Journal For Clinical Studies

The Future of Clinical Research in TunisiaAfter the Revolution CNS Watch Page FDA’s New Risk Evaluation and Mitigation Strategy for Opioids Airborne Particle MonitoringImpact of ISO 21501-4 Calibration Novel Angiogenesis Inhibitor in DevelopmentAt Competence Centre for Cancer Research

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Volume 3 - Issue 4

PEER REVIEWED

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EDITORIAL ADVISORS KEyNOTE

WATCh PAgES

The Collaborative Opportunities for Research Excellence (CORE) Programme Supports Nanotechnology StudiesIn February 2010 the National Science and Technology Council’s Subcommittee on Nanoscale Science, Engineering, and Technology released a supplement to the President’s 2011 Budget entitled The National Nanotechnology Initiative: Research and Development Leading to a Revolution in Technology and Industry. This publication describes research and development programmes planned for 2011 by those US government agencies that are participants in the National Nanotechnology Initiative (NNI) and notes the establishment of the Collaborative Opportunities for Research Excellence (CORE) programme. By: Walter Chalkley, of Thomson Reuters

Cardiovascular Safety Watch ColumnA potential cardiovascular safety biomarker that is currently receiving a lot of attention is blood pressure. More specifically, the biomarker of interest is drug-induced changes in blood pressure (increases or decreases) for non-cardiovascular drugs. While antihypertensive drugs, for example, are designed to have an effect on blood pressure (lowering it), non-cardiovascular drugs are not expected to change blood pressure in either direction, and any such change would be considered an off-target effect. By: J. Rick Turner of Quintiles

Current Status of International Multicentre Clinical Trials in ChinaIn recent years, an increasing number of multinational companies have established their late stage clinical trial centres in China. On September 6th 2009 the State Food and Drug Administration (SFDA), P.R. China, first released its Annual Report on Drug Registration Approval, showing a progressive increase in synchronous research participation of new global drug development, as well as a steady rise in applications for clinical trials in international multicentres. By: May Lan of The Scott Partnership

FDA’s New Risk Evaluation and Mitigation Strategy for Opioids – CNS Watch According to a recent report by the Substance Abuse and Mental Health Services Administration, prescription drug abuse continues to be a grave problem. The US Food and Drug Administration (FDA) had also recognised a substantial increase in the number of postmarketing reports of abuse, misuse, addiction and overdose resulting in fatalities associated with extended-release and/or long-acting opioid drugs. By Henry Riordan of – Worldwide Clinical Trials

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MANAgINg DIRECTOR Martin Wright

PUBLIShERMark A. Barker

MANAgINg EDITOR Jake Tong

EDITORIAL COORDINATORJaypreet Dhillon

EDITORIAL ASSISTANTSNick Love, Kevin Cross, Lanny McEnzie

DESIgN DIRECTOR Ricky Elizabeth

RESEARCh & CIRCULATION MANAgERDorothy Brooks

BUSINESS DEVELOPMENTClive Baigent, Lucy Beard

ADMINISTRATOR Barbara Lasco

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PUBLIShED By Pharma PublicationsBuilding K, Unit 104Tower Bridge Business Complex,100 Clements Road, London, SE16 4DG, UK

Tel: +44 (0) 207 2375685 Fax: +44 (0)207 3947415Email: [email protected]

The Journal for Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.

2011 PHARMA PUBLICATIONS

Volume 3 Issue 4 (July 2011)

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Contents

Contents

Volume 3 Issue 42 Journal for Clinical Studies

REgULATORy

Airborne Particle Monitoring: Impact of ISO 21501-4 Calibration Dependable, consistent and repeatable results in monitoring airborne particles in cleanrooms and clean zones depends both on the sampling technique of the analyst and on the performance of the particle counting instrument. The control of the sampling technique often is the subject of a unique SOP (standard operating procedure) while the performance of the instrument is typically reviewed and verified through an annual or semi-annual calibration process. The calibration process itself has been subject to a greater degree of variability in actual practice and throughout the lengthy life of the instrument than would be desired, due to different calibration techniques magnified by infrequent maintenance and calibration. Joe Gecsey of Met One (Hach) explains how this variability can be minimised by the implementation of the ISO 21501-4 calibration standard.

MARKET EVALUATION

The Future of Clinical Research in Tunisia after the Revolution.On January 14th, 2011, Tunisia was marked by an unprecedented revolution, and for the first time in its whole history, the Tunisian people were invited to drive their own destiny. Prof Habib GHEDIRA, Principal Investigator and Professor of Pneumology at the Faculty of Medicine of Tunis, Tunisia answers the question on many people’s minds: “What is the future of company-sponsored clinical research after the unprecedented revolution that shook the country and the whole Arab world?”

BRIC AND MORTARClinical Trial growth in Latin America, Eastern Europe and AsiaBrazil, Russia, India and China — collectively known as the BRIC — are four countries on similarly accelerated paths of economic development spurring a groundswell of R&D activity. In this report Diana L. Anderson of DAC Patient Recruitment Services gives us a thorough review of the guidelines which govern the recruitment of study volunteers to participate in clinical trials of investigational medical products in these countries.

ThERAPEUTICS

Predictive Value of Molecular-Cellular Methodologies for Response to Chemotherapy with CisPlatin/5Fu in Colon TumoursCisplatin as monotherapy or in combination with 5-Fluorouracil (5FU) is currently the first-line treatment of stage III or IV colorectal cancers. Predicting the efficacy of these drugs in individual patients before the establishment of a treatment regimen is essential. The aim of the present study was to develop a method to predict the response to cisplatin/5FU therapy in colorectal carcinomas using the minimum required number of cancer cells from each patient. Study y: Panagiotis Apostolou, Maria Toloudi, Marina Chatziioannou & Ioannis Papasotiriou of Research Genetic Cancer Center (RGCC Ltd).

Novel Angiogenesis Inhibitor in Development at Competence Centre for Cancer ResearchTargeting of tumour angiogenesis is an attractive strategy in cancer cure. In the past 30 years signalling pathways that drive specific angiogenic events in tumour tissue have been elucidated. The results from these studies encourage development of different anti-angiogenic drugs that interfere with tumour angiogenesis and block tumour development. In this article Andres Valkna & Riin Ehin of Competence Centre for Cancer Research Ltd. show how SB101 (a small recombinant protein that inhibits angiogenesis) is able to inhibit human tumour growth of various origins.

IT & LOgISTICS

Cardiac Safety Monitoring and Centralised Medical Imaging in Clinical TrialsCardiac safety monitoring in clinical trials is more prevalent and attracting more attention every day, as regulatory agencies demand a more comprehensive demonstration of pharmaceutical and medical device safety and efficacy. Nicholas R. Enus & Peter Gardiner of Perceptive Informatics discuss why the evaluation of cardiac safety in clinical trials is a critically important and continuously evolving field that requires close and productive collaboration between the clinical investigators, the study sponsor, and the cardiac imaging core laboratory.

The Future of Electronic Data Capture Tools What is the future of electronic data capture tools? Kris Gustafson of ICON looks into portability and a single data source, provides a vision of the future. The article looks into first and second generation EDC and how the third-generation EDC will move to a more integrated model.

Social Media/Internet Use for Clinical Trial Patient Recruitment & Retention EffortsThe technological landscape has grown in size, format, and complexity in the past three to five years. This has been demonstrated by the role that mobile technologies, internet, and social media played in the recent political unrest in the Middle East and the first initial public offering of a major United States (US) social media site, LinkedIn. Yet the use of social media and the internet by the highly regulated pharmaceutical and medical device industry has been tenuous and reticent. Katie Stewart of PharmaNet views how social media and the internet should become additional techniques in the cache of recruitment and retention methods.

Thinking Outside the Box – Technical Challenges for the Cool Chain Sector when Approaching the Middle EastSupply chain partners, specialising in the safe and effective transport of clinical trial materials around the globe, are continuing to expand into the Middle East supporting client demand. Roland Nicholas and Karen Adams, from SCA Cool Logistics, give their viewpoint on the technical challenges that are being encountered by the cool chain sector during their journeys into this uncharted territory.

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Clinical Trials in India: Managing Distribution Timelines through the Efficient Importation of Investigational Drugs With a population of over 1.1 billion and an increasingly large pool of patients suffering from deadly modern diseases like cancer, diabetes and cardiovascular disease, India has emerged as a thriving hub for clinical trials over the past decade. Although all appears perfect on the surface, sponsors and drug development professionals should recognise that India is still considered an emerging nation and, as such, delicate clinical product and materials must successfully navigate its developing regulatory environment and customs administration before victory can be declared. In this paper Anthony Leone of World Courier Inc. (USA), discuss India’s importation procedure for investigational drugs , outline strategies for overcoming the logistical challenges faced by pharmaceutical shippers conducting business here and create a realistic understanding of the timelines required in implementing drug administration schedules

ExhIBITION PREVIEWS & REVIEWS

DIA Annual Meeting, Chicago 2011The 47th Annual DIA Meeting was held at the McCormick Place Conference Center in Chicago between 19th and 23rd June, 2011. The conference programme explored the theme of “Convergence of Science, Medicine and Health”. In the words of the Conference Chairman, Kenneth Getz, Chairman, CISCRP and Senior Research Fellow, Tufts Center for the Study of Drug Development, in the present turbulent times, convergence is the essence of successful pharmaceutical innovation as we enter into a new era of open and integrated R&D. In order to facilitate discussion and networking in keeping with the conference theme, the programme consolidated tracks and combined topics that have been separated at previous DIA Annual Meetings. Further study volunteer, patient group and public perspectives were encouraged throughout the sessions. By: Dr Nermeen Varawalla, MD, DPhil (Oxon), MBA, Founder & CEO, ECCRO.

CPhI Worldwide, ICSE, InnoPack and P-MEC Europe Offer a Dynamic Line-up in Frankfurt for 2011UBM Live is gearing up for what promises to be the largest year ever of their flagship pharmaceutical ingredients event, CPhI Worldwide 2011, being held from 25-27 October 2011 at the Messe Frankfurt, Germany. Alongside the co-located events, ICSE for contract and outsourced services, P-MEC Europe for pharmaceutical machinery and equipment, and the newly introduced InnoPack for pharmaceutical packaging solutions, UBM Live is projecting a large increase in attendance over the 2010 event.

JCS NEWS

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Editorial Advisors Keynote


One of the central goals of the United States

(US) Food and Drug Administration (FDA) is to

increase its transparency agency-wide. Toward

that end, the FDA recently outlined key priorities

and goals for the next few years in its report

Strategic Priorities 2011-2015: Responding to

the Public Health Challenges of the 21st Century,

issued this April. The FDA plans to post implementation plans for these

priorities on its website by early 2012. Among the 5 “cross-cutting” areas

identified to serve as strategic priorities is the advancement of regulatory

science and innovation.

Regulatory science involves the development of new tools, standards,

and approaches to evaluate the safety, efficacy, quality, and performance

of FDA-regulated products. The FDA envisions the establishment of a strong

field of regulatory science that will ensure the safety and effectiveness of

new medical products throughout their life cycles.

Given the progressively global nature of drug development and

distribution, the FDA recognizes that its role as a regulatory agency has

become much more complex compared to even just a few years ago. It

is noted that up to 40% of the drugs taken by Americans are imported

and up to 80% of the active pharmaceutical ingredients in those drugs

originate from foreign sources. Critical reasons driving the FDA to refocus its

drug evaluation process to permit full product life cycle review are the new

challenges presented by globalization, outsourcing, and increasingly large,

multi-facility clinical trials.

By advancing the field of regulatory science, the FDA predicts a range

of regulatory activities will follow, including setting standards for products

that address unmet public health needs and identifying and mitigating

the spread of disease using informatics. A specific area of interest to the

FDA is subpopulation treatment responses. Although the FDA houses the

largest known repository of clinical data on the safety, effectiveness, and

performance of drugs, biologics, and devices, both before and after approval,

questions remain on subpopulation effects.

To gain insight on estimating treatment responses in subpopulations,

the Partnership in Applied Comparative Effectiveness Science for Medical

Products (PACES) program is underway in collaboration with FDA scientists

and reviewers to conduct patient-centered outcomes research. An update on

4 major PACES projects was provided at the FDA’s Science Board meeting

this May. One of the projects is aimed at promoting the early consideration

of adaptive trial designs and methods/tools for learning in what contexts

they might be the most useful. Potential benefits of adaptive designs include

yielding studies that determine which subpopulations would benefit most,

and reducing trial cost, duration, and number of study participants. The

project is expected to generate both analytic and software tools.

In pursuing its strategic priorities, the FDA emphasizes the value of

collaborations. The agency aims to strengthen its partnerships with other

public health agencies and leverage expertise and resources of colleagues

at the international, federal, state, and local levels. “This edition of JCS

includes coverage on another of the FDA’s partnerships, the Collaborative

Opportunities for Research Excellence (CORE) program, which is supporting

research in nanotechnology regulatory science (article by Walter Chalkey,

page 8). “

The importance of and requirement for collaborations will undoubtedly

increase as clinical trial sites continue to become established in various

places around the globe. Content featured here includes discussions on

clinical trial developments in China (article by May Lan, page 12), Tunisia

(article by Pr Habib GHEDIRA, page 20) as well as a report on the guidelines

for recruitment of volunteers to partake in clinical trials of investigational

medical products in the BRIC countries, Brazil, Russia, India, and China

(article by Diana L. Anderson, page 26). Please read on to enjoy these and

the several other interesting contributions in this month’s journal.

Deborah A. Komlos, MS, Senior Medical & Regulatory Writer, Thomson

Reuters

Editorial Advisory Board

Andrew King, Managing Director, Biocair International. Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc. Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories Catherine Lund, Vice Chairman, OnQ Consulting Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe Charles Horth – Senior Life Sciences Consultant Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Elizabeth Moench, President and CEO of Medici Global Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH Janet Jones, Senior Director, ICON Clinical Research Jerry Boxall, Managing Director, ACM Global Central Laboratory Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma. Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Kamal Shahani, Managing Director of Cliniminds - Unit of Teneth Health Edutech Pvt. Ltd. Karl M Eckl, Co-founder, Executive and Medical Director, InnoPhaR Innovative Pharma Research Eastern Europe GmbH Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRPNermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation Patricia Lobo, Managing Director, Life Sciences Business Consulting Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories Rabinder Buttar – President & Chief Executive Officer of ClinTec International Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Rob Nichols, Director of Commercial Development, PHASE Forward Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA - Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

In February 2010 the National Science and Technology Council’s Subcommittee on Nanoscale Science, Engineering, and Technology released a supplement to the President’s 2011 Budget entitled The National Nanotechnology Initiative: Research and Development Leading to a Revolution in Technology and Industry. This publication describes research and development programmes planned for 2011 by those US government agencies that are participants in the National Nanotechnology Initiative (NNI) and notes the establishment of the Collaborative Opportunities for Research Excellence (CORE) programme.1

According to the NNI document, CORE is designed to support priority studies in the area of nanotechnology regulatory science, particularly those highlighting inter-agency endeavours, including more projects between the FDA and myriad health and science-based federal agencies with coordination running through the NNI structure. An additional objective of the CORE programme focuses on the encouragement of joint FDA-academia projects. The FDA believes that such projects can benefit the development of enhanced safety studies and toxicity programmes, as well as spur the development of internal FDA research priorities and the anticipated cross-centre projects.

During the first year of funding, CORE has focused on setting up and training staff for its primary laboratory facilities as well as establishing the research priorities of the programme. These priorities include characterising nanomaterials through the definition of their chemical characteristics that affect safety and efficacy; targeting the understanding of the biocompatibility and pharmacokinetics of nanomaterials; and determining the safety issues surrounding the use of nanomaterials through toxicokinetics, in vitro testing, and in vivo testing.

Over the course of fiscal year 2011, the FDA intends to continue to develop CORE to support studies that show relevance in the development of safe and effective nanotechnology-based products.2 The CORE programme also developed a template for submitting regulatory science proposals, and has set up a grant mechanism review process to handle those study proposals that require funding and seek the opportunity for collaboration. This review process includes determining the appropriateness of the study to the targeted topic areas and then having experts inside and outside the FDA review the proposal.

In addition, the successful coordination of CORE is dependent on aligning the activities to address CORE’s priorities, facilitating the collaborations mentioned previously, and ensuring transparency and efficient use of resources. Other aspects of the programme include tracking the approved projects with an eye towards developing an internal database and monitoring the progress of the projects to quickly identify gaps in the knowledge base.

The perceived need to develop CORE and, indeed, the development of the entire NNI, stems from the re

commendations in the 2007 FDA Nanotechnology Task Force report, which noted the speed of innovation in the field of nanotechnology. The report stressed the importance of regulatory bodies keeping pace with the increased development of these products and having the expertise to understand the biological interactions and properties of nanomaterials. Without this knowledge, safety and efficacy could not be determined with any speed or certainty, and could lead either to beneficial products being kept off the market or harmful products being allowed on the market, neither option fulfilling the FDA’s mission.3

References 1 The National Nanotechnology Initiative: Research and

Development Leading to a Revolution in Technology and Industry. National Science and Technology Council, Committee on Technology, Subcommittee on Nanoscale Science, Engineering, and Technology. February 2010.

2 Department of Health and Human Services Strategic Plan FY 2010-2015. Appendix B: Performance indicators. Available at: http://www.hhs.gov/secretary/about/appendixb_goal2.html. Accessed June 2, 2011.

3 Nanotechnology Task Force Report 2007. July 23, 2007. Available at http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/NanotechnologyTaskForceReport2007/default.htm. Accessed June 3, 2011.

Walter Chalkley is a senior editorial project manager for Thomson Reuters. He is the current editorial manager for IDRAC’s AdComm Bulletin. Mr. Chalkley achieved his Regulatory Affairs Certification (RAC) in 2006 and his regulatory interests include pathways to approval of biologic products

with emphasis on vaccine development. He has authored several published articles on pharmaceutical regulatory affairs topics. Email: [email protected]

Watch Pages


The Collaborative Opportunities for Research Excellence (CORE) Programme Supports Nanotechnology Studies


Previous columns in this series have addressed different cardiovascular safety biomarkers, including QT interval prolongation (a marker for proarrhythmic liability for all non-cardiac drugs) and MACE (Major Adverse Cardiovascular Endpoint) adverse events during the development of new anti-diabetic drugs for Type 2 Diabetes Mellitus (T2DM). Another potential cardiovascular safety biomarker that is currently receiving a lot of attention is blood pressure. More specifically, the biomarker of interest is drug-induced changes in blood pressure (increases or decreases) for non-cardiovascular drugs. While antihypertensive drugs, for example, are designed to have an effect on blood pressure (lowering it), non-cardiovascular drugs are not expected to change blood pressure in either direction, and any such change would be considered an off-target effect.

There is continuous pressure in the arteries of the circulatory system to drive blood through the arteries. This pressure is known formally as arterial blood pressure, but in practice the term is shortened to just blood pressure. The level of blood pressure fluctuates during each cardiac cycle. Blood pressure is highest during systole (contraction), when blood is ejected from the left ventricle into the aorta and hence the entire systemic vasculature, and lowest during diastole (relaxation), when the heart prepares to beat again. Systolic blood pressure (SBP) represents the maximum pressure in the arterial system, which occurs as the left ventricle contracts and ejects blood, and diastolic blood pressure (DBP) represents the lowest pressure in the arterial system between heartbeats. Both are measured in millimeters of mercury (mmHg). These parameters are assessed in routine physical check-ups, other medical circumstances, and clinical trials. A derived parameter of interest is mean arterial pressure (MAP), a way of expressing a representative pressure across the entire cardiac cycle: MAP = DBP + 1/3(SBP-DBP).

Two primary determinants of blood pressure are total peripheral resistance of the systemic vasculature (TPR) and cardiac output (CO). TPR represents the resistance of the vasculature as blood is pumped through it by the heart, and CO is the amount of blood ejected by the heart in a unit of time (e.g., litres per minute). Blood pressure is a manifestation of the interaction between the heart and the vasculature, as captured by the following equation: MAP = CO x TPR. This equation demonstrates that if either CO or TPR increases (or decreases) while the other remains constant, an increase (or decrease) in MAP will occur. A given change in MAP can therefore be the result of a change in CO, a change in TPR, or a combination of changes in both. Therefore, a non-cardiovascular drug that affects the heart or the vasculature (or both) in an off-target manner will impact blood pressure.

There are guidance documents in place that govern specific assessments of other cardiovascular biomarkers, including QT interval prolongation for non-cardiac drugs1 and MACE events during the development of new anti-diabetic drugs for T2DMsee 2 & 3. In contrast, there are currently no regulations governing the specific assessment of blood pressure as a cardiovascular safety biomarker. Certainly, blood pressure will be measured throughout preapproval clinical trials, but not, for example, in a focused strategy that

includes comparison of observed blood pressure changes with a threshold of regulatory concern. Hence, there is currently no clear standard methodology to quantify a drug-induced increase in cardiovascular risk attributable to an increase or decrease in blood pressure. However, this topic is increasingly being discussed.

Two central components of these discussions are: What degree of off-target blood pressure change should be deemed to be of concern, and how best should changes in blood pressure be captured? As with QT interval prolongation and MACE events, a three-component model utilised for the prospective exclusion of unacceptable risk would require the choice of a threshold of regulatory concern4, hence requiring the combination of clinical, regulatory, and statistical sciences. With regard to the second component, two methodologies are relevant: standard auscultatory blood pressure measurement, and ambulatory blood pressure measurement (ABPM). The auscultatory methodology was introduced into clinical medicine at the end of the nineteenth century and has been employed in a largely unchanged manner for over 100 years5. As O’Brien5 observed, in addition to other limitations, this methodology can only provide a ‘snapshot’ of blood pressure at the time the measurement is made. In contrast, the technique of ABPM can provide automated profiles of blood pressure variation over a 24-hour period. It will be interesting to follow ongoing discussions over the coming months.

References 1. ICH Guidance E14, 2005, The Clinical Evaluation of QT/QTc

Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs.

2. Caveney E, Turner JR, 2010, Regulatory Landscapes for Future Antidiabetic Drug Development (Part I): FDA Guidance on Assessment of Cardiovascular Risks. Journal for Clinical Studies, January issue, 34-36.

3. Turner JR, Caveney S, 2010, Regulatory Landscapes for Future Antidiabetic Drug Development (Part II): EMA Guidance on Assessment of Cardiovascular Risks. Journal for Clinical Studies, March issue, 38-40.

4. Turner JR, 2010, Integrated Cardiovascular Safety: Employing a Three-component Risk Exclusion Model in the Assessment of Investigational Drugs. Applied Clinical Trials, June issue, 76-79.

5. O’Brien EO, 2011, Why ABPM Should be Mandatory in all Trials of Blood Pressure-Lowering Drugs. Drug Information Journal, 3:233-240.

Dr. Rick Turner, is Senior Director, Cardiovascular Safety, Quintiles, and Affiliate Clinical Associate Professor, University of Florida College of Pharmacy. He specializes in the design and analysis of clinical trials, with a special interest in the cardiac and cardiovascular safety of non-

cardiac drugs. He has published over 50 peer-reviewed papers and 10 books. Email: [email protected]

Watch Pages

Cardiovascular Safety Watch

Watch Pages


In recent years, an increasing number of multinational companies have established their late stage clinical trial centres in China. On September 6th 2009 the State Food and Drug Administration, P.R. China (SFDA), first released its Annual Report on Drug Registration Approval, showing a progressive increase in synchronous research participation of new global drug development, as well as a steady rise in applications for clinical trials in international multicentres.

2009 saw the most significant increase in multicentre global trial applications and approvals in China. There were 205 applications for international multicentre clinical trials among new foreign applications, showing acceleration in growth compared to before 2008 (Figure 1). Among the clinical trials of 320 foreign applications approved in 2009, 132 were for clinical trials in an international multicentre, a remarkable increase compared to the roughly 40 cases in 2008 (Figure 2) (Source: 2009 Annual Report on Drug Registration Approval).

Recently, most of the international multicentre clinical trials in China have been conducted by large Western multinational pharmaceutical companies, including Pfizer, GlaxoSmithKline, Sanofi-Aventis, Roche, Bayer Schering Pharma, Lilly, Wyeth, etc. Most of the drugs are new compounds in therapeutic areas such as cancer, cardiovascular diseases, neurological diseases and infectious diseases.

In the last several years East Asian countries have been actively participating in international multicentre clinical trials, with countries like South Korea, Japan and Singapore accumulating a wealth of experience in this area. South Korea in particular has been very prominent in clinical studies. Research has revealed that the Korea Food and Drug Administration (KFDA) implemented a separate management of Investigational New Drug (IND) and New Drug Application (NDA); the international multicentre clinical trials in South Korea increased by 241% from 2004 to 2009. However, most of the international multicentre clinical trials in China are Phase III clinical trials and are large-scale trials with a big sample size and many study sites. Currently there are no Phase I trials in China.

Since SFDA promulgated the Drug Registration Regulation in 2003, international multicentre clinical trials increased in China because of the new regulation that clearly explained approval conditions, declaration materials, and validation periods of international multicentre clinical trials. Compared to the application and approval process for imported drugs, international multicentre clinical trials require fewer declaration materials and a shorter validation period, and undergo an easier approval process. However, according to the latest Drug Registration Regulation (issued in 2007), foreign applicants who want to conduct research in

international multicentre clinical studies in China may only conduct late stage clinical trials. In other words, drugs used for international multicentre clinical studies must be already registered in a foreign country or be in Phase II or III clinical trials. In addition, compared to other countries or regions, the approval of an international multicentre clinical trial in China requires more declaration materials, takes more time, and has a more complicated process. This dissimilarity is the main impediment of growth of international multicentre clinical trials in China.

May Lan joined The Scott Partnership as a Senior Account Executive in October 2010. May has a double MSc degree in Bioinformatics from The University of Edinburgh and in Information Technology from The University of Abertay Dundee. She also has a background in pharmacy.

Prior to joining The Scott Partnership, May worked in public relations for the chemical and pharmaceutical industries. Email: [email protected]

Current Status of International Multicentre Clinical Trials in China

Figure 1: Amount of Applications for International Multicentre Clinical Trials in 2009

Figure 2: Numbers of International Multicentre Clinical Trials Approved between 2005 and 2009

Watch Pages


According to a recent report by the Substance Abuse and Mental Health Services Administration, prescription drug abuse continues to be a grave problem in the United States (US)1. A prominent shift in the misuse of prescription opiates between 1999 and 2009 (which increased steadily from 1% of admissions for those aged 12 and older in 1999 to 7% in 2009, and increased from 8% to 33% of all opiate admissions) was reported. Alternately, during the same time period hospital admissions related to methamphetamine/amphetamines rose from 4% to 6%, marijuana admissions increased from 13% to 18%, and cocaine-related admissions decreased from 14% to 9%1. These figures highlight the relative rise in prescription drug misuse compared to illicit drugs. Of interest in relation to last issue’s CNS Watch on suicidality, another report suggested suicide attempts involving narcotic pain relievers increased by 79.5% for males of 35 to 49 years of age, and by 193.3% for those 50 years and older from 2005 to 2009

2. Clearly, prescription abuse is a major issue for clinicians and CNS drug developers, and this data lends credence to some of the long-held perceptions of misuse and diversion that are barriers to ensuring proper pain treatment.

The US Food and Drug Administration (FDA) had also recognised a substantial increase in the number of post-marketing reports of abuse, misuse, addiction and overdose in this time period resulting in fatalities associated with extended-release and/or long-acting opioid drugs. It was this trend that led to the deliberation of various risk mitigation strategies over the past several years, as evidenced by various public and private meetings with a variety of pain and healthcare specialists, patients, and pharmaceutical industry members. These meetings eventually culminated in the FDA’s announcement this April that all long-acting and extended-release opioid medications will be required to have a Risk Evaluation and Mitigation Strategy (REMS).

The opioid REMS mandate was carried out under section 505-1 of the Federal Food, Drug, and Cosmetic Act, and as a crucial element of a multi-agency plan to reduce prescription drug abuse. The FDA Amendments Act (FDAAA) of 2007 grants the FDA the authority to require a REMS from manufacturers “…to ensure that the benefits of the drug continue to outweigh the risks of adverse outcomes (addiction, unintentional overdose, and death) resulting from inappropriate prescribing, abuse, and misuse”. Thus, in “the interest of public health and to minimize the burden on the healthcare delivery system of having multiple unique REMS programs, a single, shared system should be used to implement the REMS for all members of the class”3.

Although many companies and organisations have endorsed the employment of a class-wide REMS programme, others have suggested that the FDA has failed to meet the scientific burden to impose a REMS programme on a

class-wide basis. They suggest instead that REMS must be product-specific according to the FDAAA; and that class-wide REMS are by nature cumbersome, impractical and most importantly lack the flexibility to effectively address issues unique to specific medications4. It should be noted that individual REMS for several analgesic drug products have already been in use, including generic morphine sulfate alone, which has a Medication Guide, and morphine sulfate and naltrexone hydrochloride (HCL) extended-release capsules (EMBEDATM) which has a Medication Guide and Communication Plan as part of the REMS. Furthermore, the notion of class-wide REMS has already been advanced and is well accepted (e.g., erythropoiesis-stimulating agents) in other therapeutic areas.

Nonetheless, the current class-wide REMS constitutes the most far-reaching REMS to date with implications for practitioners, hospital staff, pharmacists, patients and analgesia drug developers. Specifically, the current REMS mandate affects multiple CNS drug developers and numerous drugs including, but not limited to, hydromorphone HCL extended-release capsules, methadone HCL tablets, morphine sulfate extended-, controlled- and sustained-release capsules, morphine sulfate and naltrexone extended-release capsules, oxycodone HCL controlled-release tablets, oxymorphone HCL extended-release tablets, hydromorphone HCL extended-release tablets, and Fentanyl Transdermal System, Buprenorphine Transdermal System, as well as innumerable generic drug products.

The scope of this class-wide REMS programme was outlined in a letter to sponsor companies from Bob A. Rappaport, M.D., the Director of the Division of Anesthesia and Analgesia Products at the FDA. This letter delineated the key elements of the REMS including both a Medication Guide and elements to assure safe use (“ETASU”), as well as a timetable for submission of assessments3. In this letter the FDA noted that a Medication Guide was necessary for patients’ safe and effective use of drug, and that this Medication Guide should have both common content applicable to all extended-release and long-acting opioids, as well as product specific information necessary for safe and effective use of the drug.

Under 21 CFR 208, sponsor companies are responsible for ensuring that the Medication Guide is available for distribution to patients who are dispensed drug products. The REMS must also minimally ensure that training is provided to prescribers who prescribe these drugs. To aid this, a summary of the content of such a training programme was provided, including information on patient selection and assessment, considerations when prescribing opioids, managing patients taking opioids, initiating and modifying doses of opioids for chronic pain, maintenance over time, as well as product specific information and

FDA’s New Risk Evaluation and Mitigation Strategy for Opioids

patent counselling3. The FDA expects that the training will be conducted by an accredited, independent continuing medical education (CME) provider. In terms of duration, the FDA expects the training to take at least a couple of hours; however, the length of time will depend on how the CME and CE providers develop the programme. It is also possible to link the training required under the REMS to general training in pain management5.

The FDA anticipates that appropriate sponsor companies will provide unrestricted grants to CME/CE providers to help pay for the development and execution of these educational programmes, and that cost-sharing amongst sponsor companies would occur. An independent audit of the quality of the content of educational materials used by CME providers is also required as part of the REMS assessment plan, with audit frequency to be specified. This audit would need to be performed by a third party with the goal of keeping the educational material free of any promotional content5. Also required is an assessment of how many prescribers of long-acting and extended-release opioids have successfully completed the training, with performance goals related to how many prescribers are expected to be trained within certain periods of time (e.g., 50% of prescribers trained within six months; 70% within 12 months).

The assessment plan should also include the following elements along with the methodology for each element: an evaluation of patients’ understanding of the serious risks of these drug products; an evaluation of drug utilisation patterns; an evaluation of changes in prescribing behavior; a surveillance plan that includes monitoring for misuse, abuse, overdose, addiction, and death as well as any intervention to be taken resulting from signals of these metrics. An evaluation of healthcare providers’ awareness and understanding of the serious risks associated with these products must also be included. Last of all, the REMS must also incorporate a proposed timetable for submission of assessments that should be no less frequent than six months, 12 months, and annually, after the REMS is initially approved. The letter ends by stating that within 120 days of the date of this letter, the sponsor must submit the proposed REMS as a supplement to their NDA. These REMS will need to be updated periodically as new products are approved3.

It is acknowledged that it may take several months to develop these REMS. In the meantime, healthcare professionals should continue to prescribe long-acting and extended-release opioids, and are encouraged to thoroughly discuss the risks and benefits of these products with their patients. Patients who are currently taking long-acting or extended-release opioids should continue to take their medications as directed, and any patients who have concerns about their medications should consult with their

healthcare professional. The FDA fully appreciates that the institution of a class-wide programme such as this might make it more cumbersome for patients to receive the proper pain treatment that they need. Therefore, as part of the REMS, the FDA will monitor patient access to medicines and continue to dialogue with patients and physicians to ensure that patients are treated properly. Finally, it should be noted that the FDA is open to additional discussions with industry before August 17, the REMS due date. For questions and further information please refer to the FDA’s website on Opioid Drugs and Risk Evaluation and Mitigation Strategies6, or contact them directly at [email protected].

References:1. Treatment Episode Data Set (TEDS) 1999 – 2009. National

Admissions to Substance Abuse Treatment Services. Dept. of Health and Human Services Substance Abuse and Mental Health Services Administration. http://wwwdasis.samhsa.gov/teds09/teds2k9nweb.pdf

2. Trends in Emergency Department Visits for Drug-Related Suicide Attempts among Males: 2005 and 2009. The Drug Abuse Warning Network Report. http://oas.samhsa.gov/2k11/DAWN018/DAWN018.htm

3. Letter Sent to Opioid Manufacturers Outlining Opioid REMS Implementation. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM251595.pdf

4. A Review of the FDA’s Approach to Implementing a Class-Wide REMS for Long-Acting and Extended-Release Opioids. Center for Lawful Access and Abuse Deterrence. Jan 4, 2010. http://www.claad.org/downloads/REMS%20-%20FDA%20Approach%20Critique%20Final.pdf

5. FDA Opioid REMS Meeting with Industry May 16, 2011. Kirkland Conference Center, Nation Labor College. Silver Spring, MD 20993. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm258184.htm

6. Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS). http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm

Henry J. Riordan, Ph.D. is Senior Vice President of Medical and Scientific Affairs at Worldwide Clinical Trials. Dr. Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. He has been the primary author of >75 CNS protocols as well as several clinical development programs. Dr. Riordan specializes in clinical trials methodology and has advanced training in biostatistics, experimental design, neurophysiology, neuroimaging and clinical neuropsychology. He has over 65 publications including two books focusing on innovative CNS trials methods. Email: [email protected]

Watch Pages

Journal for Clinical Studies 15www.jforcs.com


Regulatory

Airborne Particle Monitoring:Impact of ISO 21501-4 Calibration

Dependable, consistent and repeatable results in monitoring airborne particles in cleanrooms and clean zones depends both on the sampling technique of the analyst and on the performance of the particle counting instrument. The control of the sampling technique often is the subject of a unique SOP (standard operating procedure) while the performance of the instrument is typically reviewed and verified through an annual or semi-annual calibration process.

The calibration process itself has been subject to a greater degree of variability in actual practice and throughout the lengthy life of the instrument than would be desired, due to different calibration techniques magnified by infrequent maintenance and calibration. This variability can be minimised by the implementation of the ISO 21501-4 calibration standard. Although there will be additional time and cost in the calibration process, the end result will be a noteworthy improvement in repeatability over the lifetime of the instrument and also improvement in reproducibility between instruments.

International standards for the monitoring of airborne particles are used by all industries that employ cleanrooms or clean zones. Some form of airborne sampling for particles is needed for these controlled environments in order to ensure the quality of the product being manufactured or the success of the process that is being conducted in this controlled or critical environment. Many variables will affect the success of the operations in these areas; the particulate levels in the air are often a significant element in the control of the risk of failure (or, inversely, the likelihood of success!) for the controlled operation.

The initial standard for classification of cleanrooms and clean zones from the United States, known as “Federal Standard 209E”, had a global impact for many years but was officially replaced in 1999 by a new global standard, ISO 14644-1.

Revision of ISO 14644-1 and -2 (TC209 Working group 1)For the past several years, an international committee known as TC209 Working Group 1 (WG1) has been examining potential revisions to the first two sections of the ISO 14644 document. The initial general vote on the proposed revisions by the larger body of nations

closed 02 May 2011; there is the potential that the effective date of the revisions could be placed six months thereafter, or as early as November 2011.

One key change in the proposed revision of ISO 14644-1 is the normative reference to a calibration standard for the instrument to be used for cleanroom classification. Previously, no mention of a calibration method had been made in ISO 14644-1.

But it is well-known that the variability of the calibration techniques or methods can have a significant effect on the performance of a particle counting instrument and on the reproducibility between instruments.

The Ultimate QuestA common expectation for customers having multiple particle counting instruments is that each instrument would give the same result as any other when sampling in the same physical space. This is an unrealistic hope, due to the reality that the same aerosol cannot be simultaneously or even sequentially sampled by a pair of instruments. The particle levels in a room or zone are highly variable over time, depending on activity, number of personnel, speed of activity (even walking), temperature gradients, and changes in air flow rates - to name just a few of the variables. Airborne particle counts in an active area could be compared to counting cars on a road or freeway: each sample might be quite valid for the time it was taken but the numbers one might obtain during the middle of the night could be markedly different than those obtained at the peak of the commute hours! Add into this any concern with the reliability of the instrument being used, and the effort to define the airborne particle levels becomes even more challenging!

Controlling Variability Between Instruments through ISO 21501-4The variability of the concentration of airborne particles is a matter of cleanroom design, coupled with the control of the process and activities with the clean zone, whereas the variability of the measuring instrument is one of calibration, proper use and maintenance. ISO 21501-4 provides a thorough platform to gain control of the

“The purpose of this part of ISO 21501 is to provide a calibration procedure and verification method for particle counters, so as to minimise the inaccuracy in the measurement result by a counter, as well as the differences in the results measured by different instruments.”

Translation:What you’ll get if you use ISO 21501-4 methods:1. Better repeatability over the lifetime of the instrument2. Better agreement between different instruments

And it will probably cost more because:1. more tests = more technician time2. extra tests = extra test equipment

Proposed wording of Section 2 of 2011 revision of ISO 14644-12 Normative referenceThe following normative document contains provisions, which, through reference in this text, constituteprovisions of this part of ISO 14644. Subsequent amendments to or revisions of this publication do not apply.However, parties to agreements based on this part of ISO 14644 are encouraged to investigate the possibility of applying the most recent editions of the normative document indicated below.

ISO 21501-4:2007, Determination of particle size distribution — Single particle light interaction methods —Part 4: Light scattering airborne particle counter for clean spaces


potential variability of the instruments. In many cases, calibrations of an instrument done in the years following its initial manufacture could take many forms. Stories abound of one-point “calibrations” performed by independent or unqualified contractors with little or no traceability to national standards organisations such as NIST, DANAK, BSI, DIN, JIS, etc. Methods also varied between different instrument manufacturers. Most calibrations done by qualified technicians in the field can often consist of only three or four tests. When a calibration is performed following ISO 21501-4, typically at least eight different tests are executed. These tests require both additional time and additional equipment. Although calibration according to ISO 21501-4 will likely create some additional cost in comparison to what is currently performed, there will be noteworthy benefits in both the repeatability and the reproducibility of measurements obtained.

Repeatability refers to the stability of the values obtained by a given instrument when taking multiple measurements of the same environment with a consistent particulate level. Reproducibility refers to the ability of two or more instruments to obtain the same results when measuring the same environment with a consistent particulate level.

As noted previously, it is almost impossible to have a consistent level of airborne particulates in an environment in the real world, so the variation of readings from one instrument taking consecutive readings, or between two instruments taking parallel readings, will always exist.

What ISO 21501-4 provides is verification that under controlled circumstances and in testing a controlled and consistent aerosol, the instrument can provide predictable and consistent readings. This process thus creates the basis for confidence that the readings obtained “in the real world” - with its inherent variability - will be a true reflection of the contamination level at a given moment.

ResourcesDirect assistance: contact ISO 21501 Support at iso21501 @hach.comFor assistance in auditing your particle counter fleet, 1. Request a more detailed review of ISO 21501-4– Whitepaper: ISO-21501-4: Calibration of Air Particle

Counters from a Metrology Perspective (Latimer and Ping)2. Request an ISO 21501 Source Book– Whitepaper: ISO 21501 – A Standard Methodology to

Optical Particle Counter Calibration and What it Means to Cleanroom Owners.

– Whitepaper: Optical Particle Counters and Counting Efficiency

Published articles:1. Gecsey, J. Airborne Particle Monitoring: Satisfying

the Changing Demands in Regulations and Methods, Cleanrooms Magazine, September 2009, pages 14-18

2. Harrison, T., ISO 21501 - A Standard Methodology to Optical Particle Counter Calibration and What it Means to Cleanroom Owners, The Cleanroom Monitor, August 2009, Issue 61, The Scottish Society for Contamination Control

Joe Gecsey is the Life Sciences Application Manager at HACH in Grants Pass, Oregon, USA. He is responsible for tracking regulatory changes regarding particulate counting in the life science industry, and is one of two US representatives on the TC 209 Working

Group (WG1) tasked with finalising the revisions to ISO 14644-1 and 14644-2. He has conducted seminars throughout the world on particle counter design and applications. He received a Bachelor of Science degree in Electronic Engineering from the University of California in 1974 and has been employed as an engineer and technical advisor by Hach (previously Met One) since 1984. Email: [email protected].

ISO 21501-4 Parameters

Size Calibration

Counting Efficiency at First Channel

Counting Efficiency at Particle Size 1.5 to 2 Times First Channel

Instrument Resolution (at the Size Specified by Manufacturer)

Zero Count Test

Maximum Particle Number Concentration (Specified by Manufacturer)

Sampling Flow Rate (Volumetric)

Sampling Time

Calibration Interval

Target Limit

± 5%

50% ± 20%

100% ± 10%

≤ 15%

≤ 1 count in 5 mins

≤ 10%

± 5%

± 1%

≤ 1 year

Regulatory


Regulatory

On January 14th, 2011, Tunisia was marked by an unprecedented revolution, and for the first time in its whole history, the Tunisian people were invited to drive their own destiny. Originally occupied by Berbers, a historic unit comprised of various ethnic blocks, Tunisia has always been an occupied country for 3000 years of its history, beginning with the Phoenician occupation in 800 BC.

In 1956, a national movement led by Bourguiba brought independence. At that time, democracy was not considered as a huge priority, but education, health and birth control were seen as urgent challenges. Bourguiba’s government policy was based upon implementing pioneers in each domain, and many young postgraduates were asked to drive the development of the young republic. For public health, several physicians with interesting jobs or training positions in France were asked to come back to head different medical hospital and university departments. Clinical research at that time, being mostly academic, was conducted in close relationship with French departments.

Actually, the history of company-sponsored trials began in the early nineties, just after the famous despot Ben Ali became the second president and had a run of 23 years of non-shared power.

In Ben Ali’s era, the development of any programme was put under the direct supervision of a trusted man around the president. Thus, the first trials were conducted thanks to a direct relationship between one of Ben Ali’s closest advisors and a French CRO. Despite the lack of adequate laws and GCP implementation, trials were conducted considering the Tunisian sites as French offshore sites. A crucial point at that time was that the Tunisian sites showed a recruitment potential which exceeded all expectations. This skill changed companies’ view of this small country, but the absence of a related law and GCP implementation were dissuading factors.

In 1990, the department of Pharmacology in the Faculty of Medicine of Tunis joined its efforts with the most important multinational pharmaceutical company in Tunisia, to stress the need for the health department in implementing the law, the regulations and the GCP, and to create an adequate research ethical environment.

From that time, a decree, known as “Décret n° 90—1401 du 3 Septembre 1990” was prepared and voted by the chamber of deputies, but was nevertheless restrictive, excluding persons under age, and pregnant or breast-feeding women. The GCP request of the proposal for clinical research was also mandatory, and must be signed by both the research sponsor representative and the investigator coordinator. Ethics committees were also developed in most teaching hospitals.

The number of clinical trials then increased quickly, but the company and CRO complained about an incomplete transparency concerning agreement decisions and suspecting the intervention of an influential relationship.

Nowadays, many are questioning the future of company-sponsored clinical research after the unprecedented revolution that shook the country and the whole Arab world.An important factor in predicting the future of the company-sponsored clinical research after the revolution is to gain insights into the anger that led to this revolution. One of the main

reasons for the so called “Dignity Revolution” is unemployment of university graduates who, thanks to their skills in communicating using electronic social networks, made all the population aware of their poor condition and desperate feelings caused by their unemployment. Among these unemployed university graduates, many were educated and trained in the health field, and may represent fruitful clinical research resources.

When asking the different protagonists in the clinical research field, all seem convinced of a hopeful further development of clinical research in Tunisia, and many facts reinforce these beliefs:1- In Tunisia, many resources are educated and trained in fields

related to clinical research, and implementing more clinical trials will certainly help reduce unemployment. Indeed, as reported by the World Bank1 “In spite of solid growth, unemployment in Tunisia remains persistent. With growth levels near 5 percent over the last eight years, Tunisia still has a relatively high unemployment rate at 14.7 percent (which was more than double the 6.4 percent for all middle income countries in 2008). The overall rate masks a striking divergence by age, with younger groups of the labor force being more affected. Unemployment also increasingly affects the better-educated. The overall unemployment rate of higher education graduates, which was below 5 percent in 1994, has increased significantly to 23 percent in 2009. Recent graduates face 46 percent unemployment 18 months after graduation.”

2- The clinical research environment exists, and has been tested as being very efficient in recruiting patients and as being very professional in conducting GCP-based clinical trials. This efficiency is partly due to the willingness of the investigators, most of whom are based in teaching hospitals, to be partners in clinical research, since academic research is not fulfilling their professional time dedicated to research. Efficiency is also the result of an excellent relationship between the investigators and their patients. This trustworthy relationship increased after the revolution due to an overall better feeling of trustworthiness among the Tunisian people. Also, CROs with experienced CRAs and project managers are now in place in Tunisia, allowing a close monitoring of clinical studies and reducing the costs of monitors based offshore.

3- The new democracy and transparency in administrative and regulatory management of files and agreements will certainly encourage companies who were experiencing difficulties before the revolution, to implement more trials. This is related to a global willingness of the country to boost investment. Tunisia has effectively adopted policies that are designed to promote foreign investment and prepare the Tunisian industry and services for foreign competition.

4- The willingness of the developed world to support Tunisia, and the G8 leaders’ promise of substantial aid to Tunisia aimed at fostering changes, will help developing more substantial clinical research sites and facilities. During the last G8 meeting in Deauville (France), Cameron, the UK prime minister, described the money provided to Tunisia and Egypt as an investment in success and part of an enduring partnership. “If we get this wrong,

The Future of Clinical Research in Tunisia after the Revolution

Regulatory


if we fail to support these countries, we risk giving oxygen to the extremists who prey on the aspirations and frustrations of young people. If we fail we would see more terrorism, more immigration and more instability coming from Europe’s southern borders and

that affects us back at home,” he said. This indicates that the support of western countries is not an opportunistic matter but a sustained development policy that will drive Tunisia in that way.

Finally, the revolution that shook Tunisia will not add uncertainty to sponsored clinical research, but conversely will provide opportunities for more transparency in regulatory and administrative management, and will be fostered for its capability in reducing graduate unemployed resources, and will be boosted by the western countries’ support.

1- The World Bank. Labor Market reform. Boosting Employment in Tunisia http://web.worldbank.org/WBSITE/EXTERNAL/COUNTRIES/MENAEXT/TUNISIAEXTN/0,,contentMDK:22716743~pagePK:1497618~piPK:217854~theSitePK:310015,00.html?cid=3001_6 Last accessed on 20th June, 2011.

Pr GHEDIRA Habib is a MD, Professor in the Faculty of Medicine of Tunis and head of a Pulmonary Diseases’ Department in teaching Thoracic Hospital of Ariana. He coordinates International company-sponsored Studies in Tunisia and is Principal Investigator of many observational and interventional

studies. He is also companies and CRO’s senior advisor for sites’ selection, relationship with ethic committee and patient enrollment. Email: [email protected] or [email protected]


Regulatory

BrazilReported as the gateway to Latin America, Brazil’s strength as a clinical research centre lies in numbers: a large, ethnically diverse, treatment-naïve population of 201 million people; 8000 hospitals; 96 medical schools; and 415 institutional review boards. While those figures are impressive for a developing country, perhaps the most important calculation is Brazil’s pharmaceutical market index — a 14.5% compound annual growth rate forecast through 2014.

Brazil is home to South America’s first academic research organisation, the Brazilian Clinical Research Institute (BCRI),

which was inaugurated on 16 September 2009 in San Paulo. Located on the Federal University campus, BCRI was founded to advance clinical research in South America as a whole and Brazil in particular. Organisational goals include conducting and coordinating high-quality clinical research in an academic manner in Brazil and South America; providing clinical research training to medical students, doctors, and others; helping Brazil and South America realise better positions as global clinical research leaders; and improving the quality of research currently being conducted in Brazil.

BRIC and Mortar: Clinical Trial Growth in Latin America, Eastern Europe and Asia


Market Review

1. What laws or guidelines govern the advertising for study volunteers to participate in clinical trials of investigational medical products in Brazil?

Brazil has rather extensive and sophisticated guidelines governing the conduct of clinical trials as detailed in Rules on Research on Human Subjects (Resolution CNS 196/96 — Normas Para Pesquisa Envolvendo Seres Humanos).

Four related resolutions include: • Resolution 251/9 — Research involving human subjects in

studying new pharmaceuticals, medicines, vaccines and diagnostic tests

• Resolution 292/99 — Research with foreigner cooperation• Resolution 303/00 — Research in human reproduction• Resolution 304/00 — Rules on research involving indigenous

people

Additional guidance comes from the National Committee on Ethics in Research (CONEP/CNS/MS) which published the CEP Qualifying Manual (Manual de Capacitação dos CEP) and the User’s Manual (Manual do Usuário). 2. What are accepted patient recruitment practices in Brazil?

Is it typical to advertise for study volunteers?Print and broadcast media are frequently used to recruit study participants, though direct mail is not. Additionally, banners and information sheets may be found in hospital facilities asking physicians to refer patients. All of these methods must be approved by the ethics committee.

It is most common for investigators to select patients from their own university or private practice. Similarly, doctors or care team members contact patients who regularly visit outpatient institutions for health assistance.

3. Are study volunteers compensated for participating in clinical trials?

In Brazil, only out-of-pocket expenses are reimbursed. Patients receive trial-related medical care at no cost, but no other financial incentive is permitted. This information is stated in numerous places in Resolution 196/96.

4. What is the name of the regulatory agency in Brazil?Created in 1999, Agência Nacional de Vigilância Sanitária (ANVISA) approves all clinical trial protocols. Submission to ANVISA and the National Ethics Committee may be done simultaneously, reducing approval time to an average six to seven months.

RussiaOpen Studies: 414Clinical trial guidelines are fairly new in the former USSR, with the first Good Clinical Practice-style clinical trial taking place there in 1989, though GCP was non-existent in Russia at that time and clinical trials were not regulated.

It was 1998 when the president of the Russian Federation signed into effect the first Russian Federal Law on Medicinal Products. It was quickly followed in 1999 by OST-42-511-99, Rules of Clinical Trials Conduct in Russian Federation. The law outlines a national system for quality, efficacy and

safety of medicinal products and addresses a number of issues including clinical trials.

1. What guidelines govern the advertising for study volunteers to participate in clinical trials of investigational medical products in Russia?

• Russian Federation Federal Law on Medicinal Products. • The Standardization System in the Russian Federation

Health Care System Clinico-Economic Studies (OST 91500.14.0001-2002). This is a code of rules governing the conduct of clinical trials that focus on economic analysis, i.e., comparing the economic impact of two or more interventions.

2. Which of these guidelines has the most impact on the conduct of clinical trials today?

The Federal Law is the main piece of legislation governing clinical trials in Russia today. It is a decree of the Minister of Health that has been adopted by the Minister of Justice, meaning that it has legal status.Whereas the former guidelines, OST-42-511-99, were merely a Russian translation of the ICH-GCP Guidelines, the Federal Law lays out the rules for initiating a clinical trial, filing for a clinical trial, the documents that have to be presented, and timeline for approval.

3. Where are clinical trials conducted in Russia?According to the Federal Law, only certain healthcare institutions are entitled to conduct clinical trials (Figure 1). For the most part, these healthcare institutions are large facilities where the majority of patients go for treatment, reflecting the centralised nature of healthcare in Russia. The institutions either specialise in each field of medicine (e.g., oncology, cardiology, etc.) or are multipurpose regional hospitals that cover almost all medical specialities in a certain geographical area. This facilitates ease of access to patients.

4. How are study participants recruited?Usually investigators recruit patients whom they routinely treat or who are referred to them from other clinics. In most instances, patients are asked to participate in a clinical trial during personal meetings with the investigators at their routine visits or while at the clinic during hospitalisation.

Figure 1

Where Clinical Trials Are to be Conducted

Article 37 (3): Clinical trials are conducted at healthcare institutions.

Article 37 (4): The list of healthcare institutions entitled to conduct clinical trials is made up and published by the federal executive body in the field of healthcare.

Source: Federal Law on Medicinal Products

Figure 2

Compensating Study Volunteers in Russia

6.9 “The EC should be convinced that the information about material compensation of patients, including methods, the sums and the order of payments, is completely reflected in the form of the written informed consent and (or) other materials with the indication of the study phase”

Source: Federal Law on Medicinal Products (translation by V. Bokovanov)


Market Evaluation

Direct mail and advertising are rare but are sometimes used when the recruitment criteria are very restricting and the investigator has a database of patients.

5. Are study volunteers compensated for participating in clinical trials?

In Russia, compensation to patients — beyond payment for out-of-pocket expenses — is not prohibited, but it is not accepted practice. Patients receive trial-related medical care at no cost but no other financial incentives.

Healthy volunteers participating in Phase I studies and bioequivalence studies are generally compensated, as allowed in Sections 4.8.10(k) and (l) and 5.8.3 of ICH-GCP.

Information about compensation, such as amount and method of payment, must be presented to the ethics committee and described in the informed consent. This information appears in Section 6.9 of the Federal Law (see Figure 2).

6. Are there any additional factors that are important to understanding the conduct of clinical trials in Russia and patient recruitment specifically?

New federal law titled “On Circulation of Medicines” (24 March 2010) states a new drug can only be registered in Russia if the international multicenter clinical trial for the drug was conducted at Russian sites. Further, generic drugs may only be registered in Russia if the bioequivalence study was performed there.

Russian study volunteers are generally very compliant in terms of keeping appointments, taking study medications, recording in patient diaries, and rarely withdrawing consent. They also seem to be highly motivated to participate in studies to gain access to the best facilities and the best physicians at no cost. Their high level of compliance may be because, in Russia, doctors continue to be seen as influential authority figures, and patients value their opinions. Some research suggests that, on average, study subjects tend to be fairly well-educated.

7. What is the name of the regulatory agency in Russia?The primary regulatory body in Russia is the Ministry of Healthcare and Social Development of the Russian Federation.

IndiaOpen Studies: 500With 1.1 billion inhabitants, India ranks second to China among the world’s most populous countries. The region is ripe for clinical research studies due to its large pool of treatment-naïve patients and English-speaking doctors educated in the West. Prior to 2006, the country was often overlooked by pharmaceutical companies for global studies, in part because of limited intellectual property protection and the preponderance of generic pharmaceuticals produced by indigenous companies. Trial ethics also came into question following a survey by the former US National Bioethics Advisory Commission which revealed that 25 per cent of clinical trials conducted in developing countries did not undergo ethical review.

Today, however, patent protection is no longer a barrier as

India now complies with Trade-Related Aspects of Intellectual Property Rights. Additionally, the Academy for Clinical Excellence and Institute of Clinical Research educate doctors in ICH-GCP guidelines and ethical trial requirements.

India, among other developing countries, anticipates a great increase in clinical trials given global pressure to recruit more patients faster.

1. What laws or guidelines govern the advertising for study volunteers to participate in clinical trials of investigational medical products in India?

Ethical Guidelines for Biomedical Research on Human Subjects, launched in 2000 by the Indian Council of Medical Research (ICMR), details the many guidelines affecting the conduct of clinical trials in India. The Central Ethics Committee on Human Research, a special committee convened by the ICMR, developed the document.

The document states that when an investigator submits an application for a proposed clinical trial to the institutional ethics committee (IEC) for review, it is to contain a number of specific items, including information on subject recruitment procedures (p.14). In the case of multicentre trials, it is recommended that all investigative sites standardise their methods of patient recruitment (p.28). Compensation is permitted (Figure 3).

Additionally, Good Clinical Practices for Clinical Research in India contains a set of guidelines detailing steps to protect the rights of human subjects and the authenticity of biomedical data. Within these regulations are several mentions of “advertising” for study subjects.

2. Are there any recruitment issues of note?In the case of genetics research, Ethical Guidelines for

Figure 3

Compensation for Participation

“Subjects may be paid for the inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgement (inducement). All payments, reimbursement and medical services to be provided to research subjects should be approved by the IEC.”

Source: Ethical Guidelines for Biomedical Research on Human Subjects, p.19

Figure 4

Source: A.T. Kearney, 2009

Biomedical Research on Human Subjects states that particular care must be used in subject recruitment because of the extremely confidential nature of the research and the potential for social stigmatisation and discrimination. Consequently, direct recruitment by telephone is not to be used and contact by the personal physician may be interpreted as coercive.

3. What is the name of the regulatory agency in India?The regulatory agency in India is the Central Drugs Standard Control Administration.

ChinaOpen Studies: 1089China’s double-digit annual growth rate in research and development surpasses expansion in established markets such as the United States, the United Kingdom and Japan. According to the 2010 Global R&D Funding Forecast, the country outspent Japan in R&D in 2009, and is expected to match aggressive spending in Europe in 2018 and rival US R&D spending in 2022. This phenomenon is fuelled by several factors, including establishment of clinical trial laws, alliance with the World Trade Organization in 2001 and formation of the State Food and Drug Administration (SFDA) in 2003. But with progress comes new challenges, namely increased competition, cost concerns and trial delays.

Increased competition seems largely the result of continued industry consolidation — a consequence of 2009’s global recession, which decreased the number of biotech companies and reduced R&D funds. Further eroding industry investments are declining numbers of new products in the pipeline and increasing numbers of generic drugs. The pharmaceutical market experienced a 2 per cent decline in 2009, representing the first decrease in 50 years. Projections through 2011 only anticipate a 2.2 per cent annual growth rate.

Despite general downturns, the Asian markets remain resilient, offering many potential advantages from a patient recruitment perspective, including access to a larger number of treatment-naive patients. A.T. Kearney, a global management consultant firm, conducted an analysis in 2009 highlighting preferred global destinations for clinical research. Among the 16 countries making the cut, five were in Asia, including the number one-ranked China (Figure 4).

1. What are standard recruiting practices in China?Subjects are recruited in a limited number of ways, starting with heavy reliance on the investigator to tell appropriate patients about the study, followed by the use of posters and fliers in waiting rooms at accredited clinical trial sites.

Hospitals in the major cities, such as Beijing, Shanghai, Ghangzhou, Chongqing, and Nanjing, tend to be very large by Western standards, many with more than 1000 beds, reflecting the centralised nature of healthcare delivery in China. As a result, doctors in those institutions are extremely busy, seeing as many as 50 patients most mornings. Patients generally do not see the same physician each time they visit a clinic, so the promise of seeing the same physician over the course of a clinical trial may spur interest.

Posters in the waiting rooms may make patients aware of

ongoing trials but, according to Shanghai Pharma Engine, a Chinese CRO, patients rarely initiate discussions about them and generally look to the doctor to start this type of conversation.

Notification by physicians and posters may be the key modalities used to recruit subjects, but evidence suggests that other tools such as web promotion and newspaper advertising are used as well, but to a lesser degree.

2. Is compensation to study volunteers allowed in China?GCP Guidelines allow for compensation of study volunteers, provided this information appears in the informed consent document, which has the written approval of the appropriate institutional review board or ethics committee (ICH-GCP Sec. 4.8 and Guideline 7 of CIOMS).

3. What other information is useful in terms of understanding clinical trials and patient recruitment practices in China?

Investigators in China are pre-selected and designated by the SFDA and the Ministry of Health. The Division of Pharmaceuticals and the Division of Traditional Chinese Medicine (TCM) are both part of the Department of Drug Registration within SFDA and have equal status. The purpose of the Division of TCM is to organise and draft national standards and research guidelines for traditional Chinese medicine preparations, and evaluate and approve clinical trials for them. As global clinical trials expand, investigators are in need of greater experience in multicentre international trials and GCP training.

Our experiences reveal, and sources confirm, that patient retention is the most critical issue facing trial investigators compared to patient recruitment. Doctors in Asia are highly revered and their relationships with patients largely paternalistic. Therefore, patients are highly compliant with their doctors’ requests to participate in clinical research. Retention issues arise due to inadequate emphasis on informed consent and patient education about the participation process.

SourcesClinicalTrials.govAnderson, Diana L. “International Patient Recruitment Regulatory Guidelines, Customs and Practices.” Dallas: D.L. Anderson International; 2007 2010 Global R&D Funding ForecastEthical Guidelines for Biomedical Research on Human Subjects, Indian Council of Medical ResearchFederal Law on Medicinal Products, Russian Federation

Diana L. Anderson, Ph.D.As president of DAC Patient Recruitment Services, Dr. Anderson is an international thought leader in patient recruitment and retention for clinical trials. She is a coveted speaker and author of five industry books, including “Global Issues

in Patient Recruitment and Retention,” set for release in 2012.Email. [email protected]


Market Evaluation


Therapeutics

Cisplatin as monotherapy or in combination with 5-Fluorouracil (5FU) is currently the first-line treatment of stage III or IV colorectal cancers. Predicting the efficacy of these drugs in individual patients before the establishment of a treatment regimen is essential. The aim of the present study was to develop a method to predict the response to cisplatin/5FU therapy in colorectal carcinomas using the minimum required number of cancer cells from each patient. Single cell gel electrophoresis (COMET assay) was used to assess the effect of cisplatin treatment, and quantitative real-time PCR (qRT-PCR) was used to detect the expression of thymidylate synthase (TYMS), dihydrofolate reductase (DHFR), serine hydrate methyltransferase (SHMT1) and dihydropyrimidine dehydrogenase (DPYD) in human colon carcinoma cell lines. The application of these methods for predicting the response to combination drug therapy in a simple and rapid manner would help physicians tailor treatment strategies to individual patients, even those with the same type of cancer.

Key Words: Colorectal carcinomas, CisPlatin, 5-Fluorouracil, qRT-PCR, COMET assay.

IntroductionCisplatin (CDDP) is a platinum-based drug used for the treatment of various types of cancer1. 5-Fluoruracil (5FU) is a pyrimidine analog that is also commonly used as an anticancer drug2. Using these two drugs as monotherapy is inefficient due to both acquired and intrinsic resistance mechanisms. Cisplatin and 5FU combination therapy or each drug as monotherapy is the first-line treatment for colorectal cancers, although combination treatment shows better efficacy3,4,5,6,7,8,9,10.

The ability to predict the response to treatment in individual patients is essential, and evaluating the response to chemotherapy using methods with few requirements is important to assist clinical or medical oncologists in the determination of adequate treatment strategies.

Single cell gel electrophoresis is a rapid and sensitive technique commonly used to measure the efficacy of anti-tumour treatments by evaluating DNA damage in individual cells11. The principle of the COMET assay is that unfragmented DNA maintains a well-organised structure in the nucleus, but when the cell is damaged, this organisation is disrupted. When an electric field is applied to the DNA, the unfragmented parts are too large and move slowly, while the fragmented parts move faster due to their molecular weight and dense conformation. The amount of genetic material in the nucleus (called “head”) and the amount included in the fragmented pieces (called “tail”) reflect the effect of a drug on the DNA chains. During measurement, the percentage from the total DNA of a single cell distributed to the tail part reflects the fragmented DNA, and that distributed to the head part reflects the unfragmented DNA. Thus the final outcome is a percentage with no units. 5FU is a thymidylate synthase (TYMS) inhibitor. Dihydropyrimidine dehydrogenase (DPYD) is the main enzyme involved in the degradation of 5FU12. TYMS, dihydrofolate reductase (DHFR) and serine hydrate methyltransferase (SHMT1) are the three

enzymes that constitute the de novo thymidylate synthesis pathway in mammals13,14,15. In the present study, quantitative real-time PCR was used to analyse the gene expression pattern of these enzymes in human cancer cell lines derived from colorectal carcinomas in response to treatment with 5FU according to a previously published method16.

Materials and MethodsThe human colon carcinoma cell lines LoVo, HCT-116, HT55 and HCT-15 used in the present study were obtained from the European Collection of Cell Cultures (ECACC, UK). The COMET assay and qRT-PCR were used to predict the response to 5FU/cisplatin chemotherapy in these cell lines.

Cell Culture: Cells were cultured in 75cm2 flasks (Orange Scientific, 5520200, Belgium) in the medium indicated for each line with the appropriate amount for each cell line of heat inactivated fetal bovine serum (FBS, Invitrogen, 10106-169, California) and 2mM L-Glutamine (Sigma, G5792, Germany), and incubated at 37oC, in a 5% CO2 atmosphere. Cells were divided into three 75cm2 flasks that contained no added drug, cisplatin (1μg/ml) (P4394, Sigma-Aldrich, Germany) or 5-FU (750μg/ml) (Teva Pharma B.V., Netherlands). After 24 h of incubation, cells were detached by trypsinisation (Trypsin-0.25% EDTA, Invitrogen, 25200-072, California).

COMET Assay: Single cell gel electrophoresis was performed using the IKZUS COMET assay kit (Cat. No. 0905-050-K, Italy) with alkaline lysis. CDDP-treated and untreated cells were seeded onto slides specifically designed for the COMET assay using low-melting-point agarose, and incubated with lysis solution for 1 h, followed by alkaline solution incubation for 30 min. Slides were then subjected to electrophoresis for 20 min at 25V in 0.5X TBE and cells were fixed with 70% ethanol in phosphate buffered saline (PBS) (P3813, Sigma-Aldrich, Germany). Slides were stained with staining solution and then observed in a UV light microscope. Data were analysed using the Comet Score software (TriTek Corp., USA).

qRT-PCRRNA from 5FU-treated and untreated cells was extracted using the RNase mini kit (74104, Qiagen, Germany) in the QIAcube system (9001293, Qiagen, Germany) and used as a template to generate cDNA using the first strand cDNA synthesis kit (K1612, Fermentas, Canada). Genomic DNA was removed from RNA preparations and oligo-dT primers were used for first strand cDNA synthesis. The first strand cDNA was used as a template for the real-time PCR reaction, which was performed using the Maxima SYBR Green qPCR Master Mix (K0221, Fermentas, Canada) and primers designed with Gene Expression 1.1 software. The PCR conditions were set as follows: initial denaturation at 95oC for 10 min to activate the polymerase, 50 cycles of denaturation at 94oC for 30 sec, followed by annealing at 59oC for 30 sec and an extension step at 72oC for 45 sec. A final extension step was performed at 72oC for 10 min. The primers used are shown in Table 1.

Predictive Value of Molecular-Cellular Methodologies for Response to Chemotherapy with CisPlatin/5Fu in Colon Tumours


Therapeutics

ResultsTable 2 shows the results of single cell electrophoresis in the different cell lines analysed. The results varied according to the cell line and the differences were statistically significant with the exception of the LoVo cell line. The statistical evaluation was performed by measuring the difference of the mean. The percentages of DNA in the head and the tail are shown in Table 2. Cisplatin treatment had a significant effect in all cases, suggesting that these cancer cell lines respond to this chemotherapeutic agent. Figures 1 and 2 illustrate the efficacy of CDDP in the HT55 cell line.

The results of the qRT-PCR analysis in cells treated with 5FU are shown in Table 3 and show variable effects of 5FU on the different genes in the different cell lines. The data are expressed as the threshold cycle (CT) parameter, which is an indicator of the expression of a gene. Cycle threshold is called the cycle at which the fluorescence from a sample crosses the threshold, and is proportional to the expression of the gene studied25. The key gene affected by 5FU is TYMS, while the other genes played secondary roles. In the cancer cell lines LoVo, HCT-15 and HCT-116, 5FU treatment had an effect on the TYMS gene, by decreasing the gene expression, that was not observed in the HT55 cancer cell line, which indicates resistance to this chemotherapeutic agent. Expression of the SHMT1 gene was not significantly affected by 5FU treatment, while the expression of the DPYD gene was altered by 5FU in all the cell lines studied. Statistical analysis was performed by measuring the difference of the mean.

DiscussionOne of the most commonly used strategies for the treatment of colorectal carcinomas is a combination of cisplatin and 5FU. Because of the toxicity associated with this line of treatment,

assays capable of predicting the response of individual patients to these drugs are essential for oncologists before drug administration.

Cisplatin reacts with DNA in vivo, causing cross-linking of DNA, which ultimately leads to programmed cell death (apoptosis)17. The single cell electrophoresis assay (COMET assay) can measure the effect of cisplatin treatment using only a few flowing cancer cells from each patient. Single cell gel electrophoresis can detect the damage to DNA as single strand and double strand breaks. This technique allows the evaluation of the effect of platinum on the integrity of the DNA. Because the effect of different drugs vary even in the same type of tumour cell lines, COMET assay can determine the effect of each drug on the DNA18,19,20. On the other hand, 5-fluorouracil causes cell cycle arrest in the post-G1/pre-S phase and induces apoptosis by inhibiting DNA synthesis and by interacting directly or indirectly with several enzymes21. qRT-PCR is used to determine the effect of 5FU in different cell lines. This technique enables the comparison of the gene expression patterns of reference and endogenous genes. In the present study, the endogenous gene analysed was glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which catalyses the conversion of glyceraldehyde 3-phosphate during glycolysis, and it is used as an endogenous-housekeeping gene in qRT-PCR reactions22,23,24. This method is very sensitive, requires only small amounts of RNA, and is based on the detection and quantification of a fluorescence reporter (SYBR Green). The parameter that was studied was the CT25. The enzymes analysed in the present study were TYMS, SHMT1, DPYD and DHFR. TYMS catalyses the methylation of deoxyuridylate to deoxythymidine, while DPYD is responsible for the degradation of uracil and thymine. SHMT1 plays an important role in

Figure 1: Representative cell from the cancer cell line HT55 without drug treatment subjected to the Comet Assay protocol. The percentage of DNA in the tail was ~19% and that in the head was ~81%

Figure 2: Representative cell from the cancer cell line HT55 treated with cisplatin and subjected to the Comet Assay protocol after 24 h of incubation. The percentage of DNA in the tail was ~9% and that in the head was ~91%

Table1: Primer Sequence for genes and endogenous genes studied

Table2: Comet Assay results (Mean-SD*1.96, Mean+SD*1.96)

Table 3: Real-Time PCR results (CT±SD*1.96)

nucleic acid biosynthesis, and DHFR reduces dihydrofolic acid to tetrahydrofolic acid. Tetrahydrofolate and its derivatives are essential for purine and thymidylate synthesis26,27,28,29.

The two techniques described in the present study are simple and have few requirements, and their use will allow physicians to evaluate patient response to drug treatment in advance, thus facilitating the selection of appropriate therapeutic strategies.

ConclusionThe heterogeneity and genetic instability of cancer make it necessary to personalise treatment. The results of the present study suggested that the response of cell lines to cisplatin and 5FU treatment vary, even in cell lines derived from the same type of cancer. In this pilot study, a new robust and effective method to predict the response of individual patients to a drug is described. Further investigations using additional drugs and a wider population of tumour cell lines would be of great value.

Panagiotis ApostolouI graduated from the Department of Molecular Biology and Genetics, Democritus University of Thrace, in 2007. Since October 2008 I’m working in the research and development department of Research Genetic Cancer Center Ltd,

which activates especially in the field of cancer genetics. Email: [email protected]

Maria Toloudi I studied Molecular Biology and Genetics in the University of Thrace and now I am working for about 3 years in R.G.C.C (Research Genetic Cancer Center) as member of the research and development department. I am activating especially in the field of cellular and molecular biology

dealing with human cancer stem cells. Email: [email protected]

Marina ChatziioannouI was born and grew up in Greece. I’ve studied Biochemistry and Biotechnology at the University of Thessaly (2001-2006). I’m working at R.G.C.C. laboratory (Research Genetic Cancer Centre, www.rgcc-genlab.com) since 2006, at the clinical

department, section of Flow Cytometry. As from the company’s name, I’m working on Human Circulating Tumor Cells (CTCs) mainly. Email: [email protected]

Ioannis PapasotiriouI was born in Germany in 1973 and after years I return in childhood in Greece where I studied in Medical school of Thessaloniki and I specialized in Human Genetics in Switzerland. Two master degree rewards have been obtained in molecular biology

Therapeutics


Therapeutics

in Medicine from the Westminster University (UK) and in oncology from the University of Nottingham (UK). A promotion have been performed (MD) in MLU in Germany under the field of evaluation of TKIs in human cancer cell lines. Since 2004 I am the director and founder of RGCC Ltd which is activated in both areas of services (Research and Clinical) Email: [email protected]

References:1. Trzaska S. The top pharmaceuticals that changed the world. C

& EN News 83 (25): 3 (2005).2. Longley D., DP Harkin, et al. 5-fluorouracil: mechanisms of

action and clinical strategies. Nat Rev Cancer 3 (5): 330-338 (2003).

3. Dy C, GA, Algarra SM, Aparicio LA, Calvo F, Herranz P. Combination chemotherapy of cisplatin and 5-FU in advanced colorectal carcinoma. Cancer Treat Rep 70 (4): 465-468 (1986).

4. Galligioni E, L. Canobbio et al. Cisplatin and 5-fluorouracil combination chemotherapy in advanced and/or metastatic colorectal carcinoma: a phase II study. Eur J Cancer Clin Oncol 23 (6): 657-661 (1987).

5. Petrelli NJ, MS, Rustum Y, Herrera L, Creaven PJ, Plager Joloman J. and A. Mittelman. Combination chemotherapy of cisplatin and 5-fluorouracil for advanced colorectal adenocarcinoma. Cancer Chemother Pharmacol 23 (1): 57-60 (1989).

6. Whitehead RP, FT, Macdonald JS, Ahmann FR, Garewal HS, Kuebler JP. A phase II study of chemotherapy of metastatic colorectal carcinoma with 5-fluorouracil plus cisplatin. A Southwest Oncology Group study. Invest New Drugs 9 (4): 345-347 (1991).

7. Tsuji A, Morita S, Horimi T, Takasaki M, Takahashi I, Shirasaka T. Combination chemotherapy of continuous 5-FU infusion and low-dose cisplatin infusion for the treatment of advanced and recurrent gastric and colorectal adenocarcinomas. Gan To Kagaku Ryoho 27 (2): 528-534 (2000).

8. Suzuki H, Kanou Y, Ooshima H, Kawase J, Kudou J, Mizuno Y et al. Trial of outpatient anti-cancer chemotherapy with infusion of 5-FU and cisplatin for advanced gastric and colorectal cancers. Gan To Kagaku Ryoho 32 (3): 189-193 (2005).

9. Oh DY, Kim TY, Kwon JH, Lee JJ, Joh Y, Kim DW et al. Docetaxel + 5-fluorouracil + cisplatin 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer. Jpn J Clin Oncol 37 (5): 380-385 (2005).

10. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20 (4): 666-673 (2009).

11. Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175 (1): 184-191 (1988).

12. Schneider HB, Becker H. Impact of dihydropyrimidine dehydrogenase on 5-fluorouracil treatment in cancer patients. Eur J Med Res 8 (5): 226–8 (2004).

13. Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J et al. The functional human dihydrofolate reductase gene. J Biol Chem 259 (6): 3933-3943 (1984).

14. Rao NA, Talwar R, Savithri HS. Molecular organization, catalytic mechanism and function of serine hydroxymethyltransferase-

-a potential target for cancer chemotherapy. Int J Biochem Cell Biol 32 (4): 405-416 (2000).

15. Chu E, Allegra CJ. The role of thymidylate synthase in cellular regulation. Adv Enzyme Regul 36: 146-163 (1996).

16. Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc 1 (3): 1559-1582 (2006).

17. Samuel SK, Spencer VA, Bajno L, Sun JM, Holth LT, Oesterreich S et al. In situ cross-linking by cisplatin of nuclear matrix-bound transcription factors to nuclear DNA of human breast cancer cells. Cancer Res 58 (14): 3004-3008 (1998).

18. Miwa M, Hongo Y. Application of a single-cell gel electrophoresis (comet) assay to screen the antimutagenic activity in foods. Biosci Biotechnol Biochem 64 (4):1292-1294 (2000).

19. Morris ID, Ilott S, Dixon L, Brison DR. The spectrum of DNA damage in human sperm assessed by single cell gel electrophoresis (Comet assay) and its relationship to fertilization and embryo development. Hum Reprod 17 (4): 990-998 (2002).

20. Kido R, Sato I, Tsuda S. Detection of in vivo DNA damage induced by ethanol in multiple organs of pregnant mice using the alkaline single cell gel electrophoresis (Comet) assay. J Vet Med Sci 68 (1): 41-47 (2006).

21. Yoshikawa R, Kusunoki M, Yanagi H, Noda M, Furuyama JI, Yamamura T et al. Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy. Cancer Res 61 (3): 1029-1037 (2001).

22. Barber RD, Harmer DW, Coleman RA, Clark BJ. GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics 21 (3): 289-295 (2005).

23. Zainuddin A, Makpol S, Chua KH, Abdul Rahim N, Yusof YA, Ngah WZ. GAPDH as housekeeping gene for human skin fibroblast senescent model. Med J Malaysia 63 Suppl A: 73-74 (2008).

24. Bustin SA. Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): trends and problems. J Mol Endocrinol 29 (1): 23-39 (2002).

25. Tevfik Dorak. Real-Time PCR. Taylor & Francis Group Press. 2006.

26. Jensen SA, Vainer B, Witton CJ, Jorgensen JT, Sorensen JB. Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer. Acta Oncol 47 (6): 1054-1061 (2008).

27. Ichikawa W, Uetake H, Shirota Y, Yamada H, Nishi N, Nihei Z et al. Combination of dihydropyrimidine dehydrogenase and thymidylate synthase gene expressions in primary tumors as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Clin Cancer Res 9 (2): 786-791 (2003).

28. Steck SE, Keku T, Butler LM, Galanko J, Massa B, Millikan RC et al. Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. J Nutrigenet Nutrigenomics 1 (4): 196-204 (2008).

29. DiPaolo A, Chu E. The role of thymidylate synthase as a molecular biomarker. Clin Cancer Res 10 (2): 411-412 (2004).


Therapeutics

Targeting of tumour angiogenesis is an attractive strategy in cancer cure. In the past 30 years signalling pathways that drive specific angiogenic events in tumour tissue have been elucidated. The results from these studies encourage development of different anti-angiogenic drugs that interfere with tumour angiogenesis and block tumour development.

SB101 is a small recombinant protein that inhibits angiogenesis. SB101 is a soluble recombinant fragment of human protein CD44. It inhibits directly the proliferation of the cells that form new blood vessels in tumour tissue- endothelial cells. Thus counteracting the critical step in the angiogenesis process, SB101 is able to inhibit human tumour growth of various origins.

Competence Centre for Cancer Research was established with a focus on the development of new generation cancer drug candidates and novel diagnostic platforms. One of the largest projects of the CCCR is the development of a novel angiogenesis inhibitor SB101. Angiogenesis and Anti-Angiogenic TherapyThe correct formation of new blood vessels from existing vasculature (angiogenesis) is essential for embryogenesis and the effective repair of damaged or wounded tissues. However, excessive and detrimental vascularisation also occurs in neoplasia, promoting tumour growth. Already in 1971, Judah Folkman published that cells in cancer tissue are angiogenesis-dependent and proposed that if a tumour tissue could be stopped from growing new vasculature, its growth could be inhibited1. From these early suggestions an anti-angiogenesis therapy has been under extensive research and development and in clinical use in recent years. Avastin, a humanised monoclonal antibody that recognises and blocks vascular endothelial growth factor A (VEGF-A) stimulating the growth of new blood vessel was the first angiogenesis inhibitor to be approved by FDA in 2004 for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer2.

Several different types of angiogenesis inhibitors — including endostatin, angiostatin, 2-methoxyestradiol (2ME2, Panzem), and a thrombospondin — are in clinical development for cancer treatment today. Some of these include unanticipated anti-angiogenic effects without a clearly understandable mechanism of action. These include the anti-inflammatory drug celecoxib3; rosiglitazone4, a drug for type 2 diabetes; doxycycline5, a common antibiotic but also some anticancer drugs including Erbitux6, Herceptin7, Bortezomib8 and Tarceva9. Even some conventional chemotherapy drugs have demonstrated anti-angiogenic effects when given frequently in smaller doses10.

Despite the success story of Avastin as a blockbuster, anti-angiogenic therapies have not fulfilled the initial expectations of turning cancer into a chronic disease. Tumours can progress

in an angiogenesis-independent way and exhibit high vessel heterogeneity11. Under selective pressure by anti-angiogenic drugs some tumours develop hypoxia resistance. A study released in 2009 found that Avastin is not effective at preventing recurrences of non-metastatic colon cancer following surgery11. In July 2010, the FDA announced that there is not enough of a benefit from Avastin in advanced breast cancer to justify its serious risks. It is therefore clear that patients may benefit from additional anti-vascular therapies. To target the heterogeneous tumour vasculature there is a need for appropriate mixtures of different drugs that inhibit blood vessels in a variety of tumour tissue.

Solid tumours depend on the formation of new blood vessels that form from pre-existing ones to supply them with nutrients and oxygen. Tumour angiogenesis also propagates tumour allowing cancer cells to enter the circulation and form metastases. Angiogenesis is a complex process, which starts with VEGF-induced vasodilatation and increased vascular permeability of existing capillaries. The vascular permeability allows the extravasations of plasma proteins such as fibrinogen that is converted to fibrin, which serves as a matrix for migrating endothelial cells. To allow endothelial cells to migrate, the pre-existing capillaries are degraded by proteases secreted by tumour cells. Endothelial cells then proliferate, invade the surrounding extracellular matrix and adhere to each other to form hollow tubes. Finally, blood vessel sprouts fuse to form vascular loops. Blood vessel maturation is incomplete during tumour-associated angiogenesis, leading to the formation of tumour vessels that are fenotypically different from normal microvasculature.

It is obvious that the preferred strategy to inhibit tumour angiogenesis would be direct inhibition of endothelial cells rather than interfering with growth factors like VEGF that have several other physiological functions. Endothelial cells are well accessible to intravenously administered compounds and are differently from cells in tumour tissue stable, reducing the risk of therapy resistance. Importantly, therapy directed against tumour vasculature may be effective against a range of tumour types. Since endothelial cells in different tissues and tumours display specific antigens it can be assumed that also quiescent tumour endothelial cells will be subject to factors secreted by tumours and hence have alterations in their proteomes which can be targeted.

SB101- an Angiogenesis Inhibitor Hyaluronic acid (HA), a linear glycosaminoglycan (GAG) is ubiquitously expressed in the extracellular matrix (ECM) of tissues. It has been shown that in addition to other angiogenic biomolecules HA is a potent mediator of this process13. Native high molecular weight HA is anti-angiogenic, whereas HA degradation products stimulate endothelial cell (EC) proliferation, migration and tube formation following activation

Novel Angiogenesis Inhibitor in Development at Competence Centre for Cancer Research

of specific HA receptors, in particular CD44 and Receptor for HA-Mediated Motility (RHAMM, CD168)14. The use of HA as anti- or pro-angiogenic factor has not been successful so far, mainly because of the interference with its prominent native functions.

We have discovered that a fragment derived from the extracellular part of HA receptor CD44 is also a very potent modulator of angiogenesis15. CD44 is a transmembrane receptor for HA. CD44 is involved in HA-dependent cell migration, cell adhesion and HA metabolism. The highly conserved link domain that is located in the amino-terminal part of the extracellular domain of CD44 is the binding site of HA. SB101 is 113 amino acid long fragment from human CD44 hyaluronic acid binding domain (HABD, amino-acids 21-132) with three-point mutations: R41A, R78S, Y79S. These amino acids are reported as pharmacophores for HA binding and mutations in these sites disrupt CD44 HABD binding to HA.

SB101 Inhibits human Tumour growth in Animal Models According to current paradigm all solid tumours need to induce angiogenesis to cover their metabolic needs and grow over millimetre size. Therefore a possibility to inhibit tumour growth by reducing the neovascularisation within tumour tissue would be most useful as adjuvant therapy for cancer cure. We have demonstrated that SB101 inhibits effectively the growth of various human tumours grafted into athymic mice, including prostate adenocarcinoma, melanoma, pancreatic adenocarcinoma and hepatic adenocarcinoma. SB101 shows similar efficacy in all tumour types tested so far.

Administration of 10μg of SB101 three times a week decreases tumour growth significantly. We have also shown that SB101 effect on tumour growth is dose-dependent. Administration of SB101 in the range of 2-50μg /mouse (0.1-2.5mg/kg) inhibits tumour growth in a dose-dependent manner (Fig. 1). We have tested both intraperitoneal and intravenous routes of administration of SB101, and no significant differences were observed between administrations.

Taking into account that SB101 is a protein of small size that has relatively short clearance kinetics, we have also used constant drug administration through intraperitoneal micro-osmotic pump for a period of 14 days. Such an administration routine gives a consistent level of SB101 and might improve the anti-angiogenic and anti-tumour efficacy. We have shown that SB101 administered using a micro-osmotic pump giving the dose of 1μg/mouse/day inhibits tumour growth significantly more effectively than the same dose administered intraperitoneally (data not shown).

We have also compared the effects of SB101 and anti-VEGF antibody (Avastin, bevacizumab, Roche). Avastin is an approved angiogenesis inhibitor indicated for first- or second-


Therapeutics

line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy. In combination with carboplatin and paclitaxel, it is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer. In combination with paclitaxel, Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer. It has been shown in animal model that Avastin inhibits grafted human tumour growth in mice also as a monotherapy16. We have compared Avastin efficacy with SB101. The experimental conditions were similar to those reported earlier16. In this model, SB101 treatment gives a similar effect compared to anti-VEGF therapy (Fig. 1, lower panel).

SB101 Targets Endothelial Cells Directly and Inhibits Angiogenesis in vitro Chicken chorion-allantoic membrane (CAM) assay is widely used in in vivo angiogenesis assay, where the extent of blood vessel growth is evaluated in the chorion-allantoic membrane. The chorioallantois is highly vascular extra-embryonic membrane formed at day four to five of development by the fusion of the allantois and the chorion. Between day seven and the stage of hatching at day 20, chorioallantois serves as the respiratory organ of the embryo. Endothelial cells are showing rapid proliferation during E4-11 and between E10-12 dense capillary plexus in the chorionic epithelium is established. Experiments are performed in the timeframe between days 10 and 13, and started at day 10 when the endogenous angiogenesis is at a peak. We induced angiogenesis in CAM directly under paper filter discs saturated with TGF-alfa, and observed the complete inhibition of blood vessel growth back to the basal level by the topical addition of SB101.

The inhibitory effect of SB101 on the growth of blood vessels was confirmed also in ex vivo chick aortic ring assay. In this system, aortic rings cultured in collagen gel give rise to micro-vascular networks composed of branching endothelial channels. By using intact vascular explants, it reproduces more accurately the environment in which angiogenesis takes place than those with isolated endothelial cells. The growth of blood vessels from chicken embryo aortic ring embedded into collagen-I gel was induced by VEGF. A significant reduction of VEGF-induced angiogenesis after SB101 treatment was observed.

We demonstrated that SB101 treatment leads to G1 phase cell-cycle arrest of endothelial cells in a dose-responsive way (Figure 2). SB101 is also non-toxic to endothelial cells as demonstrated using MTT assay, and does not induce apoptosis (data not shown).

Acute Toxicity of SB101In an acute toxicity study in female HanRcc:NMRI mice were administered intraperitoneally with 25 and 250 times higher dose compared to treatment dose (calculated per body weight 0.4mg/kg). The first group of mice received the treatment 10mg/kg SB101. A hunched posture was noted in animals two to five hours after dosing, but otherwise they were absent of findings. The second group of mice was treated i.p. at 100mg/kg SB101. Moderate clinical signs (ruffled fur, hunched posture, sedation) were noted on the day of dosing but were no longer present on the following days. Single dose treatment 10mg/kg and 100mg/

Figure 1: Tumour growth assay with Hep3b human hepatoma cells in nude mice. Hep3b cells (3.5x106 ) were injected subcutaneously into Foxn1 athymic nude mice. Intraperitoneal treatment with drugs started on day 14 post-inoculation when the average tumour volume reached 150mm3. SB101 and PBS (control) were administered thrice a week. Tumour length (L) and width (W) were measured throughout the study. Relative tumour volumes were calculated using the formula V=L*W2/2. The final weight of dissected tumours was directly measured. On the lower panel, Avastin dosing was 400μg per animal twice a week. Error bars indicate SEM.

Figure 2: Cell proliferation assay of HUVE cells. SB101 inhibits endothelial cell proliferation in a dose-responsive way. Exponentially growing HUVE cell populations were treated with respective proteins for 24h. Cells were double-stained with propidium iodide and BrdU and analysed by FACS.

Therapeutics


kg do not cause any persistent clinical sign.

DiscussionCD44 is an integral cell membrane glycoprotein playing a role as a cell surface adhesion molecule in lymphocyte migration to lymph nodes. SB101 is a protein derived from extracellular portion of CD44 and has been modified in a way that does not allow binding of hyaluronic acid. Therefore SB101 does not have any effect on HA binding. SB101 is a protein fragment that also does not contain any fragments from CD44 part that is a subject of alternative splicing. Therefore SB101 is not an analog of those CD44 splice variants that may be associated with metastases reported by Matsumura and Tarin17.

Indeed, SB101 is a potent inhibitor of tumour growth. We have shown that it causes a remarkable reduction of tumour growth in all animal models tested so far. In some cases the effect is even stronger than with VEGF-neutralising antibody Avastin – a drug that has been approved for several years already. The reason why we compare SB101 with Avastin stems from the fact that SB101 does not interfere with the tumour-forming cells, either in vitro (MTT test, apoptosis markers, cell cycle, data not shown) nor in vivo (post-mortem tumour tissue does not show elevated levels of apoptosis) but reduces tumour tissue volume. SB101 effect is caused by a direct effect on vascular endothelial cells that form neovasculature within tumour tissue.

SB101 does not interfere directly with VEGF-exerted functions – we have shown that SB101 does not bind to the VEGF receptors, neither does it affect the VEGF-induced signal transduction pathway. We examined the expression level of Act, p-Act, Nos and Src, which are the mediators of VEGF signal, and found that SB101 does not cause any change in the levels of these proteins (data not shown).

It is possible that SB101 interferes with those processes of angiogenetic cascade downstream of mitogen activation of endothelial cells, as SB101 binding is enhanced by mitogen activation of endothelial cells. If this is true then SB101 is more universal than specific inhibitors of VEGF signalling (e.g. Avastin and VEGFR inhibitors currently under development) as it also inhibits endothelial cells activated by other growth factors like placental growth factor (PIGF), basic fibroblast growth factor (bFGF), and others shown to be involved in EC activation in angiogenic cascade. The latter hypothesis has to be proven yet, but observed results in animals confirm that SB101 is universally effective in various models. Regardless of the mechanism behind SB101 anti-tumoural activity, it is clear that SB101 is a potent anti-tumoural protein – a drug candidate.

Future PlansWe shall continue work on the final clarification of the molecular mechanisms behind the effects of SB101 on angiogenesis inhibition. In parallel we shall run a series of studies to clarify the biodistribution of SB101 in tissues (most probably at Turku PET Centre in Finland), where in addition to the previous models we look at the in vivo and in situ effects of SB101 in combination therapy with Avastin and some widely-used chemoterapeuticums.

According to our plans, we shall enter into the clinical research phase in about a year. Our primary partner for clinical research will be the North Estonian Medical Centre in Tallinn, but additional strategic alliances may also become possibility.

Andres Valkna, PhD,. molecular biologist and biochemist. Assistant professor , Tallinn University of Technology Gene Technology Institute Department of Molecular Biology. Has worked in the Laboratory of Molecular Genetics at NICBP, Scripps Research Institute, USA,

University of Tartu, Estonia and Institute of Neurochemistry and Neurotoxicology, Stockholm University. Founder and Member of board of biotechnology companies Celecure and Inbio , member of board of the Competence Centre for Cancer Research.Email: [email protected]

Riin Ehin has studied medicine and biology in Estonia and in Finland. She has a MSc. in Biology from the University of Tartu and a MSc. in Mathematics and Life Sciences from the University of Helsinki. In her work Ms. Ehin has mainly focused on biotechnology knowledge transfer and

management. Ms. Ehin has been the CEO of the Competence Centre for Cancer Research since its foundation in 2005. She is also the Chairwoman of the Board of the Estonian Biotechnology Association and belongs to the supervisory council of the Institute of Clinical Medicine of Tallinn University of Technology. Email: [email protected]

References1. Folkman J, 1971, N Engl J Med; 285,1182–6.2. FDA Consum. 2004 May-Jun; 38(3):17.3. Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ,

Tarnawski AS, Nat Med. 1999 Dec; 5(12):1418-23.4. Sheu WH, Ou HC, Chou FP, Lin TM, Yang CH, Life Sci. 2006 Feb

23; 78(13):1520-8.5. Lee CZ, Xu B, Hashimoto T, McCulloch CE, Yang GY, Young WL,

Stroke. 2004 Jul; 35(7):1715-9. 6. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ,

Radinsky R, Dinney CP, Clin Cancer Res. 1999 Feb; 5(2):257-65.7. Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK, Nature. 2002

Mar 21; 416(6878):279-80.8. Williams S, Pettaway C, Song R, Papandreou C, Logothetis C,

McConkey DJ, Mol Cancer Ther. 2003 Sep; 2(9):835-43.9. Byers LA, Heymach JV, Clin Lung Cancer. 2007 Feb; 8 Suppl

2:S79-85. 10. Kerbel RS, Viloria-Petit A, Klement G, Rak J, Eur J Cancer. 2000

Jun; 36(10):1248-57.11. Azam F, Mehta S, Harris AL, Eur J Cancer. 2010 May;

46(8):1323-32. 12. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Colangelo LH, Lopa

SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O’Reilly S, Chu L, Azar CA, Wolmark N, J Clin Oncol. 2009 Jul 10; 27(20):3385-90.

13. Götte M, Yip GW, Cancer Res. 2006 Nov 1; 66(21):10233-7. 14. Slevin M, Krupinski J, Gaffney J, Matou S, West D, Delisser H,

Savani RC, Kumar S, Matrix Biol. 2007 Jan; 26(1):58-68.15. Päll T, Gad A, Kasak L, Drews M, Strömblad S, Kogerman P,

Oncogene. 2004 Oct 14; 23(47):7874-81.16. Borgström P, Hillan KJ, Sriramarao P, Ferrara N, Cancer Res.

1996 Sep 1; 56(17):4032-9.17. Tarin D, Matsumura Y, J Clin Pathol. 1994 May; 47(5):385-90.


IT & Logistics

As regulatory agencies demand a more comprehensive demonstration of safety and efficacy for pharmaceuticals and medical devices, cardiac safety monitoring in clinical trials is becoming more prevalent and attracting more attention. A recent example is the scrutiny of the cardiac safety of the diabetes drug rosiglitazone (Avandia; glaxoSmithKline). This culminated in unprecedented, simultaneous regulatory actions by the European Medicines Agency and the US Food and Drug Administration (FDA), including market withdrawal in Europe and restriction of new use to patients unable to achieve glycemic control using other medications in the United States. In addition, the prescribing physician has to attest to and document the patient’s eligibility for the drug (Woodcock 2010).

Just as demonstrating many common clinical trial endpoints can be imaging-dependent (e.g: time to tumour progression), demonstrating cardiac safety can often depend on cardiovascular (CV) imaging. Thus, sponsors are increasingly turning to independent central imaging laboratories to standardise the collection, independent review and reporting of these data for internal purposes and submission to regulatory agencies.

Cardiac Risks in Product Development and their EvaluationAdverse CV effects associated with the administration of drugs intended to treat non-cardiac conditions are well recognised. These have ranged from cardiac arrhythmias with antihistamines (Monahan 1990) or antidepressants (Vieweg 2004), to thrombosis with the contraceptive pill, to cardiac muscle damage and reduced left ventricular (LV) function with chemotherapeutic agents (Swain 2003). Public and regulatory agency attention increased with the cardiac valve damage allegedly associated with the “diet drugs” phentermine/fenfluramine (“phen-fen”) and dexfenfluramine. Subsequently, the public debates on the safety of the anti-arthritis drugs that selectively inhibit cyclo-oxygenase-2 (COX-2) (Celebrex (celecoxib; Pfizer), Vioxx (rofecoxib; Merck) and Bextra (valdecoxib; Merck)) and the diabetes drugs Avandia and Actos (pioglitazone; Takeda Pharmaceuticals) have led to significant regulatory actions. These have included market withdrawals and “black box” warnings, stringent REMS (Risk Evaluation and Mitigation Strategy) requirements, and the discontinuation of development programmes following substantial investment in large Phase III clinical programmes.

One example in the medical device arena is the rare, but potentially significant, complication of pulmonary vein (PV) stenosis following radiofrequency catheter ablation for atrial fibrillation. Computed tomography or magnetic resonance imaging (MRI) is the only reliable way to assess this complication. Such imaging is incorporated into clinical trials of new catheters to exclude patients with significant pre-existing PV stenosis and to assess its presence post-procedure (Mansour 2004).

Clearly, it is necessary to evaluate the cardiac safety of a potential new drug or device early in development, in order to avoid the time-consuming and expensive consequences of not

identifying a significant cardiac risk until later, even possibly post-approval. Low frequency adverse cardiac effects may not become evident until the substantial patient exposure that occurs after commercial introduction. Hence, the search for reliable biomarkers or imaging surrogates of CV toxicity is of great importance to sponsor companies and to the imaging research and services companies that support them.

Pro-arrhythmic PotentialEvaluation of the possible pro-arrhythmic potential of a new drug has received the most attention from academic and regulatory communities. Following initial guidance and concept papers from European, US and Canadian regulatory authorities, formal guidance was issued by the International Conference on Harmonization (ICH). This covers non-clinical (US FDA 2005; S7B) and clinical evaluation (US FDA 2005; E14) of the potential for QT/QTc (corrected QT) interval prolongation and proarrhythmic risk for non-antiarrhythmic drugs. In general, this is applicable to all non-cardiac drugs with systemic bioavailability and includes the assessment of the effect of the drug on cardiac repolarisation (the electrical recovery of the heart following each contraction). Delayed repolarisation can be associated with ventricular arrhythmias, in particular a potentially life-threatening tachycardia, torsade de pointes, which can rapidly deteriorate into ventricular fibrillation and sudden death.

Whilst the ICH guidance describes an overall approach of caution, in terms of study enrolment criteria and safety monitoring, the cornerstone of E14 is the conduct of the “Thorough QT/QTc Study”. This study is typically conducted during Phase I or early in Phase II and would include placebo and active controls, and potentially two doses of test drug. If the study is negative, then subsequent assessments should follow “current practice” for that therapeutic class of drug. If the study is positive, expanded ECG safety evaluation is likely to be required. This has been facilitated by the availability of digital, ambulatory 12-lead “Holter” ECG monitoring. Central core laboratory management and reporting of Holter monitoring allows standardisation of data acquisition, analysis and reporting in Phase II and III trials.

Cardiovascular ThrombosisAlthough the thrombotic risks associated with the contraceptive pill, and other hormone therapies, were first recognised many years ago, the increased incidence of sudden CV death, myocardial infarction or stroke in patients taking Vioxx (Bresalier 2005) and its subsequent voluntary withdrawal from the market, focused considerable attention on these risks. Subsequently, attention turned to the thiazolidinediones that were widely used in patients with Type 2 diabetes. A meta-analysis reported a significant increase in the risk of myocardial infarction and, potentially, CV death associated with Avandia (Nissen 2007). These findings were extensively debated and further data resulted, in September 2010, in European and US regulatory action, as described earlier.

Cardiac Safety Monitoring and Centralised Medical Imaging in Clinical Trials

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The etiology of thrombotic risks associated with drugs is complex and multifactorial. Its evaluation during drug development is likely to involve a combination of plasma and imaging biomarkers. Plasma biomarkers offer possible early identification of thrombogenic potential, such as atherosclerotic plaque rupture or increased blood thrombogenicity. Imaging tools, such as sensitive assessments of vascular reactivity, blood flow or LV function, can provide useful information but require validation in this context. This represents an opportunity for collaboration between industry, academia and regulatory authorities and the development of an integrated biomarker package.

Cardiac Function: Valves and the Left VentricleThe appetite suppressants, phentermine, fenfluramine, and dexfenfluramine were withdrawn in 1997 following reports of valvular heart disease and pulmonary hypertension. Echocardiography played a pivotal role in the assessment and evaluation of these patients (Shively 1999) and in describing the natural history of these abnormalities (Weissman 2001). Echocardiography is non-invasive and provides anatomical assessment of valve structure, such as leaflet thickening and mobility, as well as a quantitative assessment of regurgitation using colour Doppler techniques. Calculation of indices, such as pulmonary artery pressures and LV ejection fraction, provide additional information on the hemodynamic significance of any valvular damage.

One of the most widely applied uses of cardiac imaging, and echocardiography in particular, is the assessment of the effect of drugs on LV function. Chemotherapeutic agents, such as the anthracyclines (eg: Adriamycin; doxorubicin), have long been known to have a dose-related detrimental effect on LV function. More recently, cardiac toxicity has been associated with: anti-human epidermal growth factor receptor-2 (HER2) agents, including trastuzumab; angiogenesis inhibitors, including bavacizumab, sorafenib, and sunitinib; and new targeted therapies such as phosphoinositide 3-kinase (PI3K) inhibitors (Eschenhagen 2011). Echocardiographic assessments include overall and regional LV function, LV wall motion and thickening, and indices of LV diastolic function. Also, the application of Tissue Doppler techniques can provide a more quantitative assessment.

There are no formal regulatory guidelines for the assessment of potential adverse effects on cardiac function. Recommendations from the American Society of Echocardiography address the use of echocardiography in clinical trials, with specific suggestions on the opportunities and challenges of echocardiographic assessment of cardiac toxicity (Gottdiener 2004). These include the use of blinded control groups, avoidance of arbitrary cutpoints, well defined image acquisition, interpretation and analysis plans, and adequate training of sonographers and reviewers. The recent statement from the Heart Failure Association of the European Society of Cardiology endorses the use of objective assessment of cardiac function with echocardiography and, when appropriate, other imaging modalities, such as MRI, in clinical trials of novel anti-cancer agents (Eschenhagen 2011). Another cardiac imaging modality widely used to assess and monitor the cardiac toxicity of chemotherapeutic agents is

equilibrium radionuclide angiography (ERNA), also referred to as MUGA (multiple gated acquisition). This is a well validated imaging method involving labelling of the subject’s red blood cells with technetium-99m and the acquisition of multiple planar images, gated to the cardiac cycle, of the blood passing through the LV. Using semi-automated tools, the LV end-diastolic and end-systolic radioactivity is assessed and ejection fraction calculated. Other indices of cardiac function can also be derived. The use of MUGA to assess the cardiac toxicity of chemotherapeutic drugs is one of its major applications today, with serial measurements of resting ejection fraction able to provide evidence of impending cardiac dysfunction before overt clinical evidence of cardiac failure.

More recently, gated cardiac SPECT (single photon emission computed tomography) has become widely utilised in nuclear cardiology for the evaluation of myocardial perfusion and function. Tomographic imaging offers greater spatial resolution than planar techniques; however, the added complexity and expense is not offset by a clinically significant benefit, as compared to MUGA.

Finally, cardiac MRI has emerged as the “gold standard” for the non-invasive assessment of cardiac function. Cardiac MRI provides images with exquisite resolution and is accurate and reproducible in normal and abnormally contracting ventricles. Although it does not involve ionising radiation, cardiac MRI is expensive and not widely available. Echocardiography is readily available and inexpensive, but more subject- and operator-dependent than MUGA or MRI. Typically, adequate echocardiographic images cannot be obtained in 10-20% of patients (Mulvagh 2000), although this is likely to decrease with the availability of ultrasound contrast agents and improved imaging technologies. Planar MUGA involves a small dose of ionising radiation but is generally more accurate and reproducible than echocardiography.

In many cases, the choice between echocardiography or MUGA to evaluate LV function may come down to the specific expertise at a given site. The choice of imaging modality and its application should be a key part of the ongoing dialogue with regulatory agencies during the development programme.

Planning and LogisticsA successful independent imaging analysis of cardiac safety requires proper planning and implementation, beginning with protocol design and continuing through regulatory submission. With proper planning and collaboration, a sponsor can rely on an Independent Imaging Core Laboratory (IICL) to set up, manage, and deliver this component of their clinical trial with minimal involvement on their part.

First, it is important to identify the imaging modality or modalities necessary to assess any cardiac safety risks of the investigational compound under study. Sponsors should utilise the consultative services typically provided by an IICL, together with discussion with appropriate regulatory agencies, to assist in making this decision. Considerations such as validation, cost, and geographic availability of imaging technology, will play a role in this decision.

Next, it is critical to identify an IICL that is well-equipped and experienced in providing cardiac safety analysis and reporting for the particular modalities to be utilised. In order to minimise errors or inconsistencies in the imaging data


IT & Logistics

provided to the sponsor, it is critical that the IICL provide the following:• Ability to service all imaging components of the clinical trial

(cardiac safety, as well as efficacy).• Ability to standardise, collect, and process CV images from

multiple, international investigator sites for independent review.

• Specialised medical expertise to aid in protocol design, image acquisition requirements and independent review planning, as well as in assessing and analysing the specific CV modality utilised.

• Integrated and automated image analysis software and electronic case report forms (eCRF).

• Industry validated image analysis software.• Intelligent eCRF design.• 21CFR Part 11 compliance with full audit trail.

Selecting an IICL to service all imaging components of a clinical trial will not only have logistical benefits for a sponsor but will likely result in significantly decreased costs.

The logistics of standardisation, collection, and processing of cardiac safety images are typically no different than for efficacy imaging. For example, if the imaging modality is echocardiography, the IICL will work with the sponsor to ensure the echocardiograms (echos) being acquired and submitted are of the highest possible quality. This includes ensuring that echo quality is as consistent as possible across the clinical sites, between patients, and within a given patient. Lastly, the IICL must employ well-trained technicians to process and prepare the echos for independent review and to perform preliminary measurements (e.g.: ventricular volumes). Having technicians perform such preliminary measurements saves time for the echocardiologist performing the final echo analysis, resulting in significant cost savings.

There are two components to truly specialised medical expertise in the evaluation of cardiac safety. The first is the expertise of the IICL in-house medical experts who should be well-experienced and knowledgeable about cardiac safety monitoring in clinical trials. They should be available to the sponsor to aid in protocol design and identifying appropriate image acquisition parameters and image analysis workflow. The second component is the expertise of the physicians who will actually read the images. It is critical that these physicians are not only experienced in analysing echos in general, but also in analysing echos in the specific population being studied. Thus, it becomes critical that the IICL be able to identify, train and work with true, sub-specialist experts in the assessment of the cardiac safety imaging in any given clinical trial.

Equally important is the analysis technology (the analysis software and the eCRF) used to perform and record the analysis data. An experienced cardiologist will not be effective if using sub-par analysis technology. This technology must be designed intelligently to maximise quality and accuracy, and minimise errors and inconsistencies. Thus, the image analysis software must meet or exceed industry standards and be well-validated, as well as automated and integrated with the accompanying eCRF. Assesments using the image analysis software should result in a seamless and automatic data flow into the eCRF, with no manual transcription of measurements or calculations. Additionally, the eCRF must be designed

intelligently with beneficial features such as:• Soft edit checks – to alert the physician to a possible error

during the analysis: the checks will request a correction or comment.

• Hard edit checks – to stop the physician from proceeding until an error is corrected.

• Radio buttons, drop-down menus, and check-boxes, where and when appropriate - these can help or hinder and the experienced IICL will design the eCRF to obtain maximum benefit from the technology.

Lastly, all of the features and expertise will not stand up to regulatory scrutiny if 21CFR Part 11 compliance, with a full audit trail, is not present. The technology used by the IICL for cardiac safety image processing and analysis must be fully auditable such that, each time an image is touched, which image, who accessed it, and what action was taken are recorded. This applies to the technicians processing the images and the physicians reading and analysing them.

There are obviously many different, significant components to the successful planning and execution of cardiac safety assessment in a clinical trial of a pharmaceutical or medical device. The partnership between the sponsor and a well-experienced IICL allows for this collaboration to be a successful and predictable portion of a clinical trial.

ConclusionBased on clinical experience over the past 10-15 years, increasing scrutiny is being applied to the cardiac safety of new pharmaceuticals and medical devices by regulatory authorities and by the media. Together with the growing expectations of the developers of such products for cost-effective solutions, this has led to the clear need for focused, competent and fully-integrated cardiac imaging core laboratories. These core laboratories require the right combination of human technical and medical expertise, both in-house and available from the academic and clinical communities, together with appropriate, fully-integrated, and easy-to-use analytic technology that can be applied to the cardiac images collected for any given clinical trial. In addition, the core laboratory must be able to provide clear guidance to study sites, on a global basis, regarding cardiac image acquisition and transfer. Finally, the output of the image analysis should be seamlessly transferable to the study sponsor and must be able to withstand the highest level of regulatory scrutiny.

The evaluation of cardiac safety in clinical trials is a critically important and continuously evolving field that requires close and productive collaboration between the clinical investigators, the study sponsor, and the cardiac imaging core laboratory.

Peter Gardiner MB ChB, MRCP, a Scientific Advisor with over 25 years of global pharmaceutical industry experience in cardiovascular therapeutic and diagnostic products. Expertise spans invasive and noninvasive cardiovascular procedures, including cardiac catheterization,

coronary angiography, electrophysiology, pacemaker insertion, echocardiography, and radionuclide imaging.

Nicholas R. Enus is Associate Director of the Cardiology Medical Imaging Group at Perceptive Informatics. Nicholas joined Perceptive in 2003. During the past seven years, he has had extensive experience in a wide range of global clinical trials and imaging techniques, including oncology,

cardiovascular and CNS. Nicholas graduated cum laude with a Bachelor of Science degree in Exercise Physiology from the University of Massachusetts, with a double Minor in Clinical Lab Sciences and Psychology.

References• Bresalier RS, et al. Cardiovascular events associated with rofecoxib

in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-102

• Eschenhagen T, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Failure 2011;13:1-10

• Gottdiener JS, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004;17:1086-119

• Mansour M, et al. Assessment of pulmonary vein anatomic variability by magnetic resonance imaging: implications for catheter ablation techniques for atrial fibrillation. J Cardiovasc Electrphysiol 2004;15:387-93

• Monahan BP, et al. Torsade de pointes occurring in association

with terfenadine use. JAMA 1990;264:2788-90• Mulvagh SL, et al. Contrast echocardiography: current and future

applications. J Am Soc Echocardiogr 2000;13:331-42• Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial

infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71

• Shively BK, et al. Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 1999;100:2161-7

• Swain SM, et al. Congestive heart failure in patients treated with doxorubicin. Cancer 2003;97:2869

• US Food and Drug Administration. Guidance for Industry: E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. October 2005

• US Food and Drug Administration. Guidance for Industry: S7B Nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. October 2005

• Vieweg WVR, Wood MA. Tricyclic antidepressants, QT interval prolongation, and torsade de pointes. Psychosomatics 2004;45:371-7

• Weissman NJ, et al. Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy. Ann Intern Med 2001;134:267-73

• Woodcock J, et al. Regulatory action on rosiglitazone by the US Food and Drug Administration. New Engl J Med 2010;363:1489-91

IT & Logistics


IT & Logistics

Portability and a Single Data SourceDr Kenny arrives at his office on Monday morning. He opens his iPad and begins to review his scheduled caseload for the day. He recognises his first patient, Mrs Johnson, who is scheduled for 11am. As he flips through Mrs Johnson’s chart, he realises that she might be a perfect candidate for the new ABC Pharma clinical trial XYZ.

Dr Kenny realises it has been a few months since he has reviewed the protocol for Clinical Trial XYZ so he opens his iPad and begins to review the animated protocol to refresh himself and his staff on the screening requirements for enrolling Mrs Johnson in the clinical trial. As he is reviewing the protocol he has a concern about a specific screening requirement and Mrs Johnson’s previous medical history, so he initiates a live video chat with a medical monitor from within his iPad to get clarification.

At 11am, when Mrs Johnson arrives, he reviews the screening information with her and simultaneously, in real time, he reviews the informed consent with her, line by line. He then records the review of the consent and documents her authorisation and signature all within the same application on his iPad. Now that Mrs Johnson has passed the screening requirements, the animated protocol application walks Dr Kenny through the visit schedule. The first visit requires enrolment and randomisation, so the application gives Dr Kenny the opportunity to randomise her within the application. From his iPad, Dr Kenny was able to screen Mrs Johnson, document her consent and subsequently enroll and randomise her into the clinical trial, and assign blinded study medication; all from a single application within a matter of minutes.

Vision of the FutureIn the not-so-distant future, medical practitioners will have 24/7 access to an iPad or digital tablet. They will be able to review laboratory data directly from an iPad, review significant alerts from a clinical trial such as adverse events that arise from the electronic patient-reported outcome (ePRO) system and automatically look at the trend of a single patient’s data within the system using a full featured but easy-to-use business intelligence reporting tool.

For the end user this is seamless, but behind the scenes the data must be transferred in real time between various systems and devices. Data can be collected from, for example, electronic data capture (EDC), iPad, IVR or ePRO systems, and collated in a central data warehouse behind the scenes. In addition to an iPad or smartphone, the end user also has the capability to review the data from the CRO’s portal on a laptop. Each data point is being pulled (or pushed) from a central data warehouse providing a single version of the truth.

First and Second generation EDCEDC is the current standard practice for data collection

in a clinical trial. It has effectively replaced paper as the primary data-collection medium. The introduction of EDC has gained continued traction over the past decade. The majority of clinical trials use some form of EDC, but there is still significant room for improvement.

First-generation EDC systems such as early optical character recognition (OCR) systems, thick-client based systems (where the application and logic reside locally on the user’s computer) and early versions of IVR, simply migrated the paper process to an electronic medium. The process was unchanged but the modality for data collection had changed. They were effectively just data collection tools that mimicked the paper-based process in electronic format. They improved the accuracy of the data and improved efficiencies by eliminating some of the data entry requirements within the pharma company or CRO that was responsible for transferring the data from paper case report forms to a database for analysis and query resolution.

Second-generation systems, where we are now, brought newer technology such as thin-clients (where the application logic resides primarily on the server), browser-based software, site management tools and improved edit checks and query resolution tools. They provided better reporting tools and enabled more transparency into the EDC data, but are still limited and unable to provide full transparency across systems. All major second-generation EDC systems are browser-based, feature-rich, and extremely adept at bringing electronic case report forms from the site to the data management teams behind the scenes.

However, the current systems are still siloed and very disparate. A site is often required to maintain unique computers for multiple EDC systems. In addition, the computers are often in a separate room, out of the way of the normal process within a clinic. Sites will typically enter the EDC data from a visit 2-4 weeks after the patient visit. This means that the EDC enrolment data cannot be fully trusted. The sponsor often looks to alternative sources of information to verify the data when decisions need to be made.

In addition to EDC data, most modern clinical trials employ a number of different technologies that the sites must be trained and kept updated on. Technologies such as IVR for patient enrolment and clinical supplies management are typically employed. IVR data is consistently more real-time than other data collection tools. This can present a problem when the IVR data is real-time and the EDC data is 2-4 weeks behind.

Another technology which is increasingly common, due to the recent FDA guidance, is electronic patient-reported outcomes (ePRO). ePRO can consist of numerous technologies, each with its own challenges. The utilisation of ePRO can be crucial in a clinical trial but also adds one more piece of information that complicates the ability for a clinical team to accurately analyse the data.

The Future of Electronic Data Capture Tools


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Next-generation EDCTThird-generation EDC will move to a more integrated model. These systems will be fully integrated with many other clinical systems such as ePRO, IVR and CTMS, collectively known as electronic data collection tools (EDCT). Using third-generation tools, EDC data will flow bi-directionally between the various applications and the clinical data warehouse. Third-generation systems will integrate all of the various and complex data collection tools allowing the study teams a “single version of the truth”.

This single source of information supports the acquisition and management of data from multiple data sources into a single, standard infrastructure for data access, transformation, and distribution. This single centralised clinical data warehouse will afford full transparency and visibility of the data.

To achieve the fully integrated model, back-end services and systems will need to be created. A handful of forward-thinking companies are beginning to develop the back-end clinical data warehouse infrastructure needed to support such a fully integrated front end.

The architecture would be similar to a hub-and-spoke type model. The central data warehouse would be the hub employing an open architecture that can be commonly used across multiple systems and technologies.

Examples of information available at the study level include status, progress and trending, from study start to database lock. At the patient level it includes access to adverse event data within a patient and between patients.

This technology allows for adaptive trial design, whereby a sponsor can adapt a clinical trial based on the availability of near real-time data collected while the trial is ongoing. In addition, it can have a positive impact on facilitating audit trails, data-mining and combatting human error to prevent mistakes. For a sponsor, this solution provides a ‘one-stop data shop’, with web-based access via a single portal. It enables study comparisons, quicker patient enrolment and database lock. Improved quality and speed of data collection can help to achieve shorter time to market and lower drug development costs.

ConclusionThe future solution optimises the management and aggregation of clinical trial data in near real time, allowing data to be maintained in a single standardised format, with appropriate controls, providing an auditable chain of custody and the ability to create customised performance metrics. It provides a ‘one-stop shop’ for all teams for any study-related questions and a single source of information when making critical decisions.

It enables the management, reporting, analysis and visualisation of all data relating to a clinical trial, by maintaining the data in a single, standardised format. The end user front end is customised to allow real-time access to the data and metrics of interest with different views for different types of user needs.

Data will be integrated from several different sources. These include operational sources such as the CTMS, investigator payment system and information database. Data is also integrated from clinical sources including

the EDC system, IVR, patient diaries, central laboratory output and central imaging laboratory. When combined, these data provide a single repository of information for a particular study, allowing the sites and clinical teams to make decisions from a single, standardised source improving quality through consistency.

A primary factor that is emerging as critical to sponsor choices of an EDC system is total integration with other platforms. The need for integrated data is evident with the emergence of data warehouses. Data warehouses are key to integrating data for cleaning and analysis, but sponsors are increasingly interested in the benefits of integrating data processing early in the process. Integrated randomisation, clinical data collection and site management will be critical going forward.

Kris Gustafson has been with ICON since 2000 in multiple roles and positions. In January 2007 he was promoted into his current role as Global Head of the Interactive Technologies business unit and the Life Sciences business unit. Prior to ICON, Kris was President and

co-founder of Electronic Trial Management Technologies, a technology company specializing in IVR and IWR solutions for clinical trials, which was acquired by ICON in 2000. From 1995-1999 he served as Senior Director of Information Management at Applied Logic Associates. From 1990-1995 he worked as a Mechanical Engineer in the Nuclear sector. Kris received his Bachelor of Science degree Mechanical Engineering from Washington State University in 1990. Email: [email protected]


IT & Logistics

The technological landscape has grown in size, format, and complexity in the past three to five years. This has been demonstrated by the role that mobile technologies, internet, and social media played in the recent political unrest in the Middle East and the first initial public offering of a major United States (US) social media site, LinkedIn1. Yet the use of social media and the internet by the highly regulated pharmaceutical and medical device industry has been tenuous and reticent. The industry had been anticipating US Food and Drug Administration (FDA) guidance regarding social media and internet use in direct-to-consumer communication, but the issue was recently removed from the FDA’s 2011 Guidance Agenda2,3. Clinical trials have therefore lagged behind the general public use of the latest technological communication avenues – mobile phones, internet, YouTube, Facebook and Twitter -- for recruitment and retention purposes.

The Global Attitudes Project of the Pew Research Center4 noted a significant increase in cell phone ownership and computer usage over the past three years. Evaluating sixteen countries in 2002 (including the US, Russia, China, Kenya, and Argentina), the median ownership of cell phones was 45%, and as of 2010 was 81%. About eight in ten Russians own cell phones and China’s usage increased 40 percentage points4.

When individuals use the internet, even in low to middle income countries, it is being used for social networking purposes4. However, usage is skewed towards 18- to 29-year-olds, being 50 percentage points ahead of 50-plus-year-olds. Conversely, a recent study of the use of Facebook groups pertaining to breast cancer showed that 55-plus-year-olds are using social media sites, such as Facebook5. Furthermore, research conducted by Age UK, a charitable organisation, and Eurostat, the European Union’s statistical office, found that 58% of the Luxemburg population aged 55 to 74 were online, while 43% of the UK’s 55- to 74-year-olds use the internet frequently6.

A cross-sectional survey was conducted in Japan involving 10,875 internet users, excluding 5.5% (593) who were healthcare professionals (total of 10,282)7. Kishimoto and Fukushima found that 47.3% used the internet to research drug information. Twenty-nine per cent were taking prescribed medicine. Fifty-one per cent used social media sites for information on drugs. These same researchers found that 47.2% used web communities and anonymous information provider sites for data on drugs, and 15.9% used these sites exclusively (7, p.689). Since user-generated web communities and anonymous information provider sites may be providing drug information that is not verifiable or valid, these findings are concerning. However, use of social media sites for clinical trial purposes wherein the information on the site is approved by the physicians and investigators, regulatory bodies, and research staff, can then reach a large audience and provide accurate information. Valuable and viable education of the patient and recruitment and retention are possible in this venue.

Kontos et al. examined data for inequalities in social networking use in a sample of US adults from the National Cancer Institute’s (NCI’s) Health Information National Trends Survey (HINTS)8. The digital divide was apparent in social networking sites’ (SNS) use, with half of Hispanics and 40% of non-Hispanic Blacks in the sample lacking access to the internet (8, p.6). However, for those racial/ethnic minorities using SNS, particularly individuals with lower income and education levels, SNS use was higher than those with a college degree and earning $75,000 plus8. Since racial/ethnic minorities are under-represented in clinical trials overall, SNS use could be a window of opportunity to increase racial/ethnic minority participation. Nonetheless, requirement of SNS use for a clinical trial may introduce bias. Eligibility requirements of internet and social media access will exclude those individuals who do not have access to the internet, a mobile phone or social media sites for financial or other access reasons2.

A challenge for social media use in clinical trials is maintaining privacy of the participant as well as preparing for the potential confounding factor of sharing between participants. For instance, if a participant uses the public library for their internet/social media use and unknowingly leaves a browser window open, data security and privacy could be breached2. Creative methods to protect the data as well as the patient and their information will be required. Sharing information with other participants and the potential social support gained could be a confounding factor that is weighed in the analysis process, as with other demographic data. Privacy of the participants was planned in a Cameroon study using mobile phones. Mbuagbaw et al. reported on the study to be conducted to improve and maintain adherence to a highly active anti-retroviral therapy (HAART) in HIV patients9. In this study, the research staff will use one phone with prepaid airtime to preserve the privacy of the participant’s health status and the type of drugs participants are taking (which could reveal their health status). Confidentiality and anonymity of the participants will be upheld by avoiding the use of the mobile operators (9, p.6; see also 10). The privacy factor could also be addressed in the consent process, by stating in the informed consent form (ICF) that the subject agrees to reveal certain information to link with other subjects. If a subject is concerned about privacy, instructions could also be supplied regarding privacy settings on social networking sites, without assuming that the subjects understand the privacy controls.

The reticence of many pharmaceutical companies to expand promotion of prescription products to the internet and social media may also be attributed to the necessity to maintain the “fair balance” requirement in “content and presentation of the information” (balanced attention to risks and benefits of a product)11. A public hearing was held in 2009 regarding the use of the internet and social media for promotion of FDA-regulated medical products (prescription drugs and medical devices)12. Understandably,

Social Media/Internet Use for Clinical Trial Patient Recruitment & Retention Efforts


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many pharmaceutical companies and those promoting their products have been waiting for guidance before investing in these advertising mediums and to remain compliant12. At the public hearing in 2009, the FDA detailed the issues it was considering in deciding what guidance to provide to these entities for the use of social media and the internet for promotional purposes. The hearings included the presentation of risk information “one click” away so that complete product and safety information is just “one click” for the user to view, adherence to the FDA regulations with space limitations on social media sites, and unintended and intended reporting of adverse events by users12. The FDA decision to remove guidance for social media and internet use from the FDA’s 2011 Guidance Agenda leaves pharmaceutical companies and its product promoters in a quandary.

Social media and internet use in clinical trials will now be decided by sponsors, CROs, and clinical trial regulatory bodies who will continue to weigh the risks and benefits of the use of certain methods for recruitment and retention to maintain protection of subjects and the reliability, validity, and generalisability of the study. In the case of the internet and social media, one of the issues to consider is the balance between maintaining the scientific integrity of research with that which may be helpful to the patient, e.g., sharing with other patients on a social media site2. As mentioned above, some of these issues can be addressed in the ICF, providing explicit instructions as to the parameters of internet and social media use during the study period2. Specifically, patients would need to be prohibited from posting pictures of the study drug they are taking to avoid the potential for unblinding the participants to which is the study drug and which is the placebo2. To avoid further lengthening the ICF, one suggestion is to prepare a separate document specifically dedicated to the terms and conditions of internet and social media use during the study period which would be part of the consenting process2. If the patient could not agree to these terms and conditions (similar to other inclusion/exclusion criteria), then they would be ineligible to participate.

As mentioned above, there is a potential for a positive impact on users in terms of support, connection and retention due to sharing between subjects with social media use5,8,13. Since the information is user-generated, the information is patient-centred8,13. Numerous internet studies are being conducted for the purpose of support, education, and for examination of website use14. AstraZeneca created a Twitter feed for provision of patient assistance for some of their products15,16. Sanofi-Aventis had a dedicated page for video, which was just recently moved to YouTube in French and English16,17. The site provides patient education and company information. In a virtual summit sponsored by the online Medical Monitoring & Media journal, Gwee and Monseau16 stated that these examples demonstrate social media use by pharmaceutical companies with adherence to regulations. Also, as with any other communication with a subject or potential subject, consideration of the target population must be incorporated into the planning of social media use. This includes health literacy of the target population, as well as other demographic characteristics.

How effective is social media use or internet use in clinical trials for recruitment efforts? Whittaker and colleagues18 fell

far short of their recruitment goal in a randomised controlled trial involving theory-based video messaging on mobile phones for the purpose of increasing smoking cessation rates in New Zealand adults, 16-65 years old. However, a competing text messaging study regarding smoking cessation was held with approximately 4000 recruited patients18. This same group of authors recruited 1200 participants to a text messaging study during 30 school weeks for prevention of adolescent depression18. Perhaps such success with recruitment and particularly for adherence to the study timeline in clinical trials could be achieved with the use of mobile phones and text messages.

Since social media allows users to post comments without providing the user’s qualifications or expertise to verify the veracity of their comment, the health information may or may not be legitimate. In addition, any person may comment on the brand or non-brand issue positively or negatively, as well as inadvertently refer to adverse events or off-label use. On Facebook, sponsors have been controlling this by whitelisting, disabling user comments on their pages. Facebook just recently notified pharmaceutical companies that beginning August 15, 2011, whitelisting will no longer be permitted19,20. A branded page for a single product may continue to disable comments20. If social media is used for the purpose of retention in a clinical trial, access and comment posting could be limited to participants who have consented, and guidelines for use could be given to patients prior to using the page. If clinical trial pages would be permitted to review comments prior to posting, this too would allow for some control over inaccurate, negative, and/or side-effect reporting, and provide pharmaceutical companies with the ability to comply with regulatory agencies.

Monitoring of the social media site would be required. The web or social media site monitoring could be performed every day without twenty-four/seven (24/7) coverage allowing for regulatory compliance since there is a small window of time for reporting. Continuous monitoring of a site is unrealistic2 and not financially feasible. Furthermore, use of the FDA’s Medwatch icon could assist with adverse event reporting2,21. As ongoing studies are completed, evidence for use of social media and the internet in the clinical trials will be available. For instance, there is recruitment ongoing to a web-based methodology trial to evaluate the efficacy and safety of Tolterodine ER in subjects with overactive bladder14.

The FDA removed social media and internet use from its 2011 Guidance Agenda within the first two weeks of June. Facebook announced its new policy regarding the necessity of pharmaceutical companies to allow comments on its pages within the same time period. The technology and their companies will continue to produce products with the latest novel application, and social media use will continue to evolve. At the same time, the social media entities will institute policies and change existing policies for financial benefit and legal protection as they reach maximum usage. Attempting to navigate this fast-paced and ever-changing venue is daunting, and perhaps the FDA withheld its guidance for this very reason. In fact, the content of this document is only as current as the day on which it is written2.

Facebook boasts more than 500 million active users with fifty per cent (50%) visiting the site every day22.The internet

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and social media are a means to reach a large sector of society in the US and throughout the globe, and perhaps those individuals who have been unreachable for clinical trials. Participation in clinical trials remains low, which impacts the generalisability of the findings to the general population, as well as the lengthy approval time for new drugs. Creative means are needed to educate potential patients about what clinical trials are and what those trials entail, as well as to encourage enrollment in trials for which they are eligible. However, reliance upon a single means of recruitment and retention would be misdirected. A potential participant may hear about a clinical trial on the radio or on television, may be informed of the trial at a community group meeting or through an online support group, and see a poster about the trial in their physician’s office. These recruitment means may prompt a potential participant to ask for additional information while visiting a physician, or prompt the physician to mention the trial to an already familiar patient23. Social media and the internet should become additional techniques in the cache of recruitment and retention methods.

Katie Stewart, MSPH, CHES has five years experience with quantitative and qualitative research in cancer patients on chemotherapy, involving recruitment, data collection/management, and manuscript preparation. Katie presently works at PharmaNet, LLC as a Clinical

Trial Recruitment Associate II in the Patient Recruitment Group. She has a professional and personal passion for writing and patient care. Email: kstewart.pharmanet.com

References1. Pepitone, J. LinkedIn stock more than doubles in IPO.

CNNMoney.com. http://money.cnn.com/2011/05/19/technology/linkedin_IPO/index.htm, posted 19 May, 2011.

2. Buchanan, E. A., Personal communication by telephone. Elizabeth A. Buchanan, Ph.D., Endowed Chair in Ethics, Director, Center for Applied Ethics, University of Wisconsin-Stout, (17 Jun 2011).

3. http://pharmamkting.blogspot.com/2011/06/fda-drops-social-media-from-its-2011.html.

4. PewResearchCenter (www.pewglobal.org), Computer and cell phone usage up around the world: Global publics embrace social networking. Global Attitudes Project, 15 Dec 2010, http://pewresearch.org/pubs/1830/social-networking-computer-cell-phone-usage-around-the-world visited 28 Mar 2011.

5. Bender, J. L., Jimenez-Marroquin, M-C., & Jadad, A. R., Seeking support on Facebook: A content analysis of breast cancer groups. Journal of Medical Internet Research, 13(1) (2011); www.jmir.org/2011/1/e16/.

6. Skinner, C-A., 43% of 55 to 74 year olds use the web frequently: Net offers a great way of staying in touch with friends and family. PC Advisor, (2011), http://pcadvisor.co.uk/news/index.cfm?newsid=3266450, visited 28 Mar 2011.

7. Kishimoto, K., & Fukushima, N., Use of anonymous web communities and websites by medical consumers in Japan to research drug information. Yakugaku Zasshi, 131(5), 685-695 (2011).

8. Kontos, E. Z., Emmons, K. M., Puleo, E., & Viswanath, K. (2010). Communication inequalities and public health implications of adult social networking site use in the United States. Journal of Health Communications, 15 (Suppl 3): 216-235; NIH Public Access, doi:10.1080/10810730.2010.522689.

9. Mbuagbaw, L., Thabane, L., Ongolo-Zogo, P., Lester, R. T., Mills, E., Volmink, J., et al. The Cameroon mobile phone sms (CAMPS) trial: A protocol for a randomized controlled trial of mobile phone text messaging versus usual care for improving adherence to highly active anti-retroviral therapy. Trials, 12(5). NIH Public Access, http://www.trialsjournal.com/content/12/1/5 (2011).

10. Lester, R. T., Mills, E. J., Kariri, A., Ritvo, P., Chung, M., Jack, W., et al., The HAART cell phone adherence trial (WelTel Kenya1): A randomized controlled trial protocol. Trials, 10(87); NIH Public Access, doi: 10.1186/1745-6215-10-87, (2009).

11. Federal Drug Administration, DHHS, Agency Information Collection Activities; Proposed Collection; Comment Request; Examination of Online Direct-to-Consumer Prescription Drug Promotion, (76)82, Notices, Docket No. FDA-2011-N-0230 (28 Apr 2011). Noted: 21 CFR 202.1(e)(5)(ii).

12. Federal Drug Administration, DHHS, Promotion of food and drug administration-regulated medical products using the internet and social media tools; Notice of Public Hearing, (74)181, Notices, Docket No. FDA-2009-N-0441 (21 Sep 2009).

13. Chou, W. S., Hunt, Y. M., Beckjord, E. B., Moser, R. P., & Hesse, B. W., Social media use in the United States: Implications for health communication. Journal of Medical Internet Research, 11(4), e48 (27 Nov 2009).

14. ClinicalTrials.gov, www.clinicaltrials.gov. 15. AstraZeneca Helps, www.twitter.com/#!/AZhelps. 16. Gwee, S., & Monseau, M., We’ve got your social media

guidelines right here sponsored by The Oncologist. Medical Marketing & Media Virtual Summit, http://www.mmm-online.com/mmm-virtual-summit/section/2139/, (24 May 2011).

17. Sanofi-Aventis TV, www.youtube.com/sanofiaventisTV.en. 18. Whittaker, R., Dorey, E., Bramley, D., Bullen, C., Denny, S.,

Elley, C. R., et al., A Theory-based video messaging mobile phone intervention for smoking cessation: Randomized controlled trial. Journal of Medical Internet Research, 13(1), (Jan-Mar 2011).

19. Arnold, M., Facebook: Pharmas must enable comments by August 15. Medical Marketing & Media, (24 May 2011), http://www.mmm-online.com/facebook-pharmas-must-enable-comments-by-august-15/article/203637/ visited on 25 May 2011.

20. Dayton, J. How Facebook’s new comment policy impacts your pharma Facebook page. InTouch Solutions, (19 May 2011), http://www.intouchsol.com/insights/articles/05-19-11/how_facebook_s_new_comment_policy_impacts_your_pharma_facebook_page.aspx, visited on 25 May 2011.

21. Kupchyk, A., & Madagan, K., Coming soon! FDA’s current thinking on social media and production promotion, http://www.corporatecomplianceinsights.com/2010/fda-policy-social-media-product-promotion/ visited on 17 Jun 2011.

22. Facebook, www.facebook.com/press/info.php?statistics.23. Ware, K. W. Personal communication. Keith Ware, Clinical

Trial Recruitment Associate II, PharmaNet, LLC, (16 June 2011).


IT & Logistics

Supply chain partners, specialising in the safe and effective transport of clinical trial materials around the globe, are continuing to expand into the Middle East supporting client demand. Roland Nicholas and Karen Adams, from SCA Cool Logistics, give their viewpoint on the technical challenges that are being encountered by the cool chain sector during their journeys into this uncharted territory.

A Landing BaseWhen transporting clinical trial material around the globe, two factors are of upmost importance – the transport infrastructure and the ambient temperature experienced. The western world seems almost privileged with its logistics infrastructure, with its well-maintained transport links and sympathetic climate, where ambient temperatures encountered are not too sporadic. These factors result in a testing but consistent and stable environment to deliver clinical trial materials in a timely and safe manner.

However, if you turn to the Middle East and Northern Africa you will see a very different story. Less qualified infrastructure leads to longer lead times, using up precious time permitted to get product from A to B, whilst ambient temperatures soar. In some areas of the Middle East and Northern Africa, temperatures have been known to reach up to +50ºC.

Still the pharmaceutical industry is increasingly undertaking clinical trials in this part of the globe – in fact there has been a distinct rise in the demand for this type of service over the last five years as trade flows more easily within the region. Service providers are constantly looking for ways to overcome the challenges presented to them, striving to deliver the support for their clients.

Sporadic Transport hubs ChallengeNothing beats having a base central to the area, to control, support and be a landing base for clinical trials making their way through the region. Being strategically placed means global service providers have the distinct advantage of having a retreat to either break up a journey, or act as a warehouse to send out, and receive returns of, reusable packaging. These supply chain partners are able to reduce lead times associated with the supply of high quality temperature-controlled packaging, an essential part of a successful clinical trial shipment.

Roland Nicholas, SCA Cool Logistics’ product manager, whose company has just opened a temperature-controlled packaging (TCP) logistics services office in Dubai for this very reason, explains: “Providing packaging that can minimise the risk of keeping product maintained between certain temperatures, is crucial in the pharmaceutical supply chain strategy. By having the additional advantage of being strategically placed in the Middle East, you can have more control over what could be seen as a rather uncontrollable environment.”

Supply chain partners are striving to do all they can to

reduce lead times associated with the supply of high quality temperature-controlled packaging. Time is of the essence, and anything that can be done to reduce the duration of a journey from A to B is welcomed with open arms. Temperature-controlled packaging providers who are based in the Middle East are more able to provide timely expert technical support and troubleshooting if any discrepancies do occur - a difficult task if based on the other side of the world.

However, the challenge here is the shortage of hubs through the Middle East. The vast geographical scale presented by the Middle East means the hubs available are few and far between. There has been a growth of pioneering third party logistics (3PLs) hubs in the Middle East, which occurred in response to increased foreign direct investment by some of the big pharmaceutical players. Back in 2007, 3PLs such as DHL started spreading their wings and set up hubs in the Middle East to act as stepping stones for transporting goods - a move which was welcomed by the cool chain sector.

Unpredictable External Environment ChallengeCool chain suppliers rely on trusted real-world data of ambient transport temperature history, and profiles for certain routes around the globe have been analysed and perfected over the years. However, with the move to the Middle East, which in profile terms can be seen as uncharted territory, there is a lack of data support. Routes across this area have been rarely undertaken, meaning there is a lack of knowledge of potential ambient temperatures the product will need to travel to before arriving at its destination.

Temperature-controlled packaging companies are able to undertake a performance qualification which can help anticipate the environment of certain routes, known as real-world temperature monitoring. Data loggers are used, which are small electronic devices that travel on the packaging during test runs to the client’s chosen destination, tracking exposed ambient temperatures in real time. Every five to ten minutes the data logger will track the external ambient temperatures it is being exposed to. Data is collected and slowly the cool chain providers become experts in these new remits, building up a database for this area of the globe, which is currently unexplored.

Unknown Supply Chain Infrastructure ChallengeAs well as the unknown temperatures that the product will tackle, there is also the unknown in the infrastructure in the Middle East. Airports, motorways, border crossings, main roads, and trade zones all make up inefficient distribution channels which can affect consistent trip profiles, thus increasing system performance risk.

Karen Adams, senior product development engineer for SCA Cool Logistics, explains: “In our experience, different countries

Thinking Outside the Box – Technical Challenges for the Cool Chain Sector when Approaching the Middle East


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have vastly different logistic risks. For example, a product, worth potentially millions, might haphazardly get left on the shelf for a few weeks at customs. Because of these unknowns, two factors are vital for our customers. The first is building the knowledge of how different markets work across the Middle East, so we are able to pre-empt and advise customers on the best route and approach. The second is to offer intelligent packaging, that can react to these situations on our behalf, protecting the product regardless of the environment it encounters.”

SCA Cool Logistics, market leaders in temperature-controlled packaging for the healthcare sector, has recently launched the ZeoCool range, intelligent packaging developed for shipping temperature-sensitive material between +2.0°C and +8.0°C. Depending on the ambient profile the packaging encounters, ZeoCool can think for itself, heating and cooling the internal payload space by combining both heating and cooling technology. Cooling is undertaken through evaporation (rather than melting, as evaporation is seven times more efficient at cooling than using icepacks). Heating occurs through an exothermic reaction where the thermostat employed reacts to the ambient temperature for maximum stability. With packaging solutions getting more and more intelligent, the uncontrollable environment becomes more controllable and less of a challenge.

Product Stability Data ChallengeIn our experience regulatory bodies are not receptive to drug stability data in relation to system qualification. Previous experience in this field has enabled cool chain providers to utilise drug stability data to support any small excursions seen during the qualification of packaging. In recent months, it has been

noted that having access to this data has declined, making it harder to forecast the journey ahead. When qualifying standard packaging, the customer – whether it is a big pharmaceutical or an individual clinical trial – has detailed knowledge surrounding the product being shipped and its reaction in environments outside of the normal +2.0°C to +8.0°C. It is this information that can enable the qualification of the packaging to be completed quickly to get to the completed result. The lack of data around the Middle East adds complexity, which needs to be built into the qualification, increasing time and costs associated with the project.

ConclusionThe Middle East is certainly a complicated area of the globe to operate in, but a requirement for those who want to stay ahead of the game. The pull to this area is becoming greater by the day, and cool chain suppliers must invest energy and resources to keep up with this ever-growing demand into what often feels like uncharted territory.

In the long run, improved infrastructure and the arrival of more strategically-based hubs will help to ensure a smooth ride across the Middle East. However, in the shorter term,

supply chain partners are investing heavily in the right research to gain trusted temperature profiles and achieve knowledge of how the new market operates. In addition to this, temperature-controlled packaging manufacturers are coming into their own, offering intelligent systems that can react to the unpredictable.

This winning combination will separate the wheat from the chaff, allowing those who are prepared to invest in tackling the technical challenge presented by the Middle East, to conquer.

Karen Adams - Senior Product Development Engineer Karen is responsible for all aspects of new product development within SCA Cool Logistics. Karen joined SCA Cool Logistics three years ago, with several years experience in both the Pharmaceutical and FMCG sectors. Karen is a time-served,

indentured apprentice and has a Bachelor of Engineering (BEng) in Mechanical Engineering Design. Email: [email protected]

Roland Nicholas - Product ManagerJoining SCA Cool Logistics in 2010, Roland is responsible for SCA Cool Logistics product portfolio management. He also has previous experience in the Pharmaceutical industry that includes roles within both medical devices and consumer products

sectors. Roland holds a Bachelor of Science (BSc) in Mechanical Engineering (new product development), a Master of Science (MSc) in Industrial Design (packaging design) and a Masters of Business Administration in innovation management (MBA).Email: [email protected]


IT & Logistics

With a population of over 1.1 billion and an increasingly large pool of patients suffering from deadly modern diseases like cancer, diabetes and cardiovascular disease, India has emerged as a thriving hub for clinical trials over the past decade. Rapid recruitment, low costs, a technically competent workforce, English fluency, a growing number of world-class research facilities − many complete with specialised clinical trial units, adherence to international good practice standards and an established drug control system continue to make India an attractive prospect for future studies.

According to National Institutes of Health (NIH) statistics, India currently hosts over 1600 studies1. Clinical trial investment in India by the global pharmaceutical community was estimated at over $1 billion in 2010, with continued growth expected. Today virtually every major pharmaceutical organisation in the world has established an active presence in this pivotal country.

Although all appears perfect on the surface, sponsors and drug development professionals should recognise that India is still considered an emerging nation and, as such, delicate clinical product and materials must successfully navigate its developing regulatory environment and customs administration before victory can be declared.

In this paper, we will: • discuss India’s importation procedure for investigational

drugs • outline strategies for overcoming the logistical challenges

faced by pharmaceutical shippers conducting business here • create a realistic understanding of the timelines required in

implementing drug administration schedules

Pre-trial Approval and Licensing A clinical trial in India cannot be initiated without a No Objection Certificate (NOC) from the Drug Controller General of India (DCGI) which confirms that the trial has been approved. Acquired by the sponsor as the preliminary step in the clinical trial process, the NOC takes a minimum of 45 working days (nine weeks) to receive, assuming there are no inquiries about the content. If the DCGI has further questions with regard to the application, these queries must be addressed in full, extending the process accordingly. At the present time, there appear to frequent queries from the DCGI, extending timelines to approval.

In addition to the NOC, the sponsor, CRO, or Importer of Record (IOR)2 must also obtain an import permit (also referred to as a “CT License”) from the DCGI. The import permit will indicate the name of the drug(s) to be imported as well as the quantities that are permitted to be shipped for the study. The import permit is valid for a period of one year and must be renewed annually thereafter. The importer must also prepare a manual tally sheet which permits customs officials to deduct the actual quantity of each importation and maintain a running balance. Application for the import permit can be made at the same time as the NOC. Both of these documents must be in the sponsor/CRO’s possession before the first physical shipment can

be forwarded. Original documents (NOC and the CT License) are required for each import. Scanned copies and photocopies are not acceptable.

The Import Process Once the NOC and import permit have been obtained, importation of investigational drugs can commence. Each individual shipment must be accompanied by a commercial invoice, printed on the shipper’s letterhead and signed in blue ink. The commercial invoice must identify the Importer of Record (IOR) even if this party differs from the actual consignee (for example, a CRO might be the IOR while an individual investigator site or storage depot might be the actual consignee). It must also reference the protocol or study ID number and indicate the name of the drug exactly as it appears on the import permit. The description of the drug unit (i.e. per capsule or per vial) must be identical to the description stated on the import permit as must its unit of measure (e.g. “mg” or “ml”).

Shippers should take care to ensure that customs officials can easily tally the exact amount of drugs included in the consignment and supported by the commercial invoice, as this total must be debited from the tally section of the import permit. Finally, the value of the shipment must be clearly and accurately stated at both a unit level (i.e. per tablet, per capsule, per vial, etc.) as well as in its totality. The invoice must clearly state the value of the shipment in real terms and should never state: “Value declared is for customs purposes only”, a standard statement that often appears on goods with no current, clearly defined commercial value.

Consignments of investigational drugs are not subject to duties, providing they can be attributed to an authorised clinical trial. Should the NOC be lost or misplaced, the IOR must inform the DCGI and obtain another original copy.

Clearance of non-temperature-controlled investigational drugs typically takes two to three business days (closed Sundays), meaning that the timeline from origin to destination can be four to five days, or longer. This should be factored into the drug administration schedule, especially in the case of shipments consigned directly to the investigator site (versus a local warehouse) or when further in-country distribution is required upon arrival in India. Temperature-controlled consignments may be pre-cleared, ensuring the availability of perishable shipments immediately after aircraft off-loading, subject to Indian customs’ approval of each shipment.

Accuracy, Consistency and Inspections The need for accuracy and consistency when preparing the export/import documentation cannot be stressed enough. Because it is a regulated industry, pharmaceutical imports garner the intense scrutiny of customs officials who hone in on any discrepancy to red-flag a shipment. Accordingly, shippers are cautioned to employ simple strategies to ensure they do not fall prey to common errors: • work directly from a copy of the import permit when creating

the commercial invoice

Clinical Trials in India: Managing Distribution Timelines through the Efficient Importation of Investigational Drugs


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• ensure that the name of the drug is recorded exactly as it appears on the import permit

• ensure that the value of the shipment reflected on all paperwork is consistent

• ensure that the number of vials, tablets, or capsules indicated on the commercial invoice accurately matches the quantity being shipped

• ensure that the unit measure of the vial, tablet or capsule corresponds on all documentation

• ensure that all documents contained inside the packaging are consistent

• check for weight discrepancies before shipping Pre-clearance of temperature-sensitive consignments is subject to a physical examination by customs, a process that can delay clearance and, as a result, may threaten product stability. The chance for delays in inspection is dramatically increased by any inaccuracies identified on the import paperwork. Letter-perfect consistency is the best way to improve the efficiency of a customs inspection, and customs clearance in general.

Areas of Responsibility A number of parties are typically involved in the importation of clinical materials − the shipper, consignee, CRO, IOR, logistics provider and broker − a reality that can make supply chain logistics even more problematic. The role of each party should be clearly defined and incorporated into an SOP before the trial gets under way to avoid confusion and reduce the potential for error. Typical areas of responsibility with respect to the importation of clinical supplies include:

Shipper • prepares required export paperwork • packages the investigational drug shipments • advises if replenishment of refrigerants is required en route or provides storage instructions for temperature-controlled shipments as required Logistics provider • consults with the shipper, consignee/IOR/CRO and broker

concerning the transport and logistics of the shipment • books space on flights and prepares the master airwaybill

(MAWB) • coordinates pick-up, delivery and replenishment of refrigerants

as required • monitors the transit • manages warehousing and in-country distribution as required Consignee/CRO/IOR • prepares the required import paperwork • remains available to provide any technical information about the product as required by customs or the Assistant Drug Controller (ADC)Broker• assists consignee in obtaining required permits • submits any required permit applications • provides timely feedback on the shipper’s paperwork • clears the shipment through customs

Minimising the Risk of Error In order to set up a clinical trial for success in India and optimise shipping and distribution timelines, the following recommendations will significantly improve study logistics and

eliminate delays to the greatest degree possible: • Be aware of all current regulatory and customs requirements.

In India, sponsors must have both a No Objection Certificate and an import permit (CT-License) prior to importing clinical materials into the country. Be well versed with all documentation required to both export investigational drugs from the country of origin and to import them into India.

• Clearly identify the roles and responsibilities of each clinical partner. To avoid confusion, clearly identify all parties who will be participating in the study and create an SOP to define the responsibilities of each. Reinforce the need for strong and timely communication between all parties.

• Understand and communicate realistic timelines. Be aware of the process that must be adhered to in India and factor in an appropriate amount of time for each step (i.e. pre-trial licensing, customs clearance at point of import and in-country delivery/distribution). Package temperature-sensitive consignments appropriately to meet these timelines as well as unexpected delays.

• Reinforce the need for accuracy. Check, check and double-check. Implement any internal processes or systems required to minimise human error.

• Consider a local warehousing solution. Importing bulk clinical shipments on a less frequent basis and storing them in a local warehouse will minimise the number of imports and help to reduce costs, eliminate the potential for error, ensure product stability by minimising unforeseen local transit delays, and streamline distribution timelines to in-country sites.

ConclusionIn truth, the documentation requirement for importing investigational drugs into India becomes fairly straightforward with practice. In reality, careful attention to detail, accuracy and consistency in the paperwork spells the difference between failure and success. The absence of required permits (the NOC and import permit/CT-License) will preclude the importation of needed clinical materials entirely − requiring that they be returned to origin or destroyed at the shipper’s (sponsor or CRO) expense.

Though perhaps not as critical, errors on import paperwork can result in lengthy customs delays. In order to rectify the situation, correct documentation may need to be presented − a situation that can be exacerbated by geographical distance and differences in time zones between shipper and consignee. Errors can also leave shippers exposed to fines, penalties, or additional scrutiny on future shipments, while putting the stability of delicate temperature-controlled products at risk and increasing the potential for missed drug administration to patients.

1. NIH website, www.clinicaltrials.gov (June 2011) 2. The Importer of Record (IOR) is the party who takes ownership or

responsibility for the materials entering the country. Depending on the logistical design of the study, the IOR may be the sponsor, the CRO, or an individual investigator si

Anthony Leone is International Customer Service Manager for World Courier Inc. (USA). For the past 15 years, Mr. Leone has worked closely with clinical trial clients, helping them improve their study logistics, optimize crucial distribution timelines and successfully manage the export/import process to and from some of the world’s most challenging geographies.


IT & Logistics

The 47th Annual DIA Meeting was held at the McCormick Place Conference Center in Chicago from 19th to 23rd June, 2011. The conference programme explored the theme of “Convergence of Science, Medicine and Health”. In the words of the Conference Chairman, Kenneth Getz, Chairman, CISCRP and Senior Research Fellow, Tufts Center for the Study of Drug Development, in the present turbulent times, convergence is the essence of successful pharmaceutical innovation as we enter into a new era of open and integrated R&D. In order to facilitate discussion and networking in keeping with the conference theme, the programme consolidated tracks and combined topics that have been separated at previous DIA Annual Meetings. Further study volunteer, patient group and public perspectives were encouraged throughout the sessions.

There were over 8000 attendees representing regulatory agencies, clinical research professionals within pharmaceutical sponsors & CROs, vendors, technology providers, academics and patient groups. There were about 500 exhibitors including the world’s leading and specialist CROs, clinical trial sites, technology vendors and providers for clinical research support services. As always, the large, diverse and global nature of attendees enabled productive and enjoyable networking. Unsurprisingly there was a risk of missing colleagues and associates amongst the large numbers, which was balanced by the opportunity to make new contacts. The vibrant and beautiful city of Chicago provided a great setting for this landmark conference.

Plenary & Special SessionsThe opening plenary session included a keynote address from David Ho, MD, the Founding Scientific Director and CEO, The Aaron Diamond AIDS Research Center and Irene Diamond, Professor, Rockefeller University, which provided an impressive overview of the progress of AIDS research in the span of just 30 years, and concluded with an update on the latest efforts to prevent this challenging disease.

Other plenary sessions included one that featured the stories of clinical trial participants where volunteer patients described their decision to participate in a clinical trial so as to benefit public health and advance medical knowledge, whilst being uncertain of the benefits and side-effects of the investigational product. A session with David Nash, Jefferson School of Population Health, and Gail Wilesnky, Project HOPE, explored how healthcare reform will impact the biopharmaceutical industry, discussing the key components of US healthcare reform and the potential effect on drug development and delivery of therapeutic and diagnostic agents.

There were three topical and interesting special sessions. The one on “Comparative Effectiveness Research and Health Technology” looked at how government-funded national agencies, including NICE, are assessing comparative effectiveness research (CER), and how their deliberations would affect the development and lifecycle management of biopharmaceuticals and medical devices. An executive round table with heads of outsourcing at Astellas Pharma, Purdue Pharma and Endo Pharmaceuticals, representing the range of large pharma, specialist pharma and a biotechnology

sponsor, candidly discussed their outsourcing strategies, the rationale for adopting these and the issues with their implementation. The ensuing discussion chaired by Patricia Leuchten, The Avoca Group, highlighted that although there could be management and financial benefits from engaging large global CROs with the whole range of required capabilities, the increasing complexity of global clinical development programmes does call for specialist skills which are best provided by niche specialist providers. Hence the ability to be nimble and flexible in one’s outsourcing strategy must be balanced with the imperatives for efficiency and cost-saving. Each of the sponsors, and indeed much of the CRO marketplace, strives to strike the right balance amongst service providers. The importance of expert site selection and management was also discussed, and challenges to do so were recognised. A well-attended session on social media discussed the regulatory and operational challenges with the effective use of digital and social media for the promotion of drugs and devices. Clearly such tools hold great promise for patient education, support, self-help and improved patient care; however there remain a number of problems with its widespread and correct adoption.

Programme OverviewThe main three-and-a-half day conference programme was structured along 18 themes, that included the longstanding topics of clinical operations, outsourcing strategies, medical writing, regulatory affairs and pharmacovigilance. New tracks included global agency and medical devices whilst clinical pharmacology and study endpoints were new areas that were featured in the extensive programme.

Select Sessions A workshop-style session examined the site selection process with a sharing of best practices related to identifying, selecting and defining a quality investigator site. Much of the discussion was focused on the US experience, however there were useful references to experiences in India and Central Europe. Concurrently there was a clinical operations session, entitled “Clinical Exchange in Emerging Regions: A Forum for Exchange”. In the spirit of sharing best practices amongst emerging countries, there were speakers from Brazil, China and Japan alongside Cynthia Kleppinger, Medical Officer, CDER, FDA, who presented the regulatory perspective on the quality of clinical data generated in emerging countries.

“Reducing Micro-Management of CROs while Maintaining Effective Quality Oversight” was chaired by Denise Calaprice-Whitty, who presented the results of a recent industry survey with participation from sponsors, CROs and regulators. The ensuing panel discussion featured panellists from Otsuka Pharmaceuticals, Eli Lilly, Covance and the FDA.

Joseph DiMasi chaired a session on emerging trends in the economics of the biopharmaceutical industry, that examined data on drug development timelines, technical success rates, development costs and the market dynamics around product launch. The relationship of these factors to R&D, productivity and innovation incentives was discussed. Continuing with the

DIA Annual Meeting, Chicago 2011

IT & Logistics

theme of financing drug development was a session entitled “Doing More with Less”, a recognised mantra of our times. The session reviewed the industry’s response to financial pressure and the outlook for CROs and other vendors.

The thinking and experience with adaptive designs can also be usefully applied to adaptation and decision-making at the development programme level. Some of the leaders in the field participated in a session that shared experiences with diabetes and pain management development programmes.

The India Regulatory Agency Town Hall was chaired by Larisa Nagra Singh, recently appointed to the DIA Board of Directors. Dr B R Jagashetty, Drugs Controller for the State of Karnataka, and Mr H G Koshia, Commissioner, Food and Drugs Control Administration, Government of Gujarat, represented the Indian regulatory agencies. They described initiatives and regulations designed to protect the rights and wellbeing of clinical trial participants in India, and to uphold the quality of CROs operating in the region. In the following discussion the need to balance firm regulation with industry-friendly, swift and streamlined regulatory approval processes was highlighted.

The Interoperability Showcase was a town hall session with five FDA officials in a panel discussion that examined technical solutions for using electronic health records in the conduct of regulated clinical research and safety reporting, as per DIA-CDISC-IHE-HIMSS interoperability standards. The recent FDA e-Source Draft Guidance Document was also discussed.

Poster SessionsProfessional and student poster sessions were an important

element of this year’s programme, partly because the revised format with consolidation of tracks resulted in fewer speaking presentation slots. These sessions enabled productive discussions in an intimate setting. Dr Nermeen Varawalla, Founder & CEO, ECCRO, presented a poster on “Protection of Clinical Trial Subjects in India”. She emphasised the imperative to ensure ethical integrity of the clinical trial data from India. Ensuring informed consent, having a robust framework of institutional ethics committees and a progressive, stable regulatory environment are essential. Further sponsors are seeking to make provisions for post-trial access programmes in India. Other emerging countries were also represented in the poster sessions; these included China, Saudi Arabia, Latin America and Eastern Europe.

Continuing the DialogueThe 47th DIA Annual Meeting was successful in providing stimulating content and an occasion for networking. The theme of the next Annual DIA Meeting will be “Collaborate to Innovate” and will be held in Philadelphia from 24th–28th June, 2012.

But before that there will be the 5th Annual DIA Clinical Forum to be held in Basel in October between 10 and 12th October. The highlights of this event will include a debate entitled “This house believes that clinical research has lost customer confidence”, and a plenary session on the impact of social media on the pharmaceutical sector. Readers are encouraged to attend this meeting, and if unable to do so, they should look out for coverage of this and other key industry meetings in forthcoming issues of Journal for Clinical Studies. By Dr Nermeen Varawalla – Founder and CEO of ECCRO.


Exhibition & Conferences

CPhI Worldwide, ICSE, InnoPack and P-MEC Europe Offer a Dynamic Line-up in Frankfurt for 2011UBM Live is gearing up for what promises to be the largest year ever of their flagship pharmaceutical ingredients event, CPhI Worldwide 2011, being held on 25-27 October 2011 at the Messe Frankfurt, Germany. Alongside co-located events, ICSE for contract and outsourced services, P-MEC Europe for pharmaceutical machinery and equipment, and the newly introduced InnoPack for pharmaceutical packaging solutions, UBM Live is projecting a large increase in attendance over the 2010 events held in Paris. Last year saw more than 28,500 attendees from over 140 countries visit the combined events, with over 1900 exhibitors participating across the events.

“CPhI Worldwide and co-located events will return to Frankfurt in 2011 for good reason. The city is not only one of the most important business and financial hubs in Europe, the region is also one of the oldest and most established pharmaceutical markets in the world, serving as a home to branches of many major players in the pharmaceutical industry,” noted Annemieke Timmers, Global Brand Director, CPhI. “Frankfurt also provides easily accessible transportation and accommodation options for visitors and is a central location to travel to, both domestically and internationally. The city always receives positive feedback and is popular with attendees. We are delighted to be hosting the events here once again.”New for 2011, UBM Live is introducing the CPhI Pre-Connect Virtual Event. On 8 September 2011, this event will be easily accessible from a PC or laptop anywhere in the world. CPhI Pre-Connect is not only an opportunity for companies who will be on site in Frankfurt to get a head start with networking and lead generation prior to the show, but also allows companies that may not be able to attend the Frankfurt events the opportunity to promote their products and services to a targeted market.

As UBM Live’s events continue to evolve and grow in tandem with industry developments, the 2011 events in Frankfurt will see other new introductions and innovations. The success of the ICSE Packaging Zone in 2010 served as a platform for UBM Live to introduce InnoPack as a stand-alone event this year. InnoPack, focused on innovative packaging concepts in the pharmaceutical packaging market, is expected to host over 80 exhibitors and will be further complemented by the return of the ‘Packaging Trail’ to provide attendees with access to specific packaging needs within the other events being hosted. Also new to the events, LABWorld will make a debut as a pavilion within P-MEC to offer resources for instrumental analysis, measuring and testing technologies, materials testing, quality control and laboratory equipment for smaller scale environments. Building on the success of the zoning that was introduced in 2010, CPhI Worldwide will host two new zones - Generic APIs and Finished Dosage - for attendees with specific interests

in these areas. In addition to the General Floor, ICSE will host dedicated zones for Contract Research and Clinical Trials, New Exhibitors, the USA, and the new Logistics and Supply Chain Zone for logistics, cold transport and supply chain solutions for the pharmaceutical industry. ICSE will also feature the return of BioPh as a pavilion, in order to offer access to resources in the biopharma sector.“The focus of these events is to continue to offer focused and comprehensive resources to our visitors,” commented Haf Cennydd, Global Brand Director ICSE, P-MEC, and InnoPack. “We conduct in-depth research around our events to garner feedback from exhibitors and attendees alike. New introductions such as InnoPack and the LABWorld pavilion reflect our ongoing commitment to keeping our events in step with the industry and providing highly relevant content.”

The Frankfurt events will also provide many opportunities for targeted learning and the discovery of new technological resources for guests to review in a hands-on environment. On Monday, 24 October, an educational ‘Pre-show Conference Series’ will be hosted that will cover a range of relevant topics and provide insights into new products and technologies. A ‘Lunch-time Educational’ series will also be hosted on each day of the show with a different topic for each day, including expectations for the future, strategies for success and compliance in emerging regions. Additionally, the CPhI, ICSE and InnoPack Speakers’ Corners and the CPhI Innovations Awards will both return in 2011. The CPhI, ICSE and InnoPack Speakers’ Corners allow exhibitors to present their company and services to a captive, qualified and highly interested audience while the CPhI Innovation Awards return for the 8th year to spotlight new and industry-changing innovations from companies and organisations that are breaking new ground in the pharmaceutical, contract services, packaging and biopharmaceutical sectors.

CPhI Worldwide and co-located events ICSE, InnoPack and P-MEC Europe will be hosted in Messe Frankfurt, Germany on October 25-27, 2011. Further information about, and free registration for, CPhI Worldwide and its co-located events can be found online at www.cphi.com, www.icsexpo.com, www.innopack-pharma.com, and www.p-mec.com. Information about CPhI Pre-Connect can be found at: www.cphi.com/pre-connect

The UBM Live annual schedule of pharma events also includes South America (24-26 August, Transamerica Expo Centre, Sao Paulo, Brazil), India (30 November – 2 December, 2011, Bombay Exhibition Centre, Mumbai, India), Japan (21-23 March, 2012, Big Sight Exhibition Centre, Tokyo, Japan) and China (26-28 June, 2012, SNIEC, Shanghai, China).

global engage Advertorial

Outsourcing Clinical Trials to the Asia Pacific RegionThe 3rd China Clinical Trials Outsourcing Congress, co-located with the Asia Clinical Trials Outsourcing Congress, will be held at the Sheraton Skyline Hotel, Heathrow, London, UK on the 19th & 20th September 2011.

This event which is gaining substantial interest from Sponsors and CROs active in China or the Asia Pacific Region will take a fresh look at the latest developments and current challenges of conducting clinical trials in China and the Asia Pacific region including Korea, Japan, Singapore, Philippines, India and Vietnam.

The interactive format of the congress will use case studies, keynote presentations, panel discussions and round table discussions to help participants understand the current clinical trial landscape in the region and how others are operating and delivering successful clinical trials there. It will also examine best practice for data collection and management, supply and distribution logistics and patient recruitment in various countries through the region.

Steve Hambrook, Founder and Conference Director of organisers, Global Engage, commented “As with previous years the congress is held in London to allow access to a wide range of delegates who are active in the region already, as well as smaller western pharma and biotech companies trying to assess how best to enter the region for the first time. It also allows a more frank debate on the challenges, ethics and benefits of each country in turn”.

Speakers include experts from sponsor organisations and CROs. Confirmed speakers in the China congress include Stephen Porter, CEO of VDDI Pharmaceutical who

will tackle some of the major issues he has encountered in conducting clinical trials in China and propose some key solutions. Li Ding, AP Trial Operation Department Head at Sanofi Aventis, China who will present a case study regarding quality assurance, including her experience of complying with quality audits and inspections. Hiroshi Sheraton, Partner, McDermott, Will & Emery who will give a much needed guide to intellectual property protection in China - from the regulations around intellectual property to patenting drug product inventions.

The Asian Congress speakers include Dr Andy Brown, Director, Pharmaceutical R&D Consulting at PricewaterhouseCoopers who will explain his framework for evaluating outsourcing destinations in Asia and maximising the value from clinical outsourcing. Kon Fung, Senior Director of Biometrics and Clinical Data Systems at Johnson and Johnson who will explain his approach to building a robust infrastructure to conduct clinical trials in Asia. Joan Shen, Senior Medical Director, Clinical Research Primary Care Unit, Pfizer will look at Asian trial design, with an emphasis on accelerating development through site selection and preparation and integrating Asian strategies into global plans.

Both conferences have provisions for one-to-one meetings, a panel discussion with audience participation, smaller round table discussions and networking receptions.

For further information and to register contact Steve Hambrook, Founder and Conference Director ([email protected]) or visit www.clinical-trials-events.com


JCS News

Emerging Markets Clinical Trials help Development Teams Meet Patient Enrollment Challenges Countries outside the BRIC markets are challenging traditional development areas for a share of pharmaceutical companies’ R&D investment, according to a Cutting Edge Information’s research on clinical trials in emerging markets.

According to the research, patient availability is one of the top drivers for drug companies looking at Emerging Markets for locating and managing clinical trials. In Mexico, for example, patient retention ranked highest on a list of key clinical trial performance metrics, according to the new study. The doctor-patient relationship is so strong there that once patients enroll in a drug study, trial operators can expect virtually all volunteers to finish.

“Emerging Markets Clinical Development Series: Brazil, Russia, India and China” provides in-depth analysis of BRIC clinical trials’ benefits, advantages and challenges. The study is part of a series of studies from Cutting Edge Information about managing clinical trials in emerging markets. The studies include strategies and tactics for successful data quality delivery, site management and technology infrastructure based on quantitative measures of clinical development operations and qualitative data from industry experts. Source: Jaypreet Dhillon, JCS Staff Reporter

Over 50% growth to 2015 seen in global clinical trials market Offshoring to emerging markets and demand for late-stage development services will help to fuel cumulative growth of more than 50% in the worldwide market for clinical trials over the next five years, a new report predicts.

Contract research organisations serving the pharmaceutical industry generated revenues of US$21.69 billion worldwide in 2010, says the visiongain report, Pharma Clinical Trial Services: World Market 2011-2021. Global revenues are expected to reach US$32.73 billion in 2015 and to exceed US$65 billion in 2021, with the top ten CROs then accounting for more than half of the overall market.

Over the next decade, full-service CROs will further benefit from multi-billion dollar strategic alliances with Big Pharma companies as outsourcing of drug development continues to provide access to strong therapeutic experience and significant cost savings, says visiongain pharmaceutical industry analyst Richard Lang.

At the same time, Lang adds, niche market players will be able to take advantage of increased demand for specialised clinical trial services, particularly in the fields of cancer and central nervous system disordersSource: Jaypreet Dhillon, JCS Staff Reporter

Roslin Cells bags stem cell evaluation agreement with Pfizer Scotland’s Roslin Cells, a leading supplier of clinical-grade pluripotent stem cells (PSCs), has raised its profile several notches with an agreement that gives Pfizer’s UK subsidiary access to Roslin’s PSC lines to assess their potential for “specific clinical therapies”.

The agreement with Pfizer Limited marks the first time Roslin Cell’s Good Manufacturing Practice (GMP)-level cell lines have been evaluated by one of the major pharmaceutical companies, it noted. No further details of the agreement or commercial terms were disclosed.

“We have made a substantial investment in establishing the capability to derive new stem cell lines to the standards required for their use as the starting material for a clinical therapy,” noted Aidan Courtney, chief executive officer of the company set up in 2006 by Edinburgh’s Roslin Institute with support from the University of Edinburgh, the Scottish National Blood Transfusion Service and Scottish Enterprise.

These cells “are already being used in our own collaborative research programmes and I am delighted that they will now be evaluated for potential use by Pfizer”, Courtney added. Source: Jaypreet Dhillon, JCS Staff Reporter

EMA seeks input on genomic markers in drug development The European Medicines Agency (EMA) has put out for consultation a reflection paper on the use of pharmacogenomic biomarkers as patient selection and treatment stratification tools in drug development.

A draft of the reflection paper was agreed by the Pharmacogenomics Working Party of the EMA’s Committee for Medicinal Products for Human Use (CPMP) in March and adopted by the CHMP for release on 9 June. The deadline for comments is 25 November 2011.

The reflection paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection discusses the role these markers can play in predicting which patients are likely to benefit from a particular medicine or which may be susceptible to side-effects. Source: Jaypreet Dhillon, JCS Staff Reporter

INC sets out its stall as Kendle acquisition closes With the acquisition of fellow contract research organisation (CRO) Kendle International under its belt, INC Research is setting out its stall as a top-tier player with some 5,000 employees spanning six continents and experience in more than 100 countries.

“Biopharmaceutical companies of all sizes are relying on outsourcing partners earlier in the clinical trials process,” said James Ogle, who was chief executive officer (CEO)


of the ‘old’ INC Research and retains that position in the combined company.

“This transaction has enhanced our value proposition to global drug developers and given us a broader range of local operations with global oversight, allowing us to maintain high standards and quality results,” Ogle added. INC claims 43 of the world’s top 50 pharmaceutical companies among its client base.Source: Jaypreet Dhillon, JCS Staff Reporter

Why QE2 Matters If you’re Watching Emerging MarketsU.S. investors have been so preoccupied with recent action by the U.S. central bank that we have neglected to recognize the impact such actions could have on the global economy.

Now that the Fed has rolled out its second round of quantitative easing, or QE2, the economic scale has officially tipped in favor of the emerging markets. There are a few ways to play that theme.

Many don’t realize that developing economies are clearly in a strong bull market. Of course, in the past couple of weeks there has been a sharp downturn in global markets, especially those under our microscope. India, which has been among the strongest markets, has shown more dramatic pullbacks. No one knows how far this fall can go, but it could sharply reverse before the end of this calendar year.

The only good story professional money managers can talk about to their clients is the same positive story driven by the long-term factors of demographics and trends in spending. That’s the emerging market story. Thus, fund managers and financial advisors of all types will try to window dress for year-end statements by piling on emerging market positions. Source: Jaypreet Dhillon, JCS Staff Reporter

Kv7.4 channel suggests new avenue for hypertension treatments Research funded by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC) and the British Heart Foundation (BHF) has suggested a new avenue for future drug treatments aimed at controlling high blood pressure.

The research published in the latest edition of the journal Circulation suggests that the potassium channel Kv7.4 could play a key role in regulating the constriction or dilation of blood vessels in animal models and, by implication, in maintaining healthy blood pressure, the BBSRC said.

A team led by Dr Iain Greenwood from St George’s, University of London studied rodents with high blood pressure and discovered that in some cases the Kv7.4 channels in the walls of the animals’ blood vessels were not functioning properly.

The channels allow the release of potassium from the muscle cells in blood vessels, and they have to be opened

and closed at the right times for the muscles to contract or relax as needed, the BBSRC explained. If the Kv7.4 channels cannot function, “the muscle cells overreact to the signals the body is giving to increase blood pressure”, Dr Greenwood added. “We think that in the animals we studied the redundant Kv7.4 channels contributed markedly to their high blood pressure.”

Whilst it is “extremely unlikely” that most people with high blood pressure have defective Kv7.4 channels, the researchers hope that understanding the role played by these channels in maintaining healthy blood pressure will help to develop new strategies for adjusting blood pressure using drug treatments, the BBSRC noted.Source: Jaypreet Dhillon, JCS Staff Reporter

New Merck and Vertex drugs raise standard of care in hepatitis CTwo new therapies to fight hepatitis C virus infections were approved by the US Food and Drug Administration in May.

The recent, near-simultaneous US Food and Drug Administration approvals of the viral protease inhibitors Victrelis (boceprevir) and Incivek (telaprevir) developed, respectively, by Merck and Vertex Pharmaceuticals, for treating hepatitis C virus (HCV) infection, represent genuine progress in an area poorly served by existing therapy. But these new therapies, approved in May, are not likely to remain in pole position for very long. Numerous other molecules in development based on various other mechanisms offer more tolerable alternatives. For those that make it to market, it will take some time to work out how best to deploy them in combinations tailored to different patient categories. Source: Jaypreet Dhillon, JCS Staff Reporter

gates Foundation to fund clinical trials at Pune’s Serum InstituteThe Bill and Melinda Gates Foundation will fund two Indian firms, including Pune-based Serum Institute of India, to develop vaccines for pneumonia and diarrhoea. “We are conducting clinical trials of a new rotavirus vaccine to prevent diarrhoea in children,” Adar Poonawalla, Executive Director, Operations, Serum Institute of India told Newsline.

The foundation will share the development and clinical trial cost and aims at encouraging low cost manufacturers to save lives, says Poonawalla. The Serum Institute plans to sell its products for half the price of existing vaccines from Merck and GlaxoSmithKline. In a recent visit to the country, Gates had urged India to intensify programmes to vaccinate children in the country, particularly against polio and tuberculosis. Source: Jaypreet Dhillon, JCS Staff Reporter

JCS News

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Ever wondered why we choose flowers as the front cover of JCS? Each of the flowers we feature on the cover represents the national flower of one of the emerging countries we highlight in that particular issue. In this issue we have featured a report on Tunisia. Jasmin is the National Flower of Tunisia, which features on the front cover.

I hope the journal guides you progressively through the maze of activities and changes taking place in the emerging countries. JCS has also launched a weekly newsletter. Please visit www.jforcs.com and sign up to receive the very informative weekly newsletter by email.

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