Journal for Clinical Studiesdracohealthcare.com/uploads/JCS_March_09_Interview... · By Russel Neal of Clinical Network Services (CNS) Pty. Ltd. ... 45 Interview with Charles River

JOURNAL FOR

Your Resource for Multisite Studies & Emerging MarketsCLINICAL STUDIESU

March 2009

Cognition andInfectious DiseasesCognitive testing to investigate

which cognitive domains are affected

Outsourcing Pre-Clinical

Drug Discovery

Current Efforts to Improve The ClinicalTrial Process and Treatment in Stroke

www.jforcs.com

IsraelA Solid Track Record in Clinical Research

KEYNOTE AdvisOr

Dr. Patricia Lobo, PhD

MANAGiNG dirECTOr

Martin Wright

PUBLisHEr

Mark Barker

MANAGiNG EdiTOr

Jake Tong

EdiTOriAL COOrdiNATOr

Janet Douglas

EdiTOriAL AssisTANTs

Nick Love, Kevin Cross, Lanny McEnzie

dEsiGN dirECTOr

Sureka Dharuman

rEsEArCH & CirCULATiON MANAGEr

Dorothy Brooks

AdvErTisiNG sALEs

Peter Campbell, Zareen Monet

AdMiNisTrATOr

Barbara Lasco

FrONT COvEr

Inhouse – Design

PUBLisHEd BY:

Pharma Publications www.pharmapubs.comAddress: Diamond Key Building, Unit 4, Burwell Industrial Estate, Burwell Road, London E10 7QG, Tel: 0044(0)2085917584. Fax: 0014802475316. Email all correspondence to: [email protected]

Journal for Clinical Studies – ISSN 1758-5678 ispublished bi - monthly by PHARMAPUBS.

The opinions and views expressed by the authors inthis journal are not necessarily those of the Publisher,the Consultant Editor and the companies namedherein are not responsible for such opinions andviews, or for any inaccuracies in the articles. The entire content of this publication is protected bycopyright, No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form, by any means – electronic,mechanical, photocopying or otherwise – withoutthe prior permission of the Publisher.

2009 PHARMA PUBLICATIONS

JCS 1www.jforcs.com2 JCS www.jforcs.com

6 EDITORIAL ADVISOR KEYNOTE

WATCH PAGES

8 FDA WATCH Latest Developments in: FDA Enforcement Politics Health Care Reform Deptartment of Health and Human Services Update R&D IRBs By Joe Pickett of EXPERTBRIEFINGS

10 US FDA-Required Clinical Trials Databases The Food and Drug Administration Amendments Act of 2007 (FDAAA) signed into law in September 2007 provides for the implementation of Title VIII—Clinical Trial Databases (Title VIII).1 Title VIII requires the National Institutes of Health (NIH) to establish and administer an expanded registry database of clinical trials in progress and a new separate database for clinical trial results. By Jane S. Ricciuti of THOMSON REUTERS

12 Drug Development in China Provisions for the Administration of Special Evaluation and Approval for the Registration of New Drugs. By Dr. Xunting Zeng of INCROM CHINA

14 Serious Adverse Event Reporting in Latin America: Confusing Regulations Which serious adverse events should be reported by the researcher to the ethics committees and when, in order to comply with current regulations in different Latin American countries and the international regulations? By Ezequiel Klimovsky, Clinical Trials Field Investigator and Evaluator at ANMAT, ARGENTINEAN REGULATORY AUTHORITY (1999 – 2003)

16 The Audacity of Hope and Clinical Trials in Africa Recently the recognition of the value of investing in health research has been gaining ground on this continent, not just among healthcare workers and groups like the World Health Organization, but also among African leaders at the national and pan-African levels. There is a clearly evolving interest in building clinical research enterprises based in Africa and ad dressed to African needs. By Francis P. Crawley of the GCP ALLIANCE (GCPA)

Contents

2 JCS www.jforcs.com

18 Australasia Watch This first Australasia Watch starts off by highlighting both Australia and New Zealand as real options for developers. Australasia cannot really be described as an emerging market having been considered a tier 1 region for phase IIb-IV studies for many years. However, with the advent of the European Directive in the mid 1990’s, Australian and New Zealand have now also emerged as first class early phase providers demonstrating great expertise and breadth of services through those critical early development steps. By Russel Neal of Clinical Network Services (CNS) Pty. Ltd.

20 Determination of shelf life and storage condition of IMPs. Dealing with temperature deviations during transport or storage at CROs Clinical samples manufactured in the EU are to be labelled with the required storage condition in accordance with Annex 13 to the EC-GMP-Guideline. The current version of CPMP guideline CPMP/QWP/609/96”Declaration of storage conditions” is a useful tool for the determination of the storage condition and its declaration for Investigational Medicinal Products (IMP). By Dr. Claudio Lorck of Temmler AG.

REGULATORY

22 “Ethics Approval for Clinical Studies: Challenging Times” This commentary by Dr. Yap Kok Wei, of Gleneagles CRC is restricted only to one specific aspect of the processes i.e., getting an approval from the local Ethics Committee (EC) or the Independent Review Board (IRB) for clinical studies and to address the challenges we faced at the various hospital sites in the Asia Pacific rim countries. Does compliance as stated in the submission guidelines in the different countries gets you the approval?

24 Some Language Aspects of Clinical Trials in India With more and more clinical trials being held outside Western Europe and North America, the language issue has become a hot item. International trials increasingly include clinics and other study centres in countries in Latin America, Africa, and Asia, and as a result language-related problems have multiplied. Simon Adriensen of Medilingua specifically discusses India as an example of a linguistic challenge in this article.

MARKET EVALUATION

28 Israel - A Solid Track Record in Clinical Research

Clinical research on behalf of international mainly European drugcompanies has been conducted in Israel since the mid 1970's. However, as a result of the harmonization process, numerous multinational drug companies established R&D centres in Israel andplaced an increasing portion of their clinical research in Israeli institutions. In addition, many global contract research organizations(CROs) have followed suit and have been enjoying impressive growthrates ever since. Dr. Heschi Rothmensch of CATO Research Israel takesyou on a complete tour of the Clinical Trial Landsacape in Israel.

Contents


31 A Hitch-hiker’s Guide to Searching for a GoodQuality Central LaboratoryMore often than not, the efficacy end point of multi-million-dollar trials is based on laboratory data.People always talk about the importance of obtaining good quality laboratory data. Unfortunately when it comes to finding a good quality central laboratory, one may be a little lost.Stanley Tam of CRL Medinet answers the big question of where and how to begin.

35 Clinical Trials in Russia: Year 2008The Federal Service on Surveillance in Healthcare andSocial Development of the Russian Federation (aliasRosZdravNadzor, RZN) approved 615 new clinical trials of all types including local and bioequivalencestudies during 2008; demonstrating a 9% increaseover last year. Igor Stefanov of Synrg Research Groupanalyses the Russian Marketplace.

39 India: The Road to SuccessThe Indian pharmaceutical industry now representsnearly 1.5 percent of India’s gross domestic product,and the market—is growing at a compound annualgrowth rate (CAGR) of 13.5 percent. In addition,India hosts the most FDA-inspected and approved manufacturing facilities, and has filed more Drug Master Files than any other country besides theUnited States. Dr. Ferzaan N. Engineer and EddieCaffrey of Quintiles looks at the opportunities inIndiaabout the future of its preclinical operation in China.

PRECLINICAL

42 Outsourcing Pre-Clinical Drug DiscoveryIt has been estimated that Western pharma companies could save 50% of their R&D budgets byoutsourcing activity to low-cost, high-skills regions ofthe world. The surprise is not that outsourcing has increased but that the increase has been modest andpharma companies still outsource only a small percentage of their R&D work. Dr Philip Huxley ofGateway Pharma argues that cultural factors havedetermined the pace of change and discusses thenature of the science-based culture which has madethe introduction of outsourcing strategies particularlydifficult in pre-clinical drug discovery.

45 Interview with Charles RiverDr. Linda Zao – President of Draco Healthcare &Member of the JCS Editorial Advisory Board talkswith Dr. Kewen Jin – General Manager of CharlesRiver China about the future of its preclinical operation in China.

THERAPEUTIC STUDIES

48 Cognition and Infectious DiseasesInfectious diseases can induce cognitive impairments which are an additional burden for thealready debilitated patient. Cognitive assessmentscan help to investigate which cognitive domains areaffected. In addition, drugs against infectious diseases can have neuropsychological side-effects.Cognitive testing should be used early on in clinicaltrials to minimise undesirable cognitive side-effectsof potential compounds. Lars Schmiedeberg of CDRLtd gives an overview of cognitive impairments inmajor infectious diseases and the cognitive side-effects of treatment against them.

52 Current Efforts to Improve the Clinical TrialProcess and Treatment in StrokeThe biopharmaceutical industry has consistentlymade large investments in improving outcomes forischemic stroke, but has only seen limited success.The industry has conducted clinical trials in large heterogeneous patient groups at widely varyingtimes following onset of symptoms, but only acutetherapy within the first few hours with revascularisation therapy has continued to demonstrate a positive clinical effect. James Vornovof Parexel explains the current state of global effortsaimed at improving stroke treatment.

IT & LOGISTICS

56 How the remotest locations are leveraging theInternet and embracing EDC technology to connect to the global clinical research community – Part II: A Case Study. By Mark Wren, Maria Sumner & Rob Nichols ofPhase Forward

60 Powering Post-Marketing Studies with Electronic Data Capture Pre-approval clinical trials conducted on pharmaceutical, biotech, device and diagnostic products are designed for the purpose of testing the safety and efficacy of the treatment before it reaches the public. The types of information that can ensure a successful launch, in-market brand management and long-term product growth often require comprehensive market intelligence that is not the purview of submission-based clinical testing. Patrick Chassaigne of Medidata Solutions explains how EDC can help address some of the challenges of late phase studies

Contents

Patricia Lobo, Managing Director &Senior Consultant, Life Science Business ConsultingI’m delighted and honoured to be invited to join the Editorial AdvisoryBoard of JCS.

We have some interesting articles inthis issue covering drug development andclinical research in China, India, Israel, Russia, Australia and New Zealand,as well as other articles such as cold chainlogistics, IT, distribution and logistics ofmedicines to remote parts of the world,

and outsourcing pre-clinical discovery. In this Spring issue there is an article by James Vornor of Parexel, who

reviews the current state of global efforts to improve stroke treatment(page 52 - 55). Every year an estimated 150,000 people in the UK have astroke. Of all people who suffer from a stroke, about a third are likely to diewithin the first 10 days, about a third are likely to make a recovery withinone month and about a third are likely to be left disabled and needing rehabilitation. Stroke has a greater disability impact than any other medical condition. A quarter of a million people are living with long-termdisability as a result of stroke in the UK.

Stroke in low-to middle income countries has doubled in 40 years according to a recent article published in The Lancet Neurology (Feb 2009).New figures show that stroke mortality rates and burden vary greatly bycountry and between regions, with low-income countries being the mostaffected. However, known risk factors for stroke, including diabetes and alcohol consumption, are poor predictors of national stroke mortality andburden and do not explain the greater burden in low-income countries.These are the conclusions of an article to be published online first and inthe April edition of The Lancet Neurology, and presented at the

International Stroke Conference in San Diego, by S Claiborne Johnstonfrom the University of California, San Francisco, which coordinated thestudy with the World Health Organization (WHO).

A second study shows that, over the past forty years, the incidence ofstroke in low-to-middle income countries has increased by more than100%, and people living in these countries face a 20% greater risk ofstroke than those living in high-income countries, where the incidence ofstroke has declined by 42%. These are some of the main findings of a Review by Valery Feigin from the National Research Centre for Stroke inNew Zealand and international colleagues, published Online First and inthe April edition of The Lancet Neurology.

Currently stroke is the number two killer in the world and if the numberof incidents in developing countries continues to rise at the same rate, itwill be number one within 20 years.

In the UK, ACT F.A.S.T. (recognizing signs in Face, Arms, Speech andTime to call the emergency services) is a new national Government campaign aimed at helping people to recognize the signs of stroke, andto act to save the lives and reduce the damage caused.

Meanwhile, Scientists have developed a tiny scaffold of stem cells tofill holes in the brain caused by stroke damage. So far tested in rats, thebiodegradable balls loaded with stem cells were able to replace brain tissuein damaged areas within a week. The team, who report the results in Biomaterials, are now planning to add in a protein to encourage new bloodvessel growth in the treated areas. But there is still a long way to go in stemcell therapy for stroke survivors. Previous research in injecting stem cellsinto rats with stroke damage has had some success but, because they lackstructural support, the cells end up migrating into surrounding healthy tissue, the researchers said.

Enjoy our March issue of JCS and I look forward to meeting you at theDIA Spring 2009 in Berlin.


Editorial Advisor Keynote

Editorial Advisory Board

Art Gertel, VP, Clinical Services, Regulatory & Medical writing,Beardsworth Consulting Group Inc.

Bakhyt Sarymsakova - Head of Department of InternationalCooperation, National Research Center of MCH, Astana,Kazakhstan

Catherine Lund, Vice Chairman, OnQ Consulting

Chris Tierney, Business Development Manager, EMEA Busi-ness Development, DHL Exel Supply Chain, DHL Global

Chris Tait, Life Science Account Manager, CHUBB InsuranceCompany of Europe

Devrim Dogan–Guner, Medical Director, ENCORIUM

Francis Crawley. Executive Director of the Good Clinical Prac-tice Alliance – Europe (GCPA) and a World Health Organiza-tion (WHO) Expert in ethics

Georg Mathis Founder and Managing Director Appletree AG

Ghassan Ahmed, Vice President, Medical & Regulatory Af-fairs, ClinArt International

Hermann Schulz, MD, CEO, INTERLAB central lab services –worldwide GmbH

Janet Jones, Senior Director, Strategic Patient Access, KENDLE

Jerry Boxall, Managing Director, ACM Pivotal.

Jeffrey W. Sherman, Chief Medical Officer and Senior VicePresident, IDM Pharma. Board Member of the Drug Informa-tion Association.

Kamal Shahani, Managing Director of Cliniminds - Unit ofTeneth Health Edutech Pvt. Ltd.

Karl M Eckl, Co-founder, Executive and Medical Director,InnoPhaR Innovative Pharma Research Eastern Europe GmbH

Linda Zao, President and CEO, Draco Healthcare ConsultingLLC.

Liz Moench, President and CEO of Medici Global

Mark Boult, Healthcare Market Sector Leader, DNV

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Maha Al-Farhan, Vice President, ClinArt International, Chairof the GCC Chapter of the ACRP

Nermeen Varawala, President and CEO, ECCRO - the panEmerging Country Contract Research Organisation.

Patricia Lobo, MSc. PhD. Managing Director & Senior Consultant, Life Science Business Consulting.

Peggy A. Farley, President and Chief Executive Officer of Ascent Capital Management Inc.

Russell Neal, COO, Clinical Network Services (CNS) Pty. Ltd.

Rob Nichols, Director of Commercial Development, PHASEForward

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Stefan Astrom, Founder and CEO, Astrom Research International

Steve Heath, Head of EMEA - Medidata Solutions, Inc

T S Jaishankar, Managing Director, QUEST Life Sciences

I am Karl M. Eckl,

In 2000, we specialised in the type of Phase I and IIa Clinical Studies which

are critical and often delay clinical development because of difficult recruitment

conditions. These studies are:

• PK studies in the target population (e.g. Oncology Patients)

• PK studies in patient populations used as pharmacological models like patients

with renal and hepatic impairment

• Proof of Concept studies in the target population (phase IIa) to speed up

strategic decisions in clinical development of new medicinal products

Why are these studies so difficult to perform? • No therapeutic benefit for patients increase reluctance to participate in such a

study.Therefore it is necessary to have a panel of such patients whenever possible.

• Reproducible boundary conditions are difficult to achieve in normal hospital

settings. Therefore our own clinical sites are exclusively used for clinical research.

I set up INNOPHAR to provide you with: • Patient populations which are the most critical ones to recruit for phase I and

IIa studies (e.g. renal or hepatic impaired or oncology patients)

• High quality services of our own clinical cites specifically tailored for these types

of clinical studies

• The service directly and not through any sub contractor

• Own patient panels, we perform these studies frequently

• Expertise, as phase I and IIa studies in these types of patients are our core business

• We recruit patients in huge polyclinics which cover patient data from 50,000 pa-

Our expertise lies in: Cardiovascular CNS (including psychiatry)EndocrinologyInfection diseaseAsthma and pulmonologyOncologyLiver disease (alcohol and toxic cirrhosis and hepatitis B and C)Kidney disease (nephrology and urology)GastroenterologyPostmenopausal womenElderly populationGynaecologyRheumatoide arthritis Male and female healthy subjects HaematologyOphtalmologyPain patientsSurgery and neurosurgery

INNOPHAR GmbH Innovative Pharma Research Eggersberg 4A. D-94375 Stallwang. Germany

Tel: +49 (0) 9964 6010216Fax: +49 (0) 9964 6010217

E-Mail: [email protected]

HELLO

Dr. Karl M. Eckl Managing DirectorINNOPHAR GmbH

Advertisement

Publisher’s Note:Correction to article published in JCS January 2009 Issue 3, page42. Social and cultural environment: line 5: …should read "culture and its result-driven expectations. In Fig. 3, last line "Length and trial" should read "Length of trial".

FDA ENFORCEMENTKV Pharma in consent decree with FDAKV Pharmaceutical Co on March 2 entered into a consent decree with UShealth regulators that would allow the company to resume manufacturing and marketing of its products, Reuters reported. The company had stopped making and marketing of all its products in January on recurring manufacturing issues of oversized tablets and said itwould cut 700 jobs last month. KV Pharmaceuticals, a maker of women'shealthcare products and pharmaceutical ingredients, said it would not marketits products until it satisfied certain measures mentioned by the regulators inthe decree. The measures are designed to demonstrate compliance with theUS Food and Drug Administration's current good manufacturing practices.

For more information, please visit: http://uk.reuters.com

POLITICSDrugmaker money to Utah senator's charity escaped disclosureThe pharmaceutical industry that long has benefited from Senator OrrinHatch´s (R-UT) legislative efforts has directed large sums of money to a charity he helped found - and still raises money for - while also hiring the Republican lawmaker's son as a lobbyist, The Washington Times reported onMarch 2.

For more information, please visit: http://washingtontimes.com

HEALTHCARE REFORMWhich healthcare companies could benefit from Obama’s governmenthealthcare plan?President Obama seems to be swiftly acting on US healthcare reform. In February, his $3.1 trillion budget proposed to establish a reserve fund in excessof $630 billion over 10 years to finance fundamental reform of the healthcaresystem. The reform seeks to bring down healthcare costs and expand coverage.

The healthcare reform is likely to provide healthcare insurance coveragefor some 46 million uninsured Americans (15% of the total population). Thereform, in all probability, is likely to expand the revenue basket for providersof medical products and services, including pharmaceutical companies. In addition, this is likely to provide substantial opportunities for life insurers inthe US. As a result, the life insurance industry’s revenue pie is expected to goup from 46.6% of the total insurance industry in 2007 to 48% by 2012.

Does this paint a rosy picture for players throughout the length andbreadth of the value chain? If you say yes, then think again.

The Obama program also calls for significant cost reductions, which wouldadversely affect the branded pharmaceutical industry in terms of both discounted pricing and contracted use of branded drugs.

Change in Medicare Part D is likely to become the key issue for the brandedpharmaceutical industry.

President Obama and congressional Democrats favour changing the programme to allow or possibly require direct government negotiations withdrug manufacturers, which is expected to sharply lower the programme's cost.Another likely money-saving tactic will be greater use of inexpensive genericsthrough new incentives.

These changes are likely to favourably impact companies such as Abbott Laboratories and Johnson & Johnson. These companies seem to bewell-positioned in growing pharmaceutical, device, and consumer healthcaremarkets. In the domestic pure play pharma segment, Bristol-Myers and Schering-Plough are likely to benefit as compared to their peers.

For more information, please go to: http://www.istockanalyst.com

DEPARTMENT OF HEALTH & HUMAN SERVICES UPDATEObama picks Kansas Governor Sibelius for HHS SecretaryPresident Barack Obama has asked Kansas Gov. Kathleen Sebelius to join hiscabinet as secretary of the US Department of Health and Human Services(HHS), and Sebelius has agreed to serve, according to major news sources reported by Medscape.com on March 2.

The President is expected to formally announce the appointment tomorrow. If she receives Senate approval, as expected, Sebelius, a formerstate insurance commissioner, would be in charge of implementing Obama's ambitious plans for overhaul of the nation's healthcare system.Obama's first choice for the post, former Senate Majority Leader Tom Daschle(D-S. Dakota), withdrew from consideration after reports surfaced that he hadfailed to pay back taxes and interest on $146,000 in income. Daschle is reportedly one of the few national leaders with a strong understanding ofboth the intricacies of the US healthcare system and the intrigues of the political process.

For more information, please go to: http://www.medscape.com

R&DGenentech may produce as many as 15 new drugs by 2015Genentech, fighting a hostile bid from majority owner Roche Holding AG, saidit may begin selling 15 new drugs from 2011 to 2015, Bloomberg.com reported on March 2.

Earnings excluding some items this year may be $3.85 a share, the SouthSan Francisco company said today in slides posted on its website. Genentechforecast an adjusted profit of $3.55 to $3.90 on Jan. 15.

Genentech said the company is worth at least $112 a share, or 29 percentmore than Roche’s $42.1 billion, $86.50-a-share bid, according to a Feb. 23regulatory filing. The company may introduce 24 new uses for existing medicines, including its top-selling cancer drug Avastin, from 2009 to 2011,according to documents posted on Genentech’s website today. The company,the second-largest maker of biotechnology drugs, held its annual businessbriefing for investors in New York on March 2.

For more information, please go to: http://www.bloomberg.com

IRBsMost IRBs in US don’t ban finder’s fees for clinical trialsThe American Medical Association, the American College of Physicians andothers have declared unethical the practice of paying doctors "finder's fees"for recruiting patients as clinical research subjects, amednews.com reportedon March 2. But only half of institutional review boards address in writing theconflict of interest these kinds of payment incentives pose, according to a survey of IRB policies at 117 medical schools that received National Institutesof Health research funding.

About a quarter of the IRB policies prohibit investigators from offeringfinder's fees to doctors or other health professionals, said the study in the January-February IRB: Ethics & Human Research, a journal published by theGarrison, N.Y.-based Hastings Center. Payments can range from $2,000 to$10,000 per patient enrolled in a clinical trial, according to published reports.

For more information, please go to: http://www.ama-assn.org


FDA WATCH

Joseph Pickett, Owner & PresidentExpertbriefings.com, a leading provider of regulatory teleconferences in clinical trials, pharmaceuticals, medical devices and biological products.For more information, please visit www.expertbriefings.com.Email: [email protected]

The Food and Drug Administration AmendmentsAct of 2007 (FDAAA), signed into law in September 2007, provides for the implementation of Title VIII—Clinical TrialDatabases (Title VIII).1 Title VIII requires the National Institutes of Health (NIH) to establishand administer an expanded registry databaseof clinical trials in progress and a new separatedatabase for clinical trial results. This increasesthe scope of the Department of Health andHuman Services’ (HHS) clinical trial databank(www.ClinicalTrials.gov) by expanding the clinical trial registry and requiring results be reported to the databank for certain clinical trialsof drugs, biologics, and devices regulated by theFood and Drug Administration (FDA). The purpose of Title VIII is to make publicly availableclinical trials in progress for public participation,and for the public to learn the results of certaintrials.

Key to the databank are its links to existingclinical trial results. The registry will also link toinformation if it is available through FDA

advisory committee documents, approval documents, and FDA assessment of the resultsif an applicable drug clinical trial was conductedunder section 505A or 505B of the Federal Food,Drug, and Cosmetic (FD&C) Act.

Title VIII of FDAAA requires that a certification accompany human drug, biological,and device product submissions made to theFDA. This provision went into effect on December 26, 2007 and requires the submitterto confirm that they have complied with all applicable requirements of Title VIII.2

At the time of submission of an applicationunder sections 505, 515, or 520(m) of the FD&CAct (21 U.S.C. 355, 360e, or 360j(m)), or undersection 351 of the PHS Act (21 U.S.C. 262), orsubmission of a report under section 510(k) ofthe FD&C Act (21 U.S.C. 360(k)), such application or submission must be accompaniedby a certification that all applicable requirementsof section 402(j) of the Public Health Service Acthave been met. For the Center of Devices andRadiological Health, premarket approval (PMA)

applications, humanitarian device exemption(HDE) applications, and premarket notifications(510(k)) require certification. Where available,such certification must include the appropriateNational Clinical Trial (NCT) numbers. Certification should be provided using Form FDA3674.3

To assist industry, on January 21, 2009 theFDA published the final Guidance for Sponsors,Industry, Researchers, Investigators, and Foodand Drug Administration Staff: Certifications ToAccompany Drug, Biological Product, and DeviceApplications/Submissions: Compliance with Section 402(j) of The Public Health Service Act,Added By Title VIII of The Food and Drug Administration Amendments Act of 2007.4

In September 2008 results informationbegan to be integrated into the clinical trialrecords (e.g., baseline characteristics, participantnumbers, outcomes data). It will not be requiredto submit adverse events data until September2009. Title VIII will be phased in over the threeyears since implementation in 2007, duringwhich time the FDA is instructed under the legislation to promulgate implementing regulations. In March 2009, the FDAAA requiresthat a public meeting is held to discuss implementation and to gather public feedback. ■


US FDA Required Clinical Trials Database

References:1. Food and Drug Administration Amendments Act of2007. Available at: http://www.fda.gov/oc/initiatives/advance/fdaaa.html2. Federal Register: December 12, 2007. Volume 72,Number 238, 70599-70601. 3. Form FDA 3674. Available at:http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3674_508.pdf 4. Federal Register: January 21, 2009. Volume 74, Number 12, 3614-3615.

Jane S. Ricciuti Jane S. Ricciuti has workedpreviously as a licensed pharmacist in acute care, oncology, and surgery. Currently, Jane Ricciuti isthe Director & Executive Edi-tor for the IDRAC UnitedStates (US) Module. Her responsibilities include managing the IDRAC database on all US regulations pertaining to drugs,biologics, and medical devices. Interactions with theFDA and product development are major areas ofresponsibilities. Email: [email protected].

Last time we presented a major introductionof the application process and time limit forthe registration of imported drugs. Application procedures shall include boththe application for clinical trial and the application for the registration of importeddrugs. On January 7, 2009, the SFDA promulgated the Provisions for the Administration of Special Evaluation and Approval for the Registration of New Drugsto encourage innovation and strengthen riskcontrol.

1. Scope of Special Evaluation and Approval:(1) Active ingredients and their preparations extracted from plant, animal, mineral and othermaterials which have not been marketed inChina, and newly-found medicinal materials andtheir preparations;(2) Chemical raw materials of medicines, as wellas the preparations and biological productsthereof, that have not been approved to be marketed at home and abroad;(3) New drugs treating AIDS, malignant tumours,rare diseases and other diseases with obviousadvantages of clinical treatment; and(4) New drugs treating diseases that cannot yetbe cured by effective means.

In the case of items (1) and (2) above, thedrug registration applicant may apply for a special evaluation and approval when submitting its application for the clinical trial ofnew drugs, and CDE shall confirm the application materials submitted by such an applicant within five working days.

In the case of items (3) and (4) above, theapplicant may not apply for special evaluationand approval until it submits the application forthe registration of imported drugs, and CDE shallorganise an expert meeting within 20 days fromreceipt of such an application. This meeting willdetermine whether to make a special evaluationand approval.

2. Advantages of Special Evaluation and Approval(1) Special channels are set up for preferentialevaluation and appraisal. The time limit for evaluation appraisal is about three-quarters ofthe time limit for the evaluation appraisal of ageneral application.(2) The applicant may, prior to the applicationfor registration, communicate with CDE on theapplication for special evaluation and approval and major technical issues, with reference to the judgment on its study results.The applicant may also, in the process of itstechnical evaluation and appraisal and clinicaltrial, communicate with CDE on the relevanttechnical issues, for certain assistance in the promotion of the study and the appraisal of results.(3) Supplementary data is allowed in respect ofan application for registration of new drugs forwhich the special evaluation and approval ismade.

Channels include: a) directly submitting thesupplementary materials for the issues discussedat the evaluation and appraisal meeting with the

applicant and experts, while holding such ameeting; b) the applicant may, after the exchange meeting proposed at its initiative, submit the supplementary materials for the issues discussed at such a meeting; c) submittingsupplementary materials for major security issues in a timely manner; d) supplementing materials under the normal registration procedure according to the Circular on Supplementing Materials; e) permitting the supplementation of materials to serve clinicalchanges, in order to improve the efficiency ofregistration; and f) extending the time for supplementing materials from four months forgeneral applications to eight months. ■


DRUG DEVELOPMENT INCHINAProvision for the Administration of SpecialEvaluation and Approval for the Registrationof New Drugs

Dr. Xunting ZengDr. Xunting Zeng has decadesof experience in the field ofClinical Trials. Dr. Zeng received his PhD at Kansai Medical University, Osaka,Japan, since then he worked as

Special Investigator at International Medical Centre ofJapan. Later he joined InCROM Group, a Japan basedleading international Contract Research Organization firm.Dr. Zeng is currently General Manager of InCROM Chinaand heading up to elevate China clinical trial with globalstandard. Email: [email protected]

Which serious adverse events should be reported by the researcher tothe ethics committees and when, in order to comply with current regulations in different Latin American countries and the international regulations?

Safety reporting to Independent Ethics Committees (IECs) and regulatory authorities is essential to the appropriate follow-up of the studydrug and the protection of participants.

According to international guidelines (ICH-GCPs), only Serious UnexpectedAdverse Drug Reactions (ADRs) should be promptly reported to the IEC andunexpected problems involving risks to subjects or others should be immedi-ately reported. There is no indication in these documents that all Serious Ad-verse Events (SAEs) occurring in a trial should be reported to the IEC or thatthey should be reported immediately.

In Peru, all SAEs should be reported immediately, both to the sponsor andthe IEC, and in Chile all SAEs should be reported to the IEC within five days; inMexico only those SAEs that are considered related to study product shouldbe reported. In all these three cases, requirements are stricter than those established by international guidelines. Beyond the differences with international guidelines, lack of detail is also observed, which hinders understanding and enforcement. For instance, no difference is made betweenAdverse Events (AEs) and SAEs in Brazilian Provision No. 346/05 or in the Mexican Regulations. According to these guidelines, the procedures to report to the EC a headache or to report an hepatic necrosis followed by deathwould be the same. Also confusing is the reference to Serious Unexpected Adverse Events in Argentinean Provision 1067/08. The problem is that thereis no definition of such a concept in this regulation or in the above-mentionedregulatory documentation.

All these regulations define Adverse Events, SAEs, and Unexpected Adverse Drug Reactions (ADRs), but no international guideline provides a definition of Unexpected SAE1 simply because an adverse event that is not related to the drug (and, therefore, is not an adverse drug reaction), shouldnot be evaluated on whether it is expected or unexpected, since the eventwould not appear in the drug package insert and it may not appear in the investigator's brochure. According to the US Code of Federal Regulations, "anyunanticipated problem" does not generally mean individual adverse eventsbut any other problem that may occur.2 Although seriousness is determinedby the researcher and causal relationship by both the researcher and the sponsor, the definition of expected or unexpected ADR is only determined bythe sponsor (Table 1, Guideline 5, Section 4.2.5). Therefore, it is impossible thatthe researcher can report a serious, unexpected ADR without previous evaluation by the sponsor.

Faster Reporting: More Protection of Subjects?To evaluate the benefit of a safety reporting guideline implies to considerwhether reporting contributes to subject protection. Many times, these guidelines, which may be confusing, inaccurate, or very strict, lead researchers and sponsors to adopt a "just-in-case" attitude, and they reportimmediately all SAEs, even when not required to do so, "in order not to haveproblems". Is this an appropriate behaviour? I have been there. I worked inregulatory affairs (1999-2002) and as Chair of an Ethic Committee

(2004-2006), and my experience indicates that too much reporting is not helpful for subjects because the EC cannot assess all individual SAEs (and all Serious, Unexpected Adverse Drug Reactions reported from all over the world) in due time and proper form. In March of2005, at a public hearing held by the FDA, many IECs reported difficulties inreviewing and interpreting the significance of information when large volumesof individual SAE reports are received.2 Many times we can´t see the forest forthe trees.

Some IEC members insist on the need to receive all SAEs in order to accurately evaluate drug safety. But is it useful for product evaluation by theIEC to learn that a study subject has been hospitalised, for instance, due to atraffic accident? These IEC members consider that, by receiving all SAEs, it maybe possible for them "to find ADRs that the sponsor cannot report". To thatend, an IEC should receive immediately all related or unrelated SAEs from theresearch site as well as all SAEs occurring around the world. And this is impossible, unmanageable, and clearly overlaps with sponsor responsibility.Only the pharmacosurveillance unit of the sponsor, which receives SAEs fromall over the world, has all the information required to perform such an analysis;therefore, it is responsible for ensuring that the study drug is harmless.

Similarly, CIOMS Working Group IV (Table 1) suggests replacing the currentpractice of sending large volumes of individual reports to the IEC. It explicitlyproposes that the routine expedited reporting to researchers and committeesshould be replaced by periodic updates of risk/benefit evaluations by the sponsor, although not complying with current guidelines, and that only newsignificant information that leads to changes in the study protocol or requiresimmediate changes to the consent documents should be reported immediately, which only occurs occasionally in the case of individual reports.

Until amendments or clarifications are made, we recommend full compliance with current guidelines. For guidelines that are not completely clear(as in the case of Argentina and Brazil), we recommend immediate reportingof serious, unexpected ADRs and periodic reporting of other SAEs. For furthersubject protection, it is regulatory authorities who may inspect sponsor pharmacovigilance units in order to check compliance with duty responsibilities. ■

This is an extract of an article included in a newsletter from FECICLA, a non-profit

organisation for ethics and quality in clinical research in Latin America. (www.fecicla.org)

www.jforcs.com

SERIOUS ADVERSE EVENT REPORTING IN LATIN AMERICA:CONFUSING REGULATIONS?

Ezequiel Klimovsky Ezequiel Klimovsky, Gynecologist; graduated from University of Buenos Airesin 1984 is Registered QA Professional-GCPs. (Society of Quality Assurance –USA -2007-10). He started his career in epidemiological and clinical research in 1989 focused on breast cancer. He attended an Internal Course organized by the BiMo Program at the FDA in 2002 and has been trained as aQMS Lead Auditor during 2003-04. He served from1999 to 2003 as Clinical Trials field investigator and

evaluator of clinical trials at ANMAT, Argentinean Regulatory Authority. He has beenmember and President of Salisbury Clinical Research Ethics Committee from 2002 to2006.

1. This term has recently begun to appear in FDA documents and in the WHO GCPs 2006, but no definition of its meaning has been provided. It also appears in the glossary of the ANMAT Provision No.5330/97.2. For more information on FDA opinion on this topic, please see: Draft Guidance Adverse Event Reporting – Improving Human Subject Protection http://www.fda.gov/ OHRMS/DOCKETS/98fr/07d-0106-gdl0001.pdf

On a recent trip from Brussels to a meetingof African experts on clinical trials at theUnited Nations Conference Centre in AddisAbaba, Ethiopia, I drove through early morning traffic along the boulevards of whatmany consider to be Africa’s capital city tothe UN enclave elevated above much of therest of the metropolis. The slow traffic produced long waits at the traffic lights, andthe familiar scene of the poor and handicapped begging and hawking goods tothe captive drivers. Most hands reaching intothe cracked windows were simply empty andin need of the next meal. Some offered tissues or bottles of water or soft drinksagainst the African sun.

One young boy – who should himself already have been behind his school bench thatmorning – had a book, in English, on offer: TheAudacity of Hope by Barack Obama. It seemedall-in-all a bit surreal, a bit beyond any sense ofthe real day-to-day lives surrounding those walking on broken sidewalks or crowded into worn-out combis on their way to their dailychores. So too might the idea of any serious engagement in clinical trials in Africa appear asbeing beyond any reasonable hope.

Many of the ethical and scientific issues thatchallenge clinical trials in other parts of the worldpale when confronted with the challenges of notonly developing state-of-the-art clinical trials inAfrica, but also setting into place a robust and progressive African clinical research enterprisethat includes African clinical research centres,African commercial pharmaceutical industry, andAfrican regulatory oversight.1 On a continent tornby decades of strife, corruption, and mismanage-ment, and where the vast majority of people areoccupied daily with struggles for water, energy,and the need to ensure some food on the table atthe end of the day, the enormous investment inhuman resources and capital required by clinicaltrials might appear an obscene luxury.

Nonetheless, recently the recognition of thevalue of investing in health research has beengaining ground on this continent, not justamong healthcare workers and groups like theWorld Health Organization, but also amongAfrican leaders at the national and pan-Africanlevels.2 There is a clearly evolving interest in

building clinical research enterprises based inAfrica and addressed to African needs.

The arguments for clinical trials on theAfrican continent are shifting from a defensive,protectionist position, toward openness andeven embracement. The threats of exploitationand misuse of populations for the benefits ofthose living on other continents, as a place to exercise protocols of interest only to foreign academics, or for pure economic misuse remainreal. At the same time, Africans recognise thattheir healthcare problems cannot be solved simply by receiving containers full of used hospital equipment or the development of foreign training programs or selective health insurance schemes. While all this helps and iseven needed in many places in the presentAfrican environment, many Africans and theirleaders are now beginning to think about long-term investments and returns in health researchthat build a social and economic infrastructure.On the African continent, the clinical trials enterprise is viewed increasingly as a potentialeconomic pillar for the development and securityof a future African renaissance.

At the end of this two-day meeting of Africanexperts on ethics and science in health research,the chairperson of the concluding session, a scientist from Nigeria, began the meeting’s conclusions with the words: ‘Now that one ofours is the leader of the world…’ However

misplaced such audacity may appear, the message of hope remains clear. A truly Africanclinical research enterprise is slowly but surelybeing transposed from a dream to a responsibility. ■


THE AUDACITY OF HOPEAND CLINICAL TRIALS INAFRICA

References:1.African Union, ‘Draft Pharmaceutical Manufacturing Planfor Africa.’ Ministers’ Meeting, Johannesburg, SouthAfrica, 10-13 April 2007; Document number:CAMH/MIN/7(111). (Accessed 23 February 2009 athttp://www.africa-union.org/root/UA/Conferences/2007/avril/SA/9-13%20avr/doc/en/PHARMACEUTICAL_MIN_DRAFT.pdf)2. See ‘Opening remarks by the representative of the AUCommission, Dr. Grace Kalimugogo’ (Accessed 23 February 2009 at http://www.doh.gov.za/docs/sp/2008/sp0218.html).

Francis P. Crawley Francis P. Crawley is the Executive Director of the Good Clinical PracticeAlliance – Europe (GCPA) in Brussels,Belgium and a World Health Organization (WHO) Expert in ethics.He is the co-founder of the StrategicInitiative for Developing Capacity inEthical Review (SIDCER). He is a

past member of the UNAIDS Ethical Review Committee and currently Chairs the Ethical ReviewCommittee at the International Network for CancerTreatment and Research (INCTR). He has played a pivotal role in developing European and internationalguidance in ethics and regulation for health research.

Email: [email protected]

Caligeo Clinical is a privately owned Contract Research

Organization (CRO) offering a wide range of clinical trial services

and training. What continues to distinguish us from other CROs

is our passion and dedication in educating and promoting clinical

trials in underrepresented communities in the United States as

well as establishing clinical trial services in Africa and the

Caribbean.

Caligeo Clinical provides initial and continuing educational

training for clinical research professionals such as Clinical

Research Associates (CRAs) and Clinical Research Coordinators

(CRCs). We ensure the highest standards of ethical conduct and

integrity in our services and continuously educate our team to

keep us abreast on current changes in the industry.

CALIGEO CLINICAL ONEVISION & CALIGEO CLINICAL TRIALS

INITIATIVE (CCTI)

Caligeo Clinical OneVision and CCTI were created to address the

underrepresentation of minorities in the pharmaceutical industry in

management positions and the marginalization of clinical trial

studies in Africa and the Caribbean.

Caligeo Clinical OneVision and CCTI are part of the non-profit

global outreach arms of Caligeo Clinical. These branches of Caligeo

Clinical focus on promoting and establishing clinical trial services in

emerging markets. The “non-profit” arms provide similar services as

our corporate “for-profit” counterpart. What is unique about the

non-profit programs is that we offer to our clients in emerging

markets, our services at a highly discounted rate as a result of

generous donations from corporate and individual sponsors.

SERVICES

Caligeo Clinical offers a full spectrum of services including:

• Monitoring Services: Site Qualification Visits, Site Initiation

Visits, Interim Monitoring Visits, and Termination Site Visits

• Project Management Services

• Protocol Review

• Informed Consent Form (ICF) Reviews

• Case Report Form (CRF) Design

• Regulatory/Essential Document Preparation and Reviews

• Site Auditing & Inspections

• Clinical Research Fundamental Training

• Computer Skills Training

• Interview/Job Search Training

• Clinical Trial Staff Training

• Clinical Trial Staffing/Recruitment/Job Placement Agency

• Mentorship “Train the Trainer” Program

In addition to the above services, Caligeo Clinical OneVision and

CCTI offer the following services:

• International Clinical Trial Consultancy in Africa and the

Caribbean

• Site Management Organization (SMO) Development Assis-

tance for Underrepresented Investigators

• High School/College Student Internship Program

• Training & Job Placement Agency for Refugees

• Professional Career Coaching

CORPORATE VISION:

• Perform quality monitoring services

• Provide global training services in clinical trials to various

countries in Africa and the Caribbean

• Provide comprehensive training in clinical research for initial

prospects and continuing professionals while promoting diver-

sity in the industry.

CORPORATE VALUES:

Our motivations are driven by our corporate values to

collaborate in global partnership campaigns resulting in

achievements of diversity and equality in the vast area of

medicine, in particular clinical research, while maintaining the

highest integrity and trust.

For more information, please contact Gbolahan

Fatuga, President/Founder of Caligeo Clinical.

Caligeo Clinical OneVision

P.O. Box 266, Lithonia, GA 30058, USA

Tel: (678)852-1355

Fax: (360) 287 – 9385

Email: [email protected] or

[email protected]

Web: www.caligeoclinical.com

Caligeo Clinical

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Integrity - Motivation - Partnership - Achievements - Collaboration - Trust

Now more than at any time in recent memory investment is hard tosecure, and not surprisingly those fortunate enough to have such secured such financial resource are looking further afield to find cost-attractive, high quality and, most importantly, fast-track partnersolutions. This is especially so during those early, milestone intensivephases of their product’s development.

This first Australasia Watch starts off by highlighting both Australia andNew Zealand as real options for developers under those pressures just described. Australasia cannot really be described as an emerging market, having been considered a tier 1 region for Phase IIb-IV studies for many years.However, with the advent of the European Directive in the mid 1990s, Australia and New Zealand have now also emerged as first class early phaseproviders demonstrating great expertise and breadth of services throughthose critical early development steps. This is highlighted by the dramatic increase in specialist Phase I units, from two to more than six such units overthe last five or so years, as well as the increasing emergence of motivated,therapeutically aligned hospital clinics with an appetite for being first inhuman research. This sector growth has unsurprisingly been supported by,and arguably driven by, a host of support service groups from manufacturing,analytical and ADME laboratories, through niche service providers of targetedclinical trial management services.

Australia was also highlighted as a prime location for clinical research byan extensive independent benchmarking study conducted by The EconomistIntelligence Unit, published in September 2005. In this study, Australia wasconsidered to be the number one location to conduct clinical trials, on suchmetrics as high percentage of ‘on-time’ trial completions and low averagecosts. Australia was also ranked second for pharmaceutical investment basedon factors including its skilled workforce, world class practices and regulatoryprocesses (Fig. 1).

So what is it that underpins Australia’s success in attracting early phaseresearch to its shores? An important competitive differentiator is the relativesimplicity of Australia’s Clinical Trial Notification (CTN) Scheme which allowssponsors to delay the traditionally labour- and time-intensive regulatory review processes required in most countries and invest precious funds into anearly insight into their product. Access to Australia’s fast-track approval shouldnot however be confused with lower regulatory standards, as a sound pre-clinical/CMC package is still a critical requirement. For those SMEs withsuch high quality packages and a global perspective, Australia is an increasingly attractive route to obtaining fast, quality answers that supportearlier go/no-go decision-making and potentially improved funding opportunities, which may then be spent on the next steps in the product development process, including the more dollar-intensive yet pivotal regulatory applications in the Northern Hemisphere.

Additionally, cost is a major consideration and Australasia’s divergencefrom recent parity with the US dollar ensures the region’s continued price advantage over many of the traditional clinical research centers such as theUSA, Canada and UK.

Over the coming issues, we will provide the reader with more insight intothe various solutions available in Australia and New Zealand, and how the region has evolved from being just a trusted late phase trial contributor to anactive research and development region from the very beginning for developers both large and especially small. ■


AUSTRALASIA WATCH

Source: Benchmarking Study of the Characteristics of the Australian and International Pharmaceutical Industries September 2005; Economist Intelligence Unit.

Fig. 1: Benchmarking Study of the Characteristics of the Australianand International Pharmaceuticals Industries

Russel Neal With almost 20 years working in the healthcare industry, for the last 16 years Russell has beenadvising clients in clinical trial management in a careerspanning Europe Asia and Australasia. He moved withQuintiles UK to Sydney in 1994 before moving to Singapore in 1999. In 2003, Russell returned to Australiafollowing three years as Regional Training Manager AsiaPacific and is currently Chief Operating Officer at ClinicalNetwork Services (CNS) Pty Ltd, a privately owned, Brisbane based, full service contract research organisation(CRO) providing clinical management support and services

to the healthcare community particularly during the early phase clinical developmentof their products.

Clinical samples manufactured in the EU are to be labelled with therequired storage condition in accordance with Annex 13 to the EC-GMP-Guideline. The current version of CPMP guidelineCPMP/QWP/609/96 “Declaration of storage conditions” is a usefultool for the determination of storage conditions and their declaration for Investigational Medicinal Products (IMP). For the determination of shelf life of IMPs, current ICH guidelines are to betaken into account (e.g. ICH Q1E). Temperature deviations during transport or storage may be assessed by calculation of themean kinetic temperature.

1. Definition of shelf life of IMPsThe available stability data are to be evaluated based on the applied analytical methods and their validation. Table 1 gives an overview of thestability test conditions and the shelf life derived there from:

If a QP likes to consider a shelf life exceeding that defined in the table,the following principles should be considered for the risk evaluation:

a) Test batches of the same composition (e.g. development batches) should be subjected to a stability study prior to the stability study of the clinical batches.

b) Clinical batches are to be tested within their running stability study for their quality, and to be confirmed for their given shelflife.

c) The stability test results of the clinical batches should be regularly compared for agreement with those of the test batches.

2. Determination and justification of storage conditionsThe storage condition is to be determined based on available stability dataof the IMP in the relevant immediate container or in a comparable one.Table 2 on the following page may serve as guidance for defining thestorage condition.

The following additional storage declarations should be used if applicable (especially if freezing to be avoided, e.g. creams, solutions, monoclonalantibodies):

• Do not freeze• Do not refrigerateIf these storage declarations are not covered by available stability data,

additional stability tests under these conditions should be considered.For multiple unit containers (e.g. bottle, aluminium pouch) the “storage

condition after first opening” is to be defined based on available (“in-use”)stability data. The “storage condition after first opening” should correspondto that of the unopened IMP container.

3. Short-term deviations from specified storage conditionsThe influence of temperature deviations on the mean kinetic temperaturecan be calculated by the following Arrhenius-derived formula:

Short-term deviations from specified storage conditions might be considered tolerable without shortening the shelf life of the concernedIMPs and without additional testing according to Table 3.

Special attention however is required for dosage forms with temperature-sensitive physico-chemical characteristics like soft or hardgelatine capsules (risk of sticking in multiple unit containers) and creamsor ointments (risk of melting or phase separation). In these cases it is advisable to declare maximum temperature values for storage and transport. ■


DETERMINATION OFSHELF LIFE AND STORAGECONDITION OF IMPSDealing with temperature deviations during transport or storage at CROs

Stability test performedStorage Condition Shelf Life

(Long-Term) (Accelerated) Assessment*

5oC ± 3oC - a Refrigerator Confirmed long-term stability

5oC ± 3oC 25oC/60%r.h a RefrigeratorConfirmed long-term

stability x1.5**

25oC/60%r.h aRoom temperature(climatic zone I + II)

Confirmed long-term stability

25oC/60%r.h 30oC/65%r.h aRoom temperature(climatic zone I + II)

Confirmed long-term stability +3 M

25oC/60%r.h 40oC/75%r.h aRoom temperature(climatic zone I + II)

Confirmed long-term stability x2***

30oC/65%r.h a Room temperature(climatic zone I + II)

Confirmed long-term stability

30oC/65%r.h 40oC/75%r.h aConfirmed long-term

stability x2***

Stability test performedStorage Condition Recommended storage declaration


5oC ± 3oC - a Refrigerator Store and transport refrigerated

5oC ± 3oC 25oC/60%r.h a Refrigerator Store in a refrigerator

25oC/60%r.h - aRoom temperature(climatic zone I + II)

Do not store above 25oC

25oC/60%r.h 30oC/65%r.h a Room temperature(climatic zone I + II)

Do not store above 30oC25oC/60%r.h 40oC/75%r.h a

30oC/65%r.h - a Room temperature(climatic zone III + IV)

Observe declaration requirements of concerned country30oC/65%r.h 40oC/75%r.h a

Stability test performedStorage Condition Recommended storage declaration

Deviation examples consideredtolerable**


5oC ± 3oC6M - • Refrigerator Store and transport refrigerated None

5oC ± 3oC6M

25oC/60%r.h1M

•Refrigerator Store in a refrigerator Up to 25oC up to 2 weeks

25oC/60%r.h6M - •

Room temperature(climatic zone I + II)

Do not store above 25oC Up to 30oC up to 2 weeks

25oC/60%r.h6M

30oC/65%r.h •Room temperature(climatic zone I + II)

Do not store above 30oC Up to 35oC up to 2 weeks

25oC/60%r.h6M

40oC/75%r.h •Room temperature(climatic zone I + II)

Do not store above 30oC Up to 45oC up to 1 week

30oC/65%r.h6M - •

Room temperature(climatic zone III + IV) Do not store above 30oC

Observe declaration requirements of concerned country

Up to 35oC up to 2 weeks

30oC/65%r.h6M

40oC/75%r.h •Room temperature

(climatic zone III + IV)Up to 45oC up to 2 weeks

References:1. ICH Q1A (R2) Stability Testing of New Drug Substances and Products2. ICH Q1E Evaluation of stability data3. USP 32-NF 27

a* no significant change according to ICH Q1A (R2)** maximal +6 months*** maximal + 12 months

a* no significant change according to ICH Q1A (R2)

Table 1:

Table 2:

Table 3:

a* no significant change according to ICH Q1A (R2)** assumed total storage period: 1 year (with longer total storage periods, deviations become even less critical)

Dr. Claudio Alexander Lorck has over 19 years experience in the fields of Quality Control and ClinicalTrial Materials Management. Having started his pharmaceutical career at Fujisawa Deutschland GmbH,Claudio now heads the business unit "Clinical Trial Materials" of Temmler Werke GmbH.


JCS 21www.jforcs.com

Over the last decade, an ever-increasing number of new chemical entities as well as biopharmaceuticals and devices have been comingonstream for clinical testing. As the industry invests more into R & D, the ever-growing pressure at the clinical test sites to conductsuch studies is mounting.

The upstream and downstream research processes such as basic laboratory research, pre-clinical studies and initial development of thestudy protocols for clinical trials are very well covered, either by the sponsoring or theoutsourcing companies.

How about the clinical research sites i.e. at the ground level? Are theclinical sites well equipped with the necessary processes or resources to conduct clinical trials?

In some of the developing and developed countries where the hospitalinfrastructure is well established and geared towards clinical research, theconstraints, such as the proper setup for clinical research at the hospital site, are not problematic.However, the search for new study subjects in countries where clinical research has been ongoingfor years can be challenging, and hence the needto search for “new frontiers” i.e. away from thehome country, to recruit study subjects. Are thesenew clinical study sites “ready” to conduct clinicalstudies?

This commentary is restricted only to one specific aspect of the processes, i.e. getting an approval from the local Ethics Committee (EC) orthe Independent Review Board (IRB) for clinicalstudies, and to address the challenges we faced atthe various hospital sites in the Asian Pacific rimcountries.

Does compliance as stated in the submissionguidelines in the different countries get you approval? Under normal circumstances, getting thenod to start the study is not an issue provided youhave an EC or IRB which understands the clinicaltrial process and also appreciates the objectives of the study.

However, the following statement also rang true: “I have submitted astudy to the ethics committee months ago for approval but have receivedno answer. Other investigators elsewhere will have this study done beforeI can even get it up and running. What is going on?”What has gone wrongin the ethics approval process which was supposedly to be transparent andvery straightforward in such a case?

Let us reflect back on the fundamentals to ensure that the frameworkthat will govern the ethics of the proposed study is appropriately applied.

Value: enhancements of health or knowledge must be derived from theresearch; Scientific Validity: the research must be methodologically rigourous; Fair Subject Selection: scientific objectives, not vulnerability or privilege,and the potential for and distribution of risks and benefits, should

determine communities selected as study sites and the inclusion criteriafor individual subjects;

Favourable Risk-Benefit Ratio: within the context of standard clinical practice and the research protocol, risks must be minimised, potential benefits enhanced, and the potential benefits to individuals and knowledgegained for society must outweigh the risks; Independent Review: unaffiliated individuals must review the researchand approve, amend, or terminate it; Informed Consent: individuals should be informed about the researchand provide their voluntary consent; and Respect for Enrolled Subjects: minimise harms and risks and maximisebenefits; respect human dignity, privacy, and autonomy; take special precautions with vulnerable populations; and strive to distribute the

benefits and burdens of research fairly.The ethical issues which need to be raised and discussed are clear, as indicated above, so why thedelay in getting a decision on the approval of astudy in an ethics submission?

Let us review briefly the EC or IRB processes andcomposition of the committee itself. Most of thedeveloping countries have instituted national research ethics guidelines, and in some countries,the ethics review is becoming more established.

In many jurisdictions, the ethics review is required and mandated by regulations and theethics committees are largely self-governing and subject only to the ethical guidelines, without anyregulatory oversight.In other jurisdictions, the ethics committee is incharge of the weighty decisions regarding thesubjects who volunteer for clinical trials and aresubject to direct regulatory oversight.

Depending upon the country or jurisdiction,different levels of ethical reviews can take place. The reviews can rangefrom (i) a single layer ethics review conducted under a national authorityto (ii) a fully decentralised process to (iii) a multilayer review with a centralised ethics committee to (iv) multiple local committees that bringlocal sensitivities to bear on the decision on whether to approve, and if sohow, in respect of every single study proposed.

This approach is part and parcel of good clinical practice followed bymany, but there are challenges which will inherently delay approvals in agiven timeframe.

There are many difficulties and challenges involved in a local reviewe.g. the lack of experience and expertise in the ethics review principles andprocesses; a conflict of interest among committee members; a lack of resources for maintaining the committees, which in turn acts as a barrierto the ethics review process; and the length of time it can take to obtainapprovals due to many unforeseen reasons, such as a lack of quorum


ETHICS APPROVAL FORCLINICAL STUDIES: CHALLENGING TIMES

“However, the following

statement also rang true:

“I have submitted a

study to the ethics

committee months ago

for approval but have

received no answer. Other

investigators elsewhere

will have this study done

before I can even get it

up and running.”

required by the committee to meet, and also problems involved with interpreting and complying with U.S. regulations if the studies are from theU.S.A.

Multicentre cooperative research projects do at times present specialproblems for ethics review. The ethics review committee of each of the participating institutions must review the same research protocol. In addition to duplication of effort, time and resources (which are scarce inmany developing countries), multiple reviews always present the possibilityof different review outcomes.

In some cases, the ethical review is actually a process of seeking permission to conduct research, and no ethical questions are raised at all.The review boards are often more concerned about the financial aspectsof the study than about ethics.

The ethics boards may also have conflict of interest regarding the approval of the study. This is because the research project in mind mightgenerate desperately needed financial gains that often provide an incentive to host institutions or governments, and as such the ethics committees and local researchers are more likely to accept such projectsregardless of ethical issues.

The other challenges include multipleEC or IRB clearances for any given project, and the frequency in which theethic committee meets, whether once amonth or at different times at the convenience of the committee members.Hence, it can result in a different time period for approvals and therefore also ina different time period for the yearly renewal. The composition of the EC or IRB members could be challenging as well.The members serving in the committeeare either appointed or invited by the institution to serve as a member. Conflictof interests does occur and this could leadto delays and sometimes non-approvalof studies, and this has nothing to dowith ethical issues.

The general rule of thumb for any submission to the EC or IRB is (i) to ensure that the content of documentsmatches the requirements of the EC/IRB,(ii) to submit the document within the required timescale of the different EC orIRB, (iii) to conduct a follow-up with theEC after their meeting if approvals arenot forthcoming, and (iv) to ensure thatthe investigators have enough information on the protocol to defendthe submitted protocol if required.

Can the clinical trial approvalprocesses by the EC or IRB be improvedto benefit the industry? The answer is adefinite yes. We can do so by having a greater investment in the ethics review committees of the host countries through training of the membersand providing materials and resources to support these committees. However, this suggestion does raise concerns about the intermingling ofethics and finances,

Furthermore, a situation that can arise and become problematic is ifthe study protocol is delayed for financial reasons rather than as a resultof ethical concerns.

If the financial resources are available, the members of the EC or IRB

are strongly encouraged to participate in continuing education in researchethics. They should be familiar with all the existing guidelines and regulations related to research ethics in their own country. As such, themembers will need to be well versed in the ICH-Good Clinical Practiceguidelines.

E-learning courses are also available to provide research ethics instruction in various aspects for the responsible conduct of research including human subject protection, health information privacy and security, research misconduct, data management, conflict of interest, mentoring and collaborative science.

Another possible way to improve the processes of the EC or the IRB isthrough accreditation, which could benefit the research organisation, theparticipants and the research industry.

In summary, there are many challenges faced by EC or IRB committees,and the only way to improve is to encourage the committee members topartake in education, and to exchange their past experiences either withinthe host country or internationally with their counterparts. ■

Dr. Yap Kok Wei, PhD is the CEO of GleneaglesCRC PteLtd; Group Vice President, Research, ParkwayHealth; Adjunct Professor, School of Pharmacy, Faculty of HealthSciences, Murdoch University, Western Australia

www.jforcs.com JCS 23

With more and more clinical trials being held outside Western Europeand North America, the language issue has become a hot item. International trials increasingly include clinics and other study centres in countries in Latin America, Africa, and Asia, and as a resultlanguage-related problems have multiplied. This article specificallydiscusses India as an example of a linguistic challenge.

Languages of IndiaIndia is a country with well over 1 billion inhabitants, who speak over athousand different languages. Not all of these languages are equally important, of course. During the most recent census (in 2001), it was established that 29 languages were each spoken by more than 1 millionnative speakers, 60 by more than 100,000, and 122 by more than 10,000.The government recognizes 22 official languages. However, these are notthe languages with the highest numbers of native speakers. The list is theresult of politics more than anything else.Some widely spoken languages (such asBhili/Bhiladi with almost 10 million speakers, and Santali with 6.5 millionspeakers) are not on the list of official languages, while several languages withless than 2 million speakers are.

In schools in India a total of 58 different languages are taught, newspapers are published in 83 languages,radio stations use a total of 71 languages,and ‘Bollywood’ produces films in 15 different Indian languages.Most of the languages of India belong totwo language families. The largest of thesegroups of languages are composed of theIndo-Aryan languages (almost 75% of thepopulation, mostly in the Northern andCentral parts of the country) and the Dravidian languages (almost 25%, mostly in the South). Within these families hundreds of different languages can be distinguished. Other languages stem from the Austro-Asiatic language family (1.2%) and theTibeto-Burman language family (0.6%). Sanskrit is one of the classical languages of India; it is spoken by only 14,000 speakers but many morestudy it for cultural reasons.

The official language of the republic of India is Hindi. Although the official use of English was to be phased out over a period of 15 years afterthe Constitution of India came into effect in 1950, today it is still the subsidiary official language; English is spoken by around 100 million people. Hindi has the most native speakers and is spoken by over 420 million inhabitants, followed by Bengali with over 80 million, Tegulu andMarathi, each with around 75 million, Tamil with 60 million, and Urdu andGujarati, each with around 50 million. Together, these seven languages arespoken by over 800 million inhabitants (around 80% of the total population).

Indian (or Indic) languages use different alphabets, with major differencesbetween the Indo-Aryan languages and the Dravidian languages. Fortunately, many of these alphabets are encoded in Unicode, which facilitates computer processing.

The literacy rate is estimated to vary between 36 and 52%.

Language Aspects of Clinical TrialsNo matter in which country a clinical trial is held, language always plays acritical role in medical research. Trial sponsors, medical ethical committeesand investigators all need to be informed about the ins and outs of thetrial, and eventually the results of research projects must be published. Andall this must be done in clear, unambiguous language, often in English. Atthe same time patients and healthy volunteers need to be informed aboutthe trial in a language they can understand. During clinical trials a rangeof different documents are used, and many of these need to be available

in the language of the study participants. During trials that are held in India, the

Study Protocol usually stays in English. Thisdocument is intended for official use. It describes the background and purpose ofthe clinical trial, the possible outcomes, theprofile and recruitment of patients, insurance issues, et cetera. The InformedConsent Form (ICF) however, should alwaysbe translated. This document informs patients suffering from a certain disease orcondition who are invited to participate inthe study. Under the Declaration of Helsinki,an initiative by the World Medical Association in 1964 (most recently updatedin 2008), participants must completely understand the information, including therisks associated with the study medicationor study treatment. Participants must sign

the Informed Consent Form to state that they fully understand the information that was provided and that they are willing to participate.

At least as important are Patient Reported Outcomes forms (PROs),such as questionnaires, which always have to be translated. Trial questionnaires are mostly used to collect information from patients, eitherdirectly (by patients filling in the questionnaire) or through an investigatoror interviewer who records the patient’s responses onto the form. PROs aremost often used to collect information on quality of life (QoL) in general,health-related quality of life (HR QoL), disability, and physical or mentalsymptoms of disorders or conditions (for example, asthma, migraine, urinary incontinence). The information collected using PROs is fed into adatabase, which is then used for further research. The original version of aPRO is usually the result of a joint effort by different researchers who spenda lot of time and energy in generating a high-quality instrument. Somewidely used questionnaires even took over a decade to develop! The authors pay a lot of attention to the precise wording of the questions, and


SOME LANGUAGE ASPECTSOF CLINICAL TRIALS ININDIA

“No matter in which country a

clinical trial is held, language

always plays a critical role in

medical research. Trial sponsors,

medical ethical committees and

investigators all need to be

informed about the ins and outs of

the trial, and eventually the

results of research projects must be

published.”

perhaps one or more other Indic languages. The problem Western CROsmay have is that there seem to be too many translation resources! Indiahouses very many translation firms and independent freelance translators.Just as in Europe or the USA, the fact that they exist does not mean thatthey can all do a decent job translating a clinical trial questionnaire, or aninformed consent form for that matter. In general it would be safer to stayaway from providers who lack relevant expertise. Translators must be experienced in medical translation, otherwise the risk is too large that theend result is not up to standard. There are several reputable translationfirms in India, and specialised medical translation providers in Western Europe and the USA will have associated themselves with qualified India-based translation resources. Certainly when compared with the

overall cost of clinical trials, translation is not all that expensive, so there isno need to look for cheap and quick. Clinical trials are simply too costly torun the risk that a poor translation compromises the trial results. ■


– in the case of multiple-choice – the answers. It is then heavily tested,both on understandability of the questions, and on measurability of theoutcomes.

TranslationsAnd then – the instrument must be translated… Translating a questionnaire for use in clinical trials is a delicate and complex task andusually quite a challenge for translators. Apart from the language aspects, there are often cultural differences, and certain concepts maynot be so easy to translate. The end result must be conceptually equivalent to the original version; but even if the translation is correct,the culture of the target language area may place a different value onwhat is measured. A translated questionnaire must reflect all the fine nuances of the original. If a question is not exactly the same in all different languagesconcerned, the answers cannot be compared, or ‘pooled’, and as a result,part of the research data may not be usable.

Guidelines for Translating PROsThe average translator or translation firm will planto spend half a day or so on a questionnaire of ahandful of pages. The big question is how realisticis it to assume that a translator can provide thesame care in a few hours translating a documentwhich may have taken months or even years to develop in the original language? It is thereforerecommended not to simply subcontract such atask out to the average translation agency, butrather to involve expert translators who under-stand what is at stake.

To provide guidance to research teams who areinvolved in producing foreign-language versions ofa questionnaire, several organisations have defined guidelines on how to produce a questionnaire in one or more languages. Withthese guidelines, research teams can make surethat translations are done properly.

EuroQolOne of these organisations is EuroQoL, based in Rotterdam. This organisation manages the (currently 83) existing language versions ofthe EQ-5D (European Quality of Life, 5 Dimensions) instrument, and isinvolved in its translation into an additional 40 languages. The EQ-5D isa widely used standardised instrument to measure health-related qualityof life. It is used to collect information from patients in a wide range ofhealth conditions and treatments; it provides a simple descriptive profileand a single index value for health status that can be used in the clinicalandeconomic evaluation of healthcare as well as population health surveys. EQ-5D has been specifically designed to complement other quality of life measures, such as the SF-36, NHP, SIP or disease-specificinstruments.

EORTCAnother organisation publishing guidelines for the translation of questionnaires is the Quality of Life Group of the European Organisationfor Research and Treatment of Cancer (EORTC), based in Brussels and established in 1962. This organisation manages, among others, theEORTC Quality of Life Questionnaire QLQ-C30, an instrument developedto assess the quality of life of cancer patients. The QLQ-C30 is an example of a questionnaire which took a very long time to develop: it waspublished in 1993 after a decade of development. It is currently availablein 81 languages, and has been used in more than 3,000 studies worldwide.

IQOLAA third organisation that should be mentioned is the International Qualityof Life Assessment (IQOLA) Project. IQOLA is based in Boston and manages the translation of the well-known SF-36 Health Survey. This shortform (SF) with 36 questions is widely used as a generic instrument to assessmental and physical health. It is available in well over 50 different languages and has been used in over 500 published studies.

How to Translate Clinical Trial Questionnaires? In general terms, the translation guidelines published by EuroQol, EORTC,and Iqola are rather similar. In order to produce a new language version,the questionnaire is first independently translated (normally from English)into the target language by two or more translators, both native speakersof the target language and familiar with the subject matter. The two translations (in this respect these are often referred to as ‘forward translation’) are evaluated by one of the translators or by a third one andon the basis of this comparison a ‘reconciled’ version is produced, if necessary after resolving any discrepancies between the different forwardtranslations. The reconciledversion is considered the ‘ideal’ version of the

translated PRO. This is back-translated into English.‘Back-translated’ means that the translated textis translated back into the original language, in thiscase English. Back-translation is done by two ormore back-translators, native speakers of Englishwith an excellent command of the language of the forward translation. The back-translations are then compared with the originalversion to check for discrepancies between theoriginal and translated versions; any issue or problem must be resolved at this stage. This maylead to revisions to the reconciled version of theforward translation but in certain cases the original (English) version is adapted in such a waythat the specific translation problems can be resolved.

Problems when Translating into HindiIn 2006, Indian researchers reported their effort to translate the EORTCBN20 questionnaire. This questionnaire is used for patients with primarybrain tumours, along with the EORTC-QLQ-C30 questionnaire, which isbroader and more generic and often used for patients with cancer. Theydescribe that the EORTC BN20 questionnaire was translated into Hindi following the standard EORTC guidelines. Two translators each produceda Hindi version of the questionnaire, after which the project coordinatorcarefully compared the two versions. He identified several issues that hadto be resolved during personal or phone conversations. One of these concerned the Hindi translation of the word ‘vision’ in the question ‘Didyou have problems reading because of your vision?’ One of the translatorsfound that the Hindi word for ‘eyes’ would be better than the more abstract concept of ‘vision’. In these cases it has to be considered whatthe patients will understand best.

Questions such as ‘Did you feel uncertain about your future’ and ‘Didyour outlook on the future worsen? ’ can easily cause problems. Thesequestions have a different impact in – say – Germany than in India. Thereare probably more people in India than in Germany who do not have sucha bright future in the first place. What is usually a normal setback the average person living in Mumbay experiences once every few days maybe perceived as a catastrophe by a German person.

Finding Reliable Translation Resources in IndiaIndia is a country with many different languages. Apart from their nativelanguage, many people with a good education speak English very well, and


“The big question is how

realistic is it to

assume that a translator

can provide the same care

in a few hours translating

a document which may

have taken months or

even years to develop in

the original language?”

Simon Andriesen Simon Andriesen has been involved in languages and translation since 1980. His company MediLingua is fully focused on medical translations and quality assurance ofmedical translations. They produce language versions ofmany different types of documents related to clinical research, registration, use, and pharmacovigilance of medicinal products; services often include back translations

and readability testing. Email: [email protected]

Recognising the high potential in Israel, numerous international drugcompanies have set up special task forces actively seeking opportunitiesto purchase early-stage drugs or the rights to develop and market them.

The Healthcare SystemIsrael has a population of over 7.3 million people and its healthcare system,governed by the National Health Insurance Law, operates 47 general hospitals and over 2,000 community-oriented primary care clinics whichemploy about 32,000 physicians. Medical centres affiliated with one ofthe country's four medical schools are heavily involved in basic and clinicalresearch, and many of their staff members have had fellowship trainingabroad in specialised fields. The hospitals have a modern infrastructure,are generally well equipped and provide medical care comparable to Western standards.

The country allocates 8.3% of its GNP to health (2004) and enjoys arelatively low infant mortality rate (4.5 per 1000 live births) and an averagelife expectancy of 81.8 years for females and 77.6 years for males.

The Clinical Trial LandscapeOver the past three decades Israel has beeninvolvedin the conduct of clinical trials. European drug companies, among them Bayer AG, BoehringerMannheim, Hoechst AG (that merged with Rohne-Poulenc to become Aventis), Hoffman-LaRoche and many others, were the first to place theirlate-stage development projects in Israel, followed byAmerican and Japanese drug companies. Israeli hospitals have since participated in numerous globalacademic (TIMI Study Group, EORTC and others) and industry trials and have consistentlydemonstrated not only exemplary enrolment rates,but a high level of data quality and compliance withapplicable guidelines and regulations. In the past 15years, the number of foreign registration studies hasgrown substantially with a shift towards more complex, early-stage clinical trials.

In 2007, 276 clinical drug trials were initiated at1,067 study sites, and their contribution to Israel'sgross domestic income, from investigator grants only,was about 400 million US dollars. In addition, about80 medical device trials were conducted in that yearat 545 study sites.

The Ministry of Health, the Israeli Medical Association and the academia appreciate the importance of clinical research to society, improved patient care, medical education and international scientific collaboration. It is therefore important that they all work in tandem to further expand the capacity and competence of clinical trial personnel. Toensure high quality, ICH-compliant clinical trials, most hospitals have madeGCP training mandatory for investigators and their study personnel, while periodic inspections and audits are conducted by the Directors of Hospitaland the Ministry of Health. Furthermore, an increasing number of clinicalresearch professionals have gained Association of Clinical Research Professionals (ACRP) certification, attesting to their drive for professionalism and excellence in that field.

Clinical Trial AuthorisationIn Israel, a sequential review process is in place, where study protocols arefirst reviewed by the Institutional Ethics Committee (EC) of each participating hospital, and subsequently by the MOH. However, so called"special trials", i.e. Phase 3 trials or trials with compounds with which theMOH is familiar based on prior review of earlier stage protocols, requireonly local EC and Director of Hospital approval. The average timeline for

approval of study protocols in that category is about six to seven weeks.Though all other trials require MOH approval, only about 30% of those"non-special trials" are reviewed by the MOH Central Committee's panelof experts. These are mainly first-in-man and paediatric clinical trials. Theaverage timelines are 12 and 18 weeks for the non-special, not first-in-man trials and those requiring Central Committee review, respectively.

Eager to further streamline the clinical trial review process, the currentdraft legislation for clinical trials in humans proposes the adoption of a parallel review process that should significantly reduce approval times.

Key Success FactorsWhat are the key success factors that drive Israel's continued growth andattractiveness for clinical research, despite the emergence of lower costcountries with several-fold larger populations?

The scientific and medical expertise in many therapeutic areas is probably one of the most important assets Israel has to offer. Clinicianshave a genuine interest and passion in pioneering novel therapeutic approaches, and when specialised expertise is required, there are manyleading names to choose from. Secondly, disease-specific, nationwide

clinical research networks have been established thatoperate under the leadership of experienced professionals providing administrative and logistic support to participating study centres. Similarly, nearlyall major medical centres have built an effective research support infrastructure accessible to cliniciansthat conduct clinical trials. Furthermore, by virtue of thepublic healthcare system, community and hospitalphysicians collaborate closely in the management oftheir patients, which facilitates the referral of patientswho wish to participate in therapeutic trials to a studysite for a specific research programme.

Since most hospitals and community clinics maintain patient records electronically, information regarding the prevalence of specific disorders and thesuitability of patients for a specific programme is easilyretrievable, which expedites the feasibility assessmentprior to committing to a clinical trial.

Foreign companies, mainly first-time sponsors,may be concerned about the security situation in Israel and how that might affect the timelines of theirclinical programme, as well as the safety and mobilityof their staff when visiting Israel. I usually recommend

that they talk to veteran companies who will unequivocally confirm that,in contrast to common perceptions, these circumstances have had minimal impact, if any, on their programmes.

SummaryAlthough Israel is no longer the cheapest country for conducting clinicaltrials, multinational drug companies acknowledge the quality of researchand the "can-do" attitude of Israeli investigators. Israeli sites have consistently lived up to their enrolment targets, and frequently exceededthem. ■


In January 1994, President Bill Clinton and Prime Minister YitzhakRabin announced the creation of the US-Israel Science and Technology Commission. One of the objectives of the commissionwas to promote cooperation between the two countries in the fieldof science and technology, with emphasis on harmonisation of regulatory standards for drug development and approval. As part ofthe programme, FDA officials provided training in GCP, GLP and GMPto both Israeli Ministry of Health officials and industry professionals.

Clinical research, on behalf of international drug companies, mainly European, has been conducted in Israel since the mid 1970's, however, asa result of the harmonisation process, numerous multinational drug companies established R&D centres in Israel and placed an increasing portion of their clinical research in Israeli institutions. In addition, manyglobal contract research organisations (CROs) have followed suit and havebeen enjoying impressive growth rates ever since.

Life Science CredentialsIsrael has emerged as one of the world's most prominent centres of R&Din biotechnology and life sciences, has the largest per capita number ofscientists in the world and is currently ranked third place in the world withregard to the number of new life science patents registered.

Through its special biotech initiative, the government has made it a toppriority to assist biotech companies to accelerate the development of early-stage drug candidates. In addition to providing research grants,

government-sponsored technology incubators offer operational, regulatoryand commercial expertise to get companies ready to attract private investment. In the past five years, several private incubators have been established based on collaboration between academic institutions, venturecapital firms and the drug industry.

Several prominent drugs, such as Copaxone®, Rebif®, Exelon®, Doxil®and Rasagaline/Azilect® originated in Israeli academic research at the Weizmann Institute of Science, the Hebrew University of Jerusalem andthe Hadassah Medical Center (see Table 1). Currently, 18 Israeli drugs arein advanced stages of clinical development, encompassing small molecules, biologics and cell therapeutics. Dozens more are in preclinical development.


ISRAEL - A SOLID TRACKRECORD IN CLINICAL RESEARCH

PRODUCT INDICATION ORIGINATOR DEVELOPER

Copaxone® Multiple SclerosisWeizmann Institute

of ScienceTEVA

Relif® Multiple SclerosisWeizmann Institute

of ScienceSerono

Gonal-F® InfertilityWeizmann Institute

of ScienceSerono

Exelon® Alzheimer's DiseaseHebrew University

of JerusalemNovartis

Doxil® Ovarian CancerHadassah Medical

CenterJohnson & Johnson

Rasagaline®Azilect®

Parkinson's DiseaseTechnion Institute of Technology

TEVA

“Foreign companies,

mainly first-time

sponsors, may be

concerned about the

security situation in

Israel and how that

might affect the

timelines of their

clinical programme, as

well as the safety and

mobility of their staff

when visiting Israel.”

Table 1: Marketed Drugs of Israeli Origin

Heschi Rotmensch, MD, MBAAs Senior Vice President, Drug Development, Dr. Rotmenschmanages the operations of Cato Research in RoW. He isboard certified in Internal Medicine and Clinical Pharmacology and served as Chief of Medicine at the Wolfson Medical Center in Holon, Israel. Prior to joiningCato Research, he served as Associate Director of the Division of Clinical Pharmacology at the Thomas JeffersonUniversity Hospital in Philadelphia and as Vice President,Clinical Research Germany for Parexel International.


Phot

ograph

:Han

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/Getty Im

ages

More often than not, the efficacy end point of multi-million-dollar trialsis based on laboratory data. People always talk about the importance of obtaining good quality laboratory data. Unfortunately when it comes to finding a good quality central laboratory, one may be a little lost. The big question is where and howto begin. A clinical laboratory, especially a central laboratory, is a veryspecialised organisation that is designed to deliver laboratory data thatcan be used for patient management, patient safety and efficacy monitoring. Naturally and hopefully, the laboratory is run by professionals who are very passionate about their profession. These arethe experts who can tell you about the differences between a good quality and a bad quality laboratory. However, subconsciously in theirconversations, they like to use jargon such as IQ (installation qualification), OQ (operation qualification), PQ(performance qualification), SD (standard deviation), CV (coefficient variation), ALE(allowable limit of error), TE (total error), GLP (Good Laboratory Practices)etc. These terminologies may be very meaningful to them but to someone who does not have a laboratory background, it is almost likelistening to the conversation of a bunch of Martians. Two minutes intothe conversation, the mind is starting to drift off into Alice’s Wonderland.The main purpose of this article is to provide readers with some very basicguidelines when one is looking for a good quality central laboratory. It isnot intended to be a comprehensive review.

FacilityThe location of the laboratory facility is not important as long as it is easilyaccessible. If it is located in an industrial estate surrounded by smog-covered buildings, it is perfectly acceptable. After all, it is a centrallaboratory. No one expects to find a central laboratory in downtown Manhattan. If you do, please be aware: the cost of the expensive propertywill be passed back to you somehow. There is no such thing as a free lunch.Instead of homing in on the location, one should pay more attention tothe design of the facility. The design should be logical, and the workflowshould be smooth to minimise redundancy. For instance, a sample shouldnot have to move back and forth a few times from one workstation to another in order to have all the testing completed. And it should be spacious enough for all the equipment and staff. If you see a laboratory istrying to jam all their equipment into a tiny room and staff have to workelbow to elbow, it is time to move on to the next. Another important thingto look for is sufficient parking space for couriers’ trucks to deliver samples.If there is no parking space available, there will be a delay with deliveryand that is not good. Finally, a very good telltale sign is the cleanliness ofthe laboratory. If the floor and workbenches are clean, tidy and well-maintained, it shows the people in the laboratory pay attention to detailsand they take care of the facility where they work. The chances are theywill take care of your samples in the same manner, and that makes yousleep better at night. Last but not least is the security of the building and

A HITCH-HIKER’S GUIDE TOSEARCHING FOR A GOODQUALITY CENTRAL LABORATORY

they have gone through these scenarios (audits) so many times that theycan respond to your questions by reflex actions. On the other hand, thejunior staff, in the absence of the senior, will tell you how things are donein reality. Sometimes, it can be an eye-opener. There is one important element that is missing quite often – a continuing education programme.Nowadays, technologies are advancing at a tremendous speed. Newequipment and new technologies are being launched every day. The technical staff must be able to keep up with the new knowledge and skills,and that requires support from management. At the end of the day, a central laboratory is in the knowledge-driven industry, and keeping abreastof new knowledge is crucial.

LogisticsA central laboratory is unique in the sense that most of the specimens areshipped from remote locations (trial sites) to the laboratory for testing.These sites can be thousands of miles away in another country. Hence, it

is critical to ship the samples in the shortest possible time. As we all know,data are only as good as samples. If the sample is already bad before itarrives the laboratory due to prolonged transit time, even though you havea world-class setup in the laboratory, your result will be of poor quality. Thisis simply a case of “garbage in, garbage out”. In order to minimise it, thelogistics personnel have the challenging task of coordinating the shipmentof samples from different countries or cities. If they are coming from various countries, he/she must ensure proper import and/or export permitsare on hand so there will be no delay. The mind-boggling and foreverchanging import and export requirements from various countries requirefull-time attention. It is always good to set aside some time to chat withthe logistics personnel to find out how much they know about the regulatory environment. It is good to ask those “dreadful” “what if” questions. For example, what do you do if the airport in country X is closeddue to protestors? What do you do if country y has an earthquake and allroads are closed? By asking these “what if” questions, you will get to knowhow well the laboratory is prepared to deal with the unexpected. In other

words, what are their risk management programmes?

Quality AssuranceAn independent in-house quality assurance (QA) auditor is valuable. The auditor is to make sure all the necessary SOPs are available for staff, that theyhave received adequate training, and that the quality programme has beencommunicated to staff and everyone understands and practises it. What youdo not want to see is beautifully written and sometimes even inspirationalquality documents sitting in the Laboratory Director’s office, which for whatever reason have not been filtered down to the bench level. It is good tofind out whether the QA program is designed from “bottom up” or from “topdown”. If it is a “bottom up” program, the chance of it being practised at thebench level is high. After all, it is being designed at the bench level. If it is a“top down” program, you must make sure it is implemented. The QA auditorplays a very important role in this matter. It is important to ask for past in-house audit reports. This actually serves two purposes. Firstly, by looking atthe number of findings, root cause analyses and time taken to close the findings, this will allow you to have a snapshot of the past problems the laboratory had encountered. Secondly, it will allow you to assess the qualityof the QA auditor. QA auditors are just like you and I: there are good QA auditors and bad QA auditors. If the laboratory is being inspected infrequently and there are many open findings from the distant

past, one should startasking more W5 questions (what, when,where, why and who).And if you are not totallysatisfied with the answers given, be prepared to spend moretime with the QA auditorthan you have planned.

ConclusionI have not touched on information technology(IT) and LIMS (Laboratory InformationManagement System).

Most central laboratories have their own proprietary software and it is ratherdifficult to comment on these specialised systems.Suffice it to say, there isno simple and easy way to identify a good quality central laboratory. Itdoes require a certain knowledge and experience. However, if one appliescommon sense and takes a logical approach to facility, management, people and equipment, one will start seeing the light and will be able totell the difference between good and bad. ■

laboratory. It should not be as tight as Fort Knox, but then again, no unauthorised person should be allowed to enter and leave freely. Thereshould be primary and secondary barriers to prevent any stranger wandering in and out of the laboratory. A security monitoring system, nomatter how basic it is, should be in place.

ManagementThere are two people you must meet and spend time with. Depending onthe organisation structure, they carry different titles. The first person is theone in charge administratively, i.e., the person who holds the purse strings.Most of the quality improvement activities and quality measures involve financial commitments – money. Obtaining international accreditationsuch as College of American Pathologists (CAP) or International Organization for Standardization (ISO) is expensive. In addition, there arenumerous external quality control/assurance (EQA) programmes out therefor laboratories to participate in. The costs from these EQA programs addup, so it is unreasonable to expect any laboratory to participate in all theEQAprograms. But it is reasonable to expect that the majority of the testson the test menu are covered by at least one EQA program. The questionthat I like to ask is what percentage of your revenue is spent on quality-Related activities? For the record, there is no pass or fail answer;every laboratory is different; for example, fifteen percent may be adequate for one laboratory but grosslyinsufficient for another.This is a psychologicalquestion rather. If theman in charge thinks hehas instituted a world-class quality program inhis operation, he will nothesitate to tell you thepercentage and go onand on about all theprogrammes that hehas put in place. That isa good sign. If the manin charge has not committed to adequatequality activities, he will give you his answer in a soft tone or he will tell youhe has no figure. If this is the case, be prepared to spend more time to findout what exactly is taking place in the laboratory.

The second person you must spend time with is the person in charge technically. He or she usually carries the generic title, Laboratory Director.It is important to ensure the Laboratory Director has the qualificationsand experience to lead the laboratory. He/she is the team captain, andneedless to say, if the captain is not well-qualified, the team will be weak.It is important to find out whether the Laboratory Director is on boardfull-time or part-time. Is the Laboratory Director an employee of the laboratory, or is he/she a part-time consultant that the laboratory hiresto fulfill certain legal and regulatory requirements? Nowadays, in thename of cost saving, some laboratories hire part-time consultants to actas their Laboratory Directors, while the laboratory is actually run by another person. If that is the case, this other person must be equally qualified to manage the laboratory and capable of making sound scientific and clinical decisions. After you are satisfied with the LaboratoryDirector’s roles and responsibilities, it is important to find out if he or shehas the authority and support of the management to implement all thequality measures he or she wants to put in place. Without full and financial support from management, the Laboratory Director’s plans cannot be acted on. As someone said – a plan without action is just adream.

EquipmentYou may be surprised to find out that this is one area that I will not spendtoo much time on. With the advancement of technologies, the majorityof modern laboratory equipment is controlled by microprocessors. Theyare so robust that hardly any maintenance is needed. As long as they havebeen set up properly and all the functionalities have been checked initially,they should be performing according to the manufacturer’s specifications.But when it comes to preventive maintenance, it is a different story. Preventive maintenance is about servicing the equipment even though itis in good working condition. During preventive maintenance, certain partsthat are subject to wear and tear will be replaced to ensure the equipmentcontinues to perform well. Preventive maintenance is recommended by all manufacturers and it is rather expensive. In some developing countrieswhere money does not come easily, they may become firm believers in thephilosophy “if it isn’t broken, don’t fix it”. It is important to ask for the preventive maintenance records for all major equipment.

StaffI am sure you have heard of it before – staff are the major assets of the company. It is especially true in a central laboratory environment. Those medical technologists who manned the workbenches are the key driversfor good quality delivery. Therefore, it is essential that they are qualifiedto do the job with suitable educational background and experience. It isimportant that they receive firm support from the management. The support should include, but not be limited to, proper training on equipmentoperation, standard operation procedures (SOP) and quality control practices. A system should be in place to monitor the performance of thelaboratory staff periodically to ensure there are no gaps. If deficiency isnoticed, there is a plan to ensure the staff are “trained” and “assessed” priorto working independently again without any supervision. The LaboratoryDirector should play a role in this process to mentor the laboratory staff. Ifyou would like to find out what is happening at ground zero in the laboratory, talk to the junior staff instead of the senior staff. Often, thesenior staff are able to provide you with typical textbook answers. After all,


“The Laboratory Director

should play a role in this

process to mentor the

laboratory staff. If you

would like to find out what is

happening at ground zero in

the laboratory, talk to the

junior staff instead of the

senior staff.”

Dr. Stanley Tam Dr. Stanley Tam is currently the General Manger and Laboratory Director at Eurofins Medinet Singapore andChina, a full service global central laboratory. Dr. Tam is well experienced in the Asia region, working actively with pharmaceutical and biotech companies. Dr. Tam helped establish the Eurofins Medinet global central laboratories inSingapore and China. He has both an in-depth understanding of the central laboratory operations in Asia,

as well as experience with their regulatory standards and logistical challenges facing central laboratories throughout Asia and China. Previously, Dr. Tam was theVice President for Quintiles Laboratories in Asia responsible for central laboratoryservices and clinical trial supplies. Email: [email protected]

“A central laboratory isunique in the sense thatmost of the specimens areshipped from remote locations (trial sites) to thelaboratory for testing. Thesesites can be thousands ofmiles away in another country.”


The FDA approved 22 new molecular entities (NME) during year 2008,five of which were approved in December when the global financialcold had finally frozen the hearts of worldwide investors; it looks as ifthe crisis had not yet affected the clinical trial industry. The reason istwofold: firstly, the development cycle of a new drug is much longerthan any crisis, and, secondly, the elasticity of a medicine is lowenough to stand the chaotic fluctuations of the world stock market.

According to the Frost & Sullivan analytics, the worldwide financial warming is expected to happen somewhere in June 2009. The forecast is asdependable as any other, moreover, we fully share their view at the crisis asan additional growth opportunity for the Russian clinical trial market. Incidentally, the Chinese hieroglyph “crisis” consists of two symbols: the first(危, wei) means “danger”, and the second (機, ji) means “chance”.

“Best-in-class companies don't view a downturn as a period in which tosimply survive. They see opportunity in the uncertainty and navigate throughthe storm with investments in growth strategies that not only help themcarry on, but also prepare them to move quickly once the economy recovers,”says David Frigstad, Chairman of Frost & Sullivan.

“To catapult ahead of the competition, companies should continue to invest in growth strategy development and seek insights and guidance fromtrusted sources," adds Frigstad. "After all, if they don't, their competitors will."

This is also true for countries. We believe that under the current globalcircumstances Russia as a clinical trial market becomes even more attractive,and there is a good chance for small and mid-size international pharmaceutical and biotechnological companies to utilise the country’s advantages to shorten the time-to-market for the drugs in their pipelines.This is one of the most critical success factors in today’s challenging environment, and for some companies becomes a question of life and death.

Year 2008The Federal Service on Surveillance in Healthcare and Social Developmentof the Russian Federation (alias RosZdravNadzor, RZN) approved 615 newclinical trials of all types including local and bioequivalence studies during2008, demonstrating a 9% increase over the previous year. As shown in Figure 1, the main contribution to the total number of studies is still madeby multinational multi-centre clinical trials (presented as MMCT in Figure 1),even though the number of these studies slightly decreased by 1.2% over2007 to stand at 364 new studies in 2008.

The number of local clinical trials conducted in Russia by domestic andforeign sponsors (the CT(R) bar in Figure 1) is up from 126 to 177 clinical trials, demonstrating a notable 40% increase over 2007.

The number of bioequivalence studies (BE in Figure 1) in 2008 stood at74 new trials, a 9% increase from the previous year’s figure.

Figure 1. Clinical

trials approved by

RZN in 2008

The proportions between different study types (multinational multi-centreclinical trials, local studies and bioequivalence trials) did not change significantly over 2007 figures. The share of multinational multi-centre clinical trials slightly decreased from last year’s figure and stood at 59% ofthe total number of clinical trials approved by RZN in 2008. The share of thelocal trials in 2008 stood at 29% of the total number of studies, while it accounted for 22% in 2007. The share of bioequivalence studies remainedthe same – 12% of the total number of trials approved during Year 2008.

Figure 2. Clinical trials by type in 2008

The lion’s share of clinical trials in Russia is still being sponsored by foreigncompanies. Whilst their share slightly decreased from 72% to 67%, theirnumber is up from 407 in 2007 to 414 new studies in 2008, since the number of local studies grew faster during the period. The number of clinicaltrials initiated by Russian sponsors, including bioequivalence studies, rosefrom 156 to 201, with their share also increasing from 28% to 33%.

Figure 3. Russian and international sponsors in 2008

Clinical trials in Russia in 2008 were sponsored by companies from 36 countries. Figure 4 demonstrates the input of the leading countries of originof sponsors into the total number of clinical trials. The greatest number oftrials (201) was initiated by Russian sponsors, while American sponsors with145 studies took the runner-up place. They are followed by German sponsorswith 60 trials, UK companies with 43 new trials, and the top five is concludedby Swiss sponsors with 34 new studies in 2008.


CLINICAL TRIALS IN RUSSIA:YEAR 2008

Table 3. The leading Russian sites by number of trials in 2008

Therapeutic areas of clinical trials in Russia in 2008During 2008 about three-quarters of the new studies in 2008, or 73%, wereconducted in seven therapeutic areas. The greatest number of trials (91)were initiated in oncology; 87 clinical trials in circulatory system diseases; 60studies were targeted at respiratory system diseases; 57 in endocrine andmetabolic diseases; 54 studies in musculoskeletal system diseases; 51 studieswere initiated in infectious diseases, and 50 new studies were instigated intodiseases of the nervous system. The proportions between different therapeutic areas are shown in Figure 8.

Figure 8. Clinical trials in Russia in 2008 by therapeutic area

Clinical trials ResultsThe Center for Drug Evaluation and Research (CDER) of the FDA approved811 new drugs during 2008; 22 of them are new molecular entities; othershad new dosages, manufacturers or indications of the already marketeddrugs. Thirty-four drugs were studied in Russia.

During the year 2008 the Committee for Medicinal Products for HumanUse (CHMP) of the European Medicine Agency (EMEA) reviewed 982

applications to market drugs in the EU. A negative result was given for thirteen drugs. Thirty-five of the drugs which received positive opinions were(or are being) tested in clinical trials in Russia.

New Investigative SitesAccording to the RZN data, as of 12 November 2008 there were 946 hospitals entitled to conduct clinical trials in Russia. Ninety-two new siteswere designated by the RZN during 2008.

More than one-third (35%) of all Russian investigative sites are locatedin Moscow and St. Petersburg. The top 10 Russian regions by the number ofnew sites are shown in Table 4.

Table 4. Top 10 Russian regions by the number of investigative sites (Source RZN)

FDA InspectionsAccording to the FDA data, as of 7 January 2009, 13 FDA inspections wereconducted in the Russian investigative sites during 2008, the greatest annualnumber since 1995 when the first FDA inspection was conducted in Russia.No objectionable conditions or practices were found during seven inspections (NAI - No Action Indicated); six inspections resulted in VAI (Voluntary Action Indicated), i.e. objectionable conditions were found butthe problems did not justify further regulatory action, and any corrective action was left to the investigator to take voluntarily. Three inspections wereconducted in Moscow, six in St. Petersburg, two in Saratov, one in Novosibirsk,and one in Yaroslavl.

In terms of data quality Russia has the lowest deficiency rate among emerging markets including India, China and Latin America – an importantsign of Russia’s bright prospects in the worldwide clinical trial community.

In the last 15 years the powerful investment resources of Big Pharmahave created a good infrastructure and established the favourable condi-tions of the Russian market for middle and small-size biotechnological and pharmaceutical companies whose venture capital makes great demands forreturn on investment, especially in today’s challenging environment. ■

Figure 4. Countries represented on the Russian clinical trials market in 2008

Austria, Belgium, Israel, Spain, Italy, Canada, the Netherlands, Norway, Pakistan, Portugal, Serbia, Sweden, Japan, Ukraine, as well as Vietnam andPuerto Rico are represented among others.

Clinical trials by PhaseThirty-eight new Phase I clinical trials were launched in 2008, which is six trials more than during 2007. The number of the Phase II trials slightly decreased from 158 trials in 2007 to 152 in 2008. The number of Phase IIItrials demonstrated a substantial 21% increase over the previous year’snumber, up from 232 to 282 studies. The number of Phase IV trials slightlyincreased from 60 in 2007 to 62 in 2008.

Figure 5. Clinical trials in Russia in 2008 by Phase

As shown in Figure 6, the share of Phase III trials in 2008 stood at 53% ofthe total number of studies, Phase II trials accounted for 28%, Phase IV trialsstood at 12%, and the share of Phase I studies amounted to 7%.

Figure 6. The proportions between study phases in Russia in 2008

The number of patients planned to be enrolled in Phase II-IV trials launchedin 2008 stood at 60,643. 1,770 subjects will be recruited to Phase I trials;12,850 patients to Phase II trials; 40,767 subjects to Phase III studies and5,256 patients will be enrolled in Phase IV studies. The minimal number ofsubjects in a single study is three, and the maximum number is 5,500.The proportions of the number of patients between different Phases isshown in Figure 7.

Figure 7. The number of patients in 2008 by study Phase

The duration of the shortest trial is three months, and the longest is sevenyears.

Rating of international sponsorsThe Swiss pharmaceutical giant Novartis, sponsoring 22 new studies, wason the top of the heap in 2008. The French sanofi-aventis with 21 new trialsin 2008 took the runner-up place, followed by the UK’s GlaxoSmithKline andtwo American pharmaceutical manufacturers – Pfizer and Merck & Co., with18 trials each, and different numbers of patients.The top five international sponsors by the number of new studies in 2008are presented in Table 1.

Table 1. Top five international study sponsors in 2008

�Rating of Russian sponsorsThe Russian company ZAO Valenta Pharmaceutica, sponsoring 14 new clinical trials enrolling more than a thousand patients in 24 sites, ranked number one among domestic pharmaceutical manufacturers by the numberof new studies in 2008.

ZAO Biocad, with 11 new trials and 630 subjects in 64 sites, took the runner-up place. It is followed by OAO Sintez, OAO Nizhpharm and FGUPNIOPIK.

Table 2. Top five Russian study sponsors in 2008

Rating of Russian investigative sitesSt. Petersburg State Medical University n/a Pavlov ranked number oneamong the Russian investigative centres by the number of new studies (104)in 2008. The Russian Scientific Oncology Center n/a Blokhin, with 84 newstudies, took the runner-up place. It is followed by the St. Petersburg MilitaryMedical Academy n/a Kirov, accommodating 78 new trials in 2008.

The leading ten Russian sites by the number of new trials in 2008 are presented in Table 3.

36 JCS www.jforcs.com JCS 37www.jforcs.com

No Sponsor No. of trials No. of patients No of sites

1 Novartis 22 1,551 148

2 sanofi-aventis 21 3,409 221

3 GlaxoSmithKline 20 8,029 153

4 Pfizer 18 1,305 79

5 Merck & Co 18 1,196 74

No Sponsor No. of trials No. of patients No of sites

1 Valenta 14 1,060 24

2 Biocad 11 630 64

3 Sintez 9 526 12

4 Nizhpharm 9 456 10

5 NIOPIK 8 295 24

No Name КИ

1 St. Petersburg State Medical University n/a Pavlov 104

2 Russian Scientific Oncology Center n/a Blokhin 82

3 St. Petersburg Military Medical Academy n/a Kirov 78

4 Clinical Hospital #6 FMBA of Russia 73

5 Moscow Medical Academy n/a Sechenov 67

6 Russian State Medical University 65

7 Moscow State Medical Dental University 56

8 St. Petersburg State Medical Academy n/a Mechnikov 54

9 Moscow City Clinical Hospital #4 50

10Russian Cardiology Scientific Complex of

Rosmedtechnology47

No Name КИ

1 Moscow 104

2 St. Petersburg 82

3 Novosibirsk region 78

4 Moscow region 73

5 Sverdlovsk region 67

6 Nizhegorod region 65

7 Tatar republic 56

8 Yaroslavl region 54

9 Perm region 50

10 Rostov region 47

Igor Stefanov, Director for Business Development for Synergy Research Group (SynRG™), a Russian CRO with offices in Moscow,St.Petersburg, Novosibirsk, Perm, Yekaterinburg and Almaty (Kazakhstan). Prior to joining SynRG in January 2007, Igor wasManaging Director for Smartlock, the Russian biometric companyand was recognized as Entrepreneur of the Month by the Russianedition of Forbes magazine in May 2005. With MBA in Economics

and strong local expertise Stefanov has been providing business consulting services tolarge multi-national companies including Pfizer, J&J, GlaxoSmithKline, F.Hoffmann-LaRoche and others in Russia since 1993.

1 CDER FDA http://www.fda.gov/cder 2 CHMP EMEA http://www.emea.europa.eu/index/indexh1.htm

India is establishing itself as a global leader for outsourcing, and although it makes headlines predominantly as a one-stop shop forservices like IT and banking, it gets far less attention for another ofits booming economic sectors—pharmaceuticals. Over the past 10years, India’s pharmaceutical industry has experienced enormousgrowth. It is now the fourth largest pharmaceutical market globallyby volume of production. The estimated value in 2007 was US$13billion, ranking it 13th in the world in terms of value, according to anOctober 2007 report from Boston Analytics, a customised knowledgeservices company based in Boston, Massachusetts, USA.

Overall, the Indian pharmaceutical industry now represents nearly 1.5percent of India’s gross domestic product, and the market is growing at acompound annual growth rate (CAGR) of 13.5 percent. In addition, Indiahosts the most FDA-inspected and approved manufacturing facilities, andhas filed more Drug Master Files than any other country besides the UnitedStates.

This dramatic growth can be attributed to a growing middle class, avast and highly skilled English-speaking workforce and a government thatis anxious to support economic development, all working together to createthe perfect economic environment for this emerging market. India’s diverse population, with demonstrated leadership skills and a high concentration of qualified and experienced scientists and doctors has alsohelped to attract international investment, transitioning India into an ideallocation for pharmaceutical manufacturing and development.

Indian companies are also both investing in new facilities and gearingup to do more of their own research and development in-country, and additionally international companies are also increasing their presencethere. A world-class IT infrastructure there supports the global drug development model.

A steady stream of multinational drug companies has already take advantage of the country’s technically educated workforce, which has established India as a key destination for a growing number of clinical research organisations and contract manufacturing organisations. A McKinsey report predicts that by 2012 the value of the market in India willbe $25 billion.

Integrated service offeringIndia is an important part of delivering integrated protocols across multiplegeographies and Quintiles has extensive operations there, including clinicalresearch, ECG, biostatistics, data management and labs. Recent regulatorychanges have allowed the conduct of Phase I studies in India by non-Indian companies, with the exception of first-in-man studies which mayonly be conducted for molecules discovered in India.

This, alongside market conditions in India, makes it a logical locationfor Quintiles’ next stage of growth, and we will be opening a Phase I unitthere in partnership with Apollo hospitals in 2010.

Phase I The need to move compounds to the next stage faster is intense. Less than1% of compounds that enter development actually make it to market, andonly 8% of compounds entering Phase I will successfully complete PhaseIII. Early clinical development is key to enabling investigation in the targetpopulation at the earliest opportunity and well designed, integrated PhaseI and IIa studies can provide the data required to make robust go/no-godecisions early on. It is these data that are pivotal to expediting the development process and ensuring that only those compounds with mostpromise are further evaluated.

Protocols should be individualised and tailored to meet the requirementsof the development plan for the compound under investigation.

It is important to develop innovative flexible study designs with a focuson the data that is critical to decision-making. The design needs to accommodate changes to doses and procedures as data emerge. A keysuccess factor is to have an integrated, multi-disciplinary, translational approach that includes pre-clinical and Phase I stages in the developmentof an overall trial plan. A prerequisite is that the optimum product profilemust be defined at the outset, as must the success factors for the exploratory clinical phases.

It is increasingly important in study design to include appropriate clinical markers, to assess safety and potential activity. The role of biomarkers and other surrogate markers of response are growing in importance and there is now a wider range of techniques that can be

INDIA: THE ROAD TOSUCCESS

Clinical Trials in Russia?

Synergy Research Group!

For more information, please contact Igor Stefanov ([email protected]), or visit www.synrg-pharm.com

utilised, including micro-dosing, imaging techniques (e.g. PET, functionalMRI), challenge tests and specialised cell culture and receptor binding assays. An integrated programme will comprise a number of single, flexibleexploratory protocols and will usually combine investigation of single andmultiple doses in one protocol. This can help to enable better dose selection for Phase II studies, provide for better candidate selection for latephase development, avoid unnecessary investigation and can also provide preliminary information on the safety, tolerability, PK, PD andPOC/POP where possible in the target patient population.

As part of an integrated programme, it may be helpful to conduct someelements of the Phase I trial programme in non-traditional regions. Countries such as India can provide insight into, for example, PK/PD, drug-to-drug interactions, or drug-to-food interactions, all within the samerobust safety and ethical framework seen in mature regions.

With plans for additional Phase I capacity in India from 2010, Quintileswill be able to run integrated studies on a global basis, efficiently and effectively for sponsors. For example, Quintiles conducts complex PET studies in Sweden, modelling and simulation in Kansas, and developmentof biomarker methodologies in London. India may conduct the drug-to-drug interaction studies, for example, which generally occur later in the development life cycle.

Phase II and III studiesIncreasingly, as the economy in India grows, there is significantly more investment in healthcare by individuals and organisations alike. In parallel,there are large patient populations in a variety of disease areas that arefound in the West and the important role that India is playing becomesclear, in terms of getting new and better medicines to patients, faster.

Our experience in clinical research and our proprietary tools and databases means thatQuintiles can quickly find high-volume prescribersacross a wide range of target conditions. Investigator alliances worldwideensure priority access — across all key therapeutic areas — to sites with aconsistent record of meeting recruitment targets on time.

With informed consent documentation growing more complex, it ismore important than ever to create a simple and effective informed consent process that complies with regulatory requirements.

When working in non-traditional regions it is essential to overcome barriers such as illiteracy, language differences and cultural conflicts. Aparticular focus in India, where more than 16 languages are spoken, shouldbe on ensuring accurate and appropriate translations and ethics committee approval in each region.

New technology is helping with the consent process. We are now ableto offer more in-depth and interactive education tools to ensure that people fully understand all the information before signing. This includesvideo and web interfaces that people can use at their own pace. In India,Quintiles recruits patients and, in time, volunteers who clearly understandthe risks and benefits of participating in clinical research.

ECGCardiac safety testing in drug development has been a growing component of clinical research on compounds that have non-cardiac applications since the implementation of the E14 guidance from the International Conference on Harmonization in 2005. One benefit of thisis the elimination of many compounds before they even reach clinical trial,and those that do progress have a much cleaner cardiac profile.

Quintiles’ core ECG analytical laboratories in the high-tech hotspots ofMumbai and Bangalore, India, are the only centralised ECG laboratoriesto have cardiologists available 24 hours a day, seven days a week, for bothreal-time and retrospective ECG review and sign-off in the laboratory.

Our standards exceed ICH/FDA/EMEA cardiac safety guidelines. Quintiles analyses five-beat complexes as standard procedure and uses allFDA accepted/best practice technologies. Our cardiologists are blinded to

time, treatment and patient identity.All ECGs are read using screen-based measurement tools. Then a

cardiologist reviews and signs off on every single one. A senior cardiologistreviews all pivotal or abnormal ECGs during the third read. Quality assurance is provided throughout by board-certified cardiologists.

In addition to cardiologists, our turnkey ECG teams can include biostatisticians, medical writers, regulatory specialists, data managers andhighly experienced project managers.

Analytical servicesIt is essential, when conducting studies in multiple geographies, to have anetwork of clinically harmonised facilities, to ensure greater control overevery step of the process.

In labs, this control ranges from laboratory kits to sample storage toanalytical methods of data capture, and ensures uniform instrumentationand standard operating procedures (SOPs) for each study. For sponsors,the benefit is that results from a patient in Pretoria are directly comparableto those from a patient in Beijing.

The same applies to data management and biostatistics. Regardlessof where the function is physically performed, there must be a consistentpoint of contact for all management activities, even across multiple siteson multiple continents.

Of course, a familiarity with local languages and customs is also essential and this is where our teams coordinate to ensure a seamless levelof service.

No other contract research organisation can match Quintiles’ breadthof services combined with cost-efficiency. Our global infrastructure provides the flexibility to keep work close to home or access low-cost operations around the globe. For example our data management servicesare provided from ten offices on four continents which allows us to shareworkload, access low-cost options, and provide a high quality service nomatter where our customers are located.

ConclusionThere is a well-established need to develop better medicines faster for thebenefit of patients around the globe. It is also imperative that if the development of new medicines is to continue, the drug development processneeds to evolve to include emerging Asian economies such as India makingdrug development more global. In addition, it is vital that new technologies,that enhance global communication and allow real-time sharing of data,are fully capitalised on.

Quintiles is able to offer a truly integrated service to its customers withservices provided across more than 50 countries. India is an important andgrowing country in the Quintiles portfolio. The recent announcement thata Quintiles Phase I facility will open there in 2010 is testament to the scientific and clinical expertise in the region and builds on our extensive experience and network of services already provided from this country. ■


Ferzaan N. Engineer, PhD, is Chief Executive Officer of Quintiles India . He oversees Quintiles operations in India which include clinical research, ECG,biostatistics, data management and labs.

Eddie Caffrey, Senior Vice President and Head ofPhase I research at Quintiles, responsible for consistentand quality delivery of services across geographies.


JCS 43www.jforcs.com42 JCS www.jforcs.com

It is a cliché to say that the pharmaceutical industry is entering anew and more challenging phase. The changing environment manifests itself in different ways: higher regulatory hurdles, morecomplex areas of unmet medical need, and relentless cost pressuresfrom governments seeking to reduce healthcare costs. Above all theindustry is challenged by declining productivity manifested by increasing research budgets and declining numbers of new drugs successfully gaining market approval. Increasing productivity istherefore the single greatest long-term challenge facing the industry.

One potential route to increasing productivity is to outsource non-coreand in some cases core activities. If performed effectively, this can lead tomore efficient production by specialised service providers and more efficient resource management by service purchasers. Outsourcing operational activities is now common practice in a wide range of manufacturing and services businesses many of which use outsourcing ata strategic level to source both core and non-core activities. It has been estimated that Western pharma companies could save 50% of their R&Dbudgets by outsourcing activity to low-cost, high-skills regions of the world,such as India or China.1 The surprise is not that outsourcing has increasedin recent years (it undoubtedly has) but that the increase has been relatively modest and most pharma companies still outsource only a smallpercentage of their R&D work. Indeed, there is evidence that the pharmaceutical industry makes less use of outsourcing than other industries of comparable size and complexity [2,3]. Although outsourcingis now common in clinical development, pre-clinical drug discovery groupsstill make relatively little use of outsourcing.

A leading big-pharma CEO has commented that culture eats strategyfor lunch [4]. This article argues that cultural factors (rather than quality ordelivery issues) have determined the pace of change and discusses the nature of the science-based culture which has made the introduction ofoutsourcing strategies particularly difficult in pre-clinical drug discovery.

The arguments in favour of outsourcing will be familiar to most readersbut still bear repeating.

1. Increased management focus on core activities.2. Outsourcing disciplines where the outsourcing company can

not achieve critical mass, to service providers who can achieve both critical mass and economies of scale.

3. Amortisation of capital costs over a large cost base.4. Better resource management in areas with large peaks and

troughs in demand for resource.5. Improved resource planning in areas where demand may be

stable in the medium term but variable over the longer term.

The benefits of outsourcing outlined above are applicable to many areasof pre-clinical drug discovery. However, both big pharma and biotech havebeen slow to outsource all but a small range of activities, often in areaswhere in-house development is difficult or impossible, for example, in vivotesting where the risk of attracting animal rights protestors has deterred companies from building in-house groups. In the discussion that

follows, this article explores cultural influences inhibiting the adoption ofoutsourcing models in drug discovery and opposing business constraintsencouraging the trend towards a more decentralised, less vertically integrated industry making increasing use of strategic outsourcing. Thefinal section of the article argues that the life-cycle of pharmaceutical research also provides strong business (and ethical) reasons to make increased use of outsourcing in pre-clinical drug discovery.

The innovation biasTraditionally the pharmaceutical industry has sought to increase productivity through technological innovation. That is, though identifyingand perfecting the application of novel technologies which offer the promise of significantly increased productivity. In the last 20 years drugdiscovery labs have successively adopted at least five different platformtechnologies (Table 1).

Each of these technologies has enjoyed its day in the sun. Almost alllarge and many mid-sized pharmaceutical companies have made significant investments in groups aimed at developing a world-class capability in all five technologies. The adoption of these new technologieshas two striking features. Firstly, the industry was prone to overestimatethe benefits and make financial investments which failed to justify the capital outlay. Secondly, with very few exceptions companies chose to develop in-house groups to support enabling technologies which were onlyindirectly related to what could be called the sharp end of pharmaceuticalresearch: projects with a clear therapeutic focus and objectives directly related to the discovery of new products. To take a specific example, HighThroughput Screening (HTS) requires a substantial capital investment inrobotics, automation and IT and by its nature can only be applied to a single point in the drug discovery process (lead identification, Table 1). Anoutside observer might have expected the industry to use outsourcing asa route to sourcing this technology. In practice what happened was thatHTS groups screening broadly similar collections of molecules were duplicated across the entire industry. To the author’s knowledge no largepharma company chose to outsource their HTS activities – even thoughHTS should have been an ideal area for a less integrated, less capital-

OUTSOURCING PRE-CLINICALDRUG DISCOVERY

TECHNOLOGY UNDERLYING TECHNOLOGIES

DRUG DISCOVERY

GenomicsIn silico modelling, automationand robotics

Target discovery and validation

ProteomicsIn silico modelling, automationand robotics

Target discovery and validation

High ThroughoutScreening

Automation and robotics Lead discovery

Molecular Modelling

In silico predictionLead identification and leadoptimisation

Combinatorial Chemistry

Automation and roboticsHit to lead and leadoptimisation

intensive approach to technology development. It is worth pointing outthat this process is self-reinforcing. As more players choose to develop resource in house, the economic environment for service providers becomes less attractive and outsourcing options for the remaining playersless satisfactory.

In spite of heavy investment in platform technologies, drug discoverycosts have continued to increase and remained stubbornly resistant totechnology-based solutions. Although there is little agreement on thecauses of this failure (and advocates of the new technologies would arguethat in their absence costs would have risen still further) it is possible todraw some conclusions on the outcome of two decades of investment innew technology.

In broad terms two different and to some extent philosophically opposed approaches to innovation were adopted. Firstly, researcherssought to exploit the decreasing cost of computers and advances in in silicomodels to reduce the number of drug candidates which need to be synthesised and tested in laboratories. This is clearly a strategy, which (ifthe predictions are accurate) will deliver substantial cost savings since running computer models is cheap and the synthesis/testing cycle is expensive and slow. The second approach sought to exploit advances inrobotics and automation technology to substantially reduce the unit costof running experiments. Whilst there is littleagreement on which of the platform technologies outlined in Table 1 have been mostsuccessful, two points of consensus haveemerged: firstly that in silico modelling has notbeen able to significantly reduce the large number of candidate drugs needed to identify asingle development candidate, and secondlythat automation has been much less successfulin the chemistry than the biology arena. Target identification, target validation and candidatedrug testing all rely on the biological scienceswhere automation has significantly reducedcosts and generated data and results whichwould have been unthinkable without its introduction. In contrast, automation andassociated platform technologies have hadmuch less impact on synthesis costs and timelines in hit to lead (H2L) and lead optimisation (LO) phases of drug discovery.

The net effect of these two ‘failures’ (in silicomodelling and chemistry automation) is thatmedicinal chemistry has become the critical resource to manage in drug discovery, since testing molecules is quick and relatively cheap while synthesising them isslow and expensive. Sourcing medicinal chemistry as efficiently as possibleis therefore a key challenge for drug discovery groups across the industry.

It is relatively easy to quantify medicinal chemistry costs – at least at abroad brush level. A typical drug discovery program takes approximately700-1000 molecules to identify a single development candidate. On average, medicinal chemists synthesise around 80 molecules per annum– so that each development candidate costs 9-12 medicinal chemistry man years.1 The cost of employing synthetic chemists in Indiaor China is approximately one-third of the cost of employing a similarlyeducated chemist in Europe or North America [5]. The availability of medicinal chemistry skills in low-cost, high-skills regions of the world therefore offers the opportunity to achieve cost savings in hit to lead (H2L)and lead optimisation (LO) phases of drug discovery comfortably exceeding anything achieved by research-led innovation over the lasttwenty years. Of course there are cultural, logistical and technical obstaclesto overcome if these costs savings are to be achieved with no loss of

quality. Medicinal chemists will not disappear from European or NorthAmerican laboratories but it seems likely (and from the point of view ofhealthcare consumers desirable) that a significant proportion of small molecule drug discovery programs will shift from West to East over the nextfive to ten years.

Core and non-core activities: which functions to outsource ?To argue that companies should outsource non-core activities begs thequestion of which functions are core and which are non-core. This can bea tricky question in any company and pharmaceutical companies are certainly no exception. A straightforward reason why pharma companieshave made relatively little use of outsourcing is that many senior researchmanagers believe that laboratory-based work is a core activity for research-based pharma, which should only be outsourced as a last resort.

In practice a company’s willingness to outsource drug discovery depends on where it draws the line between core and non-core activities.A common if not universal viewpoint is that research-based pharma’s coreexpertise is managing lab-based drug discovery programs. With this viewpoint, managers will outsource non-core activities (in vivo testing, invivo and in vitro pharmacokinetics, toxicology and scale-up chemistry) butthey will leave most drug discovery activities, and in particular hit to lead

and lead optimisation chemistry, in-house. An alternative perspective is that the company

loyalty is primarily to a portfolio of drug discoveryhypotheses or targets. Having selected the target, the company will invest in project-specificunderpinning biology and be content to outsourceas much as is practically possible of the drug discovery effort required to identify clinical candidates; which in turn will be used to validatetargets in the clinic. Using a portfolio model, companies will focus on identifying novel and well-validated targets (and the project-specific biology required to support their progression) andoutsource most of the generic disciplines requiredfor drug discovery. It remains to be seen if thismodel is feasible or cost-effective, but there arecompelling reasons for believing that the availability of drug discovery resource in India andChina, and the scope for making rational business-led decisions using an outsourcing model,could give rise to novel and cost-effective drugs ofthe future.

Life-cycle managementThe life-cycle of a typical drug discovery program spans ten years and twophases, each lasting five years. The first phase (pre-clinical drug discovery)makes use of resources and disciplines which are not required in the secondphase (clinical development). This is a simplification of a complex processbut it captures the essential elements of a key challenge in pharmaceuticalR&D, which is that therapeutic discovery requires one set of resources forthe first half of the product development cycle and a different set of resources for the second half. Viewed from a five-year timeframe the argument for outsourcing may therefore be neutral. However, over a longertimeframe arguments favouring outsourcing become much more compelling since large and hard-to-predict peaks and troughs in demandfor resource emerge over a timeframe which may appear long from a conventional resource-planning perspective, but are short when viewedfrom the perspective of employers and employees. Both large and smallpharma companies try to overcome this problem by developing a portfolioof drugs at different stages of development to ensure a steady demandfor pre-clinical and clinical teams. It is hard to judge how well large pharma

“In practice a company’s

willingness to outsource

drug discovery depends on

where it draws the line

between core and non-core

activities. A common if not

universal viewpoint is that

research-based pharma’s

core expertise is managing

lab-based drug discovery

programs.”

Table 1:

1 This does not include identifying follow-up compounds, patent exemplification or re-synthesis for in vivo studies. If these activities are included the number of man years increases significantly. Project attritionincreases the number still further.


companies succeed in achieving this objective but it seems likely that (evenin big-pharma) the current in-house model results in under-resourcing ofgood opportunities and over-resourcing of poor ones; and that a more flexible outsourcing model could match opportunities and resource moreefficiently. In the biotech sector it is clear that life-cycle management isvery problematic. Anyone who has worked in the biotech sector over thelast 20 years will be familiar with under- and over-resourced teams (in bothpre-clinical and clinical drug discovery) which result when companies switchemphasis from pre-clinical to clinical programs using an employmentmodel ill-fitted to the underlying nature of the business. It therefore seemsprobable that the biotech sector would benefit from adopting a moreflexible outsourcing model in pre-clinical as well as clinical disciplines(where the switch from in-house to outsourced resource has largely occurred).

ConclusionFor most of the last 20 years the pharmaceutical industry has focussed itsattention on innovation and the development of new technologies to find away out of the productivity impasse with relatively little emphasis on conventional cost-cutting or the adoption of new business models. In spiteof an increasing trend toward outsourcing, pre-clinical drug discovery groupsstill make little use of outsourcing compared with clinical departments orother comparable industries. Over the next five to ten years we expect thatthe trends discussed above and summarised below will give rise to greateruse of outsourcing by pre-clinical drug discovery groups.

• A more sceptical approach to investment in platform-based technologies and an increased interest in seeking to decrease costs and increase productivity by developing new business models,some of which will rely on more strategic use of out sourcing.

• The emergence of companies whose expertise lies in selecting targets and developing project-specific biology to support their progression. These companies will be prepared to outsource all of the generic aspects of drug discovery – including hard-to-outsource disciplines such as medicinal chemistry.

• A recognition by biotechnology companies that most drug discovery programs have a four to six year lifespan, which makes it difficult to justify (on business or ethical grounds) employing large numbers of permanent laboratory-based staff. ■

REFERENCES: 1. Jack, A. & Bowe, C. “Drugs companies seek new remedies for growth”, Financial Times,April 20th 2005.2. Coghlan, A. “Blockbuster Challenge”, NewScientist 12 June: 54-57, 2004.3. Rosenberg, M. & Mackenzie-Lawrie, S. “Innovation, efficiency and outsourcing”, ScripMagazine May: 45-46, 2003.4. Knezevic, S. & Woods, P. “Senior Managers Need New Skills and Solid Experience”, SCRIPWorld Pharmaceutical News, No 3426, December 26th 20085. Mottl, H., Pinto, J., Harms, B. “Sourcing of Drug Discovery Services from Offshore Locations”, Version 1.0, 3A-Strategy Consulting GmbH, Germany, February 2005.

Linda Zao: What are the major objectives of Charles River in Chinain the next two years vs. the next 5 years? What types of preclinical studies will Charles River conduct in China (GLP and non-GLP toxicology)?Dr. Kewen Jin: Due to its large population and highly educated workforce,China is an important market for global drug development and is continuing to grow as a centre of innovation in research and development.Our new facility will play a part in fostering this culture by helping both multinational and local biopharmaceutical organisations accelerate theirdrug development programs.

As a service organisation, we provide solutions for our clients’ need for toxicology expertise to help support their objectives and strategies for drugdevelopment in China.

Initially, our clients have indicated a need for discovery support throughto investigational new drug (IND)-enabling toxicology services. CharlesRiver will be one of the first major global contract research organisations(CROs) to open a GLP facility in China that will work towards meeting North American, European, and Asian regulatory requirements. We are offeringthe ability to not only perform discovery screening with a very high standard of quality, but also to take them through to early clinical trials byconducting preclinical studies to the same exacting standards that are usedin all of our other Charles River sites worldwide. As time goes on, that willprogress into longer-term studies and specialties, so we would expect tobe adding immunology, reproductive toxicology, and other services in support of our customers’ needs.

LZ: Can you briefly describe the major customers that Charles River’sisplanning to serve in China? Are they mainly international pharmaceutical companies as most other multi-national CROs aredoing? Do you consider domestic Chinese pharmaceutical companiesas your potential customers?KJ: The new facilities will help both multinational pharmaceutical clientsand local biopharmaceutical organisations accelerate their drug development programs.

LZ: Can you compare Charles River with your major competitors (multinational, national, and Chinese domestic CROs) in China in relation to your advantages AND disadvantages?KJ: As part of the Charles River organisation, the Shanghai PCS facility isable to take advantage of our worldwide resources, including our high-quality research models. In addition, we differentiate ourselves by offering:

• Highly skilled Quality Assurance staff and established processes

proven to help sustain regulatory compliance, including an understanding of OECD, FDA, and SFDA requirements thatenable clients to submit toxicology packages anywhere in the world

• Cross-training of personnel using global practices and standards to build our team around our clients’ projects, including specialised study directors, dedicated technicians, and experienced scientific, veterinary, and technical staff

• Full-service offerings with the advantage of a single integrated structure linking all scientific departments to ensure constant communication of information (analytical chemistry, bioanalysis, clinical labs, pathology, archiving, etc.) internally as well as with our clients to facilitate study monitoring

• Integrated project management services for large projects to ensure not only that timelines are met, but that they also support extensive coordination of scientific information

• Access to specialised technologies and scientific knowledge through the global network of Charles River scientists

• A senior scientific and operations management team composed of either Western expatriates or Western-trained professionals with a combined CRO/pharma experience of more than 50 years.

LZ: What challenges is Charles River currently facing, or likely to face,in China?KJ: The preclinical arena is relatively new to China. It is only in recent yearsthat the global pharmaceutical and biotechnology industry began building its presence there and that China started moving from a moregeneric industry to an innovative one. As such, the number one challengeis recruitment, training, and retention of experienced, qualified professionals in the positions critical to preclinical research such as toxicology, pathology, ophthalmology, quality assurance, and veterinarymedicine. As we discuss later on, Charles River has been proactive in setting up a recruitment and retention programme, which we believe willhelp us build a strong team.

Furthermore, there is the current global market condition that multinationals and bioteches are facing that is prompting them to look atreorganisation, consolidation, and new business models. Even though therehas been some short-term slowdown, the medium- to long-term macrotrend will see multinationals and biotechs increasing their outsourcing.

We also believe that we will see further growth of the Asia/China-basedglobal pharmaceutical and biotech R&D operation, and Charles River’s newShanghai site will be positioned to support this growth.


INTERVIEW: FUTURE OF PRE-CLINICAL OPERATIONSIN CHINADr Linda Zao of Draco Healthcare Consulting

speaks with Dr Kewen Jin, GM Charles River, China

Philip Huxley has 18 years experience in the pharmaceutical industry and played a key role in the identification of four clinical candidates. He began his career as a computationalchemist with Novartis (Basel) and has subsequently held positions of increasing seniority with British Biotech (Head ofMolecular Design), Avidex (Head of Drug Discovery), and Galapagos Genomics (Director of Drug Discovery). Philipfounded Gateway Chemicals in 2007 in order to provide

focused libraries to drug discovery groups in the pharmaceutical industry. Workingclosely with Indian offshore CROs, Gateway Chemicals can synthesize both client andGateway designed libraries for drug discovery groups wishing to explore SAR aroundnovel lead compounds. Email: [email protected]

www.jforcs.com

LZ: Can you explain the current preclinical study environment in China, including GLP standards and animal care, as well as other issues thatyou consider important for the growth of Charles River’s business inChina?KJ:As mentioned previously, Charles River will be one of the first major globalCROs to open a GLP facility in China that will work towards meeting NorthAmerican, European and Asian regulatory requirements. Our preclinical staffhas extensive knowledge, expertise, and experience in the design of bothsingle GLP studies and GLP toxicology testing programs for a wide range ofcompounds and in multiple species.

The future of our business in China is based on our quality lab with its experienced scientists and technicians that meet Chinese and internationalstandards of operation. We believe that our strategy of partnering with ourclients to help them accelerate their drug development programs by providing outstanding customer service and commitment to scientific excellence through best-in-class products, services, and procedures will leadus to establishing longstanding relationships.

LZ:What are the essential steps for the Chinese preclinical industry tomeet the US-level quality and ethics requirements?KJ: Charles River’s Shanghai facility will meet all the GLP requirements ofChina’s State Food and Drug Administration (SFDA), the US FDA, and theEuropean Agency for the Evaluation of Medicinal Products (EMEA), as wellas complying with the standards of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), the Canadian Councilon Animal Care (CCAC), and the Organization for Economic Cooperationand Development (OECD).

Meeting these diverse regulatory standards demands excellent workforcetraining. We used a number of solutions, all of them involving hands-on training. Over the last six to eight months, we brought more than 20 key Chinese staff to our Montreal facility for three- to six-month periods for intensive training in standard operating procedures (SOPs). They were theninvolved in transferring the SOPs from our global sites to our facility in China.In addition, we had staff validating the building and overseeing the training.Following that, we also have periodic transfers of approximately 20 staff inkey positions from Montreal to China to reinforce the training and bring innew capabilities.

We also transferred four senior staff to China for a three-year period. Theyhave a combined CRO experience of over 45 years with a broad base of ex-perience and will take key positions overseeing the overall process. In addition, we have scheduled regular audits from our Quality Assurance groupin Montreal who will be going to our Shanghai facility to ensure that it ismeeting the same standards we have implemented in our preclinical sites

worldwide. Furthermore, we have transferred the data acquisition and ITprocesses from our other sites into China to ensure that we operate usingthe same systems as our other Charles River sites.

LZ:What is Charles River’s strategy of recruiting and maintaining thebest talents in China with the high turnover rates going on in China?KJ: Recruiting and retaining talented employees is one of the greatest challenges for multinational corporations operating in China. We leveragevarious channels to recruit people, including e-recruitment, employee referralprograms, employment agencies, and campus recruitment. For instance,many of our technicians/junior scientists were hired directly after graduation.The students who are selected from the campus interview are typically offered an internship period during which they receive basic training. Thosestudents who have an ability to learn quickly and demonstrate a high levelof teamwork are considered for permanent employment opportunities.

We are a new company in China and as such retention is not yet an issue.However, we have been proactive in developing programmes to address future retention since this is a major contributor in ensuring the success ofour operation. Staff retention is influenced by many factors including clearleadership, competitive compensation and benefit practices, individual career development plans, employee engagement and training, and goodhealth and safety practices. The more importance we put on developing newstrategies and constantly managing our retention plan, the more likely staffwill be attracted to and remain in the organisation. Our aim is to attract andretain staff with a range of skills and experience by providing an organisationthat is committed to valuing its staff and promoting their professional andpersonal development. ■

Kewen Jin, M.D. is the general manager at CharlesRiver’s Shanghai facility. In this role, he provides strategy and guidance for the Company’s Shanghai preclinical business operations.

Dr. Linda X. Zhao is the president and CEO ofDraco Healthcare Consulting LLC, a China-focused consultancy based in San Francisco and Beijing. Dr.Zhao has more than 20 years experience in biotechand pharmaceutical industries in China, Japan andthe United States.

46 JCS

www.jforcs.com

Infectious diseases are a major cause of lethality worldwide. In addition to the physically debilitating aspects of the disease, theycan cause neuropsychological and cognitive impairments. Prime examples are infections of the brain that are caused by viruses orbacteria, or in the case of cerebral malaria, by protozoa. Other diseases that induce neuropsychological/cognitive changes areLyme disease, AIDS-associated dementia as a late stage manifestation of the HIV infection, or just the simple common coldthat virtually everybody experiences up to several times a year.However, the mechanisms of how certain diseases affect the brainare poorly understood. Cognitive assessments to evaluate whichcognitive domains are affected can help to find adequate therapies for the cognitive deficits caused by the disease.

On the other hand, certain medicines and drugs that should protectagainst or counter the very effects of an infectious disease can have neuropsychological side-effects that range from mild to severe, but can,in some cases, have a lethal outcome. Virtually every anti-malarial treatment that tourists take as a protection when they travel into tropical countries have known and wide-ranging neuropsychologicalside-effects. Another example is interferon α (IFN α) that is used as along-term therapy for Hepatitis C (HCV) infection. IFN α induces severedepression, fatigue and cognitive impairment that is an extra burden tothe already distressed patient. An involvement of cognitive testing earlyin the clinical drug development process can help to find compoundsthat have no or at least fewer neuropsychological side-effects, thandrugs currently in use against infectious diseases.

Viral and Bacterial Infections of the BrainEncephalitis is an infection of the brain parenchyma that is usually ofviral origin. Approximately 20,000 cases occur every year in the USAalone. The acute stage is characterised by fever, seizures and memorydeficits (Hokkanen and Launes, 2000). The cognitive defects can persistfor years and are a major cause of disability. Viruses known to cause encephalitis are Herpes simplex and flaviviruses. Herpes simplex rests inthe trigeminal facial nerve and if activated by stress, UV light or otherfactors will cause a “cold sore”. However in some, albeit rare, cases, it enters the brain, where it causes lesions. Due to the very high mortality,there are only a few cases of survivors, typically exhibiting symptoms ofdementia, personality disorder and motor impairment. The incidence of meningitis is approximately five cases per 100,000 people and it is usually caused by bacteria. To assess the cognitive outcome of adult survivors of bacterial meningitis, data from threeprospective multi-centre studies from the Netherlands were re-analysed(Hoogmann et al., 2007). The assessments used in each study were identical and included tests for memory, attention, motor function, intelligence and mood states. They found that survivors of bacterialmeningitis had impairments in memory, and they were significantlyslower in cognitive speed measures (Simple Reaction Times) thanhealthy controls.

COGNITION AND INFECTIOUS DISEASES

48 JCS

general intelligence, visual and verbal working memory, attention, executive function and language found that children with Lyme diseasehad lower intelligence and memory scores in addition to a higher depression rating than healthy children (Tager et al., 2001). Adult patients with encephalopathy suffer from deficits in verbal memory andvisuospatial organisation even years after the infection (Cameron, 2008;Cairns and Goodwin, 2005). This seemed to correlate with a decrease inblood flow in the white matter of the brain as compared tocontrols (Fallon et al., 2003).

SCHISTOSOMIASISIn developed countries, diseases from multi-cellular parasites are only infrequently encountered. In developing countries, chronic or recurrent parasitic infections constitute a major health problem (King and Dangerfield-Cha, 2008; Engels et al., 2002). Although there are success-ful therapies against worm infection, the environmental and social surroundings make a re-infection very likely. Schistosomiasis is a trematode infection that occurs in vast areas of Africa, Asia and SouthAmerica. It has been estimated that more than 200 million are currentlyinfected, and the majority of these people live in low-income Africancountries (Engels et al., 2002). Schistosomiasis is linked to a bad sanitarysystem, as the primary host, a snail, resides in water and the worm canenter humans when they are exposed to the water. Only half of the eggsthe worm produces are passed through the human body and the otherhalf are lodged within tissue. This causes inflammation and the symptoms take the form of a chronic disease with multiple clinical features (King and Dangerfield-Cha, 2008). A study with Tanzanian children using cognitive tests found that heavy infection was associatedwith lower performance in Choice Reaction Time, Digit Span forward andbackwards and Silly Sentence Tasks than in the healthy control group(Jukes et al., 2002).

SUMMARYThere are many infectious diseases that induce neuropsychological and cognitive impairments which are an additional burden for the already debilitated patient. The molecular mechanism is in general poorly understood and that prevents an adequate therapy.

A second aspect is that the very drugs to prevent or to cure these diseases can have severe neuropsychological side-effects.

Cognitive testing can be used to investigate which cognitive domainsare affected. It also should be used much earlier in the drug developmentprocess for treatment of infectious diseases, to rule out compounds thathave an undesirable cognitive side-effect profile. ■


Upper Respiratory Tract InfectionAlthough not life-threatening, an upper respiratory tract infection suchas the common cold, affects cognition, emotion and mood. Since everybody is expected to have at least two infections per year, the upperrespiratory tract infection is one of the most common diseases worldwideand the economic cost due to missed work days is considerable. In a recent study, 21 healthy young and old volunteers were matched with21 volunteers showing signs of a common cold infection without fever(Bucks et al., 2007). A computerised assessment battery measured attention, memory, emotional processing and subjective ratings of moodand alertness. The illness did not affect speed or accuracy of attention,or the quality of working (short-term) or episodic (long-term) memory.But the speed of accessing stored memories and the face-label reactiontime, where the participants had to match emotionally negative faceswith the respective label (angry, afraid or neutral) did not improve asmuch as in healthy volunteers. In addition, mood was negatively affectedand subjective ratings of alertness were reduced.

HIV/AIDSInfection with human deficiency virus is commonly known to target and weaken theimmune system, but there is a lesser knownand not well understood degeneration of thecentral nervous system. AIDS especially is complicated by neuropsychological disordersthat contribute to the co-morbidity and lethality of the disease. The most prominentform is AIDS dementia, which usually startswith depression and subtle neuropsychologi-cal and psychomotor changes, but often afterwards progresses rapidly into a severe dementia with fatal outcome (Anthony andBell, 2008). As HIV patients have an increased survival rate due to highly active antiretroviral therapy, there is also an increasein incidences in the neuropathies of AIDS.

Most of the studies about cognitive impairment of AIDS were conducted in theUSA and Europe where the predominant virusstrain is subtype B. In African and Asian countries, subtype C is the principal virusstrain. A study evaluated cognitive function inseropositive male and female adults (20 to 44years) from South India (Gupta et al., 2007). They were compared to gender-, education- and age-matched healthy norms. Thetest included visual and verbal memory, finger tapping and phonemic fluency tasks. The outcome showed that the patients had mildto moderate cognitive impairments with no clinically functional deficitcompared to the healthy controls. The prevalence of the cognitiveimpairment was comparable to patients infected with subtype B.

HEPATITIS CHepatitis C (HCV) is a blood-borne viral disease that is mainly transmittedvia intravenous drug abuse. Transmission via contaminated blood products for transfusion is negligible today due to the screening of blood products for viral particles prior to use. HCV is a major cause of chronicliver disease, cirrhotic liver failure and hepatocellular carcinoma. It hasbeen estimated that 200 million people worldwide, including 4 millionpeople in the USA, are infected with HCV. The current approved and onlyeffective standard combination therapy for chronic hepatitis C is recombinant interferon � (IFN �) and ribavirin. The administration ofIFN � has been linked to severe depression, fatigue, anxiety and

cognitive impairments (Saunders, 2008; Horsmans, 2005), although ithas been suggested that the patients’ awareness of the outcome andprognosis could also play a role in the higher incidence of occurrences ofmajor depressive episodes in HCV patients than in healthy controls (Cartaet al., 2007). In a study with 14 chronic HCV patients, the Montgomery-Asberg Depression Rating Scale and the Hamilton RatingScale for Anxiety increased significantly one month after the start of theIFN � therapy. In addition, serum serotonin levels decreased, althoughit is not clear if serotonin reductions have also occurred in the brain(Bonaccorso et al., 2002). This is supported by several studies that successfully treated interferon-induced depression with the selective serotonin re-uptake inhibitor citalopram (Kraus et al., 2008; Schaefer et al., 2005).

MALARIAMalaria is one of the most important causes of morbidity and mortality worldwide. Malaria is an infectious tropical disease caused by Plasmodium protozoa that are transmitted by mosquitoes. There are 4different species: P. falciparum, P. vivax, P. ovale and P. malariae that

infect red blood cells (White 1996). P. falciparum is the most common form ofmalaria infections. The most severe form,cerebral malaria (CM) is also caused by thisstrain and is characterised by seizures abnormal posturing and coma. Even withtreatment about a quarter of the patients die,and those who survive can develop persistent neuropsychological and cognitive impairments.In a study of Ugandan children with CM, itwas found that over 20% had deficits in attention and working memory six monthsafter the start of the study as compared toabout 6% in healthy children (Boivin et al.,2007). A study of Kenyan children found thatpatients who survived the acute stage of CMhad a statistically significantly higher numberof psychomotor, language and speech impairments in addition to memory and attention deficits, than participants withoutexposure to this form of malaria (Idro et al.,2006).

All anti-malarial drugs have common side-effects that range from mild to severe

(AlKadi et al., 2007). These side-effects include cardiovascular as well asneuropsychological adverse effects. A widely used anti-malarial drug isquinine-derived mefloquine (lariam). In addition to common side-effectslike vivid dreams, confusion, dizziness and inability to concentrate, thecompound has been linked to psychosis and delusion (Kukoyi and Carney,2003; Stuiver et al., 1989). The molecular basis for this change in mentalstate is poorly understood, but it could be that mefloquine triggers aspontaneous release of neurotransmitters such as GABA (Zhou et al.,2006).

CHRONIC LYME DISEASELyme disease is caused by the tick-borne spirochete Borellia burgdorferi.It was first discovered in late 1970 in Connecticut and is common in USAand Europe. At first, there are flu-like symptoms followed by a migrating erythema. At the later stage, the symptoms are multi-systemic as joints,muscle, heart and the central nervous system are affected (Westerfeltand McCaffrey, 2002). The neuropsychological symptoms manifest in encephalopathy and meningitis. A study with 40 children (20 childrenwith Lyme disease and 20 healthy controls), that used assessments for


REFERENCES:

AlKadi, H. O. (2007). Antimalarial drug toxicity: a review. Chemotherapy 53, 385-391.

Anthony, I. C., and Bell, J. E. (2008). The Neuropathology of HIV/AIDS. Int Rev Psychiatry 20, 15-24.

Boivin, M. J., Bangirana, P., Byarugaba, J., Opoka, R. O., Idro, R. et al. (2007). Cognitive impairmentafter cerebral malaria in children: a prospective study. Pediatrics 119, e360-366.

Bonaccorso, S., Marino, V., Puzella, A., Pasquini, M., Biondi, M. et al. (2002). Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psycho-pharmacol 22, 86-90.

Bucks, R., Gidron, Y., Harris, P., Teeling, J., Wesnes, K. et al. (2007). Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: A prospective study. Brain, Behaviour and Immunity.

Cairns, V., and Godwin, J. (2005). Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 34, 1340-1345.

Cameron, D. J. (2009). Clinical trials validate the severity of persistent Lyme disease symptoms. Med Hypotheses 72, 153-156.

Carta, M. G., Hardoy, M. C., Garofalo, A., Pisano, E., Nonnoi, V. et al. (2007). Association of chronichepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemol Ment Health 3, 22.

Engels, D., Chitsulo, L., Montresor, A., and Savioli, L. (2002). The global epidemiological situation ofschistosomiasis and new approaches to control and research. Acta Trop 82, 139-146.

Fallon, B. A., Keilp, J., Prohovnik, I., Heertum, R. V., and Mann, J. J. (2003). Regional cerebral blood flow and cognitive deficits in chronic lyme disease. J Neuropsychiatry Clin Neurosci 15, 326-332.

Gupta, J. D., Satishchandra, P., Gopukumar, K., Wilkie, F., Waldrop-Valverde, D. et al. 2007). Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adultsfrom South India. J Neurovirol 13, 195-202.

Hokkanen, L., and Launes, J. (2000). Cognitive outcome in acute sporadic encephalitis. Neuropsychol Rev 10, 151-167.

Hoogman, M., van de Beek, D., Weisfelt, M., de Gans, J., and Schmand, B. (2007). Cognitive outcome in adults after bacterial meningitis. J Neurol Neurosurg Psychiatry 78, 1092-1096.

Horsmans, Y. (2005). Chronic hepatitis C, depression and interferon. J Hepatol 42, 788-789.

Idro, R., Carter, J. A., Fegan, G., Neville, B. G., and Newton, C. R. (2006). Risk factors for persisting neuropsychological and cognitive impairments following cerebral malaria. Arch Dis Child 91, 142-148.

Jukes, M. C., Nokes, C. A., Alcock, K. J., Lambo, J. K., Kihamia, C. et al. (2002). Heavy schistosomiasis associated with poor short-term memory and slower reaction times in Tanzanian schoolchildren.Trop Med Int Health 7, 104-117.

King, C. H., and Dangerfield-Cha, M. (2008). The unacknowledged impact of chronic schistosomiasis.Chronic Illn 4, 65-79.

Kraus, M. R., Schafer, A., Schottker, K., Keicher, C., Weissbrich, B. et al. (2008). Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind,placebo-controlled study. Gut 57, 531-536.

Kukoyi, O., and Carney, C. P. (2003). Curses, madness, and mefloquine. Psychosomatics 44, 339-341.

Saunders, J. C. (2008). Neuropsychiatric symptoms of hepatitis C. Issues Ment Health Nurs 29, 209-220.

Schaefer, M., Schwaiger, M., Garkisch, A. S., Pich, M., Hinzpeter, A. et al. (2005). Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol42, 793-798.

Stuiver, P. C., Ligthelm, R. J., and Goud, T. J. (1989). Acute psychosis after mefloquine. Lancet 2, 282.

Tager, F. A., Fallon, B. A., Keilp, J., Rissenberg, M., Jones, C. R. et al. (2001). A controlled study of cognitive deficits in children with chronic Lyme disease. J Neuropsychiatry Clin Neurosci 13, 500-507.

Westervelt, H. J., and McCaffrey, R. J. (2002). Neuropsychological functioning in chronic Lyme disease. Neuropsychol Rev 12, 153-177.

White, N. J. (1996). The treatment of malaria. N Engl J Med 335, 800-806.

Zhou, C., Xiao, C., McArdle, J. J., and Ye, J. H. (2006). Mefloquine enhances nigral gamma-aminobutyric acid release via inhibition of cholinesterase. J Pharmacol Exp Ther 317, 1155-1160.

“AIDS especially is complicated

by neuropsychological

disorders that contribute to the

co-morbidity and lethality of

the disease. The most

prominent form is AIDS

dementia, which usually starts

with depression and subtle

neuropsychological and

psychomotor changes, but

often afterwards progresses

rapidly into a severe dementia

with fatal outcome.”

Acknowledgements:I thank Helen Brooker and Rianne Stacey for helpful comments.

Lars Schmiedeberg gained his degree in Life Science from the University of Bochum and hisPhD from the University of Jena, both in Germany.After working as a post-doctoral researcher in Edinburgh at the Wellcome Trust Centre for Cell Biology, he gathered experience in technology andconsulting companies within the Biotechnology industry. He works now as a scientific officer forCognitive Drug Research Ltd.



The biopharmaceutical industry has consistently made large investments in improving outcomes for ischemic stroke, but has onlyseen limited success. The industry has conducted clinical trials inlarge heterogenous patient groups at widely varying times followingonset of symptoms, but only acute therapy within the first few hourswith revascularisation therapy has continued to demonstrate a positive clinical effect. Revascularisation, which refers to restoringblood flow either by breaking up the clot with a thrombolytic agentor by direct intravascular approaches, has improved outcome, but unfortunately reaches small numbers of patients.

Despite this scenario, much needed improvements in stroke treatmentand clinical research are happening around the globe. Two key factors are driving these positive changes - implementation of evidence-based bestpractices at a growing network of clinical sites, and ongoing attempts toexpand the therapeutic window for the use of alteplase, a recombinant tissue plasminogen activator commonly referred to astPA. There is interest on the part of stroke experts inencouraging biopharmaceutical sponsors to studymedical therapy in combination with tPA, which is aclot-busting or thrombolytic agent, to increase theprobability of a successful outcome. In addition, thereis a rethinking of strategy aimed at identifying patients who can most benefit from new therapies instead of focusing on broad groups of patients.These constructive efforts are directed at changingthe current reality, which is that stroke treatment remains one of the biggest unmet medical needs withlimited options for therapy available to a small proportion of patients as stroke continues to be thethird most common cause of death in the industrialised world.1

This article is about the current state of global efforts aimed at improving stroke treatment. Leadingthe way is a Sweden-based academic network knownas SITS - Safe Implementation of Treatments in Stroke, which is workingtoward organising large numbers of high-performing clinical strokes sitesinto a professional collaboration. With roots in Europe, SITS has expandedinto Asia and Latin America, 55 countries in all, and expects to have 1,000sites in its network by the end of 2009. SITS has also developed a secureweb-based registry of patients to monitor safety outcomes of thrombolytictreatment, such as tPA. Through a newly-formed alliance with PAREXEL,SITS hopes to expand its capabilities and infrastructure to conduct moreclinical trials designed to treat patients rapidly and more successfully.

Focusing investigations on the first few hours after symptom onset, andcoordinating with revascularisation therapy, is gaining favour. For example,in the United States, at the recent Stroke Therapy Academic IndustryRoundtable (STAIR), participants discussed extending the therapeutic window for use of tPA in the US from its current three hours from strokeonset to 4.5 hours, similar to the practice recently recommended by theEuropean Stroke Organization (ESO). As part of this effort, it was

recommended that the study of extended time windows in clinical trialsbe focused on patient cohorts most likely to respond to investigational therapies. Likely responders would be selected based on clinical, laboratoryor neuroimaging screenings.

There are significant challenges inherent in moving the focus to earlier therapy combinations with revascularisation and identification of likely responders. First, biopharmaceutical sponsors anxious to bring new therapies to market face difficulties in organising response teams at clinicalcentres able to recognise stroke symptoms early and then recruit subjectswho arrive at the site while they are within the window to benefit from tPA.It is this issue as well as challenges linked to combining tPA with medicaltherapies that organisations such as SITS are addressing, to create benchmarks and guidelines that advance performance of clinical sites witha goal of improving the success rate of investigational compounds.

The Role of SITSUntil fairly recently, it has been particularly difficultto gather evidenced-based data on the success rateof stroke treatment or conduct well-organised clinical trials for stroke therapies. This is largely dueto the great variability in methodology among clinical sites and the limited and inconsistent imaging capability among academic medical centres and community hospitals, where manyacute stroke patients first enter the healthcare system. There has also been a lack of a centralisedinternational database of stroke patients to helpclinical centres compare their clinical outcomes withthose of other centres in their respective countriesand regions.

SITS was formed in 1998 to enable clinical research based on data from a central registry combined with a movement toward evidence-basedtreatments for stroke. Its establishment followed

landmark studies put forth by the National Institute of Neurological Disorders and Stroke (NINDS) in the United States, which documented thebenefit of administering tPA within three hours of stroke onset under theNINDS protocol; and the European Cooperative Acute Stroke Study(ECASS-I), which showed a significant difference (p=0.035) in the RankinScale in favour of tPA-treated patients as compared to placebo, using a sixhour window from onset of stroke.

Based on those results, Swedish ECASS investigators decided to formSITS to advance the cause of safe implementation of thrombolysis instroke. Monitoring of safety outcomes was deemed necessary and a prototype for the web-based registry was created.

SITS went international in 2000, and since that time has assembled anexpanding network of hundreds of international sites dedicated to improving treatment of patients suffering from acute stroke and to theconduct of Phase II – IV stroke-related clinical trials. Thus far, there arethree regions, Europe, Asia, and Latin America, each with a regional study

CURRENT EFFORTS TO IMPROVETHE CLINICAL TRIAL PROCESSAND TREATMENT IN STROKE

“There is interest on thepart of stroke experts inencouraging biopharmaceutical sponsors to study medicaltherapy in combinationwith tPA, which is a clot-busting or thrombolyticagent, to increase theprobability of a successfuloutcome.”

committee staffed with multinational stroke key opinion leaders. For eachcountry, there is a national coordinator who is a leading stroke researcher.

There are three purposes to the organisation:• Providing infrastructure for stroke registers where clinical sites

participating in clinical trials can register stroke patients• Creating a link between research and clinical implementation

by sharing best practices among global participants and creating a community for stroke investigators

• Providing a vehicle to conduct clinical trials and observational studies To create an infrastructure, allparticipating sites enter theirclinical data (Chart 1) througha secure website to form adatabase. The online registryis available to participatingsites with password-protectedaccess. It is focused on specific studies, and is usedprimarily for research. It is alsoof interest to regulatory bodies such as the EuropeanMedicines Agency (EMEA),seeking information on adverse events.

Through its research function, the registry serves as a vehicle for publication in leading medical journals, on behalf of SITS and by participating sites. Individual sites own their own data but there is also co-ownership of data within countries and regions. The national coordinator for each country owns that country’s data, and similarly, thesteering committee for a region owns its data. This arrangement createsvalue as it allows sites to use those data to produce country-specific or region-specific publications.

Global best practices can be shared among sites in both research and clinical settings. As part of this effort, there is a focus on continuous improvement through the use of benchmarks on treatmentand the generation of immediate feedback in the form of statistical reports. With this feedback mechanism, sites can compare their results tointernational best practice. For example, there are benchmarks on gettingpatients in quickly for treatment, a logistics metrics known as door-to-needle time. The system allows sites to compare their performanceto national and regional statistics on this parameter.

With its own expertise in conducting clinical trials in neuroscience,PAREXEL can leverage the growing SITS network of sites to accelerate siteselection for sponsors’ clinical trials targeting the next generation of stroketherapies in patients most likely to benefit from intervention. To supportthis effort, SITS maintains detailed information on the infrastructure andcapabilities of each site, including the experience level of clinical and support staff in various stroke-related clinical trials. With that information,SITS can direct PAREXEL to the best sites for a particular study. From thatpoint forward, due diligence can be performed in the site selection processand provide monitoring services, validation and measurements of imagingstudies, and engage with ethics committees and regulatory agencies invarious countries.

Moving to 4.5 hours A major focus of the stroke community is to expand the number of acutestroke patients who receive tPA. This thrombolytic agent, also known asalteplase, is currently approved by the Food and Drug Administration (FDA)and the European Medicines Agency (EMEA) for administration to patientswithin three hours of onset of acute ischemic stroke. There is strong interest, however, in expanding this window to 4.5 hours to allow more patients to benefit from this therapy. This approach represents a movement away from rigid time frames in favour of treatment based on

imaging that can assess brain pathophysiology and tissue viability.Two recent publications, the ECASS III study in the New England

Journal of Medicine,2 and the SITS-ISTR 3-4.5 h study in Lancet3 supportthe extension of the time window. Results of the ECASS III study, a randomised clinical trial of 821 subjects, with 418 randomised to tPA and403 randomised to placebo, were published in September 2008. The studydemonstrated that treatment with tPA administered 3 to 4.5 hours aftersymptom onset still provides modest but significant improvement in clinical outcomes after an acute ischemic stroke as compared to placebo.It also showed that symptomatic intracerebral haemorrhage was higherin treated patients, but the rate was not higher than reported previouslyin patients treated within the currently approved 3-hour window. Extending treatment to 4.5 hours was not associated with an increasedrate of mortality, and mortality did not differ significantly between thetreatment and placebo groups. Primary endpoint was disability at 90 day,as rated by the Rankin Scale. Patients with evidence of brain haemorrhageor major infarction on computed tomography scan were excluded fromthe study.

The SITS-ISTR study was observational. Using the International StrokeThrombolysis Registry, a team of SITS investigators performed a meta-analysis of randomised controlled trials, which suggested treatmentbenefit up to 4.5 hours. The study reviewed data from 478 centres in 31countries and included 664 subjects who received intravenous tPA within3 to 4.5 hours of symptom onset and 11,865 who received treatmentwithin 3 hours. Stroke severity was less in the 3 – 4.5 hour cohort than inthe < 3 hour group. Endpoints were symptomatic cerebral haemorrhageat 24 hours and mortality and independence at 90 days as determined bya modified Rankin Scale (0-2). Results showed no significant differencesin outcomes between the two groups. Interestingly, patients in the 3 – 4.5hour group were treated less frequently in new centres than in more experienced ones.

Following these results,there was a recommendationmade at the Karolinska StrokeUpdate Meeting in November2008 to change the EuropeanStroke Organization (ESO)guidelines to recommend treatment extended to 4.5hours after stroke onset (Chart2).4 This recommendation hasbeen approved by the ESO Guideline Committee and theESO Executive Committee, andwas implemented in January2009. A similar recommendation has been accepted in Canada.

In the United States, key opinion leaders at the Stroke Therapy Academic Industry Roundtable (STAIR) also recommended the expansionof the treatment window to 4.5 hours, with an initial emphasis on patientsmost likely to respond to therapy. As part of this effort, they acknowledgeda trend toward using more selective eligibility criteria in clinical trials asthere is evidence that treatment benefit declines in an overly broad population as the time from stroke onset rises. It is increasingly recognisedthat many stroke trials over the years have failed due to overly broad inclusion criteria including very delayed treatment or large areas of braintissue that have already been lost to lack of blood flow.

With a growing body of evidence, there is a movement toward expanding the therapeutic window for use of intravenous tPA. The currentvery low percentage of subjects who receive tPA, a mere 4% by some estimates,5 has much room for improvement. Not only will more patientsimprove their chances of maintaining independence but the societal costburden of stroke stands to be reduced.

54 JCS JCS 55www.jforcs.comwww.jforcs.com

ChallengesThere are multiple challenges to adopting changes in stroke treatment andclinical trials meant to improve outcomes and ultimately, the number of patients who receive and benefit from treatment. Two of the major challenges are: organising services so that more patients can receive treatment within the anticipated 4.5 hour window from onset of symptoms;and encouraging sponsors to consider a strategy of adding medical therapyto vascular therapy, such as tPA.

Current thinking is that the best chance of improving outcome furtheris early identification and treatment of stroke. Treatment should first consist of restoring blood flow, known as revascularisation. This step, either through therapy or spontaneously, is increasingly recognised as the most critical aspect for limitingbrain damage. It is equally clear that great valuewill be gained from therapies that help the brainrecover from the lack of blood flow. Treatmentscould be administered in the short term to prevent damage while blood flow is being restored, and promote survival during the criticalearly reperfusion period when free radicals andenergy imbalance threaten brain viability. Acutetherapy can be followed by drugs and therapies,such as stem cells and growth factors that enablerecovery over the longer term.

To reach this goal, there needs to be a greaterorganisational effort so that patients, ambulancepersonnel, hospital emergency rooms and strokespecialists work together to expand the number of patients who can receivetPA and other treatment modalities in a timely fashion. It has been estimated that two million nerve cells die every minute following arterialocclusion,6 and after 4.5 hours of onset, intravenous thrombolytic therapyis no longer shown to provide significant benefit in most patients. Maximising the number of patients who can be treated within the therapeutic window requires public education, so that patients, familiesand community heath workers can rapidly recognise a potential developingstroke and head to a hospital in time for treatment. This effort needs tobe coupled with education for ambulance and hospital personnel to decrease door-to-needle time.

The other challenge involves strategic approaches to the developmentof new stroke therapies. No other therapy has shown benefit besides administration of tPA within the appropriate therapeutic window. The annals of stroke research are littered with failed attempts to develop medical therapies using inclusion criteria of 12 hours or more from onsetof stroke symptoms. This approach may be tied to a focus on developinga stroke blockbuster with a broad treatment window, targeting the largenumber of patients who do not arrive at the hospital in time to receive tPAor are treated at facilities without a team trained and ready for acute therapy.

A combination approach that combines new therapy with existingrevascularisation therapy, such as tPA, might hold promise to improve outcome. If regulatory agencies require animal toxicity data from pre-clinical studies of combinations of new therapies with revascularisationprior to the start of human clinical trials, then proper planning and availability of these tests must become a priority. They could take as longas 9 – 12 months to generate the necessary data. Consequently, sponsorssometimes decide not to invest in these preclinical studies and move forward with traditional testing of their therapy in patients who do not receive tPA instead.

With the help of those experienced in designing and conducting thesestudies, animal studies can be planned and analysed to explore the pharmacokinetics and pharmacodynamics of an investigational

compound and its performance in combination with tPA without causingdelay to timelines. In addition, once the animal studies are completed,that expertise, typically from a global CRO, could play a key role in organising combination clinical trials at experienced sites where patientsare already receiving tPA, such as those in the SITS network.

Stroke Development Process Ripe for ImprovementDeath and disability from stroke comes at a huge cost, both financially andas measured by patient suffering and use of resources in the healthcare system. Laying the groundwork for meaningful change requires

an understanding of the present state of affairs,namely that not enough patients receive tPA, usually because they do not present within the therapeutic window or the site is not sufficientlyorganised to administer it on time. To make positive changes, more clinical sites need to commit to standards to improve patient outcomesand participate in global clinical trials. There alsoneeds to be a sharper focus on developing treatments that can be given in conjunction withtPA, as this approach considers the usefulness ofthis vascular therapy when given appropriately,and directs development toward patients mostlikely to benefit from intervention.

There are positive happenings in the stroke community designed to bring meaningful improvements to patient care. Perhaps the most significant is the extension of the therapeutic

window of tPA from its current 3 hour window to 4.5 hours. As shown in theECASS III and SITS-ISTR studies, there is still significant improvement in patient outcome as compared to placebo. As a result, the European StrokeOrganization and many individual experts in stroke therapy are moving forward with recommendations to extend the window and improve outcomefor more patients. This effort coupled with extensive training of the publicand healthcare professionals in the urgency of seeking healthcare as quicklyas possible holds promise for improved outcomes.

Finally, there is a real need for additional therapies, most likely to be usedin conjunction with tPA. Biopharmaceuticals developers interested in pursuing this opportunity might turn to expertise in stroke drug developmentboth in academia and among global CROs to organise and implement clinical development plans that bring this option to fruition. When all of thepositive changes are put into operation, there can be real hope for continuedimprovements in stroke treatment and outcomes.■

Data Entered into the SITS Registry

• Time delays in management

• Baseline and demographic data

• Baseline stroke severity (NIH score)

• Baseline imaging studies

• Follow-up NIH score and imaging

Chart 1Source: SITS International

Updated ESO Guidelines RegardingUse of tPA

Intravenous rtPA (0.9 mg/kg body weight,maximum 90 mg), with 10% of the dosegiven as a bolus followed by a 60 minuteinfusion, is recommended within 4.5hours of onset of ischaemic stroke (ClassI, Level A), although treatment between3 and 4.5 h is currently not included in theEuropean labelling.

Chart 2Source: European Stroke Organisation

References:1.Mackay J, Mensah G, Atlas of Heart Disease and Stroke. World Health Organization. Geneva,2004, http://www.who.int/cardiovascular_diseases/resources/atlas/en/, accessed March 6, 2009. 2. Hacke W, Kaste M, Bluhmki E, Brozman M, et.al. Thrombolysis with Alteplase 3 to 4.5 Hoursafter Acute Ischemic Stroke. N Engl J Med 2008;359:1317-29. 3. Wahlgren N, Ahmed N, Dávalos A, Hacke W, et.al. Thrombolysis with alteplase 3–4·5 Hoursafter acute ischaemic stroke (SITS-ISTR): an observational study. Lancet, published online September 15, 2008. 4. Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008, Eu-ropean Stroke Organization (ESO), http://www.eso-stroke.org/pdf/ESO_Extended_Thrombolysis_KSU.pdf, accessed March 8, 2009.5. Lyden P. Thrombolytic Therapy for Acute Stroke – Not a Moment to Lose. N Engl J Med2008;359:1393-5.6. Saver J: Time is brain: quantified. Stroke 2006;37:263–6.

James Vornov is CNS Therapeutic Area Leader, Worldwide Medical Services at PAREXEL.Dr. Vornov is an internationally known clinician-scientist with broad knowledge of bothneuroscience and drug development with nearly 20 years of academic and drug development experience. He has worked in multiple CNS therapeutic areas having directed programs in Parkinson’s Disease, stroke, neuropathic pain, diabetic andchemotherapy-induced peripheral neuropathies, anesthesia and brain tumors. As globalpractice leader for CNS physicians, he acts as Senior Technical Advisor for key CNS programs in Phases II, III, and post-approval. He also serves as a consultant to companies for clinical program development, trial design, protocol development and regulatory submissions including NDAs. E-mail: [email protected]

“Treatment should first

consist of restoring blood

flow, known as

revascularisation. This

step, either through

therapy or spontaneously,

is increasingly recognised

as the most critical aspect

for limiting brain damage.”

each of the study sites were used to dealing with the issue and had backupgenerators. The use of a laptop with battery backup made this even morerobust – a few sites were very enterprising and while the electricity was available charged up multiple laptop batteries for use when power was lost.

Where improved internet access was required, the decision was made,where possible, to install ADSL lines to ensure access. The criteria used tomake the decision were availability, time to install and cost. On occasionswhen ADSL was either not available or when lead times were deemed to betoo long, 3G technology was employed. On average, it took in the region ofeight weeks from placement of order to the installation of robust ADSL access, although in a few cases the technology was established in as littleas three weeks. User feedback from those using ADSL technology and 3Gcards has been that data submission times into the EDC system were goodusing both approaches.

CLINICAL DATA COLLECTIONConnectivity In addition to utilising either ADSL or 3G, web application acceleration technology was deployed to support optimum performance. Web latencycan occur as a result of high internet traffic and over-utilised network infrastructure within a geographical region. A web application accelerator isused to improve performance issues related to web latency and in areas particularly affected by high levels of latency (slow connection speeds) the benefits can be dramatic. In Diagram 2 the sites experiencing particularlyhigh levels of web latency are those classified in the 99th percentile; whenPhase Forward switched on the web accelerator for all trials the specific benefit for these sites can be seen.

Various strategies were employed to ensure that data could be enteredquickly and as close to the patient visit as possible. One particular exampleof creative thinking was the decision to enter data in the mornings, before the US workforce came on board and the worldwide web sloweddown. This strategy proved very successful, as did the decision to providecertain sites with more than one laptop in order for multiple people to enter the data during optimal times.

All project Clinical Research Associates were equipped with a laptopand 3G card, which allowed the monitors flexible internet access both atsites and when travelling between visits.

Throughout the study both ADSL and 3G technology proved to be verysuccessful; the only hiccup was when the telecommunication lines weredug up and stolen in the middle of the night – presumably to sell the copper! Fortunately the telecom provider responded very quickly and theissue was addressed in record time.

HardwareThe decision was made that hardware swap-out delays were to be avoidedas far as possible. Issues with customs can sometimes occur and this candelay the supply of replacement hardware, and without a robust backupstrategy in place, the processing of data. Numerous contingency plans weremade to ensure success; one of them was a hardware spares strategy. Partof this strategy was to equip sites with duplicate hardware (below we discusshow training laptops would be left with the site post-training). In addition,in order to ensure that in the event of failure spare laptops were available,each monitor was issued with an extra laptop and numerous spare batteriesand power supplies.

In the event, only one laptop failed during the duration of the study, andthis failure was due to a faulty hard drive and not due to issues with humidityor water ingress.

SUPPORTTrainingTraining was conducted using a train-the-trainer strategy over a five day period. The training image was loaded onto laptops and each trainee hadtheir own laptop to practice with (the training laptops being taken as‘spare’ laptops once training was complete). Typically the trainer ranthrough each activity on a projector so that the trainees could see whatthey were required to do, then they did the exercise themselves on theirown computer. Trainees who experienced difficulties throughout the training were identified and received additional coaching at the end ofthe day.

Both prior to and after the training, a test system was made available topractice on. In addition to training in the use of the EDC system, the trainees

were also shown how to storethe provisioned hardware toprevent damage from the elements. Judging from theresults highlighted above(only one laptop failure), thissuccessfully achieved itsgoals.

Usually train-the-trainertraining can be conducted inthree days, however, timewas put aside to make surethat trainees were competentwith a computer, accessingt h e internet and basic trouble-shooting (re-setting modems,etc).

The trained trainers then returned to their local sites and replicated thistraining. One issue that was picked up early in the local site sessions and ledto changes, was the use of the study password which included an underscore.The use of an underscore meant that two keys on the laptop had to be usedat the same time – this proved troublesome for a few and in order to preventissues an alternative password utilising single keystrokes was utilised.

Another issue that was picked up early was the use of the track wheel(mouse) on the computer. A few site staff struggled with the tool and the decision was made to disable the track wheel and to use a stand-alone mouse.

Feedback from the training sessions was very positive, with over 94%of the site staff stating that the training location, the content of the training and the knowledge of the trainer were good or very good. Theonly negative feedback received was from a couple of site staff who werea little more technologically capable, and they believed that the trainingcourse was too long. All site staff reported feeling comfortable with theE D C

JCS 57www.jforcs.comwww.jforcs.com

SUMMARYIn Part I of this article1 we outlined the wide range of potential benefits ofcollecting data in remote locations using EDC over paper-based methods: greater (earlier) visibility of results; reduced costs; increased capacity; greater speed; and improved quality. While the content of this andtheprevious article are widely applicable across global remote locations wefocus on the African continent for our specific examples. To date, Phase Forward has worked with over 800 clinical trial sites across Africa, includingover 50 remote medical centres. Phase Forward customer satisfaction surveys in Africa have revealed very high levels of end-user satisfaction andpart I of the paper outlined how we generate this through a variety of integrated approaches, including facilitating fast web connection speeds, appropriate hardware being available, training and support. Key to ensuring fast data submission speeds and robust access to the internet is theuse of ADSL broadband technology, where available, and 3G wireless technology where fixed lines are not in place. Experience has showed boththese approaches to provide strong solutions, but the additional applicationof web accelerator technology on all Phase Forward trials further reducesuser response times significantly and makes an important differentiator.

Part II of this article looks at a single study and presents in more detailhow the concepts outlined in part I were achieved on the ground.

CASE STUDYIn recent years Phase Forward has successfully run numerous Phase II/III clinical trials using EDC technology in Sub-Saharan Africa. One of the latesttrials that included sites in this region ran for approximately 12 months andhad 44 investigational sites in Burkina Faso, Ghana, Nigeria, Senegal andUganda. The breakdown of sites by country is shown in Diagram 1. In thisarticle we use this study to demonstrate the kind of issues that are encountered in the ‘real world’ when running EDC studies in remote locations. Specifically we look at the areas of site setup, data collection andsupport.

Site SetupAn in-depth investigation was carried out by Phase Forward prior to sitesbeing selected to participate in the study: these checks included the internet access options available in the region, lead-times for the installation of ADSL and 3G, as well as the reliability of electrical power. Thisdata was used for forward planning and contingency purposes.

In parallel to the investigation above being performed, a pre-study start-up site visit was being carried out by the sponsor company to each ofthe sites. In order to minimise any delay in study start-up, an automated siteassessment was completed during the visit. This assessment included a testwhere data was submitted, using the site computer, into a test EDC systemand the submit time was recorded. All the site had to do was to enter theirfirst name, last name and the site number and press ‘submit’. The utility thenran the test and told them if it was a pass or a fail. To make it even easier, ifthe result was a fail, a link was provided to tell the site and Phase Forwardwhat the issue was and how it could be rectified. An analyst then workedwith the site to review the version of the browser installed on the computerand upgrade it if applicable.

Where no computer or internet access was available, data was enteredusing a 3G-enabled laptop which had been taken to the site specifically forthe site assessment process. The specification of the laptop and the 3G cardwas a standard build that had previously been successfully used in SouthAmerica for remote site locations. Table 1 shows the results of these assessments for this study compared against historical data from each country.

Testing showed that 62% of sites, on average, successfully passed the siteassessment test using the existing infrastructure. This was slightly lower thanexperienced in previous studies undertaken throughout Sub-Saharan Africa.An additional 4% of sites were successfully upgraded, which involved an upgrade to the browser. Of the remaining 34% of sites, the ex-isting installation required an upgrade of both the hardware (computer) andinternet access. Typically the reason for failure was due to the site using alaptop that was of low specification in conjunction with dial-up internet ac-cess. All sites that were upgraded were successfully connected to the internet. Electricity supply was variable and routinely unavailable, however,

HOW THE REMOTEST LOCATIONS ARE LEVERAGING THE INTERNET AND EMBRACINGEDC TECHNOLOGY TO CONNECT TO THEGLOBAL CLINICAL RESEARCH COMMUNITY –PART II: A CASE STUDY.

56 JCS

Country

Average PGFCountry SpecificEDC Ready Results

Study SpecificEDC Ready Results

ADSL Installed*

3G Installed**

Burkina Faso 65% 57% Yes Yes

Ghana 70% 62% Yes Yes

Nigeria 70% 62% Yes Yes

Senegal 65% 60% Yes Yes

Uganda 80% 69% Yes Yes

* Yes implies that ADSL was required in at least one site in that country ** Yes implies that 3G was required in at least one site in that country

Table 1:

Diagram 2:

Diagram 1:

1 Journal of Clinical Studies, November 2008

system, the computer and the use of the internet at the end of the training.

HelpdeskA 24 x 7 multi-lingual helpdesk to assist the site staff was made available. Alot of thought was put into the language requirements of the helpdesk andvarious strategies were used to ensure that individuals who could speak locallanguages were employed as part of the helpdesk. Other actions taken included the recruitment of staff with local knowledge, as well as the use oftranslation services. Despite stressing during the training sessions that thehelpdesk was available 24 x 7, most of the site staff called the monitor inthe first instance for support.

Of those requests that were made to the helpdesk, 90% came in viaphone with 10% received via email. 54% of the requests for help to thehelpdesk came during the local working day (08:00 – 17:00), 36% between 17:00 – 23:30 and 10% of calls between 23:30 – 08:00. Understanding how and when the requests for support arrived allowed theplanning of shift rotas to ensure that staff with knowledge of the study andappropriate language skills were available when the sites needed support.

On average, the number of calls per site per month was the same as European and US-based studies. 78% of sites used the helpdesk during theduration of the study and the bulk of the calls made to the helpdesk were inEnglish (76%), with French making up the second largest category (17%).

The majority of the calls into the helpdesk were in relation to “User Management” i.e. password-related issues or the addition of new users atthe site. To help address this at source the monitors on the ground were givenaccess to a web-based utility which allowed them to make the User Management changes required.

Site feedback100% of the sites and monitors that participated in the study and provided feedback indicated they would prefer to use InForm™ in future clinical trials. This question can be seen as a marker for comfort with EDC foran audience familiar with paper. When you review the qualitative responses in more detail the traditional benefits of EDC (highlighted in part1 of this article) appear and support this hypothesis. Higher quality data is akey reason for using EDC, and the immediacy of entry, verification, cleaning and the checking of data for errors were specifically commentedupon as advantages seen. Respondents also noted the benefits of everyoneseeing a common view of the data in rapid time and adverse events beingdeclared earlier – this earlier access to the data being another primary

benefit of using EDC. Positive comments were also received in relation to the reliability of the

technology and the ease of data entry. Finally, numerous site staff commented that the technology was user-friendly and exciting to use. Feedback was received from sites in each country apart from Uganda (seeTable 2). The response given in the table is the lowest response receivedacross all responders. The scale for responses was: very good, good, poor orvery poor. In summary, all sites responding rated the quality, time to submitand ease of use as good or very good.

CONCLUSIONWhile there are unique challenges in running clinical trials in remote locations, this case study demonstrates that with appropriate preparationEDC can now be used successfully in locations previously considered off limits. Small levels of increased effort up front making sure the appropriateinfrastructure is in place, result in a trial that receives positive feedback fromthe users. In summary, technological solutions are now able to follow the patients into the most remote locations, allowing pharmaceutical and academic communities to successfully collect and process data from clinicaltrials and epidemiological studies run in non-traditional locations. ■


Would like to useInForm in a future trial

Study SpecificEDC Ready Results

ADSL Installed*

3G Installed**

Burkina Faso 65% 57% Yes Yes

Ghana 70% 62% Yes Yes

Nigeria 70% 62% Yes Yes

Senegal 65% 60% Yes Yes

Uganda 80% 69% Yes Yes

* Yes implies that ADSL was required in at least one site in that country ** Yes implies that 3G was required in at least one site in that country

Table 2:

Mark Wren (MBA) Director is responsible for theglobal implementation and support of Phase Forward’s electronic data capture software, plus thesupport of the web-integrated interactive responsetechnology. His experience spans more than 16 yearsin the Bio-Pharmaceutical industry. Most recently, hewas Director, Clinical Trial Services at Dendrite International where he successfully implementedeClinical strategies for many large global / EuropeanPharmaceutical companies. He has also held a

number of managerial positions within the Celltech Group and BritishBiotech. Email: [email protected]

Maria Sumner, has worked within the Clinical Research Service and Software Providers Industry forover 11 years. Maria held positions within Project Management and Clinical Monitoring at the CRO ClinTrials Research, before moving to Marketing. AtPhase Forward, Maria is responsible for marketing communications, public relations and product marketing within Europe and Asia Pacific. Email: [email protected]

Rob Nichols, M.Sc., C.Stat, Director, leads Phase Forward’s global Phase I clinical trial strategy. Prior tohis current role, he spent 10 years working in Phase Iclinical units. Most recently, he was director of data operations and business solutions at Quintiles wherehe managed a multidisciplinary team of Phase I specialists in data management, EDC, statistics andmedical writing. Rob has presented at numerous international conferences on Phase I automation andwas chair of the Association of Clinical Data Managers

in 2005 / 2006. He graduated with distinction in Applied Statistics from University College London. Email: [email protected]

www.jforcs.com

from worldwide regulatory and government bodies into the long-term safetyof treatments, as well as mounting pressure from physicians, payers/formulary committees and consumers. Post-approval research is expected to be one of the fastest-growing areas in clinical research.

According to the Tufts Center for the Study of Drug Development, post-marketing studies are becoming the norm in US, Europe and Japan −more than three-fourths of new pharmaceutical and biological product approvals in the US and Europe, and half of those in Japan, include post-marketing commitments.

Many strategic decisions must be made during the initial planning of post-marketing studies; the most important, of course, relates to theobjectives ofthe study. Clearly and accurately articulating the objectives is crucial, as itdrives all subsequent decisions regarding study endpoints to be collected,number ofsites and patients and overall logistics.

Other key decisions include:• What is the most appropriate study design to accomplish the

end points?• Which physicians should be targeted as investigators?• What is the scope of the monitoring plan for the study?• What expectations will the study place on the targeted

investigators?• How will data be collected from the investigators?• What method of training is most appropriate for the sites?• How will the information collected be communicated within

the sponsor?CRITICAL FACTORS FOR SELECTING EDCDesigning and implementing successful post-marketing studies is challenginggiven the broad diversity encountered within these studies on many levels. Agiven late phase study is likely to have a wide range of goals from a broadset of stakeholders. While always striving for good scientific foundation and rigorous execution, post-marketing studies can require a variety of structuresand designs to address a broad array of questions. Given their differencesfrom earlier phase studies, clearly late phase trials cannot be designed or implemented using a pre-approval study template. And due to the enormousdiversity in the types of late phase studies (ranging from Phase IIIb to observational, registry and safety surveillance) there simply is no one-size-fits-all approach to designing and implementing post-marketingstudies.

EDC, Paper or Hybrid ApproachCritically important is the question of what is the best approach to collect, manage and analyse data. Electronic data capture (EDC) systems offer manybenefits − such as automatic queries at data entry to streamline and enhancedata management processes − offering sizeable advantages at a reasonablecost. Although the specific departments sponsoring the post-approval research may be unfamiliar with managing EDC systems, the ease with whichmany current offerings can be deployed and the availability of EDC-readycontractresource organisations (CROs) and other service providers may alsohelp maximise trial efficiencies and effectiveness. By outsourcing aspects oflate phase trial management – from specific activities to the entire trial designand management – sponsors can stay focused on core key drug developmentcompetencies.

While most investigative research sites today are familiar and comfortablewith EDC for clinical research, some sites deemed important for the studymay require paper-based data collection methods, even with the understand-ing that there will be a time delay for the sponsor to access the data in orderto generate reports and perform analysis. Moreover, collecting patient re-ported outcomes (PRO) or patient generated data, forexample through sur-veys or Quality of Life (QoL) questionnaires, may be simpler and morecost-effective using traditional paper forms – even if site-generated data maybe more easily captured via an electronic system.

Technical issues such as lack of trained staff or reliable network

connectivity might also preclude the use of EDC by a small percentage of thesites. In addition, site staff may have subjective reasons, such as negativepast experiences, personal preferences or reluctance to adapt to new rolesthat may inhibit them from using EDC. Such drivers make it important thatthe EDC under consideration be examined for its capabilities to support hybrid(EDC and paper) studies, for example, providing double data entry (DDE).

Minimum Training RequiredIn pre-approval studies, sponsors will collaborate with medical specialists atresearch centres, influential therapeutic experts and key opinion leaders toserve as investigators. In contrast, post-marketing studies often enlist site investigators who are community-based physicians treating patients. It is important, therefore, that studies are planned to make it as easy as possiblefor a diverse set of investigators to participate in trials.

As part of the initial design of the study, sponsors must consider how tominimise any negative impact on the site – particularly if a large percentageof the sites have minimal or no clinical trial experience. Using an EDC systemwith an easy-to-use interface, streamlined workflow and intuitive data collection forms will ensure timely data input, drive site satisfaction and helpimprove site retention – particularly if the study is running for several years.

Local Language DiversityIn many cases, post-marketing study designs will be global in scope. However, while centrally planned and managed, they will be implementedthrough local affiliates to meet the needs of regional markets. When working with general practitioners, all documentation and electronic Case Report Forms (eCRFs) should be in local language to facilitate site and patient retention. Moreover, many product-based registries will need to incorporate portal-like components to support the sponsor’s local brandingefforts and include any messages necessary to meet specific country regulatory requirements. An EDC solution that provides multi-language support is critical to facilitating the management and execution of global latephase studies.

Lengthy Study DurationsDue to stringent regulatory requirements in North America, Europe and Japan,post-marketing studies typically have lengthy durations in order to captureextensive real-world data to thoroughly understand a product’s safety profileand treatment outcomes. Some large studies are implemented for up to tenyears. Regardless of a study’s duration, keeping momentum with the sites iscritical to the overall success of any project. Again, selecting the appropriateEDC system that requires minimum site training and that offers a very intu-itive user interface helps maintain site relations to support very large and long-running studies.

Tight Budgets Implementing a post-marketing study with EDC – as opposed to paper – willallow the sponsor to access the data in real time and generate reports usingad-hoc tools. Having a fully validated system that meets the requirements of global regulatory agencies brings significant value to sponsors by offering early access to data to support quality decision making throughout the trial. For clinical teams that perform a cost comparison of an EDC trial versus a paper approach, a thorough evaluationwill factor in the many hidden costs of paper trials – including a substantialamount of document shipping, more frequent travel to sites and the inability to re-use CRFs, edit checks and other study components for subsequent studies with similar protocols.

LESSONS LEARNED FROM IMPLEMENTING EDCMany questions are raised during the design of a post-marketing study. Spending enough time in the planning phase is critical to ensure a successful study outcome. Decisions must be made around high-level protocol

Pre-approval clinical trials conducted on pharmaceutical, biotech, device and diagnostic products are designed for the purpose of testing the safety and efficacy of the treatment before it reaches thepublic. The types of information that can ensure a successful launch, in-market brand management and long-term product growth often require comprehensive market intelligence that is not the purview of submission-based clinical testing. Comprehensive data needed to answer questions about the proper use of a new product, expectations of treatment response, key drivers for market uptake andperformance against competitors is normally difficult to collect beforethe product is available in the market. Real-world data on a broad spectrum of patients and physicians can address these questions, but the methodologies and costs for this analysis may seemdaunting.

Post-approval (a.k.a. post-marketing or late phase) research is designed,among other motivations, to address these needs. Data collection in latephase research tracks a product’s real-world impact through patient health improvement – effectiveness – and can also answer questions about long-term safety and comparative risk profiles. In general, this research provides a better understanding of the following critical concerns:

• Effectiveness (long-term and comparative) • Quality of Life (QoL)• Survival outcomes• Sub-population effects• Product utilisation patterns• Market and label expansion opportunities• Data for scientific publications and presentationsGrowth in post-approval research is largely the result of recent scrutiny

Powering Post-MarketingStudies with ElectronicData CaptureHow EDC Can Help Address Some of the Challenges of Late Phase Studies.

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Classifieddesign (e.g., what is the best study format to reach the endpoints) and studydetails (e.g., what is the most appropriate training program for investigators).

As part of this process, the study team needs to keep a focus on the mostimportant question – what are the objectives of the study? Consensus on aclear set of objectives among all stakeholders will drive all other decisionpoints. From there, study design points can be addressed, including choosingan EDC system that is flexible to meet the rigorous needs of the study.

When selecting an EDC system, the critical success factors related to siteusers are ease of use, customisable training modules within the system; support for local-language data entry and query resolution; and access to amulti-lingual helpdesk. From a sponsor’s viewpoint, the key success factorsare data cleaning at point of entry to minmise monitoring costs; ability toquickly detect issues with eCRFs, fields and sites; and cost-effective user administration, especially for very large observational studies or registries.

Ensuring Site AdoptionWith site satisfaction clearly paramount to studysuccess, choosing an easy-to-use EDC system is key.The site coordinator must be able to enter datafrom any web-enabled computer without the needto run special software or download programs.Moreover, study eCRFs should be accessible via anyinternet browser to limit any hardware or softwarerequirements on the site. Working with their systemof choice and from any location with internet accesswill drastically facilitate the rollout of the study tothe sites without costly hardware provision or firewall concerns.

To ensure acceptance by research-naïve sites,the EDC system should offer a flexible and intuitiveuser interface to allow investigators and site personnel to easily enter data, manage patient visits and run specific reports.The eCRFs should be designed with dynamic queries to automatically pose questions whenever necessary and appropriate. Features such as the abilityto add unscheduled visits are important to capture real-world data wheneveravailable.

Some post-approval studies will require the collection of patient data aspart of a six-month or yearly routine visit and will run for many years or evenon an ongoing basis. In this case, investigators may only sporadically be usingthe EDC tool. To keep them up-to-speed on trial requirements and familiar with system capabilities, sponsors should choose EDC systems thatinclude training modules available via an embedded on-demand e-Learningsystem.

Since grants to sites can be minimal, post-marketing study sponsors needto removepotential challenges for investigators to participate and even provide additional value to them. Sponsors should consider offering benchmarking data to help educate investigators about treatment options;keeping investigators informed on trial progress and therapeutic news via e-newsletters and webinars; and facilitating peer-to-peer communicationthrough online forum tools and seminars to help investigators network witheach other and benefit from each other’s experiences.

Multi-Language CapabilitiesTo ensure site and patient retention, especially for large global studies, it isimportant that the sites can enter data and manage their patients in the locallanguage. This capability will facilitate investigator recruitment – especially with research-naïve sites. The EDC system should use translationtables to assure that all fields areproperly translated as the study is implemented within a single system even if sites are located in Japan, Europe and North America. In addition, reports should be immediately available in all languages used in the study.

Early Visibility to DataUsing EDC, data can run through quality checks in real time and become immediately available for analysis and trending. Gaining immediate insight to emerging trends allows for quick and appropriate action-taking, equippingresearchers to detect specific site situations as they occur and manage them accordingly. Moreover, product safety is a key driver for implementingpost-marketing studies and the use of an EDC system can helpstreamline contact with stakeholders or regulatory agencies by providing earlier access to reliable data and rapid reporting in the necessaryformat.

The EDC system should provide users with reporting capabilities at the sitelevel and at the sponsor level based on reporting views and user rights thatare defined by the business rules. These reports and charts can be very valuable for supporting evidence in scientific articles and presentations.

Seamless Mid-Study AmendmentsPost-marketing studies will generally be implemented for several years and some eCRFsand edit checks may need to be modified oradded during the course of the study. It is criticalto have a tool that can be modified over time without threatening data integrity or study continuity. A flexible EDC system will allow for the addition of new sites and subjects, deployment ofnew eCRF versions, and migration of previouslyentered patient data to the latest version, allwithout having to reconfigure the software andlose critical time. These changes should be implemented without having to bring the systemdown for maintenance, thus providing continuityand maintaining site satisfaction.

Integrated Environment for Real-Time Data SharingFinally, with well-designed EDC systems, data obtained via outside sourcescan be loaded into the EDC system to populate the appropriate forms andfields. The ability to integrate from other disparate sources and data systems,such as electronic patient reported outcomes (ePRO) and electronic medical / health records (EMR/HER) systems and payer sources, providessponsors with a convenient and unified view of trial data to more efficientlytrack overall trial progress. EDC systems with interoperability tools that supportrapid integrations and real-time data exchange across systems will go a longway to help sponsors gain additional trial efficiencies.

CONCLUSIONOver the next few years, the sponsor’s quest to differentiate a given product in the market will require evidence – safety and outcomes data –beyond registration trials. Such data will be used to motivate the cautious primary care physicians to adopt new treatments. Likewise, collecting real-world data for scientific publications and for negotiations withcost-conscious payers will become even more important in positioningany new indication. Clearly, choosing the right EDC system can help sponsors gain efficiencies and drive effectiveness to support a post-marketing study.■

Patrick Chassaigne, DirectorLate Phase Solutions at Medidata helps pharmaceutical, biotechnology and medical devicecompanies use electronic data capture approachesto best address the challenges of post-approvalstudies. Email: [email protected]

“To keep them up-to-speed

on trial requirements and

familiar with system

capabilities, sponsors should

choose EDC systems that

include training modules

available via an embedded

on-demand e-Learning

system.”

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