Pharma Focus Asia Issue 14

Published by Verticaltalk

The B2B Division of Ochre Media

A member of CII

Issue 14 2011

New Drugs in Anaesthesia Catering to new demands

China’s Clinical Trial Boom A look at the linguistic and cultural challenges

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Novel Genetic Vaccines A key focus area

Biobanking An Enabler for Translational Medicine

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Foreword Biobanking

Moving Towards Translational Medicine Translational medicine is becoming ever-more interdisciplinary. The collaboration between scientists, clinicians and researchers is at the heart for developing effective therapies. Yet, patients’ tissue samples are crucial for generating any knowledge for new cures.

Collection of properly annotated and preserved biospecimens along with the associated data in biobank, serve the need for multiple research platforms. Biobanking, which provides high quality generation, logistics, storage and processing of samples from patients, provides hope for creating better results from collaborative efforts. A biobank provides molecular understanding of normal cells and cells in various stages of disease progression. This makes it an engine for translational research.

The collected biospecimens with clinical information provided will discover causes and mechanisms of disease resulting in a significant acceleration in healthcare research to develop new and effective therapeutic diagnostics and treatments.

These biospecimens can be used in variety of research studies to identify and validate drug targets, discover disease mechanisms, develop biomarker screening tests, group patients for testing and treatment, or for discovery of other relevant molecular signatures.

Today, the decreasing cost of genomic technologies is expanding the scale and scope of biobanking research. Many modern biobanks are concentrating on multiple disease domains such

as cancer, heart disease, arthritis and dementia, while others focus on community-specific diseases.

Establishment of biobanks involves consent from the funding agency and meeting quality standards besides adhering to certain guidelines, laws, policies, international regulations and codes of practice.

Research states that around 70 per cent biobanks are stand-alone and 30 per cent operate in partnership with other biobanks or institutions.

Within the last ten years, nearly US$ 1bn has been invested in the biobanking industry and over the next decade, a number of new, highquality biobanks will aid in the development of personalized diagnostics and therapeutics.

Also scientists in Asia are working with pharma companies to perform biomarker-supported research studies in multiple disease domains such as cardiovascular diseases or woman’s healthcare.

The cover story in this issue of Pharma Focus Asia provides insights on how the biobanks are serving the need of developing new drugs for better treatments. The article also provides answers for questions like: How can compliance with such a sensitive topic be assured in a research environment? Is the access to biospecimens aligned with novel strategic goals and effectively organised? Which challenges emerge by the focus of multinational pharma companies shifting to Asia?

Prasanthi Potluri Editor

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CoverStory

Contents

Biobanking as an Enabling Technology for Biomarker Research A Collaborative Approach in Translational Medicine Arndt A P Schmitz, Global Drug Discovery, Bayer Schering Pharma AG, Germany

Strategy 06 New Drugs in Anaesthesia Catering to new demands Swati Daftary, Consultant Anaesthesiologist, Jaslok Hospital & Research Centre, India

R&D 11 Collaborative Models for Managing Vaccine Trials in Asia Janet Robinson, FHI Director of Research, Asia Pacific Region Global Director, Laboratory Sciences, Thailand

16 Novel Genetic Vaccines A key focus area David Klatzmann, Professor, Immunology Director Immunology-Immunopathology Immunotherapy Research Laboratory, Pitié-Salpêtrière Hospital, France

Clinical Trials 19 China’s Clinical Trial Boom A look at the linguistic and cultural challenges Karen Politis Virk, Director, Biotech and Pharmaceutical Research Language Connections, USA

26 Issues & Concerns in Conducting Clinical Trials in India Milind Antani, Head, Pharma & Life Science Practice Group Nishith Desai Associates, India Gowree Gokhale, Partner, Nishith Desai Associates, India

MANUFACTURING 11

26

40 Supply Chain Design An outside-in perspective Hussain Mooraj, Vice President, Wayne McDonnell, Research Director Healthcare & Life Sciences, AMR Research, USA.

INFORMATION TECHNOLOGY 43 Business Intelligence Transforming Pharma Alan S Louie, Research Director, Health Industry Insights, IDC Company, USA

48 Industry-Academia Interactions R S Gaud, Dean, School of Pharmacy & Technology Management SVKM's Nursee Monji, Institute of Management Studies University, India

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Section

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Advisory Board

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

Christopher-Paul Milne Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

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

Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy

Copy Editor Sri Lakshmi Kolla Hemanth Reddy Sankepally Jenny Jones John Milton Sales Team Khaja Ameeruddin Aravind Maroju Jeff Kenny Ben Johnson Breiti Roger Compliance Team P Bhavani Prasad Srikanth Katragadda Sam Smith CRM Yahiya Sultan Radha Krishna Kottakki Subscriptions incharge Vijay Kumar Gaddam

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

IT Team Ifthakhar Mohammed Azeemuddin Mohammed Krishna Deepak

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

Rustom Mody Director, Quality and Strategic Research Intas Biopharmaceuticals Limited, India

Sanjoy Ray Director, Technology Innovation Merck Research Laboratories, USA

Sasikant Mishra Business, Policy and Network Strategist Pharmaceutical Industry, India P h a rm a F o c u s A s i A

Art Director M A Hannan

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

Neil J Campbell CEO, Mosaigen Inc. and Partner Endeavour Capital Asia Ltd., USA

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Editors Prasanthi Potluri Akhil

ISSUE - 14 2011

Head - Operations S V Nageswara Rao

Pharma Focus Asia is published by

A member of

Confederation of Indian Industry

Ochre Media Private Limited, Media Resource Centre 6-3-1219/1/6, Street No. 1, Uma Nagar, Begumpet, Hyderabad - 500016, Andhra Pradesh, India Tel: +91 (0) 40 30455000, Fax: +91 (0) 40 30455140 / 41 Email: pharmafocusasia@ochre-media.com www.pharmafocusasia.com|www.verticaltalk.com|www.ochre-media.com Š Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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Section Strategy

New Drugs in Anaesthesia Catering to new demands

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Strategy

With the better understanding of pharmacokinetics and pharmacodynamics, most of the new anaesthesia drugs cater to the demands of day care surgeries and primarily aim at an early and uneventful recovery.

Swati Daftary, Consultant Anaesthesiologist, Jaslok Hospital & Research Centre, India

T

he history of anaesthesia mentions use of non-pharmacological (Cold, Concussion, Carotid compression, Nerve compression, Blood letting and Hypnosis) and pharmacological techniques (use of alcohol, opium, hyoscine, cannabis, cocaine) in ancient and mediaeval times for anaesthesia.

1850 onwards, as anaesthesia became popular, more and more surgeries were carried out under general anaesthesia.

At that time, any surgery under general anaesthesia practically mandated a stay in the hospital, often to recover not from the surgery but from the effects of the anaesthesia used during the operation.

Patients were woozy for hours, unable to get out of bed, nauseated and vomiting, and even if they wanted to eat, they couldn’t because their digestive systems were paralysed. People receiving anaesthesia were also at risk—a significant number died not from their disease but from the anaesthetic drugs themselves.

Present scenario

With better understanding of surgery, instrumentation and devices like endoscopic equipments, there was an acute need for anaesthesiologists to keep up with this pace. By the mid twentieth century, we had learnt to control mortality figures to a great extent. Obviously the need then was to take care of disturbing morbidities like severe postoperative nausea vomiting, pain, delayed recovery and prolonged hospitalisation. Most of these problems are greatly reduced today thanks to some wonderful drug molecules and better understanding of pharmacokinetics and pharmacodynamics. Day care surgeries today form a single largest group of surgeries all over the world.

Most of the new anaesthesia drugs cater to the demands of these surgeries and primarily aim at an early and uneventful recovery. Some of these newer drugs which are available since last decade are reviewed below.

New formulations: New formulations of known drugs are being developed to either cut down their drawbacks or to improve their efficacy. Some of the drugs which are being worked on are Propofol, Midazolam and local anaesthetics. Drugs for hypnosis and sedation may have problems in the form of extended duration of action, unwanted cardiovascular and respiratory effects and issues with their vehicle including pain on injection, hyperlipidaemia and vulnerability to bacterial growth. Three main strategies are being employed to improve these drugs.

Reformulation: To overcome issues of formulation vehicle as in Propofol. As not a single formulation is problem free, we have multiple formulations claiming advantages. Standard- Propofol 1% and 2% in 10% soya oil as long chain triglycerides — Addition of EDTA or sodium sulphite does not support bacterial growth but can cause allergic reaction or yellowish discolouration (more with sulphite).

— An emulsion containing long and medium chain triglycerides reduces incidence of pain on injection — Propofol 6% in 10% soya oil reduces hyperlipidaemia — Propofol 1% in 5% soya oil with or without EDTA – pain on injection 4 times — Propofol in cyclodextrin based formulation Pro-drug approaches: Focused mainly on propofol to achieve good water solubility. The inherent problem is of slow onset and offset of action as they need to be rapidly metabolised to liberate the active compound. e.g.

Methyl phosphate pro-drug of propofol, Aquavan The phase III trial have been halted due to high level of adverse events.

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Strategy

Premedication – Dexmedetomidine

Specific, selective alpha-2 agonist gives excellent anxiolysis and sedation preoperatively. Its features include: • Haemodynamic stability, low heart rate and anaesthesia intra-operatively.

• The benefits also extend into the postoperative period with prophylaxis against ischaemic events, analgesia and reduced shivering.

• Available in parentral formulation. A dosage of 1-2.5 µg/kg is given over 2 minutes. Short half life of 2 hours.

• Ideal for perioperative use.

Antagonising the sedative/hypnotic effects of dexmedetomidine with atipamezole will permit rapid recovery from anaesthesia, regardless of the duration—a technique already widely and successfully practised in veterinary anaesthesia!

Induction and maintenance — Xenon

Xenon is Greek for stranger. It was discovered in 1898. Manufactured by fractional distillation of air and costs 2000 times more than N2O. Owing to environmental concerns, there may be no alternative but to use xenon in distant future even if it incurs an increase in cost.

• Colourless and odourless gas with no irritation to the respiratory tract. Well tolerated with gas induction • Low blood/gas and oil/water partition co-efficients allowing rapid induction and reduction • Produces unconsciousness with analgesia and a degree of muscle relaxation • MAC of 60-70% allows a reasonable inspired oxygen concentration • It does cause respiratory depression, to the point of apnoea • It is cardiac stable • Not metabolised in the body and is eliminated rapidly and completely via the lungs • It is non-toxic and is not associated with allergic reactions • Stable in storage, no interaction with

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anaesthesia circuits or soda lime.

Should not be used with rubber anaesthesia circuits as there is a high loss through the rubber • Non-flammable • Expensive Muscle relaxation – Cisatracurium Cisatracurium besilate is a non-depolarising neuromuscular blocking agent with an intermediate duration of action, cardiostability, and faster recovery than vecuronium. Hoffman degradation as for atracurium. Compared with atracurium, less laudanosine is produced (this is then cleared renally). Well tolerated; no significant histamine release. Recovery seems NOT to be prolonged with liver or renal dysfunction.

Neuromuscular block Reversal– ORG 25969 / Sugammadex

Rocuronium bromide

Local anaesthetics – Levobupivacaine, opivacaine

• ED90: 0.3 mg/kg —intubating dose: 0.6-1.0 mg/kg —onset: 1-1.5 minutes, clinical duration: 30-60 min • Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30 min • Metabolised by liver, 75-80% • Excreted by kidney, 20-25% • ½ life : ~ 60 minutes • Mild CV effects- vagolysis, no/minimal histamine release, • Prolonged duration in the elderly + liver disease • Only non-depolariser approved for RSI

The results of four ongoing Phase II trials indicate that a new selective relaxant binding agent, a ϒ-cyclodextrin (GC) compound, has the potential to radically change the way neuromuscular blockade is administered and reversed. Depending on the dose of the GC compound, moderate and deep neuromuscular blockade in patients receiving either rocuronium or vecuronium was reversed rapidly and safely, often in less than two minutes. This compound encapsulates muscle relaxant and promotes dissociation from Ach receptor. This is revolutionary, especially when you look at its implications in a difficult airway.

Ropivacaine: A long-acting local anaesthetic with less cardiac and central nervous system toxicity than bupivacaine, and a smaller tendency to cause motor block. It is less lipid soluble than bupivacaine and more selective for A delta and C fibres than motor nerve fibres, giving a greater degree of separation between motor and sensory blockade when used in concentrations below 0.25%. Minimum effective concentration is 0.2%. It is highly protein-bound (94%) with terminal t1/2 111 min. and maximum allowable dose is 2 mg/kg.

Strategy

Analgesics – Remifentanil

A typical μ opiate receptor agonist with ultra-rapid clearance and offset of action, that is independent of excretory organ function. It is 20 to 30 times more potent than alfentanil. Undergoes rapid hydrolysis by nonspecific esterases to almost inactive remifentanil acid. This metabolism is not altered by end-organ function or genetic variablility of specific esteraes (like plasma holinesterease); redistribution is of little consequence. Context-sensitive half time is 3-5min regardless of infusion duration. Full recovery of respiratory function occurs in ‘10 to 15 min’. Given by continuous infusion, it reduces induction dose of thiopentone by 30%; Lowers the MAC of volatile agents. Supplement with N2O, propofol or isoflurane.

Adverse effects

• Anticipate and prevent postoperative pain • Bradycardia may occur • Dose-dependent respiratory depression, Muscle rigidity occurs • NOT for epidural use as the lyophilised powder contains 15mg of glycine • If given alone, may cause awareness

The soft drug approach: This has been previously used in remifentanil, propanidid and mivacurium. The aim is to produce metabolically-labile agent which is hydrolysed rapidly by blood and tissue esterases so as to have rapid recovery profile. TD-4756, esters of barbiturates(Aryx) and benzodiazepine ligands(CeNeS) are some examples of such compounds.

Novel clinical uses of known drugs: • Intranasal Nicotine for postop. Pain treatment. Anaesthesiology 101: 1417-21, 2004 • Analgesic effects of Gabapentin on acute postop. Pain Anaesthesiology 100: 935-938,2004, Acta Anaesthesiol Scand 48: 322-327.2004 • Oral Amantadine (antiparkinson and antiviral) for postop. Pain Anaesthesiology 100: 134-141,2004 • Introp use of Adenosine is associated with reduced opioid requirement in postop period Anaesthesiology 1999; 90: 956-963.

• Effect of intraoperative magnesium infusion on perioperative analgesia Anaesthesiology. 1996 Feb; 84(2): 340-7, Eur J Anaesthesiol. 2002 Jan; 19(1):52-6. J Clin Anesth. 2004 Jun; 16(4):262-5.

The rapid rise and fall of a few new drugs: Rapacuronium, Cleofol and Rofecoxib Rapacuronium bromide: FDA approval for clinical use of this non-depolarising muscle relaxant came on August 8, 1999.

The drug was developed as a substitute for succinylcholine in the setting of a rapid sequence induction. Clinical experience with this drug showed increased incidence of severe, life-threatening bronchospasm in children with rapid injection. Nineteen months later, on March 27, 2001, the manufacturer withdrew the drug from the market voluntarily.

Rofecoxib: This selective COX-2 inhibitor was withdrawn worldwide in October

Most of the new anaesthesia drugs cater to the demands of day care surgeries and primarily aim at an early and uneventful recovery.

2004 after the reports of cardiovascular risks were published.

Cleofol®: Clear propofol promoted as ‘vegetarian’ formulation of propofol fell in disrepute after reporting of very painful injection and increased incidence of severe thrombophlebitis.

The above list is obviously not comprehensive. We are still looking for an ideal local, intravenous, inhalational anaesthetic, a safe and a very effective pain killer.

Conclusion

This disproves the concern that use of old / less expensive drugs may compromise patient outcome and satisfaction and that newer and costlier drugs are always safer. Some suggest that national societies should create guidelines for costbeneficial practice. Others favour physician autonomy in drug selection. There will be great reluctance to deny patients pharmacologically superior drugs based on cost alone, especially since drugs are such a small portion of the total surgical costs. The aim should be to manage and modify drug practice in anaesthesia depending on changing needs to provide value-based care.

A u t h o r BIO

Levobupivacaine: The S(-)enantiomer of bupivacaine, with less cardiovascular and central nervous toxicity, a slightly longer duration of sensory block, but otherwise similar to its parent. Compared to bupivacaine it is as potent, with a trend towards longer sensory block; with epidural usage it produces less prolonged motor block; Differentiation not seen with peripheral placement; lethal dose 1.3 to 1.6 times higher; less cardiac effect including less depression of contractility and fewer arrhythmias; higher convulsive doses. It has elimination t1/2 ‘1.3 hours’, and protein binding > 97%.

Recommended maximum dosage same as bupivacaine. Observe precautions as for all local anaesthetics.

Swati Daftary is specialized in Anaesthesiology at Jaslok Hospital & Research Centre in Mumbai, India.

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R&D

Collaborative Models for Managing Vaccine Trials in Asia

O

ver the past decade there has been an explosion in the number of clinical research studies being conducted globally and in particular in resource-limited settings, including in Asia. Researchers and pharmaceutical companies have worked earnestly to develop new treatment, prevention and diagnostic technologies to tackle the global public health challenges of diseases such as HIV, TB, malaria, influenza and new and emerging infectious and non-infectious diseases.

In March 2011, listings of clinical trials registered in the US FDA’s clinical trial registration database showed that almost 104,000 clinical trials are currently registered in 174 countries worldwide. Table 1 indicates the breakdown in Asia alone. This will only be a fraction of the actual clinical studies being conducted as those not intended for submission to the US FDA, or receiving financial support from US sources do not need to be registered in this database.

With so many clinical research studies being conducted or planned, there is a growing need to increase the number of sites capable of conducting clinical trials that meet international regulatory and ethical standards, including Good Clinical Practices (GCP). With too few acceptable clinical research sites, those that do exist will be overburdened and the quality of the clinical research will likely suffer as a result. Staff and investigators may have insufficient time to dedicate to each research protocol, affecting the quality of the results and possibly patient safety as well.

In high-burden research sites study findings can also become less relevant to real-life settings as patients become part of the research machine.

This can lead to health seeking behaviours and treatment or intervention compliance that differs from ‘normal’ patients and may confound the application of clinical trial results.

As the number of candidate vaccines approaching human trials increases, vaccine researchers should consider all collaborative research models, as well as look to their colleagues in prevention sciences for collaboration and to learn how to effectively conduct prevention trials.

Janet Robinson, FHI Director of Research, Asia Pacific Region Global Director, Laboratory Sciences, Thailand

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R&D

Partnership models

To expand the pool of high quality clinical research sites many research funders are establishing collaborative models or networks to build research site capacity. The structure of these networks tends to be similar, including: • Governing or oversight committee • Technical steering committee • Scientific steering and advisory committee • Multiple clinical trial sites across a number of countries and regions (selected based on access to patients affected by diseases of interest to the Network) • Central and local laboratories • Clinical trials support and monitoring function (may be a contract Clinical Research Organization (CRO)) • Other committees including pharmacy, data management and biostatistics.

This collaborative model brings many different expert groups together to build the capacity of clinical research sites to conduct high quality clinical research. This model has been used by many including the US National Institute of Health (NIH) for their HIV Prevention Trials Network , with Asian sites in China, India, Russia and Thailand, and the South East Asia Infectious Disease Clinical Research Network (SEAICRN) , with sites in Indonesia, Thailand and Vietnam. The US Center for Disease Control (CDC) is also using this model for their TB Clinical Trials Consortium with Asian sites in Hanoi and Hong Kong.

FHI has played a key role in these Networks in multiple capacities including site research capacity building. To establish such Networks requires time and financial resources; but, once established they offer the ability to conduct high quality clinical trials complying with international standards. Data from multi-site and multi-country studies are likely to be more comparable as standard and consistent study systems and procedures have been implemented across all sites. This is evidenced by the number of peer-reviewed publications resulting from the activities of these networks.

SEAICRN, for example, reported supporting 95 publications in the period 2006-2010.

A slightly different model is one where research funders seek to build the capacity of young or new research investigators particularly in resourcelimited and disease-endemic countries. In such a model, investigators receive training in all aspects of clinical research starting from designing a protocol, through research implementation and reporting. The US NIH adopts this model for their International Clinical Sciences Support Center to provide support to investigators funded by their Department of Microbiology Registered Clinical Trials in Asia Number of Trials

Countries

East Asia

8823

China, Hong Kong, Japan, Korea, Mongolia, Taiwan

North Asia

2358

Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Ukraine

South Asia

1831

Afghanistan, Bangladesh, India, Nepal, Pakistan, Sri Lanka

South East Asia

2668

Brunei, Cambodia, Indonesia, Lao, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam Source: clinicaltrials.gov

and Infectious Diseases (DMID) and the National Institute of Allergy and Infectious Diseases (NIAID).

As of March 2011, some 1500 investigators have been supported by the ICSSC worldwide, including in Bangladesh, China, Hong Kong, India, Nepal, Papua New Guinea, Philippines, South Korea, Sri Lanka, Taiwan, Thailand, and Vietnam. .

Still another model is where the preferred provider is employed by both donors and pharmaceutical companies when outsourcing clinical research. In this model, providers of clinical research services are selected or qualified to bid on proposals based on demonstrating their clinical research capacity. This model reduces the number of different CROs that a product developer might work with, helps ensure the quality of the research as suppliers have been pre-qualified, and can help reduce costs through agreed-upon pricing structures.

There are many examples of this preferred provider relationship being used by product developers and pharmaceutical companies. Government funding agencies now use this mechanism through what is called the Indefinite Delivery/ Indefinite Quantity (IDIQ) contract.

The IDIQ mechanism provides for an indefinite quantity of services during a defined period of time offered to a group of selected providers. A recent example from September 2010 is an IDIQ from the newly created Center for Global Health of the Centers for Disease Control and Prevention (CDC). This IDIQ is intended to provide technical assistance services to governments and local organizations across Africa, Asia, Latin America, Europe and the Middle East to bring additional scientific and technical assistance to the US Global Health Initiative. FHI is one of the three prime contractors to this IDIQ. Community Collaboration

Collaborations needed for clinical research should extend beyond sponsors, CROs and sites, to include the community and patient population being studied.

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R&D

Collaborate and learn from other researchers

A scan of the pharmaceutical R&D pipeline coupled with the vision of the major 14

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In March 2011, listings of clinical trials registered in the US FDA’s clinical trial registration database showed that almost 104,000 clinical trials are currently registered in 174 countries worldwide. donors, indicates that the emphasis is shifting to preventing and eradicating disease. There are a number of promising vaccine candidates being developed for malaria, dengue fever, influenza and other infectious diseases. There is also still the hope that one day there will be a vaccine for HIV. Disease prevention trials are extensive under takings requiring substantial investment and time. It is always desirable to conduct research studies based on best practices and previous experience.

However, in the field of disease prevention trials there is an even greater need to build sound experience into the study design and implementation so as to ensure success and maximize efficient use of all resources.

Prevention science is not new and over the decades there have been many research studies aimed at understanding how to prevent disease using behavioral interventions. For example, research to assess the impact of counseling in the use of condoms and other risk-reducing measures to prevent the acquisition of sexually transmitted infections including HIV. Traditional prevention and vaccine trials

There are many similarities between traditional prevention and vaccine trials including: • Identification of suitable sites in both focus on incidence data and clinical infrastructure • Both often utilize healthy normal

subjects who are nevertheless at high risk of the outcome • Community preparation is vital to both, as both ask for agreement to use a medical intervention in a healthy normal volunteer • Both types of trials may involve working with, gaining the trust of, and recruiting similar and sometimes stigmatized groups, e.g. pandemic H1N1 • Both types of trials require careful and regular patient follow-up to identify when a disease outcome is first observed • Safety monitoring processes are similar with the need to quickly identify new or emerging safety events • Biostatistical support on study design and data analysis may be similar, depending upon the statistical endpoints that are planned • Data management aspects may be similar, depending upon how data is to be captured and analyzed • Project management and clinical monitoring visits and follow-up are similar • nvestigator site preparation is similar • Laboratory diagnostic requirements are similar and critical because of the need to reliably detect disease outcomes In summary

As clinical research expands, the need for collaboration by research funders and their partners, researchers, product developers, CROs and the communities becomes even more important. Collaborative and informed clinical research of the highest quality can help ensure that studies report accurate, verifiable and relevant findings making best use of available resources.

Various successful models for collaboration already exist and should be considered for future research.

A u t h o r BIO

How clinical trials are perceived internationally and in communities where research occurs can directly affect support for research, with fears or mis-information derailing trials just as easily as operational or scientific setbacks. (see the 2010 FHI publication Communications Handbook for Clinical Trials) In 2004, for example, controversy over a planned clinical trial to test oral tenofovir in Cambodia as a potential once-a-day pill to prevent HIV forced the early abandonment of this important prevention trial. Less than a year later, similar controversy, fueled by rumours, misleading media coverage, and communications breakdowns, lead to the demise of a second HIV prevention trial in Cameroon. Together, these trials served as a wake-up call to HIV scientists and donors to re-examine the ways they communicate with local and international communities about clinical research.

When communicating about clinical research with community collaborators there is the expectation of transparency, information sharing and engagement. The HIV field is not alone in confronting changing expectations and new challenges when it comes to communicating about research. Investigators and research staff receive extensive training in GCP and specific trial protocols but are rarely trained in community engagement and communications.

Collaborative communication strategies with communities and stakeholders can help build commitment and public trust in research, create an enabling environment for work, help identify and respond to incorrect information, and encourage the uptake and eventual application of findings. Failure to attend to this new reality can occasion just the opposite: distrust, sensational or misleading media coverage, and missed opportunities to advance the research agenda.

Janet Robinson has a dual role within FHI as the Director, Research, Asia Pacific Region and also FHI’s Global Director for Laboratory Sciences.

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Section

Novel Genetic Vaccines A key focus area

In theory, there exist almost infinite number of potential vaccine platforms. In addition, for each such platform, there are many different possible engineering that could lead to different vaccine properties. So, how these be compared? The answer in part lies in standardisation of the process.

David Klatzmann, Professor, Immunology Director, Immunology-ImmunopathologyImmunotherapy, Research Laboratory, Pitié-Salpêtrière Hospital, France

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E

dward Jenner’s work in developing the world’s first smallpox vaccine in the 1790s demonstrated that it was possible to protect the general population from major threats to public health, and vaccine development aimed at combating the major concerns of the day has continued ever since. There have been many successes, and vaccines are now available to immunise people against a wide range of diseases, including measles, polyomyelitis, smallpox and tetanus. However, the pace of vaccine development over time has been extremely uneven a situation that, given the severity of the health threats currently facing the world, demands to be addressed. The resulting need for a more systematic method of vaccine development has led directly to the development of the CompuVac (Rational Design and Standardized Evaluation of Novel Genetic Vaccines) project.

Our initiative which brings together 19 mainly European institutions in the

Section R&D

search for a more effective approach to the issue is pursuing an ambitious set of objectives very much in line with the pressing nature of the problem. Indeed, this project aims to develop methodologies and tools to improve vaccine development, notably through standardisation of vaccine evaluation.

What the process comprised

(i) a large panel of vaccine vectors representing various vector platforms and all expressing the same model antigens; (ii) standardised methodologies for the evaluation of T- and B-cell responses and of molecular signatures relevant to safety and efficacy; (iii) a database for data storage and analysis of large data sets; (iv) intelligent algorithms for the rational development of prime boost vaccination.

As things stand researchers who want to develop a vaccine platform—or to improve their existing vaccine—usually

take their own vector and introduce their own antigen of choice into it.

Typically researchers then test it with their own methodologies. While the initial response to this kind of work may well be extremely enthusiastic, the longterm picture is rather more complex. In particular, the absence of standardised procedures mitigates against the accurate, effective evaluation of vaccines.

The problem is that people rarely, if ever, compare what they are obtaining with the results of others obtained with different types of vectors. This means the direct comparison of vaccines’ potential is extremely difficult. In order to allow for the comparison of results you have to first establish methods that will provide significant grounds for it.

The idea here is first to have people use the same antigens to measure immune responses. Within the project we choose two so-called ‘model antigens’—one for testing cellular immune responses and

the other for testing humoral immune responses—which are the two halves of the human immune response to vaccines.

The next step was then to standardised procedures to evaluate immune responses to these two antigens. The need for sophisticated new methods is made even more pressing by the modern advances in medical science, which have established new parameters in vaccine development.

Great advances have been made over recent times, advances which prompt us to say that we are living through a particularly important period in the history of vaccine development.

There are so many potential vectors out there. Nowadays, people are realising that they can use virtually any type of virus or even bacteria to establish a platform for the expression of heterologous antigens and turn this into a vaccine. They can likewise use the ability of our body to respond to a certain virus or bacteria to make it respond to

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The need for sophisticated new methods is made even more pressing by the modern advances in medical science, which have established new parameters in vaccine development. other. We did this by also recruiting some scientists with training in both aspects ­—biomathematics and immunology— who acted as ‘translators’ so as to help us discuss the relevant issues. If there has been a breakthrough then this is it—it brings together people from two different worlds and makes them work together to generate a meaningful database. By our commitment to making their results publicly available, the CompuVac project has added another dimension to this initiative. Indeed, their data provides an extremely solid foundation for further research, and as such the project’s work has already attracted the attention of a number of other interested parties.

The first three years of the project were really devoted to building our own vaccines, testing them and developing the database. All this preliminary work has been done and it’s provided us with proof of concept and really showed us that we can generate a meaningful comparison. We’re just starting to publicise our efforts and have already met with some success. For example, we have had contact with academic researchers, non-profit organisation as

A u t h o r BIO

something else. So there is, in theory, an almost infinite number of potential vaccine platforms. In addition, for each such platform, you have many different possible engineering that could lead to different vaccine properties. So, how are you going to compare these? The answer in part lies in standardisation of the process.

Developing a standardised means of comparison is clearly no easy task, and a number of significant questions remain unanswered. However, it is a task that CompuVac’s advanced technical expertise undoubtedly makes the project wellsuited to. Two so-called model antigens that are very well-known have been selected; these are antigens for which there are extremely good, well-known methodologies for immune response evaluation. We have put great efforts into standardising methods for evaluating immune responses against these antigens.

There is no magic wand here—it’s just standardisation. The challenge is to get the people developing vaccines to agree to use these methods and then to compare their vectors with those of others.

One of our main goals is to make publicly available this whole system and a database of results obtained with it.

People will be able to test their vaccine design with the gold standard antigens and standardised methodologies, go into the database and compare their results to those already there. Establishing this kind of database has proved to be a complex undertaking. Quite apart from the technical complexity involved, the fact that information technology and immunology are two very contrasting disciplines has added another layer of difficulty. It was very challenging for us to bring computer scientists together with immunologists, because these really are two very different worlds.

Computer scientists are often not very well-informed about immunology, and many immunologists don’t know much about databases and all the specific things surrounding that. The real challenge was to get these people to work together and really understand each

well as biotech companies. They are extremely interested in using our methodologies to advance the development of their products. This kind of response gives some idea of the potential of the CompuVac project. While such interest is of course welcome, it will not distract him from the day-to-day concerns of pursuing the project’s primary objectives. The next goal for the coming year is to present our results. A couple of meetings have already been planned to present and promote CompuVac, and we will try to get the vaccine community to accept this standard and then encourage them to contribute to its further development. We need to find sponsors for the sustainability of the project. They will agree to maintain the database available on the web for free access by researchers. Sponsors could comprise a charity, a company, or an academic institution.

A unique set of vaccines of different classes has now been assembled and compared, from viral vector derived vaccines to inert VLPs. The validated database and the tool box will be made freely available to the scientific community at the end of the project in June 2009.

A conference in Paris will be held on the June 29th of 2009, with international experts in vaccine development.

This will be the occasion to present the results of such an evaluation and how it was translated into the development of an HCV vaccine, but also to donate the database and tools to our sponsor(s), and to organise the final communication which should help the CompuVac approach to become an accepted standard in vaccine development.

David Klatzmann is a professor of Immunology at the Pierre & Marie Curie medical school. He is the Director of the ImmunologyImmunopathology-Immunotherapy Lab and the head of the Biotherapy department at the Pitié-salpêtrière hospital and medical school. His main activities have been to develop translational research in Immunology, he built-up a global organisation – research unit and hospital department – which is one of the rare structure capable of developing biotherapies from bench to bedside.

Clinical Trial

China’s Clinical Trial

A look at the linguistic and cultural challenges Despite the advantages of outsourcing to China, foreign sponsors must overcome several hurdles including significant linguistic and cultural barriers.

Companies must address these issues to ensure effective communication with patients, clinical trial staff, ethics committees, and regulatory authorities.

Karen Politis Virk, Director, Biotech and Pharmaceutical Research, Language Connections, USA

D

ue to unprecedented economic growth and increased healthcare expenditures, experts predict that by 2012 China will be the world’s fourth largest pharmaceutical market. In addition to increased production and distribution by foreign pharmaceuticals, China has become one of the region’s primary locations for outsourcing clinical trials. Growth in the clinical research sector can be

attributed to several factors, including China’s successful recruitment rates and lower costs. Multi-center trials are most prominent in China, primarily because of the government’s promotion of these trials, making them more attractive to foreign sponsors. In addition, the Chinese tend to show a cultural preference for foreign innovator drugs over domestics. Finally, regulatory reforms including the formation of a

single regulatory body, the issuing of a Chinese ICH-GCP equivalent, and improved Intellectual Property (IP) protection legislature, have all contributed to China’s recent clinical research boom. Despite this, several challenges remain for foreign sponsors, including regulatory hurdles as well as significant linguistic and cultural barriers. These issues will be addressed in the sections below. www.pharmafocusasia.com

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Clinical Trial

Advantages

Patient recruitment statistics demonstrate China’s subject enrolment advantage over most western countries. One study reported that in the United States 66 per cent of subjects in clinical trials enrolled independently of their doctor, while 90 per cent to 100 per cent of participating subjects in China enrolled as a result of their doctor’s recommendation. In China relationships are largely defined by professional position, as well as age and gender. Physicians are therefore highly respected, and patients readily accept their physician’s recommendation to participate in a clinical trial as a course of treatment. Many patients have not received any treatment, making them eligible subjects for clinical research.

Moreover, clinical trials offer patients cutting edge treatments that otherwise may not be readily available to them.

These factors, along with China’s population of 1.3 billion, greatly facilitate patient enrollment.

The cost of conducting trials in China is significantly lower relative to the west i.e. Chinese salaries are 60-80 per cent less, and clinical costs are 60-70 per cent less per patient. The high level of clinical research produced in the country can be attributed to the abundance of skilled Chinese investigators, many of whom have been educated or have experience working in the west. Most clinical trial sites are located in major urban areas where infrastructure and IT are better

Disease trends

Clinical research in China encompasses a wide range of therapeutic areas, including respiratory and cardiovascular diseases, as well as diabetes, obesity, and cancer. The incidence of cancer is growing as a result of population aging and growth as well as an adoption of cancer-associated lifestyles including smoking, physical inactivity, and ‘‘westernized’’ diets. Breast cancer is the primary cause of death in Chinese women largely due to inadequate prevention and detection during early stages. Chinese women also tend to have higher lung cancer rates than women in more developed western countries as a result of exposure to toxins.

The rate of lung cancer rates in Chinese men is also rising due to an increase in smoking. According to recent statistics, China currently has the largest diabetes patient population in the world, having recently overtaken India for first place.

established, and in the case of Shanghai, cutting edge. Reportedly 80 per cent of medical resources in China are allocated to major cities, and 30 per cent of this is focused on larger hospitals.

Regulatory environment

China’s improved regulatory environment has played a major role in the growth of outsourced clinical trials. The formation of the Chinese State Food and Drug Administration (SFDA) eliminated conflicting standards between provincial government agencies, and resulted in a centralised Chinese healthcare regulatory system with increased transparency.

These regulatory reforms, along with a shortened regulatory approval process and the presence of FDA offices in China have all been contributing factors (see Table 1).

Regulatory Environment Year

Regulatory Reforms

1999

Regulatory authorities in China formally issue GCP guidelines

2001

China joins the WTO opening its borders to foreign investors

2002

New Chinese legislature passed to improve IP protection

2003

Chinese SFDA established

2007

SFDA streamlined regulatory approval processes (9-12 months to 90 days)

2008

New healthcare legislature & improved IP protection laws passed

2008

3 U.S. FDA offices opened in China improving monitoring and oversight

Table 1 20

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Despite improvements in China’s regulatory environment, however, several challenges remain. Approval often takes several months despite efforts to streamline, and the requirement to obtain import and export licenses may further delay trial initiation. Furthermore, because the Chinese GCP equivalent is not identical to ICH-GCP guidelines, clinical trials conducted in China may not fully comply with the ICH-GCP standards. Furthermore, corruption and bureaucracy continue to create hurdles for foreign sponsors.

Another issue in China is that only SFDA-approved sites are authorized to conduct trials. SFDA-accredited sites are unique to China, since prior to the 1970s the country produced primarily generics and initiated few innovative drug studies.

However, there are a growing number of approved sites located primarily in large metropolitan hospitals. Finally, foreign sponsors often encounter logistical problems such as the restriction or prohibition of whole blood/DNA export and limited qualified logistic support, for example, central storage, IVRS, fax line, and broadband for EDC. Language & translation

Although there are a growing number of advantages for foreign sponsors outsourcing clinical research to China, there are significant linguistic and cultural barriers.

As a result, foreign pharmaceutical companies must address linguistic and cultural

Clinical Trial

issues to ensure that they communicate effectively with patients, clinical trial staff, ethics committees, and regulatory authorities.

Patient populations in China are diverse. Although the majority of China’s population speaks and understands Mandarin Chinese, for a significant portion of people, it is not their first language. Thus, despite the fact that Mandarin Chinese is China’s official language (850 million speakers) and the only written form of the language, there are several other dominant languages spoken throughout the country (see Table 2). Among the most dominant are Shanghainese (90 million speakers), Min (70 million speakers), and Cantonese (70 million speakers). Most Chinese languages are mutually unintelligible, and each language has several spoken dialects. Moreover, in addition to the official language based on the Beijing dialect, there are several other regional dialects of Mandarin Chinese. Although for the most part these are mutually intelligible, they must be considered for subtle differences in the meaning of certain words or language use.

Finally, to complicate matters further, written Mandarin has two character types.

In mainland China, the original Traditional Mandarin characters were changed to Simplified Mandarin characters to help simplify the writing system. However, some minority Chinese populations may still use Traditional Mandarin characters, especially in Taiwan and Hong Kong. Furthermore, depending on the level of literacy, proficiency in written Mandarin varies. In addition, despite English speaking proficiency among the many Chinese-born scientists educated in the west who have returned to work in China, the majority of the Chinese population is not fluent in English or other foreign languages. As a result, foreign companies must use interpreters to help them communicate with clinical trial staff. Thus, language presents a significant communication barrier for western companies working in China, making it essential to employ expert translators and interpreters.

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Languages Spoken in China Region in China

Language(s)

# of Speakers

Beijing & throughout China

Mandarin

850 million

Guangdong & Guangxi Provinces

Yue (Cantonese)

70 million

Southern, Northern, & East Central Fujian Min (Taiwanese, Hokkien, 70 million Province, Guangdong Province S., N., & E. Min) Shanghai

Wu (Shanghainese)

90 million

South Eastern China

Hakka

30 - 40 million

Hunan, Sichuan, Guangxi & Xing (Hunanese) Guangdong Provinces

Table 2

Linguistic Validation & Cultural Adaption

Most study documents must be translated into Mandarin Chinese for submission to the Chinese SFDA and Ethics Committees. Although this single translation requirement simplifies the regulatory process, translation of these documents requires a high degree of accuracy and texts must be culturally adapted for the target audience.

Professional translators know the standard terminology, can best identify language equivalents, are familiar with different cultural aspects that must be addressed, and use Translation Memory™ which decreases both the time

25 million

Reference http://www.omniglot.com/writing/chinese_spoken.htm

and cost of translation. These experts use an established process to translate clinical trial documents, and are best equipped to overcome any linguistic or cultural barriers.

Over the course of a study several types of patient-related information must commonly be translated. For example, patient questionnaires and patient reported outcomes (PROs) are primarily constructed in English and therefore they must be adapted for Chinese patients. Translating these materials involves linguistic validation and cultural adaptation, an arduous and lengthy process which can take up to several weeks.

Clinical Trial

The reason for this is that Mandarin Chinese is not closely related to most western European languages or English.

Sentence structure is significantly different, isolated phrases or words may have multiple meanings, and some words may be represented by the same characters despite differences in grammatical form.

Moreover, written Mandarin Chinese has a unique grammatical structure quite unrelated to that of English or other western European languages from which documents are commonly translated. Thus, translation typically requires a series of forward and back translations, as well as a number of reviews in order to ensure that the intended meaning is accurately and successfully conveyed. Finding the equivalent term and meaning of a phrase or word is not always straightforward, even for experienced translators.

Numerous studies have demonstrated the difficulties encountered in the translation of clinical research

documents into Mandarin Chinese, primarily from English. Many of these studies are aimed at creating effective instruments for Chinese patients. They offer insight into the unique challenges related to translating these documents into Mandarin Chinese. Primary examples involve patient reported outcomes (PROs) and Health-Related Quality of Life (HRQoL) patient questionnaires.

One study involving Chinesespeaking patients living in California encountered the following challenges when linguistically validating PROs. 1. Since written Mandarin Chinese is composed of characters and not letters, initials or abbreviations are not typically used. In order to identify initials for an abbreviation of a word, translators had to first phonetically translate Chinese names into English.

2. In Mandarin Chinese the words for ‘assess’, ‘assessing’, and ‘assessment’ all

use the same character, as do ‘treat’, ‘treating’, and ‘treatment’ thus the original English title, “Assessing and Treating Symptoms of Critically Ill ICU Patients” most closely translated into Chinese as “ICU Critically Ill Patients' Symptom Assessment and Treatment”.

3. The English term ‘short of breath’ was problematic because in Mandarin Chinese ‘short’ means ‘not long’ and ‘breath’ is not described as short or long. Thus, ‘short of breath’ was changed to ‘hard to breathe’ for Chinese patients.

Another study demonstrated other examples of issues encountered in the process of translating patient questionnaires from English into Mandarin Chinese. The goal of this study was to help define symptom scales for patients in China suffering from various diseases including arthritis, obesity, diabetes and Ankylosing Spondylitis.

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Clinical Trial

Cultural factors

In addition to language barriers, foreign sponsors must have an awareness of important aspects of Chinese culture that affect clinical research. Cultural aspects can inadvertently interfere with both reporting and interpretation of patient data, shape patient perception of disease and symptoms, and determine medical practices. Below are some examples.

Dementia & Alzheimer’s patients in China remain largely undiagnosed and untreated due to the cultural perception that memory loss is part of the aging process. In general, there is a lack of awareness about the relationship of illness and memory loss which leads to delayed treatment in Chinese patients.

One study reported that only 21 per

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The cost of conducting trials in China is significantly lower relative to the west i.e. Chinese salaries are 60-80 per cent less, and clinical costs are 60-70 per cent less per patient.

Use of traditional natural & herbal therapies by Chinese patients enrolled in a clinical trial may inadvertently affect patient data and study results if they are not reported. Since sponsors are more aware of the extent of this practice in China, this is becoming less of an issue.

Additionally, studies are being conducted to determine the effects of such practices on disease, symptoms, and conventional therapies.

Conclusions & recommendations

cent of patients in China had access to diagnostic assessment compared to over 70 per cent in Europe, largely because Chinese patients did not seek care.

Gender in Chinese society has also been identified as a barrier. One study involving Chinese-American women with cancer found that family decision-making played a major role in a woman’s decision to enroll. Several studies conducted on Chinese immigrants in the United States also identified cultural attitudes among Chinese women that interfered with both preventive care and treatment of Chinese-American breast cancer patients.

Patient reporting of the severity and impact of disease symptoms, an essential component of symptom management and treatment in clinical trials, is significantly affected by cultural attitudes. Symptoms such as pain are often under-reported

by Chinese patients. This phenomenon has commonly been observed in cancer studies, along with a less use of analgesics by Chinese patients. These differences in pain perception may lead to the misinterpretation of study results due to inaccuracies in patient data.

A u t h o r BIO

Investigators identified the following issues: 1. Mandarin Chinese does not use superlatives thus ‘the worst’ had to be translated as ‘extremely bad’ to represent extremes on a scale.

2. Chinese patients commonly receive acupuncture and massage therapy, often as a treatment in conjunction with or as an alternative to clinical treatments. These categories had to be added to the questionnaires.

3. In Mandarin Chinese questions cannot begin with ‘how often’ and had to be phrased ‘does it often.’ 4. Some patients could not understand the terms ‘full time’ and ‘part time’ and the question had to be phrased ‘Do you work full time (8 hours a day) or not full time?’

A third study, focused on creating a Chinese version of a HRQoL questionnaire for Chinese patients in Hong Kong with spinal deformity, demonstrated the importance of using cultural adaption and linguistic validation in the preparation of such a questionnaire. Scientists in the study noted that the questionnaire was valid only for one particular urban population in China, and that the same version could not be used for other Chinese populations such as those of more rural areas.

Recent economic growth, along with China’s growing potential drug market, has played a pivotal role in the increase in foreign-sponsored clinical research.

China offers several advantages over western countries, including a large diverse primarily treatment naïve patient population and significantly reduced costs. With recent improvements in regulatory procedures, an influx of Chinese-born scientists educated in the west, and changing disease trends, there is an even greater incentive to conduct clinical research in the country.

Despite the advantages, several challenges remain including significant linguistic and cultural barriers. However, if these issues are properly addressed they can be overcome. Translation experts familiar with working in China are best equipped to deal with the challenges of preparing regulatory documents in Mandarin Chinese. Studies involving linguistic validation and cultural adaptation of patient questionnaires and PROs further emphasize the importance of using a well established process. Finally, aspects of Chinese culture that affect patient reporting, enrollment, and medical practices must also be considered when conducting clinical studies in China.

Karen I Politis Virk is director of Biotech and Pharmaceutical Research at Language Connections in Boston, MA, since December, 2007. Prior to working at Language Connections, she worked in research and development at several pharmaceutical and biotech companies as a research associate in molecular biology, including MicroGeneSys, Wyeth Ayerst, TransKaryotic Therapies, and Cubist Pharmaceuticals.

Her experience includes the development of products for human clinical trials, particularly the human AIDS vaccine.

Section

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Section Trial Clinical

Issues & Concerns in Conducting Clinical Trials in India Issues like approval delays, deficiencies of functioning of CROs and other stake holders, liabilities and compensation to injured subjects, insurance issues etc still remain in India, which has made multinational companies to rethink on opting for India to conduct clinical trials in India recently.

There is a need for a law to ensure that the people who undergo clinical trials are not exploited and should be well informed about risk as well to provide clarity on regulations.

Milind Antani, Head, Pharma & Life Science Practice Group, Nishith Desai Associates, India Gowree Gokhale, Partner, Nishith Desai Associates, India

I

ndia’s strong value proposition has enticed multinational pharmaceutical companies to enter into or significantly expand existing operations in India in the fields of drug discovery, contract manufacturing and clinical research. In

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addition to huge internal market potential, India presents an attractive destination for drug companies seeking to minimize cost, while enhancing efficiency and adhering to international standards of quality for clinical research. Due to high costs

involved, drug companies are constantly exploring ways to outsource clinical trials to countries that provide services at lower costs and more efficient timelines. India, due to its large patient population and genetic pool, can provide both cost-savings and speedier trials. In addition, India’s adoptions of ICH compliant regulations governing clinical trials further its constant endeavor to take its regulatory regime to global standards.

Regulatory concerns

Although regulations relating to clinical trials have evolved considerably to match global standards, many issues still remain. There are several grey areas in the regulations that need to be clarified.

Hence, often for several issues, authorities need to be consulted or the industry practices need to be ascertained.

Section

Approval process A major concern a foreign sponsor faces in India is the extreme shortage of regulatory experts. Unlike FDA and EMEA, DCGI does not release guidance documents providing the current interpretation of the regulations. Since the regulations described are meant to be general, their interpretation is highly subjective and based upon the experience of the regulatory consultants. It is not uncommon to have several experts come to different conclusions about the same regulation.

The sponsors should be aware of differences in the Indian GCP version of ICH-GCP, including the Indian specifications for the composition of the Ethics Committee, informed consent procedures, compensation for participation, as well as the roles and responsibilities of foreign sponsors conducting clinical trials in India.

At present the regulations do not permit first-in-man studies (Phase I) for drugs discovered outside of India. More recently, there have been some discussions by the Indian government to consider removing this constraint and update schedule Y to be more consistent with US and ICH guidelines.

The approvals in relation to clinical trials and import of study drugs are regulated

by Central (Federal) law and regulations. The approvals for the same are granted by the Drugs Controller General of India (DCGI). The approval process may take 4 – 5 months. Unlike in the US, where a sponsor can proceed with a clinical trial 30 days after submission of an IND application if FDA has not commented, in India, the sponsor or its agent in India must receive written approval from the DCGI to proceed with a clinical trial. For global trials, a delay in getting DCGI approval could mean Indian sites lagging far behind sites in other countries for the same study. The shortage of adequate number of skill staff lead to delays in getting approval from the DCGI’s office. However, new DCGI has been making all the efforts to expedite the approval process.

Depending on whether the study drug is categorised as a biologic or a genetically engineered product, additional approval from other agencies such as the Indian Council of Medical Research (ICMR), the Genetic Engineering Approval Committee (GEAC), and the Department of Biotechnology (DBT) is necessary and can take up to six months or even longer time. Submission to Ethics Committees can be done simultaneously.

The registration of the clinical trial with the Clinical Trials Registry-India (CTRI), has been made mandatory by the DCGI has since 15th June 2009. Registration of the trial with CTRI involves declaration and identification of trial investigators, sponsors, interventions, patient population etc before the enrollment of the first patient in the clinical trial. Approval by the Ethics committee and DCGI approval are essential before registration of the trial with CTRI. Another major concern is lack of pre-IND meetings with the regulatory reviewers due to the extremely heavy workload, though they are granted on a case-by-case basis.

All indications are that the office is very aware of the issues and working hard to resolve them. The next year or two should be interesting for those tracking Indian regulatory processes.

The Deficiencies in the functioning of the ethics committees and CROs

There are several CROs that carry out trials on behalf of the sponsors. However, it has been noticed that some of the CROs lack adequate infrastructure and knowledge. Hence, it is advisable to carry out appropriate due diligence of CRO before appointment.

It has been observed that many clinical research institutions in India have an inadequate representation of the nontechnical personnel in Institutional Ethics Committee (IEC). Without adequate representation of persons from a nonfunctional background, the opinion of the IEC is likely to be unfair and biased in favor of the clinical study. The clinical research guidelines clearly specify the need for such personnel in the IEC. Some institutes have IEC but do not have a regular schedule of committee

meetings, lack Standard Operating Procedures (SOPs) or do not have a proper member representation according to the ICMR guidelines.

However, things are changing fast for the better. New Schedule Y1 is proposed which has mandated registration of CROs with the authorities and only these registered CROs will be allowed to manage clinical trials. The Central Ethics Committee on Human Research (CECHR) by ICMR audits the functioning of these IECs composed as per the ICMR guidelines. The DCGI’s office has been conducting training programs for members of the ethics committees across the country to improve the functioning of IEC, in collaboration with WHO, ICMR and many committed research professionals.

Clinical trial liabilities

The sensitivity of the clinical trial in view of the involvement of human subject can be well understood and appreciated. The human subject can either be healthy volunteers or patients suffering from disease for which the drug is being tested. All the stakeholders involved in conducting the trial have significant exposure to liability. Generally, the targets for litigation are the investigators and the institution involved. The company that sponsors the trial is also exposed to the risk of liability on account of improper disclosure, conflict of interest, violation of good clinical practices, injuries occurring due to the test drug.

Not many cases have reached courts in India, however, the awareness amongst patients is certainly increasing. www.pharmafocusasia.com

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India’s adoptions of ICH compliant regulations governing clinical trials further its constant endeavor to take its regulatory regime to global standards.

envisages imprisonment of five years, and fine of Rs. 20,00,000 for those found violating norms of clinical trial.

Access to drugs

Another issue that arises is the liability of the sponsor to provide access to drugs and treatment post termination of the trial. Depending upon the study protocol, availability of the drug and stage of the trial, this issue needs to be addressed.

Need for the law

the study? Usually, as stated earlier, this liability allocation is covered in the clinical trial agreements entered into between the parties.

Another factor that plays significant role in the compensation is insurance.

Unfortunately, unlike in other countries, clinical trial-related insurance is not well developed in India. The common practice with regards to insurance is that medical professionals are covered under professional indemnity insurance scheme provided by various insurance companies.

But this insurance cover does not protect medical professionals for compensation of claims arising out of their participation in clinical trials.

Government of India has proposed a comprehensive legislation called Central Drug Authority (CDA) Bill - that

A u t h o r BIO

Further, there are certain NGOs that take up the cause of study subjects.

Liabilities are likely to arise due to breach in “informed consent” rules or adverse reactions due to drugs, negligence of institution or investigator. Typically, the clinical trial agreement allocates the liability among sponsor, CRO, investigator / institution.

As far as sponsor’s responsibility for compensation for an injury related to the study drug is concerned, it would depend on the description of the ‘study’ specified in the Study Protocol (“Protocol”) and the Informed Consent Form (“ICF”). As per the regulations, the primary responsibility is that of the sponsor to provide compensation for any physical or mental injury arising out of a clinical trial OR provide an insurance coverage for any unforeseen injury. In relation to an injury to a study subject arising out of any act, omission, negligence or misconduct of the Clinical Research Organization (“CRO”) / investigator / institution, typically, the sponsor covers itself by contractually obtaining an indemnity from the CRO / investigator / institution, as the case may be. At times, the CRO / investigator / institution also insist on contractually obtaining an indemnity from the sponsor for liability arising out of administration of the study drug as per the Protocol. These indemnities are usually obtained over and above the insurance coverage, if any, taken by the parties for the purpose of any unforeseen injuries.

Recently DCGI has been instructing sponsors /CROs to include the wording in ICF that sponsor or CRO will provide complete medical care as well as compensation for the injury.

The injury may either arise out of the ‘study’ ie as specified in the Protocol and the ICF or may arise out of any act, omission, negligence or misconduct of the CRO or the investigator / institution. The question that arises, therefore, is - who would primarily be liable to compensate the study subject, whether the sponsor or the CRO or the investigator / institution in connection with

As of today there is no Act or Law to monitor clinical research and drug trials in the country. Such a law is necessary to ensure that the people who undergo clinical trials are not exploited and should be well informed about risk.

Indian Chapter of Association of Clinical Research Professionals (ACRP) has been launched. There is need to enhance capacity building to handle trials in a more scientific and rational way. The likely enactment of law and launching of the Chapter will bring in more professionalism. Indian government needs to bring regulations regarding conduct of clinical trials in India match to global standards and bring in lot of clarity in regulations and speed in licensing procedures.

However, the government is aware of this and has been making serious efforts to accomplish the same.

Milind Antani heads the Pharma and Life Sciences Practice at the multiskilled, research-based international law firm, Nishith Desai Associates. Dr. Antani received a Doctorate from Baroda Medical College, Vadodara, Gujarat and a Bachelor of Law from Sardar Patel University, Vallabh-Vidyanagar, Gujarat. His practice areas include Pharmaceutical, Life Sciences, Healthcare, Intellectual Property and Medical Devices. Dr Antani is also the member of FICCI, National Pharmaceutical Committee, FICCI-Gujarat Health care committee and the Committee of Telemedicine Society of India.

Gowree Gokhale heads the IP, technology, media and entertainment law practice of the multi-skilled, research-based international law firm, Nishith Desai Associates (www.nishithdesai.com). She is specialized in litigation and dispute resolution, franchising, pharma and life sciences laws, commercial laws, HR laws. Ms. Gokhale is a Solicitor and a registered Patent & Trade Mark attorney and has been practicing for the last 14 years. She is a visiting faculty at Institute of Intellectual Property Law Studies at Mumbai. She has authored research reports and articles on variety of subjects and has presented at various national and international seminars and conferences on IP, pharmaceutical, media and technology laws.

Section

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CoverStory

Section

Biobanking as an Enabling Technology for Biomarker Research A Collaborative Approach in Translational Medicine

Pharma research requires access to materials from today’s gold standard of medical care to discover the next generation of therapeutics. This need is increasing in the upcoming area of personalized medicine. Collaboration with MDs and their ethic committees is crucial to built up a pharma research biobank, as is the willingness of patients to donate samples. Success in this strategic area of operations requires multi-dimensional skills.

Arndt A P Schmitz, Global Drug Discovery, Bayer Schering Pharma AG, Germany

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Rationale for pharma biobanking

Despite significant advances, there is still need for better, highly effective and welltolerated therapies for many indications.

This requires the collaboration of scientists, clinicians and basic researchers from academic as well as industrial research. It is practically impossible to generate new knowledge on diseases without relevant patients’ tissue materials. Patient material is essential for microscopic, cell biological and molecular studies. It is of decisive advantage if research projects can resort to already existing samples, which has frequently only been sporadically possible if any material from an old study is available. It is then critical whether the newly planned uses of these samples are covered by the original ethics vote, the patient information and consent.

How can compliance with such a sensitive topic be assured in a research environment?

Is the access to biospecimens aligned with novel strategic goals and effectively organised?

Which challenges emerge by the focus of multinational pharma companies shifting to Asia?

The process of high quality generation, logistics, storage and processing of samples from patients is summarised in the term "biobanking", defined as "organised biological sample collections with associated personal and clinical data".

While this can be achieved without major problems in the GCP setting of a clinical trial, even at a multicentric scale across borders, this is already a challenge for a research department. Personalised medicine increases the need for specimens further, as illustrated in the following by some oncology examples. Oncology is a major indication for biomarker activities, since the somatic alterations driving tumour growth are individual hallmarks of each patient. Histological description of the tissue morphology is inadequate in describing the tumour, a molecular understanding is needed for clinical success. Therefore, the signalling networks identified in the last decade have morphed from a playground for biologists into a battle ground for pharma companies, which are competing for recruiting patients to clinical trials of inhibitors for identical or functionally interlinked targets such as from the PI3K and neighbouring pathways.

Frequently, markers require more finicky sample types than DNA, for example tissue samples for immunohistochemistry. Where tissues are unavailable, for example from patients with relapse after tumour resection and standard chemotherapy, circulating tumour cells might provide crucial information on the current status of the systemic disease characterised by unresectable biopsies.

However, these specimens have to be analysed with specialised equipment within a few days after generation.

The recent paper by Mok et al. highlights the importance of global biomarker activities for a globally operating pharma company – the prevalence of a marker crucial for prediction of therapeutic success was found increased in patients of Asian descent vs. Caucasians. Even if the marker in question is a DNA based marker, namely somatic mutations in

EGFR, it can only be analysed in diseased tissues, in contrast to pharmacogenomics markers which comparatively simply require DNA from a buccal swab.

Practical experiences in building up a biobank for biomarker research

Among joint biobank studies of MDs and PhDs, one can distinguish those carried out with or without support from contract research organisations (CROs).

Furthermore, a prospective study has to be regarded differently from a retrospective analysis of historic legacy samples and data, leading essentially to four different scenarios.

A feasible way to start scientific research on human biospecimens quickly is obtaining legacy samples from a CRO, reimbursing their efforts. Commercial companies had originally a pioneering role in building up biobanks. However, the emergence of commercial biobanks led also to questions regarding the ethical and legal aspects. Purely commercial biobanks are not without controversy.

Meanwhile, it is usually believed that the involvement of commercial partners is not objectionable if compliance with the rules of scientific and social norms is respected. Audits can ensure compliance of the external partner to the applicable guidelines and contractual obligations.

However, the needs of the pharmaceutical industry often preclude use of this strategy. For example, surrogate biomarker research in oncology requires blood samples matching to excised diseased tissue. These biofluids are usually not collected or not conserved in standard practice and thus not available from historic cases. Furthermore, even if samples exist which match the desired scientific profile, their use for research has to respect the patients from which they origin. If there is no informed consent for research purposes at all or it does not cover the intended work plan, then realisation of the intended research becomes challenging. The general

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situation is even worse in indications beyond oncology such as women’s health care or cardiovascular diseases, where hardly any biobanking CROs operate and their expertise rarely covers the specialised requirements.

Our collaborative approach built on mutual strengths of MDs and PhDs

In contrast, a joint MD / PhD prospective methods study can be custom designed to meet today’s research needs, but this might take some time. This might be explained by the cultural differences between the two partners and the need to understand each other’s situation and needs. Also the complexity of the contractual framework to be negotiated by the legal departments of the two entities has to be mentioned. A CRO can hardly improve this initial situation, but be instrumental in the operations phase of a study, such as the preparation of the sampling tubes, checking clinical data, for delivery of liquid nitrogen or transportation of the samples provided.

This is, however, marginally to the critical role of the MDs’ and nurses’ motivation.

Only they have access to the patients, can contact them for enrolment, obtain the informed consent, process the samples and fill in the case response forms. The researchers can only try to convince the medical personnel to schedule this additional task in their busy agenda of the public health system’s hospitals. Ideally, the physician is interested in the data only the researcher can obtain via his or hers bioanalytical capabilities. This results in a self-interest of the clinician to provide high quality specimens.

The interest of clinicians in a scientific collaboration can best be triggered by explaining the rationale, for example, giving a lecture or presentation to a medical audience using the poster session of a scientific conference. The researcher should also take the opportunity to convince the clinician of his professional expertise in dealing with clinical specimens. This starts with the way the samples are taken care of. Unique barcodes clearly document the history of

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Legal framework of biobanks for research purposes The main ethical and legal aspects related to biobanking can be distinguished from a legal point of view in the three consent levels involved: ownership of the body material; personal data; and informational self-determination and general personal rights. They cover aspects of patient education / patient consent (informed consent), confidentiality / anonymity, the potential multiple use of the material and the data over time, access to the results, and the sharing of data. From a practical point of view, the collection and storage of samples and associated clinical data in a human clinical prospective research methodology study affects primarily the doctor-patient relationship, privacy and safety at work. Good professional conduct of the physician requires that such studies are approved by the relevant ethics committee. Similar to a clinical trial, patient information, informed consent, and the study plan have to be submitted. It is crucial that the intended use of samples and data is on the one hand exactly, but on the other hand as far reaching as feasible described in the patient information and the consent form. The consent of the patient has to be documented by signature.

The clinical data then are pseudonymised or completely anonymised for research use. Anonymissation has the advantage that it eliminates the data protection concerns. Frequent is a collaboration between a clinician and a scientist who analyses the samples. Typically, the researcher does not receive the full name but solely the initials or even just a patient identification number in this study (not the hospital’s patient ID), neither the address or place or date of birth (only the year of birth). The key allowing reidentification of the study participant remains with the clinician. In a narrow sense, this process is pseudonymisation; however, there is a general opinion in the literature that this process can even lead to anonymisation, in particular where MD and PhD belong to two different legal entities. Finally, compliance regulations also require companies to assess the health risks for their employees during storage, processing or disposal of clinical samples. The necessary risk assessment considers the risks for the technicians associated with processing the samples based on the type of samples and the information available regarding the donors’ health.

Cover Story

In this interdisciplinary field, personal skills become crucial for success of this partnering model. We thus favour an emerging public-private partnership model of pharmaceutical research based on complementary synergies resulting in mutual benefit.

The Asian perspective

The raising awareness of pharma companies to provide innovative treatments to Asian patients leads to the requirement of their research departments to have access to samples from the local populations.

The best practice of biobanking should therefore also be deployed in Asian countries. The leading academic biobanking society, ISBER, held an international symposium in Korea already in 2009.

Interestingly, India’s IT industry has generated a software package even for biobanking. Ocimum’s relational database solution, biotracker, is according to the vendor’s homepage capable of supporting typical tasks of biobanking, such as clinical data, specimen data, tissue micro arrays, inventory and request management.

A wave of Asians who went to university abroad and then joined western pharma companies have returned to their home countries as professionals and can act in their new positions as inter-cultural ambassadors and, if now in an academic role, can educate a new A u t h o r BIO

samples and specimens. Excellent logistics is a key success factor. Many biological analytes are unstable and are damaged by repeated freezing and thawing. Aliquoting achieves that the final aliquot is as often thawed as the first, namely just two times: once for aliquoting and then for analysis.

The combination of different samples on microtiter plates results in a collective that is measured in each measurement at the same time so that measurement problems such as day-to-day variation are eliminated, in accordance with the international guideline on validation of analytical procedures for registration of pharmaceuticals for human use. Thus, individual samples are portioned in e.g. 96 well format plates and a stack of those plates is used not just for a single but several measurements, dramatically increasing the "yield" of data from a specimen. These opportunities arise from experience in automated material banks serving small molecule compound libraries and the high throughput screening departments which the pharmaceutical companies established in the past. In addition, miniaturisation by more sensitive techniques and multiplexed analytical methods can multiply the number of analytical parameters to be measured in a given sample volume. Best practice to control pre-analytical variation is here shared by conferences and trade shows, publications and, increasingly, publishing SOPs on homepages of institutions such as ISBER or NCI’s OBBR. Correlating experimental results to clinical data can lead to peer- reviewed publication. Industrial biomarker research is more freely publishable than articles describing targets or compounds. A joint MD / PhD author list acknowledges each partners’ contribution to the common work. We therefore advocate a model of partnership between industry and academia, in which the strengths of different institutions are combined with the goal of using excellent clinical material to extract as much analytical data as possible and even to make the results available to the scientific community.

A feasible way to start scientific research on human biospecimens quickly is obtaining legacy samples from a CRO, reimbursing their efforts.

generation of scientists in best practice.

They can work together with pharma companies and perform research studies on their behalf in countries which restrict export of biospecimens.

This is the most recent wave of Asians who for centuries have migrated globally, facilitated by trading relationships.

Many of their descendants have settled down, not only in the US, but also in Commonwealth countries such as Canada or Australia. As some of these individuals are afflicted by cardiovascular diseases or cancer, they become patients of Asian progeny in a western legal and healthcare system and their specimens and associated clinical data might become valuable for understanding to which extent genetic predisposition vs. environmental factors contributed to their diseases.

The next challenge will be to bring the benefits of biomarker-supported pharma research to Asian patients beyond oncology, in areas such as cardiovascular diseases or woman’s health care. Also for this reason, Bayer Healthcare’s pharma division opened a research and development centre in China in 2009. Changing demographics and life styles have brought such indications to increased awareness of Asian countries’ inhabitants and health systems alike, requiring among others novel biospecimen-based research. Our collaborative approach to translational medicine will go global, requiring intercultural skills.

Acknowledgements

This article is partly based on a forthcoming book chapter regarding research biobanking authored with J. Swifka and K. Asadullah. I would also like to thank all external and internal partners involved.

All opinions expressed are the author’s personal views.

Arndt Schmitz joined the pharmaceutical industry in 2001 after a post doc in the US. He was a biotech group leader prior to founding the Research Biobank. He is also Senior Scientist in Global Biomarker Research of Bayer Healthcare’s Pharma Division. He has contributed to international conferences covering these topics

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Research Insights Seven major trends reshaping the pharmaceutical marketplace The pharmaceutical marketplace is changing dramatically, with huge ramifications for the industry as a whole. We have identified seven major socio-economic trends.

The burden of chronic disease is soaring

The prevalence of chronic diseases like diabetes is growing everywhere.

As greater longevity forces many countries to lift the retirement age, more people will still be working at the point at which these diseases start. The social and economic value of treatments for chronic diseases will rise accordingly, but Pharma will have to reduce its prices and rely on volume sales of such products because many countries will otherwise be unable to afford them.

Healthcare policy-makers and payers are increasingly mandating what doctors can prescribe

As treatment protocols replace individual prescribing decisions, Pharma’s target audience is also becoming more consolidated and more powerful, with profound implications for its sales and marketing model. The industry will have to work much harder for its dollars, collaborate with healthcare payers and providers, and improve patient compliance.

Pay-for-performance is on the rise

A growing number of healthcare payers are measuring the pharmacoeconomic performance of different medicines. Widespread adoption of electronic medical

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records will give them the outcomes data they need to determine best medical practice, eschew products that are more expensive or less effective than comparable therapies and pay for treatments based on the outcomes they deliver. So Pharma will have to prove that its medicines really work, provide value for money and are better than alternative forms of intervention.

The boundaries between different forms of healthcare are blurring

The primary-care sector is expanding as clinical advances render previously fatal diseases chronic.

The self-medication sector is also increasing as more prescription products are switched to overthe-counter status. The needs of patients are changing accordingly.

Where treatment is migrating from the doctor to ancillary care or self-care, patients will require more comprehensive information. Where treatment is migrating from the hospital to the primary-care sector, patients will require new services such as home delivery.

The markets of the developing world, where demand for medicines is likely to grow most rapidly over the next 12 years, are highly varied

Developing countries have very different clinical and economic characteristics, healthcare systems and attitudes towards the protection of intellectual property. Any company that wants to serve these markets successfully will therefore have to devise strategies that are tailored to their individual needs.

Many governments are beginning to focus on prevention rather than treatment, although they are not yet investing very much in pre-emptive measures

This change of emphasis will enable Pharma to enter the realm of health management. But if it is to do so, it will have to rebuild its image, since healthcare professionals and patients will not trust the industry to provide such services unless they are sure it has their best interests at heart.

The regulators are becoming more risk-averse

The leading national and multinational agencies have become much more cautious about approving truly innovative medicines, in the wake of the problems with Vioxx.

Source: Pharma 2020: Virtual R&D Which path will you take?

PricewaterhouseCoopers

Emerging collaborative networks Several pharmaceutical firms have already begun to use more collaborative models. One such instance is Lilly, which is currently transforming itself from a traditional fully integrated pharmaceutical company into a fully integrated pharmaceutical network, so that it can draw on a wide range of resources beyond its own walls.

Lilly hopes that teaming up with other organisations to create virtual R&D programmes will enable it to get better access to innovation, reduce its costs, manage risks more effectively and enhance its productivity. For example, the Chorus Project is a virtual organisation to take molecules quickly to Proof of Concept.

Lilly also uses external networks comprising third parties such as Piramal Life Sciences, Hutchison

Section

MediPharma, Suven Life Sciences for the development of molecules. Swiss biopharmaceutical development specialist Debiopharm has pioneered a more radical approach. The company in-licenses promising new candidates from academic institutes and biotech companies, develops them and then out-licences them to Big Pharma.

Debiopharm’s successes include three products with combined global sales of more than US$2.6 billion in 2007.

Most of the collaborative models that currently exist are limited to R&D. But it is easy to envisage various other permutations, including networks focusing on different therapeutic areas and covering everything from R&D through to sales and marketing; networks focusing on different enabling technologies, such as genomics, proteomics and stem cell research; and networks focusing on the management of outcomes in specific patient segments.

Source: Pharma 2020: Challenging business models Which path will you take?, PricewaterhouseCoopers

India's potential cannot be ignored by global pharma

The pharmaceutical industry’s main markets are under serious pressure.

North America, Europe and Japan jointly account for 82% of audited and unaudited drug sales; total sales reached US$773 billion in 2008, according to IMS Health. Annual growth in the European Union (EU) has slowed to 5.8%, and sales are increasing at an even more sluggish rate in Japan (2.1%) and

North America (1.4%). Impending policy changes, promoting the use of generics in these key markets are expected to further dent the topand bottom-line of global pharma majors. The industry is bracing itself for some fundamental changes in the marketplace and is looking at newer ways to drive growth.

Further, higher R&D costs, a relatively dry pipeline for new drugs, increasing pressure from payers and providers for reduced healthcare costs and a host of other factors are putting pressure on the global pharmaceutical companies. Pharma companies are looking for new ways to boost drug discovery potential, reduce time to market and squeeze costs along the whole value chain.

How can industry leaders best face these challenges? Analysis by PricewaterhouseCoopers (PwC) shows that several regions offer considerable promise, either as places with untapped demand for effective drugs or as suitable areas for conducting research and development (R&D) and/or clinical trials. In this paper we shall examine the opportunities available in India.

India’s population is growing rapidly, as is its economy – creating a large middle class with the resources to afford Western medicines. Further, India’s epidemiological profile is changing, so demand is likely to increase for drugs for cardio-vascular problems, disorders of the central nervous system and other chronic diseases.

Together these factors mean that India represents a promising potential market for global pharmaceutical manufacturers.

More than that, India has a growing pharmaceutical industry of its own. It is likely to become a competitor of global pharma in some key areas, and a potential

partner in others. India has considerable manufacturing expertise; Indian companies are among the world leaders in the production of generics and vaccines.

As both of these areas become more important, Indian producers are likely to take a large role on the world stage – and potentially partner with global pharma companies to market their wares outside of India.

Indian companies have also started entering into the realm of R&D; some of the leading local producers have now started conducting original research. India has the world’s second biggest pool of English speakers and a strong system of higher education, so it should be well-positioned to serve as a source for research talent. A new patent regime provides better protection of intellectual property rights, although some issues remain.

Clinical trials can also be conducted here much more cost-effectively than in many developed nations, and some local companies are beginning to develop the required expertise. All of these factors add up to a strong case for partnering with Indian companies around R&D, including clinical testing.

Further, healthcare has become one of the key priorities of the Indian Government and it has launched new policies and programmes to boost local access and affordability to quality healthcare.

Global players in the pharma industry cannot afford to ignore India. The country, many predict, will be the most populous in the world by 2050. India will make its mark as a growing market, potential competitor or partner in manufacturing and R&D, and as a location for clinical trials.

Source: Global pharma looks to India: Prospects for growth, PricewaterhouseCoopers

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Section

SECUREJECT®: THE FUTURE OF PRE-FILLED SYRINGES Healthcare professionals from all over the world appreciate and count on the advantages offered by the prefilled syringes. Prefillable syringes provide convenient, sterile, fixed dosages. Till date several manufactures have designed and have commercialized prefilled syringes in various sizes, shapes and made from various materials offering wide range of functional variations.

Most of these pre-fillable syringes are commercialized in nests or matrix of few tens up to hundreds of sterile ready to be filled syringes. Nested pre-fillable syringes and associated filling machine still is most popular, albeit most expensive. In spite the fact that health care professionals recognize that pre-filled syringes are distinctly advantageous compared to conventional method of reconstitution or using single use empty syringes to draw the drug from ampoule or vial, even today, the prefilled syringes are used for packing expensive drugs or drugs required for emergency use.

The production of nested pre-fillable syringes require several production steps independently of whether it is a glass pre-fillable syringe or plastic pre-fillable syringe made from COC (Cyclo-olefin copolymer), COP (cyclo olefin polymer) or PP (Polypropylene). Each manufacturing step increase risk of contamination, and also the cost of production.

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The nested pre-fillable syringes are made of several components and several of them can remain in direct contact with the drug which shall be filled in the syringes. Each additional component increase risk of contamination and also contribute to the cost of final product.

The advantages of plastic over glass specially in context of Prefilled syringes are well known, like: • Plastic does not break under normal usage and transportation conditions • Plastic syringes can have tighter tolerance on the inner diameter compared to glass syringe, plus the plastic syringe barrel can be made perfectly round unlike glass cylinder which could be oval to some extent. Thus, to overcome this non uniformity, glass syringe require greater interference between the diameter of plunger and the barrel resulting in higher force to move the plunger. On the other hand plastic syringe has more uniform diameter and tighter tolerance enabling to reduce the interference between plunger. This reduces the force to move the plunger.

• Plastic syringe does not have issues related to traces of Tungsten. (Presence of Tungsten can cause catalytic breakdown or create agglomerate with tungsten residues with some biological compounds and proteins )

Section

• It is a known issue that siliconization process of glass barrel may not be uniform. Plastic barrel does not require lubrication, so only siliconisation of the plunger may be sufficient in most of the cases.

This reduces the problem of compatibility between drug and silicon oil, and also eliminates problem related to uneven siliconisation of syringe barrel.

• Plastic syringe does not face problems which glass prefilled syringes typically face due to presence of particulates, the glass's reactivity to the drug product, and potential leachables from adhesive which is used to hold the needle in place.

SECUREJECT® - PREFILLED SYRINGES, are made using Advanced Blow Fill Seal process. SYFPAC SECUREJECT is a new generation of BFS machine specially designed for manufacture of prefilled syringe.

After plastic granules are extruded at temperature exceeding 190° C, and formed in to the shape of syringes and a needle is introduced at the bottom of syringe body while being formed. The newly originated syringe is filled from top with medicine/vaccine/ liquid excipient, and pre sterilized plunger is introduced at the top of the syringe body. After insertion of the premade plunger it is covered and sealed hermetically with secure plastic capsule. All the above operations take place within SYFPAC® and exposed parts of SYRINGE and components (plunger and needle) are protected under sterile air shower to ensure assembly and filling under aseptic conditions.

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- SYFPAC® machine employs philosophy of worldwide renowned Blow-Fill-Seal technology - The core zone where filling, assembly of components and sealing occurs, is protected against contamination by a shower of sterile air. Additionally, machine has automatic internal CIP/SIP procedures to sterilize and clean the circuit where solution and process air can pass.

• Only three components are in direct contact with the filled product(medicine/vaccine/liquid excipient), and these are: blow moulded syringe barrel and tip closure made from medical grade inert polymer, Plunger made from compatible material. Both sides of syringe (needle at the bottom and plunger on top) are secured with hermetic plastic covers which are formed during moulding process. These covers protect syringe from contamination and from accidental pushing.

The our new manufacturing process, we can reduce the number of components from which a Prefilled syringe is composed of, thus reducing risk of contamination and the cost. With this new process, the exposure time of the primary container (in this case syringe barrel and the tip closure ) is reduced to just few seconds. The needle embedding, realization of the tip closure and barrel formation are done in a unique step, followed by filling and plunger insertion, resulting in further reduction of contamination risk and one of the most cost effective manufacturing process. So, just one equipment carries out all manufacturing steps in just few seconds to realize syringes already filled and sealed.

Above factors make SECUREJECT® - PREFILLED SYRINGES very useful tool for routine administration of drug through injection by nurses and doctors. Prefilled excipient is handy in reconstitution of powdered or lyophilized injections, because after resolution it can be sucked back and injected with the same needle (without additional syringe). Being ready to use and needs just twisting off before administration, Secureject could be very useful for safe mass vaccination campaign.

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MANUFACTURING

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 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 inside-out 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

Supply Chain Design An outside-in perspective 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.

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

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MANUFACTURING

the patient. This inside-out, and in many cases, one-size-fits-all approach to supply chain design sub-optimised the company’s total product supply capability.

In today’s environment, leaders are designing their supply chains from an outside-in perspective to adaptively translate 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 top-down 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, 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 enterpriselevel business strategy and operationallevel 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 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?).

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MANUFACTURING

Developing product supply capabilities – A focus on Asia

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To create opportunity at the lowest cost and maximise value to both trading partners and the end customer (i.e. the patient) by adaptively translating actual demand from the customer into trade-offs that profitably fulfill perfect orders, leaders are designing their supply chains from an outside-in perspective.

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 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?

A u t h o r BIO

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: • 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 Get started on your transformation – Ask the right questions 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

• 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, win-win relationships or are they one off, short-term collaborative projects?

• Have you defined a business performance 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 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.

INFORMATION TECHNOLOGY

Access to accurate real-time information during every phase of development can significantly improve the effectiveness of strategic decisionmaking, increasing the likelihood of long-term success.

Business Intelligence Alan S Louie, Research Director, Health Industry Insights, IDC Company, USA

Transforming Pharma T

he pharmaceutical industry is in the midst of fundamental changes. The changes have been brought on by the increasing concerns over expiry of patents for major blockbuster drugs, weak product pipelines, heightened awareness of drug safety, globalisation, competition from generics and growing value considerations with regards to access to and reimbursement of new speciality therapeutics. These issues, and more, have forced top pharmaceutical companies to change their current course, in search of a stable and sustainable path that can help them maintain and improve their current profitability levels.

Near-term strategic efforts in the path towards sustainability include traditional business approaches that aspire to fully address shortcomings, but are more likely to only produce incremental improvements.

More tactical changes are also being implemented in hope of better leveraging of resources within the increasingly distributed, global pharmaceutical organisation. Key among the tactical changes that are being implemented are efforts in pursuit of information transparency.

Looking significantly beyond consolidated data warehouses, pharmaceutical companies are working to bring all

data (from initial laboratory e-Notebooks in discovery through to Phase IV clinical trial data reporting) into a broadly accessible and usable form that fully captures knowledge accumulated during the course of R&D. This includes supporting information (i.e. metadata) that provides procedural and analytical insights surrounding experimental data, related knowledge available from a wide variety of sources (both external and internal), analytical and visualisation tools to simplify knowledge extraction, and real-time tools to enhance collaboration across the organisation to more effectively exploit the collective brain trust. www.pharmafocusasia.com

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INFORMATION TECHNOLOGY

Phases Involved in Drug Development Pre-clinical

Phase 1

Phase 2

Phase 3

Phase 4

fda

approval

To establish an effective information transparency infrastructure in the nearterm, an organisation needs to improve its ability to rapidly and regularly extract real-time data that reflects the status of projects and processes ongoing within it.

Access to accurate real-time information during every phase of development can significantly improve the effectiveness of strategic decision-making, increasing the likelihood of long-term success. It can help companies to better reach project milestones with regards to experimental progress, optimise utilisation of project resources and enable comparative analysis of specific projects undertaken by the different divisions of the company.

Heavily validated in other industries, Business Intelligence (BI) is increasingly becoming an essential part of the pharmaceutical industry. Apart from establishing an effective information transparency infrastructure, BI directly enables both senior management and project line managers to make better decisions to help their companies move forward.

reasons for investing in BI, anticipated benefits, and future plans expected over the next five years.

Moving beyond operational excellence With total US spending on BI in 2007 at US$ 168.7 million and a growth rate roughly double that of the overall IT spending (12.7 per cent versus 7.3 per cent, Source: Health Industry Insights, 2007), it is clear that leaders in the pharmaceutical industry have recognised the potential of BI and are speeding up the implementation of this approach across their organisations. While the opportunity for BI to pursue operational excellence is an obvious first step (e.g. more efficient utilisation of available resources and the elimination of redundant or unproductive efforts), it is interesting to note that BI is also being applied to the technical and scientific efforts within the organisation. Specifically, BI solutions are beginning to be used to improve research and clinical performance with the goal of both accelerating organisational growth as well as saving costs.

Methodology

A Health Industry Insights' simplified definition of Business Intelligence:

Based on telephone and in-person surveys across all aspects of the health industry, Health Industry Insights analysts assessed the industry’s use, expectations, and aspirations of adopting business intelligence solutions within their organisations.

Discussions focussed on a number of specific factors, including top business

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Systems and solutions that improve organisational decision making through regular access to detailed quantitative organisational data.

Generally, BI solutions are implemented in different parts of the

organisation under the common direction of the CIO. Having been successful in achieving operational excellence and improving the research / clinical performance of the companies, these solutions have been increasingly adopted, albeit at a varied pace, by pharmaceutical organisations. With many validated examples of successful implementations focussed on operational excellence from other industries (especially the financial, manufacturing, and retail industries), BI is finding a new prominent position within pharmaceutical organisations, including project resource management, sales force tracking, and regulatory compliance reporting. From a research / clinical performance perspective, however, there have been few cross-industry examples to leverage. This has led to BI solutions for pharmaceutical organisations being developed organically. Specific applications in this area include: better ability to access and use research data from across the organisation (through elimination of data silos), improved use of data analytics and visualisation tools to extract information, and more effective comparison of project and therapeutic areas on a common value scale.

While assessing industry sentiment regarding BI, some industry-wide goals were identified which benefited the organisations significantly beyond pilot project boundaries, often leading to opportunities for new BI applications. In general, three key goals for BI were identified:

Section

Advanced manufacturing technologies

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INFORMATION TECHNOLOGY

Succeeding in a new global ecosystem At the beginning of the discussion of BI adoption, interviewees were asked whether ROI was a prerequisite to initiate pilot efforts. In all cases, it was reported that an ROI justification was not required and that initial key decision makers (typically the CIO) recognised the greater opportunity and benefits that an effective BI and supporting IT infrastructure could enable. Despite this unconstrained commitment, it was often possible in many cases to produce a demonstrable ROI from pilot efforts.

A shift towards a transparent information ecosystem that effectively leverages data and information regardless of its source will be a key differentiator for pharmaceutical companies moving forward. To be successful, drug developers (and senior management) need to have timely access to key information (both internal proprietary and external data including academic discoveries, publicly available academic research, competitive clinical data etc.) in order to minimise development risk and to ensure that all critical factors have been fully taken into consideration before advancing specific projects forward. With the amount of available data continuing to grow at exponential rates, it is becoming increasingly impossible to manually keep up with progress.

Harnessing the collective organisational brain trust in conjunction with evolving bioinformatics, BI, and content resources will be the key to success in this highly dynamic environment.

Driving organisational change

All of the companies interviewed had access to one or more of the commercial BI software tools and services available in the market today. Major commercial BI solution vendors used in the industry include: Business Objects (now part of SAP), Cognos (now part of IBM), Hyperion (now part of Oracle) and SAS. However, the availability of commercial BI solutions plays a minor role in the implementation of an effective BI solution within these organisations.

Successful implementation of BI in the pharmaceutical industry requires

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significant changes in organisational thinking across the organisation, impacting researchers at the bench, the CIO, and all levels in-between. Failure to recognise and adopt these philosophical changes significantly reduces the potential opportunity for BI and results in the wastage of valuable company resources.

Changes to both broad organisational mindset around data and supporting IT infrastructure are needed to enable BI to be successful. To gather good data on a A u t h o r BIO

• Gather good data • Translate data into actionable information • Use information to effect organisational change.

regular basis, everyone in the organisation, from researchers to line management to senior leadership must recognise that accurate, quality data brings value to the organisation and that isolated silos of data significantly impair an organisation’s efforts to be successful. With quality data in hand, it then becomes necessary to have easy-to-use portals, analytical tools, and simple, but powerful report generators to begin to translate this data into actionable information. Finally, it must be clear and transparent to the organisation that the data and the information derived from the data, is actively being acted upon and used to drive the organisation forward.

As BI implementations begin to regularly yield successful outcomes (efforts that should be highlighted regularly and often within the company), success should breed success spurring further adoption and support for new BI initiatives.

A number of collateral benefits become possible with the creation of a fluid information infrastructure. It becomes possible to benchmark key projects, processes, and programmes, laying the foundation for future process improvements which can be better quantified for effectiveness and value. Metrics supporting Return-on-Investment (ROI) become possible, even at early stages of adoption. Efficient and routine data collection can be expected to simplify ever growing regulatory compliance and reporting requirements. And with proper analytical efforts, it becomes easier to establish enterprise-wide standardised data definitions, which enable effective comparisons of projects and processes across the organisation, including the ability to effectively transcend geographical, divisional, and cultural boundaries.

Alan Louie is Research Director at Health Industry Insights. He leads HII’s pharmaceutical R&D market research efforts, with an emphasis on technology and innovation in clinical development, personalised medicine, and BI. Louie brings to HII more than 24 years of experience from the diagnostics, biotechnology, and consulting industries.

Section

Social media and the pharma industry Every other industry is getting on the social media bandwagon. But could social media actually prove beneficial to the world of pharma?

Outside of the pharmaceutical industry, business is continually finding innovative ways to make use of social media to engage with customers in order to drive sales, maintain relationships and uncover issues. Within the world of pharma, however, an intense regulatory environment and over-protectiveness of intellectual property have proven a minefield for pharma companies keen to dip their toes into the social media pool.

One of the key stumbling blocks for pharma companies wishing to fully embrace the social media revolution is the strict regulatory environment, particularly when it comes to Adverse Event (AE) reactions to clinical trials. Currently, every time a patient tweets/ blogs/comments about an AE, the FDA and EMEA become involved. In this context, pharma’s obligation to its regulatory bodies has, without doubt, stifled its progression into the social media nucleus.

The requirement for promotional labelling and advertising to be submitted to regulatory bodies also severely restricts companies’ ability to do any real-time social blogging relating to any of their products.

Next Generation Pharmaceuticals Summit Asia 2011 in Kuala Lumpur from 12-14 July 2011 sponsored by GDS International features some of Asia’s leading pharma executives discussing about social media, other topics for discussion include trends shaping the future of pharma and pharma manufacturing, brand protection and anti-counterfeiting, packaging trends and the best way to streamline the value chain.

It is an exclusive C-level event reserved for 100 participants that includes expert workshops, facilitated roundtables, peer-to-peer networks and co-ordinated meetings For more information, visit www.ngpharmasummit. asia GDS International is a leading business-to-business events company. We offer financial, healthcare, IT service management, telecoms and oil and gas summits for senior executives throughout the Asia Pacific, Africa, China, Europe, North America and Russia markets. Our value proposition is simple: we deliver real results. And we’re very good at it.

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INFORMATION TECHNOLOGY

Industry-Academia Interactions In the Indian scenario, teachers are overburdened and are involved in too many non-academic activities resulting in poor research output. There are only a handful of universities and institutions with a serious focus on research.

R S Gaud, Dean, School of Pharmacy & Technology Management, SVKM's Nursee Monji, Institute of Management Studies University, India

basis. They have identified faculty exclusively to carry out such research activities with few academic commitments.

In the Indian scenario, teachers are overburdened and are involved in too many non-academic activities resulting in poor research output. There are only a handful of universities and institutions with a serious focus on research. Moreover, the industries here are very conservative and do not encourage funding for research activities carried out in institutions.

How different are the industry-academia relations in India compared with the US and European countries?

In India, industry-academia interrelations are not very strong. Both industry and academia are not taking necessary initiatives to strengthen the relations as they do not consider this as a priority issue. On the contrary, in the US and European countries there is a strong bond between industry and academia with industry sponsoring many projects in universities and reputed institutions. Many universities have undertaken pioneering research projects and also established research companies on a commercial

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Indian pharma companies are shifting from generic-based business model to that of an innovation-based business model. How do you see the industry-academia interactions in light of these developments?

In post-GATT era with product patents in place, the Indian pharma companies have to come up with their own drug molecules and formulations which need innovative research. Academic institutions and universities can carry out basic research to achieve these targets. Industry with the institutional involvement will be able to accelerate their New Chemical Entities projects and other research activities using younger scientists and faculty from the institutions. They can as well use the infrastructure and human

resources provided by these institutions in other priority areas. Academia has more vision and expertise in developing newer technology which is essential for innovative research. Academia also has enough database for such research approaches due to continuous education programmes. Many educational centres have not commercialised their research activities and limited research to academic purposes. With industry involvement, these ideas can be brought to reality for the benefit of the society. Thus, industry can also benefit provided they encourage tie-ups with academia.

Academia in the US holds more patents than its counterparts elsewhere in the world. What are the factors that hinder the Indian academia to actively participate in the drug R&D? In India, research is not a priority and wherever research is carried out is not focussed and is of purely academic interest. Academia and industry lack the patent awareness and are mostly dependant on research that is done abroad.

Secondly, there is lack of infrastructure and motivation for innovative research.

Even if research facilities are available, more often they are not accessible to young scientists. The availability and

INFORMATION TECHNOLOGY

Can you suggest ways to overcome these hurdles?

We must encourage younger faculty to engage themselves in research activities by providing more grants and opportunities to interact with pharma companies and by arranging awareness workshops on Intellectual Property Rights (IPR).

Incentives should be given to faculty engaged in research activities.

All postgraduate and doctoral research should be focussed on industrial needs and should not be only of academic value. Workshops on newer research approaches must be conducted regularly. Faculty / student exchange programmes at national / international levels must be encouraged.

Government funding procedures must be time-bound and simple in operation.

Faculty with research inclination should be identified and encouraged to carry out research activities.

Recruiting right talent is very crucial for the success of the industry. In what ways can the academia help the industry in this direction?

Academia should interact with companies of repute to provide training to their students. They should also look into the critical evaluation and suggestions made by the industry to improve their curriculum.

All the changes made to the curriculum must be acknowledged by the industry experts. Industry experts should voluntarily interact with university academia for making curriculum more relevant to the end-user i.e. the industry as it is meant for their own survival. The changes thus made to curriculum should reflect the respective changes in the industry.

Unfortunately, industry experts take it as a burden and quite often they remain absent on such occasions. I have experienced this many times in my 30 years of

academic experience. While suggesting change in the syllabus, industry should also provide a framework for "train the trainer" approaches. The industry should consider it as a long-term investment.

What is the role of government in promoting the relationship between industry and the academia?

The Government of India through its various agencies provides huge funds for such interactions. However, there is lack of awareness about such facilities and lack of commitment amongst the faculty. Also, institutions are not encouraging such activities as faculty members are already overburdened. They have limited time for academic delivery and most of the managements are casual in their approach to strengthen industryinstitute interaction. All India Council for Technical Education, Department of Science and Technology, Universal Grants Commission, Indian Council of Medical Research are a few bodies that look towards participating actively in such interactions. But response from majority of the academia is far from satisfactory.

Also, these grants are given mainly to the A u t h o r BIO

operation of research grants for academia from government bodies involves a lot of formalities due to which the academia stay away from utilising these facilities.

In US and Europe, strong bond between industry and academia with industry sponsoring many projects in universities and reputed institutions whereas in India, industry-academia interrelations are not very strong and they donot consider this as a priority issue.

limited government / government-aided institutions. Unfortunately, these grants are not given to the capable investigators from private sector which constitutes a major chunk of the education system.

What are the benefits that the industry and academia can derive from each other in the long run?

The interaction would result in developing faculty and providing necessary human resources to the industry. Faculty members have to update their knowledge bank and industry must get workforce of the quality they look for. This is possible only through this interaction. The industry, by using the innovative approaches of the younger generation, can face the global competition effectively.

The benefits that industry can derive from the interaction with academia are many.

Firstly, the industry will save many precious man hours in training their employees at its own cost. They can get the human resources of acceptable quality right at the entry point. They can also develop their Intellectual Property and improve their research potential. They will also have an opportunity to improve and economise their products and activities.

There will be a fresh flow of information to increase their data bank. Such efforts may lead the industry to new discoveries.

Academic institutions can redesign their courses, teaching, learning methodologies and research activities as per the needs of the industry. This will facilitate students' placement and will improve the quality of the curriculum. Institutions can develop themselves as focussed and need-based research centres by utilising opportunities from both government agencies and the industry.

R S Gaud is a senior academician in Pharma Sciences since the last 30 years and is responsible for shaping the Pharmacy division at NMIMS University. He also has worked as an advisor at All India Council Technical Education for five years. He is also a member of CII National Committee of Drugs & Pharmaceuticals. He has presented and published more than 150 research papers. He has authored nine pharmacy books and has two patents under process.

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Section

The “One-Stop Shop” Fully Integrated Solid-State Research CRO

The Case for Choosing Crystal Pharmatech Crystal Pharmatech Co., is the leading dedicated solid state research company based in China. Our executive team has an average of 10 years experience in top-tier pharmaceutical companies focusing on solid state API and drug development issues.

Crystal Pharmatech researchers have extensive experience with solid-state issues from pre-clinical development through supply. We support all solid state aspects of drug discovery, organic process development, formulation development, regulatory support and intellectual property protection. We have been at the bench level for many years at large pharmaceutical companies and have encountered numerous solid state problems. This experience has given us strong instincts on solid state issue resolution leading to a model for being fast and efficient with the cost savings trickled down to the customer.

Crystal Pharmatech realises the critical interplay between API and drug product. We are not ‘API-centric’ and thus offer many pre-formulation and formulation research services. Crystal Pharmatech does not merely provide data, we partner with you to ensure comprehensive, integrated solutions to solve your solid state issues.

The Pharmaceutical ‘White Powder Syndrome’ Often times, early in drug candidate program lifecycle, the main driver for chemists, engineers and formulators is to produce solid material of acceptable yield and chemical purity. Solid state properties can often take a back seat until the program progresses beyond a certain milestone. This lack of understanding can lead to process robustness issues, formulation problems and regulatory gaps, to name a few.

It is well known that the solid state of a drug substance can impact drug properties, API and formulation processing, as well as drug product performance in a multitude of areas. For instance, a crystalline salt and a crystalline neutral form of a drug can have drastically different physicochemical

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properties; two polymorphs of a drug can show very different bioavailability; a solvate and an anhydrate can have very different impurity rejection in crystallisation; a crystalline API and its amorphous state can have very different stability behaviour. Therefore, a thorough understanding of solid phases of a drug substance is crucial in the whole drug discovery and development life cycle.

Crystal Pharmatech Solution Crystal Pharmatech researchers can address all solid state aspects of comprehensive drug candidate development including, but not limited to: • Drug discovery • Organic Process Development • Pharmaceutical Development • Regulatory • Intellectual Property Based on a candidates’ lifecycle, there are several common milestones that represent a unique level of integrated solid state solutions that can be provided

by Crystal Pharmatech.

Key Fundamental Services • Salt/polymorph/co-crystal screening • Solid state characterisation • Preformulation studies • Single crystal growth and structure determination • API form selection and process optimisation • Crystallisation development and optimisation • Amorphous solid dispersion screens and characterisation • Drug-excipient compatibility testing Formulation characterisation Crystal Pharmatech has all the high-end solidstate research equipments, workflows and talented researchers to handle the solid state issues of any project at any stage of development. The main attribute which differentiates Crystal Pharmatech is data quality and integrity. With our years of experience, we realise the value of scrutinising all data and under-

Section

standing the process impact to all the data generated towards solving problems. As an example of this, we have developed a comprehensive phase characterisation workflow that is implemented whenever a new crystalline phase is discovered. This rigorous workflow will ultimately determine the impact of this new phase to either API or drug product processes. We feel this is an absolutely critical attribute.

Questions Every Development Program Should Address • Which salt/polymorph should be selected for further development?

• What is the most stable API phase at processing (Organic and formulation) and storage conditions?

• Will API phase have adequate solubility and exposure?

• Are there chemical or physical stability concerns of chosen phase in either API or drug product?

• Can particle attributes be controlled?

• Is API process robust and scalable with respect to physical attributes?

• Is the phase map for the chosen API phase fully understood?

• What particle attributes (size, shape, surface area, etc.) are critical to process and drug product performance?

• Is there sensitivity of the drug product process to raw material attributes?

What Crystal Pharmatech Provides to Answer These Questions: • Guidance in choosing the appropriate API phase.

• Understanding the kinetic and thermodynamic stability of your phase of choice at processing and storage conditions.

• Providing a full thermodynamic phase stability map around the desired API phase.

• Complete understanding of particle attributes.

• Understanding how morphology can be changed and controlled.

• Guiding choice of solvents and temperatures to optimise yield and productivity.

• Detecting and quantifying undesired solid phase for API quality assurance.

• Investigation of intermediates crystallisation to improve process.

• Designing optimal crystallisation for chiral ee upgrades.

• Ensuring impurity rejection in the chosen crystallisation solvents.

• Supporting small-scale dry milling assessment with

respect to particle size and amorphous generation.

• Providing physiochemical data for regulatory dossier submission.

• Developing, validating, and transferring any physiochemical method used for specification setting.

Crystal Pharmatech—A Truly CustomerOriented Problem Solving CRO At Crystal Pharmatech, our most important objective is to provide satisfactory solutions to our customers. In addition to typical transactional or preferred provider models, we also offer integrated partnership opportunities for all solid state research projects (both API and formulation) at any stage of development (preclinical to supply). Whether you are looking for project based service or long term partnership, we have the right collaboration model for you to suit your needs in solid state research.

Our differentiating feature is the minimal need of oversight from the customers. We can work directly with chemists and engineers to guide processes and make decisions with minimal oversight from the client.

We include all data interpretation and relevancy to processes from an expert’s eyes.

An evolutionary step in collaboration is Crystal Pharmatech's proposed ‘integrated partnership’ that allows for seamless integration of the CRO into company workflows. We can fully follow our client’s SOP's, essentially acting as a true flexible resource for your company. This model is ideal for large companies with significant work in the foreseeable future needing support from a CRO. This model is also ideal for small to middle-sized companies that would like a dedicated partner to handle all of their solid state research needs for the entire company. Think of us as part of your company.

We believe our integrated partnership model offers the highest degree of efficiency and productivity, while minimising oversight, all at a significant cost savings compared to a transaction or preferred vendor model.

In summary, Crystal Pharmatech offers high-quality data, fast turnaround and cost-effective services.

We offer a full range of services from being the solid state support arm of your company to consultation on a specific issue. We hope you consider us as your ideal partner and we will tailor our business to your specific needs.

To find out more about how we can solve your solid state pharmaceutical issues contact us at contact@crystalpharmatech.com.

Advertorial www.pharmafocusasia.com

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Section

Books

Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing Authors: David J. am Ende No of Pages: 887 Year of Publishing: 2010 Description: This book deals with various unique elements in the drug development process within chemical engineering science and pharmaceutical R&D. This book is intended to provide many of those important concepts that R&D Engineers and manufacturing Engineers should know and be familiar if they are going to be successful in the Pharmaceutical Industry. These include basic analytics for quantitation of reaction components– often skipped in ChE Reaction Engineering and kinetics books. In addition Chemical Engineering in the Pharmaceutical Industry introduces contemporary methods of data analysis for kinetic modeling and extends these concepts into Quality by Design strategies for regulatory filings.

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Pharmaceutical and Biomedical Project Management in a Changing Global Environment Authors: Scott D. Babler No of Pages: 400 Year of Publishing: 2010 Description: Pharmaceutical and Biomedical Portfolio Management in a Changing Global Environment explores some of the critical forces at work today in the complex endeavour of pharmaceutical and medical product development.

Written by experienced professionals, and including real-world approaches and best practice examples, this new title addresses three key areas – small molecules, large molecules, and medical devices - and provides hard-to-find, consolidated information relevant to and needed by pharmaceutical, biotech, and medical device company managers. .

Outstanding Biopharma R&D to India: A Practical Guide Authors: Probir Roy Chowdhury No of Pages: 220 Year of Publishing: 2011 Description: The trend of outsourcing to India for research and development is catching on fast, which led to several multinational companies opening up production plants in India, primarily due to the globalization of the Indian economy and offshoring jobs to India. Alongside, several global pharma-biotech majors ascertained large market requirements within the country and capitalized the advantage of serving Indian customers.

Strategies were devised to optimize operational expenses with the setting up of on-site R&D to develop products for local requirements. In view of this, this book seeks to explore various nuances of the outsourcing sector with respect to biopharma in India. This book constitutes the first ever comprehensive insight on the Indian biopharma sector. The author provides a perspective based on practical hands-on legal experience.

The book is simply structured, clearly presented and free from excessive legal jargon * A clear understanding of the market is provided.

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The Agile Approach to Adaptive Research: Optimizing Efficiency in Clinical Development Authors: Michael J. Rosenberg, Sean Ekins No of Pages: 274 Year of Publishing: 2010 Description: Apply adaptive research to improve results in drug development The pharmaceutical industry today faces a deepening crisis: inefficiency in its core business, the development of new drugs. The Agile Approach to Adaptive Research offers a solution. It outlines how adaptive research, using already-available tools and techniques, can enable the industry to streamline clinical trials and reach decision points faster and more efficiently.

With a wealth of real-world cases and examples, author Michael Rosenberg gives readers a practical overview of drug development, the problems inherent in current practices, and the advantages of adaptive research technology and methods. He explains the concepts, principles, and specific techniques of adaptive research, and demonstrates why it is an essential evolutionary step toward improving drug research and development.

Drug Safety Data: How to Analyze, Summarize, and Interpret to Determine Risk

Knowledge Accumulation and Industry Evolution: The Case of Pharma-Biotech

Authors: Michael J. Klepper, Barton Cobert No of Pages: 316 Year of Publishing: 2010 Description: Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Was Selected For The First Clinical Research Bookshelf - Essential Reading For Clinical Research Professionals By The Journal Of Clinical Research Best Practices. Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Provides Drug Safety/Pharmacovogilance Professionals, Pharmaceutical And Clinical Research Scientists, Statisticians, Programmers, Medical Writers, And Technicians With An Accessible, Practical Framework For The Analysis, Summary And Interpretation Of Drug Safety Data.

The Only Guide Of Its Kind, Drug Safety Data: How To Analyze, Summarize And Interpret To Determine Risk Is An Invaluable Reference For Pre- And PostMarketing Risk Assessment.

Authors: Mariana Mazzucato, Giovanni Dosi No of Pages: 468 Year of Publishing: 2010 Description: Written by internationally acclaimed experts in the economics of innovation, this volume examines how the biotechnology and pharmaceutical sector is affected by the dynamics of innovation, institutions, and public policy. It contributes both theoretically and empirically to the increasingly influential Schumpetarian framework in industrial economics, which places innovation at the centre of the analysis of competition. Both quantitative and qualitative studies are included, and this varied perspective adds to the richness of the volume's insights. The contributors explore different ideas regarding the historical evolution of technology in the sector, and how firms and industry structure have co-evolved with innovation dynamics. Important policy questions are considered regarding the future of innovation in this sector and its impact on the economy.

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News Amgen and UCBs’ AMG 785/CDP7851 Successfully Passes Phase II Amgen and UCB announced that Phase 2 clinical study comparing sclerostin-antibody AMG 785/CDP7851 to placebo in postmenopausal women with low bone mineral density (BMD) for the treatment of postmenopausal osteoporosis (PMO) has shown its positive top-line results.

The study shows that there is a significant increase in lumbar spine bone mineral density at month 12 for the AMG 785/ CDP7851 active arms when compared with the placebo arm and the study also compared AMG 785/CDP7851 positively with the two active comparators, teriparatide and alendronate.

The study enrolled 400 postmenopausal women with low BMD (T-scores between -2.0 and -3.5) to see the effect of AMG 785/CDP7851 compared to placebo in women with low BMD, and to characterize the safety and tolerability of AMG 785/CDP7851.

AMG 785/CDP7851 is a humanized monoclonal antibody that binds to and inhibits sclerostin, a protein secreted by bone cells that inhibits bone formation. By binding to and blocking sclerostin, AMG 785/ CDP7851 is designed to allow the body to add more bone to the skeleton.

AMG 785/CDP7851 treats bone-related conditions, including PMO and fracture healing.

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small molecule, will serve the people with BRAF V600 mutationpositive metastatic melanoma, the deadliest and most aggressive form of skin cancer. Vemurafenib is being co-developed under a 2006 license and collaboration agreement between Roche/Genentech and Plexxikon.

The cobas 4800 BRAF V600 Mutation Test, being developed by Roche, will diagnose people whose tumours carry the BRAF V600 mutation. A Premarket Approval Application for the test was submitted in the US and will also be registered in Europe.

Roche submits Applications in US Mochida Receives and Europe for Japanese MHLW Vemurafenib Inhibitor Approval for Lexapro and Mutation Test for Advanced Skin Cancer Patients Roche has submitted a New Drug Application to the US Food and Drug Administration (FDA) and a Marketing Authorization Application to the European Medicines Agency (EMA) for vemurafenib (RG7204, PLX4032).

Roche also submitted an application for the cobas 4800 BRAF V600 Mutation Test.

Vemurafenib, a “BRAFinhibitor,” an investigational, oral,

H. Lundbeck A/S announced that its partner Mochida Pharmaceutical Co., Ltd. has obtained approval of Lexapro® 10 mg (escitalopram) from the Japanese Ministry of Health, Labour and Welfare (MHLW).

Lexapro® will serve patients suffering from depression.

Mochida and Mitsubishi Tanabe Pharma Corporation will co-promote the product with Yoshitomiyakuhin Corporation, a subsidiary of Mitsubishi Tanabe.

The schedule for the launch of Lexapro® will be announced after its National Health Insurance price listing.

Section

Events Aug 28 - Sep 1, 2011

ISN-ESN 2011 Biennial Meeting May 10 - May 12, 2011

International Pharmaceutical Exhibition Charlotte Convention Center, Charlotte, United States Of America Arosa Exhibitions Limited May 18 - May 19, 2011

6th Annual European Biomarkers Summit London, England Select Biosciences Jun 1, 2011

Biosimilars: Drugs for Life

Hotel Shivalik View, Chandigarh, India Jun 1 - Jun 2, 2011

Megaron Athens International Conference Centre , Athens, Attica, Greece International Society of Neuroscience Sep 18 - Sep 22, 2011

2nd World Conference on Physico Chemical Methods in Drug Discovery and Development Falkensteiner Hotel Borik, Zadar, Croatia Inernational Association of Physical Chemists Sep 27 - Sep 30, 2011

Pharmaceutical Cold Chain Management & Good Distribution Practice Berlin, Germany PDA Europe

Clinical Trial Supply West Coast USA Conference

Oct 10 - Oct 12, 2011

San Francisco, USA VIBpharma

Congress Center Basel , Basel, Switzerland DIA Europe

Jun 6 - Jun 8, 2011

Oct 18 - Oct 21, 2011

5th Annual Clinical Forum 2011

4th Monoclonal Antibodies Workshop

7th Annual SCM Logistics World 2011

Basel, Switzerland PDA Europe

Singapore Terrapinn Pte Ltd

Jun 7 - Jun 9, 2011

Oct 25 - Oct 27, 2011

Pharma Manufacturing Summit 2011

CPhI Worldwide 2011

The Intercontinental, Vienna, Austria NGP

Messe Frankfurt, Germany UBM Live

Jun 20 - Jun 21, 2011

Nov 7 - Nov 10, 2011

Global Pharma Manufacturing Summit 2011

Sheraton Meadowlands Hotel & Conference Center, New Jersey, USA World Trade Group Jun 26 - Jun 29, 2011

The Manufacturing Show Asia 2011 Singapore Terrapinn Pte Ltd Jul 5 - Jul 6, 2011

Pharmacovigilance China 2011

Renaissance Beijing Capital Hotel, Beijing, China IQPC Jul 11 - Jul 13, 2011

Ubiquitin Drug Discovery & Diagnostics 2011 The Four Seasons Hotel, Philadelphia, Pennsylvania, USA VLI Research, Inc

The Universe of Pre-filled Syringes and Injection Devices Basel, Switzerland PDA Europe

Nov 29 - Dec 1, 2011

10th Annual World Drug Manufacturing Summit 2011 Berlin, Germany World Trade Group Nov 30 - Dec 2, 2011

CPhI India 2011

Bombay Exhibition Centre, Mumbai, India UBM Live Dec 6 - Dec 8, 2011

9th BioPharma India Convention 2011 Mumbai, India

Terrapinn Pte Ltd

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Products&Services

Section Company........................................... Page no.

STRATEGY Brevetti Angela....................................................45 Crystal Pharmatech Co Ltd.................................10 MB Sugars & Pharmaceuticals Limited..............23 NextGen..............................................................47 Emirates.......................................................... OBC UBM India Pvt Ltd.............................................IBC CLINICAL TRIALS Crystal Pharmatech Co Ltd.................................10 RESEARCH & DEVELOPMENT Crystal Pharmatech Co Ltd.................................10 Lotus Labs Pvt Ltd..............................................39 MB Sugars & Pharmaceuticals Limited..............23 MANUFACTURING Brevetti Angela....................................................45 MB Sugars & Pharmaceuticals Limited..............23 Catalent...................................................... 13 & 15 UPM Raflatac.................................................... IFC

SuppliersGuide

INFORMATION TECHNOLOGY Airtel....................................................................05 NextGen..............................................................47

Company...........................................Page no.

Airtel................................................................... 05 www.airtel.in/mpls Brevetti Angela................................................... 45 www.brevettiangela.com Crystal Pharmatech Co Ltd................................ 10 www.crystalpharmatech.com Lotus Labs Pvt Ltd............................................. 39 www.lotuslabs.com MB Sugars & Pharmaceuticals Limited............. 23 www.mbsugars.com NextGen............................................................. 47 www.ngpharmasummit.asia Emirates..........................................................OBC www.skycargo.com Catalent...................................................... 13 & 15 www.catalent.com UBM India Pvt Ltd............................................ IBC www.cphi-india.com UPM Raflatac....................................................IFC www.upmraflatac.com To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link.

1.IFC: Inside Front Cover 2.IBC: Inside Back Cover 3.OBC: Outside Back Cover

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