

316L SS Vessel

Disposable Bag with Reusable Support Container

Purification

Intermediate Product Hold

316L SS Vessel

Disposable Bag with Reusable Support Container

Viral Filtration

Disposable element in reusable housing

Disposable element and housing

Product Hold

316L SS Vessel

Disposable Bag

Recovery Suite

Media & Buffer Preparation

Final Bulk Product Hold

Table 1

Portable equipment requires staging space and space for equipment movement. This requires a facility with a more robust design (floors, doors and walls) to handle the portable equipment traffic. Additionally, the material flow-driven nature of the layout favours a single-level, as opposed to a multilevel, production operation. The smaller scale purification process utilising buffers supplied in disposable bags leads to interesting material flow and layout challenges. In many instances, the equipment footprint required for the buffer containers is greater than the process equipment footprint. This can be readily visualised for a 63 cm chromatography operation supported by two 1,000 litre buffer bags; two 500 litre buffer bags, two 250 litre buffer bags and two 500 litre product bags. The footprint for the chromatography pumping skid and chromatography column is approximately 1 metre wide by 3 metres long. Each buffer container is approximately 1.3 metres by 0.9 metres. This requires that the buffers are either stacked, temporarily staged or share the buffer staging space with adjacent unit operations to minimise the required processing area. Warehouse, in-process storage and waste disposal are important issues to consider. By utilising significant quantities of

single-use/disposable items, the warehouse and in-process storage requirements are significantly increased over facilities utilising traditional reusable technology. Space should be strategically located to assemble the single-use/disposable items near their points of use to minimise material traffic. Additionally, a room should be located near the glass-wash and waste dock to disassemble items.

Level of automation differences Many different types of instrumentation are employed to perform online analysis (pH, dissolved oxygen, conductivity, temperature and pressure) and flow control (on/off and control valves) in biopharmaceutical applications. All of these, with the exception of temperature and pressure, require an instrument to be in contact with the process solution. Many of these online probes currently lack equivalent SU / DT counterparts. SU / DT can employ automated pinch valves for on/off flow control, but lack an equivalent flow-control valve. However, some degree of flow control can be achieved using peristaltic pumps. This limitation frequently leads to hybrid systems that employ reusable probes with SU / DT, leading to components that still require cleaning and sanitisation. A number of vendors are now developing

disposable sensors to avoid the necessity of using reusable probes. However, these appear to be a long way from being commercially available. By their very nature, SU / DT requires more extensive set-up that readily lends itself to manual operations. Together with current limitations in instrumentation availability results in SU / DT-based facilities that favour a lower automation level. This also has the advantage of decreasing the initial project capital cost.

Intangible issues Beyond cost, scale and layout issues, there are a number of intangible issues that are important to consider when evaluating SU / DT (Sandstrom and Schmidt 2005). These intangible considerations include: • Mixing • Line sizes and connection types • Container integrity • “Practical” vs. “Possible” • Leachables, extractables and chemical compatibility • Safety • Flexibility • Risk Both disposable bags and reusable vessels can be mixed, although the degree of agitation is different. Containers are vigorously agitated to rapidly blend materi-

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als, gently agitated to provide a uniform been questionable. Hygienic connections sample and prevent segregation, and modare available in larger line sizes, with 1Â˝erately agitated to enhance heat transfer. inch being the current upper limit. These The degree of agitation can be almost arbiline size limitations impose significant trarily selected for fixed vessels. However, practical limitations on usable disposable the degree of agitation in bags is generally bag capacities. limited. This requires careful evaluation and procedure development for media/buffer preparation applications to Disposable bags offer a great deal ensure successful design and of flexibility for contract manufacturing, operations when using disposclinical trial and initial product able bags. SU / DT applications have launch facilities that require frequent limitations on the available line reconfiguration. sizes and connection types. Table 3 shows flow rates for water through various nominal line sizes and the corresponding time required to transfer 100 L. A sigLeachables, extractables and cheminificant factor is the need for an aseptic or cal compatibility is an issue for both trahygienic connection. Aseptic connections ditional reusable and SU / DT. Corrosion are currently limited to Â˝-inch line sizes. is the primary concern in traditional reusSterile tube welders are available for line able technology, with high chloride/low sizes up to â…ž-inch, but their reliability has pH solutions presenting the most signifi-

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cant challenges for stainless steels (Peckner 1977). For SU / DT, it is very important for material compatibility testing to be performed with the process solutions of interest. Cleaning and sanitisation requirements are very different between SU / DT and TRT. A significant advantage with SU / DT is that they can be presterilised, and because they are disposable, they do not require cleaning. The clean-in-place (CIP) and clean steam systems required for TRT involve significant capital investments and their elimination, or at least minimisation, are a major part of the cost savings associated with SU / DT. Container integrity and safety may also be an issue with SU / DT. Disposable bags need to be protected from accidental puncture and loss of container integrity. Additionally, disposable bags have a burst pressure of approximately 15 psig, and

M at e rials , M a n u fact u ri n g & packagi n g

their design does not facilitate relief device installation. Finally, disposable bags will melt when exposed to excessive heat, for example, from a fire. Disposable bag integrity and safety can be enhanced using the appropriate support containers. These containers provide a ridged barrier to prevent accidental puncture and can minimise any splashing associated with loss of containment. Even with these, however, disposable bags may not be suitable for use with flammable or hazardous solutions. Finally, the use of single-use/disposable bioreactors may be limited to GLSP and BL1-LS biosafety-level applications where closed systems require designs to “reduce the potential for biohazard release” as opposed to the BL2-LS where closed systems require designs to “prevent potential biohazard release” (NIH Guidelines 2002). SU / DT offers a more flexible design option than TRT. This is especially important for facilities that routinely undergo reconfiguration, such as multiproduct, clinical trial and pilot facilities. A disposable bag size can be more readily changed than a fixed vessel size. Additionally, a disposable bag can be moved to accommodate process changes more easily and with less cost and associated construction time than required to remove and install new process piping. There are risks associated with implementing SU / DT. These risks are categorised in Figure 1. The supply chain management risk can be mitigated by qualifying at least two SU / DT vendors. This risk can also be mitigated with a larger warehouse inventory to allow time to investigate suitable alternatives in the event of a supply chain disruption. Of the risks associated with the various process applications, the breach of container integrity and failure of aseptic connections are the most serious. Integrity testing disposable bags before use is very important for applications with potential high-value product loss. Operator training and selection of robust connections are very important for applications requiring aseptic connections.

Summary Single-use/disposable systems are now a well-established technology that offer a cost-effective and flexible process design

Summary of Single-use / Disposable Technology by Unit Operation Unit Operation

Current Maximum Size

Ready for GMP Manufacturing

Solution Preparation

2,500 L Bags

Yes

Solution Hold

2,500 L Bags

Yes

Seed Bioreactors

500 L

Yes

Production Bioreactors

1,000 L

Yes

Depth Filtration

Single elements

Yes

Cartridge Filtration

30-inch elements

Yes

Viral Filtration

Same as Cartridge Filtration

Yes

Tangential Flow Filtration

2.0 m2

Chromatography

n/a

No Table 2

Flow Rate and Transfer Times for Various Line Sizes. Nominal Line Size

Flow Rate (5 psid/100 ft)

100 L Transfer Time

0.6

2hr 55 min

3/8

1.5

1hr 6 min

3.4

30 min

7min

3min

1½

120

<1min Table 3

Manufacturing risks associated with using single-use / disposable technology. Risks associated with the vendor/supply chain management include the following: Vendor goes out of business Vendor material change Vendor supplier goes out of business Vendor supplier material change Transportation Material fails to meet quality-control standards Risks associated with process include the following: Loss of system integrity Connection failure (i.e., contamination associated with aseptic connections, etc.) Procedural errors (i.e., select incorrect container, make incorrect connection, etc.) Material compatibility Risks associated with portable equipment: Facility damage as a result of transport Personnel injury as a result of transport Figure 1

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for clinical, initial product launch, and commercial production biopharmaceutical facilities. Their requirements, advantages and disa vantages lead to different facility designs when compared with TRT. Facilities designed for SU / DT have layouts that are driven by material flow issues and favour a lower level of automation compared to facilities designed for TRT that are driven by equipment adjacencies and may have a high level of automation. Additionally, SU / DT provides flexibility to accommodate process modification that may otherwise require facility renovations, and thus minimise or avoid subsequent construction costs and lost production time. Overall, the cost advantages and flexibility makes SU / DT especially attractive for small, multiproduct facilities, clinical trial and initial product launch facilities, and pilot facilities. Full references are available on www.pharmafocusasia.com/magazine/

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BOOK Shelf

Encyclopedia of Pharmaceutical Technology 3rd Edition Edited by: James Swarbrick Year of Publication: 2006 Pages: 5536 Description: Presenting authoritative and engaging articles on all aspects of drug development, dosage, manufacturing, and regulation, this Third Edition enables the pharmaceutical specialist and novice alike to keep abreast of developments in this rapidly evolving and highly competitive field. A dependable reference tool and constant companion for years to come, the Third Edition will offer completely new entries that cover critical issues in the field such as the impact of genomics, biotechnology, and implants on drug discovery, targeting, delivery, and formulation. In addition, it will address new regulatory issues, such as the changes in advertising regulations, and emerging FDA procedures.

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Improving Pharmaceutical Manufacturing Performance A four-year research project began in 2002 to study pharmaceutical manufacturing and deviation management performance. The analysis reveals five key outcomes that influence manufacturing performance.

Jeffrey Macher, Assistant Professor of Strategy, McDonough School of Business, Georgetown University Jackson Nickerson, Professor of Organization and Strategy, John M. Olin School of Business, Washington University in St. Louis USA

he Pharmaceutical Research Manufacturing Project was launched in 2002. The project’s goals are two-fold: first, to investigate the likelihood and type of enforcement efforts utilised by the US FDA; and second, to investigate the effects of managerial, technical and organisational practices on pharmaceutical manufacturing and deviation management performance. By studying these relationships, the project’s objective was to generate new insights into the management of pharmaceutical manufacturing, as well as into strategies for improving product and workplace safety in the pharma and other industries. The project was implemented in two stages. The first stage focussed on FDA oversight of pharmaceutical manufacturing. The second stage focussed on manufacturing and deviation management performance of pharmaceutical manufacturing facilities. In this article we summarise some of the results of the latter study, which we refer to as the “Pharmaceutical Manufacturing Study”.

Scope Working with 19 manufacturers, the project team collected data on 42 phar-

maceutical manufacturing facilities for the Pharmaceutical Manufacturing Study. Data collection included information about the firm and the manufacturing facilities, human resource management, the management of deviations, the use of various teams, shop floor performance metrics, process development metrics, and regulatory performance. Types of facilities included oral and topical manufacturing facilities (22 in all), injectable manufacturing facilities (8 in all), active pharmaceutical ingredients manufacturing facilities (15 in all), and biologic manufacturing facilities (5 in all). Unfortunately, only one biologic facility provided complete performance metric information, due to which we were unable to provide benchmarking data on performance for biologics. Nonetheless, data from this facility and other biologic facilities were used in several of the statistical analyses. Manufacturers spent substantial effort collecting the data and entering it into a secure website. Confidentiality agreements prevent us from disclosing any firm or facility-specific information, as such the firm or facility cannot be identified. Thus, each manufacturing facility is identified by a unique number, which is meant to allow

the reader to make comparisons across different responses while maintaining firm and facility anonymity.

Summary of results The report presents and discusses results from 27 statistical analyses exploring how organisational practices impact various manufacturing performance metrics for facilities producing Active Pharmaceutical Ingredients (API) and facilities producing Oral, Topical, or Injectables (OTI). Our statistical analyses focus on those factors correlated with cycle time, yield performance, deviation management outcomes, product unavailability, and process development along with analyses that identify factors corresponding to changes in each one of these metrics. Thus, statistical analyses provide insight into the managerial, technical and organisational practices that correspond with improving various manufacturing and deviation management performance metrics as well as to achieving high performance in these metrics. Given the large number of statistical analyses and the even larger number of variables used in these analyses, we present here a qualitative assessment of all findings. We identify five findings that are generally consistent across these analyses. We first find that the extent and use of Information Technology (IT) almost universally corresponds to achieving superior manufacturing performance metrics. By IT, we mean those investments that enable manufacturers to electronically and automatically report deviations; track deviations by lot, by type of issue, and people assigned to resolving the deviation; and the central storing of data to facilitate problem solving. OTI facilities that scored highly with respect to these investments had low The volume of data collected and presented in the final report is immense. The full report can be found at http://www.olin.wustl.edu/faculty/nickerson/results/ and http://faculty.msb.edu/jtm4/PMRP Results/

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er cycle times, reduced batches failed over time, greater product availability, lower equipment deviations and reduced raw material and component deviations over time. API facilities that scored highly with respect to these investments had lower cycle time, higher yield, lower raw material deviations, lower equipment deviations, and reduced equipment and process deviations over time. Second, the locus of decision rights within the organisation matters, especially with respect to deviation management, lot failure, lot review, and process validation. Generally speaking, the closer these decision rights are to the “shop floor” as opposed to being held by higher-level management, the higher was manufacturing performance. Decision rights located closer to the process tended to benefit OTI facilities more than API facilities; although, performance benefits were found in both types of facilities. Third, facilities engaged in contract manufacturing, either in part of the facility or as a facility that specialised in contract manufacturing, generally, although not in all instances, correspond to inferior performance in at least some metrics. These results were largely found for API facilities. For instance, API facilities engaged in at least some contract manufacturing tended to have more failed batches, lower yield, higher cycle time and a performance that worsened along these dimensions over time. API facilities, however, had lower raw material deviations and tended to reduce process deviations overtime even though equipment deviations increased overtime. That said, our conclusion does not mean that contract manufacturers are inherently poorer performers. Instead, our conclusion implies that facilities that engage in at least some contract manufacturing suffer in some dimensions of performance. This correspondence also does not imply causation. Our analysis could not distinguish whether contract manufacturing was the “cause” of poor manufacturing performance, or, because certain types of difficult to produce compounds are outsourced. Fourth, the use of Process Analytical Technology (PAT) tools generally, although not in all instances, correspond to poorer performance metrics. This correspondence again does not imply causation. PAT tools

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may be adopted for good reason—manufacturing processes might be particularly problematic and therefore, such tools are adopted because of their superior capabilities in finding root causes. Our analysis does not determine causation. Finally, scale and scope of the manufacturing facility have a complex interplay associated with manufacturing and deviation management performance. Scale and scope can be both a benefit and a detriment to manufacturing and deviation management performance depending on the metric of interest and the type of production process. In addition to the statistical analyses summarised above, the report provides hundreds of graphs that provide direct benchmarking comparisons. This benchmarking data allows direct comparison across pharmaceutical manufacturing facilities on hundreds of important metrics. Pharmaceutical manufacturing managers can begin to explore trade-offs among variables using these benchmarking charts. For instance, some facilities experienced high rates of employee turnover, which might translate into performance differences compared to those facilities that experienced low turnover. The same type of analysis can be made regarding the extent of human capital manifested in the distribution of educational degrees. An area where such comparisons may be particularly fruitful is new process development. Facilities demonstrated wide-ranging differences in how processes are developed with respect to the location of development, utilisation of development resources, and time utilised to develop processes. The benchmarking data contained within this report can be used to identify such differences and can be used to augment results from our statistical analyses.

Conclusion Our study is one of the most detailed and broadest studies of pharmaceutical manufacturing across firms ever attempted. We reported in this article statistical analyses that summarise the data and identify statistically significant correlations between a variety of organisational factors and important pharmaceutical manufacturing performance metrics. These analyses begin to provide evidence-based insight in the

organisational practices that correspond to improving various manufacturing performance metrics as well as to achieving high performance in pharmaceutical manufacturing. These analyses, however, are just beginning. The data can be used to statistically analyse a wide variety of manufacturing-related questions that can bring new understanding to the pharmaceutical industry. Full references are available on www.pharmafocusasia.com/magazine/

BOOK Shelf

Pharmaceutical Manufacturing Encyclopedia 3rd Edition Edited by: William Andrew Publishing Year of Publication: 2006 Pages: 4,000 Description: The database gives details for the manufacture of 2226 pharmaceuticals that are being marketed as a trade-named product somewhere in the world. Each entry includes: • Therapeutic function • Chemical and common name • Structural Formula • Chemical Abstracts Registry no. • Trade name, manufacturer, country, and year introduced • Raw Materials • Manufacturing Process In addition, references are also cited under each drug’s entry to major pharmaceutical works where additional information can be obtained on synthesis and the pharmacology of the individual products

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Decision Making in Drug Development Innovative designs

Bayesian designs are particularly suited for early drug development as they combine historical information with current trial data to make decisions on toxicity, efficacy or futility.

Miklos Schulz, President and Chief Executive Officer, and St. Clare Chung, Director, Bio-Statistics & CDM SciAn Services Inc., Canada

arly clinical drug development is targeted at gathering information about the toxicity and efficacy of a new drug compound. Phase I trials determine the maximum tolerated dose of a drug while Phase II trials explore efficacy and lead to a critical decision of go-no-go in terms of continuing a drug’s clinical program. Bayesian designs are particularly suited for early drug development as they combine historical information with current trial data to make decisions on toxicity, efficacy or futility. Traditional designs, e.g. parallel group, have long been the mainstay of clinical trials. These designs are appealing because they are rigorous, robust and focussed. Yet at the same time, these desirable qualities often place limits on innovation and analysis. Some limitations include: • Inflexibility; design parameters cannot be changed without affecting robustness • Inability to focus on single therapeutic agents • Employ different endpoints in Phase II (short-term) vs. Phase III (long-term) • Restriction on statistical inferences to information in the current trial Traditional designs are more appropri-

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ately suited to Phase III studies. However, during early drug development, more innovative designs that allow effective decision-making are needed and by doing so, overall drug development time may be reduced.

Frequentist vs. Bayesian approach In statistics, there are two schools of thought—Frequentist and Bayesian. Most traditional designs have their roots in Frequentist statistics and although one may or may not be aware of it, when we employ terminology such as "confidence intervals" and "p-values", we are describing Frequentist characteristics of data. Bayesian statistics is based on a theorem known as “Bayes Theorem”. This theorem provides a method for updating historical or prior information with current information to determine if a hypothesis is true. In contrast, the Frequentist approach ignores any historical or prior information and all inferences are based on the observed data.

Phase I designs The objective of a Phase I study is to determine the maximum tolerated dose (MTD) of a new drug compound that produces a

specified level of toxicity. The traditional design for a Phase I study has often been the “1-in-3”, “3+3” design or variations thereof. The approach is deterministic in nature and one variation is described as follows: • Treat 3 patients at the starting dose level Di • If 0 patients experience dose-limiting toxicity (DLT), escalate to dose Di+1 • If 1 or more patients experience(s) DLT, treat 3 more patients at dose level Di • If 1 of 6 experiences DLT, escalate to dose Di+1 • If 2 or more experience DLT, MTD = Di-1 Dose escalation stops when 1/3 patients (33%) have DLT at a given dose level; MTD is the next lower dose level. Although inherently simple to use, this approach has several limitations: • Inability to account for indication or patient populations with specific dose limiting toxicity rates • Dose levels need to be defined in advance • Sample size is variable • Confidence in the chosen MTD is poor • Difficult to modify for different DLT rates

Continual reassessment method The Continual Reassessment Method (CRM) introduced by O’Quigley, Pepe and Fisher (1990) provided the first formal ‘statistical’ approach to determining the MTD. The method is Bayesian in nature and allowed the MTD to be determined with continually updated data. The method is described as follows: • Determine the range of doses to be explored • Assign a probability of toxicity to each dose based on historical data or investi-

C li n ical trials

Summary of the formal statistical differences between the Frequentist and Bayesian approaches Issue

Frequentist

Bayesian

Prior information other than that in study being analysed

Informally used in design

Used formally by specifying a prior probability distribution

Interpretation of parameter of interest

A fixed state of nature

An unknown quantity that can have a probability distribution

Basic question

How likely is the data given a particular value of the parameter?

How likely is a particular value of the parameter given the data?

Presentation of results

Likelihood functions, p-values and confidence intervals

Plots of posterior distribution of parameters, calculation of specific posterior probabilities of interest, and use of the posterior distribution in formal decision analysis

Interim analyses

p-values and estimates adjusted for number of analyses

Inference not affected by number or timing of analyses

Interim predictions

Conditional power analyses

Predictive probability of getting a firm conclusion

Dealing with subsets in trials

Adjusted p-values (e.g. Bonferroni)

Subset effects shrunk towards zero by a "skeptical prior"

David J Spiegelhalter etc., An introduction to Bayesian Methods in Health Technology Assessment, BMJ, 319,508-511 (1999)

gator input; this represents prior information and is the starting point for the search • Define a model that represents the doseresponse relationship; e.g. a tangent hyperbolic or other logistic regression model • Treat patients at the starting dose • Observe dose-limiting toxicities • Calculate the next best estimate of the MTD based on the prior information and the current results of the study Based on this approach, patients are treated at the dose at which currently available evidence indicates to be the best estimate of the MTD. The CRM is flexible and allows different number of patients to be treated per dose and could target a preselected dose limiting toxicity rate.

Maximum tolerated schedule Phase I designs usually involve a single administration of the drug. However, in some situations, investigators may administer a drug repeatedly and monitor long-term effects of toxicity. In these cases, the objective of the trial may not be to determine the MTD but rather the maximum tolerated schedule (MTS) of a drug. Braun et al. (2005) proposed a new method for this setting. The proposed method uses patient’s time to toxicity as the outcome, with the hazard of toxicity modelled as the sum of a sequence of hazards, each associated with one administration. The MTS that the patient may receive is based on the risk of tox-

icity occurring within a specified follow-up period that includes the maximum schedule being considered. Patient accrual, data monitoring, and outcome-adaptive decision making are done continuously throughout the trial under a Bayesian formulation. Each time a new patient is accrued, the most recent data is used to evaluate criteria that defines the optimal schedule, which is assigned to the new patient.

Efficacy-toxicity tradeoffs Thall et al. (2004) extended the Phase I paradigm to include not just safety, but also efficacy. Their argument was that Phase I design is too limited and ignores several important factors: • Response. No patient hopes only for “No toxicity” • Assumes that the probability of response is monotone with dose • May be inefficient when the probability of toxicity is low for all doses but that the probability of response increases with dose. In this case, the superior higher dose may not be found. The approach of Thall et al. combines the objectives of Phase I and Phase II trials. Patient outcome in the trial is a bivariate outcome consisting of the possible set of outcomes for toxicity and for response and like the CRM method the efficacy-toxicity tradeoff method is Bayesian in nature. The investigator would define the following:

Table 1

• lowest acceptable level of response • highest acceptable level of toxicity • three equally desirable levels of response, toxicity The three desirable targets, π1*, π2* and π3* set up the initial efficacy-toxicity tradeoff contours (dimension reduction). The first target, π1*, represents the minimum probability of efficacy when toxicity is not expected (i.e. probability of toxicity = 0) while π2* is the maximum probability of toxicity when efficacy is certain (i.e. probability = 1). The final target π3* is an intermediate point between the smallest efficacy and largest toxicity probabilities. These construct the target contour C as in Figure 1 (Thall & Cook, 2004). As illustrated in Figure 1, π1* is (0.15, 0), π2* is (1.0, 0.55) and π3* is (0.25, 0.30). The contour C is then used to define desirable probabilities for any pair of probabilities q which in turn determines the desirability of the doses under investigation. A family of trade-off contours can then be constructed (see Figure 1). Once this structure has been defined, the dose-finding algorithm is as follows: 1. Investigator chooses the starting dose 2. Dose x is acceptable if the dose has acceptable probabilities of efficacy and toxicity or if the dose is the lowest untried dose and has an acceptable probability of toxicity 3. Treat each group of subjects at the current most desirable dose

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4. Do not skip untried doses 5. If no dose is acceptable, stop the trial 6. At the end of the trial, select the most desirable dose Figure 1 Efficacy-toxicity trade-off contours. The three elicited target points that determine the target contour C are given by round dots. The two triangular points illustrate the desirability of any pair of probabilities

ficacy and (ii) stops if no dose is acceptable.

Phase II proof-of-concept studies The proof-of-concept study represents another area that is an ideal target for innovative designs. Proof-of-concept studies are carried out to determine if there is early evidence of clinical efficacy using a small, targeted number of subjects, to

Efficacy-toxicity trade-off contours - Target Contour C

1.0 0.8 Prob(Toxicity)

0.6

0.4

L(q)

π*3

0.2 0.0 0.0

π*1

π*2

0.2

0.4

0.6

0.8

1.0

Prob(efficacy) Figure 1

Efficacy-toxicity tradeoff contours – Selection

1.0

Summary

Prob(Toxicity)

0.8

0.6 q2

0.4

L(q2)

L(q1)

0.2 0.0 0.0

0.2

0.4

0.6

0.8

1.0

Prob(efficacy) Figure 2

Figure 2 illustrates the selection process with 2 pairs of points, q1 and q2. The point q2 is more desirable because its contour is closest to the desired C contour. Two key advantages to this approach are: (i) the method reliably finds safe doses with high ef-

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once the study is completed, etc. Designs that address these limitations include twostage Simon designs, three-stage designs, optimal flexible two-stage designs and adaptive two-stage designs. As their name suggests, the study is implemented in stages. At each stage, the data from subjects in the study are examined and a decision is made to stop the study early or to enroll additional subjects into the next stage. Adaptive designs refer to designs in which the design factors can be adjusted during the trial. Design factors that can be adjusted include sample size, dropping ineffective treatment arms, randomisation, stopping early rules, etc. The decision is usually based on accumulating data in the current trial but can also accommodate data from other ongoing trials. The Continual Reassessment Method is an example of an adaptive design. Other Bayesian examples can be found in articles by Thall, Sung & Estey (2002) and Thall & Wathen (2005). In the latter paper, the study was designed to address patient heterogeneity (covariates) and multi-stage therapies. Benefits of adaptive designs include reduction in sample size, the ability to assess predictive probabilities of statistical significance and terminate early if there is no evidence of drug effect, reduction of total drug development time and the availability of long term safety data earlier.

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warrant taking a drug further into development. Traditional designs may not be appropriate for a number of reasons: designs with a placebo arm may be unethical, designs are based on a fixed sample size and conclusions can only be drawn

Innovative designs such as those described in this article present valid, efficient alternatives to traditional designs typically used in early drug development. The Bayesian approach seems ideally suited to early phase trials for the following reasons: • borrows strength from combining historical/prior information with accumulating data • supports model-based estimation, thereby improving efficiency • has practical applications in situations where it is necessary to make design changes; e.g. covariate adaptive randomisation • naturally provides an ideal framework for decision making, as opposed to hypothesis testing. Full references are available on www.pharmafocusasia.com/magazine/

C li n ical trials

Emerging trends Asian countries seem to be welcoming foreign clinical trials, which create job opportunities for researchers, scientists and medical professionals and also bring new therapies to the country.

t has been suggested that the biotech sector in the Asia Pacific region is rapidly growing and could become a serious competitor to the US biotech industry. However, regulatory hurdles, lack of intellectual property protection as well as cultural factors could slow down the sector’s development. In this rapidly globalising world, drug companies wishing to conduct clinical trials are looking beyond the borders of the countries in which they are situated. Increasingly, they are gazing eastwards. This movement is motivated in a large part by increasing hesitation on the part of Westerners, who are concerned about the impact of drugs used in clinical trials on their health—to participate in clinical trials. Such concerns are stimulated by wellpublicised failures such as the UK clinical trial of an experimental drug, which left six healthy volunteers seriously ill. As drugs are increasingly based in biotechnology, companies find increased hesitation on the part of Westerners to participate in clinical trials.

Recent statistics indicate that only 6% of eligible patients in the US actually participate in clinical trials. As a result, 87% of trials in the US are behind in their recruitment and enrollment. It is not surprising that drug companies are now looking to the East to fulfil clinical trial requirements, to countries with large populations of relatively naïve patients. In many instances, this move eastwards is being welcomed, as countries recognise that clinical trials bring investment. Regulatory requirements have been simplified in order to facilitate foreign clinical trials. However, concerns remain in both the West and the East about the “exploitation” of Eastern clinical trial subjects and the transferability of results from trials conducted in the East. Although worldwide harmonisation is touted to reduce costs, protect clinical trial participants and improve the relevance of results, questions about the ability to harmonise in light of the distinct cultures of the East remain.

Shonagh McVean, Partner, and Sara Zborovski, Partner, Gilbert’s LLP Canada

The lure of Asia Within the last decade, there has been much discussion about the benefits of conducting drug and biotech clinical trials in Asia due to the lower costs. One author estimates the cost of conducting biomedical research in China as approximately 20% of the cost in the West because, among other things, Chinese researchers’ salaries are as little as 10% of those in the West. As a result, the cost of bringing a new drug to market in China could be as little as US$ 5.9 million compared to more than US$ 800 million in the West. Consider too the reduced cost of doing clinical trials in India—approximately US$ 3,000 per patient in India, compared to approximately US$ 30,000 per patient in the US. Another recognised benefit of conducting clinical trials in Asia is easy access to large patient populations located in major cities with well developed transportation systems and large number of medical centres. Because foreign clinical trials are a relatively new phenomenon in Asia, there

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is little competition among drug manufacturers for trial participants. In addition, the large patient populations are relatively drug naïve—many potential participants have not been exposed to a large number of drugs, making them suitable candidates for clinical trials.

The lure of foreign clinical trials Asian countries seem to be welcoming foreign clinical trials which create job opportunities for researchers, scientists and medical professionals and, in many cases, bring new therapies to the country. As a result, some Asian countries have reformed regulatory regimes to simplify the procedure for approving clinical trials. There are other strategies which can also increase the amount of foreign clinical trials to Asian countries, including ensuring speedy conduct of clinical trials, making available educated and experienced clinical trial investigators, and compliance with the principles of Good Clinical Practice (GCP). Asian countries need to look no further than Australia for a model of a regulatory regime which has had success in attracting international clinical trials. As a result of regulatory reforms, Australia is seen as a country with expeditious clinical trial approvals by review boards and regulators. In addition, Australia boasts quick initiation of and patient enrollment in clinical trials, GCP compliance, experienced clinical investigators and high quality results. India is also a preferred country to conduct clinical trials because it boasts many of the benefits recognised above, such as lower costs, a large number of treatment naïve patients and faster enrollment in clinical trials. In addition, India also benefits from a Western system of medicine, English source documents and genetic diversity.

Harmonisation Authorities in Asian countries are becoming increasingly aware of the need to internationalise their standards and requirements, particularly with respect to clinical trials, and many have adopted GCP guidelines similar to those in the West. Harmonisation through the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) seems the next logical step. The move towards harmonisation of the

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regulatory requirements for the approval of drugs was initiated in the 1980s by the European Community. Today, the ICH brings together the regulatory authorities of Europe, Japan and the US and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. The stated goal of ICH is to reduce duplication in testing during the development of new medicines. A number of Asian countries though not members of ICH currently, have recognised the importance of the global movement towards harmonisation and have met to discuss GCP differences in the region and the ethics of extrapolating clinical trial data from one country to another. We believe that continued movement towards harmonisation is inevitable (although perhaps not through ICH). However, harmonisation alone may not guarantee the growth of the Asian biotech sector through foreign clinical trials.

Some hurdles remain Although harmonisation and regulatory reforms are attractive, the uniqueness of Asian countries makes assimilation difficult and challenges remain. These include: regulatory delays, concern about inadequate intellectual property protection, ethical issues (including inability to obtain informed consent and lack of adverse event reporting), and the impact of racial and ethnic diversity. Continued regulatory delays Despite attempts at facilitating the approval and conduct of foreign clinical trials, drug companies still face considerable delays in obtaining approval in some Asian countries. In China, for example, delays in obtaining authorisation from China’s State Food and Drug Administration can mean that drug companies wait as long as 8 to 12 months before receiving approval. Lack of intellectual property protection Another concern is the perceived (and in some cases, actual) lack of adequate protection for intellectual property. According to a 2005 survey by Ernst & Young, 70% of US drug company executives classify threats to their intellectual property as a risk to their doing business in China. There remains a risk of counterfeit drugs through the use of a foreign drug company’s clinical data by local companies. An innova-

tor must provide confidential details (such as chemistry, manufacturing and analysis) to the regulatory authorities of the country to which it wishes to bring its product. We are aware of rumours that this information is leaked to local pharmaceutical companies which then make counterfeit versions of the drug. In contrast, companies view the risk in the West of misuse of confidential information as much lower, possibly due to more robust legal remedies. Ethical issues Obtaining informed consent for clinical trials by Asian subjects may also pose a challenge. In China, for example, obtaining informed consent is particularly difficult. Traditionally, Chinese people have enormous respect for doctors, and accordingly will not question a doctor’s suggestion to become involved in a clinical trial. There are also reports of Chinese participants not being properly informed of the risks of clinical trials, including the nature of the trial and possible adverse events. Finally, there is concern about the inadequate reporting of adverse events. While in theory, clinical trials in China are supposed to comply with international GCP standards, including the obtaining of true informed consent and the approval of trial protocols by regulatory authorities and institutional review boards, in practice, enforcement of these standards has been piecemeal.

Conclusion While harmonisation of regulatory requirements and standardising informed consent and adverse events reporting is simple in practice, enforcement is sometimes lacking. In addition, the transferability of results from trials conducted in the East is not always possible. While there appears to be some consensus that the Western standards for GCP should be mirrored in the East, there remain outstanding questions about the adoption of Western standards and the acceptance of clinical trial data. Thus, while it makes sense to focus on regulatory reform, the cultural, economic and genetic East-West differences must be kept in mind when designing a successful clinical trial system. The authors wish to thank Nathaniel Lipkus, student-atlaw at Gilbert’s LLP for his research assistance.

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

C li n ical trials

Ethics in Clinical Trials and Drug Development Ethical considerations have a multiplicity of roles during the conduct of clinical trialsâ€”from matters related to the design of a study, to the conduct and even to the reporting of results.

Agnes V. Klein, Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Biologics and Genetic Therapies Directorate Health Products and Food Branch, Health Canada, Canada

thical considerations have been part of the conduct of studies with humans for several decades. However, it is only since WW II and several abusive trial situations coming to attention that ethical considerations have become a prominent and critical part of the conduct of clinical trials both for safety and well-being of the subjects or volunteers enrolled in these studies. One of the elements that should be noted is that ethical considerations are never black & white but exist in multiple shades of grey. The nature of ethics is such that there is never one single answer to any question, but a series of dilemmas for debate and consensus building within the context of the sometimes widely-divergent opinions. Ethics is anything but exact science and one must understand that the resolution of any one ethical question will, by necessity, remain highly personal. It is clear, however, that the consensus building process noted above can shed light and allow for progression on any particular issue that is being debated.

the conduct and even to the reporting of the results obtained. Each of these needs to be carefully considered and explained in the context of international and national principles and guidelines. It is also very important, in those jurisdictions where wellestablished governance of ethics committees is in place, to conform to, and follow the principles, laws, guidances and processes that have been prescribed. It is noted that, depending on the legislation in each jurisdiction, the ethics process is more or less formalised and centralised. Philosophical, legal and even religious and moral beliefs have a direct influence on the ethical approach to clinical trials. Customs and morals that reflect on disclosure of the subjectâ€™s disease or state thereof, have, in the past, heavily influenced all ethical considerations when treating subjects and when approaching them to be included into clinical trials. This article focusses exclusively on those clinical trials that are conducted to prove the safety and efficacy of the therapeutic product being tested.

Role of ethics in clinical trials

Preparing to conduct a clinical trial

Ethical considerations have a multiplicity of roles during the conduct of clinical trials. These roles span a broad rangeâ€”from matters related to the design of a study, to

While preparing to conduct a clinical trial, it is useful to review the main elements noted above in order to ensure that the

framework that will govern the ethics of the proposed trial is appropriately applied.

Design and conduct The design of a study is critical in the ethical consideration of the trial. It has generally been recognised that, if the design of a trial is not sound so that the probability of a meaningful outcome (whether positive or negative) cannot be achieved and as a result the hypothesis being tested can not be proven or disproven, it is generally considered unethical. It is because the human beings enrolled in a trial will have been subjected to potential or real risks for no benefit to either themselves or even to society. All the comments on the other elements of a clinical trial flow from this one.

Inclusion criteria and selection of patients One of the critical elements which ensures the success of a study is the inclusion criteria that is considered for the proposed study. Without this consideration, there is a very low probability that all of those to be treated and those who can potentially benefit from a newly developed treatment will derive maximum benefit from the treatment they will undergo. This is also important to ensure that the entire treatable population will not be exposed to undue risks either during the study or once the therapy is marketed, because health professionals will be able to provide patients with adequate directions for use tailored to their needs, which include age and sex considerations. While it is to be noted that most study protocols also contain exclusion criteria, their role is to increase the focus as well as the safety of the trials conducted.

Patient follow-up The implications of patient follow-up during the conduct of clinical trials apply to their medical/healthcare, the close

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monitoring to discover adverse events and reactions, the clear delineation of roles and responsibilities between the treating health professional and the one who is the investigator. The intent of this approach is to ensure that some of the most controllable conflicts of interest are prevented and that the data reported reflects actual outcomes of those trials, thus lending confidence on the part of regulators and others in the integrity of the data generated.

Informed consent When recruiting and enrolling subjects into clinical trials, adequate information needs to be imparted to these subjects. It is neither acceptable nor ethical to represent the situation into which these subjects enter in an unfair and unbalanced manner. Exposing subjects to risks that have not been disclosed is not only counterproductive but also increases the risks of research procedures. Subjects who are not aware of the potential risks they may run into, cannot report untoward effects in a timely manner and, in some instances, will not even report illness that they might consider directly related to the study or the product administered. Enrolling subjects into trials without full and fair disclosure has been considered to be unethical in most jurisdictions. Further, in such instances, the integrity of the data generated cannot be assured.

Ensuring ethics are followed Depending upon the country or jurisdiction, different levels of ethical reviews take place. These reviews can range form a single layer ethics review conducted under a national authority, to fully decentralised processes, to multilayer review, with a centralised ethics committee and multiple local committees that bring local sensitivities to bear on the decision on whether to approve and if so how, in respect of every single study proposed. This approach is a part and parcel of good clinical practices followed by many.

Need for ethical review A large number and a significant variety of issues come to the fore when preparing to conduct a clinical trial. Many of them are easier to pinpoint and deal with by means of precise rules. These include the issues of

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conflicts of interest such as the one already noted above on the potential conflict of the role of the clinician as an investigator. Others are more subtle such as the vested interest of the investigator to publish, to gain prestige, to yield to commercial pressures and interest. Ethical conundrums, however, are not limited to the ones noted in this article so far. There are several others that have been highlighted and in the public eye in the past two years and these will also be discussed in general terms in this article. They include public demands for openness and full disclosure of data on clinical trials, the use of placebos in clinical trials, issues of ethics governance, how to best â€œregulate ethicsâ€?, etc. The most salient ones are discussed here.

Public demands for openness and disclosure In general, mistrust exists amongst the public, health professionals and others on the accuracy and veracity of the outcomes for clinical trials. Consequently, moves around the world to generate registries where clinical trials are registered and their results posted. There are several already in existence, but the current endeavours are intended to ensure that these become of universal scope. WHO has established a series of standards that can be used as a primary register with individual countries cross-referencing to these as secondary registers. In this manner, a network of linked registries can be created to make all clinical trials and their results accessible to all interested parties whether lay people or health professionals.

Use of placebos The use of a placebo in clinical trials has become one of the most controversial topics in biomedical sciences. Much discussion has been generated as to how the use of a placebo will affect the health and well-being of subjects enrolled in trials and whether the use of placebos should be permitted at all in the face of the existence of accepted treatment. Unfortunately, accepted therapy may not have always been based on rigorous research and the evidence for such use may be slim. However, the use of placebos is permissible under certain conditions, even though the Declaration of

Helsinki, the biomedical ethics literature and some guidelines have come down opposing their use. It is to be noted that placebos in themselves can, and do have, therapeutic effects. Placebo response in upper gastrointestinal disease, especially ulcer disease, is well documented and in the range of 40% or even higher; in the range of 20% in both depression and schizophrenia in short term studies; not to mention the findings in some studies in Parkinsonâ€™s disease where dopamine production has been proven to increase in the hypothalamus with placebo alone. This leads to the conclusion, therefore, that in many instances science can resolve the rationale behind the use of a placebo. This is the approach that is proposed, in fact, for most instances where there is controversy around the use of a placebo in a specific study.

Issues of governance In many jurisdictions, while ethics review is required and mandated by regulations, ethics committees themselves are largely self-governing and subject only to ethical guidelines without any regulatory oversight. In other jurisdictions, ethics committees in charge of the weighty decisions regarding the subjects who volunteer for clinical trials are subject to direct regulatory oversight. This oversight is in the form of direct regulation of these boards and/or indirect regulation via the ICH Good Clinical Practices. At the very least, there are national ethical guidelines which draw much wisdom from the international ones, there is a notation in regulations of the need for ethics review as part of good clinical practices as a generic mandate, and clinical trials are inspected to provide assurance that all provisions, including the ethical ones found in the guidelines have been respected.

Conclusion It is hoped that the preceding have provided some basis on which to build the ethical review of clinical trials in a manner such that its complexities are recognised, that the dilemmas if not resolved are, at the very least, debated. Also, that the vigour and health of the clinical trial enterprise is strengthened to the benefit of patients and the overall health of the public.

I n f o rmati o n T e ch n o l o gy

Operational Excellence

IT governance, Enterprise Architecture and service management IT governance defines a structure of relationships, processes and measures to direct and control IT in order to achieve the enterprise's goals.

Serge Thorn, Director, IT Research and Innovation, Merck Serono, Switzerland

T governance is currently a key topic for many IT functions. Its definition varies very often, but key themes remain essential for all companies: effectiveness, efficiency and reliability. Business value and risk mitigation are also at the centre of this domain. It represents a significant part of enterprise governance, and due to the horizontal nature of IT, wherein almost everyone in the enterprise uses IT assets to complete their responsibilities, the impact of effective IT governance is most visible. IT governance defines a structure of relationships, processes and measures to direct and control IT assets (e.g. people, finance, infrastructure) in order to achieve the enterprise's goals by adding value while balancing risk with return. It helps to define roles and responsibilities and specify accountability framework to encourage desirable behaviour in IT and accountability for the use of IT assets. IT governance also helps to standardise best practices and define monitoring methods. For Merck Serono International SA, IT governance has always been the responsibility of the IT management team, being an integral part of Merck Serono’s governance, and consists of the leadership and organisational structures and processes that ensure that the IT function

sustains and extends the company’s strategies and objectives to deliver value. IT does this within acceptable risk boundaries while taking into account culture, organisational structure and maturity. For the Merck Serono IT function, IT governance ensures that delivery expectations are fulfilled, IT resource deployment is continuously planned, targeted and optimised while IT performance is measurable and that the risks are minimised. Among the various components of an IT governance framework, the following domains were retained as being key themes to reach a high level of quality and excellence through continuous improvement: • Quality management • Balance scorecard • Risk management • Skills management • Project and portfolio management • Service management • Enterprise Architecture • Information security management • Audit management • IT performance and value management Quality management was initially the main focus for IT, and since 1999, has been certified worldwide in ISO 9001. For the last two years, quality management has also included risk management

(identifying risks from strategy down to operations and providing mitigation) as well as skills management (ensuring that the staff in the IT function have the appropriate skills in line with the strategy). Since 2001, IT measures its business alignment, which is highly integrated within the business strategy, using the IT balance scorecard tool. For more than three years, service management and IT Infrastructure Library (ITIL) have been the drivers to improve the quality of services for the end users. Merck Serono’s IT function deployed the ITIL processes covering both service support and service delivery. The purpose of this initiative was to: • Increase customer satisfaction with IT • Enhance communication with clients • Achieve higher reliability in missioncritical systems and infrastructure • Improve the cost-benefit of services • Create a “common sense” among staff These processes are mostly supported by tools from HP-Peregrine and IBM Tivoli. Project management has always been a key practice for IT people. Based on a traditional System Development Life Cycle (SDLC), the methodology has been widely used by the IT function for many years. All projects have to comply with documentation, templates and checkpoints where project progress is monitored. Committees validate the various steps of the methodology and give their approval to move to the next phase. Portfolio management is known internally as the “Funnel”. The portfolio governance process starts when a business user requests or suggests a new capability. The request is automatically routed to an information manager (internal relationship manager), then to a business analyst or team for an initial business case before

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being routed to the IT management committee for review and scoring. The IT management team then evaluates the prioritised, ranked projects to determine the proper portfolio mix and whether to accept the recent request. The “Funnel” is: • A categorisation model • A common language for business and IT to: > Support business strategy > Organise investments > Evaluate and prioritise IT projects > Govern and manage applications portfolio > Decide when and how to make changes > Understand what can and cannot be changed > Provide real-time visibility into resources, budgets, costs, programmes, projects, and overall IT demand • An input to the IT strategic plan Solutions from HP-Mercury help Merck Serono to support both project and portfolio management. An Enterprise Architecture (EA) consists of the vision, principles, standards and processes that guide the purchase, design and deployment of technology within an enterprise. EA describes the interrelationships between business processes, information, applications and underlying infrastructure for that enterprise, and provides best practices for technology purchase, design and deployment. EA structures and processes govern adherence to an organisation’s technology strategy and provide a managed environment for the use of new technology.

Enterprise Architecture • Allows alignment with the company’s business model and strategy • Enables business changes, technologically based business opportunities • Easier introduction of new technologies • Allows standardisation • Drives information/data consolidation • Reduces enterprise-application integration complexity • Facilitates outsourcing as appropriate • Utilises assets more efficiently • Provides the facility to better assess the impact of changes • Ultimately, reduces time to market Architecture governance is essentially

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a control or series of controls in the development process which is efficient when supported by good documentation (principles, guidelines, standards) and communicated effectively. To build such an Enterprise Architecture, Merck Serono considered the use of both the Zachman and the Open Group TOGAF’s frameworks. Such a programme requires solid processes with ownership and accountability. Enterprise Architecture is a component of IT governance which interacts with most of the other frameworks such as project and portfolio management, quality, maturity and security management. To manage EA, the company decided to use the Metis-Troux technologies solution. Security management is another component of the IT governance programme, covering both information security and technical security. The BS 7799 certification was obtained in 2005 for Geneva HQ and ISO 27001 obtained on a worldwide basis in 2006. At the beginning of 2006, a new position reporting directly to the CIO was created to further develop IT performance and value management. Key drivers for this are: optimising IT value, demonstrating IT value as a critical component of business processes, improving the quality of IT value measurement and reporting and becoming a potential source of innovation. Performance management is not a stand-alone initiative; it is a process that needs to be established and fully integrated in strategic alignment with the business, value delivery and company performance management. This performance framework consistently ensures that IT: 1. Is adding business value to the corporation 2. Is meeting the real customers’ real needs 3. Is running well as a business Control Objectives for Information and related Technology (COBIT) provides a set of best practices and tools for auditing IT processes and assessing standards compliance, maturity and associated risks. COBIT can be associated to other frameworks, as architecture can be audited with certain KPIs. In the frame of an IT research and innovation initiative, CMMi has been

under evaluation. It is the Capability Maturity Model Integration which has been developed by the Carnegie Mellon University – Software Engineering Institute, a suite of products used for process improvement. It consists of best practices that address the development and maintenance of products and services covering the product life cycle from conception through delivery and maintenance. CCMi models could be used in conjunction with all Merck Serono’s IT processes found in service management (ITIL), COBIT, project management (SDLC/Prince), Enterprise Architecture (Zachman-TOGAF), quality (ISO 9001), security management (ISO 27001), but the programme has not yet been considered. IT governance at Merck Serono encompasses many disciplines within the organisation including IT strategy, risk management, IT service management and compliance management to name a few. Understandably, this presents a significant challenge for companies seeking to identify a starting point for their IT governance initiative. Fortunately, best practice governance guidelines and procedures do exist within the industry. Firms, moving ahead with the adoption of a standard will be well served to utilise a phased implementation project approach and start with elements of the standard that will yield their organisation the most benefits— • Optimised IT strategy and execution • Improve resource utilisation • Improve planning and resourcing • Risk assessment • Real-time management reporting In 2005, a benchmark with KPMG positioned Merck Serono’s IT as number one among 119 other companies in the life sciences industry. In 2006, the number one position was maintained while the number of organisations increased to 125. This recognition states that the IT function is using IT best practices to support the business and that Merck Serono IT controls can now be classed as “excellent”. This was driven by major improvements in the areas of IT operations (incident, problem, operation, and configuration management), security (ISO27001), control assurance (risk, audit, planning management) and Sarbanes Oxley (SOX).

I n f o rmati o n T e ch n o l o gy

IT in Pharma

Countering the information security risk IT breaches lead to identity theft, counterfeit drugs, low productivity and revenue loss.

Pamela Campbell, Partner, Life Sciences Compliance Practice, BusinessEdge Solutions, Inc., USA

outine security procedures and regulations fall desperately short of securing a pharmaceutical company’s IT systems, putting trade secrets as well as employee and customer information at risk of devastating losses. Electronic thieves and hackers have evolved from juveniles taking a joyride through corporate networks into organised criminals in remote regions of the world tapping into your IT systems, stealing confidential company and employee information and either selling it or using it to counterfeit drugs, commit identity theft or fraud. Hidden behind national boundaries and laws, many crime syndicates operate without fear of retaliation. Data thieves maliciously hack pharma IT systems, confident that the governments of many countries, notably those in Asia, will be unable or unwilling to extradite or prosecute them. Consequently, security violations continue to explode in terms of severity and number, meaning that even apparently secure pharmaceutical companies remain at risk of potentially catastrophic losses. Unfortunately, most companies do not realise the severity of these risks or the frequency of occurrences, as many of their counterparts choose not to report these crimes, thereby drastically distorting the difference between reported scenario and reality.

Common security violations Talk to any seasoned IT security professional in the pharmaceutical world and you will uncover a host of security violations, which plague companies worldwide and often originate within their own walls. Overall, employees and contract workers pose the greatest security risk to pharma and account for the majority of security violations and approximately 50% of all data thefts. Some violations are relatively harmless, such as an employee’s kin hacking into an HR database after he spotted his relative’s user ID and password, posted next to the home PC. If malicious, the hacker could have sold employee social security numbers, home addresses, salary and other personal information to identity thieves and scalpers in moments, long before the network administrator noticed an unauthorised breach into the confidential database, tracked it to the executive’s home office, and verified the executive was working onsite during the breach. Unfortunately, most intruders do not stumble into confidential data out of curiosity but rather seek to exploit a weakness for profit. For example, a security professional at a large pharmaceutical company in north-eastern United States caught an IT subcontractor who was literally stealing

networking equipment from a company closet and selling it on eBay. The company investigation after an internal audit revealed the missing equipment and tracked it to the subcontractor. A subsequent search uncovered the equipment in his garage. Although subcontractors are considered a greater security risk than regular employees, this individual subcontractor was not considered a high risk, as he passed a thorough background security check prior to being hired at the pharma company. Though bold, this move is not uncommon as many pharma IT departments buy and install hardware without following company procedures, simply because servers are inexpensive and provide fast and easy fixes for bandwidth constraints. Therefore, unused equipment can reside for months in a closet or warehouse, representing a temptation to the criminally minded working inside the company. To make matters worse, just before his arrest, the same subcontractor accessed a backdoor into the enterprise network, which he previously created using an undocumented account, and deleted numerous files. Only aggressive network monitoring and security practices can stop a malicious, internal hacker in his tracks. Regulations and out-of-the-box security software provide only partial protection against many crimes that originate behind pharma firewalls although they do represent an important part of a more comprehensive security framework, discussed later.

Identifying global threats National and international crime syndicates find pharmaceutical companies especially appealing for two reasons. Pharma develops, manufactures, sells and distributes billions of dollars of drugs every year.

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Pharma companies also maintain personal information on thousands of employees and clinical trial participants—a valuable commodity for identity thieves. Common incidents like a stolen laptop or lost magnetic storage tape, can lead to costly losses, as thieves seek any opportunity to seize classified and proprietary information. Information on drug distribution channels now represents an open door for thieves and a potentially catastrophic risk for the pharmaceutical industry. Organised crime now routinely exploits pharma operational weaknesses to infiltrate pharma IT systems and seize lucrative prescription drug data so they can resell the drugs on the black market. Crime syndicates now use hackers to extract data that they can use to steal drugs, often replacing them with counterfeits that are sold to pharmacies and eventually patients. Recent counterfeit drugs include life-saving anti-rejection, cancer and diabetic medications as well as popular drugs, such as Viagra and Cialis. Knock off or counterfeit drugs are often sold on the Internet as well as the black market.

Emerging threats: Using technology against pharma Pharma risks continue to intensify with emerging technologies that provide access to company data, whether residing on remote devices or on the network. New viruses and worms are attacking cell phones and spreading quickly using wireless technology to contact compatible cell phones and install the bug. For example, Cabir is a malicious piece of code that jumps from one Bluetooth-enabled phone to another, draining the phone’s battery and searching for more victims. New bluesnarking viruses spread more malice as they exploit security holes in the phones to steal personal information. Another new threat, bluebugging enables hackers to execute files that attack a victim’s phone from another phone. Meanwhile bluejacking invades upon the user’s privacy by forcing long messages onto the victim’s phone without requesting permission. Instant Messaging (IM) within the pharma walls is not immune to security breaches, as viruses have been penetrating networks through IM and stealing data or planting malicious rogue code.

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Designed to streamline inventory management and secure distribution, RFID has now become a target of thieves who have learned how to break into and corrupt the RFID tag, enabling thieves to swap the products for counterfeits or less valuable products. Initially, RFID appeared poised to prevent counterfeit drugs from compromising shipments by authenticating each product, unit, case and pallet repeatedly throughout the distribution chain, via embedded RFID tags and scanners. Now RFID has become a target of savvy thieves who have learned how to break into and corrupt the numbering scheme on the shipment or product and thereby swap good drugs for counterfeit ones without being detected.

Establishing a line of defense Even though the pharma companies cannot protect themselves against every virus or new attack, they can ward off some threats by aggressively pursuing available security measures. The pharma industry can also minimise losses by deploying appropriate procedures and technologies to catch violations in progress, identify areas breached and work to fortify them against further attacks. However, security measures for many pharma companies stop at the research and development department. Pharma recognises the need to protect drug formulas and routinely blocks off access to labs and related classified data. Unfortunately, it has yet to provide the same due diligence to their overall network or fully grasp the potential damage security violations can cause to manufacturing and the business. The pharma industry should establish a security framework for the entire organisation, which implements procedures and technology for securing data, improving data recovery, defining and restricting data access, as well as user training. Securing the physical equipment represents an important first step and related best practices should extend to all IT hardware and software, including remote devices.

Start minimising risks now Enhancing security can begin with simple, ongoing practices, such as installing and updating antivirus software, spam and pop-up blockers and monitoring the

internal network and ancillary devices for suspicious activities. Conducting routine inventory and asset management audits presents another routine practice that can help pharma identify vulnerabilities and breaches. Pharma should also immediately leverage existing technology to identify and trace all authorised access to the data and immediately notify officials for unauthorised access attempts as well as breaches. Data recovery measures should be in place to recover any data lost by a user, application or network problem.

Putting regulations to work National and international regulations provide the first line of defense against security threats, making compliance to voluntary standards, as well as government mandates, a cornerstone. The Asian pharma can start with the Japanese Ministry of Health’s Guideline on Control of Computerised Systems in Drug Manufacturing. Another key regulation for South Asian facilities originates in India from the National Good Laboratory Practice (GLP) Compliance Monitoring Authority, Department of Science and Technology. Since many pharma companies span multiple borders, they should also abide by national regulations within each operating region. Therefore, the pharma industry should track and support recommendations from the Council of Europe Convention on Cybercrime. This Convention presents the only legally-binding, multilateral regulation addressing computer-related crime. Another important global source is the International Standardization Organization (ISO), which regularly develops new standards that, though not legally binding, receive widespread adoption on a global basis. Standards within the 17000 series lay a good business practice foundation for network security, with the ISO/IEC 17799:2005 defining a code of practice for information security management. Even though these standards and regulations represent a great starting point for building a security framework, they cannot alone provide the protection companies need, as they cannot provide the evidence needed to successfully prosecute cyber criminals nor can they guarantee protection to all pharma assets at all times. The effectiveness of security meas-

I n f o rmati o n T e ch n o l o gy

ures and regulations revolve around the pharma industry's ability to monitor their implementation and effectiveness while proactively monitoring IT resources. In addition to deploying network monitoring software, IT staff must continually monitor the network for unauthorised access, security breaches and any abnormal activity. All pharma employees should be trained to recognise abnormal behaviour by their peers and understand the reporting process.

Balancing security needs and costs Numerous software packages and tools claim to protect IT from security breaches. Instead of randomly deploying security tools and hoping they block intruders, identifying breaches and preventing unauthorised network access, companies would better protect their resources by devising the end-to-end strategy before implementing new technology solutions. Pharma companies should perform a detailed risk analysis that evaluates impending threats

against: • Attack probability • Potential loss • Remediation costs • Long-term impact to business goals • Damage to reputation • Liability to litigation Studying each threat from its organisational impact can help the pharma company identify vulnerabilities that it could easily overlook. For example, failure to prevent access to shipping information could make it easier for organised crime to swap drug shipments with counterfeit drugs. Substituting life-saving medication with a look-alike could result in serious harm or death, which would expose the company to hefty lawsuits if a court rules that the company did not take adequate measures to protect its shipping information. After analysing risks, the pharma company can determine how to allocate available financial and human resources as it will probably not have adequate funds to counter every potential threat with soft-

ware and personnel. The company must address internal risks as well and can implement policies that minimise risks of employee theft, such as background criminal checks, reference checks, routine asset and inventory management and ongoing network monitoring. Pharma companies face many of the same security risks confronting other large companies, ranging from theft of sensitive information to IT equipment. However, the nature of the business and value of the pharmaceutical intensifies these risks by attracting sophisticated, crime syndicates as well as disgruntled employees who can use stolen information to hijack drug shipments and replace them with dangerous counterfeits. Management must provide leadership that “does the right thing,” beyond the traditional confines of ROI, and even well beyond the boundaries of the company itself, to include partners, suppliers, customers and communities. Pharmaceutical companies can’t just buy security, but must genuinely buy into security.

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Knowledge Tools

Increasing role in drug development

By using knowledge tools to better understand a potential new drugâ€™s effectiveness and safety early in the development process, it becomes possible to terminate potentially problematic drugs earlier, saving both time and money.

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

oth academia and the health industry generate immense amounts of scientific data during their research efforts. As a result, the academic and industry researchers often find themselves in a position of having more data than they can effectively manage and interpret. In addition to data generated directly by researchers, huge amount of data is accessible from public or collaborative resources, generated by research programmes including the human genome and HapMap projects. A key factor in successful research programmes is the ability to effectively transform data into knowledge. In research, it is not uncommon to have gigabytes and even terabytes of data that require effective analysis. Managing these large amounts of data can tax even the experienced researchers. The development of new drugs is a knowledge intensive process that requires a wide variety of information at each stage of development. With the increasing shift towards translational medicine and the use of biomarkers in drug development, knowledge is now playing an increasingly important role in efficiently advancing new drugs through the development process. This shift has been further supported by efforts to increase the historically low efficiency of drug development. By using knowledge tools to better understand a potential new

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drugâ€™s effectiveness and safety, early in the development process, it becomes possible to terminate potentially problematic drugs earlier, saving both time and money. In addition, by leveraging emerging knowledge in genetics and genomics, it is becoming increasingly possible to identify likely responders and non-responders to drugs, enabling the basic promise of personalised medicine. Concurrent with the growth in research data has been the growth in the development and commercialisation of software tools to simplify data collection, access and analysis. With global bioinformatics software sales at US$ 1.3 billion and growing at an annual rate of 7%, this market continues to be attractive for future investment. Including such areas as complex analytics, systems biology solutions, Laboratory Information Management System (LIMS), and workflow management, these bioinformatics software tools are enabling researchers to significantly improve productivity and streamline research. More detailed discussion of these knowledgebased software/bioinformatics solutions is provided below.

Complex analytics Software providing data analysis and visualisation are among the most mature of

bioinformatics programmes. Typically built around well characterised and generally accepted analytical processes, including statistics, chemical modelling, and physical properties, these programmes embed formulas into easy-to-use packaged solutions that enable scientists and other researchers to rapidly transform data into knowledge. Key innovations in drug development analytics software include codification of increasingly complex biological knowledge into software applications, application of analytic solutions into the highly regulated clinical development environment, and improved connectivity between analytics applications and other drug development software (more details to follow below). Specific vendors contributing analytics software to the drug development industry include Accelrys, Insightful, IntelliChem, MDL, Mathworks, SAS, Spotfire and Symyx.

Systems biology solutions Bioinformatics software tools have also increased in complexity to directly incorporate significant chemical and biological knowledge into programmes. These knowledge-based tools enable more complex analyses that can be used to create higher level interpretations. Systems biology software tools are representative of this type of drug development software tool. Commercial software solutions include pathway analysis software products by Ingenuity Systems, GeneGo and Ariadne Genomics; high throughput data driven systems biology model companies, including BG Medicine, BioSeek and the Icoria division of Clinical Data; and high level systems biology modeling solutions, including solutions from Entelos, Gene Network Sciences, Genomatica, Genstruct and Optimata.

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LIMS LIMS software enables direct connectivity between data generated by laboratory instruments and research databases. Early expansion of LIMS applications included streamlined automation of sample management and targeted applications focussing on use of LIMS in the QA/QC and manufacturing environments. Key recent innovations include linkage of experimental design automation to automated experimentation and expansion of LIMS applications to improve ease-of-use, including transformation of LIMS into a web-based solution and incorporation of specialised product templates into manufacturing LIMS to improve new product LIMS implementations. Specific LIMS vendors include ABI, Lab Vantage, LabWare, StarLIMS, Teranode and Thermo Fisher Scientific.

Workflow management Workflow oriented bioinformatics programmes that automatically bring data together are important efficiency tools that free up researchers to concentrate on data analysis and interpretation instead of wasting time on repetitive time consuming supporting efforts. Workflow software extends to enable connectivity with LIMS, data visualisation, and analytics software as well as a variety of data resources. Key innovations in workflow software include improvements in researcher interfaces to enhance ease-of-use and continuing efforts to expand connectivity between software applications. Key vendors in workflow management include IBM, InforSense and Scitegic.

Current knowledge tool software development Knowledge-based bioinformatics software tools are increasingly addressing this need through improvements in the user interface, expansion of applications to incorporate new available research knowledge, and expansion of product offerings to incorporate application areas peripheral to the primary target market. Current trends in knowledge tool software development include:

Connectivity, interoperability and improved access: With improved efficiency continuing to be a major driver for

pharmaceutical R&D, streamlining of data processes is becoming increasingly important. Current efforts to improve connectivity and interoperability are enabling software applications to pass data back and forth seamlessly, enabling improved productivity. Enabling semantics: While clearly an emerging informatics approach, the use of the semantic web in drug development is increasing. IT web enables incorporation of semantic relationships into data analyses and has the capability to enhance connectivity between disparate data resources. Increasing complexity of systems biology product solutions: In drug development applications, systems biology promises to provide holistic understanding of disease, normal and diseased organ systems, and the human body as a collective system. Pathway analysis and high-throughput data driven systems biology approaches are beginning to incorporate the features of high level physiological models. Increased bioinformatics applications for the clinical development environment: Consistent with other clinical development requirements, software must be fully validated to be used in the clinical development environment. This added level of stringency has limited the use of emerging bioinformatics software applications in clinical development. Leading knowledgebased software applications in the clinical development space initially focus on adaptive clinical trials, but broader applications, including clinical data mining and genetic profiling are expected as personalised health efforts advance.

The future of knowledge tools Over the long term, knowledge-based software tools are expected to become a core element of the drug development process. With the idealised goal of development of a comprehensive in silico human model that accurately reflects the potential impacts of a new drug (both positive and negative) on the human body. In the interim, there are a number of application and process innovations that will transform knowledge-based software tools in the future. Application innovations

Key innovations that offer the potential to transform drug development include: • Development of in silico biology

simulations, beginning with cell, organ and disease modelling supported by empirical experimental data and eventually developing into complex mechanistic models that reflect experimental biology • Increased complexity of visualisation tools, including complex 3-D applications and visualisation of high resolution molecular imaging data, all in near realtime • Full interoperability of software applications, including transparent data sharing between silos and across the web • Cradle-to-grave workflow connectivity, beginning with e-notebooks and enabling data connectivity through product commercialisation Business process innovations

As global markets become increasingly skilled and accessible, commercial life science software development companies (primarily US companies) are increasingly able to leverage low cost development resources to competitive advantage. In addition to direct cost savings, it becomes possible to apply increased development resources to accelerate software development. Looking forward, key considerations from the business perspective include: • Drug development software tools will play a growing role in biotechnology and pharmaceutical R&D • Contributions from software tools are increasingly becoming important key components of regulatory submissions, resulting in more robust applications with higher potential for approval and potentially shorter review times • New software applications will continue to originate from leading academic life science research with increasingly rapid productisation

Conclusions Technology innovation, practical business drivers, and the shift towards more mechanism-of-action based drug development ensure that knowledge-based software tools will play an increasingly important role in drug development for the foreseeable future. Future growth is assured and will occur through systematic expansion of product offerings towards more comprehensive solutions with global influences potentially changing the process of software development.

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Information Technology

Right prescription for the growth of pharmaceutical companies The IT spending of companies reflects their strategies to introduce new drugs, enter new markets, and be more competitive in the challenging Asian pharmaceutical market. pore, Taiwan, and Thailand registered a growth of only 3.6% in 2001. However, the market has recorded a consistent double digit growth since 2002. In 2005, the Asian pharmaceutical market registered a growth of over 11% as compared to the total world growth rate of around 7%. The Indian pharmaceutical market is growing at a rate of 9% per year. This market is the fourth largest in the world by volume and has emerged as the thirteenth largest by value. The other giant, China on the other hand is the biggest pharmaceutical market in Asia. The annual growth rate of pharmaceutical sales in this country was over 20% in 2005. Singapore continues to be a global pharmaceutical R&D and production hub. The pharmaceutical markets in its neighbouring Southeast Asian nations such as Indonesia, Thailand, and Malaysia are also showing tremendous growth potential.

Sourabh Kankhar, Research Analyst, Life Science Practice - Asia Pacific, Frost & Sullivan, Singapore

IT adoption levels in a pharmaceutical company

Level 4

IT setup that automates the entire organization

Level 3

Well integrated enterprise applications such as business intelligence

Level 2

Solutions like ERP that integrate multiple functional areas

Level 1

The pharmaceutical value chain and IT applications

Department-specific solutions

Source: Frost & Sullivan

Figure 1

he pharmaceutical market in Asia has undergone a paradigm shift in the past few years. The major global pharmaceutical companies have shifted their focus to this region to drive their revenue growth. Moreover, the domestic companies in Asia are also actively participating in the global drug development process. At present, the pharmaceutical market in the region is challenging due to changes in the

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competitive landscape, increasing R&D costs, and the need to develop the right marketing strategies. In 2005, the pharmaceutical market in Asia was estimated to be around US$ 21 billion and is expected to double in value in the next ten years. The ten leading Asian pharmaceutical markets namely China, India, South Korea, Hong Kong, Indonesia, Malaysia, Philippines, Singa-

The major stages of the pharmaceutical value chain comprise drug discovery, drug development, manufacturing, distribution, and sales and marketing. Improving efficiency for a speedy ROI in every stage has become a critical factor to ensure the success of the company. Strategic adoption of Information Technology (IT) is also essential to speed up the process of research, development and sales of drugs. Mounting focus on drug discovery has led to an exponential growth in creation of intellectual property (IP). In such a scenario, pharmaceutical companies have come to realise the importance of IT solutions. They have started implementing knowledge management solutions for data management and security solutions

I n f o rmati o n T e ch n o l o gy

to protect their IP. ERP solutions are also being implemented for optimising the use of resources and maximising returns. The pharmaceutical companies are using the Internet technology for web-based data capture, mining, reporting for clinical trials, eDetailing and eSampling for sales and marketing. There are specific IT solutions for various stages of the pharmaceutical value chain. Solutions such as electronic data capture for drug development, enterprise resource planning for manufacturing and sales force automation for sales and marketing are just a few examples to share. There are many other solutions such as business intelligence, supply chain management and knowledge management that are spread across two or more stages of the value chain.

IT adoption pattern for a pharmaceutical company IT adoption in a pharmaceutical company can be characterised by four different levels. The level 1 companies have only department-specific solutions, which automate a single department and are not integrated. The implementation of IT solutions in level 2 companies is pretty integrated into multiple functional areas. An ERP solution which integrates the company’s financial, manufacturing, sales and human resources department is a typical example of level 2 companies. Solutions such as business intelligence, data warehousing, data mining along with the enterprise-wide solutions for instance SCM, form the IT set up of the level 3 companies. These solutions assist the company to make informed decisions after extensive data analysis. The level 4 companies are totally automated with the help of solutions such as enterprise application integration.

Asian pharmaceutical IT market - Current adoption and future potential The pharmaceutical companies in Asia are slowly starting to adopt IT solutions in their value chain. At present, majority of them are focusing on automating the manufacturing, distribution and sales and marketing process. There is a major demand for solutions such as ERP, SCM, CRM and sales force automation. In fu-

IT applications for the pharmaceutical value chain

Drug Development

Drug Discovery

In-Silico research

Electronic data caputre

Manufacturing

ERP Production planning Quality control

Sales and Marketing

Distribution

Warehouse management

Sales force automation CRM

Supply Chain Management Business Intelligence/Data Warehousing/Knowledge Management Integration/ Data Mining/Enterprise Application Integration Source: Frost & Sullivan Figure 2

Asian Pharmaceutical IT market – Demand and potential Demand in next 3-5 years

Present Demand Stand-alone solutions for operations management, quality control, financial systems

Business Intelligence, data warehousing, data mining, IT based drug discovery

ERP, SCM, CRM, sales force automation

Source: Frost & Sullivan Figure 3

KM, enterprise application integration, information security solutions

Demand in next 2-3 years

ture, as IT component becomes critical for pharmaceutical research, a major market for drug discovery-related IT solutions is foreseen. Demand for enterprise-wide solutions such as data mining, knowledge management and business intelligence will be on a rise when companies realise the need to integrate and analyse data for informed decision making.

Major drivers for the Asian pharmaceutical IT market • The booming pharmaceutical market in Asia • Growing competition between multinational and local pharmaceutical companies in this market • Growing awareness of the advantages of IT adoption by the pharmaceutical companies in Asia • Growth in the number of clinical trials as an increasing number of pharmaceutical companies in Asia have started focussing on R&D initiatives

Major restraints for the Asian pharmaceutical IT market • Resistance to change by the business users of the IT solutions • Information security concerns • Lack of knowledge about the technology and not being articulate about the benefits of the solutions • Conservative nature shown by Asian pharmaceutical industry towards investment in IT solutions

Conclusion Information technology is seen to be a very important factor for the success of the pharmaceutical market in Asia. Many pharmaceutical companies are expected to use IT to completely transform their business. The IT spending of companies will reflect their strategies to introduce new drugs, enter new markets, and be more competitive in the challenging Asian pharmaceutical market.

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Events

April, 2007

May 17 2007 - May 18 2007

April 16 2007 – April 17 2007 Drug InfoTech, Le Meridien, Bangalore, India Event Organiser : Marcus Evans Event Email

: revathyv@marcusevanskl.com

Event Web Link : www.marcusevans.com

April 17 2007 – April 19 2007

The First Conference in Japan for Asian New Drug Development, Aioi Sonpo Shinjuku Building Hall, Tokyo Event Organiser : Drug Information Association Event Email

: diajapan@diajapan.org

Event Web Link : www.diahome.org/product/13455/07302.pdf

June, 2007

Promoting Innovation & Generating Returns in R&D 2007, Renaissance Shanghai Pudong Hotel, Shanghai, China

Jun 4 2007 - Jun 6 2007

Event Organiser : IQPC International Quality & Productivity Center

World Vaccine Congress Asia 2007, Meritus Mandarin, Singapore

Event Email

: scott.xu@iqpc.com.cn

Event Web Link : www.iqpc.com/cgi-bin/templates

Event Organiser : Terrapinn Event Email

April 18 2007 – April 20 2007

: lynn.chew@terrapinn.com

Event Web Link : www.terrapinn.com/2007/wvc_sg

ICSE Japan, Big Sight Tokyo Event Organiser : CMP Business Media Co Ltd

Jun 4 2007 - Jun 6 2007

Event Email

China 2007 R&D Summit, Shanghai, China

: CPhI@cmpi.biz

Event Web Link : www.cphijapan.com/eng

Event Organiser : IBC Life Sciences Event Email

: custserv@ibcusa.com

April 25 2007 - April 27 2007

Event Web Link : www.ibclifesciences.com/china/5061.xml

Drug Discovery and Development Partnering, Licensing and R&D Innovation Summit JAPAN, Tower Hall Funabori - Tokyo, Japan

June 10 2007 - June 12 2007

Event Organiser : IBC Life Sciences

ISPE Singapore Conference 2007,

Event Email

Event Organiser : International Society for Pharmaceutical Engineering (ISPE) REED Exhibitions

: info@ibcasia.com.sg

Event Web Link : www.ibclifesciences.com/japan/4386.xml

Event Email

: Vincent.lee@reedexpo.com.sg

Event Web link : www.ispesingaporeconference.com/index.htm

May, 2007 May 14 2007 – May 18 2007

Achemasia 2007

July, 2007

7th International Exhibition-Congress on Chemical Engineering and Biotechnology, Beijing, China

Jul 27 2007 - Jul 29 2007

Event Organisers : DECHEMA

Event Organisers : Intel Trade Fairs & Expositions Private Limited, Mumbai

Gesellschaft für Chemische Technik und Biotechnologie e.V. Chemical Industry and Engineering Society of China (CIESC) Event Email

PharmaPack, Chennai Trade Centre, Chennai, India

Event Email

: intelexpo@vsnl.net

Event Web Link : www.intelexpo.com/html/Events.htm

: strauss@dechema.de

Event Web Link : www.achemasia.de

May 16 2007 - May 18 2007

September, 2007 Sep 12 2007 - Sep 14 2007

RFID Solutions Expo, Big Sight Tokyo

HOSPIMedica THAILAND, Bangkok, Thailand

Event Organiser : Reed Exhibitions Japan

Event Organisers : Messe Duesseldorf Asia

Event Email

: ridex@reedexpo.co.jp

Event Web Link : www.ridex.jp/en

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: hospimedica-thai@mda.com.sg

Event Web Link : www.hospimedica-thailand.com

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Products & Services Company

Verbatim Page No.

Clinical Trails Notox

OBC

Materials, Manufacturing & Packaging Biocult BV

IBC

Bonfiglioli Pharma Machinery

IFC

Delta T GmbH

Lomapharm

SMB International GmbH

Soham Organics Private Limited

Stamfag Punching Tools

Research & Development Bonfiglioli Pharma Machinery

Vertis Biotechnologie AG

Strategy Lyric Labs

Page No.

Biocult BV http://www.biocult.com/

IBC

Bonfiglioli Pharma Machinery http://www.bonfigliolipharma.com/

IFC

Delta T GmbH http://www.deltat.de/

Health Protection Agency http://www.hpa.org.uk/

Lomapharm http://www.lomapharm.de/

Lyric Labs http://www.lyriclabs.com/

Notox http://www.notox.nl/

OBC

SMB International GmbH http://www.smb-gmbh.de/

Soham Organics Private Limited http://soham.exportersindia.com/contact-us.htm

Stamfag Punching Tools http://www.stamfag.ch/

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link. 1. IFC: Inside Front Cover 2. IBC: Inside Back Cover 3. OBC: Outside Back cover

60 P h a r m a F o c u s A s iA

ISSUE - 4 2007

“This investment will significantly boost our research capabilities in two critical areas of medical need, and two areas where we have tremendous heritage.” David Brennan, Chief Executive Officer of AstraZeneca, after the announcement of a $100m investment at the Boston R&D centre for work on infectious diseases and cancer research

Suppliers Guide

Vertis Biotechnologie AG http://www.vertis-biotech.com/

Jeffrey Kindler, CEO of Pfizer, expressing disappointment after the failure of the company’s new cholesterol drug, Torcetrapib

IFC

Health Protection Agency

Company

“We know we need to have a lower cost base and a more flexible cost structure. Second of all, we are relentlessly focused on total shareholder value which includes earnings growth, dividend and share buybacks.”

“This undoubtedly will have a positive economic benefit to patients, as well as to the U.S. healthcare system.” Jim Meehan, Vice President of Sales and Marketing, Ranbaxy Pharmaceuticals Inc. (RPI) after it received the US FDA approval for Simvastatin Tablets USP

“The laboratory diagnostics market has changed considerably in the last decade. Innovation in this segment will be increasingly driven by automation, system integration and a host of skills that GE can offer.” Miles D. White, Chairman and Chief Executive Officer, Abbott, after the sale of Abbott’s Core Laboratory Diagnostics Business, Including Point of Care, to GE Healthcare

“We believe NPIL has the strategic interest and capabilities to advance these Lilly molecules through early clinical development, and we are excited to explore this innovative drug development model with them.” Robert W. Armstrong, Vice President, Global External Research and Development, Eli Lilly, after it signed a drug development agreement with India’s Nicholas Piramal

61 P h a r m a F o c u s A s iA

ISSUE - 4 2007

62 P h a r m a F o c u s A s iA

ISSUE - 4 2007