Pharma Focus Asia - Issue 09

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Research & Development

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Clinical Trials

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Manufacturing

Issue 9

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2008

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y ar rs e ve u ni Iss An

Strategy

ÂŁ12 â‚Ź18 $25 Rs.300

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Transforming Drug Development A fully outsourced model

Paediatric Drug Innovative IT Development Enabling Taking a practical approach w w w . p h pharmaceutical a r m a f o c u s a s i a . cR&D om

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Foreword Pharma’s Future

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he pharma industry today operates in an uncertain environment. Intensifying cost pressures, declining revenue streams, increasing late-stage failures, stringent price controls and an uncertain global economy add to its woes. In the rapidly changing pharma landscape worldwide, the traditional business model no longer meets the requirements and hence, the industry needs to move away from it. The biggest concern for the industry right now, however, is what the future has in store for them.

Companies are increasingly focussing on outsourcing, emerging economies, personalised medicine, developing therapeutics for highly unmet medical needs and risk-sharing with partners. The anniversary issue of Pharma Focus Asia lines up a collection of thoughtprovoking articles from the best minds in the industry that deal with the most pressing issues for the pharma industry and try to provide possible solutions.

The cover story, Pharma’s Future, sheds light on the future of the industry and how a significant transformation can help it survive these uncertain times and emerge as a stronger industry. The era of blockbusters might come to an end and personalised medicine could be a major driver behind it. Michael Liebman from Strategic Medicine provides more details on it. Outsourcing in the industry is here to stay and India is a front-runner. JB Gupta from GVK Biosciences discusses the opportunity that lies in India and how it will be a force to reckon with in the future. Kenneth Kaitin from Tufts University highlights the role of emerging economies in reducing R&D costs and speeding development times while also becoming large potential markets.

Pharma for long has been criticised for not addressing the medical needs in the developing world. Adam Renslo from University of California analyses the situation and suggests ways the industry can work with non-profit and academic organisations to address the issue. Antibodies represent a major breakthrough in treating cancer, a major cause for deaths worldwide. Horst Lindhofer from TRION Pharma explains the concept of Trifunctional antibodies, the first drug candidate and how they represent a promising new cancer therapeutic with their unique mode of action. Supply chains play a major role in optimising the capacity and boosting the profitability of a company in any industry. Hussain Mooraj and Wayne McDonnell from AMR Research take the concept forward by discussing how supply chains that are designed with outside-in perspective help companies meet demand from the customers efficiently.

If there was a time for a change, it is now. And the change is evident in small measures across the world. The future is bright for those willing to embrace change and place their bets intelligently.

Aala Santhosh Reddy Editor

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Contents Research & Development 24 When medical need is not matched by market opportunity Adam R Renslo, University of California

27 Oral Inhalation Technology Impact of nanotechnology Ola Nerbrink, NovoNordisk A/S

32 New Drugs in Japan Conditional authorisation Osamu Doi and Shigeki Tsuda, Society of Japanese Pharmacopoeia

36 Changing Face of GPCR Drug Discovery Opportunistic future Anindya Bhattacharya, Johnson and Johnson Pharmaceutical Research and Development

CaseStudy

39 Transforming Drug Development A fully outsourced model Neil V Smith and Terri A Roberson, Chorus, Lilly Research Laboratories

Clinical Trials CoverStory

42 Asian Clinical Trials Managing patient reported outcomes Gergana Zlateva and Alesia Sadosky, Pfizer Inc

14 2012 and beyond What lies ahead?

47 Paediatric Drug Development Taking a practical approach

Frank A Jaeger, Solvay Pharmaceuticals, Inc.

Laurence Flint, Schering-Plough Research Institute

18 Anticipating the Future Biorepositories hold the key

50 Optimising Development Costs

Patrice M Milos, Helicos BioSciences Corporation

Christopher R Albani and Yorozu Tabata, PRTM Management Consultants

51 Trifunctional Antibody Format Concept and first drug candidate Horst Lindhofer, TRION Pharma GmbH

55 Offshoring Cost-effective clinical research

Strategy 04 Personalised Medicine End of the blockbuster?

Michael N Liebman, Strategic Medicine

09 Drug Discovery and India A force to reckon with JB Gupta, GVK Biosciences Pvt. Ltd.

CaseStudy

21 Asia’s Antibody Market Realising the potential through strategic alliances Frank Grams and Anton Haselbeck, Roche

Kenneth I Kaitin, Tufts University

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Senior Product Manager and Editor Aala Santhosh Reddy Assistant Product Manager Bhamoti Basu

58 The Biomarkers Consortium Advancing Biomarkers Research

Editorial Associate and Copy editor Prity Jaiswal

Shawnmarie Mayrand-Chung, National Institutes of Health

Manufacturing

Editorial Advisor Sasikant Misra

63 Demand-driven Manufacturing Designing profitable supply chain

Deputy Director, Confederation of Indian Industry

Art Director M A Hannan

Hussain Mooraj and Wayne McDonnell, AMR Research

Visualiser Sk Mastan Sharief

66 Biopharmaceutical Operations Developing the Science Rick Johnston and Phil Kaminsky, University of California

Graphic Designer Ayodhya Pendem

68 Buying into Lean Pharma

Sales Manager Rajkiran Boda

William Botha, Baxter Healthcare

Sales Associates Kunal Ahuja Murali Manohar John Milton

Information Technology CaseStudy

Assistant Manager – Compliance P Bhavani Prasad

72 Data Mining in Clinical IT A real life industrialised model

CRM Yahiya Sultan Vijay Gaddam

Michele Pontinen, Capgemini

76 A Compliant IT Environment with IT Service Management Software

Subscriptions Head Sasidhar Kasina

David A Medina, Hewlett-Packard

IT Team Ifthakhar Mohammed Azeemuddin Mohammed Sankar Kodali Thirupathi Botla N Saritha

79 Innovative IT Enabling pharmaceutical R&D

features

Sanjoy Ray, Merck Research Laboratories

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TechnoTrends 2009 Events Our Authors Looking Back Verbatim Flashback

Chief Executive Officer Vijay Chintamaneni Managing Director Ashok Nair

Pharma Focus Asia is published by

A member of

Confederation of Indian Industry

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Personalised Medicine

End of the Blockbuster?

There is significant concern that Personalised Medicine will cause the end of the blockbuster era in pharmaceuticals. The reality is that what must evolve is the model for financial return, application of stratification in medicine and focussed research on drug safety.

Michael N Liebman, Managing Director, Strategic Medicine, Inc., USA

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he pharmaceutical industry appears to be at a nexus of its evolution. It has been observed that new drug pipelines are less than adequate to continue its recent rate of growth and off-target safety issues are causing critical post-marketing failures.

Added to this global economic pressures may impose greater constraints on drug pricing and the introduction of personalised medicine suggest a reduction in the marketing opportunity for new drugs based on genetic make-up of the patient. Collectively, these issues indicate that the concept of the blockbuster drug needs to evolve to address these challenges.

Redefining “Blockbuster”

A “blockbuster drug” is conventionally defined as one that produces sales revenue in excess of US$ 1

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billion per year, with “super-blockbusters” reaching US$ 2 billion per year.

This barrier contrasts with the current cost-estimate for new drug development reaching US$ 1.7 billion. Currently there are approximately 100 drugs that meet the blockbuster definition with only five attaining super-blockbuster status (Lipitor, Plavix, Celebrex, Prilosec and Nexium). Figure 1 contrasts the existing blockbuster model (Figure 1a) with the challenges to that model that are noted above (Figure 1b). A significant opportunity exists to overcome these challenges by redefining “blockbuster” from annual revenue levels to the total revenue produced for the company while under patent protection (i.e. the integral, not the peak in Figure 2). Several changes in the drug development process would facilitate a transition to this new model, and personalised medicine, which is currently viewed as a threat to the existing markets, can provide a positive impact if implemented in a strategic manner.

Stratified medicine or personalised medicine

For some time, the spectre of personalised

Strategy

medicine (or pharmacogenomics as it frequently called) has met with concern in the pharmaceutical industry because of the impression that it would reduce the market potential for new drugs. This centres on the application of genomic screening of individuals to determine their potential response to a specific drug, e.g. presence of SNPs in a population or individual, and the potential impact on labelling a drug to address a significantly reduced population. As the technology continues to become more cost-effective, the collection of detailed polymorphisms in the population increases and the appropriate integration of the data into knowledge bases proceeds, regulatory agencies, e.g. FDA, EMEA, will further require such testing and incorporation into labelling guidelines for new drugs.

The key question to address is: to what granularity can personalised medicine be pushed and still remain economically feasible for both drug development and the provision of healthcare while delivering the best quality of life for the patient? Most physicians would already contend that medicine is practiced in a “personalised manner” although pressures from reimbursement for services impacts this significantly.

At least two confounders merit consideration in this view of personalised medicine: 1) While it is clear that the identification of a genetic mutation in a given enzyme may significantly impact a patient’s response to a specific drug, the

ability to quantify this may be clouded by the biological reality that every enzyme is part of a complex pathway involving multiple enzymes and mutations in these pathway-related enzymes. This may more than compensate for the activity lost (or gained) in enzyme under study; 2) Disease is a process, not a state, meaning that it evolves over time under the influence of environment and lifestyle and patient reaction (interaction) with the disease, itself. Thus, clinical and molecular observations on a patient need to be measured over time, to create a temporal picture of the patient and the disease process. A patient can be represented as a vector, moving through time in a high-dimensional space that is determined by the number of parameters, clinical and molecular, that are being sampled.

In this respect, every patient will be extremely unique and conventional analysis by statistical methods will always be limited in its ability to evaluate and define a “disease” rather than a patient, where n=1. Neither the healthcare system nor the drug development industry are equipped to succeed in a situation where n=1, but an option that provides benefit to both systems and to the patient is one that embraces stratified medicine rather than personalised medicine. In stratified medicine we are looking at how subgroups of patients may present disease or respond to treatment in a similar manner, within the group, but differing significantly from those in other groups. The

basis for this stratification may be of genomic origin but also may reflect true differences in the disease presentation, itself, which have not been adequately identified, evaluated and addressed in clinical practice or in drug research.

Both of these confounders can play a significant role in impacting the potential for “blockbuster drug” development, but reflect the true complexity of the biology that must be addressed, and in manners that reach beyond current systems biology approaches.

Personalised medicine Is it more than just genomics?

As noted above, much of personalised medicine has focussed on differences in genetic make-up amongst individuals, as measured by either micro-array technologies, e.g. gene expression, SNPs etc. or most recently, full genome sequencing (e.g. 23andMe, Navigenics, KNOME).

While these approaches have provided additional observations on the source of differences amongst individuals, the views that they provide may be too limited, because they are based on application of available, high-throughput technology rather than addressing the true biological complexity that exists. Much of systems biology has evolved from the application of high throughput technologies to provide a more robust “picture” of the patient and of the disease, but while the goal is correct, the approach may be limited to the “looking for keys under the lamp post” syndrome.

Defining a “Blockbuster”

Challenges

Cost of drug development US$ 1.7bn

US$

Cost of drug development US$ 1.7bn

“Blockbuster” (US$ 1bn threshold) (“Super” US$ 2bn/year “Mega” US$ 10bn/year)

Patent protection

US$

Market segmentation (“Personalised Medicine”) 0

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Increased R&D costs Figure 1a

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Post-Launch failure (Safety / Efficacy) Figure 1b

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Strategy

The biology of the human system operates in a multi-dimensional, multi-scalar manner ranging from proteins to metabolites, to genes and gene regulation, to differences in time-scales and conditions across multiple tissue types and both macro and microenvironmental differences. While correlations with biological observations may be readily derived with the application of high-throughput technology, a distinct limitation exists in these correlations addressing the mechanistic or causal basis.

Current observations suggest limitations even in the use of Genome Wide Association Studies (GWAS) to yield biomarkers / diagnostics / therapeutic targets specific to a disease and not confounded by the multitude of ancillary differences between individual’s genomes that give rise to the degree of variation exhibited in the human population. In addition, studies also have shown that copy number variation in the genome can not only produce significant associations with disease presentation but also reverse the potential impact of mutations within a single copy of a gene, as evidenced in Craig Venter’s genome.

A more correct representation of biology involves the identification of all its components and the ability to apply the chemical and biological processes as operators on these entities, all integrated to represent the underlying complexity. We are a long way from building an accurate representation of the dynamics of these systems, based on the series of differential equations that can describe the behaviour of each component, but the methodologies exist to enable representation and qualitative reasoning about the systems.

This type of modelling, using modelling approaches that have been established in engineering disciplines (e.g. stochastic activity networks, hybrid Petri networks), has the potential to support reasoning with limited data and generate hypotheses leading to rational experimental design and a paradigm that integrates experimental results into the refinement of the models.

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Personalised medicine and animal models

As noted above, the limitations in implementing personalised or even stratified medicine into drug development are significant both because of the degree of genomics variation already observed between individuals and the fact that functional biologic variability extends beyond the genome.

This contrasts with the existing variation between species and the dependence on animal models in drug development for toxicity, ADME evaluation and as a model for disease. Significant problems exist in successfully transferring results in animal studies (and even cell lines) to success in humans. Perhaps one of the confounding factors for this problem is the inability to adequately stratify the disease and the patient to enable the effective development of appropriate animal models for the true sub-type of disease or to account for individual variation amongst patients.

Drug safety issues

As noted, a key challenge to the “blockbuster drug” is the impact of drug safety failures. This can be observed in Vioxx, which was a US$ 2.5 billion per year franchise at the time it was pulled from the market and subsequently has led to a US$ 5 billion settlement of legal proceedings from affected patients. An additional impact of the Vioxx situation was Merck’s loss of approximately onethird of its stock value at the time Vioxx was withdrawn (e.g. US$ 44 per share, ~2,100 million shares pre-Vioxx withdrawal, US$ 28 per share, immediately post-withdrawal). The Vioxx lawsuits, numbering 23,800, represented 41,750 plaintiffs, which is likely to be far more than the actual affected population, particularly since the side-effect was only observed in patients on chronic treatment for over 18 months.

Attempts to mitigate drug safety issues have focussed on an ADME / Toxbased perspective, attempting to predict, for a given therapeutic, what the risks are

due to its potential for off-target effects.

This has emphasised the observation that specificity towards a selected target is difficult to achieve outside of the laboratory because of biological processing, transport, compartmentalisation etc. that comprises the actual physiology in the patient. Obviously differences between individuals at the genomic / proteomic and functional levels (e.g. pathways, networks and processes) all contribute to these problems. A significant opportunity exists that may complete this approach and support identification of potential off-target effects prior to clinical trials.

In a collaborative programme with BIOBASE, Strategic Medicine, Inc. has begun the development and analysis of the complex biological networks occurring at the protein, gene and gene regulation and metabolomics levels, and is building representations of the internetwork connectivity. Using network modelling approaches to support qualitative reasoning about the relative “strengths” of these connections, linkages within the network are evaluated to determine their relative strength, i.e. sensitivity and specificity within the network for producing perturbations to its overall function. The nodes connecting these linkages, which are proteins / enzymes / genes etc. are analysed to

Modelling Biological Complexity

Gene Regulation Layer

Expanded Protein Network Layer

Metabolite Layer Figure 2

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Strategy

Personalised medicine is about biological complexity

This article is intended to present a perspective on whether personalised

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medicine will drive the end of the blockbuster era for drug development.

I have attempted to provide some insights into the current definition of “blockbuster drugs” and how changes to the current model may be achieved in a manner that has both a positive impact on the patient as well as on the economic opportunities for pharmaceutical and biotech development. The key perspective is to recognise both the challenges and the opportunities that the needed changes present to the

Author

identify populations that may be at risk due to polymorphisms or mutations that are prevalent, and then enhanced clinical trial design can proceed to include or exclude such groups from consideration and / or potential labelling of the drug when it proceeds to market, all to lower the overall risk of post-market drug failure.

The goal of this approach is to reduce the failure rate of drugs through the early identification of target-based risk populations and thus enhance their probability for success. This is intended to address some of the current failures presenting in the “blockbuster” model as noted in the earlier part of this article.

industry. It may be time to focus on developing a “win-win” strategy that is keen to understand the human physiology and systems thoroughly and thereby enable the successful evolution of “blockbuster drugs” that have long-term, sustainable growth. This can establish the application of personalised medicine for both the patient as well as the pharmaceutical industry in a more systemic and long-reaching manner and produce a highly successful and beneficial synergy.

Michael N Liebman, is the Managing Director of Strategic Medicine, Inc, after serving as Executive Director of Windber Research Institute since November, 2003. Previously, he was Director, Computational Biology and Biomedical Informatics at the Abramson Family Cancer Research Institute of the University of Pennsylvania Cancer Center since September, 2000. He served as Global Head of Computational Genomics at Roche Pharmaceuticals and Director, Bioinformatics and Pharmacogenomics at Wyeth Pharmaceuticals.

Strategy

Drug Discovery and India A force to reckon with

The pharmaceutical industry is going through a tough time due to drying R&D pipeline, poor productivity, spiralling cost of research and cash crunch. However, India is emerging as a favourable country for research collaboration to provide solutions through cost competitiveness and innovative drug discovery capabilities.

J B Gupta, Senior Vice President – Collaborative Research, GVK Biosciences Pvt. Ltd., India

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lobal pharmaceutical industry is at the crossroads. On the one side market demand for novel and better medicines is getting redefined and growing due to demographic, economic and epidemiological trends.

But at the same time, pharmaceutical companies are finding it difficult to survive since they are unable to innovate and discover new molecules. The pipeline of the new drug molecules is drying fast due to poor R&D productivity, high failure rate and generic competition.

Traditionally pharmaceutical companies relied on spending big dollars on discovering possible blockbuster molecules for large patient population through internal research. However, new molecule innovation from in-house research is declining and companies are forced to increase their R&D spending as well as to scout in-licensing opportunities for new molecules.

The importance of biotech companies as an alternative source of innovative potential therapies and to fill the void has been widely noted in recent years. According to a survey published in Nature Review / Drug Discovery, based on the new approvals between January 2006 and December 2007, 65 per cent of the US FDA filing was contributed

by biotech industries and mainstream pharma companies were responsible only for 35 per cent of the drugs. However, the disappointing part is that during this period 91 products failed in Phase III and 95 per cent of these failed products originated from biotech companies. Also when it comes to new chemical entity based novel medicines, the mainstream pharma companies were two-fold more successful than biotech companies. High failure rate and less innovative pipeline raise concerns on the robustness of R&D process being followed by biotech industry and is certainly not helping the drug industry to reduce its cost of discovery.

The recent economic crisis has further hit the biotech industry very hard.

Recently Steven Burrill of Burrill & Company observed that most of the biotech companies have limited cash and are pruning down their operation by reducing work forces and eliminating / limiting research and drug development projects in a desperate effort to extend their runway. This will further erode the global pipeline of the innovative products in coming years.

These factors have forced pharmaceutical companies to think out of the box and look eastward for innovative solutions.

Strong CRO base to support R&D

In recent years India and China have established themselves as strong players in outsourcing of research and manufacturing. Today India has the largest number of FDA-approved manufacturing plants outside the United States and is a force to reckon in custom synthesis and contract manufacturing. The CRO activities in discovery and clinical development space are also growing fast. For the last five years or so, several companies like GVK Biosciences, Aurigene, Syngene, Advinus, Jubilant, Suven lifesciences, Sai Lab, Accunova, iGate etc. have come into prominence both for discovery and development. As a result, several landmark deals were signed between Indian CROs and global pharmaceutical giants. In early 2006, Wyeth Pharmaceuticals struck a multi-year outsourcing deal with GVK Biosciences involving 150 chemists working exclusively on Wyeth projects and providing a range of services in synthetic chemistry research. For this purpose, a dedicated research centre equipped with the latest high-end scientific equipment and instrumentation—GVK BIO Wyeth Hyderabad Chemistry Research Center— was built in Hyderabad. Last year on the same line, Bristol-Myers Squibb (BMS) and Syngene announced a

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multi-year collaboration to develop integrated capabilities in India in medicinal chemistry, biology, drug metabolism, and pharmaceutical development. This collaboration is intended to advance the discovery and early development projects of BMS. Syngene is on its way to recruit 400 scientists and building dedicated laboratories for this purpose.

India offers several advantages for clinical research like large patient population not exposed to treatment (treatment naĂŻve population), world class health services along with well trained doctors and has emerged as a strong base for clinical trials. The clinical trials market is expected to grow at a CAGR of nearly 36 per cent till 2011 to register revenues more than US$ 600 million. Today there is hardly any major to mid-size global pharmaceutical company that does not engage itself in R&D activities in India.

Pharmaceutical companies have started relying on Indian CROs for their chemistry, clinical development and manufacturing requirement.

Vast talent pool to support discovery

Research outsourcing is a matter of trust and since this trust has already been built through chemistry and clinical services, CROs in the country are confident that pharmaceutical companies would be willing to outsource more value-added services. As a result, Indian CROs are fast moving up the value chain from order takers to problem solvers and value cocreators. The initial concerns like intellectual properties and regulatory issues are gradually being addressed through reforms in law as well as through sensitivities shown by CROs to address them upfront. Companies are expanding into other disciplines like pharmacology, cell biology and pharmacokinetics. Though India is considered weak in biology research, the country has an impressive number of biological scientists. According to IMA India’s estimations, every year India produces half a million graduates in biological sciences, biotechnology and

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R&D spending vs. FDA approvals, 1996-2006 50

R&D costs continue to soar ...

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60 50 40

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0 96 97 98 99 00 01 02 03 04 05 06 Sources: PhRMA 2007; FDA, 2007

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96 97 98 99 00 01 02 03 04 05 06 Figure 1

bioinformatics and awards more than a quarter million postgraduates and 1,500 PhDs in the biosciences. India has a thriving generic, formulation and bulk drug industry but lagged behind in developing skills to support discoveryoriented innovative research. As a result, the discovery-focussed biology research remained at a nascent stage. However, after upholding the Intellectual properties agreement (TRIPS) and commitment to recognise product patents, for last decade or so Indian companies have invested in innovation-led drug discovery and produced a reasonable talent pool in biological sciences. As the opportunities are increasing, the number of US trained Indian scientists including biologists are returning to India and being recruited

by Indian CROs.

with established pharmaceutical companies for discovering drugs rather than limiting themselves to provide services and are hoping to get a bigger pie in intellectual properties.

The pace at which these discovery collaborations are being established indicate that Western Pharmaceutical Industry is relying more on India for their brain power and source of innovative research rather than for cost cutting measures. Time will tell if Indian CROs and pharmaceutical companies can prove themselves. However, initial milestones awarded to some of these collaborations indicate that Indian scientists have not disappointed their western counterparts.

Initial success story

In order to leverage the opportunities for drug discovery, Indian CROs are facing several challenges as well.

Investors in India have no culture of investing in risky research leading to drug discovery. The first wave of investment in drug discovery came from large Indian pharmaceutical companies like Ranbaxy, Dr. Reddy’s, Nicholas Piramal, Zydus, Wockhardt etc. when they

Based on these strengths India has staked its claim to become a frontrunner in innovation-led collaboration leading to intellectual property generation through discovery research and are ahead of their Chinese counterparts as reported in the recently published report sponsored by Kauffman Foundation. On the ground Indian CROs have closer collaboration

Challenges of innovation based collaboration

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Discovery Research – Recent deal flow with Indian CROs and pharmaceutical companies Discovery CROs • Advinus – Merck, Johnson & Johnson, DNDi, MMV • Aurigene – Novo Nordisk, Rheosciences, Debiopharm, Merck Sereno and Forest Labs • Chembiotek – Forest Labs • GVK Biosciences – Wyeth and one more • Jubilant – Lilly, Forest Labs and Amgen • Suven – Lilly Pharma companies • Ranbaxy – GSK, Merck • Orchid – Merck Preclinical and Development • Ranbaxy – GSK, Medicines for Malaria Venture • Nicholas – Lilly • Dr Reddy's – 7TM • Jubilant & Lilly

programmes. India is strong in informatics and chemistry but still needs personnel in medicinal chemistry, in vitro biology and efficacy related animal models. Traditional education system produces brilliant chemists and biologists but they are not employable for industrial research and there is limited leadership available in these disciplines within industries. More recently industry and government have taken concrete steps to bolster the R&D capabilities.

Industries are providing more on the job training and recruiting aggressively the key personnel from US and Europe to fill the gaps. Due to increased opportunities in India, increasing number of Indian scientists working in American and European pharmaceutical laboratories are attracted to take up a career in India.

In recent years India has strengthened the patent laws which are more in

Author

themselves entered in this arena. The efforts yielded results but limited funding and lack of experience clearly reflected in the outcomes and were short on impacting the global scene. This next wave of focussed efforts to collaborate on drug discovery projects with global pharmaceutical companies has come from CROs having a revenue generating stream through their contract services. Many CROs like GVK Biosciences, Jubilant, Advinus, Aurigene etc. spearhead such efforts. However, these companies have limited financial surplus and hence are restricted in taking risks. An innovative financial model that can attract funding from local and global investors for such activities is yet to emerge.

The Indian Government has initiated several measures to encourage public private partnership or direct investments towards discovery related activities in private sectors. Department of Biotechnology has formulated a comprehensive National Biotech Development Strategy to incentivise public-private partnership, has contributed to the development of regional biotechnology clusters and provided greater financial support to industry-oriented early stage research etc. The Technology Development Board of Department of Science and Technology has invested hundreds of millions of dollars in small molecules, biopharmaceuticals and herbal drug discovery related projects.

New Millennium Indian Technology Leadership Initiative of Council of Scientific and Industrial Research has made significant investment in discovery programmes to bring together industries, national research laboratories and academia. However, the outcome of all these initiatives indicates that these initiatives have not been able to win the confidence of the industries so far and the overall impact and effectiveness of such measures may require close monitoring.

Another major challenge is the trained manpower particularly in the areas critical for the success of discovery

compliance with the global practices. This has changed the IP scenario in favour of innovative research and global companies have slowly started responding positively by outsourcing their IP-sensitive research to India. However, there is a need to build a strong proactive law-enforcing system so that the confidence building and global perception on IP protection are changed favourably to create a positive environment for discovery-based collaboration.

Efficacy and safety of new chemical entities are based on their evaluation in different animal models. Access to the quality animals is central to any drug discovery endeavour. More flexible system has to be put in place to procure small and large animals through quality animal breeders based out of India or abroad through importation with minimal administrative and regulatory hurdles.

J B Gupta is the Senior Vice President – Collaborative Research, in GVK Biosciences, Asia’s leading Contract Research Organisation delivering integrated research services to Pharma, Biotech and Life Sciences companies globally. He has over 15 years of drug discovery experience having worked with Bayer HealthCare, Germany; Bayer Yakuhin, Japan and Ranbaxy, India.

CoverStory

The pharmaceutical industry is facing a tough road ahead in the future market place.

While not entirely doom and gloom, many in the industry are faced with uncertainty on the future of their position in the marketplace and are left wondering what the future holds.

The future business model will utilise differential resourcing as a way to achieve efficiency and leverage technology as a way to improve effectiveness.

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CoverStory

2012

and beyond What lies ahead The pharmaceutical industry is facing a tough road ahead in the future marketplace. Though pharmaceuticals remain the most cost-effective healthcare intervention, they should bring about a significant transformation in their organisations to realise the glorious future.

Frank A Jaeger, Director, New Business Development, Solvay Pharmaceuticals, Inc., USA

O

ne thing is for certain, today’s pharmaceutical marketplace is punctuated by change and uncertainty. The pharmaceutical industry is facing a tough road ahead in the future market place. Major products are facing patent expiry and pipelines are not replacing the ageing products.

Approvals of NMEs continue to decline while development and commercialisation costs continue to skyrocket. While not entirely doom and gloom, many in the industry are faced with uncertainty on the future of their position in the marketplace and are left wondering what the future holds.

It is clear that there is increasing competitive pressure in the pharma

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industry and the breakneck rate of spending cannot continue ad infinitum.

Pharmaceuticals remain the most costeffective healthcare intervention and there will always be a market for good medicines. Many trends are currently adaptive and will continue, while others will need to be transformed. This transformation will require significant changes throughout pharmaceutical organisations.

The changing landscape of the pharmaceutical industry

The current state of the pharmaceutical industry is not good. IMS says that the US prescription drug sales growth is just 4 per cent. Wholesale prices

grew by just 3.8 per cent which is the lowest increase since 1961. Just open up any recent news story and one will see companies making changes in response to the unfolding pressures in the industry. GlaxoSmithKline is set to cut down 12 per cent of its US sales force in a move to re-focus on therapeutic areas and respond to changing customer demands. Other companies like UCB, Pfizer, BMS etc. have also responded to the changes with layoffs.

Several key challenges are currently facing the industry: Increasing public pressure

With an abundance of information, the health awareness among consumers is increasing at an exponential rate.

They are demanding fair value and are constantly looking for greater value for the money they spend on medicine. For example, seniors under the US Government’s Medicare programme consistently prefer generic alternatives to branded drugs. They are astute shoppers who look for innovation. They expect pharma to tackle the tough diseases like diabetes, obesity, and cancers to name a few. They are growing increasingly impatient with incrementalism.

Increasing payer pressure

Similar to the society as a whole, payers are pushing for more innovation as they manage ever tightening budgets looking for increased health outcomes. The tougher cost-containment practices by payers are forcing pharma companies to bring forth innovation while at the same time providing disincentives for products with marginal benefits. It will be harder for me-too or me-better medicines to be successful. In most countries, payers are becoming even more active in determining which treatments are appropriate.

For example, the National Institute for Health and Clinical Excellence (NICE) can prevent a product from being used in the UK. Currently, even the Institute for Quality and Efficiency in Healthcare (IQWiG) and the Academy of Managed Care Pharmacy (AMCP) do not have that authority. Pricing transparency is

increasing as well (formerly confidential contracting information is now becoming public).

Increasing patent expirations

It is forecasted that US$ 115 billion worth of branded drugs will become generic during the period 2007 through 2012. Numerous large blockbusters that are the backbone of the organisation’s top-line and more importantly profit are expected to be eroded by 2012 (e.g.

Prevacid, Flomax, Lipitor, Crestor, Seroquel). To illustrate, Merck & Co. is expected to face generic competition from three of its top selling products (Fosamax, Singulair, and Cozaar)—which represent 44 per cent of the company’s revenues. This problem has only been exacerbated by the slowing degree of FDA approvals. In 2007, the FDA only approved 19 new products and is on track to have another record year of low approvals.

Decreased R&D output

The average cost to develop innovative therapies is skyrocketing. The average price of bringing a drug to market is now

US$ 800 million. Due to the increasing costs, large pharma is increasingly turning to in-licensing to compensate for decreases in R&D production. Since 2002, in-licensing will increase from 17.5 to 34.4 per cent by 2012. If a company seeks to in-license later stage at the last minute (and hence reduce the risk), the law of supply and demand would govern and escalate the price level to a new height. When seeking to acquire new assets, it is also clear that the small molecules continue to be the target of choice (MAbs and therapeutic proteins being the preferred ones).

Increased focus by regulators on safety

While drug re-importation continues to be on the radar screen for many (including FDA), regulators continue to impress the need for safety in the development process. FDA mandates even greater number of patients to be used for clinical trials. Relatedly, they are looking for comparative safety of the New Chemical Entities (NCEs) to already marketed products. This has been even more manifest by the recent imple-

mentation by the FDA Amendments Act and the “Safety First” initiative.

Outsourcing

Clinical studies have long been outsourced as a more efficient way to get drugs to market. Contract manufacturing has also been around as a viable source (dating back into the early 1980s). In the 1990s, the outsourcing of the sales force became a popular decision in order to avoid the initial capital outlays and to have a more scalable solution. This is an ever growing popular trend as of late, and will no doubt expand into other commercial areas. Even more interesting are decisions to decouple once traditional mainstays of the organisation like HR, finance, and accounting. However, organisations haven’t stopped there as they are still pushing the envelope to extract value in innovative ways as evidenced by the Lilly/Chorus relationship. In essence, Lilly licenses the drug to Chorus and has the option to buy back after Phase II. This not only reduces the infrastructural needs of Lilly but also increases its productivity and

Key elements of competitive dynamics

1 Research

Innovative & Focussed

Example: Strategic Business Model

2 Clinical Development

Effective

Product Leadership

3 Commercial

Customer Intimacy

Medium Pharma Company

4 Manufacturing

Lean / Expertise

5 Capital

Strength / Leverage

6 Lifecycle Management

Value Add

7 Intellectual Property

Strategic

8 Distribution

Optimised

9 Support Systems

Customer centric

• Focus on research • Invest in innovative biologics • Outsource clinical development • Strategic partnerships • Strong IP positions • In-licensing as growth driver • Non value-add levers unadjusted

10 Regulatory

Adaptable

Geographical Presence

Low / No Legend -

Big Pharma

Mid Pharma

High Biotech

Example new model

Product Offering • Specialty drugs • Oncology, Cardiovascular, Neuroscience Strategic Choices

• Transnational organisation • Focus on emerging markets Figure 1

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CoverStory

Heterogeneous or Homogenous?

The rationalisation of the business model

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hese trends as mentioned previously are being manifest in the marketplace today as is evidenced by the current events seen in the industry as well as discussed in the recent press. Diversification companies like Abbott, Solvay, and Bayer are conglomerates that have sought to balance the higher risk of pharmaceuticals with the lower risk of other businesses like agriculture, consumer, and chemicals. These types of companies currently have higher PE ratios. Investors have largely been unimpressed though.

Instead of selecting a single company for their portfolios, the investors more often look to balance portfolio risk on their own with both high risk and low risk companies.

Focussed companies, on the other hand, are choosing to slough off many of their traditional core businesses in favour of reinvesting cash back into R&D to fund innovation. The rationale is that they can reap benefits through the development cycle with higher sales, earnings and ultimately

capital efficiency. This will also have an impact on the time-to-market of their new products.

Successful transformation will require a cohesive strategy

Traditionally, working capital has not been a management issue for Big Pharma.

However moving forward, there will be a need to be more diligent in creating lean organisations. Successful transformation will require changes throughout the entire organisation. The future business model will utilise differential resourcing as a way to achieve efficiency and leverage technology as a way to improve effectiveness.

Blockbuster drugs, large general market sales forces, specialised tactical groups, competitive benchmarking all seek to disentangle a company from its strategic focus and direction.

“Hey, we’ve been successful and it’s been working… If it aint broke, don’t fix it.”

The challenge is that in a hypercompetitive marketplace, a company must continually seek to reinvent itself while

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valuations. The reality is that very rarely will the choice be so dichotomous, the rationalisation will lead to hybrid organisations that will reflect additional clarity within pharma with other related businesses (e.g. diagnostics, chemicals). This approach allows the most flexibility for existing diversified companies to innovate, yet keep to their strategy and culture. Although flexible, the hybrid approach may not be as competitive and fit for the market.

Because of the pressures, companies are wrestling with various means to enhance individual product lifecycle management, profitability and the health of the company. As a consequence, companies are being forced to rationalise their business model. It is clear that the questions like the following are being carefully considered:

Should the company specialise?

BMS, Pfizer, and Wyeth have been recent examples of pharma giants that have announced that they will be exiting traditional therapeutic areas (e.g., Women’s Health, Cardiovascular). Pfizer most recently announced that they will be segmenting and reorganising into three business units (primary care, speciality and emerging markets).

Maybe biologics are the answer?

The traditional pharma business model has come under fire and is being redefined as evidenced by pharma trying to buy up smaller biotech companies as they look to large molecules for innovation. Recent examples include BMS / ImClone, Roche / Genentech, and speculation that

ensuring that they are committed to the strategic intent.

Companies should be reminded that the fundamentals of competitive advantage rest on the ability to construct a meaningful and defendable competitive position. Assuming that a well-articulated vision has been communicated from the top-down, the only way to get to this position is through a strong and unrelenting strategy.

Treacy and Wiersema in their seminal work state that a company must be disciplined in their strategic choice to focus on operational excellence (e.g. WalMart), product leadership (e.g. Sony), or customer intimacy (e.g. Ritz-Carlton Hotels). Their fundamental posit rests on the fact that an organisation must meet the industry standards on two of the three distinct dimensions and differentiate on the third. Wal-Mart whose slogan is “Always Low Prices” can’t support the same structure that also brings overwhelming customer service like the Ritz-Carlton. These are two separate organisational structures that have

been established to meet very different needs of the customers.

Think of it in a more relevant way to this discussion, operational efficiency is the cheapest player in town (e.g. generics), product leadership is synonymous with innovation (e.g. biotech) and customer intimacy is having the products and services that customers are looking for (e.g. Big Pharma). Daichii-Sankyo’s acquisition of Ranbaxy is doomed to fail and is already coming under pressure by the market as individuals ponder how the creation of distinct strategies will create value. Each company must identify where their strategic focus will lie. Failure to do so will result in mixed messages and decreased company valuation.

Some of the first strategic choices that must be decided are actually more formed by the guiding vision of the organisation. These choices such as therapeutic areas (set by the company’s vision), geographic presence (e.g. emerging markets), and degree of management control (e.g. globalised, hybrid transna-

GSK will acquire Genmab. Biologics are expected to be responsible for driving growth through 2012.

the acquisition of Innogenetics comes more into strategic focus as biomarkers are expected to play a greater role in personalised medicine.

Should areas be de-prioritised?

Is therapeutic segmentation the solution?

Bristol-Myers Squibb has also announced a restructuring plan to cut its workforce by 10 per cent, close half of its manufacturing plants and move production to Asia and Latin America. Novartis has been forced to rationalise itself and has restructured in order to reduce the number of management levels, decrease bureaucracy, as well as reexamine the use of external companies to conduct drug testing. They may even close a manufacturing or research site.

What about shifting resources to focus on different parts of the value chain?

On the research and development side, companies are now looking at more effective strategies. Eli Lilly recently sold its early stage discovery and development. They have embraced the outsourcing model—40 per cent of information technology, 20 per cent of manufacturing, and 20 per cent of sales force.

Can personalised medicine be the answer?

Solvay Pharmaceuticals is also reacting to the changing marketplace. With the sustained commitment to “Inspire 2010” to focus on profitable growth, portfolio focus, and efficiency improvements, Solvay has decreased its commercial footprint, divested non-strategic assets, increased outsourcing, and divested manufacturing sites. Moreover, in the “Transformation 2015” plan,

Adopting a strategic business model

When deciding to change the strategic business model, companies must consider the pre-existing culture, infrastructure, controls, communication, and leadership as the prerequisites that will allow

Should therapeutics and diagnostics be combined?

Although the idea of this combination has been around for some time with companies like Roche, the application is really in its infancy. Vanda Pharmaceuticals is a recent example of a company trying to combine their antipsychotic and a commercially available test to detect relevant efficacy biomarkers. Although the FDA rejected Vanda’s bid for approval for Iloperidone, the need for biomarkers and a commercially available test to predict response is clear. The question is: Are the two intertwined? Will diagnostics be adopted by healthcare providers? Will the bundling of the diagnostic to the therapeutic be adopted by healthcare providers?

for a clear and focussed strategy that is implementable. An overarching principle needs to be stuck to in order to create uncontested space where competitors are not able to easily reproduce these results.

As can be shown from the fictitious example, one can graph the traditional levers of the value chain and determine the levers that the organisation chooses to place more or less emphasis on in relation to the other competitors (i.e. types or nearest companies). Careful consideration must be given to the interdependencies that exist between levers. In this illustrative example, a decision has been made to invest at the levels in research like a biotech does while outsourcing the clinical development and manufacturing. This frees up capital to allow the Author

tional) are key pre-requisites that need to be decided before even discussing the strategy of the organisation.

Firms need to understand where they intend to compete on the value chain from development through to commercialisation, and pull those respective competitive levers (See Figure 1).

There is no magic bullet when it comes to picking which distinct strategic approach is correct. The point is a unified and fundamental decision needs to be taken —one that is differentiated from the competitive set and then very diligently followed. It takes discipline and courage especially when the market criticises and focusses on rewarding short-sighted quarterly share growth versus long-term value creation.

Recent companies like Pfizer and Wyeth (among numerous others) have announced that they will trim down their focus. In light of future patent expirations, the expectation is that the organisation can’t support as many therapeutic areas and programmes due to projected decreased ability to fund R&D. Moreover, focussing on delivering innovative and differentiated products tailored to speciality physicians should result in higher profits for the companies. Traditionally, drugs that are tailored to the larger primary care prescriber tended to be the blockbusters; generally, promotionally-intensive types have become genericised and tougher for reimbursement.

organisation to be more like Big Pharma and focus its resources on in-licensing new compounds and providing additional resources to drive closer customer connections in speciality. Notice though on the levers that are not manipulated the new model that the medium pharma company embraces remain fairly similar. The sound is not optimised by an equaliser when all levers are up or down, it is the mix of the levers as it relates to the signal (i.e. market) that makes the output synchronised. The object of the game is to not have all the curves look alike—a vision of where the company wants to be and needs to be in place so that a strategy map can be created.

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

Frank Jaeger is currently Director of New Business Development in the NeuroScience division at Solvay Pharmaceuticals. Frank has held cross-disciplinary positions previously in Clinical Research, Medical Services, and Marketing.

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CoverStory

Anticipating the Future Biorepositories hold the key

To fully realise the potential gains of human genome diversity and its relationship to human disease, biorepositories must play an integral role. Through optimal utilisation of such repositories, comprehensive human phenotype data can be united with corresponding genomic and proteomic samples to shed new light on the underlying basis of human disease and offer new hope for a better understanding of how to diagnose and treat patients.

Patrice M Milos, Vice President and Chief Scientific Officer, Helicos BioSciences Corporation, USA

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he first complete human genome sequence was published in 2003 and laid the foundation for a more comprehensive understanding of human disease. When this sequence was published, many felt as though the era of personalised medicine was around the corner and that pharmaceutical companies should embrace this new knowledge to better design personalised therapies which could treat and potentially even prevent human disease. Yet those closest to the Human Genome Project recognised that this initial landmark was simply the beginning of years of science and innovation required to fully unlock the secrets of the genome.

Unlocking the secrets of genome

Today, we have learned much from this

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one human genome sequence, but we have also seen, with the subsequent completion of two additional genomes namely by Dr James Watson and Dr Craig Venter, that our genomes are incredibly diverse and contain significantly more variation, both at the single nucleotide level as well as structural diversity. More recently, new knowledge has been gained by publication of the first complete tumour genome sequence from an acute myeloid leukaemia patient. Our challenge today is to uncover the full diversity of the human genome and utilise this comprehensive knowledge to better diagnose, treat and perhaps even prevent disease. Key to gaining this knowledge is fully realising the potential of clinical trials and biological and genomic samples collected during these trials.

• Will pharmaceutical companies be poised to achieve these goals?

• What does your company’s biorepository hold today?

• Will you be positioned for the innovative technologies and emerging scientific discoveries occurring at lightning speed across the globe?

My hope is to provide you with additional impetus to ensure the ethical collection of genomic samples as well as the safe, secure storage of samples to allow the full investigation of genomic diversity and to gain the knowledge that may finally herald in the new era of individualised therapies.

As a founding member of the pharmacogenomics group at Pfizer Global Research and Development in 1996, our group recognised the increasing

knowledge of genome diversity which was emerging from the Human Genome Project. Yet at that time, studies investigating the diversity of the genome and the relation of this diversity to disease and drug response involved limited sets of genetic markers in candidate genes.

These studies were quite limited in two ways—limited knowledge of common genetic differences and the technology to allow the analysis of these common differences, referred to as Single Nucleotide Polymorphisms (SNPs), across hundreds of thousands of patients. Genotyping technologies involved standard PCR reactions followed by restriction fragment length polymorphism detection.

In concert with the Human Genome Project, genotyping technologies were rapidly emerging to drive scale up and cost down. Innovative technologies emerged and quickly outpaced our imagination. We realised that the fundamental enabler in genotype / phenotype studies was the availability of large numbers of well-phenotyped patient samples to provide a whole new opportunity for merging human genomics and drug discovery and development.

Establishment of biorepository

To fully leverage the new science and technology, a key strategic imperative of the group was the establishment of a biorepository to serve as the underlying foundation for pharmacogenomic investigations. Key in this development was ensuring the appropriate standard operating procedures for the collection of clinical samples including informed consent documentation, educational materials for institutional review boards, effective integration of sample collection (predominantly whole blood for DNA isolation) into clinical trial protocols, training for colleagues and physicians involved in clinical trials and effective laboratory mechanisms for storage and processing of these large numbers of samples. A considerable amount was invested with clarity of vision for the future knowledge to be gained as tech-

nologies emerged. Looking back on these early days, it was these visionary leaders who could look into the future and imagine the potential unlocked by a biorepository containing hundreds of thousands of biological specimens.

To further demonstrate the commitment to a central biorepository was the correct one, an early study provided the necessary demonstration of the importance of stored clinical samples. Prior to fully implementing the biorepository, we performed a retrospective collection of samples from patients enrolled in clinical trials in which an adverse event was seen in a small fraction of patients. The challenge to reconnect with study sites several years after the clinical trials were completed, obtain appropriate informed consent from affected patients and control patients proved quite more complex and expensive than imagined. We wound up with only a subset of the affected patients and a reasonable number of controls but again, lost precious time during the cumbersome process. In the end, the limited data set proved interesting but far from conclusive. This study was a powerful memory when Pfizer officially opened the doors of the world’s first -80°C automated biorepository on a hot summer day in 2006.

As we were building the infrastructure, the pace of technology development quickly outpaced our imagination—in fact, when one considers a scientific need or challenge, the scientific community quickly delivers often exceeding the expected timeline for technology delivery.

When one looks back over the last ten years, and views the success of global initiatives such as the pharmaceutical companies combined efforts in the The SNP Consortium (TSC), Phases I, II and now III of the public HapMap initiative and the recent Genetic Association Information Network (GAIN), the pace of genome knowledge has been remarkable. But yet this is simply the foundation required to fully understand the intimate relationship of an individual’s genome, the diversity contained within,

the consequences of this diversity, the interaction with the individual’s environment and finally the successful integration of this knowledge to better diagnose and treat disease. With each step we get a bit closer to the knowledge of genomic factors which contribute to disease, but we still have much to learn.

Again, possessing the genomic samples which will allow this knowledge to be fully investigated is critical.

Other efforts

The Cancer Genome Atlas (TGCA) provides an excellent demonstration of the importance of appropriately collected and stored human biospecimens. Launched in later 2005, the TCGA seeks to investigate the genetic differences seen in tumours obtained from three distinct cancers—brain, lung and ovarian. Stored biological samples from patients were intended for the pilot study in which a full genomic characterisation of the tumours was planned including both extensive sequencing of candidate genes to catalogue the somatic changes present in tumour patients as well as comprehensive gene expression profiling to provide further insight into genes which may be altered in regulation. The initial publication emerging from the pilot study describes the investigation of gene sequence information in 206 glioblastoma patients and revealed new insight into genes and gene pathways involved in this devastating disease.

Much learning has emerged from these initial pilot studies including the need for biological specimens which have been collected appropriately to ensure that the genomic material present in the samples is preserved effectively. Many samples collected for the purpose of genomic studies proved to contain genomic material of insufficient quality for sequencing or expression analyses. The pilot project provided much key learning and has led to a very extensive review of the process for sample collection and curation to maintain the high quality of specimens required for such analyses. The National

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CoverStory

Emerging technologies

Finally, we have seen a whole new invigoration of the DNA sequencing field with the launch of the next-generation sequencing technologies as well as the newest addition to this innovative field— that of direct single molecule sequencing such as that of Helicos BioSciences, my newest venture into the pursuit of individualised approaches to healthcare.

With a remarkable trajectory with the throughput and scale by which we can measure the true biology of the genome,

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the pace of technology innovative will continue in earnest. It is my belief that in the next two to three years, the genomic samples contained within your growing biorepositories will hold a wealth of new knowledge directly interrogating genome sequence, the expressed genome and the translated genome to allow a full and complete picture of the biology of health and disease. You might imagine that once again, as we did in our initial search for a comprehensive map of common variation, we will arrive at a time where complete genome sequencing becomes cost-effective and the statistical Author

Cancer Institute officially created the Office of Biorepositories and Biospecimen Research at the same time the TCGA was launched to “guide, coordinate, and develop the Institute’s biospecimen resources and capabilities” and has developed comprehensive resources for physicians and researchers to facilitate their efforts in such collections.

methods will allow the complex analyses required to build relationships between rare and common SNPs as well as structural variation to build a comprehensive view of the personal genome and its intimate relationship with environment and resulting phenotypes. I look forward to participating in the science and innovation required to fully unlocking the secrets of the genome and to the opportunity this knowledge heralds for patients across the globe.

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

Patrice M Milos joined Helicos in June 2007 to advance the company’s efforts to develop innovative and breakthrough technology. Dr Milos serves on the National Advisory Council for Human Genome Research and was pivotal in the establishment and oversight of key Pfizer strategic investments in the genomics area, most notably, the Genetic Association Information Network.

CaseStudy

Asia’s Antibody Market

Realising the potential through strategic alliances The antibody market is a key growth area for biologics, re-energising pharma R&D and delivering next-generation medicines.

For Roche, the world’s biggest biologics company, Asia is a key part of the company’s future strategy, thanks to the region’s boom in antibody development, opening the door to new collaborations.

Frank Grams, Business Development Director, Roche Global Pharma Partnering Asia, China Anton Haselbeck, Head of New Technologies, Roche Pharma Research, Roche, Germany

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he R&D sites of most big pharmaceutical companies are undergoing significant change.

Historically, Big Pharma has focussed on the development of small, chemical molecules but in recent times, investment has broadened to include the development of large molecule biologics, such as therapeutic proteins and monoclonal antibodies.

The future is biologics

Roche has approximately sixty per cent of its pipeline invested in biologics and has already seen the benefits of early blockbuster biologics such as Avastin and Herceptin in targeted cancer therapies. According to the industry research analysts BCC Research, other companies are set to follow suit. It predicts that sixty per cent of future growth in pharmaceuticals will come from biologics, with annual sales increasing to up to US$ 30 billion by 2010 compared to a US$ 13 billion increase from small molecules (Figure 1).

The growth in biologics is fuelled primarily by monoclonal antibodies (mAbs). Hailed by many as the medicines of the future, mAbs deliver a targeted

attack on specific disease-causing cells and have proven effective across a broad range of disease areas, including autoimmune, cardiovascular, infectious diseases, cancer and inflammation. Offering potentially Powerful combination of emerging markets and molecules: China The Chinese biopharmaceutical sector continues to grow by 20 per cent each year, according to a study published in August by BioPlan Associates and the Society for industrial Microbiology. The study states that there are more than 500 biopharmaceutical enterprises in China producing about 2,000 Chinese biologic drugs.

The biopharmaceutical sector is predicted to accelerate its growth in the coming years thanks to the Chinese government’s 11th five year plan, which aims to make biopharmaceuticals one of China’s leading industries in 15 years.

Although still a fledgling industry in China accounting for only 8.46 per cent of China’s pharmaceutical revenue, the five-year plan, effective from 2006—2011 gives biotechnology start-ups priority for bank loans grants and research and development tax breaks. With this support it has been speculated that the Chinese biotechnology industry will produce 15 to 20 new products within the next five to 10 years.

higher efficacy than conventional medicines, the mAbs also offer advantages of low or negligible toxicity and are able to inflict a direct attack on their target, as well as acting as a carrier to deliver other drugs to target.

Asia as an emerging economic power

At the same time as mAb growth starts to overtake traditional small molecules, the search for new antibody technologies is spreading beyond the traditional pharmaceutical markets of the US and Europe to emerging markets, such as Asia.

The reasons are clear. As the recent report Pharma 2020 by Pricewaterhouse Cooper predicts, Asia’s market will grow at a rate of 10-22 per cent in the coming years, much faster than the mature markets of United States and Western Europe with growth predicted at just 2-4 per cent a year (Figure 2).

In addition, the Economic Intelligence Unit suggests that by 2017 Asia will host three of the world’s largest economies, with China moving into second place above Japan and India leaping from 12th to 5th position.

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Strategy

Realising the potential through partnerships

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30,000 25,000 US$ Millions

The convergence of a powerful Asian economy coupled with a future focus on biologics has led to new thinking in the corridors of Roche.

While other pharmaceutical companies are using Asia for manufacturing sites or to run clinical trials, Roche sees further potential in realising the innovation in drug discovery and development that is growing in this market. This has been demonstrated through the ongoing partnership presence Roche has in Japan, with employees based in Tokyo dedicated to building alliances and existing partnerships including Japan Tobacco and notably Chugai, who Roche have partnered since 2002. This close partnership has seen a sharing of intellectual and infrastructure resource, whilst the importance of retaining independent integrity is felt to be of high importance.

In addition, the company has recently opened a dedicated partnering office in Shanghai to foster new collaborations in the region, with an emphasis on the North Asian markets of China, South Korea and, Taiwan and Singapore in South East Asia, which is already a leader in pharmaceutical research in the region. For Roche, it’s essential to have people on the ground able to spot opportunities first-hand and to understand local requirements.

It’s difficult to do that from a desk in New York or Basel.

Top of Roche’s wish list are technologies to administer future mAb therapies. Currently, most antibody-based treatments are given intravenously as they are based on large molecules and given at high doses, requiring costly time in hospital and reducing a patient’s quality of life. Subcutaneous drug delivery may be one new option and Roche is actively looking for other ideas.

Roche has a long-standing reputation of tailoring its alliances to meet the needs and growth ambitions of its

The worldwide market for therapeutic and diagnostic antibodies

20,000 15,000 10,000 5,000 0

2002

2003

2004

Therapeutic

2005

2010

Diagnostic imaging

Source: BCC research

Figure 1

Mature and emerging pharmaceutical markets, 2008

Mature markets(G7 countries) Emerging markets(E7 Countries) Other emerging markets Source: Decision Resources Inc.

Based on information from Pharma 2020: The Vision: Which path will you take? by PricewaterhouseCooper, 2007

Figure 2

Roche partnering approach Want Defining our search

Find Identifying partners

Get Personalising deals

Manage Building collaborations

Strategic fit • Alignment with Roche R&D / Opportunistic

Empowered negotiation team • Decision-making authority • Direct access to top management

Scientific value • Will this result in a differentiated medicine providing significant clinical benefit to patients?

One size doesn't fit all • Tailored deals • Creative variations on known themes – License, option, portfolio, acquisition

Business case • Will this bring value to both companies?

Philosophy of partnership • Dedicated alliance management • Long-term view • Seat at the development table

Source: Roche Pharmaceuticals, 2008

Figure 3

Public investment helps

Authors

Without investment from large pharmaceutical companies, the fledgling biotech industry in Asia may have difficulty maturing. However, public support is certainly helping.

CaseStudy

partners when constructing deals and is bringing this collaborative approach to Asian academia and biotechs in the hope that it will result in new and differentiated medicines (Figure 3).

Biologics is an area that Roche knows well. In 1997, it launched Rituxan / MabThera (rituximab), the first monoclonal antibody treatment for non-Hodgkin’s Lymphoma (NHL). This was the result of a partnership between Genentech, Idec (now Biogen Idec) and Roche.

With efficacy which, when added to normal chemotherapy, substantially increases time living without disease progression and can increase overall survival without adding to the burden of toxicity. The drug became established as the gold-standard treatment for NHL and became the first launched mAb product to achieve blockbuster status.

Following on from this success, Roche has continued to launch leading antibody therapies, the most successful in recent years being Avastin, an anti-angiogenic treatment approved for the treatment of colorectal, breast, lung and kidney cancers, and developed in partnership with Genentech.

China has publicly stated its commitment to develop biopharmaceuticals as one of its leading industries of the future and is giving biotechnology start-ups priority for bank loans and R&D tax breaks. In addition, China has streamlined its drugs approval process and issued comprehensive IP protection plans, while reforms to the Shanghai and Shenzen stock exchanges will promote market activity and make it easier to invest. Overseaseducated Chinese talent is also returning home.

Recently such commitment in China saw the foundation of the Shanghai Cell Engineering and Antibody Centre, formed to bring together five academic and private companies with government supported funding. Its focus is to develop effective cancer vaccinations and monoclonal antibody-based immunotherapies.

It is the combination of public and private investment that will create the critical mass that Asia needs to become a truly global player in biotechnology.

With true innovation starting to appear from the laboratories of China and other Asian countries, western pharmaceutical companies are strengthening their relationships beyond the usual collaborations of drug manufacturing and clinical trials.

The time is right for significant partnerships to be developed between pharma and Asian biotechs, which have the potential to exponentially grow the Asian biotech market and turn early companies into global biotech leaders.

Frank Grams was instrumental in setting up the new Shanghai office of Roche Pharma Partnering. He has managed pivotal research alliances such as Chugai, Evotec, SGX, Syrrx and Biotie for Roche.

Anton Haselbeck is currently Head of New Technologies at Roche Pharma Research in Penzberg, Germany, and responsible for external access to technologies in the area of protein therapeutics.

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Research & Development

When medical need is not matched by market opportunity Tropical parasitic diseases are major contributors to mortality and morbidity in the developing world, yet fail to offer a compelling market opportunity for new pharmaceutical development. The industry can and should contribute to such efforts by collaborating with academic and non-profit organisations involved in such endeavours.

Adam R Renslo, Associate Director of Chemistry, Small Molecule Discovery Center, University of California, USA

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here is an urgent need for new drugs to treat tropical parasitic diseases like malaria, leishmaniasis, trypanosomiasis and schistosomiasis. These diseases affect hundreds of millions of people and are major contributors to mortality and morbidity in the developing world.

Malarial disease caused by the parasite Plasmodium falciparum is responsible for more than a million deaths annually.

Once-effective therapies like chloroquine and sulfadoxine-pyrimethamine have become practically useless in recent years due to the emergence of drug resistance. The currently available therapies for trypanosomiasis suffer from significant toxicity and / or limited efficacy.

In Chagas’ disease therapy for example, the use of benznidazole and nifurtimox is associated with undesirable side effects and, more significantly, does not address the chronic form of disease that causes cardiomyopathy. Treatment options for the cerebral form of Sleeping Sickness are similarly poor. The arsenic derivative melarsoprol causes fatal encephalopathy in ~5 per cent of patients while the much

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safer alternative eflornithine is difficult to administer in rural settings and is effective only in disease caused by T. brucei gambiense. A cheap and effective drug is available for schistosomiasis—the re-purposed veterinary drug praziquantel—but with hundreds of millions infected and resistance on the horizon, a back-up drug is needed.

Few pharmaceutical companies are pursuing antiparasitic drug discovery in a serious way, despite clear evidence of medical need. Among those companies that are engaged, Novartis and its Institute for Tropical Diseases in Singapore, and GlaxoSmithKline and its ongoing work with Medicines for Malaria Venture (MMV) bear mention.

From a business perspective, it is unsurprising that parasitic diseases attract little attention from the industry. The market forces that are so effective at driving pharmaceutical development in the industrialised world are largely absent in the regions of the world where parasitic diseases figure prominently. However, it is also clear that the pharmaceutical industry, with its incredible potential to

impact human health for the better, bears a special responsibility to weigh medical need alongside market opportunity in arranging its priorities. This was a less controversial position in past decades than it is perhaps in the post-merger climate of the industry today. Therefore, those companies that are engaged in antiparasitic drug discovery have to be commended and encouraged.

A path forward

With the industry less than fully engaged, the responsibility of discovery and development of new antiparasitics has largely fallen on academic researchers and not-for-profit drug discovery organisations. These efforts have been significantly boosted in the past decade by the munificence of major philanthropic organisations including the Wellcome Trust, the Sandler Foundation and most notably, the Gates Foundation.

This much needed funding has been directed mostly to University-based drug discovery consortia and not-for-profit drug development organisations like MMV and Drugs for Neglected Diseases

Research & Development

initiative (DNDi). These groups have in turn recruited scientists with drug discovery and development experience out of the pharmaceutical industry.

What has emerged in the past decade then is a navigable pathway for drug discovery for tropical parasitic diseases.

The efforts of parasite biologists in academia reveal a variety of new drug targets that are validated by traditional genetic and / or newer RNA-silencing techniques. High-throughput assays are then developed at University-based drug discovery centres, thereby allowing the screening of large small-molecule libraries. Chemical optimisation of leads is then carried out in those same centres, or elsewhere with funding and oversight from organisations like MMV or DNDi. The latter organisations have the resources and development expertise to bring preclinical candidates though INDenabling studies and into human clinical trials. While this drug discovery paradigm appears to circumvent the pharmaceutical industry, industry partnerships can and do play important roles at various stages in the discovery and development process. Examples of such collaborations are provided in the following section,

with an emphasis on some of the recent success stories.

A role for the industry

Current drug discovery efforts for parasitic disease are focussed either on improving existing agents or on exploiting new drug targets in parasite biology to identify first-in-class agents. Presented below are some recent examples from various stages of the discovery process (Table 1).

One of the more interesting findings of the past decade is that fully synthetic molecules bearing a peroxide function can exhibit antimalarial properties quite comparable to artemisinin—the current gold standard in antimalarial therapy.

The advent of the synthetic peroxides portends future combination therapies that confer a single-dose cure and are inexpensive to manufacture and administer. The 1,2,4-trioxolane OZ277 (Figure 1) is the most advanced of the synthetic peroxides, having progressed into Phase II clinical trials. This class of antimalarials was discovered by a group at the University of Nebraska and their clinical development is being managed by MMV in partnership with the Indian drug firm Ranbaxy. Although OZ277

itself will not move beyond Phase II for pharmacokinetic reasons, the improved variant OZ439 which confers single-dose oral cure in animal models is progressing towards human trials.

A number of groups are developing improved quinoline antimalarials that are effective against chloroquine-resistant parasites. Notable among such molecules are second-generation amodiaquine analogs dubbed isoquines. The isoquines were designed by a group at the University of Liverpool with the objective of eliminating the hepatotoxic effects occasionally associated with amodiaquine therapy.

Isoquines are regioisomeric analogs of amodiaquine that cannot form the reactive quinone imine intermediates thought to be responsible for amodiaquine toxicity. Like amodiaquine, the isoquines are effective against chloroquine-resistant strains of P. falciparum. Among the various isoquines prepared, the N-tert butyl analog (Figure 1) was selected as a clinical candidate. The compound is being developed by MMV in partnership with GSK, with first-in-human dosing expected to have commenced in spring of 2008 according to the MMV website (www.mmv.org).

Selected antiparasitic drug discovery projects involving collaboration between academics, not-for-profit research organisations and pharmaceutical companies Disease

Target / Molecule

Stage

Academic site

Partners and Funders

Malaria

OZ277/RBx11160 & nextgeneration analog OZ439

Phase II and preclinical

University of Nebraska

Ranbaxy, MMV

Malaria

N-t-butyl isoquine

Phase I

University of Liverpool

GSK, MMV

Leishmaniasis

8-aminoquinoline NPC1161B

Preclinical

University of Mississippi

DNDi

Malaria

falcipain inhibitors

lead optimisation

University of California, San Francisco

GSK, MMV

Trypanosomiasis

kinase inhibitors

hit ID through lead optimisation

University of Dundee (DDU)

Wellcome Trust

Trypanosomiasis, Leishmaniasis

diamidines, others

hit ID through preclinical

University of North Carolina (CPDD)

DNDi, MMV

Malaria

artemisinin analogs

lead optimisation

Johns Hopkins University

Novartis (NITD), Wellcome Trust

Trypanosomiasis, Schistosomiasis, Malaria

cysteine protease inhibitors

lead ID, lead optimisation

University of California, San Francisco

Celera Genomics, Sandler Foundation Table 1

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Two examples of new antiparasitic agents currently in development

O

O O

O NH H2N

OZ277/RBx11160

OH

HN

Cl

emerge from such efforts, a licensing agreement could be arranged between the owner of the intellectual property and the organisation seeking to develop the compound. This paradigm is very powerful as it leverages chemical entities already in hand for a new purpose. It is akin to the re-purposing of approved drugs except that it occurs at an earlier stage and therefore allows for optimisation of molecular properties appropriate to the antiparasitic indication.

The future

NH

N N-tert-butyl isoquine Figure 1

farnesyltransferases are but three examples that are being explored. The human proteases cathepsin K and cathepsin S are validated drug targets in osteoporosis and autoimmune disease, respectively.

Screening libraries of cathepsin inhibitors from industry is then a pragmatic approach to quickly identify high quality lead compounds that inhibit homologous parasitic proteases like cruzain and falcipain. The success of this approach requires only a willingness on behalf of the pharma partner to allow screening of parts of its compound collection.

In fact, a number of large and small companies have done just this, typically under agreements that stipulate use of the libraries for research purposes only.

Should a clinical candidate eventually

Author

Lead optimisation is often neglected in academic drug discovery programmes, mostly for a lack of funds to support the significant synthetic chemistry and animal resources required. At least two models have emerged to successfully accomplish this work. Large, well funded academic centres like the Drug Discovery Unit at the University of Dundee employ their own teams of medicinal chemists, with many members recruited out of the industry. It is also possible to pursue lead optimisation within traditional academic groups (i.e. employing students and post-doctoral researchers), assuming that funding for such work can be secured. Another model moves beyond the academic setting and involves collaboration with industry researchers, managed and funded by organisations like MMV or DNDi. Representative of this approach is a falcipain inhibitor programme managed by MMV and involving the academic laboratory at UCSF that identified the falcipains as drug targets in malaria, and a team of experienced chemists and biologists from the GSK site in Tres Cantos, Spain.

Here then is an example of a large pharmaceutical company making available its drug discovery expertise and human resources to advance the discovery of new antiparasitic therapies.

The collaborative model described above requires that industry partners devote the full-time efforts of at least some of their scientists to a therapeutic area with little market opportunity.

Many companies are reluctant to do this, even if the costs of the research effort are subsidised by organisations like MMV or DNDi. At earlier stages of the discovery process, however, the industry can contribute in ways that have no significant impact on the bottom line and yet can significantly advance efforts to identify new antiparasitic agents. A number of the recently identified drug targets in parasitic disease have close homologs in other diseases where a more significant market incentive exists. Cysteine proteases, kinases and

The prospects are good that the next decade will see entirely new classes of antiparasitic agents brought into clinical use. As with any drug discovery effort, significant hurdles remain; some of these have been identified here. The emergence of organisations like MMV, DNDi and iOWH, made possible by major philanthropy, has created a clear path for the clinical development of promising new agents. At the same time, new drug targets will continue to emerge as our understanding of parasite biology expands at an ever increasing rate in a post-genomics era. Moving from promising drug target to promising drug candidate remains the central challenge.

How will quality lead molecules be identified? How will the properties of these molecules be optimised to yield drug candidates with a reasonable chance of clinical success? Who will do this work and how will it be funded? Some likely answers to these important questions have been provided here. There can be little doubt that sharing of information and coordination of efforts between academics, foundations, and industrial partners will be essential components of future successes.

Adam Renslo is Associate Director of Chemistry at the Small Molecule Discovery Center and holds an adjunct appointment at the University of California, San Francisco, USA. Previously, he led antibacterial and antifungal discovery chemistry teams at Vicuron Pharmaceuticals.

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Oral Inhalation Technology

Impact of nanotechnology Regulatory awareness has led to the need for new approaches when regulating nanotechnology in the inhaled area. Opportunities as well as challenges exist. If addressed, they can open the doors for new IP to be generated along with considerations that can be incorporated in Life Cycle Management.

Ola Nerbrink, Principal Scientist, NovoNordisk A/S, Denmark

T

he FDA announced in August 2006 that it will form an internal FDA Nanotechnology Task Force. The group responsibilities will be to establish regulatory approaches in the development of safe and effective FDAregulated products that use nanotechnology, affecting virtually every product category that FDA regulates—from pharmaceuticals and devices to cosmetics and food supplements. In July 2007 the FDA released a report that recommends the agency to consider guidance and steps to address benefits and risks of drugs and medical devices using nanotechnology.

Eschenbach (MD), a Food and Drug commissioner stated that “Nanotechnology holds enormous potential for use in a vast array of products”.

Guidance would clarify what information needs to be supplied to the FDA when developing nanotechnology-based products and, as the uncertain nature of nanotechnology and the potential rapid development clearly highlights the need for predictable, transparent and consistent regulatory pathways. A need to identify and access data needs in the FDA

regulatory process of nanotechnology and products and will cover both interactions and possible biological effects of nanosized materials. The report also flags for a commitment to a more transparent public process when FDA develops its regulatory policies around nanotechnology. Public participation will ultimately win public confidence and be paramount when developing good policies in the agency’s oversight of nanotechnology and nanotech products.

Many of the products that incorporate nanotechnology are non-pharmaceuticals comprising materials and line extensions of these. In the next five years it is foreseen that we will see products in the field of solar energy, batteries, displays and e-paper, nanotubes and nanoparticle composites, catalysts, coatings, paints, alloys, insulation, filters, glues, abrasives, lubricants etc. The time to market these products varies and depends both on the technological complexity as well as the regulatory complexity and product life cycle as can be seen in Figure 1.

The sale of these products has increased substantially over the years; in 2004, the revenues were almost

US$ 13 billion and are projected to be over US$ 500 billion by 2010. This figure is comparable to the total revenues of the pharmaceutical industry in 2004, surpassing US$ 500 billion this year.

The driver for growth is surprisingly not NCEs or NBEs within the pharmaceutical sector, as the R&D spendings and cost increases the development time increases, thereby decreasing the time of exclusivity. Pharmaceutical companies claim that the non-invasive routes of administration for protein therapeutics are selected mainly to bring about differentiation, user compliance and Life Cycle Management (LCM). New dosage forms and reformulation pose a challenge to LCM of drugs due to various factors

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Market Impact will take time...

Horizon 3 Horizon 2 Horizon 1 • High

Timeframe

0-3 years

3-7 years

• Systems • None • Non-volatile memory

7+ years • Biomimetic meterials • Bioelectronics • Nanowire memory and logic

• Structures and devices • Displays • Sensors, diagnostics, assays • Novel therapeutics through

• Fuel cells functionalised dendrimers, Technological • Solar cells nanotubes, other nanoparticles for complexity targeted drug therapy

• Low

• Passive / materials

Changing diabetes

• Low

• Nanoparticles • Bulk composites • Coatings • Catalysts • Tools

• High performance nanocomposites • ??? ceramics, metals

• Regulatory complexity and product life cycles

Source: Atomworks

Figure 1

such as solubility, stability, potency and compliance / convenience. Poor solubility and frequent dosing schedules are two drivers of innovation in drug delivery for nanotechnology where the technology can be used to improve or control release / uptake of drug compounds.

We have already seen efforts in the area: NanoCrystals® from Elan Corporation (Rapamune®, Emand®, TriCor®, Megace®), Baxter DissoCubes®, SkyPharma NanoEdge® Abraxis Abraxane® and Bioaqueous Solution technology from Dow Pharma (license from University of Texas). Current trends in protein formulation and drug delivery lie in the selection of the route of administration of the NBE and drug delivery formulation, together with tailored device development. Typical examples are transdermal implants and sustained release and inhalation therapeutics; however, the latter has declined substantially at the moment due to the discontinuation of inhaled insulin therapy. Looking closer at the pipeline for protein and peptide drug delivery, the development in the inhaled

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• High

ISSUE - 9 2008

field is similar to that of oral and injectables (SR) during Phase I and II and the industry is showing a substantial interest in this field.

From the above it can be concluded that future development of inhaled therapeutics will focus more on LCM of existing products along with development of NCEs / NBEs where improved particle design and engineering will be key development trends. The size, shape and composition are the main factors of interest to exploit further. Both the size and the shape factors such as structure, form and topology will have an influence on the drug delivery from the device as the binding or connecting forces can be moderated to improve small or nanoparticle dispersion during delivery.

Classically, drug delivery via inhalation has predominately centred on micron particles as these have been able to deliver defined metered dose during one or more inhalations. Switching to submicron or nanoparticles, the number of particles easily increases by a factor of thousand or million for the same dosing

regime and the adhesive / cohesive forces multiply to the same extent. Exploiting options around shape and composition is a must to minimise the effect of cohesion / adhesion in drug delivery. The composition, shape, density and the total number of particles (e.g. the total surface coating of the lung) may have an effect on the dissolution rate, uptake and biodegradability of the particles when they reach the lung as compared to larger micron sized particles.

This also reflects the possibilities of using nanoparticles and nanomaterials in potential rapid topical drug delivery.

Nanoparticles can also be a catalyst in the development of new carrier molecules and materials such as nanoshells and assembled structures. All of these features can of course be incorporated into the future inhalation therapy.

The inhalers that are offered today are divided into three segments—Dry Powder Inhalers (DPI), pressurised Metered Dose Inhalers (pMDI) and nebulisers or Soft Mist Inhalers (SMI). In DPI, the drug is formulated as a dry powder, containing

Research & Development

Example Fomulation : CFC to HFA conversion Gamma scintigraphic images of HFA (QVAR®) and CFC beclomethasone pMDI

Region Device

HFA BDP 40 µg

CFC BDP 42 µg

Oral

31%

94%

Lung

51%

04%

Exhaled

18%

01%

Observe: Both particle and plume velocity dependent

Ref: 3M Website Table 1

on the nature of the formulatin used and opens for both issues and possibilities when employing nanotechnology (particles and structures) in inhalationbased delivery of drugs. After solving these issues, there may still be other issues to address when looking at PK / PD profiles. This is especially critical of generic applications where equivalent PK / PD profiles and dosing to marketed products are essential. The difference in particle size and surface area coverage along with possible differences in dissolution and biodegradability / availability can have a major impact and must be addressed early in the development.

A wide range of possibilities in which nanoparticles can be used in inhalation therapy is felt since long. When IVAX and 3M developed the QVAR® pMDI system as a CFC to HFA conversion of an existing CFC product containing a micron-sized suspension, the resulting HFA formulation became a solution and not a suspension. When activating the QVAR® pMDI, the HFA boils off resulting in solid particles whose size depended on the drug concentration in the HFA formulation and the initial droplet size of the HFA droplet distribution. The resulting solid particles were much smaller than the

Author

the active drug component and excipient or carriers. A variety of DPIs are available today and they can have either a reservoir of powder or be supplied with a number of unit blisters / capsules for individual dosing. The pMDI and the SMI (nebuliser) use a dry powder formulation but the powder is suspended in a Hydro Fluoro Alkanes (HFA) or Chloro Fluoro Carbons (CFC) propellant in the case of pMDIs and in water in the case of a nebuliser or SMI. A pMDI is a reservoir system and often holds 60 to 120 doses in the reservoir. The SMI is a reservoir system containing multiple highly concentrated µl doses (typically10 to 50 µl) whereas the nebuliser uses a lower concentrated ml dose (typically 1 to 3 ml). Stability and degradation is an issue and is more accentuated in the water-based nebuliser / SMI systems than in pMDI and DPI systems due to the better chemical stability in nonaqueous systems.

Inhaler devices can of course be used for delivering nanoparticles, both as a drug and as a carrier system for various purposes. Care has to be taken as the implementation of nanoparticles in inhalation therapy poses some major challenges to the developer. Due to the nature of nanoparticles, they will give rise to many formulation issues when blended with excipients as the surface to area ratio is large compared to micron-sized particles and thus will have an impact on blending and aggregation properties of the formulation.

For liquid (aqueous and HFA systems) aggregation resulting in flocculation and caking together with risk of adhesion to walls and device mechanism may have an impact on device dosing properties (uniformity and over time).

Dispersion of the particles can also pose some challenges, especially for DPIs where the patient inhalation effort drives the de-aggregation of particles, a factor that is known to vary substantially depending on the disease and state of the patient. The residue in the blister / capsule and device will also be dependent

suspended particles in the CFC suspension formulation and were more likely to penetrate into the lung as compared to the CFC suspension particles. The reported results can be seen in Table 1 which clearly shows an enhanced lung deposition of the QVAR® as compared to the conventional CFC product on the market. This clearly highlights opportunities for nanoparticle applications.

But, it also highlights the differences in dosing and possible PK / PD issues for generica or line extension (LCM) applications.

The success of nanoparticle applications in the inhaled field depends on the feasibility of designing nanoparticle formulations that are stable and can be delivered successfully and repeatedly to the patient. Many issues need to be considered and thoroughly tested in order to achieve the goals set in the development phase. If this is successfully done, new options securing IP-enabling novel NCE / NBE or even line extension applications may be thought of. At the moment, this area is fairly unexploited generating new IP in the field giving a cutting edge to novel products in the future for those pharmaceutical companies working in the inhaled product segment.

Ola Nerbrink is a Principal Scientist at Novo Nordisk A/S in Denmark. He obtained a Bachelors degree in chemistry/physics from Lunds University in Sweden in 1981, a Licentiate degree in Occupational Hygiene with emphasis on inhalation topics from Lund University in 1997 and in 2001 he finalised a PhD in Occupational Medicine from Karolinska Institute in Stockholm.

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New Drugs in Japan Conditional authorisation Conditional authorisation and early post-marketing phase vigilance systems constitute an integral part of new drug approval and risk management in Japan. They intend to ensure safe launch and early access to patients of new drugs.

Osamu Doi, Chief Executive Shigeki Tsuda, Executive Director Society of Japanese Pharmacopoeia, Japan

T

he challenge to ensure early access to new drugs and their safe launch is growing globally, particularly after a number of large scale Adverse Drug Reactions (ADRs) were identified and attracted much attention from public, and blockbusters were withdrawn from the market. US FDA intensified its authority of managing post-market safety of new drugs but this resulted in prolonged reviews causing a lot of distress to sponsors.

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Under such an environment, introducing the unique systems of conditional authorisation and Early Postmarketing Phase Vigilance (EPPV) for new drugs followed in Japan is worth discussing. A mechanism similar to conditional authorisation has recently been introduced in EU, and also in US with the enforcement of FDAAA (FDA Amendment Acts of 2007).

Figure 1 shows the risk management system of new drugs from the authorisa-

tion to post-marketing phase in Japan.

Certain conditions have been prescribed for authorisation of new drug mainly to ensure its safety, according to its needs.

Further to prevent serious ADRs from occurring just after its marketing, it is mandatory to conduct EPPV for six months after the marketing. Other requirements include Expedited Safety Report to collect information such as unknown and serious ADRs, periodic report on infection that was caused by

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biologics and periodic report of unexpected but non-serious ADRs. Conditional authorisation

The legal background of conditional authorisation involves Articles 79 and 74-2. The Article 79 was included in the original Japanese Pharmaceutical Affairs Law (PAL) enacted in 1960. The outline is that certain conditions may be prescribed for the authorisation but they shall be confined to the minimum that is required to prevent the occurrence of hazards to public health. Importantly, it says that conditions shall not impose unreasonable obligations on the person intending to obtain it.

The Article 74-2 was introduced by the amendment of PAL in 2002 in which the regulation on conditional authorisation has been strengthened.

The background of this revision is that though conditions were appended at the time of authorisation, companies did not necessarily abide by them as there were no punitive provisions for noncompliance. The major revised point is the introduction of a regulation that allows the Ministry of Health, Labour and Welfare (MHLW) to order the revocation or partial change of the authorisation when companies do not comply with the conditions.

Type of the conditions

The first type is the All Cases Surveillance. There are several purposes in conducting this survey. First, this is to obtain high quality information on all the cases to ensure, in particular, safety of the drug. Secondly, it is conducted to detect rare ADRs, which cannot be detected during the drug development phase, by studying a larger number of patients. The Surveillance is also conducted to study the impact the drug may have on the special populations, such as children, patients with hepatic or renal dysfunctions, or elderly people. Furthermore, since information obtained during the drug development phase is from a very limited group of

patients reflecting limited circumstances, the information from medical institutions where the drug is administered to patients with various backgrounds becomes extremely important. That is why post-marketing information is necessary and important.

The second type is the condition to conduct additional clinical studies after the drug has been authorised: the practice of post-marketing clinical studies. It may be important to make clear even the frequency of rare ADRs on all drugs in the development phase, or to pursue the possibility of expansion of efficacy claims to include children.

However, this kind of work would cause a huge delay in the development. By carrying out these analyses as much as possible in the post-marketing stage, the pre-marketing development time can be made shorter. But in order for that to happen, a strict post-marketing safety control must be in place after the authorisation.

Third one is the access control of the product, i.e. access is limited to specified medical institutions or doctors only, for a specified period of time after the authorisation. The access control on medical institutions also helps prevent the range of the drug use from expanding rapidly before the company has

provided adequate information on its product to those institutions.

EPPV

EPPV was introduced in 2001 as a legal requirement (MHLW Ordinance) and now constitutes one type of post-marketing conditions. The conduct of EPPV has been applied, not to an individual product, but uniformly to all new drugs as an obligation.

Figure 2 outlines the EPPV system.

It is known globally that new drugs have the highest risk at the early post-marketing stage. Before new drug products are delivered to medical institutions, companies provide product information obtained during the development phase to such institutions and request the proper use of the new products. In the event of serious ADRs, the companies request that medical institutions expeditiously report the information to the company. These requests to medical institutions are carried out repeatedly for over six months. This process is intended to prevent medical institutions from starting to use the new products without understanding them, and also to help formulate risk management measures to address possible serious ADRs by speedily collecting information on them.

Risk managment of new drugs in Japan – Pre-and post authorisation

Authorisation

From Industries

Conditional Authorisation 4-10 years

Re-examination

Re-evaluation

Periodic Safety Report EPPV-report (6 months)

Expedited Safety report (ex. individual report on unknown and serious ADRs) From Industries

Periodic infection report (semi-annual report) for biologics Periodic report of unexpected and non-serious ADRs Figure 1

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Research & Development

studies can be conducted in the postmarketing phase, and which part must be done in the development phase, is extremely important both for companies and the regulatory authorities for medicinal products. These will, of course, require case-by-case decisions.

Other effects can also be expected from conditional authorisations. Medical institutions that are allowed to use new drugs under authorisation conditions can prevent serious ADRs caused by their improper use. Eventually, these conditions lead to longer life of the new drugs that were developed with huge investment.

EPPV System Implementation plan development

Launch 2 weeks

2 months

6 months

8 months

End of the Report on vigilance the results period to PMDA

MR visits medical institutions before the delivery of new products.

Explanation on EPPV & request for cooperation.

Information provision

Documentary explanation and request for cooperation before the delivery

MR Visit

Periodic reminders by: visits, letters, fax, e-mail, wholesalers ADR case report

Though EPPV was introduced in 2001, many patients died from serious ADRs in 2002 because of improper use of the anti-cancer drug, Iressa, gefitinib, just after its marketing. Therefore, MHLW is now working to ensure that the EPPV is thoroughly implemented and it becomes more effective. The review includes the scope of the new drugs to be subject to EPPV, possible extension of the EPPV period that has been six months in principle depending on the type of new drugs, exemption of drugs with expanded indications other than new active substances.

Impacts of the conditions

One of the effects that can be expected from conditional authorisations is increased safety of new drugs. With such conditions, there is a possibility of detecting safety issues including those in long term administration which are not easy to find in clinical studies in the development phase. They may also allow us to check the safety of a new drug in special populations and look into its safety with concomitant medications.

The conditions may lead to the improvement of efficacy. In the development phase, efficacy is often evaluated

Current status of conditional authorisations

Figure 2

on the basis of surrogate endpoint(s).

However, by doing post-marketing analysis on long-term administration data, efficacy on the true-endpoint, such as the effectiveness on prolonged survival, could be confirmed. Verifying the efficacy of drug for special populations, such as children, may also be possible.

In obtaining indication for children, it is more desirable to collect and submit children’s data after marketing, as opposed to delaying the authorisation until all data on children are collected.

Another potential effect of conditional authorisations, i.e. the shortening of the development time is perhaps the most enticing of all for companies.

Making wise use of authorisation conditions can lead to shorter development time. The decision on which part of the

As clinical data of orphan drugs in the development phase are limited, the conditions associated with the authorisations of orphan drugs have been to follow-up all the patients dosed with the drug for a limited or a 10-year period— the drug re-examination period.

For other new drugs, conditional authorisations are given on a case-bycase basis. The authors see the increase of new drug authorisations with conditions prescribed. When conditions are appended, it is obligatory to indicate them on the package insert until the regulatory authority confirms that the obligations under the conditions are met.

Table 1 shows the recent conditions appended to authorisations in the past three years, from 2005 to 2007. Seventy five new active substances were authorised during the three years, of which 25

Some recent data on new drugs with authorisation conditions No. of total authorised ingredients

Authorised ingredients with conditions

New active substances

75

25(33%)

Additional use etc.*

148

32(22%)

From 2005 to 2007 No. of total authorised ingredients: Combination etc. is counted as one *Additional use etc.: Authorised variations including extended indication, addition of paediatric dose and change of manufacturing method etc.

Table 1

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Examples of the conditions

An example of Access Control of Medical Institutions and Doctors is Erlotinib, its product name Tarceva. The Condition says “The MAH (marketing authorisation holder) should take appropriate measures to ensure that the drug is only used under the supervision of a physician, a medical centre, all with expertise in lung cancer diagnosis and chemotherapy as well as the potential risks of the drug.”

Interferon Beta-1a, product name AVONEX is an example of Conduct of Post-Marketing Clinical Trial. The Condition says “The MAH should conduct (a) clinical trial(s) to investigate efficacy and safety in long term administration, as a measure of recurrence rate of Multiple Sclerosis, and to report the result to the authority.”

Type of requirements in the authorisation conditions Total No. of authorised ingredients*

223

No. of ingredients with conditions

57

Type of the authorisation conditions Conduct of Post-marketing Clinical Trials

10

Conduct of Post-marketing Surveillance

48

Access control of Medical Institutions and Doctors etc.

4

Thorough Proper Use and/or Informed Consent etc.

10

Other**

9

From 2005 to 2007 * Authorised ingredients include new active substances and those with additional uses. **Other : Report to MHLW/PMDA of results etc. of clinical studies being conducted in other countries

Table 2

An example of Conduct of PostMarketing Surveillance on the new drug is Pemetrexed Sodium Hydrate, with product name ALIMTA. The Condition says “The MAH should collect data on safety and efficacy of the drug as well as grasp the background information of the patients by conducting drug use investigation on all the cases until data on a certain number of patients is accumulated after its marketing, because the number of cases in clinical trials in Japan was very limited.”

Future expectations and possibilities of the conditional authorisations

By improving the quality of post-marketing surveillance, the increase in the number of trial subjects needed in the development phase could be curtailed.

Authors

(33 per cent of the total) were appended with conditions.

As for other new drugs such as extended indications, 148 ingredients were authorised in the three years and of which 32 (22 per cent of the total) were appended with conditions.

Table 2 shows the type of the requirements in the authorisation conditions in the past three years. Conditions were appended to 57 drugs in total.

The conditions include 10 drugs with those of conduct of post-marketing clinical trials such as trials focussing on true endpoint of prolonged survival.

Conditions of conduct of post-marketing surveillance were appended to 48 drugs and what were required included “All case surveillance” and “Post-marketing study” aimed at special populations.

Access control related to doctors and medical institutions was appended to four drugs and, for 10 drugs, provision of particularly emphasised information on proper use and obtaining informed consent from the patients concerned were required. The other conditions applied to nine drugs include report to the authority of test results conducted in other countries.

The authors also think that conditional authorisations could pave the way for a wider use of post-marketing surveillance and test results, so that additional indications could be offered to special populations, such as children.

Another major issue—factors such as ethnicity difference that could be demonstrated by post-marketing surveillance or post-marketing clinical tests should have their information collected in the post-marketing phase as much as possible. It is essential to prevent the extension of development time and the delays in submitting authorisation applications, i.e. “drug lag”, as much as possible.

The wise use of the authorisation conditions as well as EPPV provide a firm basis for better risk and lifecycle management of new drugs.

Osamu Doi was trained as a biochemist and after working as a researcher in NIH of Japan and in US, he joined the Ministry of Health and Welfare (MHW), where he was one of the founding members of ICH, and left there as the Councilor for MHW.

Shigeki Tsuda worked in the Ministry of Health and Welfare, mainly in international affairs and, drug and chemical safety.

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Research & Development

Changing Face of GPCR Drug Discovery Opportunistic future

Although GPCR drug hunters can boast of a successful and glorious past, the present and future challenges remain high. Some of the changing paradigms in GPCR research that may aid in confronting the challenging environment of GPCR drug discovery are discussed here.

Anindya Bhattacharya, Senior Scientist, Johnson & Johnson Pharmaceutical Research & Development, USA

A

t the outset, we should challenge the basic dogma of receptor pharmacology, i.e. one ligand, one receptor texture and singular efficacy. There is emerging evidence to the contrary, i.e. one ligand, differential pharmacology and multiple mechanisms of action. GPCR drug hunters and thought leaders have started to accept this paradigm shift and I believe that similar analogies can be drawn for other druggable target classes as well.

The plethora of GPCR targets (class A, B, C, frizzled and their respective orphans; IUPHAR reference at http://www.iuphar-db.org/GPCR/ ReceptorListForward) is promising but discovery teams must appreciate the evolving concepts and differential in vivo efficacy profiles for ligands (selective for the GPCR of interest) that maybe a result of GPCR oligomerisation, GPCR allosterism and functional selectivity. All of these will be covered in some detail in the following sections. The impact of such evolving concepts can be immense both in terms of screening and finding novel mechanisms for clinically validated targets. As an example, more often than not HTS campaigns for GPCR drug

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targets are set up with a single readout using recombinant receptors in isolation from their native milieu. While discovery project teams assume and sincerely hope for a carryover pharmacology from the recombinant receptor to the ‘diseased’ receptor, it is to the project team’s benefit if a screening campaign or lead optimisation exercise can incorporate orthogonal screening cascades (incorporate > 1 signalling pathway) and if possible, target human cells / tissue so that any differential pharmacology (due to GPCR oligomers and permissive / restrictive conformation) can be accounted for as early as possible. Another approach that has been gaining steam is to exploit GPCR allostery as a versatile way of finetuning the endogenous ligand’s affinity for the target. I advocate for HTS screens that will differentiate between allosterism and orthosterism, both for agonists and antagonists.

GPCR allosterism

Recent elegant pharmacological studies have identified several GPCRs (muscarinic, adenosine, dopamine, chemokine, CRF1, CaR, mGluRs and GABAB) with allosteric modulatory sites

(Gao and Jacobson, 2006; Langmead and Christopoulos, 2006; Milligan and Smith, 2007; Schwartz and Holst, 2007).

Several allosteric ligands have now entered into early development; the marketed drug Cinacalcet is in fact a positive allosteric enhancer for the Calcium-sensing Receptor (CaR) and Maraviroc is a negative allosteric modulator of the CCR5 receptor. As a result, modelling of receptor-ligand interactions has evolved to incorporate allosteric ternary complex models (Christopoulos and Kenakin. 2002; May et. al., 2007).

Allosteric modulators (both positive and negative) can have different effects on the endogenous ligand’s affinity and efficacy and hence offer a texture to the pharmacology. Allosteric and orthosteric sites on a GPCR are conformationally linked; it can be argued that GPCRs are naturally allosteric as they do interact with multiple protein subunits and binding of a ligand conformationally selects one over the other. Receptor dimers / higher order oligomers can also be allosterically modulated (allosteric protomer) as was recently demonstrated by Redka et. al., (2008) for the M2 muscarinic receptor.

The concept and success of allosterism

Research & Development

has opened up the field and brings in immense hype and also genuine promise to feed the GPCR pipeline. From a medicinal chemist’s point of view, it opens up endless possibilities to fine tune a GPCR that may not be restrictive from an IP perspective; i.e. a novel chemotype on a novel GPCR or even on a GPCR that ‘has been around’ for a long time.

A unique property of allosteric modulator is their specificity or dependency on the orthosteric agonist and its ability to impart a different texture depending on receptor conformation. This concept can be immensely beneficial in drug discovery and may aid in sparing the physiological roles of GPCR and only modulate the ‘diseased’ receptor, which is conformationally different (for example, a sensitised state of a GPCR that contributes to pain perception).

Another important feature of allosterism is their saturable effect that may translate to less probability of adverse / toxic effects even at full target occupancy and may dissociate duration (function of compound exposure) of action from maximal efficacy (saturable). A big hurdle in allosteric drug discovery is to settle on a screening strategy for a GPCR that is expressed recombinantly in a host cell (conformation ‘A’) in a way that is conformationally different from the GPCR under pathology (conformation ‘B’). In my opinion, it is always advisable to use a native cell system where the receptor is captured in some conformationally restricted state that may mimic the druggable receptor.

Because of agonist dependency, it is also

critical that allosteric screens use the endogenous agonist where possible, to probe the target of interest. From that perspective, orphan GPCRs may present some operational challenges. There are many GPCR targets, many of which have been clinically validated, that offer a renewed hope for allosteric approach where one may embark on novel chemistry (targets that are chemically intractable for orthosteric ligands) and may eventually improve the therapeutic window and balance the discovery portfolio with low-risk high-reward targets.

Functional selectivity

Although intrinsic efficacy has been viewed as a system-independent pharmacological parameter since the dawn of receptor theory, it is becoming apparent that many ligands (agonists) function differentially and efficacy may swing like a pendulum and it is often difficult to assess the fulcrum in the balance of efficacy-adverse effect profile. Several lines of evidence (reviewed in Mailman, 2007; Urban et. al., 2007) support the notion of functional selectivity: (i) agonist pairs possess different potency ratios for probing different signalling pathways in vitro that cannot be accounted for methodological differences (ii) (partial) agonist pairs exhibiting different intrinsic activity ratios (sometimes completely opposite) dependent on the receptor-effector coupling system being tested.

In other words, agonists (full, partial,

inverse and ago-allosteric) display functional selectivity or display a protean texture to the agonism. As an example, the antipsychotic aripiprazole (partial D2 agonist) is believed to manifest its efficacy on positive symptoms of schizophrenia (high local dopamine concentrations) by competing with and causing partial antagonism of dopamine stimulus. Contrary to this, when endogenous dopamine levels drop, aripiprazole can then cause partial agonism, highlighting a case of a launched product whose intrinsic activity is dependent on the levels of the endogenous ligand (functionally selective).

Whether functional selectivity is a result of one GPCR with many conformation states, GPCR oligomerisation or GPCRmany effector interactions, remain to be elucidated; nonetheless it brings in a lot of promise and hope to find safe and efficacious molecules targeting a GPCR that is otherwise often thought to be a liability for drug development. It is possible to reconcile a scenario where a typical agonist that derives affinity for a single receptor state (and thereby transduce via the same signalling cascade(s) every time the GPCR is turned on) can lead to both efficacy and adverse effects whereas a functionally selective agonist can, in theory at least, with the application of sophisticated pharmacology and medicinal chemistry be tuned to dissociate efficacy from sideeffects. Similar concepts can be applied towards antagonists that can also be functionally selective. How can one screen for functional selectivity in early discovery?

The answer to this question is to run HTS

Selected examples of allosteric ligands, their targets and some perceived advantages GPCR

Allosterism

GPCR

Allosterism

A1

PD81723 SCH202676

A3

VUF5455 DU124183

CB1

ORG27569 ORG29647

CXCR1

Repertaxin

CCR5

TAK779 SCH351125

M1-M5

Gallamine Alcuronium AC-42

5-HT7

Oleamide

CRF1

Antalarmin NBI35965 R121919

Glucagon

L-168049

CaR

Cinacalcet NPS568

GABA

CGP7930

mGluR1

RO016128

mGluR2

LY181837

mGluR5

MPEP CDPPB

Advantages of allostery over orthostery i)

Agonist-dependent pharmacology for a given target; degree of allosterism is dependent on what, how and when the receptor is modulated (ii) Allosteric texture is observed: i.e. compounds with similar affinities can have different effects (iii) Antagonism reaches a ceiling effect; less probability of side effects (iv) Can generate receptor selectivity by targeting non-conserved sites

Table 1

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Research & Development

GPCR oligomerisation

This evolving concept of GPCR oligomers has taken a new turn and several companies have embarked on screening platforms to identify novel chemotypes that targets more than one GPCR unit (CARA Therapeutics, Dimerix Bioscience, PatoBIOS Incorporated). The savvy drug hunter can appreciate that GPCR homo and / or heterodimers can have a significant impact on signalling and eventually on the success of drug discovery projects that often begin with a singular target in mind. For example, GABAB receptor exits as dimers and GABABR2 is required for GABABR1 cell-surface expression and the latter possesses the orthosteric ligand-binding domain whereas the former aids in G-protein coupling. Several other examples of GPCR hetero-dimerisation have recently resurfaced: β2 adrenergic & prostaglandin EP1 receptor, KOR & DOR (opioids), CB1 & A2A and AT1-B2 (reviewed in Panetta and Greenwood, 2008). Although we appreciate the function of GPCR oligomers (expression, internalisation, signalling via different G proteins), it is often difficult to apply a GPCR oligomeric drug discovery approach because of the unknown receptor mix (monomers or dimers or higher order oligomers) in pathology. It might be more rational to begin with the diseased tissue of interest, assess the GPCR by biochemical means as to whether it exists as monomers or dimers and then reconstitute the receptor pair in cells for screenings that may have a direct impact on the disease itself. The other approach is to choose native cell systems that may

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Newer concepts in GPCR Research Allosteric modulator Ligand that increases or decreases the efficacy and / or affinity of an orthosteric ligand (endogenous agonists) Ago-allosterism An allosteric ligand that is an agonist alone and also a modulator of the orthosteric ligand Allosteric protomer Used to define receptor dimmers where one receptor unit accepts the allosteric ligand to modulate the activity of the orthosteric ligand and the second receptor Neutral allosteric modulator An allosteric ligand that has zero efficacy and neutralises the effect of positive and negative allosteric modulators Inverse agonist Ligand that drives the receptor equilibrium from active to the inactive state; inhibits constitutive activation.

Collateral efficacy Changing paradigm from linear efficacy; receptors via conformation changes recruit distinct effectors that may not be manifestations of a singular line of descent from GPCR activation to cellular / tissue / organ effect.

Functional selectivity Ligands that are selective for a receptor-effector conformation resulting in selective activation of a signal transuction pathway over another; terms such as protean agonism, permissive agonism, conformational selectivity also encompass the concept of functional selectivity.

Author

campaigns or lead optimisation activities with multidimensional pharmacology screens. In other words, there must be a paradigm shift in screening from a single functional assay (example, calcium flux in FLIPR) to other end points that the receptor of interest couples in the host cell being studied (example, MAPK activation or other determinants of cell morphology) which can be translated to pathophysiology.

express both receptor pairs, as was the case of GPR50-MT1 receptor in a human endothelial cerebral cell line (hCMEC/ D3). Whether such efforts will lead to GPCR oligomer selective ligands with therapeutic benefits remains to be seen (Milligan, 2008).

Future of GPCR research

The future of GPCR research is full of optimism and it is upon us, the research community, to tackle the challenges thrown by Mother Nature, expand the pharmacological toolbox and convert new discoveries to medicines. In addition to the three areas of changing paradigms discussed, some other paradigm shifts, although not mentioned in this article should not be forgotten, i.e. role of RGS proteins, G-protein independent GPCR signalling (7-TM receptors), G-protein activation without GPCR activation and the role of accessory proteins in shaping GPCR pharmacology. In the end, GPCR drug discovery should aim at addressing allosteric modulators and also try to address target tissue pharmacology as early in the discovery cascade with different readouts with a view to capture different states of the receptor. From a drug hunter’s perspective, it can be said that the screening strategy is critical to the success of the project: for a given GPCR project it is best to frame a hypothesis, settle on a mechanism (orthosteric versus allosteric; monomers versus dimers) and cast a wide fishing net to capture a broad set of compounds. It is better to have a peripheral vision than a tunnel vision in our ever so challenging business of drug discovery and development.

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

Anindya Bhattacharya is a molecular pharmacologist with expertise in GPCR and ion channel drug discovery. He has several years of drug discovery experience in pain, inflammation, and urology.

Completing B Pharm. from Jadavpur University India and PhD in Pharmacology from SUNY Buffalo, USA, he has worked for major pharmaceutical companies like Eli Lilly, Roche and is currently employed by Johnson & Johnson PRD, USA.

CaseStudy

Transforming Drug Development

A fully outsourced model The pharmaceutical industry is not transforming fast enough to address the persistent decline in productivity. Alternative drug development models are being explored in an effort to jumpstart transformation. Eli Lilly and Company has created and successfully implemented Chorus, an autonomous early phase drug development group operating on a fully outsourced model to cost-effectively advance candidate molecules from discovery through clinical Proof of Concept.

Neil V Smith, Director – Regulatory Affairs Terri A Roberson, Director – Operations Chorus, Lilly Research Laboratories, Eli Lilly and Company, USA

I

n a recent article in Scrip, Anju Ghangurde reported on Eli Lilly and Company’s efforts to effect transformation from a Fully Integrated Pharmaceutical Company (FIPCo) to a Fully Integrated Pharmaceutical Network (FIPNet). The foundational thinking in the move to FIPNet is simply that the current pharmaceutical development process is broken and does not meet today’s market demands; the square block won’t fit into the circular hole… no matter how big your hammer is. This call for transformation is not unique to Eli Lilly and Company but a herald throughout industry. Describing developments in medicine, current head of the U.S. Food and Drug Administration, Andrew Von Eschenbach recently stated, “The transformation is not a linear extrapolation of the past. It’s a metamorphosis. The future will look no more like the past than a butterfly looks like a caterpillar.”

With the ever rising cost of drug devel-

opment coupled to the apparent dearth of new molecular entities entering the marketplace, it would appear that transformation is not occurring fast enough.

To borrow Dr Von Eschenbach’s analogy, the pharmaceutical industry has too many caterpillars.

Transformation to FIPNet – A success story

With the need for transformation in mind, in 2002 Eli Lilly and Company created Chorus via its eLilly initiative.

Chorus is a collection of experienced individuals from pharmaceutical industry that functions as an autonomous early phase drug development group empowered to quickly and cost-effectively advance candidate molecules from discovery through clinical Proof of Concept (PoC). A fully functional example of FIPNet, Chorus has adopted a fully outsourced model in which work product gets completed via a network of Third Party Providers (TPP), external consultants, and internal

core expertise. Chorus has grown and evolved considerably. Six years into existence, Chorus has taken more than two dozen assets into development from discovery to clinical PoC at a mean cycle time and cost per asset of just under 32 months and US$ 4.5 million, respectively.

Data from a 2000 Tufts report place the cost of Phase 1 development without getting to a PoC at US$ 15.2 million.

In a subsequent analysis published in early 2006, Adams and Brantner place the mean cost of Phase 1 development at US$ 32 million.

Chorus strategically embraces three core ideals:

1. Increase efficiency over traditional drug development—Lower cost, faster cycle times to drive higher productivity; 2. Faster, more effective decision-making to drive rapidly to value inflection and an earlier investment decision point; and 3. Limit parallel processing and gate

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Research & Development

resource utilisation pending discharge of target and molecule risk (i.e. execute a development plan that discharges key risks early at low cost to drive a large change in technical probability of success for a modest investment).

Today, Chorus manages a significant percentage of Lilly’s early phase portfolio with a multi-functional research and development infrastructure consisting of approximately 30 internal experienced drug development experts. Individuals are responsible for the core functions of Medical, Regulatory, Toxicology, ADME, CM&C, Clinical Operations, Statistics and Quality. Chorus’ small size and flat structure has multiple benefits. First, the minimal infrastructure allows for a low operating cost. The ratio of fixed versus flexible development costs is more favourable for Chorus when compared to traditional FIPCo infrastructure. Second, it allows for quick decision-making and promotes efficiency in seeking new data or reacting to incoming data. Lastly, it fosters an “act like an owner” culture and functional ownership for delivering lean experimental plans designed to directly contribute to the next decision point in each asset’s development plan. As such, the focus is on optimising the molecule and not the functional infrastructure of traditional FIPNets.

Chorus’ external network consists of approximately 30 external consultants and over 200 global TPPs. With a fully outsourcing model, TPPs are considered an integral part of the team (a virtual project team member). Therefore, Chorus only selects TPPs that can work independently, demonstrate and maintain a track record for on-time milestone delivery, function well with compressed timelines, and bring creativity and innovation to the team. Whenever possible, Chorus uses TPPs’ processes, tools, and templates to minimise imposed sponsor burdens to its partners. To aid in effective global, virtual collaboration, Chorus utilises Voice©, a proprietary, integrated IT system of custom and packaged applications, developed by Chorus in collaboration with an

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Schematic depiction of variables contributing to the success of Chorus

Structure

System i.e.

VOICE©

Strategy

CHORUS' SUCCESS

Skills

Processes

Staff Figure 1

external consulting company exclusively for the pharmaceutical industry. Voice© enables small, virtual teams to globally interact and collaborate on pharmaceutical drug development plans and priorities. Voice© conveys accountability and leverages defined processes to integrate information across a development plan to facilitate real-time planning and quicker strategic decision-making.

Integrated decisions

Chorus’ strategic focus, autonomy, structure, streamlined SOPs and business processes, experienced personnel, skilled TPPs, and innovative IT system Voice© interplay in decision-making and contribute to its success (Figure 1).

Strategic short and long-term goals are set for each project plan to ensure optimal productivity. Factors such as disease prevalence by geography, subject / patient availability, TPP expertise, regulatory environment, investigator expertise, and standards of care are discussed and vetted as a functional collaboration. Final operational plans are determined through these collaborative discussions, relying on quality, speed, and innovation as the key driving factors.

Chorus country and site selection illustrates this dynamic. A survey

of Clinicaltrials.gov shows that 56 per cent of the clinical trials are currently being conducted in the United States, while approximately 23 per cent are being conducted in Europe. Competition for subjects / patients in these geographies can be fierce and plays an important role in slow recruitment time. While arguably the US and Europe offer the greatest experience in conducting clinical trials, Chorus has found multiple Clinical Research Units (CRUs) of excellent quality in other countries to conduct their early phase clinical trials. These CRUs are often headed by physicians and clinical pharmacologists who have been trained in the US or Europe, practiced in these countries for a significant time, and who have returned to their native countries to continue their research. Tapping into these experienced investigators often provides real, tangible benefits for a drug development organisation. The challenges in the process include: difficult to find patient populations (e.g., biologic naïve patients, rare tumours or diseases, etc.), high quality, GCP trained CRUs, decreased trial costs, and in some instances faster regulatory review timelines. A Chorus crossfunctional team weighs these operational challenges with their own functional strategy in arriving at the overall drug devel-

In conclusion

Authors

Although the Pharmaceutical Industry may not be transforming fast enough, Chorus’ “out of the gate” initiative is producing tangible results. Chorus’ alternative drug development model, has utilised a full outsourced model and is cost-effectively advancing molecules from discovery through clinical PoC. Over six years into existence, Chorus has successfully implemented over two dozen development plans at a fraction of the traditional cost utilising a FIPNet strategy. To further illustrate Lilly’s confidence in the Chorus drug development model, Lilly has recently announced the formation of an equally-owned joint venture with Jubilant Organosys to be located in India that will focus on providing drug development services exclusively to Jubilantand Lilly-partnered molecules. The joint venture, known as Vanthys and based out of Bangalore, is modelled after Chorus, and will have the goal of providing fast and capable drug development for Lilly and Jubilant through the utilisation of external contract companies.

CaseStudy

opment plan including country and site selection. Thus, Chorus operates globally in multiple geographies that offer clinical expertise beyond traditional Phase 1 and Phase 2a locales. While these non-traditional countries may not be appropriate for every molecule or development plan, they are selected as a result of carefully considered, integrated decision-making and consequently produce, with rare exception, resounding success.

As additional alternative early development models are contemplated, there are several key learnings that have contributed to Chorus’ substantial productivity improvements and overall success that may be worthy of consideration. These include but are not limited to: • Get to the key studies that have maximal risk as rapidly as possible, minimising parallel processing until data supports an investment decision • Streamline SOPs and business processes • Staff with experienced drug developers • Minimise governance, maximise leadership accountability • Provide sufficient autonomy to facilitate rapid decision-making • Provide budgetary, sourcing, procurement and contracting authority to create an “act like an owner” culture • Consider TPPs an integral part of the team with decision-making authority • Utilise TPPs processes, tools, and templates when possible • Integrate functional strategies into long-term molecule development planning • Invest in technology to assist in effective communication and collaboration in a virtual environment.

As the pharmaceutical industry transforms its business practices, it will be interesting to see how many and what variety of butterflies are produced.

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

Neil V Smith is the Director of Regulatory Affairs for Chorus. He brings nearly 10 years of pharmaceutical research experience.

As Regulatory Manager, he is responsible for global regulatory strategy and submissions for all Chorus new molecule entities.

Terri A Roberson is the Director of Operations for Chorus. She brings over 15 years of pharmaceutical research experience. She is responsible for setting strategic direction and management of Clinical Operations, Portfolio Management and Information Technology at Chorus.

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Clinical Trials

Asian Clinical Trials

Managing patient reported outcomes Selecting the appropriate method/type of Patient Reported Outcomes administration has strategic importance in the preparatory stage of clinical trials.

In the results phase, PROs bring to the fore the patient’s perception of treatment benefit and its impact on function and quality of life with distinct influences from the countries and regions where data have been collected.

Gergana Zlateva, Director Alesia Sadosky, Director Global Outcomes Research, Pfizer Inc., USA Disclosure: Gergana Zlateva and Alesia Sadosky are full time employees of Pfizer Inc, USA.

T

he process of bringing innovative medicines to market has become increasingly more difficult and complex in the last decade.

More rigorous regulatory requirements coupled with restrictive policies for drug reimbursement have slowed down the rate with which major pharmaceutical companies are able to reach patient populations with new molecules.

Some recent evaluations point that it takes on average 14 years to bring a compound from discovery to approval with an average cost of US$ 1.2 billion.

Within these constraints, drug development programmes have begun including Patient Reported Outcomes (PROs) at early phases to explore opportunities for demonstrating product benefit in addition to well-established clinical markers assessed directly by physicians or diagnostic tests. PROs bring a very diverse perspective on medication benefit as

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perceived by the patient and thus offer a host of opportunities to substantiate the value of medicines. In order to be credible as evidence and acceptable to regulatory authorities, the process of selection, validation and administration of

PRO labels in drug promotion The inclusion of PROs in labels and advertising materials has been an important part of drug promotion in countries around the world. Mapi Research Trust has created the PROLabel Database examining the wording and types of PROs contained within approved product labels. The data comes from human medical products published on the websites of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Available at http://www.mapi-prolabels.org/

PROs in Clinical Trials (CTs) has to be carefully planned and executed.

Why use PROs in medical product development?

PROs bring a very enticing proposition to the clinical research front by allowing patients to provide additional confirmation of treatment benefit. Some treatment effects are known only to the patient and cannot be captured through formal clinical assessments. For example, pain intensity and pain relief are symptomatic measures reported by the patient and used in the development of analgesic products.

Other aspects of assessing the impact of a medication, such as capturing treatment satisfaction or preference for one type of drug administration versus other, are also solely based on patient input.

PRO measures can also augment clinical and psychological measures by providing evidence for patient improvement

Clinical Trials

that does not necessarily correlate with clinical measures. Finally, the significance of PROs in capturing changes in patient’s functioning and quality of life deserves attention as they are often used as a proxy measure in health economic modelling. These are just a few examples of the unique contribution of PROs. Linguistic validation

PROs are often developed in English and need to be translated in other languages before they are used. There are accepted standards for PRO translation, commonly referred to as linguistic validation. Standard practice includes four main steps: 1. Forward Translation: Two forward translations into the target language by qualified translators who should be native speakers of the target language, and fluent in English and production of a first consensus version from the two forward translations.

2. Backward Translation: Two back translations of the consensus version into English. Comparison of the back translations with the original version.

3. Respondent Testing and Cultural Validation: Testing of the second consensus version on a sample of lay respondents, native speakers of the target language. The lay respondents should include healthy individuals as well as patients.

4. Final Version: The final version produced after reconciliation of feedback from step 3.

Logistics of linguistic validation in Asia

A number of studies today are carried out in multiple countries and have a sponsor located in North America or Western Europe. Clinical trials in Asia, for example, would require a longer lead time to prepare the necessary linguistic validations. Asian countries typically have multiple dialects and identifying the appropriate language for the target PRO(s) will depend on site location and feasibility assessment. It is important to

What is a PRO? The United States agency regulating drug approval, the Food and Drug Administration (FDA), defines PRO as “A measurement of any aspect of the patient’s health status that comes directly from the patient (i.e. without the interpretation of the patient’s response by physician or anyone else).”

The European Medicines Agency (EMEA) gives a more detailed description of PROs: “Any outcome based on a patient’s perception of a disease and its treatment(s) scored by the patient himself is called a Patient-Reported Outcome (PRO). PROs are a large set of patient-assessed measures ranging from single item (e.g. pain VAS, overall treatment evaluation, and clinical global improvement) to multi-item tools. Multi-item tools can be mono-dimensional (e.g. measuring a single dimension such as physical functioning, fatigue, and sexual function) or multidimensional questionnaires measuring several of the following: symptoms, functional status, satisfaction, well-being, or health-related quality of life (HRQL). In general terms, PROs provide information on the patient’s perspective of a disease and its treatment.”

Demographics of patient population by region Characterstic

Asia (n=163)

Latin America (n=110)

Middle East (n=128)

Female, n (%)

92.0 (56.0)

77.0 (70.0)

75.0 (59.0)

Age, mean (SD) yr

56.6 (10.0)

59.4 (11.1)

55.9 (09.3)

• White

00.0

33.6

64.1

• Black

00.0

10.9

00.0

• Asian

100

00.0

34.4

• Other

00.0

55.5

01.6

BMI, mean (SD) kg/m2

25.5 (3.9)

29.0 (5.6)

30.6 (5.6)

Duration of DPN, mean (SD) years

02.4 (1.2)

02.9 (2.1)

02.9 (1.3)

Race, %

Table 1

Source: Pfizer data on file

start planning early when these languages fall in the “rare” group and when linguistic experts may not be easily available in the country where the sponsor is located.

Finally, respondent testing and cultural validation may require travelling to a remote location. Given the wide use of PROs in CTs, some widely used instruments have translations in many languages available on specialised websites, such as: www.proqolid.org, www.olga.org.

The EuroQol EQ-5D questionnaire, for example has currently 83 official language versions.

Choosing the appropriate data collection method for CTs in Asia

There are two major types of PRO

Countries enrolled in Asia, Latin America and the Middle East

Asia

N=413 Ecuador Argentina Chile Mexico Colombia Brazil Venezuela

Arab Emirates Jordan Lebanon Saudi Arabia Turkey

Source: Pfizer data on file

Korea Taiwan Philippines Indonesia Thailand Malaysia Singapore Figure 1

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Clinical Trials

Administration Types of PRO Administration • Self-administered • Interviewer-administered Mode of PRO Administration • Paper and pencil • Electronic (PDA, websites) • Telephone recording (IVRS) • Interviewer-administered

Pain severity and interference with function in DPN patients by region Asia (n=163) Latin America (n=110) Middle East (n=128)

10 9

Mean mBPI-sr item score

8 6.9 7.0

7

6.2

6

5.6 5.5 4.7

5 4 3 2 1 0

Pain Severity

Pain Interference

Source: Pfizer data on file

Figure 2

Mood impairment in DPN patients by region Worst Possible 21 Asia (n=163) Latin America (n=110) Middle East (n=128)

Mean HADS subscale scores

18 15 12 9

9.7 9.6 7.9

6

7.1

8.2 8.7

3 0

Optimal

HADS Anxiety subscale

HADS Depression subscale

Source: Pfizer data on file

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Figure 3

ISSUE - 9 2008

administration: self-administered and interviewer-administered. Both types can have multiple modalities of implementation. Among the self-administered methods, the most common ones are paper and pencil, a Personal Digital Assistant (PDA) or electronic diary, and a survey posted on a secure website.

Interviewer-administered methods include in-person interview, telephone interview with a trained interviewer, or prerecorded interview administered over Interactive Voice Response System (IVRS).

The choice of a PRO administration method should take into consideration cultural and ethnical specifics of patients to be enrolled in the trial. Important consideration of the method of administration of the PRO include: level of literacy of the subjects (intervieweradministered version is better for low literacy subjects), access to telephone or Internet (assessments via phone would not be possible in many cases), the presence of a large extended family who may bias the patient’s response if the questionnaire is completed at home. In the scenarios described above, a preferred approach has been investment in training site staff members in the patient interview process.

This approach secures consistent PRO administration over multiple protocol visits, allows patients to develop relationship of trust, and avoids the use of telephone, Internet and other media, as well as possible literacy issues.

What makes PROs so special? – A case study from Asia, Latin America and Middle East

When eliciting patient response using PROs, CT sponsors need to be aware of the impact culture, social norms, religion, health system, and social class among others, can play on the outcomes.

Subjects living in different countries report differences in health status perception as measured by the EuroQol-5D questionnaire. This variability in subjective assessments is well pronounced in multi-country trials, especially those conducted across continents. Below we

review an example from a randomised clinical trial conducted in patients with painful Diabetic Peripheral Neuropathy (DPN) in Asia, Latin America and the Middle East.

Case Study

The burden of painful DPN is a common complication of diabetes. The objective of this study was to expand on the human burden of painful DPN by quantifying the functional and health status impairment among international patients from a randomised, double-blind, placebocontrolled trial. The trial was conducted in 19 countries across three regions of the world; Asia, Latin America, and the Middle East (Figure 1). Seven countries or 40 per cent of the study population was from Asia.

A total of 401 patients met the study eligibility criteria and had baseline data collected. Of these, 163 patients were from Asia. The demographic characteristics of the study population (Table 1) reveal that Asian patients had a lower per cent of females, lower Body Mass Index (BMI) and a shorter duration of DPN. Pain severity and interference with function were measured using the short form of the modified Brief Pain Inventory (mBPI-sf ), consisting of three questions related to pain severity and seven questions related to interference with walking ability, general activity, normal work, mood, sleep, relations with other people, and enjoyment of life. The average of the three severity items and seven interference items allow one to calculate the Pain Severity Index and Pain Interference Index, respectively.

Using an 11-point numeric rating scale (0 = no pain, 10 = worst possible pain), Figure 2 demonstrates the moderate to severe levels of pain and interference in DPN patients. Notably, Asian patients reported the lowest levels of pain severity and interference among the three regions.

Mood was assessed using the Hospital Anxiety and Depression Scale (HADS),

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Sleep impairment in DPN patients by region

Asia (n=163) Latin America (n=110) Middle East (n=128)

90 80 70 60 50 40

49.4 47.7 43.8

25.8 47.1

30 20

US DPN sample (n=255)

Asia

0 Optimal

US general population

10 Latin America

Mean MOS sleep problems index scores

100

Middle East

Worst Possible

Figure 4

Source: Pfizer data on file

Health status in DPN patients by region 100 82.7

60

56.7

53.2

77.8

49.3

40

20

Source: Pfizer data on file

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Japan general population

UK general population

Middle East (n=128)

Latin America (n=110)

Asia (n=136)

0

Figure 5

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Authors

Mean EQ-50 VAS(0-100)

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which consists of seven items contributing to an anxiety subscale and another seven to a depression subscale. On a scale of 0-21, patients reporting 0-7 are categorised as normal, 8-10 mild, 1114 moderate and 15-21 severe. While most patients reported mild levels of anxiety and depression, Asian patients reported the lowest levels of the three regions (Figure 3).

Patients with painful DPN commonly experience sleep problems and the Medical Outcomes Study (MOS) Sleep Scale was completed by patients to assess sleep. The MOS Sleep Scale is a 12-item measure that produces six subscales in addition to a 9-item Sleep Problems Index. Comparing subjects from Asia, Latin America, and the Middle East to general population norms in the US (Figure 4), it is apparent that DPN patients have higher scores (0-100 range, higher scores indicate more of the problem) or greater sleep impairment than the US population. Scores were comparable to a separate US study in DPN patients, suggesting the difference is not due to cultural differences between the US and abroad. Again, Asian patients tended to report lower levels of sleep disturbance of the three regions although still well above general population norms.

Health status of patients was examined using the EQ-5D, a wellestablished self-report measure consisting of five items that assess the level of difficulty for five domains; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-

5D also includes a Visual Analog Scale (VAS) that assesses patients’ perceptions of their overall health status (0-100 range, 0=worst imaginable health state, 100=best imaginable health state). Scores for patients with painful DPN were consistently lower than those reported for the general population of Japan or the UK. More importantly, Asians perceived their overall current health status to be better than those patients in the other two regions.

Summary

Patients in Asia, Latin America and the Middle East reported substantial burden of illness attributable to their painful DPN, consistent with what has been reported in the US and Europe. Patients in Asia reported less severe problems overall with respect to pain, pain-related interference on routine activities, sleep, depression, and anxiety relative to patients in Latin America or the Middle East.

Factors that may influence lower scores include lower BMI and shorter duration of illness in Asian patients.

Cultural differences may also contribute to patients’ perceptions, beliefs and coping strategies regarding pain and health perception. Instrument differences may also play a role in how patients rate the relative importance of quality of life measures.

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

Gergana Zlateva is currently the Team Leader for the Lyrica Outcomes Research team at Pfizer. She holds a PhD in Economics from Fordham University, NY and a BA and MPA from Southern Illinois University, USA.

Alesia Sadosky supports Lyrica’s pain indications in Outcomes Research at Pfizer. She holds a PhD in Biological Chemistry from Penn State’s College of Medicine, completed a postdoctoral fellowship and MPH from Columbia University and holds an MBA in Finance from the University of Connecticut.

Clinical Trials

Paediatric Drug Development

Taking a practical approach Conducting clinical studies in children is often a difficult undertaking. However, with proper planning and using the right resources, one can run safe, timely and successful trials in this challenging population.

Laurence Flint, Associate Director, Clinical Research, Schering-Plough Research Institute, USA

I

t’s no secret that clinical research has steadily become more challenging and costly. Patients are difficult to recruit, regulations are more stringent and complex, and patient expectations are very high. However, these realities of our field can be seen no more clearly than when attempting to develop medicines for children.

With the advent of legislations aimed at boosting paediatric drug trials, such as the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) in the US and, most recently, the 2007 Paediatric Regulation in the EU, paediatric clinical research is a hot topic for regulatory agencies and subsequently for sponsors as well.

Goals of paediatric development

Considering that the needs of the patient are always our first priority, our primary goal as researchers is to decrease the disease burden on the subject (and ultimately the paediatric population as a whole) while minimising their risk and discomfort. In order to reach this goal and to maximise time and resources, one must try to optimise protocol

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design, and boost subject recruitment and retention while adhering to applicable regulatory guidelines. Once these patient-centred goals are met, the sponsor should then seek to achieve alignment of the clinical needs and regulatory requirements with the commercial objectives of the company.

Historical context

Until recently, most drugs used in children did not have paediatric labelling or the clinical research to support that labelling. Barriers to paediatric research that led to this lack of information include logistical and technical constraints, limited study populations, and most importantly, the economic disincentive to run expensive trials often for a very small return on investment. Additionally, efforts over the last half of the 20th century, such as the Declaration of Helsinki, intended to protect human subjects (particularly “vulnerable” populations such as children), while going far to achieve that goal, had the unfortunate side effect of severely limiting much of the research on those populations as the ethical bar was raised. In 1963, Dr Harry Shirkey first used the term, “therapeutic orphan” to describe the predicament that children are in within the context of inadequate drug research.

The current environment

Patient safety and the use of evidencebased medicine are of vital importance to the current medical treatment paradigm. In order to make good clinical decisions, healthcare providers need information that is only available from well-executed clinical research across all age groups. This information now becomes even more critical as many more children are taking prescription medication than ever before. A recent study of US prescription claims data from 2002 to 2005 of children 5 to 19 years of age revealed that the use of chronic medication (such as used in type 2 antidiabetic, ADHD and

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Practical tips for planning your paediatric trials Plan early and engage all key players at the beginning of strategic development Do your competitive and regulatory intelligence Develop a global network of paediatric KOLs and investigators Be creative in your clinical designs, e.g. adaptive trials Aim to do the trials you have to do, while doing the trials you want to do Approach health authorities with the ideas and science to back up your plans Always keep the patient and the parent in mind Know your adult data Know your customer: use patient advocacy groups, blogs, chat rooms etc.

Identify the critical developmental changes in drug metabolism, actions and effects on organ systems in your target paediatric population

asthma) increased, often dramatically, across all therapy classes assessed.

However, compare these findings with those obtained in a 2008 University of Michigan study which showed that 77 per cent of parents want only FDAapproved medicines for their children, yet only 30 per cent said they would allow their children to participate in research. In addition to reasonable concerns over the safety of their children, the public generally have a negative view of the pharmaceutical industry and are often wary of the healthcare system in general.

So, as researchers, we must balance the need for creating more paediatric drug knowledge with limiting exposure to risk in this unique population. We must also contend with the reality that parents demand only the best for their children, but are often unwilling to put them in clinical studies that yield the critical information needed to provide this quality data. With this in mind, how does one approach the enigma of paediatric research?

Paediatric study design

A well-written and straightforward protocol is the cornerstone of a good trial, and will go a long way towards assuring reliable data and optimal enrollment timing. Choosing clear and reasonable endpoints that answer the most important clinical questions being asked in the study should always be a priority, and in order to maximise the pool of potential subjects, one should minimise inclusion / exclusion criteria to only what’s absolutely necessary.

One fundamental step towards optimal recruitment and retention would be to ensure that minimum burdens are placed on subjects and their patients.

Anyone with children knows how busy life can be! Consider the modern realities of single parent households, families where both parents work outside of the home, and how today’s children are woefully overscheduled. Clinical researchers need to design studies

Clinical Trials

Recruitment and retention

Parents or guardians are generally very concerned about their children’s health, even if they are not necessarily as vigilant about their own. Because of regularly scheduled well-child visits and the need for frequent vaccinations, families are often in regular contact with their paediatricians. Therefore, parents usually put great trust in the opinion of their paediatrician and generally consult them about what they think about the clinical study.

Protocols, informed consent forms and other documents that will be read by parents and healthcare providers need to be straightforward and well written, and also fully explain the study’s procedures, schedules, and risks and benefits. Parents, particularly those with children who have rare or serious diseases, or have multiple health problems, are very informationliterate and will go onto the Internet not only to do research, but to share the details of the trial and compare notes with others in chat rooms, blogs or on specific support group sites. Safety is of paramount importance, and all current preclinical and clinical safety data derived from other paediatric trials, adult trials and, if applicable, marketing experience should be provided. Sponsors should be prepared to answer very pointed questions about their trial in an honest, intelligent and clear way.

Parents expect nothing less than complete transparency and an experience that preserves the dignity of their children. Poorly designed trials or research groups who provide anything less than excellent service and caring will not only fail to recruit or retain subjects, they will quickly gain a bad reputation as word spreads fast among online communities of parents and healthcare providers.

Use the best resources available

There are people and resources with the paediatric expertise that can assist you with your studies. First, consider those who are close at hand. Identify colleagues with paediatric experience and training within your own organisations who can assist with the review of paediatric clinical protocols and trial data, address national and global paediatric policy and regulations, and work with others to create

Author

around the lifestyles of all impacted parties, keeping in mind that parents work, older children attend school and that there may be siblings who require time and attention as well. This does not leave much time for participation in a complicated and / or lengthy clinical trial. Some of the ways that help to streamline trials include limited diary and recordkeeping requirements for the subjects, and minimal lab draws and / or study visits. Consider scheduling enrollment period during “child-friendly” times such as over summer vacation, allowing less intensive follow-up visits to be done during the school year. Also, if at all practical, substituting house calls for clinic visits can be a tremendous aid in assisting families to participate.

Fear of procedures is big concern for children. This should be addressed upfront, and all efforts to minimise the number of procedures (particularly invasive ones such as needle sticks) should be taken. When procedures are unavoidable, pain and discomfort need to be decreased as much as possible. Measures to achieve these ends include the use of topical anaesthetics (e.g. EMLA cream) for all needle sticks, and attempting to use facilities that have professionals (i.e. child-life specialists) whose job it is to minimise the negative impacts of medical treatment, including procedures, through age-appropriate education and interaction and a variety of distraction or coping techniques (e.g. bubble-blowing, story-telling).

unified paediatric processes, templates etc. Outside your organisation, there are investigators, study coordinators, IRBs and CROs with expertise to study drugs in children who may be available to help you. There are many dedicated paediatric research centres and collaborative research groups (e.g. Children’s Oncology Group) who already have networked centres able to provide access to sub-specialists and their patients. Paediatric formulation experience is also generally needed as many adult drug forms or strengths are inappropriate for children. This may mean formulating syrups, liquids or chewable tablets with palatable flavourings suitable to children. Sponsors should allow adequate lead-time for reformulation efforts. For laboratory testing, analytical methods that allow for smaller clinical sample sizes should be sought out.

Finally, one should consider unique solutions such as adaptive clinical study designs, and take a global approach to studies. A successful study involves identifying locations of subject populations and centres of excellence that have the necessary capabilities. This may involve considering the inclusion of subjects in the developing world where opportunities to make a significant impact on the health of children are numerous.

While running clinical studies on children is difficult, it is by no means impossible. Success not only requires that researchers expand their skill sets and acquire the specialised resources to assist them, but it also calls for a personal commitment to this very special population of subjects and the families that care for them.

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

Laurence Flint is a board certified paediatrician and Associate Director of Clinical Research in the Allergy, Immunology, and Respiratory group at Schering-Plough Research Institute. Laurence holds a BS in Biology and English from the University of Scranton, an MS in Biology and an MBA from Fairleigh Dickinson University, and a medical degree from UMDNJ-New Jersey Medical School.

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Optimising Development Costs PRTM Management Consultants, Japan

T

he global financial crisis is impacting almost all industries—including pharmaceuticals. Minimising cost is a growing focus in the industry. In Asia, the impact comes in two forms. On one hand, pharma companies are motivated to scale their development operations to cover low cost countries. On the other hand, there is increasing scrutiny on development costs in Japan. Indeed, it has become a pressing issue for the heads of R&D in Japanese subsidiaries of global pharma companies. Many say that clinical development costs in Japan are at least twice as much as those in the US. Meanwhile, PRTM survey data shows that even the best companies run at about a 30 per cent premium in Japan.

Executives have three “levers” available to them to manage clinical development operational costs such as: 1) Taking advantage of low cost countries in Asia and other areas around the world, 2) Outsourcing specific operational activities, and 3) Implementing “lean” clinical development practices.

With deep experience in the pharmaceutical development, PRTM understands that none of these levers are easy to use.

However, successful companies are developing the necessary management discipline to effectively utilise these levers.

1. Off-shoring clinical development operations—to low cost countries in Asia and elsewhere in the world—will soon become a standard tool in defining a global clinical development strategy. Plans now need to take care of many requirements

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such as diverging regulatory requirements from a wide variety of countries—as well as total program cost. Cost data shows that cost per patient runs as much as 60 per cent lower in Asia than that in the US (2007 data). Meanwhile, Japan’s regulatory agency, MHLW, has become open to using global and Asian patient data for filing. However, this requires the proper infrastructure and processes for success. At this time, most global pharma organisations are not organised properly in Asia.

Cost per patient index 2007 (US=100) 100 All TAs

US

47

41

37

Taiwan

Korea

China

33

India

2. Outsourcing clinical operations is also an increasingly common practice— including in Japan. This often provides organisations with increased resource flexibility and can help reduce overall cost. In spite of this goal, operational managers in pharma companies often complain that using CROs results in higher costs than using employees. Some global companies

Authors

Christopher R Albani, Managing Director Yorozu Tabata, Partner

have even decided to reduce outsourcing.

On the other hand, successful pharma companies are able to realise reductions of as much as 20 per cent. Successful companies have established specific management practices to effectively work with outsourcing partners.

3. The third lever is to establish lean clinical development practices.

This involves the concept of solving the fundamental issue of clinical operations— namely inefficient site-management.

Leading pharma companies are applying global best practices such as preferred site selection, remote monitoring, or sampling Source Data Verification (SDV). Often, companies try to apply these practices, but give up midway. However, successful implementations of global best practices have resulted in productivity improvements of around 30 per cent.

Pharmaceutical industry executives have various levers available for optimising development operational costs.

The core of competition is developing a disciplined management team which effectively creates a sense of organisational urgency, understands the nature of the effort, and skillfully operates the available levers to achieve cost targets. With the right approach, companies can achieve significant improvements.

For more information, please contact calbani@prtm.com or ytabata@prtm.com

Christopher Albani is a partner with PRTM and leads our Japan business as well as our Asia life sciences team. With more than 23 years of experience in healthcare, Chris has worked with companies around the world on many areas—including clinical development.

Yorozu Tabata is a partner with PRTM Japan specialised in life sciences in Japan. Yorozu has worked with global and domestic pharmaceutical as well as medical device companies.

Trifunctional Antibody Format

Concept and first drug candidate Trifunctional antibodies represent promising new cancer therapeutics based on a unique mode of action. The first drug candidate catumaxomab showed strong anti-tumour efficacy in a pivotal phase II / III trial in advanced cancer patients. The clinically relevant primary and several other secondary endpoints were reached with high statistical significance resulting in a clear clinical benefit for the patients. Thus, the expected European market approval for catumaxomab will mark a prominent milestone in the development of bispecific antibodies per se.

Horst Lindhofer, CEO, TRION Pharma GmbH, Germany

T

riomab® antibodies represent a new generation of antibodies that incorporate a novel mechanism for the treatment of cancer.

Trifunctional antibody chimaeras consist of light and heavy chains originating from parental mouse IgG2a and rat IgG2b monoclonal antibodies each with different antigen binding properties: • One binding site for the interaction with tumourassociated antigens (TAA) like EpCAM and HER2/neu or CD20 on appropriate tumour target cells like carcinomas or lymphomas, respectively; • The other binding site for CD3 recognition on polyclonal T lymphocytes; and • Finally, the intact Fc region with its functional binding features for activating Fcγ receptor type I (CD64)-, IIa (CD32a)- and III (CD16)- expressed on accessory cells.

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Importantly, this chimeric mouse / rat Fc portion does not or only marginally bind to the inhibitory receptor FcγRIIb e.g. on B lymphocytes and platelets.

In contrast, most of the approved therapeutic antibodies exert their antitumour efficacy via antibody-dependent cellular cytotoxicity (ADCC) evoked

by FcγR-binding on accessory cells alone.

Taken together, as immunotherapeutic, success critically depends on the number of recruitable effector cells at the site of tumour growth, the triomab® antibody format utilises different cellular defence pathways leading to enhanced elimination of malignant cells.

Triomab® antibodies for cancer therapy – Mode of action

The triomab® antibody concept is conceived as a platform technology in the development of trifunctional antitumour antibodies by utilising anti-CD3 engagement. Three antibody products of the triomab® family are currently in clinical development: anti-EpCAM x anti-CD3 catumaxomab (Removab®), anti-HER2/neu x anti-CD3 ertumaxomab (Rexomun®) and anti-CD20 x anti-CD3 FBTA05.

Ideally, the triomab® antibody configuration enables the formation of tri-cell complex composed of three cell types: tumour cell, T-cell and accessory cell like monocytes, macrophages, natural killer or dendritic cells. The juxtaposition of polyclonal T-cells and accessory cells within these complexes promote the costimulation and synchronous activation of both effector cells in the close vicinity to tumour cells. Co-ordinated signalling events required for efficient tumour cell destruction are induced subsequently. As a final result, the tumour target cells are simultaneously subjected to a variety of immune effector mechanisms regulating destructive processes, such as phagocytosis and perforin-mediated necrosis.

One of the important hallmarks of triomab® therapeutics is described

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Triomab® Antibody Technology The triomab® technology is a major step forward in the development of intact bispecific antibodies for cancer therapy. By addressing the CD3 signalling properties together with the stimulatory FcγR-directed features, efficacious immune effector mechanisms are combined for concerted tumour defence.The implication of FcγR+ cells has additional impact on stimulating immune responses towards longlasting anti-tumour immunity.

Furthermore, the utilisation of the heterodimeric structure of the murine / rat Fc region represents an important breakthrough in the manufacturing of these biopharmaceuticals at industrial scale.

by the efficient dose-response profile.

Already four intraperitoneal catumaxomab infusions of 10, 20, 50, 150 µg within 11 days sufficed for clinical benefit against Malignant Ascites (MA) in a pivotal phase II / III study.

In vitro, this favourable dose-response

relationship of triomab® products at ng/ ml concentrations is best documented by the efficient capacity to mediate lysis of tumour cells even with low surface density of the target antigen.

For the induction and maintenance of an efficacious anti-tumour response, the pro-inflammatory cytokine milieu (e.g. interferon-γ, interleukin (IL)-1, IL-6, IL-12 and tumour necrosis factorα) stimulated by triomab® antibodies is especially important. By secretion of IL-2 the self-supporting maintenance of the immune response is provided without the need for further co- or restimulation in vivo (e.g. w/o additional administration of IL-2). All these specific triomab® properties are aided by the reasonable pharmacokinetic and toxicological profile of these antibodies (e.g. slow renal clearance rate and avoidance of severe adverse events such as a devastating ‘cytokine storm’).

Remarkably, the activation of monocytes, macrophages and dendritic cells with subsequent phagocytosis of tumour cells is a prerequisite for the induction of an anti-tumour immunity and links thereby passive to active immunisation.

Thus, secondary humoral and cell-mediated immune responses are raised even against TAA different from the antigen targeted by the therapeutic antibody.

These active in situ immunisation events highlight the underlying therapeutic opportunities as long-standing antitumour responses could be induced.

Consistently, preliminary analysis of autologous antibodies in sera from head and neck carcinoma patients resulted in 6-fold increased humoral anti-tumour IgG3 titres lasting longer than three months after catumaxomab therapy.

Thus, triomab® antibody therapy has the capacity to immunise patients specifically against their own primary tumours.

In summary, triomab® tumour destruction is mediated both by targeted anti-tumour cytotoxicity and the co-ordinated induction of innate, humoral and cell-mediated immune responses.

CLINICAL TRIALS

First triomab® pivotal study – AntiEpCAM x anti-CD3 catumaxomab

Based on these structural and therapeutic features one important candidate of the triomab® family catumaxomab represents the first bispecific anti-tumour antibody per se that clearly meets its expected clinical endpoints in a pivotal phase II / III study. Due to the high medical need, patients suffering from malignant ascites received priority in the clinic development programme for catumaxomab of our partner Fresenius Biotech. Malignant ascites is a manifestation of an advanced disease in a variety of indications like ovarian, breast or gastric cancer and is characterised by strong fluid influx and tumour growth into the peritoneal cavity. The onset and progression of MA is associated with significant morbidity and deterioration in quality of life. The prognosis of MA patients is generally poor. The median survival following diagnosis of ascites varies from 75 days (non-ovarian) up to 7-12 months (ovarian).

Briefly, more than 250 patients suffering from epithelial ovarian cancer or non-ovarian cancer with confirmed EpCAM+ MA were enrolled and randomised to catumaxomab treatment (one paracentesis plus four subsequent intraperitoneal infusions of 10, 20, 50, 150 µg within 11 days) or to control intervention (paracentesis alone as best supportive care). Puncture-free survival was defined as the primary endpoint of the pivotal clinical trial. With 46 days for catumaxomab therapy versus 11 days for control treatment the median of puncture-free survival reached high statistical significance (P<0.0001) underlining the potency of the catumaxomab treatment even in MA patients with such a poor prognosis. Moreover, median puncture-free time was 77 versus 13 days (P<0.0001) demonstrating a clear gain in life quality. Most importantly, tumour cells were nearly completely eliminated from ascites fluid indicating the induction of prominent catumaxomab-mediated anti-tumour responses.

Self-supporting Proliferation

Killing MHC-independent

T-Cell

Tumour Cell TAA or CD20

IL-2

CD3

Activation IL-1, IL-2, IL-6, IL-12 TNF-α,IFN-γ

CD40L / CD28 / CD2 CD40 / CD80-CD86 / LFA-3

ADCC Phagocytosis FcyRI/IIa/III+

Accessory Cell (e.g. monocytes, macrophages, natural killer or dendritic cells)

anti-TAA anti-CD20 mouse IgG2a

anti-CD3 rat IgG2b

triomab® antibody heterodimers

Figure 1

Pyrexia, nausea, vomiting and a transient elevation of liver enzymes representing the most frequent adverse events were generally mild to moderate and fully reversible. In summary, patients with EpCAM+ MA did benefit from catumaxomab therapy by the prolongation of puncture-free survival and the reduction of ascites symptoms in comparison with MA patients receiving palliative paracentesis only. Furthermore, as EpCAM is frequently over-expressed, e.g. on prostate, breast, lung, colon, ovarian or gastric carcinomas, catumaxomab may offer novel future treatment opportunities against a variety of cancer diseases.

Immunogenicity and the therapeutic concept behind triomab® antibodies

As triomab® antibodies are of foreign nature with respect to the human immune system, it is not surprising that human anti-mouse (HAMA) and antirat antibodies (HARA) were induced in patients with proceeding antibody applications. Nevertheless, results from clinical studies demonstrate that triomab® antibodies given within a treatment window of 2-4 weeks—prior to the induction of neutralising HAMA / HARA responses—may be sufficient for the therapeutic benefit in many cancer indications. Furthermore, triomab® antibodies may be central to the induction of long-lasting secondary anti-tumour

responses as shown by the induction of anti-idiotype antibodies in an immunocompetent mouse tumour model. What is the immunological concept behind this mechanism?

Briefly, consistent with the danger model self-tolerance is acquired through reduction of the relative immunogenicity of self-antigens like the idiotype of a B cell or other TAA, whereas foreign antigens like microbial proteins, typically not presented during induction of deletional tolerance in the thymus, retain a high degree of relative immunogenicity such as in case of the foreign triomab® antibodies. Thus, TAA that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. Accordingly, any given TAA auto-antigen can attain a high level of relative immunogenicity, provided that

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potency of this promising IgG-like antibody format in vivo. Nevertheless, in terms of clinical development the two anti-CD3 binding sites of this structure bear increasingly the inherent risk of stimulating adverse events such as the ‘cytokine storm’. Taken together, the triomab® antibody catumaxomab with ‘natural’ IgG shape currently represents the only bispecific antibody format that already met therapeutic expectations in a pivotal phase II / III trial.

Future perspectives

Other bispecific antibody approaches

As the biopharmaceutical manufacturing of bispecific antibody represents a real challenge, many different antibody formats have evolved along the progress in recombinant protein expression. In contrast to trifunctional triomab® antibodies produced by quadromas (hybrid-hybridoma cells), nearly all of these recombinant formats lack the Fc region. Due to their small size these antibodies have a short half-life in vivo, thus continuous infusions are usually required to maintain serum antibody concentrations that are central to efficacious anti-tumour responses.

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A recombinant bispecific antibody format with IgG-like shape but tetravalent binding specificities for epidermal growth factor receptor (EGFR) and CD3 has been described recently. This Fc region-bearing antibody assembles from two different (scFvA)-CL and (scFvB)-CH1-CH2-CH3 entities due to the preferential interaction of the CL light with the CH1 heavy chain domain of human IgG1 molecules. Therefore, this bispecific antibody represents a homodimeric structure consisting of Fc region and two recognition sites for EGFR and CD3 binding, respectively, on each half-antibody. In vitro killing experiments of tumour cells in the presence of peripheral blood mononuclear cells showed that this tetravalent bispecific antibody format was in the efficacy range of triomab® antibodies. Future preclinical experiments may prove the anti-tumour

Author

it is presented at sufficiently high levels accompanied in a pro-inflammatory micro-environment. Catumaxomab and other triomab® antibodies induce this beneficial Th1-biased cytokine milieu with the release of IFN-γ, IL-2 and IL-12 for the priming of long-lasting tumour defence mechanisms by (i) their per se foreignness and by (ii) their anti-CD3 and anti-FcγR engagement leading to phagocytosis of tumour cells.

Besides the clinical development programme of catumaxomab against EpCAM+ cancer diseases, ertumaxomab treatment of HER2 / neu-expressing breast cancer patients and FBTA05 against B cell malignancies, novel target antigens will be implemented into the triomab® technology platform as e.g. proteoglycans for melanoma. To a certain extent, the further development of the triomab® platform itself e.g. towards antibody chimerisation is conceivable provided that the heterodimeric nature of these antibodies will be retained for certain downstream processing steps. In the light of long-lasting antitumour responses immunomonitoring will be broadened during future clinical trials with triomab® antibodies (e.g. catumaxomab). This surveillance of the immune status will also comprise analysis of CD4+ CD25+ FOXP3+ regulatory T cells and humoral anti-tumour responses. Importantly, as anti-CD3 triggering by triomab® antibodies affect regulatory T cells the behaviour of this T cell subpopuation in context with effector CD4+ and CD8+ T cells may also give a better understanding of this regulatory network behind cell-mediated anti-tumour immunity.

Horst Lindhofer is the founder and CEO of TRION Pharma GmbH. TRION Pharma is a privately held biopharmaceutical company that has established the triomab® approach towards cancer immunotherapy.

CLINICAL TRIALS

Offshoring

Cost-effective clinical research In response to growing pressure to improve the efficiency of the drug development process, many pharmaceutical and biopharmaceutical companies are turning to emerging markets to reduce R&D costs and speed development times.

Kenneth I Kaitin, Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA

T

hese are very challenging times for the research-based pharmaceutical and biopharmaceutical industry. While profits have remained relatively high for many of the top-tier companies, stock prices have tumbled precipitously. Since 2001, market capitalisation for the major companies has dropped cumulatively about US$ 580 trillion. In other words, over the last seven years, despite positive revenue growth, the large pharma sector has lost over a half trillion dollars in value. How does one explain the counter-intuitive finding of high profits and low stock values?

The likely answer is that investors have lost faith in the ability of pharmaceutical firms to bring new drugs to market, to contain spiralling research and development costs, and to mitigate the high rate of pipeline failures. The substantial decline over the past decade in the rate of new drug introductions globally dramatically underscores the scope of the problem.

Over the past 32 years, the Tufts Center for the Study of Drug Development (Tufts CSDD) has documented the time, cost, and risk of new drug development.

Based on recently published data, Tufts CSDD estimates that the average capitalised cost to bring one new biopharmaceutical product to market, including the cost of failures is US$ 1.24 billion in 2005.

These high R&D costs can be attributed

to a variety of factors, including industry’s growing utilisation of expensive discovery technologies, such as high-throughput screening, combinatorial chemistry, and pharmacogenomics. Other factors include industry’s increasing emphasis on developing products for chronic and complex indications, and the rapid growth in the size of clinical studies. Larger clinical studies require the recruitment and retention of greater numbers of study volunteers. As a result, subject enrollment has become a formidable bottleneck in many drug development programmes. Finally, high candidate attrition rates and late-stage failures in the development process, two areas where industry has not been able to improve significantly its performance over the years, continue to exert a profound impact on high overall R&D costs.

Current Tufts CSDD data indicate that the average time to bring a new pharmaceutical product to market, from the start of clinical testing to FDA approval, is 8.5 years, and the clinical success rate is 21.5 per cent. (Clinical success rate refers to the likelihood that a candidate beginning clinical testing will eventually reach the marketplace.) It should be noted, however, that these figures vary considerably based on therapeutic class. For example, in the neuropharmacologic area, which includes drugs for Alzheimer’s disease, schizophrenia and depression, the time from initiation of clinical studies to regulatory approval

is 10.8 years, and the likelihood of clinical success is 14 per cent, and for oncology drugs, those numbers are 9.3 years and a very dismal 8 per cent, respectively.

Across the pharmaceutical and biotechnology industry spectrum, companies are re-examining old and inefficient models of R&D and embracing new approaches to enhance productivity and performance, in an attempt to bolster efficiency. In particular, companies are expanding their R&D activities into emerging and lower cost markets, increasing their utilisation of strategic outsourcing, growing their use of information technologies in clinical trial protocols and patient recruitment, and speeding the adoption of enhanced clinical study designs, including adaptive clinical trials. In addition, many companies are re-evaluating their emphasis on blockbuster drug development strategies, that is, those focussing on broad disease areas with large sales potential, and are turning their attention to R&D strategies that address narrower patient populations, unmet medical needs, and personalised medicines. Across the industry, many companies now acknowledge that small incremental improvements in R&D efficiency will not be sufficient to remain competitive in today’s challenging economic environment. Rather, companies must embrace transformational change in the R&D paradigm, by identifying and eliminating inefficiencies in the

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CLINICAL TRIALS

Offshoring opportunities

Today, nearly every major pharmaceutical company is conducting a portion—in some cases over 50 per cent—of its ongoing clinical studies in emerging markets, and that number is certain to grow in the coming years. In fact, major drug sponsors project that, within the next three years, up to 65 per cent of Food and Drug Administration (FDA) regulated clinical studies will be conducted outside the US. The move of US- and Western Europe-based pharmaceutical companies to conduct an increasing share of clinical studies in emerging markets has fuelled a rapid growth in the number of clinical investigators registered to conduct FDA regulated clinical studies. A recent Tufts CSDD analysis of the FDA’s Bioresearch Monitoring Information System (BMIS) database reveals a staggering 379 per cent increase between 2000 and 2006 in the number of registered clinical investigators in China and Russia, and a whopping 433 per cent increase in India.

Initially, the primary inducement for moving drug development activities outside of the US and Western Europe was the opportunity to conduct trials at a fraction of the cost of conducting those same studies in the companies’ home market.

For example, an analysis by A.T. Kearney estimated that the average cost to conduct a clinical study in one of the so-called BRIC countries (Brazil, Russia, India, and China) ranges from 61 per cent of US costs in Brazil, to 40 per cent of US costs in Russia. Similar savings are seen in other Central and Eastern European, as well as Latin and South American countries.

Despite the cost advantages, many major pharmaceutical companies now suggest that cost savings is no longer the primary reason for conducting clinical studies in emerging markets. Rather, companies are attracted by the opportunity for rapid enrollment of subjects for clinical trials, a major bottleneck in the drug development process in the West, and the resultant

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promise of obtaining regulatory approval and reaching the marketplace more rapidly.

Faster access to the market means that companies can start generating revenues on the product earlier and can extend the period of effective patent life.

Rapid patient enrollment also means that sponsors can establish proof-ofconcept more quickly, and can potentially avoid expensive and unnecessary Phase III trials on products that are destined to fail in development. Moreover, studies conducted concurrently in a developing country and in the US or Europe can provide data to supplement FDA or European Medicines Agency (EMEA) applications. Also, large patient populations and disease-specific clinics can facilitate clinical trials on disease subsets and speed the development of personalised or stratified medicines.

There is an additional reason why companies are interested in establishing a presence in certain emerging markets.

The reason is that some of these countries will likely be significant economic forces and offer large potential markets in the future. According to the Indian Council for Research on International Economic Relations, the US currently comprises 21 per cent of the world’s Gross Domestic Product (GDP), but that number is expected to drop to 15 per cent by 2035. During the same time period, however, India’s share will grow from 6 per cent to 15 per cent, and China’s will grow from 11 per cent to 27 per cent. Those companies that have development and manufacturing capabilities and a distribution network already established in these emerging markets will have a distinct competitive advantage in the coming years over companies without such capabilities.

The interest of Big Pharma in conducting an increasing share of cliniAuthor

drug development process, and adopting approaches that will boost performance and productivity.

cal studies in emerging markets has not been overlooked by the governments of these countries. Seeing the opportunity to bring needed money and staff training to hospitals, medical schools, and regional research centres, stimulate the domestic life sciences industry, and boost local economic growth, many developing countries have invested heavily in improving drug development infrastructure and reducing bureaucratic obstacles.

Many emerging markets, including Brazil, Chile, Argentina, China, India, and the countries of Central and Eastern Europe, have bolstered the local drug development landscape in an effort to attract Western investment. These efforts not only resulted in growth in their clinical development capabilities, but also significant expansion of research and discovery capabilities.

In addition, many developing countries now offer a broad availability of trained and skilled human resources, a growing number of both local and multinational Contract Research Organisations (CROs) and other service providers, improved standards for pharmaceutical manufacturing, and more efficient regulatory oversight of the drug development process.

Despite these efforts, many challenges remain for emerging markets that wish to be major players in the global drug development landscape. Underdeveloped infrastructure, ethical oversight, inadequately trained local investigators, and unreasonable bureaucratic hurdles in developing countries continue to represent significant concerns for drug sponsors. Much work still needs to be done to reassure drug developers and regulatory agencies that studies conducted in emerging markets conform to the highest standards of ethics and quality. Achieving that could be a win-win situation for the multinational research-based industry, developing countries, and waiting patients.

Kenneth Kaitin is Director of the Tufts Center for the Study of Drug Development, an academic drug policy research group, and Professor of Medicine at Tufts University School of Medicine in Boston, Massachusetts, USA.

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SpecialFeature

The Biomarkers Consortium is an opportunity for public and private entities to join forces and pool resources in order to advance biomarkers research, an exciting and challenging mission. This novel experiment is an exciting and challenging endeavour that is presently undergoing evaluation and restructuring in some areas, to improve and optimise the identification, funding, and implementation of crosssector biomarker projects.

The Biomarkers Consortium Advancing Biomarkers Research

B

Shawnmarie Mayrand-Chung is the Director for the Biomarkers Consortium at the National Institutes of Health. She facilitates NIHâ&#x20AC;&#x2122;s collaborations that improve the public health through biomedical research by providing guidance and advice to NIH scientists and their potential partners. Additionally, she works directly with the NIH directors and scientists on all aspects of the Consortium, and works closely with the foundation for NIH.

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iomarkers have the potential to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials, and regulatory decision-making for drugs and therapeutics. This promise serves as the foundation and impetus for a novel public-private partnership initiated in October 2006 and known as The Biomarkers Consortium (BC). BC partners represent government, pharmaceutical and biotechnology industry, patient advocacy groups, private organisations and the public. All partners share the common interests of discovery, development and qualification of biomarkers for use across the spectrum of biomedical research and practice. The Foundation for the National Institutes of Health (FNIH), a free-standing charitable foundation with a congressionally-mandated mission to support the mission of the NIH, is the managing partner for the BC. The National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), The Pharmaceutical Research and Manufacturers of America (PhRMA) are the consortiumâ&#x20AC;&#x2122;s founding partners. The BC is unique in its commitment to working together in a cross-sector and pre-competitive fashion.

Mission

The genesis of the Biomarkers Consortium was initially with PhRMA, the trade organisation for the pharmaceutical industry. In discussion with the NIH and FDA, the shared need for robust and meaningful biomarkers, well characterised for use and widely available to all, was self-evident.

In light of the differing missions of the parties, the value of biomarkers to each also differs somewhat, but the need is compelling for each of the partners. Furthermore, the value proposition for working in the context of a public-private partnership provides additional motivation for each of the parties participating in the BC. The value proposition for NIH lies within the agencyâ&#x20AC;&#x2122;s mission to improve the public health through biomedical research. The scope of the research undertaken within the NIHâ&#x20AC;&#x2122;s 27 institutes and centres ranges from basic mechanistic work, to elucidate underlying biological mechanisms of health and disease all the way, to late phase clinical trials, and includes everything between those two poles.

Biomarkers are indicators of biological mechanisms and also serve as probes for pathobiological processes. To the extent that biomarkers may serve as a bridge connecting animal models of disease with human signs and symptoms of disease, they provide an excellent tool for translational research. Biomarkers in the setting of clinical research allow for the detailed characterisation of patients, allow stratification of subjects in clinical trials, and can demonstrate evidence of the effect of study interventions.

And finally, biomarkers will provide useful and novel tools for clinical decision-making.

Biomarkers provide metrics and indicators of both safety and toxicity for drugs and interventions. Having an available corpus of research information and consensually recognised regarding the nature, character and utility of biomarkers will facilitate the FDAâ&#x20AC;&#x2122;s ability to make informed and timely decisions on regulatory matters. Having biomarkers that are generally accepted and supported by a peer-reviewed literature improves the body of regulatory science on which regulatory decisions can be based.

Furthermore, the availability of consensually agreed upon biomarkers used broadly by sponsors working in the same therapeutic areas provides a basis for comparison that also may ease and speed regulatory decision-making.

The industry is facing a crisis in drug development that is manifest, in part, by rapidly and steeply rising costs to drug development programmes. The cost is related, in part, to the need to do extensive clinical trials involving large numbers of subjects and with relatively distant endpoints. The availability of robust and qualified biomarkers is expected to facilitate the identification of patients for clinical trials who are likely to benefit from an intervention and are less likely to experience adverse effects as a result of the intervention. Such pre hoc stratification of potential trial participants is expected to permit the enrollment of smaller numbers of patients in trials in order to show efficacy, fewer trials discontinued as a result of toxicity, and thereby lower costs as well as potentially reduce the likelihood of post-marketing failures due to toxicity.

Furthermore, biomarkers qualified to function as surrogate endpoints will allow clinical trials of shorter duration, also providing potential for significant cost savings.

Taken together, these benefits derived from the availability of robust and qualified biomarkers should serve to improve the ability to do discovery science relevant to

disease and treatment, promote drug development by both speeding the process and reducing the overall development costs, and improve the ability to make timely and informed regulatory decisions, thus providing a nexus of common interest for all of the founding partners.

The value proposition, however, extends beyond the interests of the founding partners. The development of the notion of personalised medicine is dedicated to the provision of the right treatment (or intervention) for the right patient at the right time. Patient groups and clinicians can benefit from the availability of biomarkers for the assessment of risk; for diagnosis; for stratifying patients with a given risk or diagnosis into prognostic categories; for assessing status of a disease with respect to disease activity and disease-related organ damage; as well as for assessing beneficial and / or adverse effects of a therapy or intervention. In recognition of the uses and needs for biomarkers, a number of patient advocacy groups and professional organisations have also joined the BC.

Structure

The process of forming the BC was characterised by several important lessons: Key lessons related to communication, cross-cultural understanding, and negotiation.

A critical element to the success of the organising process was the fact that all of the founding partners were committed to making a consortium and were therefore committed to making all reasonable efforts to come to an agreeable structure and process, even when coming to consensus was difficult or time-consuming.

An organising committee was composed of high level staff from all founding partners as well as legal counsel when needed. This group was charged with the task of defining the specific goals of the BC, suggesting a structure that would permit the accomplishment of these goals and which would be sensitive to the different practices, cultures and constraints of all of the partners. Over the space of months and many meetings, an umbrella structure was developed which was presented to the initial executive committee and ratified without significant change.

The structure of the BC rests on the premise that all activities of the BC will be pre-competitive in nature. This translates to mean that the goal and expected outcome of BC activities is not to generate new intellectual property, but rather to generate new knowledge and information that will be made available to the public (There are a number of nuances to this statement relating to human subjects protections, the use and contribution of pre-existing IP to the activities undertaken within the BC, and possible regulatory applications that may relate to BC generated work products that will be discussed further below). Working together in pre-competitive projects will, the BC expects, generate information and knowledge that will be the basis for future commercial applications such as the development of tests and diagnostics that extend and apply the information and knowledge generated in the BC.

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SpecialFeature

Function

As of November 2008, the Executive Committee of the BC has developed and implemented five biomarkers projects: Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) for lung and lymphoma These two studies are NIH-managed via the National Cancer Institute (NCI) and aimed at evaluating the use of FDG-PET as a potential biomarker for clinical trials conducted in cancer, specifically, non-Hodgkin’s lymphoma and non-small cell lung cancer. The goal of these projects is to improve patient management and care by validation of a tool that can measure response to treatment and accelerate drug development. Additionally, it is anticipated that these first two trials to evaluate FDG-PET in non-Hodgkin’s lymphoma and lung cancer will provide guidance to the FDA in their regulatory review process, and deliver to the Centres for Medicare & Medicaid Services (CMS) a evidence-based measure by which to inform reimbursement decisions. (This project is supported by a core investment from the NIH-NCI in conjunction with contributions from Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck & Co. Inc., Pfizer Inc., and Wyeth, in conjunction with substantial core investment by NCI).

Evaluate the utility of adiponectin as a biomarker predictive of glycemic efficacy This project involves pooling existing clinical trial data from previously conducted studies in an effort to evaluate whether adiponectin, a soluble protein, has utility as a predictive biomarker of glycemic control in normal non-diabetic subjects and patients with type 2 diabetes following treatment with peroxisome proliferator-activated receptor (PPAR) agonists. If validated, adiponectin would be a useful biomarker in the development of new therapies for diabetes. The data for this study is being provided from Phase II clinical trials conducted by GlaxoSmithKline, Eli Lilly and Company, Merck and Co. Inc., and F. Hoffmann-La Roche. The statistical analysis for this study is being provided (in-kind) by the National Institute of Diabetes and Digestive and Kidney Diseases and Quintiles Transnational Corp.

Carotid Magnetic Resonance Imaging (MRI) reproducibility study This study is being conducted in conjunction with the National Heart, Lung and Blood Institute (NHLBI) AIMHIGH Study—Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-cholesterol / High Triglyceride and Impact on Global Health Outcomes. This AIM-HIGH substudy is aimed at improving patient management by validating a tool that can help identify therapeutic response and facilitate drug development. Specifically, this AIM-HIGH substudy involves an 80-patient reproducibility study, being conducted at 15 established clinical sites, to determine the reproducibility of the non-invasive technique of carotid MRI, a well-known imaging biomarker.

This project is supported by a core investment from the

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NIH-NHBLI in conjunction with contributions from Abbott, Merck & Co. Inc., and Pfizer Inc. Plasma-based biomarkers in Alzheimer’s disease This study is an extension of a large five year longitudinal natural history study known as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which was conducted as a partnership among the National Institute of Aging, private entities and pharmaceutical companies in an effort to identify imaging and biochemical biomarkers for disease state and disease progression. The goal of the add-on biomarker project is designed to use targeted approaches and whole proteome profiling approaches to identify and validate plasma-based biomarkers of Alzheimer’s Disease. Results from this studies aid in the idenfication of biomarker candidates to study disease state and/or disease progression in Alzheimer’s Disease, and serve as tools for clinical drug development and assessment of disease in Alzheimer’s Disease patients.

The BC’s mission to serve as a means for public and private entities to join forces and pool resources to advance biomarkers research is exciting and challenging. And as with any exciting and challenging endeavour, some aspects work well as originally designed and other aspects require rethinking. The BC, like any experiment, is no different and is presently undergoing evaluation and restructuring in some areas. In January 2008, the BC Executive Committee adopted a proactive effort to identify new “High Impact Biomarker Initiatives” (HIBOs), which will be rapidly feasible and provide highly focussed utility.

Future

The BC recently adopted a new proactive approach for the identification of HIBOs in an effort to identify biomarker projects that are cross-cutting and overarch multiple therapeutic areas. The previous “bottom-up” approach, whereby projects were sought exclusively from the public applications, is now supplemented with a “top-down” approach, which involves project identification within the BC (specifically the steering committees). The impetus for this change is to identify biomarker projects that all sectors (industry, government, private organisations and academia) can champion and support. Biomarkers projects addressing big questions or issues of interest to multiple sectors and overarch therapeutic areas are most likely to find broad support and resources for implementation and dissemination. In an effort to assist in the identification of HIBOs has developed a number of key criteria for defining what a HIBO would look like, including the following: Important – Projects should address a significant unmet medical or scientific need in biomarkers with a potentially considerable impact on public health; Translational – Projects should result in significant improvement in the development, approval, or delivery of care to patients (i.e. diagnostics, therapeutics, clinical practice);

Transformational – Projects should address critical gaps in the biomarkers qualification / validation process and/or may otherwise transform the process of how biomarkers are developed, approved, and applied in the future; Feasible – Projects should convey an idea or programme whose end goals can likely be achieved in a specific timeframe, and that has a reasonable prospect of producing the expected outcomes; ideal programmes are those which could result in regulatory qualification of a biomarker in three years; Practical – Projects should leverage pre-existing resources (e.g. intellectual capital, personnel, facilities, specimens, reagents, data) wherever possible; Fundable – Projects should be capable of generating the required funding and stakeholder support needed for implementation; and Collaborative – Projects should uniquely benefit from the multi-stakeholder composition and approach of The Biomarkers Consortium, and feasibly executed under its policies.

The HIBOs identified as “wave one” projects are those most critical to move forward: those which the Executive Committee believes to have the greatest and most proximal impact on future diagnosis and treatment of patients and drug development, helping the medical community realise the promise of personalised medicine. By selecting high profile, cutting-edge projects for development in the BC, the expectation is that all sectors will unite to support these HIBO projects.

The Biomarkers Consortium anticipates launching four to five new “high-impact” biomarker projects this year, while a second wave of HIBOs is being developed concurrently to commence during 2009. The candidates for a 2009 launch include: Evaluation and validation of Circulating Tumour Cells (CTC) as biomarkers of castration-resistant metastatic prostate cancer This project is aimed at predicting response and survival to an investigational agent to treat men afflicted with progressive castration-resistant prostate cancer. The goal of this research is to validate CTC number as a biomarker for survival, which could ultimately guide treatment and accelerate drug development. The project proposes to conduct CTC analyses on blood samples from men already participating in a phase III randomised registration trial in order to evaluate the association between post-treatment change in CTC number and survival.

Comparison of two PET radioligands labelled with 11C or 18F to quantify the peripheral benzodiazepine receptor, a potential biomarker of inflammation The goal of this project will be to assess the utility of two newly developed PET radioligands to image and quantify inflammation in periphery and brain. These newly devel-

oped PET radioligands will be tested in Alzheimer’s disease and atherosclerosis, which were selected because both result in significant disability and often death. Also, these two diseases are representative of inflammation in the brain or periphery, respectively. An ultimate application of the results of this study might extend to neurodegenerative and psychiatric diseases, as well as serve as a tool for developing new drug delivery systems and brain cancer treatment regimens.

It is the ability to step back and evaluate the structures and methods being used to implement projects that characterises an important strength of the BC. The promise of biomarkers to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials and regulatory decision-making for drugs and therapeutics, needs to be realised in an efficient, rapid and effective manner—and it is the hope of the BC that the identification of HIBOs will help make this happen!

The BC is presently in the process of developing project plans for five proposed second wave HIBOs: • I-SPY TRIAL-2 (Investigation of serial studies to predict your therapeutic response with imaging and molecular analysis): An adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy • Detection and characterisation of CTCs in prospective cancer treatment trials • DCE-MRI technique optimisation study using prostate cancer as a model system • Use of targeted multiplex proteomic strategies to identify CSF-based biomarkers in Alzheimer’s disease • Biomarkers for immunosuppression Through the development and approval of these high impact biomarkers opportunities, the BC is moving into a new phase of growth, initiating new, highly focussed, projects; and collecting and synthesising data from ongoing projects. The promise of biomarkers to streamline and even revolutionise investigations of pathobiology, the conduct of clinical trials and regulatory decision-making for drugs and therapeutics, needs to be realised in an efficient, rapid and effective manner—and it is the hope of the BC that the identification of HIBOs will help make this happen!

Challenges

The BC has provided a new direction to healthcare research and medical product development. It brings together leaders from the biotechnology and pharmaceutical industries, government, academia, and nonprofit organisations. This unified effort to accelerate the identification, development, and regulatory acceptance of biomarkers in four key areas: cancer, inflammation and immunity, metabolic disorders, and neuroscience is transforming biomarkers research. The BC is evidence of a new culture of cross-sector collaboration and partnership in order to rapidly, economically, and collaboratively accomplishing the partners’ shared goals to increase the availability and utility of biomarkers in all areas of biomedical science.

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

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Manufacturing

Demand-driven Manufacturing Designing profitable supply chain In life sciences, traditional supply chains were designed from the inside-out perspective. To adaptively meet actual demand from the customer and translate it into global trade-offs, supply chains need to be designed from an outside-in perspective.

T

he global pharmaceutical market has never been more competitive, and therefore, companies are searching for sources of sustainable value. Consider the increased competition created by a flood of “me-too” drugs, combined with ever-decreasing rates of pipeline productivity and the need for the significant changes to healthcare delivery models. As margins continue to shrink, both investors and patients are demanding that more efficacious products are delivered to market faster than ever before. These changes in the market have helped pharmaceutical companies realise the value of their supply chain.

Recent supply chain operations’ discussions with a number of large pharmaceutical companies clearly indicate what separates the leaders from the rest of the pack. Taking cue from consumer products and high-tech companies, pharmaceutical leaders are beginning to think of their supply chains as strategic weapons! The rest of the pack still struggles to consider their supply chain as anything more than a procurement

Hussain Mooraj, Vice President Wayne McDonnell, Research Director Healthcare & Life Sciences AMR Research, USA

or logistics function. Leaders are driving the transformation from the top-down, eliminating any cultural or organisational impediments to change. However, as one supply chain executive from a large global pharmaceutical company noted, the issue before the rest of the pack is that they have to convince their businesses that they can’t win without superior supply chain capabilities.

What is demand-driven manufacturing?

In life sciences, traditional supply chains were designed and operated with insideout thinking. All supply chain and operations processes—from planning, sourcing, manufacturing, and distribution—were designed without considering the needs of upstream and downstream trading partners, let alone the patient. This insideout, and in many cases, one-size-fits-all approach to supply chain design suboptimised the company’s total product supply capability.

In today’s environment, leaders are designing their supply chains from an outside-in perspective to adaptively trans-

late actual demand from the customer into trade-offs that profitably fulfill perfect orders. The goal is to create opportunity at the lowest cost and maximise value to both trading partners and the end customer (i.e. the patient). Supply chain teams at leading companies are focussed on the synchronisation of demand and designing the most profitable response, which means focussing holistically on each interaction across the value chain. This is a significant shift from existing thinking. Driving this point of view within the business and inspiring the traditional life sciences supply chain organisation is a major challenge. Again, this wave of change needs to be led from the topdown in order to be successful.

Design your supply chains to win

Supply chains need to be designed for profitability, not inherited and operated as non-value adding cost centres. In the early stage of supply chain, most companies identify their supply chains by product families or physical product flows.

Leading companies identify their supply chains by a variety of characteristics,

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Manufacturing

• Achieving compliant, right first time manufacturing response to demand • Driving a balance between compliance and cost, while eliminating waste and inefficiency along the way • Leveraging third party capabilities to improve new product development, launch processes and to help lower costs • Driving collaboration across the various functional groups throughout the enterprise

Large company-volume, demand variability, technology and lifecycle clusters Commoditised

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Get started on your transformation – Ask the right questions

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including demand and supply variability, volume, technological complexity, asset constraints, marketing channels or stage of product life cycle. These companies then design their supply chain response capabilities to provide the optimal balance of supply chain efficiency and agility.

The result is a fundamental shift on the part of leading life sciences companies towards aligning supply chain strategy with both enterprise-level business strategy and operational-level procedures.

So, an interesting question to be asked in this context would be “How many supply chains one should really have?”

Consider one global company that wanted to migrate from a one-supply-chain-fitsall strategy to a network design based on an understanding of how technology, demand, and product variability translate into operational excellence. To accomplish this task, the company evaluated its product profile of tens of thousands of items using a new framework (see Figure 1).

For each circle, the company developed an operating strategy. Each of the 16 different value networks was redesigned using value-network principles: • For high-volume products with predictable demand, the focus of the value network was on efficiency.

• For products with highly variable

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demand and short product lifecycles, the focus was on responsiveness.

• For low-volume products with highly variable demand and short product lifecycles, the focus was on portfolio rationalisation.

The company drove improvements over the last year through flexible manufacturing work centres, postponement strategies, and pooled inventories for products. These networks were continuously tweaked in Sales and Operation Planning (S&OP) processes by aligning demand-shaping and agility levers (See AMR Report How Do I Drive Value Through a Value Network?)

Developing product supply capabilities – A focus on Asia

In a recent survey, AMR Research studied Asian pharmaceutical companies’ efforts to develop demand-driven product supply capabilities. The survey included 50 Asian life sciences manufacturers (i.e. pharmaceutical, biotech and medical device companies). The size of these companies was decided on the basis of their annual revenues. Survey questions related to product supplies were designed to identify the gaps in their current performance.

The results of these inquiries revealed the following gaps in their top product supply performance:

Pharmaceutical companies in Asia need to rethink and redesign their supply chain processes to address the performance gaps identified above. The following guiding principles will help lay the foundation for transformational change: 1. Align the organisational structure: Companies must think outside-in from the definition of right first time (or perfect order) all the way back to sources of materials and supplies. This will help align organisational incentives and drive effective team management of transformation processes.

2. Design business processes for compliance and efficiency: Companies must design operational and supply chain processes from the inside-out to ensure quality and compliance, and minimise the time and resources required to deliver products “right first time”.

3. Provide support with Information Technology: Systems, databases, and tools must provide end-to-end value chain visibility and provide a platform for scenario modelling, impact analysis, and broad project collaboration and management.

Building from these guiding principles, specific recommendations for pharmaceutical companies in Asia lie in addressing the following key strategic questions: • Does your top management see supply chain as a strategic priority?

• How is your company organised? Are incentives aligned across functions to

Manufacturing

ance measurement strategy and a set of relevant, interdependent metrics that support your business strategy and influence the right behaviours?

• How are you managing risk and complexity?

• How do you pull all of this together into a supply chain strategy?

There are no “one dose, one tablet” therapies for driving transformational

Author

drive the desired behaviour and business outcomes?

• How do you see end-customer (i.e. patient) demand? How long does it take to sense changes to demand?

• Most importantly, what do you do with this demand information? Do you use demand data in global supply chain trade-off decision processes?

• How effective are your global sales and operation planning processes?

• Do you have visibility across your endto-end supply chain? Can you readily and accurately identify inventory across your supply chain?

• Do you have Joint Value Creation (JVC) strategies in place with both upstream and downstream trading partners? Do these JVC strategies focus on developing long-term, winwin relationships or are they one off, short-term collaborative projects?

• Have you defined a business perform-

change of your supply chain capabilities. In fact, it is an organisational journey best embarked upon with a spirit of relentless improvement and a hefty dose of change management expertise.

Specifically, life sciences companies in Asia must realise that simply implementing a software application or commissioning a low-level, under-resourced project will not successfully transform supply chain capabilities.

Hussain Mooraj brings more than 15 years of experience in manufacturing, supply chain, life sciences consulting, strategy consulting, strategic marketing, and technology consulting to his role of Vice President, Healthcare & Life Sciences, at AMR Research, USA.

Wayne McDonnell brings 18 years of experience to his role as Research Director, Life Sciences, at AMR Research, USA where he is responsible for research across the life sciences and healthcare value chain, including the pharmaceutical, biotech, medical device, wholesale, and hospital industries.

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Biopharmaceutical Operations

Developing the science Drawing parallels with the semiconductor industry, the authors argue that biopharmaceutical firms are finally reaching a point where efficient operations are becoming critical, thus necessitating advanced research in biopharmaceutical operations.

The arguments are based on preliminary investigations at the University of California, Berkeley, identifying key needs in a variety of areas.

Rick Johnston, Founder Phil Kaminsky, Founder Center for Biopharmaceutical Operations, University of California, Berkeley, USA

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hirty years ago, the semiconductor industry was a growing technology-focussed industry and for the first time was beginning to face cost pressures. For years, the focus had been on superior technology, and manufacturing was an afterthought. As long as the products were manufactured as they were envisioned by their inventors, there was little need to pay attention to capacity utilisation, operational efficiency, inventory levels, or risk management—if you made them, profits would come. However, as the semiconductor industry matured and competitive pressures grew, firms began to focus on operations—utilising resources effectively and efficiently, optimising systems and dealing effectively with uncertainty and risk. However, significant advances in the science of operations were required to bring about these changes.

Working together with each other as well as with academia through organisations such as SEMATECH and the Center for Competitive Semiconductor Manufacturing at UC Berkeley, semiconductor firms were able to make great strides, pushing the state-of-theart in semiconductor operations to new heights.

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Biopharmaceutical firms now find themselves at similar crossroads. Over the last several decades, billions of dollars have been invested in the research and development of medicines, leading to ground breaking advances in the treatment of many severe illnesses from arthritis to cancer to haemophilia.

There has been significantly less research focus, however, on operational issues, in spite of the fact that the biopharmaceutical supply chain presents a unique set of operational challenges— demand is highly uncertain and dependent on the results of clinical trials and competitors’ actions; supply is highly uncertain due to complex and incompletely understood biological processes; the regulatory demands of agencies in multiple jurisdictions add untold layers of complexity to operations; and capacity is extremely expensive and requires long lead times to build or acquire. Adding to the complexity, mechanisms for drug production are typically not standardised even within firms, technologies continue to change, and generics are perhaps poised to dramatically impact the industry.

Key operational issues

Over the past three years, a variety of workshops at the University of California Berkeley, have focussed on biopharmaceutical operations, and have provided a forum for interaction between operations managers from many large and small biopharmaceutical firms, and operations experts in academia. The goal of these sessions was to discuss, characterise, and prioritise operational problems faced by the industry, as a precursor to an organised effort to address these issues.

Through panel discussions, industry talks and breakout discussions, it became apparent that there are a number of key operational issues on the minds of biopharmaceutical operations executives.

Risk management tools and approaches: Almost every firm is focussed on identifying and working to hedge or manage the risk associated with their operations.

In spite of this, there is a lack of basic research on the nature of risk in biopharmaceutical operations, and a lack of tools, techniques, and approaches for managing this risk.

Long-term capacity planning tools: Most firms have efforts in place to constantly reevaluate long-term capacity requirements, and to ensure that the

Manufacturing

Strategies for process improvement and the integration of new technologies in the face of regulation: One of the unique challenges faced by the industry is the regulatory implications of process improvements, and many firms are struggling with appropriate strategies for introducing process improvements for existing products.

Research projects at UC Berkeley have already started to address some of these issues. With a major biopharmaceutical firm, we have developed a planning tool that integrates with SAP to plan production of a complex multistep product. The firm currently uses this tool daily to plan production at one of their biggest plants. With another firm, we have developed a series of simulation tools to help the management fully understand the impact of introducing new technologies into existing production facilities. This tool has proved to be so successful that the technology invented for this project is currently being utilised in the development of an advanced supply network simulator so that the firm can fully understand the impact of rare high impact events on the supply network, and assess the effectiveness of intended responses to these events. Working with a large biopharmaceutical firm, we have also developed a capacity planning tool to help strategic planners understand more completely the cost and value of delaying costly decisions.

The need for a centre

The results of many of these projects were presented at the recent 2008 UC

Authors

right amount of capacity will be available in the future. There is a need, however, for standardised tools to address this issue in an analytically rigorous way.

Although each firm is facing a similar set of questions, many firms have developed their own ad hoc approaches to answer them. Managers perceive a need to design and implement new, effective, and analytically sound tools to assess the long-term capacity picture.

Operational supply chain management decision support tools: In the short term, firms need to make the most effective and efficient use of their available capacity. However, this is typically done using general purpose tools that donâ&#x20AC;&#x2122;t adequately address the specialised requirements of the biopharmaceutical supply chain. There is a need for advanced and specialised tools, approaches and algorithms that effectively address day-to-day supply chain decisions.

Approaches to assess lean supply chain and operational excellence efforts: Many firms are currently engaged in operational excellence or lean supply chain efforts. There is a lack of tools and techniques to assess the impact and cost-effectiveness of these efforts.

Tools for inventory management: More and more firms are focussing on inventory levels throughout the supply chain.

However, there is a lack of approaches and theories that take the specialised nature of biopharmaceutical operations into account when determining what these inventory levels should be, and a lack of benchmarking data with which to assess supply chain inventory performance.

An understanding of the impact of personalised medicine and supply chain fragmentation: Most experts expect that the biopharmaceutical industry will increasingly focus on a larger set of more specialised products, each of which will have relatively smaller demand than todayâ&#x20AC;&#x2122;s blockbuster drugs. There is a need for research into how this will impact supply chains in the future.

Berkeley Center for Biopharmaceutical Operations Workshop. The participants of that workshop agreed that the impact of these projects, and others like them could be dramatically increased with the establishment of a centre of excellence focussed on improving operations.

There is a compelling need for such a centre as the industry matures and shifts its focus from discovering new process technologies towards cost-efficiency and robustness.

Indeed, faculty at UC Berkeley are currently working to establish such a centre, the UC Berkeley Center for Biopharmaceutical Operations, with the mission of bringing together academic researchers with diverse expertise and industrial experience and biopharmaceutical professionals to advance the state-of-the-art of biopharmaceutical operations with focus on cost-effective, reliable biopharmaceutical production systems and supply chains.

The centre will work to facilitate collaboration between multiple firms and academia for pre-competitive research addressing the issues listed above, provide firms with a forum to share ideas and best practices, provide world-class students with exposure to and training in biopharmaceutical operations ultimately providing the industry with world-class employees, and develop data-driven tools, techniques, and approaches that help the biopharmaceutical industry address its most pressing operational problems.

Rick Johnston is one of the founders of the Center for Biopharmaceutical Operations at University of California at Berkeley. He holds advanced degrees in Decision Analysis from Stanford and in Operations Research from UC Berkeley.

Phil Kaminsky is an associate professor in the Industrial Engineering and Operations Research Department, and one of the founders of Center for Biopharmaceutical Operations at the University of California at Berkeley. For more information contact him at kaminsky@berkeley.edu

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Buying into Lean Pharma The article is a 30,000 feet fly-by of the essential stepping stones leading to a sustained lean deployment.

This pragmatic approach, based on personal successes and failures, has been proven in several industries and across three continents by the author.

William Botha, Director, Manufacturing, Pharma BU, Los Angeles Fractionation Facility, BioScience Division, Baxter Healthcare, USA

you want to be an Army Officer? So My teeth were chattering against one this phase is now considered complete. another with my uncontrolled shiverWe really did not need this weather to ing. I was physically exhausted, mentally make this exercise more effective. Yet drained after three days of continual we should have another day of marchmarching, thinking and worrying about ing in front of us to finish this the right walking off the edge of the mountain. way. You have a choice now; one, you Everything was damp. It had been rainremain in ranks and when we’re done, ing all night and we hadn’t been able to you get your gear on the trucks that will make a dry camp. We had just heard the be here in about an hour to truck you news that snow was rolling in across out of here. Two, you break ranks and the mountain. And I had just volunteered for more. What had made me choose the route of more hardship over the seemFirst piece of advice is spend a lot of ingly logical choice of warmth, time asking what is going on outside of safety and comfort? the firm, then turn inside and delve into It was the fourth day of the the real machinations of the ‘company’ School of Infantry’s annual crosscountry march. Each company upon which you’re about to inflict Lean. of around 120 candidate officers had been given a series of way points to make over a fiveday period with minimal rations and step across here and stand with me. We even more minimalistic comforts. It will complete the march as expected. had started raining on Day Two. We Some of us may be injured in the next had repeatedly lost our way in the foot24 hours. There will be no demerits for hills since we had lost the advantage of those who choose to stay in ranks, who taking visual bearings. It was like stumchoose to get in the trucks.” Followed bling through an ethereal misty Harry by dead silence.

Potter-like maze.

Most of Charlie Company broke Our Company Commander had ranks and formed up behind the Major. formed us up in front of a huge roaring We all made it through that day and the bonfire and had told us the truth under long night that followed. the soggy, dripping trees; “The weather Why do I start what should be a dry, has forced you all to reconsider how badly theoretical article about Lean deployLeadership

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ment with this story from my experience?

Because it carries all of the elements of the answer to the real question; “How do I deploy Lean into my organisation?”

Like a classic Greek tragedy; Act One introduces the players and describes the stage they’re playing on—and the audience they’re playing to.

Environment – Market

This is fundamental to the course chosen by the actors, this first Act lays out the minefield. What state is your industry in? What opportunities and threats are there out there? With the global economy in the tank right now—you are in a very, very different position if you’re selling a discretionary product like high-end cosmetics versus those of us who are producing life-saving therapies.

Is your API supply constrained or not? Who are you selling your drugs to? (I know, I know—that should have been ‘To whom are you selling your pharmaceuticals’ but as Winston Churchill would have said—“That is English up with which I will not put!”) What is your vision? How deeply ingrained is your vision in your workforce? Is it a Lean vision?

Vision

So my first piece of advice is spend a lot of time asking what is going on outside of

Manufacturing

the firm, then turn inside and delve into the real machinations of the ‘company’ upon which you’re about to inflict Lean.

The link between the two is the Vision.

Who knows it? Who believes it? These are two very different questions. If you asked 10 senior members of the company the same question: “What is the company going to look like in five years’ time?” I would hazard a guess that nine of the ten will differ significantly from the Boss’s vision. The tenth vision is the Boss’s.

Then you need to dissect the vision and see how truly Lean it is. Then you have to try and align it.

Structure, staff, skills

The structure of the company must fit the vision. It doesn’t help to take a knife to a gunfight and neither will it suffice to take a functionally-oriented behemoth to Lean (For functionally-oriented read ‘silos, lots of isolated silos’). Lean demands tight,

incessant teamwork and silos do not support team work. A team architecture is easy to design yet very difficult to build.

You have to break down the territorial domains of entrenched managers at the middle level by training, educating and leading them to more mature styles of leadership.

The positions within the structure have to be filled. In this case it is better to have the position filled rather than to wait for the ‘right’ person for the role. I shudder every time I hear a fellow Lean practitioner say that they budget to staff a hundred people, then they plan to only have 95 of those positions filled at any one time! How much sense does that make?

Finally select your people in a focussed fashion; technical skills for technical positions, change skills for Lean senses and finally the most critical positions of all—leadership skills for

supervisory positions. You can train technical skills in and some say that you can train leadership skills in. That is not my experience. So recruit leaders, proven leaders, with hard degrees (engineering or sciences) from the military. The confidence these leaders bring to the game are invaluable at the front-line supervision level.

Style

Silos work very well in an autocratic system but they make inter-function communication almost impossible to achieve while a team-oriented structure demands its leaders use influencing skills rather than positional or informational power bases. This is where my story comes in.

Consider the Major’s style. Note how he changes from acknowledging that the march has been hard, to the use of ‘you’ singular to isolate the individual, followed

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by ‘we’—insinuating that he, too, is going to continue the march. His mind is made up. He has decided where he wants to go. He is merely affording his friends the opportunity to do it with him because it is a worthwhile thing to do. Great sales skills. He also then closes the deal by forcing those who are ‘on side’ to DO SOMETHING! He asks them to ‘break ranks’ and form up behind him (Which, now that I think of it, was much closer to the comforting heat of the fire!).

That brings me to the vector of change—top-down or bottom-up.

Top-down / Bottom-up?

that you are going to use to illustrate the benefits of turning the firm into a Toyota lookalike. These people are not going to be at the bottom of the organisation. Are they?

So my preferred change vector is neither top-down nor bottom up – it is ‘leader-forward.’

Benefits and sales skills

The words ‘buy-in’ in the tag line to the sub-title are important. If there is a buyer—then there must be a seller, no?

And what skills must good salespeople have? Sales skills! Go straight to the top of the class.

The first thing they’re going to learn when you send them on a sales skills course is the need to identify the benefit to the customer. This ‘customer’ is not the

There is no bottom-up. When last did an entry-level employee recruit a change agent, force everybody round them to respond to an analysis and start doing something new? Eh? Never.

What do people mean when they say they took a ‘bottomThere is no bottom-up. When last up’ approach? They mean that did an entry-level employee recruit a either change agent, force everybody round a)they could not convince the top dog or them to respond to an analysis and b)the top dog did not have the start doing something new? Eh? Never. intestinal fortitude to drive the change.

What would have been the outcome if one of the sergeants had customer of the product; the customer gathered a bunch of his people round we’re talking about is the customer of the fire and asked who wanted to finish the change; the person either asking the march? I suspect that he would have you to lead the change. This is either been laughed out of court. the person either asking you to lead the Whenever a change evolution has change or, and this is important; write been successful it has been led by inspiit down—the employees who are going rational leaders within the organisation. to have to change the most.

And when this person has not been the If you can’t identify these individual head honcho, their leadership skills and benefits, you’re going to feel like a oneability to influence has been momenlegged man in a butt-kicking contest. tous—prior to the change, not because You will have no leverage. Why do you of it. The controlling keiretsu of Toyota think the used-car salesgirl asks you so kept Mr Taaiichi Ohno in place when many questions when you sidle up to that Toyota workers went on strike midway luscious wine-red ten year-old Suburban? through the last century—and he was She is searching for the ‘benefit’—the not the CEO of the company.

Holy Grail of the sales world. If she So simply stated, find the real leaddiscovers you have four young kids and ers in your firm and spend your time you crave safety then she is most likely with them; learning what turns them going to subtly direct you to a Volvo on, because it is their wants and needs sedan somewhere. And won’t it be a Jeep

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if it is the great outdoors you crave?

When I started in plasma therapeutics I used to try and sell the ability to cut cost until a senior VP sat me down and said very carefully and slowly so that even a slow South African like myself could understand; “William, don’t tell me about cost when I can sell everything I make and I don’t have enough API to fill the market—tell me about yield, tell me about the ability to limit discards—but DO NOT TELL ME ABOUT COSTS!” I still smile when I recollect that little session.

Your change agents will get to those benefits by asking questions, lots of them.

If they stop asking questions and start making statements that is a red flag warning of a firestorm of assumptions. And even when they’re selling, they’re going to be selling by asking questions.

So send your change agents to class again—sales skills classes.

First steps

Where do you start? Why, at the beginning of course! Remember the Toyota model—or house of Lean? What is in the top lefthand corner? Forget that. It is a house, remember? Where do you start with a house? At the bottom!

What is at the bottom of the house? The fundamental disciplines of 5S, mistake proofing, standard work, that’s what. It will take two to five years for these fundamentals to be instilled in your business. And how do you do that? You need to start a formal training process to develop specialist skills in house, yet—simultaneously—you need to engage the employees on the floor with kaizen activity.

Offer voluntary classes on skills that are going to make them more valuable to the company, and – incidentally— will make them more marketable in the marketplace. Record carefully who attends and who doesn’t. They will notice and the message will be clear. Short topics like ‘Presentation Skills,’ ‘Root Cause Analysis’ and ‘Mistake Proofing’ will

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Lean enterprise or lean toolkit?

we come full circle. What is it that you really need? A slightly better firm that only runs out of gas every six months as opposed to every other day? Or an agile, responsive, customer-focussed, profitpumping business enterprise? They’re equally honourable objectives.

The Major in my story was sincere.

And we could tell he told us the truth.

The trucks did arrive. He did walk with us. In front. All the way. He stopped and took a rest only when we could

Author

not only lead to fewer repeat process excursions in your business but will also develop depth in the crew. But get them to DO SOMETHING. Them? Oh. Sorry, I meant the informal leaders in the work force.

Start a Kaizen Promotion Office.

Led by a specialist, it is an office that is responsible for supplying the resources to map value streams, prepare for and facilitate kaizens. And, train the employees in the kaizen. And that is probably the most important function of a Kaizen Promotion Office—to train your employees. The first morning of a kaizen is spent in training the members on the specific skills they will be using in the next couple of days, isn’t it? And won’t their skill retention be awesome since they will be practicing that skill immediately?

not continue, or to keep the company together.

So, if you only want to use some of the tools—say so. They’re good tools. They’ll work for you. They work wonderfully in concert with the Six Sigma tools of DMADV and DMAIC. But remember that when the kaizen fails or when the 5S campaign does not drop your Recordable Injury Rate—“A Bad Workman Always Blames His Tools.”

William Botha has installed and sustained significant changes across three continents and within many diverse industries. His most recent success is his appointment to a senior manufacturing position in the quality-critical biologics pharmaceutical industry where he has lifted customer fulfillment, driven inventories down, erased cost and maintained world-beating low rates of discard.

Known by his reports, his peers and superiors as a results-driven leader, he still inspires his team and those around him with an engaging style and a warm, self-deprecating sense of humour.

I started this article with Vision and so

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Data Mining in Clinical IT A real life industrialised model Data mining has always been important to our industry. Having the ability to mine across the entire product lifecycle has always been the goal. To date, data and systems' ‘non-interoperability’ has been one of the major challenges to this effort. This case study will describe how data mining capability was enabled initially by Clinical IT. This work set the foundation for data mining across R&D and positioned the enterprise to realise their new product development strategy—connecting the dots between molecular discoveries and human health and disease.

Michele Pontinen, R&D Practice Lead, Life Sciences, Capgemini US, LLC, USA

T

he absence of data interoperability and standardisation is just one of the challenges faced by the pharma industry today. Data are expensive and difficult to collect with limited ROI after product registration.

Increasingly, health authorities are moving to require a clearer understanding of product safety and efficacy—not only earlier in the development process but throughout the product lifecycle.

Pharmacy benefits managers are pressuring industry to provide evidence of efficacy and a good safety profile for favourable reimbursement rates and in some cases formulary placement.

Patients and their advocacy groups are becoming more vocal in demanding that centralised trial information be easily accessible to clinicians.

Additionally, they call loudly for presenting product contraindications and side effect information in a meaningful and understandable language—more than just an aggregation of statistical information on the product insert. At the same time, the industry faces severe pressure to innovate: To move to adaptive trials,

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translational science, and focus new products and diagnostics on targeted treatment groups. And most important for their competitive edge in today’s environment, a company needs to ‘kill early and cheap.’

These challenges all share a common problem—the inability to access, analyse, share and mine interoperable data. If an organisation is able to make their product data both syntactically and semantically interoperable, they can transform data into information and finally into knowledge—creating a unique competitive advantage.

This article describes how a transformation initiative of the business and clinical IT delivered data mining capabilities to the enterprise. Enabling data mining initially in full development (trial Phase IIB through product registration),

the initiative built the foundation to effectively launch a new strategy for product development—“to connect the dots between molecular discoveries and human health and disease.”

A definition of data interoperability

For some the term “interoperable” maybe new or it may mean different things to different people. In the context of this article, the term is defined as: Transforming the enterprise – Doing more with less

This company began a full transformation of their organisation by implementing their strategy across a number of different functions overtime. This meant changing the way they did business. They needed to do more with less, and deliver on their vision for the future.

Syntactic Interoperability

The ability of multiple entities to exchange data (information) and to be able to use the data (information) that has been exchanged Semantic Interoperability

• Support for Modelling and Simulation (M&S) in full development • Identify additional indications to enable diagnostic and combinational product development • Support genomics / biomarker use in preclinical and clinical studies • Speed dossier compilation • Real-time research, clinical trial data capture and processing (reducing errors in data collection and speed analysis and reporting) • Compliance maintained throughout the life cycle of the product.

Transforming the enterprise in this manner enables the company to identify and move to retain critical, core capabilities in-house. They improve their decision-making process by eliminating the “white spaces” between current operations and “best-in-class.” They eliminate all legacy “silos” of information and data

about their products while they move to adopt novel new technologies—those that will provide their research scientists with the tools necessary to increase their understanding of disease.

CaseStudy

By manipulating key transformational levers (people, process and technology) the groundwork for their new operational model is laid: • Interoperable data across all business functions • Both syntactic and semantic interoperability • Standard data representation • Industry-evolving standards (i.e.

CDISC, HL7, MIGS (Minimum information about Genome Sequence), MIMS (metagenomics), etc.)

• Single repository for all regulated data (JANUS-like architecture) • Data mining capability • Discovery through the end of the product life cycle • Future integration with patient Electronic Health Records (EHRs) • Enhanced pharmacovigilance activities

Corporate information governance

The company established Information Governance at the corporate level. This move not only assured that “isolated silos of data” would not re-establish posttransformation, but it positioned them to realise their long-term goal of accessing and mining external repositories—and eventually to interface with patient Electronic Medical Records (EMRs).

Their governance structure comprises three separate areas of Information Stewardship: 1. Business stewards: Accountable for consistent implementation of standard business rules for all future state

The Transformation Model Today

2015

Short-term

Transformation vision – changing the paradigm

Product innovation & differentiation

Clinical development redefined

Clinical operations optimisation

Efficient data management

Long-term

• Corporate vision describing the need for change, effective governance • Balanced approach between “mastering the basics” and “adapting to change” • Company alignment & mobilisation

• Move from “NDA-centric” to “stakeholder-centric” approach • Encouragement of “early failures” • Adoption of critical path initiatives • Institutionalisation and industrialisation of processes to improve efficiency and effectiveness

• Implement predictive models and simulations; “capability-specific” expert systems; establishment of adaptive trials • Development of personalised medicine • Early piloting and adoption of new technologies

• Enterprise-wide technology integration (when it made sense) – across discovery, preclinical, clinical and with external partners • Effective product life cycle management strategies • Partnership with technology vendors, universities, start-ups, etc. to maximise probability of success

• Corporate Information Governance to assure standardisation & data interoperability across the enterprise • Integration of systems (when it made sense) to enable rapid and effective decision making • Effective knowledge management, content management, document management

Figure 1

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information systems. Looking across initiatives, business stewards ensure business rules for data are defined in the context of requirements for the entire programme—for today and in the future.

2. Metadata stewards: Assure the enterprise has a single “source of truth” for metadata definitions and business rules. These artifacts are managed and maintained in a central repository at the corporate level.

3. Integration stewards: Identify and maintain that conversion, interface, data analysis, data standardisation and data architecture work done by individual projects that can be leveraged across the enterprise. The stewards also support projects by providing standard toolsets, templates and usage tips that can be leveraged by multiple teams, in multiple functional areas.

Several factors drove the decision to adopt a more centralised model. The model provides a formal command and control structure that assures all necessary processes and standards are in place to enable data interoperability and standardisation. A single group or function controls master metadata and data standardisation—providing a good leadership framework for delivering the vision, both near-term and future. The model also fits well with their approach to change management, critical for driving change across the enterprise. Finally, although governance is maintained at the corporate level, ownership is cascaded down into each discipline through the Stewards.

The data interoperability

Product data from all current and legacy clinical research trials (Phase III, IV) is being converted into CDISC SDTM for loading into their central repository.

The decision to convert to CDISC met metadata and data interoperability acceptance criteria for eCDT submissions to the US health authorities (FDA). Other CDISC standards (ADaMs, LAB, ODM and BRIDG) are now being implemented

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Impact areas for successful change management CELL WORKING

How can crossfunctional teams be used to replace the functional structure?

EMPOWER

(DE-) CENTRALISE

How must the management style and culture be adapted to broaden the process responsibilities to process users?

What decisions should be centralised or decentralised?

BOUNDARIES

PROJECT ORIENTATION

CONTINUOUS IMPROVEMENT

Where can the process boundaries be changed to resolve cross-functional issues?

How can the processes be managed on a project basis to sharpen accountability?

How can the organisation be designed to support learning and continuous improvement?

DELAYER

How can management layers be reduced to speed decisions and streamline the structure?

ENABLING TECHNOLOGIES

Where can Enabling Technologies be used to streamline or automate a process?

RESOURCE

SELF DIRECTED

How can flexibility be increased by adopting an industrialised, outsourced model?

How can self-directed team working principles be introduced to reduce management layers?

Figure 2

to enable full electronic submission and to bridge HL7. The company plans on adopting SEND for their preclinical data once FDA reviews and advises on findings from the pilot. As standards evolve for new technologies, the company is positioned to generate, store and analyse enormous quantities of interoperable epidemiologic, genotypic and phenotypic data.

A JANUS-like data repository houses all of their product data in standard, interoperable format. This provides a single, centralised solution for not only preserving the knowledge (data) but also providing controlled access to those who wish to and are entitled to use it. This solution not only reduces the time and effort to locate and access meaningful data but also provides users the opportunity to access and mine all legacy product data.

Organisational change management

Managing change is a critical component of any business transformation. An

effective change management programme delivers results by building sponsorship from the top, creating leaders who will act as change agents, and by changing behaviours at both the team and individual employee levels. For our initiative, the company implemented a robust, change management programme and communication plan across multiple functions and at multiple levels addressing each and every component of transformation.

Delivering the correct approach for each and every functional area and driving change across the enterprise, required balancing and instantiating a hierarchy of information (in multiple formats and each with different, directed content) without contradiction. The approach to change management addressed enterprise-level themes, operationallevel messages and individual-level information. The message was always consistent and ownership for the new ways of working was internalised with the aid of a variety of change management tools.

Beyond data mining capabilities

Traditionally, data mining activities have centered around pharmacovigilance.

Historically, most have experienced limited success either because trending is difficult with a small sample size or because submission timelines are so tight they force us to put scarce resources on meeting the submission deadline. As a result, all of the challenges and frustrations led the company to realise they could no longer conduct business as usual. The transformation needed to give them more than just data mining capability. Today, the company is realising the near-term goal of mining clinical data with the capability and capacity to deliver in three critical areas: Realise an immediate ROI on all of their product data; reduce their regulatory exposure; and deliver on the pressures to innovate by realising their competitive edge and building on it.

Realising an immediate ROI on the data

With the transformation of people, process and technology platform, the company immediately began to see ROI on their product data. This included the ability to mine across compounds and actually support intense pharmacovigilance activities. “One version of the truth” is replacing and eliminating duplicate

product data. In the area of clinical trials, clinicians and data management no longer need to re-invent the wheel each time a new trial is designed and rolled out into production. Industry standards are reducing trial set-up costs.

The adoption of industry standards is reducing the timeline for data integration, analysis and report out. By moving all on-going clinical trials to their EDC platform and adopting CDISC standards, trials are set up, data are captured and accessible in real time, data moves nightly (in SDTM format) into the repository. Data sets are pushed out to their analytical application (SDD) in record time. The access to data in real time coupled with reducing the time to conduct and report out on a trial, is improving their patient safety monitoring, thereby significantly reducing publication time for submission.

From clinical development through product launch and marketing, the barriers for collaboration with co-development partners and external vendors (i.e.

CROs) are being eliminated. Data suitable for mining no longer needs to be located, reformatted, and / or reprocessed when the company receives a request from health authorities. The adoption of industry standards is also impacting how the company contracts clinical trial services. CROs are now required to return trial data in CDISC format.

Reducing regulatory exposure

By mapping all regulated trial data to a single repository, the company is now able to retire their legacy systems and reduce their risk of non-compliance for electronic record and electronic signature regulation (21 CFR Part 11). As noted earlier, the repository also gives

the company the ability to quickly respond to questions from regulatory authorities —as end-users no longer have to get access to, locate, and reformat data to respond. In addition, data quality, a critical component of the transformation, has been built into the new way of working and their regulated product information meets data veracity, authenticity and non-refutability requirements throughout the life of the record.

CaseStudy

The challenge of converting all clinical research data into industry standards was great, given the company’s limited resources. The amount of clinical research data, its location (found in many current and legacy applications) and format meant the cost and resource requirements were going to be high. To bring down the cost and reduce the burden on internal resources, we developed an “industrialised” or “factory model”. As a partner in the transformation, we moved SDTM mapping to facilities offshore and set up a factory solution that reduced the cost and produced high quality SDTM maps and ADaM data sets.

Author

Industrialising the solution

Transforming data into knowledge

With data interoperability, the company is now realising their competitive advantage and building on it. With interoperable data, they have turned data into information and into knowledge. This advantage positions them to evaluate their earlier work using new technologies such as biomarkers helping them to re-evaluate earlier discovery efforts that failed target nomination, candidate optimisation or candidate readiness milestones as well as the possibility of combinational product opportunities. The company now fully supports modelling and simulation in clinical development and is beginning to move to adaptive trials and translational science capabilities.

They now possess the capability and capacity to generate, store and analyse enormous quantities of epidemiologic, genotypic and phenotypic data. They are moving forward with gene-based clinical trials that hopefully will increase their knowledge of the biology and phenotypes of disease. All of these capabilities increase their understanding of disease and move them closer to targeted treatment products and innovative diagnostics. The company is now positioned to adopt and leverage all new industry standards as they evolve.

Michele Pontinen is a Senior Manager in the Life Sciences Transformation Consulting Practice at Capgemini US, LLC. Michele leads the R&D consulting practice. She has over 25 years experience in the biopharmaceutical industry—both commercial and government research development.

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A compliant IT environment with IT service management software IT can play a key role in cutting down the costs of production and helping biopharmaceutical companies maintain regulatory compliance. IT service management software can be an essential element in this process which will not only help biopharma companies meet their ever changing business requirements, but also help them ensure a stable IT operating environment.

David A Medina, Chief Technologist, Worldwide Health & Life Sciences, Hewlett Packard, USA

A

s the complexity of the biotechnology industry increased, pharmaceutical companies have struggled to ensure that their IT organisations keep pace with the latest hardware and software applications. Yet, the need to maintain regulatory compliance while ensuring that an organisation’s IT infrastructure meet its ever-changing business requirements, is a significant challenge that industry faces today.

Biopharmaceutical companies must deal with the regulatory pressures of cost-effectively maintaining a qualified IT infrastructure with validated business applications, while dealing with the business demands of managing and controlling an IT infrastructure through effective IT Service Management (for example: change control or incident management). IT service management software can help companies cost-effectively meet their needs in both of these arenas.

ITIL – A framework for compliant IT service management

Regulatory compliance is one of the critical elements in the pharmaceutical industry that drives a significant portion of IT spending. Consequently, proper IT service management plays a significant role in reducing company risk by maintaining

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compliance in a cost-effective fashion.

One of the most effective methods of achieving IT compliance is by adopting a process management framework such as Information Technology Infrastructure Library (ITIL®). The ITIL framework is a proven and accepted model for regulatory compliance, especially since process requirements for a mature ITIL model are in line with FDA requirements.

By using ITIL as a framework and incorporating common enhancements to ensure FDA regulatory compliance, such as approval levels, record controls, and integrating risk management techniques, a pharmaceutical company’s IT department can cost-effectively maintain compliance. Adopting ITIL allows companies to measure, monitor and analyse processes that enable implementation, management and continuous improvement of their IT services and underlying infrastructure. ITIL also enables companies to better incorporate risk analysis and management in their procedures.

Many pharmaceutical companies are moving towards, or have adopted an ITIL-based approach to IT service management. However, due to the documentation required to demonstrate regulatory compliance, most pharma IT processes are paper-based and not easily

accessible throughout the enterprise. As a result, there is a significant opportunity to reduce the cost of managing IT infrastructures while increasing the level of regulatory compliance. This can be accomplished by automating ITIL processes using IT service management software.

Driving consistent processes through automation

From the perspective of managing IT delivery, IT service management software can help ensure compliance through the integration of all IT processes. These software tools allow for the continuous flow and visibility of information.

IT Service Management can provide a single, enterprise-wide platform for incident management, problem management, change and configuration management, release management and service level management.

IT Service Management will also reduce the cost of maintaining IT infrastructure in a compliant state by allowing for optimisation and stabilisation of existing processes and electronic management (authorisation and approval) of IT infrastructure management process and procedures. This will reduce the cost of IT Infrastructure compliance and qualification by eliminating much of the

information technology

Accelerating the validation process through automation

Another area where software can drive compliance as well as help to better manage the IT infrastructure is in the area of computer software validation. Processes and tools must be developed and implemented to maintain the software and hardware involved in FDA-regulated processes in a validated state. ITIL and IT automation software tools in combination with some specific enhancements, can help biopharmaceutical companies automate the processes around software validation in order to ensure that they are able to take advantage of the latest IT technologies, while lowering costs and risk and maintaining compliance with regulatory requirements for IT qualification and validation.

It should be recognised that computer software validation does make good business sense. It is less expensive to validate proper system functionality up front than to deal with inconsistent

performance later. However, effective computer software validation must be an integral part of IT operations. The need to maintain applications in a validated state has encouraged some negative behaviours, such as: â&#x20AC;˘ Reluctance to perform patches or upgrades because of need to revalidate applications â&#x20AC;˘ Manual validation processes often result in out-of-date IT environments that can be very difficult and costly to maintain.

Leveraging test management and automation software will allow biopharma companies to improve their validation processes and reduce compliance risk through the automation of their current paper-based processes. These benefits include time and cost reduction, increased consistency and quality, repeatability and enhanced agility, and automatic report generation. The end result will enable companies to deploy application patches and upgrades more frequently keeping IT infrastructures technologically current and compliant. This can be accomplished by incorporating automated functional testing, automated performance testing, test management and monitoring managed through software automation tools into the process.

IT infrastructure software accelerates the validation effort by helping to automate elements of the validation process particularly Operational Qualification (OQ), Performance Qualification (PQ), traceability matrix and the summary report. The role of OQ and PQ in software validation is to assess the key metric of whether or not applications function according to their intended use.

Regression testing helps assure that the functionality and performance of applications continue to meet expectations over time as changes occur to the system.

However, manually maintaining a regression suite is costly and labour-intensive, and they must be re-run after patches or major software updates. These software tools reduce the amount of time devoted to OQ and PQ by automating and accel-

Time savings from use of automated testing and test management software

Savings from reduced oq/pq time Time

paper-based documentation and process / procedure approvals.

For example, in the realm of change control, IT management software with ITIL-based procedures can help streamline processes and approvals while reducing the risk of implementing unauthorised changes. Pharma companies can benefit from software that allows them to quickly implement standard processes throughout an enterprise, with proper approval controls and mechanisms, while maintaining 21 CFR compliant digital signatures, audit trails etc. The software should also be able to track all changes, allowing IT managers to look at the overall processes from a workflow perspective where they can evaluate and control the impact of system-wide changes. With IT Service Management, IT managers can easily manage all related tasks and actions in a change process, tracking action items through completion. From a compliance perspective, IT (and compliance) managers can more easily capture, and manage, exceptions and deviations.

Savings from reduced OQ/PQ plus automatically generated TM and VSR

Manual Validation

Automated Automated Testing Testing and Test Mgmt.

Figure 1

erating regression testing to dramatically reduce execution times while providing fixed and repeatable sets of tests. The result is that automated testing will reduce time, and costs in the areas of OQ, PQ, generating a Traceability Matrix and Validation Summary Report.

These tools also allow organisations to better incorporate a risk-based approach by allowing them to look at their integrated applications and focus on areas of the application that are critical to human safety. For example, should a company identify, through their risk-based analysis, an application that has a high-risk profile for drug safety; they can use them, in conjunction with a risk-based approach, to perform more rigorous testing on those application areas of highest risk.

Once a company completes its validation and automation, thereby improving its efficiencies and reducing the cost of initial testing, they can be further used to perform periodic testing. Good validation SOPs and IT processes also call for regulated companies to periodically test their IT environments. This is a perfect situation where biopharmaceutical companies can use automated testing tools for scheduling and conducting the required testing and save the results for later review and action. The use of these tools will allow an organisation to quickly and cheaply verify that their environment is in a validated state. Thus, management

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IT management and compliance through software automation

IT infrastructure software management tools can be a key weapon in the arsenal of pharmaceutical companies to help ensure both compliance and cost-effective management of their IT infrastructures.

Many companies are discovering that deploying software tools for incident, problem, change and configuration, release and service level management as well as test management can actually help reduce compliance uncertainty and greatly streamline operations.

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Properly deployed IT management tools and automation technology actually lowers compliance risk by enforcing standard policies and procedures to ensure a stable IT infrastructure.

Coupled with ITIL practices these tools will allow organisations to evaluate and analyse their processes and procedures in terms of best-IT practices and their risk management profile. Validation processes are more efficient and effective with automation testing technology, which helps to ensure a thorough testing of validated IT environments.

Automated tests reduce the time required

Author

of an IT infrastructure becomes much more agile when companies can increase their testing to a more frequent basis through automation. The result is better assurance of a validated state and preparedness for validation audits as well as a better understanding of the operational status of their IT environment.

for complex testing as well as ensuring their repeatability and consistency. The result is that organisations are able to better maintain an effective and available software environment that is current with the latest patches and upgrades.

Any life science organisation that is interested in the cost-effective, compliant management of its IT infrastructure can use IT Service Management software to help implement its ITIL service delivery strategies to positively impact the business in the highly- regulated environment of the pharmaceutical industry.

David Medina is responsible for the pharmaceutical and life science research segments in HPâ&#x20AC;&#x2122;s Worldwide Health & Life Science group.

Prior to that he held leadership positions with Quintiles Consulting, Medical Manager, Dianon Systems, and Confer Software.

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At Merck Research Laboratories (MRL), bridging this gap effectively has led to the creation of a new group known as MRL Information Technology Innovation. The group identifies compelling new information technology, and uses its privileged internal knowledge of current and emerging MRL business needs to orchestrate opportunities to apply these new technologies to business challenges in the form of short agile experiments.

A hypothesis-driven approach to ensure business relevance

In contrast to activities where innovation is directed at the company’s primary

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Sanjoy Ray, Director, Technology Innovation, Merck Research Laboratories, USA

nformation-related challenges are pervasive throughout modern drug discovery. They are becoming ever more draconian as the industry leverages powerful new experimental capabilities to create novel therapeutics for unmet medical needs. In parallel, breathtaking advances in Information Technology (IT) make possible effective responses to these challenges and promise the advent of revolutionary business capabilities previously thought to be unachievable.

Effectively translating the potential of innovative new IT to deliver novel R&D capabilities requires bridging the gaps between external IT innovators and internal R&D and IT personnel.

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The pharmaceutical industry is facing increasingly severe challenges to its mission of delivering novel therapeutic solutions for unmet medical needs.

Today, a heightened focus is being placed on leveraging maximum value from its core asset—information. Continual advances in information technology promise substantial benefits throughout the pipeline, both from the prospects of improving existing business capabilities, and enabling revolutionary new ones.

Merck has created a group which focusses on ensuring rapid translation of these IT advances to enable pharmaceutical R&D.

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Innovative IT Enabling pharmaceutical

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information technology

product, (for example, where the outcome is an innovative therapeutic agent), novel IT is not itself directly a pharmaceutical industry product. Yet people possessing strong IT skill sets are essential for a deep understanding of the capabilities and potential of new IT. There is a risk, however, of focus on innovative IT which, while compelling to an information technologist, may lead to little or no business value to the company. Mitigation of this risk, which is sometimes known as “technology for technology’s sake,” has led to the development of a formal methodology which is based loosely on the scientific method.

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information technology

For any initiative involving innovative IT, a hypothesis is developed.

This is a candidate explanation of an existing or anticipated future business challenge or gap. A prediction is then developed of the expected impact of the new IT on the business scenario described in the hypothesis. This is then followed by the design and execution of an experiment to test the prediction.

The explicit separation of the business target (the hypothesis) from the new IT (the prediction) is important because it allows the business targets to be considered without the distracting allure of the new IT. Hence, the business targets can be validated for the internal logical consistency of their explanations independently of considerations of the applicability of the technology. It also affords prioritisation on the basis of the importance of the business target, which drives rational choices between multiple experiments. Focus on business relevance is further enforced by the requirement that an MRL business group commit to participation in the experiment before approval to execute is granted.

Collaborative experimentation encourages risk taking

Experiments are conducted in such a way as to provide enough knowledge to guide evidence-based investment decisions. Typically this involves making baseline observations to quantify the current state, application of the new technology and subsequent measurement of the effects.

To avoid delay from otherwise lengthy planning, experiments are limited to a maximum of three months’ duration.

This allows quicker decision-making and encourages wider testing of speculative ideas, particularly those which have the potential for high value, but appear counter-intuitive initially. Moreover, they require relatively minimum investments compared to longer initiatives.

To further lower the extensive planning barriers which would otherwise arise, a new lightweight procurement process has been created. The standard procurement process is inappropriate for these short experiments for two reasons.

First, the time required for a standard procurement negotiation often exceeds the duration of an experiment. Second, these experiments provide evidence which inform rigorous procurement negotiations in the event of a positive experimental outcome, so the experiments can be viewed as a part of the more rigorous procurement process required for delivery of a production capability. Accordingly, the procurement processes which enable experiments are lightweight, fast, apply only for the period of the experiment and are subject to renegotiation as necessary after the experiment completes.

Currently, any systems which are created during an experiment must be decommissioned at the conclusion of the experiment. This removes the burden of planning for any subsequent ongoing maintenance and operations effort.

The resources and effort required for this planning would increase barriers to rapid execution and agile testing of new ideas.

It also ensures explicit hand off to larger groups possessing delivery expertise in the event of a success. This allows the Technology Innovation group to focus on the exploration of as many new IT opportunities as possible. The potential business partners are made aware, well before the experiment begins, that the aim is only to provide evidence for correct investment decisions and not to immediately deliver IT capability described in the prediction.

This raises a challenge because the typical expectation of a business customer is that they will immediately gain a concrete IT capability in return for the investment of their time. The challenge is addressed by clear initial communication that delivery in the event of a success requires significantly greater supporting capabilities than possible in a short experiment designed only as a “proof of concept”, and as such the decision to invest in those capabilities must be made explicitly as a part of the business’s standard resource allocation process. The motivation for business customers to participate is that they can better plan their future business strategy on the basis of experimentally verified capabilities of new IT. Risk taking is further encouraged by the visible celebration of “good failures” which are well-executed experiments whose outcomes differ from the expectations described in their predictions.

These are celebrated for the subsequent avoidance of cost, time and effort due to an “early kill” happening far in advance of production delivery to a customer for

The technology innovation experimental process

Identify Priority Business Targets

Identify New Information Technologies

Identify Talent Internal & External

Design Collaborative Experiments

Communicate Results

Go / No Go

Figure 1

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that specific business target. They are also celebrated because they offer a better, evidence-based understanding of the current capabilities and promise inherent in both the new technology and in the external innovator. This sometimes allows alternative applications to be determined for the new technology, or allows a determination of what further investment would need to be made to create the capability of most value.

The knowledge gained may also allow innovative combinations of seemingly unrelated new IT to be identified.

Crucially these combinations are rarely visible to the external innovators because the technologies involved have no clear linkage. The insight required to connect them arises only from deep knowledge of emerging business needs combined with an equally deep knowledge of the real capabilities of the technologies.

The experiments are widely collaborative to ensure the greatest cross-disciplinary exposure and evaluation. They involve the complex orchestration of personnel from disparate areas both inside and outside the company. A clear communication plan is created at inception, ensuring broad dissemination of the results. This maximises the chances of value arising in unexpected parts of the company where the correct application becomes apparent only after the experimental outcomes are known.

Wide and open collaboration with business leaders is essential. One surprising consequence arises due to their assumptions about the capabilities of technology.

These assumptions arise from common

experience of the technology norms of the present day. Furthermore, they are often implicit and therefore unquestioned; leading to the belief that certain capabilities are so totally out of the bounds of possibility that they are unworthy of even the tiniest consideration. However, innovative new technology can make possible radically new business functions of high value, which were previously assumed to be impossible. As business leaders are able to see evidence of the capabilities of new technologies in their own business scenarios through these experiments, they challenge these assumptions, and identify opportunities to realise revolutionary new business capabilities.

The agile creation, execution, and readout of these experiments present a demanding challenge given their short three-month (maximum) duration.

Expertise in doing this well is a key differentiated capability of the Technology Innovation group.

Critical success factors

During the 18 months of its operation, this group has established the business value of the experimental methodology described above. The agility and risktaking encouraged by these rapid short experiments where â&#x20AC;&#x153;good failuresâ&#x20AC;? are celebrated have proved to be of value to the company and to external partners.

Moreover, the benefits of collaborative execution and effective communication have been clearly demonstrated. In addition to these, several other critical success factors have become apparent during the process.

Success has been enabled by members of the Technology Innovation group who have specific skill sets and capabilities.

This includes mental agility, strong technology and business skills, which are essential to quick understanding of new business challenges and new technology characteristics. Also critical is a flexible associative mindset which is open enough to visualise novel combinations of new technology. Just as importantly, strong collaborative partnering skills are required, as is a positive mindset where, instead of immediately finding reasons why something will not work, the response is to consider under what circumstances it would work. The acquisition of these skills, mindsets and operational methods by other Merck employees who rotate temporarily through the group creates a legacy of lasting value to the company.

A key success factor is to align experiments with the driving motivations of all of the participants. This approach, which emphasises the strengths of the participants, has been extended fruitfully to the external innovators. During the initial approach to an external innovator, they are asked what it is that they really want, what they wish we should try, and what really drives and excites them. These are then borne in mind when designing the experiment. This is in sharp contrast to their typical interaction with other potential customers, who usually request activity which may be exciting to the customer, but may not necessarily enthuse the innovator. This approach has led to extraordinary performance and

An example of an experiment Proof-of-concept experiment July

August Setup and preparation

September Process analysis

October Technology deployment

November Process re-analysis

December â&#x2020;&#x2019; 2008 Communicate Results Figure 2

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Future prospects

The experimental approach described above has led to the delivery of new capabilities which would not otherwise have been possible. However, much greater value will arise from the extension of this approach.

Beyond immediate application of experimental successes, there is a further more powerful opportunity.

Situations may arise where the evidence gathered from a set of disparate experiments can be combined to suggest a powerful new aggregate capability,

Author

commitment, even under challenging conditions, solely because all involved have outperformed in ways which were driven largely by their sheer excitement about the experiment. It has also fostered enduring positive relationships after the experiments have completed, opening doors to greater future value as a result of mutual good will.

Finally, visible and enthusiastic executive sponsorship has been critical because at inception, innovation was largely regarded as discretionary. The group simply could not have delivered any of the positive outcomes described above were it not for the vision, commitment and support of senior Merck leadership. Since the group explicitly does not deliver capability directly, the advocacy of senior leadership is critical for driving a positive outcome through to a realised capability for MRL researchers.

which can then be realised by appropriate investments in the external innovators. This could lead to the creation of technology with capabilities which exceed by orders of magnitude what is possible today.

Harnessing the continual and extraordinary innovations of the IT industry in this way to yield powerful enabling capabilities holds the enticing promise of enabling the industry to reduce the human suffering that exists due to unmet medical needs.

Sanjoy Ray has a PhD in Protein Engineering from Imperial College, London and held a postdoctoral research fellowship in Structural Biophysics at Harvard University. He has 14 years of IT experience, enabling scientific high-performance computing at Bostonâ&#x20AC;&#x2122;s Childrenâ&#x20AC;&#x2122;s Hospital and the Whitehead Institute / MIT. He created and currently leads a new information technology innovation group at Merck & Co., Inc.

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Nanoscale double-emulsions hold potential for targeted drug delivery

R

esearchers at the University of California, Timothy Deming and Thomas Mason, have succeeded in making unique nanoscale droplets smaller than human cells for delivering pharmaceuticals. These are double emulsion droplets with a water droplet embedded within each oil droplet and the two liquids do not mix. This comes as a new tool in the field of drug delivery and anticancer applications.

Deming and Mason have made nanoemulsions containing billions of double nanodroplets. The big challenge, according to Deming, was to make the double emulsion droplets in the sub-100 nanometre size and yet stabilise them, while retaining their properties. They have demonstrated these droplets to be stable in this size range, which was not possible in earlier studies. Usually, they are hard to form and very unstable. The unique feature of nanoemulsions carrying these nanodroplets is that both water soluble as well as water insoluble drugs can be loaded inside and delivered simultaneously. This approach is effective where one wants to deliver two drugs simultaneously at a fixed ratio in the same location.

TechnoTrends

102, Bharat Bhavan-B,1360 Shukrawar Peth, Pune-411002.

Email: intimatepuf@gmail.com Cell: 09325357497

Deming and Mason caution that while this approach holds promise for fighting cancer, there are still many steps, and likely many years of research, before patients could be treated in this way. NanoPacific Holdings Inc. has licensed this nanodroplet technology from UCLA to develop and commercialise the technology in a variety of applications. In the emerging field of nanoemulsions, this research is a big step, says Mason.

Timothy Deming , Professor and Chair of Department of Bioengineering. Thomas G Mason, Associate Professor of Chemistry and Physics

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2009Events January - june

January

21-22 January Pre-Filled Syringes www.smi-online.co.uk 21-22 January Pharmapack 2009 www.pharmapack.com.fr 21-24 January Nanobiophysics & Chemistry Conference 2009 www.zingconferences.com

07-08 January GLP Bioanalysis www.healthtech.com

27-28 January Forced Degradation Studies www.iir-events.com 27-30 January Clinical Outsourcing World Europe 2009 www.terrapinn.com

11-16 January PEPTALK 2009 www.chi-peptalk.com

28-29 January 6th National Conference on Pharma / Biotech IP Due Diligence www.americanconference.com

12-13 January Model Based Drug Development www.exlpharma.com 4th Annual Clinical Data Disclosure Summit www.exlpharma.com

28-29 January Clinical Trials for Special Populations www.iir-events.com

22-24 January Asia Pharma Expo 2009 www.asiapharma.org 26-27 January Biotech and Pharmaceutical Patenting www.iir-events.com

12-14 January Lyophilization 2009 www.chi-peptalk.com

26-27 January Reducing Toxicity in Drug Compound www.iqpc.com

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26-27 January Partnerships in Oncology Clinical Trials www.exlpharma.com

14-16 January Protein Production www.chi-peptalk.com 15-16 January Current Trends in Dosage Form Development and Biologics Formulation www.chi-peptalk.com 19-20 January Paediatric Clinical Trials www.smi-online.co.uk

26-27 January CBI’s 6th Annual Pharmaceutical Compliance CongressTM www.cbinet.com 26-27 January Biotech and Pharmaceutical Patenting www.iir-events.com 26-28 January CHI’S Biomarker Assay Development www.healthtech.com 26-28 January Phacilitate Cell & Gene Therapy Forum 2009 www.phacilitate.co.uk 26-28 January Phacilitate Vaccine Forum Washington 2009 www.phacilitate.co.uk

19-20 January BIO-Asia 2009 www.bioasia.bio.org

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27-28 January Clinical Trial Performance Metrics www.iir-events.com

27-28 January Aseptic Filling & Processing www.iir-events.com

11-15 January 8th Annual DIA Conference for Contemporary Pharmacovigilance and Risk Management Strategies www.diahome.org

12-14 January Protein Therapeutics www.chi-peptalk.com

27-28 January Biomanufacturing Summit 2009 www.biomansummit.com

27-28 January 2009 7th Annual Global Pricing and Reimbursement Congress 2009 www.iir-events.com

05-09 January CHI’S High-Content Analysis 2009 www.highcontentanalysis.com

12-14 January Processes to Optimize Protein Purification & Recovery www.chi-peptalk.com

26-28 January Phacilitate Cell & Gene Therapy Forum 2009 www.phacilitate.co.uk

28-29 January Cool Chain Europe 2009 www.site-members.com 28-29 January Electronic Laboratory Notebooks www.smi-online.co.uk

03-04 February Comparability Challenges: Regulatory and Scientific Issues in the Assessment of Biopharmaceuticals www.diahome.org 03-04 February CBI’s 2nd Annual Clinical Trial Forecasting and Budgeting www.cbinet.com 04-05 February Adaptive Designs in Clinical Drug Development www.smi-online.co.uk 05-06 February CBI’s 5th Post-Marketing Studies Conference www.cbinet.com 05-08 February Global Secure Summit 2009 www.globalsecuresummit.com 08-10 February BioPartnering North America www.techvision.com 09-10 February CBI’s 2nd Annual Bio / Pharmaceutical and Medical Device Forum on Knowledge Management for Medical Affairs www.cbinet.com 09-11 February Clinical Trials Congress www.clinicalevent.com 09-12 February ASAP 2009 Global Alliance Summit www.healthtech.com 09-12 February 10th Annual Phase I Clinical

28-31 January Enabling Technologies in Drug Discovery and Process Research-Microwaves, Flow, and Beyond www.zingconferences.com 29-30 January 12th Annual Workshop in Japan for Clinical Data Management: Who should be “Superman” in CDM? www.diahome.org

February 01-01 February Medicinal Chemistry Conference 2009 www.zingconferences.com 02-03 February Biomarkers Summit www.smi-online.co.uk 02-04 February Bio-Asia 2009 www.bioasia.in 02-03 February Process Manufacturing Congress 2009 www.processmanufacturingcongress.com

Trials Conference www.iir-events.com 10-13 February 22nd Annual DIA Conference for Electronic Document Management: Addressing Challenges in an Electronic World www.diahome.org 11-12 February Bioanalysis in Clinical Research www.iir-events.com 11-12 February Pharmaceutical Parallel Trade www.smi-online.co.uk 12 – 12 February The Pharma Summit www.guest.cvent.com 12-16 February Chemtech + Pharma World Expo 2009 www.chemtech-online.com

26-27 February CBI’s 6th Annual Medical Imaging for Clinical Trials www.cbinet.com 27-28 February Advances and Progress in Drug Design VIII www.smi-online.co.uk

March 13-16 February The 19th Conference of the APASL 2009 www.apasl2009hongkong.org 16-18 February Advanced Pharma Packaging www.iqpc.com 16-18 February CMC Regulatory and Technical Strategies: Global CMC Dossier Life Cycle Management www.diahome.org 16-17 February Stem Cells: Drug Discovery and Therapeutics www.smi-online.co.uk 16-20 February The Pharma Executive Mini-MBA www.iir-events.com 18-19 February Examining Commercial Strategies for Maximising HEOR Data www.marcusevans.com 23 – 23 February 3rd Clinical Research Billing Compliance www.exlpharma.com 23-24 February Advances and Progress in Drug Design VIII www.smi-online.co.uk 23-25 February 7th Lean Six Sigma for Pharmaceutical, Biotech, Medical Device Excellence www.iqpc.com 24 – 24 February The 3rd Pharmaceutical Search Engine Marketing Strategies Conference www.exlpharma.com 24-26 February Pharmaceutical Analysis Course www.iir-events.com 24-27 February World Generic Medicines Congress Europe 2009 www.terrapinn.com 24-27 February 7th Cold Chain Management & Temperature Control Summit www.coldchainpharm.com 26-27 February Biomarkers Congress 2009 www.biomarkers-congress.com

02-06 March Cell Line Development and Engineering www.iir-events.com 03-04 March 8th Annual Protein Kinases Congress 2009 www.iir-events.com 03-04 March Drug Discovery Targets & Tools www.iir-events.com 03-04 March 7th Annual Congress: G ProteinCoupled Receptors in Drug Discovery www.iir-events.com

17-19 March Pharma MedDevice 2009 www.pharmamedevice.com 17-19 March Interphex 2009 www.interphex.com 23-25 March BioSysBio 2009 www.conferences.theiet.org 23-25 March Discovery 2009 www.discovery-summit.com 29-31 March Duphat www.duphat.ae

April 01-03 April China 2009 Pharmaceutical R&D Summit www.ibclifesciences.com 06-08 April Chronic Disease Management Australia 2009 www.terrapinn.com

03-05 March Bio-Pharma: Mastering the Business of Science www.babson.edu

26-30 April Bioassay & Technology Innovation: 15 Years of Shaping Drug Discovery www.sbsonline.or 27-28 April Pharmaceutical Packaging and Labelling Innovations www.smi-online.co.uk 28-29 April Post-Approval Summit www.postapproval.org 28 April-01 May Pharma Pricing & Market Access Outlook Europe 2009 www.terrapinn.com 29-30 April Drug Development Summit 2009 www.drugdevelopment-summit.com

May 11-14 May 9th Annual Shared Services and Outsourcing Week www.sharedservicesweek.co.uk 12-14 May Generic Medicines Australia 2009 www.terrapinn.com 12-14 May European Stem Cells & Regenerative Medicine Congress 2009 www.terrapinn.com

03-05 March 2nd Annual Ion Channel Targets Congress www.iir-events.com 04-05 March 8th Annual Global Generic Strategy Summit www.iir-events.com

13-14 April CBI’s 4th Annual Bio / Pharmaceutical Market Research Summit www.cbinet.com

12-15 May Exploratory Clinical Development World Europe 2009 www.terrapinn.com

05-08 March International Outsourcing Forum 2009 www.tioforum.com

13-16 April World Vaccine Congress Washington 2009 www.terrapinn.com

June

09-10 March CHI’S Drug Development Latin America www.healthtech.com 10-11 March Successfully Implementing PAT and QbD www.iir-events.com 10-11 March CBI’s 8th Annual Forum on eMarketing for the Pharmaceutical Industry www.cbinet.com 11-12 March Electronic Data in Clinical Trials www.healthtech.com 16-17 March 5th Annual Pharmaceutical / Biotech Accounting and Reporting Conference www.cbinet.com 16-19 March Biomedical Asia 2009 www.terrapinn.com 16-19 March BioLogistics Asia 2009 www.terrapinn.com

20-22 April Pharmaceutical & Biotechnology Middle East www.pabme.com 20-23 April World Vaccine Congress Washington 2009 www.terrapinn.com 20-24 April 2009 PDA Annual Meeting www.pda.org 21 – 21 April World Vaccine Congress Washington Awards 2009 www.terrapinn.com 21-24 April World Drug Safety Congress Americas 2009 www.terrapinn.com 23-24 April Advanced Aerospace Conference April 2009 www.gmpgroupconferences.com

08-11 June Cardiotoxicity and Drug Safety www.worldpharmacongress.com 08-11 June World Vaccine Congress Asia 2009 www.terrapinn.com 10-11 June Hepatoxicity and Drug Safety www.worldpharmacongress.com 14-19 June 11th International Workshop on Physical Characterization of Pharmaceutical Solids www.assainternational.com 15-16 June Drug Discovery Summit 2009 www.drugdiscovery-summit.com 22-24 June Phacilitate Active Immunotherapeutics Forum 2009 www.pharmiweb.com 22-24 June Phacilitate Vaccine Forum Barcelona 2009 www.phacilitate.co.uk www.pharmafocusasia.com

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OurAuthors Issue 5 - Issue 8

STRATEGY Abdel Aziz Saleh

Ex-Special Adviser to the Regional Director for Medicine WHO / EMRO

Andre Hoekema

Senior Vice President Galapagos

Athos C Rosselli

Sales & Marketing Manager Pacific Rim Teledyne Isco, Inc.

Jack E Silver

Chris Lee

Regional Head Bayer Schering Pharma

Product Manager Chromatography Scientific Instruments Teledyne Isco, Inc.

Christopher-Paul Milne

Bernard A Fox

Associate Director Tufts University

NIH-funded Researcher Oregon Health and Science University

David Twinberrow

Chwee Teck LIM

Deputy Director and Associate Professor NUS Life Sciences Institute National University of Singapore

Senior Director Oncology IMS Health

Dilip Shah

David Andrew Jans

CEO Vision Consulting Group

Professor and Head Monash University

Harjit Singh

Senior Development Consultant Clinical Research

Joachim M Greuel

Founding and Managing Partner Bioscience Valuation BSV GmbH

Mark J Benedyk

Dominik Rüttinger

Surgical Oncologist Laboratory of Clinical and Experimental Tumor Immunology Ludwig-Maximilians-University

Furong Ye

Indeed, I must confess , I had not been aware of Pharma Focu s Asia, but was quite pleasantly surprised at the excellent content.

I am quite proud to ha ve been included in such a fine journal. Ind eed, I would be quite happy to contribute ag ain, should you so desire. It is a plus to ha ve your journal’s name on my list of pu blications.

Emil W Ciurczak,

Chief Technical Officer , Cadrai Technology Group

Jan Möschwitzer

Pele Choi-Sing Chong

K K Bhutani

Philippe Stas

Senior Pharmaceutical Scientist CPD-PSA Solvay Pharmaceuticals B.V. Head Department of Natural Products and Dean NIPER

Keith Russell

Investigator and Director Vaccine Research and Development Center National Health Research Institutes Chief Operating Officer AlgoNomics NV

Rishikesh Sawant

Director, Enhancing Product Delivery AstraZeneca

Doctoral Candidate in Pharmaceutics and Drug Delivery Systems Northeastern University

Head, La Jolla Incubator The Pfizer Incubator, LLC

Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah

Kylie M Wagstaff

Sarathi V Boddapati

Nayan Nanavati

Georg C Terstappen

Mansoor M Amji

Shriram Raghavan

Vice President PAREXEL International

Woodford L and Ann A Flowers University Professor Harvard University

Gerard G M D’Souza

Maung Kyaw Khaing Oo

George M Whitesides

CEO & Partner Mosaigen, Inc. and Endeavour Capital Asia Ltd.

Reinhard Angelmar

The Salmon and Rameau Fellow Healthcare Management and Professor of Marketing, INSEAD

Stephen M Sammut

Senior Fellow Wharton Health Care Systems and Entrepreneurship

Vijay Soni

Formulation Development Scientist Bouve College of Health Sciences Northeastern University

Han Op’t Land

Harpreet Singh

Mrinalkanti Kundu

Vipin K Garg

Henry Du

Chief Executive Officer GNI Ltd. / Shanghai Genomics, Inc.

RESEARCH & DEVELOPMENT Afif Abdel Nour

Research Scientist in Molecular Biotechnology Institut Polytechnique LaSalle Beauvais P h a r m a F o c u s A s iA

ISSUE - 9 2008

Michael D Dickey Post Doctoral Fellow Whitesides Group Harvard University

Managing Director and Chief Scientific Officer immatics biotechnologies GmbH

Ying Luo

Doctoral Candidate in Materials Science Stevens Institute of Technology

Head of the Biopharmaceutical Platform Solvay Pharmaceuticals B.V.

Executive Vice President – IP Glenmark Generics Inc President and CEO Tranzyme Pharma

Post-doctoral Researcher Monash University Professor and Associate Department Chairman Department of Pharmaceutical Sciences School of Pharmacy and Co-Director Nanomedicine Education and Research Consortium Northeastern University

Chief Scientific Officer Siena Biotech S.p.A

Neil J Campbell

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Anshul Agarwal Doctoral Candidate in Biomedical Engineering Louisiana Tech University

Professor and Director Chemical Engineering and Materials Science Stevens Institute of Technology

Hongjun Wang

Associate Director Orchid Research Laboratories Ltd.

Nathalie Garçon

Vice President Head of Global Adjuvant Center for Vaccine Development GlaxoSmithKline Biologicals

Padmaja Magadala

Assistant Professor, Biomedical Engineering Stevens Institute of Technology

Department of Pharmaceutical Sciences School of Pharmacy Bouve College of Health Sciences Northeastern University

Hong-Ming Hu

Panchapagesa Muthuswamy Murali

NIH-funded Immunologist Oregon Health and Science University

Managing Director Evolva Biotech Private Limited

Formulation Development Scientist Novavax Inc Head Compound Assessment Evolva Biotech Private Limited

Stefan Barth

Head Department of Pharmaceutical Product Development Fraunhofer IME

Thierry Aussenac

Scientific Director Institut Polytechnique LaSalle Beauvais

Toni Weinschenk

Head of Discovery immatics biotechnologies GmbH

Uma Ramachandran

Vice President Orchid Research Laboratories Ltd.

Vladimir Torchilin

Distinguished Professor of Pharmaceutical Sciences Chair and Director Northeastern University

Volkmar Weissig

Associate Professor of Pharmacology Department of Pharmaceutical Sciences College of Pharmacy Glendale Midwestern University

Yoshinobu Horiuchi

Head, Laboratory of Pertussis

The editorial team of Pharma Focus Asia takes this opportunity to thank our esteemed authors for sharing their valuable views on the pharmaceutical industry.

and Endotoxin Control Department of Bacterial Pathogenesis and Infection Control National Institute of Infectious Diseases

RS Kumar

Dennis Constantinou

Yuri Lvov

Sean Stevens

Emil W Ciurczak

Chemistry Professor and Tolbert Pipes Eminent Endowed Chair on Micro and Nanosystems Louisiana Tech University

Senior Manager Life Sciences Practice BearingPoint

Senior Director LifeSciences Oracle

Associate Director Inflammation and Immune Diseases Regeneron Pharmaceuticals Inc.

Sergei Drapkin

Zheng-Rong Lu

Assistant Professor University of Utah

Zhenping Zhu

Director FastTrack Biopharma Services GE Healthcare

Shannon A Graver

Frank E Sistare

Solomon Shacter

Director, Product Management - Platform Solutions ClinPhone Plc

CLINICAL TRIALS Catherine Hall

Supply Chain Coordinator Pfizer Global Research and Development Supply Chain Management

Christopher R Albani

Partner PRTM Management Consultants

Stefan J Scherer

Senior Biomarker Program Leader Angiogenesis PDEO F Hoffmann-La Roche

Toshiyoshi Tominaga

Senior Director Strategic Drug Development Group Quintiles Limited

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

D Thomas Oakley

Yoruzu Tabata

Colin W Vose

Principal PRTM Management Consultants

President and CEO Bridge Laboratories

Daniel Chelsky

Chief Scientific Officer Caprion Proteomics, Inc. Vice President Administration Daiichi Sankyo Development Ltd

Mark Chang

Bruce Sawyer

Scientific Fellow, Biostatics and Medical Writing Millennium Pharmaceuticals Inc

Matej Orešic

Senior Director Operations Excellence GPSG Johnson & Johnson

Research Professor, Systems Biology and Bioinformatics VTT Technical Research Centre of Finland

ine The magaz

Daniel N Galbraith Head, Operations BioOutsource Ltd

eful.

ve and us is informati

of Organisation General, I), India P P (O irector D y, of India Tapan Ra Producers Pharmaceutical

Director of Education The Shingo Prize - for Operational Excellence Jon M Huntsman School of Business Utah State University

Swapnil Ballal

Head Biopharmaceutical Bulk Manufacturing Intas Biopharmaceuticals Ltd

Thomas Völcker

Marketing & Sales Director Schreiner ProSecure

Uwe Gottschalk

Vice-President Sartorius-Stedim Biotech

INFORMATION TECHNOLOGY

Consultant Innovative Technologies, Competence Centre Phamaceutics Siemens AG

Alan S Louie

Jacob Raymer

CEO CeuticalSoft Inc.

Assistant Director of Education The Shingo Prize - for Operational Excellence Jon M Huntsman School of Business Utah State University

Research Director Health Industry Insights

Chip Allee

Daniel Matlis President Axendia

John E Danese

Douglas Meyer

Product Strategy Director Oracle

Senior Director Aptuit Informatics Inc.

Jukka Rantanen

Simon Revell

Managing Director AC Serendip Limited

Associate Professor Business Administration The Shingo Prize - for Operational Excellence Jon M Huntsman School of Business Utah State University

President Clinical Research Services and Perceptive Informatics Inc. PAREXEL International Corporation

Ingrid Maes

Ludger Fischer

Brian Atwater

Mark A Goldberg

Assistant Professor University of Copenhagen

Andrew Upsall

Business Consultant Pharmaceutical Industry SEA Siemens AG

IRTA Postdoctoral Fellow National Institutes of Health

Holger Grohganz

MANUFACTURING

Bart Moors

Leticia Cano

Principal PAT Scientist CAMO Technologies Inc.

Professor University of Copenhagen

Head, In vitro services BioOutsource Ltd

J Findlay Walker

Eric Grund

Managing Director ERGOMED Clinical Research Global Studies Operations Manager PDOC F Hoffmann-La Roche

Vice President Antibody Technology ImClone Systems Incorporated

Chief Technical Officer Cadrai Technology Group

Randy Cook

Marc Sluijs

EMEA Business Development Director Life Sciences Oracle Healthcare & Life Sciences

Marjatta Louhi-Kultanen

Research Lecturer Docent in Industrial Crystallization Lappeenranta University of Technology

Mark Albano

Life Sciences Marketing Manager Honeywell

Pala Bushanam Janardhan

Business Consultant Manufacturing and Plant Automation Services Life Sciences and Healthcare Practice HCL Technologies Ltd.

Petter Moree

Director, Online Products Umetrics AB

Rajeev Joshi

Manager of Enterprise 2.0 Technology Development Information and Knowledge Management Pfizer Inc

EXPERT TALK Cecil Nick

Principal Consultant PAREXEL Consulting

Joseph Manoj Victor

Senior Research Analyst Healthcare Practice Frost & Sullivan

Mark Engel

Chairman Excel PharmaStudies

R B Smarta

Founder and Managing Director Interlink Marketing Consultancy Pvt Ltd.

R S Gaud

Dean SVKM’s Nursee Monji Institute of Management Studies University

Rustom Mody

Director Quality and Strategic Research Intas Biopharmaceuticals Limited

Manager Development Engineering Honeywell www.pharmafocusasia.com

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LookingBack GlaxoSmithKline and OncoMed Pharmaceuticals announced that they have entered into an alliance to discover, develop and market novel antibody therapeutics to target cancer stem cells. Such stem cells play a key role in the establishment, metastasis and recurrence of cancer. The alliance includes OncoMed’s lead antibody product candidate OMP- 21M18, a monoclonal antibody, which is scheduled to enter the clinic in 2008.

While in alliance, OncoMed will utilise the xenocraft cancer stem cell models to identify monoclonal antibodies in a specific, undisclosed cancer stem cell pathway. Upon OncoMed’s achievement of clinical proof of concept in an agreed indication, GSK will license the same.

Possible new way to detect, monitor liver disease without painful liver biopsy Scientists working at the Hepatitis B Foundation, in partnership with Drexel University College of Medicine, may have discovered a reliable alternative to liver biopsy for the early detection of liver fibrosis and cirrhosis. They discovered that the blood of most people they tested with a diagnosis of liver cirrhosis, contained high levels of a special antibody that recognises a carbohydrate sugar commonly found on bacteria. Detection of this antibody in the blood of an affected person correlates very well with a diagnosis of increasing fibrosis and cirrhosis in the new study. The scientists think that the test, still in its experimental stage, if validated may offer a new, non-invasive way of testing for liver disease which as of now requires a surgical liver biopsy.

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Teva acquires CoGenesys Teva Pharmaceutical Industries Ltd. announced that it has entered into a definitive agreement to acquire CoGenesys, Inc. The company is focussed on the development of peptide and protein-based medicines across broad therapeutic categories. As part of the agreement, Teva will gain access to technologies and innovative pipelines as a step towards entering the biogenerics market. Teva will also have access to the biopharmaceutical research and development capabilities of CoGenesys.

Barr receives approval for generic KYTRIL® tablets Barr Pharmaceuticals, Inc. announced that it has received final approval from the US FDA for the generic version of Roche Laboratories Inc.’s KYTRIL® Tablets, 1mg. KYTRIL (Granisetron Hydrochloride) Tablets, 1 mg is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin and also for nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation

Newly approved HIV drug shows great promise FDA approved the first new nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC125/etravirine, developed by Tibotec Pharmaceuticals, Ltd. The drug priced at US$ 21.80 per day, is substantially cheaper than other antiretrovirals. The first NNRTI to show antiviral activity in treatmentexperienced adult patients with HIV resistant to an NNRTI and other antiretroviral (ARV) agents, received an accelerated approval from the FDA.

February 2008

GlaxoSmithKline and OncoMed enter into agreement for stem cell therapeutics

January 2008

December 2007

THE YEAR GONE BY

Sigma-Aldrich and MorphoSys collaborate for antibodies Sigma-Aldrich™ announced that it has entered into a collaboration agreement with MorphoSys AG to design, produce and distribute recombinant research antibodies using MorphoSys’s HuCAL GOLD® technology. MorphoSys’s AbD Serotec unit will develop and qualify antibodies from MorphoSys’s proprietary HuCAL GOLD library against a committed number of targets identified and supplied by SigmaAldrich. HuCAL GOLD is a phagedisplay library developed for the in vitro generation of specific and fully human antibodies.

Nicholas Piramal ties up with institutions for biological drugs Nicholas Piramal India Limited’s research unit has tied up with the Department of Biotechnology to identify biological molecules that can be developed into drugs to treat various diseases. The project will work towards the screening of potential candidates for anti-cancer, anti-infective, anti-diabetes and anti-inflammation properties. This project will involve nine other institutes besides Nicholas Piramal.

Glenmark’s molecule for Rheumatoid Arthritis enters Phase I trials Glenmark Pharmaceuticals Ltd. announced that its candidate for Rheumatoid Arthritis, Inflammation and Multiple Sclerosis—GRC 4039, has entered Phase I trials. It is entering the trials with approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K. GRC 4039, a PDE 4 inhibitor, in Rheumatoid Arthritis is to be developed by Glenmark as the primary indication.

Under the agreement, Suven will be responsible for the discovery activities concerned with the identification and selection of clinical candidates with respect to the central nervous system disorders, in close association with Eli Lilly.

Marcadia Biotech and Merck collaborate for biopharmaceutical therapies Marcadia Biotech, Inc. announced that it has entered into collaboration with Merck & Co., Inc. to jointly discover, develop and commercialise novel biopharmaceutical therapies targeting the glucagon and related receptors for the treatment of diabetes and obesity.

Under the agreement, Merck has obtained a worldwide license to certain Marcadia development candidates and intellectual property.

DiObex and Camurus sign license agreement for the Development of DIO-901 in FluidCrystal(R) Extended Release Technology DiObex and Camurus announced that they have entered into an agreement to develop DIO-901 in the Camurus drug delivery technology, FluidCrystal®. The development candidate is an extended release formulation of low dose glucagon for the prevention of insulininduced hypoglycemia in patients with diabetes. There is no such product approved till now.

MHLW – Japan authorises Ranbaxy’s generic product, developed independently outside Japan Ranbaxy Laboratories Limited announced that it has received authorisation from Ministry of Health and Labour Welfare (MHLW-Japan) for marketing the generic version of Amlodipine tablets 2.5mg and 5mg. Amlodipine Tablet is the first independent product approval received

by Ranbaxy in Japan. It is the first product developed by any foreign generic pharmaceutical company outside Japan and subsequently being granted approval by MHLW (Japan).

Stanford University finds unique technology to develop cancer stem cells Researchers at the Stanford University School of Medicine announced that they have transformed normal skin cells into cancer stem cells, a step that will make these naturally rare cells easier to study. The study demonstrated that cancer stem cells are similar to the stem cells found in embryos and are helpful in generating all types of tissue. These findings would be helpful in researching cells as they progress towards becoming cancerous.

Dr. Reddy’s acquires BASF’s pharmaceutical contract manufacturing business Dr. Reddy’s Laboratories announced that it has entered into a definitive agreement for the acquisition of BASF’s pharmaceutical contract manufacturing business and related facility in Louisiana, USA. The acquisition will involve the contract manufacturing of generic prescription and over-thecounter products for branded and generic companies in the US.

May 2008

Suven Life Sciences announced that it has entered into an agreement with Eli Lilly for the preclinical research of molecules in the therapeutic area of central nervous system disorders.

April 2008

March 2008

Suven Life Sciences and Eli Lilly collaborate for preclinical research

Ranbaxy and Merck sign antiinfective drug discovery and development agreement Ranbaxy Laboratories Ltd. and Merck & Co., Inc. announced that they have entered into an agreement for collaboration in drug discovery and clinical development for new products, in the anti-infective field. Ranbaxy and Merck will work together to develop clinically validated anti-bacterial and anti-fungal drug candidates. Ranbaxy will carry-out drug discovery and clinical development through Phase IIa clinical trials, with Merck conducting development and commercialisation of drug candidates thereafter.

Lupin receives US FDA approval for topiramate tablets Lupin Pharmaceuticals, Inc. announced that it has received tentative approval from US FDA for the Company’s Abbreviated New Drug Application (ANDA) for Topiramate tablets, 25 mg, 50 mg, 100 mg and 200 mg.

Topiramate tablets are the AB-rated generic equivalent of Ortho-McNeil’s TOPAMAX® tablets, indicated for the treatment of seizures.

Takeda completes acquisition of Millennium Takeda Pharmaceutical Company Limited and Millennium Pharmaceuticals, Inc. announced the completion of Takeda’s acquisition of Millennium. “The successful completion of this transaction underscores our ongoing commitment to becoming a global leader in oncology by delivering novel therapies that improve the standards of care for patients.

Additionally, the Millennium clinical trial programs for irritable bowel disease (IBD) will enhance our GI franchise.

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LookingBack Ranbaxy Laboratories Limited and Daiichi Sankyo Company, Limited announced that Daiichi Sankyo will acquire the entire shareholding of the Sellers in Ranbaxy and further seek to acquire the majority of the voting capital of Ranbaxy. Malvinder Singh will continue to lead the company as its CEO and Managing Director while additionally assuming the position of Chairman of the Board.

US FDA licenses Sanofi Pasteur’s new paediatric combination vaccine, Pentacel® Sanofi Pasteur announced that US FDA has licensed Pentacel®, Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine. It is indicated for active immunisation against diphtheria, tetanus, pertussis, poliomyelitis, and invasive disease due to Haemophilus influenzae type b (Hib).

Watson receives FDA Approval of Potassium Chloride Extended-Release Capsules Watson Pharmaceuticals, Inc. announced that it has received approval from US FDA for PotassiumChloride Extended-Release Capsules USP in the 8mEq and 10mEq strengths. PotassiumChloride is the generic equivalent to KV Pharmaceutical’s Micro-K(R) Extencaps(R) USP and is indicated for the treatment of patients with hypokalemia, with or without metabolic alkalosis, in digitalis intoxications, and in patients with hypokalemic familial periodic paralysis.

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ISSUE - 9 2008

Teva to acquire Barr Teva Pharmaceutical Industries Ltd. and Barr Pharmaceuticals, Inc. announced that they have entered into an agreement under which Teva will acquire Barr. Shlomo Yanai, President and Chief Executive Officer, Teva, said, “The acquisition of Barr will elevate Teva’s market leadership to a new level. The combination of our two companies provides an outstanding opportunity strategically and economically: It will enhance our market share and leadership position in the US and key global markets, further strengthen our portfolio and pipeline, and provide upside to our strategic plan, by allowing us to exceed our 20/20 goals for 2012.”

August 2008

Ranbaxy to bring in Daiichi Sankyo Company Limited as majority partner

July 2008

June 2008

THE YEAR GONE BY

AstraZeneca partners with Singapore institutions to develop anti-cancer compounds AstraZeneca will partner with the National Cancer Center Singapore and National University Hospital to develop anti-cancer compounds. A Memorandum of Understanding (MoU) was signed to enable AstraZeneca in drug development and provide potential benefits to patients with inoperable Hepatocellular Carcinoma (HCC). HCC is a cancer that is prevalent in Asia and is accountable for nearly one million deaths annually worldwide. Under the MOU, AstraZeneca and the Singapore institutions will collaborate for both clinical and preclinical development activities.

Abeome and Cato research to collaborate on ovarian cancer therapeutic

Medco announces research collaboration with FDA focussed on personalised medicine

Abeome Corporation announced that they have entered into collaboration with Cato Research Ltd. for continued development of Abeome’s ovarian cancer project. Abeome’s technology improves the development of monoclonal antibodies and it will deploy this technology to help develop an array of antibodies for an ovarian cancer therapeutic target.

Medco Health Solutions, Inc. announced that it has entered into a research partnership with US FDA to study genetic testing and the impact of genetics on the efficacy of prescription drugs. Under the partnership, Medco and the FDA will jointly develop research projects, programmes and strategies in the area of pharmacogenomics, collectively aimed at improving patient health and quality in the delivery of care.

Sangamo BioSciences and Sigma-Aldrich enter research agreement with Roche for ZFN technology Sigma-Aldrich Corporation and Sangamo BioSciences, Inc. announced that they have entered into research and license agreement to provide Roche with the rights to use its Zinc Finger Nuclease (ZFN) technology to develop cell-lines having targeted modifications in a specified gene in a specified species.

PAREXEL closes the acquisition of ClinPhone PAREXEL International Corporation announced the successful closing of the acquisition of ClinPhone plc. The combined company offers unprecedented access to eClinical technologies and resources, providing clients and service providers with the benefits of an extensive line of products and services throughout the entire clinical development lifecycle.

NicOx signs agreement with Capsugel for the commercial manufacture of Naproxcinod oral capsules NicOx S.A. announced that it has signed an exclusive agreement with Capsugel for the commercial manufacturing and global supply of naproxcinod capsules. Staffan Stromberg, VP, Technical Development and Operations, NicOx, said, “We are very happy to have concluded this agreement with Capsugel, which is recognised as the world leader in capsule manufacturing."

Merck Serono and Ablynx enter into an agreement to co-discover and co-develop Nanobodies(R) Merck Serono announced that it has entered into an agreement with Ablynx to co-discover and co-develop Nanobodies(R) against two targets in oncology and immunology. The partners will collaborate for the research and development of Nanobody(R)-based therapeutics against two disease targets exploiting some of the key benefits Nanobodies(R) have over conventional antibodies and other fragments.

GlaxoSmithKline to acquire Biotene GlaxoSmithKline announced its agreement with Laclede, a privately held company, to purchase the leading Dry Mouth brand Biotene® for US$ 170 million. The transaction is expected to be complete by early 2009 as it is subject to regulatory review. Cancer chemotherapy or radiation treatment, and some 400 medications can cause Dry Mouth as a side-effect. One in five adults is affected with dry mouth globally.

FDA approves orphan drug status for revolutionary cancer drug for children This new drug combines biotechnology and nanotechnology and is analogous to the concept of a Trojan Horse. It is expected to have very far reaching implications for other cancer treatments. The product consists of cell matter that is modified to have the same genetic code as the cancer cells, but that matter is not viable food for the tumour cells.

The cell matter is then placed in a nanotechnology formulation which allows the matter to migrate through the body’s own vessels directly into the tumour cells. When the tumour cells uptake the matter, they cannot reproduce, and they die.

Athera Biotechnologies and Dyax announce collaboration to discover and develop antibodies for cardiovascular inflammation Athera Biotechnologies AB and Dyax Corp. announced that they have entered into collaboration for the discovery and development of therapeutic products for the prevention or treatment of cardiovascular inflammatory diseases.

November 2008

Teva Pharmaceutical Industries Ltd. and Kowa Company, Ltd. announced that they have signed a definitive agreement to establish a leading generic pharmaceutical company in Japan. The company, Teva-Kowa Pharma Co., Ltd. will leverage the marketing, research and development, manufacturing and distribution capabilities of each company to become a broad-based supplier of high quality generic pharmaceutical products for the Japanese market.

October 2008

September 2008

Teva and Kowa announce strategic partnership to create a leading generic pharmaceutical company in Japan

Ranbaxy and Daiichi Sankyo successfully complete landmark deal Daiichi Sankyo Company Limited and Ranbaxy Laboratories Limited announced the successful closure of their transformational deal with the execution of the final transfer of the remaining shares of the Singh family, in Ranbaxy.

University of Florida and Cyntellect collaborate to unlock mysteries of cancer stem cells Cyntellect announced that it has entered into a research collaboration agreement with the University of Florida Interdisciplinary Center for Biotechnology Research. The agreement will focus on a variety of research areas including the purification and analysis of Cancer Stem Cells (CSCs). The collaboration will exploit Cyntellect’s proprietary LEAP system to purify these CSCs and their progeny without disturbing them from their growing environment—a feat that should improve scientists’ ability to study the natural properties and responses of these cells

Daiichi Sankyo and ArQule partner to progress novel compounds to target cancer ArQule, Inc. and Daiichi Sankyo Co., Ltd. announced that they have entered into two agreements for a strategic relationship for the development and discovery of novel oncology therapeutics. ArQule and Daiichi Sankyo will co-develop ARQ 197, an orally administered, small molecule inhibitor of the c-Met receptor tyrosine kinase, to treat cancer. In addition, ArQule and Daiichi Sankyo will advance the application of ArQule’s kinase inhibitor discovery platform (AKIP(TM)).

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Verbatim what the leaders say

The era of dependence on a single or a couple of large blockbuster drugs certainly should be over.

Lipitor sells US$ 12 billion a year. I don’t think you’re going to see very many more of those. ... you can’t build a company on the belief that you’re going to find such a drug.

Jeffrey Kindler, Chairman and Chief Executive Officer, Pfizer expressing his views on the end of the blockbuster era.

Externalising R&D enables GSK to capture scientific diversity and balance expenditure and risk in drug development. In the future, we believe that up to 50 per cent of GSK’s drug discovery could be sourced from outside the company.

Andrew Witty, Chief Executive Officer, GlaxoSmithKline expressing his views on increasing collaboration with external R&D partners for drug discovery.

This is not a knee-jerk reaction. This is something we have been working on and it is important strategically. It is a sustained success story that I’m looking for. The business is almost 150 years old. We aren’t going to make decisions on a quarter-to-quarter basis.

Richard T Clark, Chief Executive Officer, Merck & Co. after the company’s announcement to cut 7,200 jobs.

It is worth noting that by 2012, we expect more than 75 per cent of our revenue will be generated by biotechnology, vaccines, nutritionals, consumer health and animal health products. Not many companies in our industry, not even the largest, are able to line up such a diversified line of technologies, businesses or customers.

Bernard Poussot, Chairman, President and Chief Executive Officer, Wyeth in Wyeth's Q3 2008 Earnings Conference.

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Some say we need a business relationship with big pharma – for what? There’s nothing we need help from strategically or in terms of operations from big pharma.

Jim Mullen, Chief Executive Officer, Biogen Idec observing that the company has brought many drugs to market on its own and has a healthy pipeline of drugs in development.

Abbott has taken a deliberate approach to acquisitions, identifying and pursuing transactions that either complement our existing portfolio or allow us to enter new innovation-driven markets with leadership potential.

Miles D White, Chairman and Chief Executive Officer, Abbott after the company being named as winner of a magazine’s Most Admired Corporate Dealmakers Award in the healthcare sector.

The first gorilla is the image of the pharmaceutical industry — and he’s one ugly dude. He can barely win a beauty contest against tobacco or big oil. The second gorilla is the innovation drought demonstrated by FDA approval of only 19 new medicines last year, the lowest number since 1983. The third gorilla is company stock prices, which have dropped from an average of US$ 100 per share to the mid-US$ 30s since 2000.

John C Lechleiter, President and CEO, Eli Lilly and Company comparing the major challenges facing the pharma industry with three 800-pound gorillas.

Developing a pipeline independently is best, but there is almost no company that can do so. It’s important to take in products by alliances with other companies.

Masafumi Nogimori, President, Astellas Pharma Inc on the company’s acquisition strategy.

I believe that this agreement is the right business decision and gives increased clarity and stability to allow us to continue investing substantially in our growing pipeline of new medicines for patients. We continue to have confidence in the strength of our patents and will vigorously defend our intellectual property.

David Brennan, Chief Executive Officer, AstraZeneca after the company settled US Nexium Patent Litigation with Ranbaxy.

Ventana broadens Roche’s diagnostic offerings and complements Roche’s strong existing position in in vitro diagnostic systems. Incorporating Ventana will enhance our position as the world’s leading personalized healthcare company.

Franz B Humer, Former Chairman and Chief Executive Officer, Roche outlining the role of Ventana in the company’s vision of personalised health care.

I actually think the reverse. When you think about gigantism in our business, the idea of “big” and “innovation” aren’t two words you usually put together. As you look at the examples where this has been tried, I think there’s a general belief that gigantism is antithetical to biopharmaceutical innovation.

Kevin Sharer, Chief Executive Officer, Amgen answering a query on whether a merger or acquisition with another big pharma company would give it an advantage in terms of size and scale.

You’d want to target the high growth markets. The high growth markets today are Central and Eastern Europe, Russia, South America, as opposed to say the EU, where the markets are not growing that rapidly for generics.

Paul Bisaro, Chief Executive Officer, Watson Pharmaceuticals Inc looking at a global presence to scout for deals in the generic space.

The fundamental situation in the pharmaceutical industry has not changed. Big pharma needs innovative treatments to revive its pipelines and biotech is increasingly the source of these products. A challenging financial environment will only increase the need for mutually rewarding partnerships.

Simon Moroney, Chief Executive Officer, MorphoSys on innovation and the challenging environment in which the industry operates today.

The goal at AstraZeneca is to align all business development activities behind the delivery of clearly articulated strategic priorities, and the current economic climate hasn’t changed the fundamental principles of what makes for a successful partnership. Where an opportunity fits a strategic need and offers the potential to create value, we expect to see partnering playing an increasingly important role across the entire value chain in shapes and forms well beyond inlicensing and acquisitions.

Shaun Grady, Vice President of Deal Management, Strategic Planning and Business Development, AstraZeneca shares his perspective on partnering for innovation during challenging times.

I’m not so interested in making expensive drugs.

Investors expect healthy returns for financing research, clinical trials and costly manufacturing plants. You either have an expensive drug but you have a drug, or you have nothing.

Emil Kakkis, Chief Medical Officer, BioMarin Pharmaceutical Inc. whose research on Mucopolysaccharidosis, a rare disease, helped Biomarin develop its first product Adurazyme. A year’s treatment for MPS I with the drug costs an average US$ 220,000.

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Flashback Issue 5 - Issue 8

ts in Natural Prodeurcy Drug Disconavtural products has reclaimed

y from and is on the “Drug discover arma industry ph e th inputs of n io technological the attent k due to new ac eb m co t.” a en of verge investm tter returns on that promise be in drug tural products ra potential of na ars. Ignored fo ye y an m r The role and fo d te gies lo ba no de ch en te be phisticated discovery has e to lack of so g huge du in e uc tim od le pr in ab consider ’s success ve torial chemistry l products ha overy, natura and combina sc di ug dr r fo ries y. synthetic libra drug discover comeback in made a strong essure r immense pr today are unde es, es lin ni pe pa pi t m uc co Pharma shrinking prod as scovery ch di su s ug or dr r owing to fact rs and shorte te us kb oc ue bl iq s of ol of un patent expirie ith its rich po me a few. W timelines, to na

Issue 5 gh h higher, thou re offers a muc . tu try na is , ks em or ch l ew m combinatoria molecular fra diversity than al ic em ch , complex es rely on arma compani r of smaller ph d many be an m s nu ad a le y, ug Toda generating dr r fo d or ts ne uc w od so natural pr which had di a companies, looking at m e ar ar s, ph on al si ob vi gl ts di While natural produc ug discovery. sold off their ucts-based dr t od no pr l ve ra ha tu ts na tural produc outsourcing emistry and na tion of the ch l na bi ria m to co na a bi com eir own, ical success on th gy and chem tasted much es in technolo nc va . ad ry e st th du in two along with ahead for this show the way synthesis can

Partnerships Win-Win Strate gy

“The pharma industry is tread ing a new path sustaining grow for th—partnersh ips.”

Caught in the “Innovation De ficiency Synd under serious rome”, and pressure to co mpensate de streams from clining revenu saturated mar e ke ts, soon-to-e expired blockb xpire / alread usters, pharm y a companies partnering with are increasing biotechs to he ly lp reduce thei r losses.

The complem entary streng ths of biotechs companies es and pharma pecially Big Ph arma promise dividends in th to pay rich e long run. Am ong the many available to th options e pharma com panies to over current challe come their nges, partner ships and stra seem to have tegic alliances the potential to open the do collaborations ors for synerg to create win ic -w in situations in run. The pres ent day partn the longerships are be ing tailored to

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Issue 6 help compani es find the m uch required economies of blockbusters scale, cost-effe , ctive clinical tri creators such als and marke as personalis ed medicine. t Strategic partn erships and ac quisitions are companies w bringing ith complemen tary strengths segments and from different countries toge th of success. An er to boost th eir chances d a very prom ising model is pharma compa that of the nies working together with companies. St biotech anding to gain so much by w partnerships orking togeth could be the er, right path for overcome its the industry to hurdles.

R&D@Nano Level Research Insights

“Nanotechnology is pla ying a major role in hel ping companies engineer dru gs that can cross the blo odbrain barrier, have greate r solubility, stability and bioavailability and targe t-based drug delivery sys tems.”

Nanotechnology in pha rmaceutical R&D, though in its infancy, is attracting lot of attention from the ind ustry.

Nanotechnology will hav e a bigger role to play in the coming days for the pha rma industry, more so with the problems that the indust ry is facing, especially with the diminishing returns on investment in resear ch and development.

The issue featured res earch carried out by som e of the premier institutions in applying nanotechnolo gy to improve the properties of existin g drugs and identify new drug candidates.

Issue 7 The technology has bee n instrumental in unders tanding the human pathology at nan o level and is helping researchers immensely in understan ding the nature of the human cells and the associated dis eases to design and pro duce better drugs.

Nanotechnology has ma de it possible to engine er drugs that are more stable, sol uble and allow for targ eted delivery thereby increasing the efficacy and reducing the side effects. The technolog y has proved to be a boo n to the industry as it helps in developing efficient dru g delivery systems and also in imp roving diagnostic proces ses and tools. With so ma ny benefits to leverage, pharma companies have started adopting nanotechnolo gy and nano tools in their mo st crucial function—R& D.

hain C ly p p u S l ia r T Clinical Key to Success d internal an s induced by ge an ch e al within th to etion of the tri “Adapting ensure compl to s rtant or po ct im fa is al extern d budgets role time frame an ’s in ed at ha ul C ip ly st pp e th ical Trial Su lin C a re he w and this is ess of a trial.” cal to the succ becomes criti

e ent programm drug developm a of s al es ic cc lin e su als. C The key to th t of clinical tri e managemen spread across , ex pl m is the effectiv co e timelines e bigger, mor ever-shrinking trials today ar conducted in issue d is an Th s . te sk si ta le g multip ent a dauntin em al Trials ag ic an lin m C r of ei making th management al tim ucting op e nd th rtant role in co highlights how d play an impo ul co in ha C Supply inical trials. tions, successful cl y sites, regula ructure at stud anges st ch fra t in en er qu op fre Lack of pr y personnel, ud st ed ifi al qu availability of

Issue 8 clinical the demand of me of uncertainty in so d e an ar n gn si io nt de te in the trial ble patient re ta ic ical lin ed C pr . al un to a clinical tri supplies due in conducting ng on es di ng en le sp al l ta ch to or e the maj cent of th for 50-70 per average of 10 trials account t and take an ke ar m to ug dr w Trial Supply ne al a ic lin ng C gi brin . An efficient ed et pl m of the huge co t ou years to be tions arising ria va l al at th al supply s the clinical tri Chain ensure ists between ex process at ly th pp ct su ne e discon sting and th ca re fo , ng ni e. demand plan t with in real tim d for and deal are accounte

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