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JOURNAL FOR

Volume 3 - Issue 1

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets PEER REVIEWED

Clinical Trials in Children Challenge Central Laboratories Phase I Adding Value in Drug Development?

FDA’s New Guidance on Biomarkers and Patient Reported Outcome Qualification (CNS Watch, Page 12)

Africa Subsection (Page 50)

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Contents JOURNAL FOR

U CLINICAL STUDIES

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Watch Pages

Your Resource for Multisite Studies & Emerging Markets

MANAGING DIRECTOR Martin Wright

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Revised Safety Reporting Regulations for Drugs and Biologics and Bioavailability and Bioequivalence Studies Effective March 2011, a final rule issued by the FDA revises the safety reporting requirements for investigational new drug applications (INDs) for human drug and biological products, as well as for bioavailability and bioequivalence studies in humans. The rule amends 21 Code of Federal Regulations (CFR) parts 312 and 320, and its anticipated outcomes include better protecting human participants in clinical trials and promoting a consistent approach to safety reporting internationally. By: Deborah A. Komlos of Thomson Reuters.

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Clinical Research in China: Opportunities and Challenges China has become one of the countries that international pharmaceutical enterprises are most focused on. The rapid growth of clinical requirements brings new opportunities to the Chinese clinical research industry. By: Jacky Cheng of Scott Partnership – China.

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Cardiovascular Safety Watch column This Cardiovascular Safety Watch column provides an introduction to the Cardiac Safety Research Consortium (CSRC), and a review of its 2010 Annual Meeting and accompanying Pediatric Drug and Devices Cardiovascular Safety Think Tank, held last month at the FDA Headquarters in Maryland. By: Dr Rick Turner, Cardiovascular Safety, Quintiles, and Affiliate Clinical Associate Professor, University of Florida College of Pharmacy.

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FDA’s New Guidance on Biomarkers and Patient Reported Outcome Qualification In autumn of 2010 the FDA issued draft guidance related to the Qualification Process for Drug Development Tools (DDTs). This guidance emphasises two DDTs that have special relevance to developing CNS drugs, namely biomarkers and patient reported outcome (PRO) measures. By: Henry J. Riordan of Worldwide Clinical Trials.

PUBLISHER Mark A. Barker MANAGING EDITOR Jake Tong EDITORIAL COORDINATOR Janet Douglas EDITORIAL ASSISTANTS Nick Love, Kevin Cross, Lanny McEnzie DESIGN DIRECTOR Ricky Elizabeth RESEARCH & CIRCULATION MANAGER Dorothy Brooks BUSINESS DEVELOPMENT Delano Johnson ADMINISTRATOR Barbara Lasco FRONT COVER © iStockphoto PUBLISHED BY Pharma Publications Building K, Unit 104 Tower Bridge Business Complex, 100 Clements Road, London, SE16 4DG, UK Tel: +44 0207 2375685 Fax: +44 0207 3947415 Email: info@pharmapubs.com www.jforcs.com The Journal for Clinical Studies – ISSN 1758-5678 is published by-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

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Editorial Advisor Keynote

Regulatory 14

Steps towards Effective Pharmaceutical Product Safety Risk Management Systems European medicines Agency (EMA) describes a risk management system as a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products. Dr Joy Chukwujindu of Crown Drug Safety and Crown Consultants (Lon) Ltd explains that when planning risk assessment and risk minimisation activities, sponsors should consider input from healthcare participants likely to be affected by these activities.

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Clinical Trials in Children Challenge Central Laboratories Regulatory authorities and pharmaceutical manufacturers have found agreement in the need to run paediatrics studies to reduce the “off-label” use of drugs in children. Paediatric clinical trials are demanding as they represent significant challenges. Journal for Clinical Studies 1


Contents Dr Katja Neuer-Etscheidt & Dr Hermann Schulz of INTERLAB Central Laboratories GmbH show how involving experienced professionals in the investigational sites and in the laboratory sector, e.g. by selecting a central laboratory, may contribute to a successful completion of each paediatric study. Market Review 20

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Delivering Top Performance across Cultures Clinical research is conducted on a global scale. Many studies are not just international but intercontinental. Pharmaceutical and biotech companies, as well as CROs, need to be able to operate worldwide and yet have local knowledge and expertise. Martin Robinson, Director of Dovetail Clinical, identifies key factors that can be implemented to create a committed and motivated workforce that is striving for both individual and collective performance excellence. Clinical Trials in Russia – Report on the 3rd Quarter of 2010 The new law “On circulation of medicines” became effective on 1st September 2010. According to this law, the right to issue licenses for performing clinical research was transferred from RosZdravNadzor, RZN to the Ministry of Healthcare and Social Development. Igor Stefanov of Synergy Research Group brings us a detailed analysis of how the Russian market has performed in the stated quarter. Therapeutic

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Chemotherapy Combination Products Natalia Safronova of SRC Pharma studies the efficacy and toxicity of bevacizumab in combination with two chemotherapy programmes in patients with metastatic colorectal cancers. The outpatient use of bevacizumab in combination with different chemotherapy regimens in patients with metastatic colorectal cancer is followed by the low risk of complications, and increases the time to progression, which gives hope for improved longterm results of treatment of this patient group. Phase I: Adding Value in Drug Development? For many working in the industry, Phase I studies are viewed as a stage in the drug development cycle that must be done, and is not necessarily considered to “add value” to a drug’s portfolio. Dr Brian Sanderson of Chiltern Early Phase Ltd discusses the notion that although these new studies like proof of concept (POC) and microdosing have their place, the more traditional Phase I studies have evolved over the years, with new thinking being applied which, together with the wealth of expertise available, will add value. IT & Logistics

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ABPM in Clinical Trials – Logistics (Part 2) ABPM is a mature and simple procedure that does not require highly sophisticated equipment or specialist staff to perform. This article by Neil Atkins of dabl Ltd discusses the issues involved in conducting trials using ABPM, and demonstrates why a centralised ABPM system is necessary.

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40 Efficient and Cost-Effective Monitoring for Observational Studies The growing importance of evaluating products in the real world has led to an increase in the conduct of registries and other types of observational studies. Changing patterns have focused attention on the need to carefully evaluate the methods employed for monitoring observational studies. Dr Ronald E. Weishaar of PharmaNet’s Phase IV Development Group discusses methods to yield reliable results that will satisfy all stakeholders involved. 46 Leveraging Clinical Logistics to Improve Trial Efficiency This detailed article from Jens Mattuschka of Parexel International concentrates on leveraging clinical logistics to improve trial efficiency, and how taking a coordinated approach to clinical logistics services ensures that supplies reach the right locations, in the right conditions, at the right time, thereby reducing costs and avoiding trial delays in today’s competitive biopharmaceutical environment. Africa Subsection 50 Clinical Trials South Africa 2010 – Regulatory Perspective The South African clinical trial regulatory landscape in 2010 can best be described as one of change and collaborative efforts. Revisions were proposed to the current legislation, and to facilitate the formation of the South African Health Products Regulatory Authority (SAHPRA). By: Savi Chetty-Tulsee of SACRA (South African Clinical Research Association). 52 The Transformation of the Nigerian Clinical Trial Sector Professor Ifeoma J. Okoye, Chair of AGCPN - The Association for Good Clinical Practice in Nigeria - writes on the transformation of the Nigerian clinical trial sector. Professor Okoye, summarises the many positive milestones achieved. 56 Destination: South Africa South Africa has always delivered substantial contributions to medical innovation. Mr Van Wyk of ACRO (African Clinical Research Organisation) highlights how South Africa and its clinical trials industry remain focused on maintaining exceptional standards, innovation and patient care, not only in the southernmost part of Africa, but also around the globe. 60 Cradle to Grave or Cradle to Cradle…Banking for the Continuity of Life The number of clinical trial registrations in South Africa alone rose from a median of 39 in 2002-04 to 187 in 200509. BioAnalytical Research Corporation (BARC) South Africa responded with a world-class offering, structured for the challenges of doing clinical research in Africa with a commitment to change the face of Africa as the disease basketcase of the world. Dr Jessica Trusler and her team from BARC South Africa tell us about their clinical laboratory and how its biobanking facility is geared to store samples today to change Africa’s disease burden, and create new possibilities for disease control tomorrow.

January 2011


Keynote Only twenty one new drugs were approved by the U.S. Food and Drug Administration in 2010, the fewest since 2007, a reflection of the FDA’s willingness to delay or reject medicines with potential safety risks or uncertain benefits as compared to available treatments. This compares with 25 approvals last year, 24 in 2008 and only 19 new drugs in 2007, the fewest in 24 years. Further in 2010 the FDA restricted the use of GlaxoSmithKline Plc’s diabetes medication Avandia and withdrew Abbott Laboratories weight-loss drug Meridia. These events highlight the increased industry wide caution with respect to drug safety. In addition pharmaceutical and biotechnology sponsors are under pressure to demonstrate that their new product delivers additional value and benefits as compared to existing treatments. Demonstrating equally or marginally improved efficacy does not appear to be good enough anymore. The financial constraints remain, albeit to a lesser extent than in previous years. Given this back drop, 2011 promises to be a challenging year for us engaged in developing safer, more efficacious and innovative medicines. The first 2011 issue of Journal for Clinical Studies covers a wide and relevant range of topics. Addressing pharmacovigilance and drug safety; we are informed of the revised FDA Safety Reporting Regulations for investigational new drug applications and the deliberations of the Cardiac Safety Research Consortium (CSRC). Dr Joy Chukwujindu of Crown Drug Safety and Crown Consultants advises that when developing risk assessment and minimization plans, sponsors should consider input from affected healthcare delivery partners.

Providing updates on the continually evolving global clinical trial landscape, the issue features articles on the clinical research opportunities in China and a report on FDA’s New Guidance on Biomarkers and Patient Reported Outcome Qualification for neurological drugs, Also there is a report the new law in Russia “On circulation of medicines” which became effective on 1st September 2010, transferring the right to issue licenses for performing clinical research from The Federal Service on Surveillance in Healthcare and Social Development of the Russian Federation (alias RosZdravNadzor, RZN) to the Ministry of Healthcare and Social Development. Africa is highlighted; with articles on the evolving South African clinical trial regulatory landscape and Professor Ifeoma J. Okoye, Chair of The Association for Good Clinical Practice in Nigeria is optimistic about Africa wide collaboration, harmonised clinical trial regulations across Africa and an evolving Nigerian clinical trial sector. Sharing best industry practices there are articles on Phase I studies and where it can add value in Drug Development, Efficient and Cost-Effective Monitoring for Observational Studies, and central laboratory expertise for paediatric clinical trials, latest thinking in Phase I research and coordinated clinical supplies logistics. I know you will find this rich selection of articles to be thought provoking and I hope this issue and the other 2011 issues will keep you abreast of developments in the sector and help you innovate and develop new practices which in due course you too will share with our readership. Happy reading and all best wishes for a productive 2011! Dr Nermeen Varawalla, MD, DPhil(Oxon), MBA CEO and Founder, ECCRO

Publishers Note: In the November 2010 Issue the article titled “Central or Local IECs: Current Situation in Argentina”, was credited to Oscar Podesta as the author. Infact it was authored by Mr. Ezequiel Klimovsky who is currently the Associate Director of QUID Consulting and Secretary of FECICLA (Ethics and Quality in Clinical Research in LATAM Foundation). We apologise for this oversight. If you wish to respond to the previous article please email directly to Mr. Klimovsky at - (eklimovsky@quid-consulting.com). In the forthcoming Issue, we will be featuring an article by Mr. Klimovsky on a “New Regulation for Pharmacological Clinical Trials which has been established in Argentina”. I hope you find these articles informative, and look out for more pertinent topics in our journal.

Editorial Advisory Board

Georg Mathis Founder and Managing Director, Appletree AG

Nermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Patricia Lobo, Managing Director, Life Sciences Business Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Janet Jones, Senior Director, ICON Clinical Research

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

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

Jerry Boxall, Managing Director, ACM Global Central Laboratory

Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

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

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma. Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Charles Horth – Senior Life Sciences Consultant 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

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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 ACRP

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

January 2011


Watch pages

Revised Safety Reporting Regulations for Drugs and Biologics and Bioavailability and Bioequivalence Studies Effective this March, a final rule issued by the FDA revises the safety reporting requirements for investigational new drug application (IND) human drug and biological products, as well as for bioavailability and bioequivalence studies in humans.1 The rule amends 21 Code of Federal Regulations (CFR) parts 3122 and 3203, and its anticipated outcomes include better protecting human participants in clinical trials and promoting a consistent approach to safety reporting internationally. The final rule reflects amendments that the FDA made in response to comments received on the proposed rule4, which was published in March 2003, along with other revisions, including editorial changes to clarify provisions and support the agency’s plain language initiative. The 2003 proposal also addressed changes to post-marketing safety reporting regulations found in 21 CFR parts 310, 314, 600, 601, and 606. The FDA is working on modifications to those regulations and will address these sections in a future rule. The majority of the final rule revisions relate to part 312.32 (IND safety reports). In part 312.32(a), the FDA has amended and clarified terms and definitions. For instance, the two terms ‘‘adverse event’’ and ‘‘suspected adverse reaction’’ have replaced the proposed definition of ‘‘suspected adverse drug reaction (SADR).” The agency explains that the definitions included for the two terms should contribute to harmonisation of safety reporting to regulatory authorities worldwide, because they are consistent with the concepts and definitions adopted by the ICH–E2A guidance5 and the Council for International Organizations of Medical Sciences (CIOMS). Another change to section 312.32(a) is clarification of what adverse events (AEs) or suspected adverse reactions are considered unexpected. In particular, it is made clear that “unexpected” AEs or suspected adverse reactions include those that may be predicted from the pharmacological properties of the drug, or that occur with members of the drug class, but that have not previously been observed with the drug under investigation. For part 312.32(b), the final rule clarifies the types of safety information that must be reviewed by the sponsor. The FDA notes that it expects sponsors to review all information, but to avoid duplicate reporting to the agency. Various revisions were made to part 312.32(c), which clarifies how and when to submit IND safety reports to the FDA and participating investigators. In part 312.32(d) on follow-up reporting requirements, minor editorial changes were made and a provision that is covered elsewhere in part 312.32 was deleted. Pertaining to part 312.64(b), the final rule clarifies requirements for investigators to submit reports of serious AEs (SAEs) to the sponsor, and also clarifies the requirement 6 Journal for Clinical Studies

for reporting study endpoints that are SAEs. It is specified that investigators must immediately report to the sponsor any SAE and include an assessment of whether there is a reasonable possibility that the drug caused the event. The final rule’s last amendments are to part 320.31(d), which now mandates that all SAEs from bioavailability and bioequivalence studies must be reported. The FDA explains that, in general, the occurrence of an SAE is very unusual in a bioavailability or bioequivalence study because the number of subjects enrolled in the study is small, the subjects are usually healthy volunteers, and drug exposure is typically brief. Thus, the occurrence of any SAE is of interest. The FDA also modified 320.31(d) to make it consistent with requirements for submission of IND safety reports and reports of any fatal or life-threatening AE. In addition to improving the protection of human study subjects and encouraging consistency in safety reporting, the FDA expects the final rule to enhance the utility of IND safety reports and to reduce the number of reports that do not contribute in a meaningful way to the developing safety profile of a drug. The FDA also anticipates the final rule to expedite the agency’s review of critical safety information. References 1. Federal Register: September 29, 2010. Volume 75, Number 188, 59935-59963. 2. 21 Code of Federal Regulations, part 312. Available at: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch. cfm?CFRPart=312 3. 21 Code of Federal Regulations, part 320. Available at: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch. cfm?CFRPart=320 4. Federal Register: March 14, 2003. Volume 68, Number 50, 12406-12497. 5. ICH–E2A Guideline for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, March 1995. Available at: http://www.fda.gov/downloads/ D r u g s / G u i da n c e Co m p l i a n c e Re g u l a t o r y I n fo r m a t i o n / Guidances/ucm073087.pdf

Deborah A. Komlos, Deborah A. Komlos, MS, is the Senior Medical & Regulatory Writer for the IDRAC United States (US) Module at Thomson Reuters. Her previous roles have included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work. Email: deborah.komlos@thomsonreuters.com January 2011


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Clinical Research in China: Opportunities and Challenges With a large population, high-tech talent pool and research ability, along with lower costs, China has become one of the countries that international pharmaceutical enterprises are most focused on. In recent years, more and more pharmaceutical giants have set up R&D centres in China, including Lilly, Roche, Pfizer and GSK. A report from IMS predicted that with its $8 trillion GDP, China’s pharmaceutical market would leap to No.3 in the world pharmaceutical market in 2011 compared with No.8 in 2006. The rapid growth of clinical requirements brings new opportunities to the Chinese clinical research industry. In order to meet the huge requirements of the Chinese pharmaceutical market, pharmaceutical companies must develop more drugs which are suitable for the Chinese disease spectrum, such as hepatitis, diabetes, gastric cancers, esophagus cancers, etc. As a result, clinical research localisation is an important stage in drug development.. There are mainly three types of clinical research organizations in China: full foreign owned Contract Research Organizations (CROs), for example, Quintiles, Covance and Parexel; local CROs, focusing on clinical research, such as Tigermed Consulting Co., Ltd; and Chinese foreign joint venture CROs, for example Excel PharmaStudies, Inc, which is a part of PPD. Local clinical research organisations have the advantage of being familiar with Chinese Good Clinical Practice (GCP) and related pharmaceutical laws and regulations, as well as local resources and cost advantages. In addition, more and more of their clinical researchers have overseas backgrounds or working experience. However, the international clinical research organisations can provide higher quality services to customers with years of clinical research experience and well-established service systems. Even though a large number of local CROs have been established in China in recent years, specialised clinical research suppliers are still lacking due to the need for quality control systems to be improved, with clinical results from some local CROs not reaching the international standards. This raises concerns with pharmaceutical companies about the authenticity and reliability of the clinical data. In addition, the approval process for clinical research for new drugs in China is more complicated, strict and lengthy than many other countries such as the US or Europe. The approval of applications in the US usually takes 30 days. In China, this period can take six months 8 Journal for Clinical Studies

or even over a year. As a result, lots of local CROs are good at preclinical research such as chemosynthesis, but currently need to improve their clinical research abilities. In China, the rate of clinical research in the whole CRO market is less than 15%, while in the US the rate is approximately 40%. On the other hand, this figure shows that the Chinese clinical research market has great potential. As a new industry in China, the development of clinical research is highly linked to the policies and regulations of the Chinese government and drug administration. With the rapid growth of the Chinese pharmaceutical industry, the Chinese government and drug administration are paying increased attention to this area and have started to amend the administration system to support its development. One example is that previously, a new drug application in China could only be approved after first being approved by international administration. This meant that it would take around four years before the drug could be used on the Chinese market. The new rule allows new drug and clinical research applications to be initiated in China at the same time as global applications, which shortens the approval period to two years. Other measures include trying to increase the efficiency of clinical research approval, improving clinical quality control systems and amending clinical research regulations to meet international standards. In addition, the Contract Research Organisation Union (CROU), the association of the Chinese CRO industry, has started to draft several standards for Chinese clinical researchers. These include standards such as the China Clinical Research Organisation Service Standard, the Clinical Research Organisation Practice, and the Quality Control Standard and Procedure of CROs. New developments in the global pharmaceutical industry bring significant opportunities to the Chinese clinical research industry. However, in order to continue and ensure this growth, the Chinese clinical research industry also faces many challenges, including raising the efficiency and quality of new drug applications, improving quality control systems and standardising service procedures. As a clinical research base with great potential, China is getting more and more attention from the pharmaceutical industry and is predicted to contribute more to the global pharmaceutical industry in the coming years. Jacky Cheng, Managing Director – Scott Partnership - China Jacky leads the Asia Pacific business for The Scott Partnership (www.scottpr.com), a global business communications consultancy. Based in Pudong, Shanghai, Jacky leads a team which specializes in servicing the B2B sector in China. Jacky is a chemistry graduate, and a former journalist with Ringier Publications. Prior to joining The Scott Partnership, Jacky founded EMG China, which he grew from inception to a 20-strong team. Email: jacky.cheng@scottpr.cn January 2011


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Cardiovascular Safety Watch column The Cardiovascular Safety Watch columns published in 2010 each focused on a particular topic within the field of cardiovascular safety, hence providing insight into specific issues. This column is more comprehensive in nature, providing an introduction to the Cardiac Safety Research Consortium (CSRC) and a review of its 2010 Annual Meeting and accompanying Pediatric Drug and Devices Cardiovascular Safety Think Tank, held last month at the FDA Headquarters (Silver Spring, Maryland). The CSRC was formed in 2006 through an FDA Critical Path Initiative “Memorandum of Understanding” with Duke University. As noted on its website1, its mission statement is: To advance scientific knowledge on cardiac safety for new and existing medical products by building a collaborative environment based upon the principles of the FDA’s Critical Path Initiative as well as other public health priorities. The Consortium advances the science of cardiac safety by bringing together interested parties from industry, academia, and government in a neutral, precompetitive paradigm to share data and expertise, and to support research into medical product cardiac and cardiovascular safety: all of the issues discussed in previous columns fall within its remit. The Consortium’s neutrality and precompetitive stance allows individuals from regulatory agencies to participate in its meetings and activities to a greater extent than is possible at many other conferences. Key objectives for the CSRC include: • Facilitation of focused, pragmatic research to inform regulatory processes with regard to cardiac safety. • Development of knowledge and strategies intended to improve the evaluative sciences in relation to cardiac safety and product development. • Development of expert consensus around common nomenclature, standards, and key definitions, and the publication of White Papers in challenging areas. These papers describe what is known and unknown, and propose paths forward to address such knowledge gaps. • Coordination of Think Tanks and other programmes and public forums for open discussion and updates on topics in cardiovascular safety pertaining to drug and device development. The Annual Meeting contained several themed presentation sessions, and also plenty of time for questions and debate amongst the presenters and members of the audience2. The opening Plenary Session was entitled “Cardiac Safety in Medical Product Development: Critical Path Collaborations, Public Private Partnerships & Comparative Effectiveness--Where Are We and Where Do We Need to Go?” Moderated by the Co-chairs of the Consortium’s Executive Committee, the speakers included the Deputy Director and the Deputy Director of Science of the FDA’s Center for Drug Evaluation and Research and its Center for Devices and Radiological Health (CDRH), respectively; the President of the American College of Cardiology; and the Worldwide Executive Director of the Drug Information 10 Journal for Clinical Studies

Journal. This array of influential stakeholders bears witness to the importance of the Consortium’s activities. In addition to representatives from the FDA being present, regulators from Health Canada were attending via teleconference. Following a day of excellent presentations, the meeting concluded with a session entitled “CSRC Future Directions: Open Discussion on Procedures, Priorities, Topical Areas of Focus, and Strategic Relationships.” Following welcoming comments, the next day’s Think Tank started with a Plenary Session entitled “Pediatric Cardiovascular Safety in New Drug and Device Development”3. Two of the speakers again were representatives from the FDA, the Director of the Office of Pediatric Therapeutics and CDRH’s Chief Pediatric Medical Officer. Paediatric clinical research and pharmacotherapy is a topic that is currently attracting a lot of attention from many stakeholders. A recent paper in this journal provided an overview, including a summary of regulatory activities in the United States and Europe4. As the authors noted, “The world of paediatric clinical research is evolving quickly. The need for pharmaceutical agents tested in, and labelled for, pae¬diatric populations continues. International harmonisation of regulations and principles of paediatric research would go far to simplify the complicated process currently required. The issues of growth, development, and surmounting ethical challenges will continue to require trained and dedicated individuals to de¬sign, conduct, and complete trials in this patient population.” Following a day of excellent presentations, the Think Tank concluded with an Open Panel Roundtable entitled “Priorities & Next Steps.” The Consortium publishes a series of White Papers in the American Heart Journal, and a paper on paediatric medical product cardiovascular safety will follow in due course. Readers are encouraged to navigate the CSRC’s website to get a more detailed view of its many activities. References 1. www.cardiac-safety.org (accessed 3rd January 2011) 2. w ww.cardiac-safety.org/think-tanks/december-2010/ csrc-annual-meeting-2010 (accessed 3rd January 2011) 3. www.cardiac-safety.org/think-tanks/december-2010/pediatriccv-safety-think-tank-meeting (accessed 3rd January 2011) 4. Jackson C, Turner JR, 2010, Paediatric Pharmaceutical Medicine: Paediatric Clinical Research and Considerations for Clinical Trials. Journal for Clinical Studies, November issue, 28-31. 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 noncardiac drugs. He has published over 50 peer-reviewed papers and 10 books. Email: Rick.Turner@quintiles.com January 2011


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FDA’s New Guidance on Biomarkers and Patient Reported Outcome Qualification Last fall the FDA issued draft guidance related to the Qualification Process for Drug Development Tools (DDTs). Although intended for use across a wide array of therapeutic areas, this guidance emphasises two DDTs that have special relevance to developing CNS drugs, namely biomarkers and patient reported outcome (PRO) measures. This brief review will summarise this guidance, outline the mechanism for ensuring DDT qualification, and suggest areas for further elucidation. The Qualification Process for Drug Development Tools Draft Guidance (which can be found at http://www.fda.gov/downloads/ D r u g s / G u i d a n c e Co m p l i a n c e Re g u l a t o r y I n fo r m a t i o n / Guidances/UCM230597.pdf) stems from the Critical Path Initiative (CPI) which was designed to stimulate and facilitate efforts to modernise the process through which potential drugs, biological products, and medical devices are transformed from discovery into prescribed treatments. The CPI identifies and prioritises the most pressing clinical development problems, and defines the ones that may provide the greatest opportunity for rapid improvement and public health benefit. This is accomplished by directing research not only towards novel medical breakthroughs and discoveries, but also toward the creation of novel DDTs. More information on the CPI can be found at http://www.fda.gov/oc/initiatives/criticalpath/. The intended goal of qualification is to permit the use of DDTs across multiple drug development programmes by multiple customers, theoretically speeding up the development of safer and more effective drugs for better-characterised patient populations. Once a DDT is qualified within a specific context of use, any members of the pharmaceutical industry can readily use the DDT for its qualified purpose, and Center for Drug Evaluation and Research (CDER) reviewers can be confident in applying the DDT for this qualified use without the need to reconfirm the DDT’s suitability, thus expediting successful marketing applications. Thus, qualification automatically confers some degree of generalisability of the DDT’s utility across multiple indications, multiple drugs, or even multiple drug classes. Given the burden of development and qualification of DDTs, in terms of both time and cost, the FDA recommends the formation of collaborative groups to undertake these efforts, providing an opportunity for meaningful industry-academia-government collaboration. Although not intended to be inclusive, the bulk of the efforts in developing DDTs thus far has been in the area of biomarkers and PROs. Both of these areas are of keen interest to CNS drug developers who, in addition to relying on existing PROs, have led the way in the development of novel and automated/ electronic PROs (ePROs), and have utilised various biomarkers (both predictive and pharmacodynamic) at all phases of psychiatric and neurologic drug development programmes. The FDA defines a biomarker as a characteristic that 12 Journal for Clinical Studies

is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention, and common examples in CNS research include neuroimaging, electrophysiological and CSF (cerebro spinal fluid) measures. Changes in biomarkers associated with treatment reflect the biological response to the product, and may predict or identify safety problems related to a drug, or even reveal a pharmacological activity expected to predict an eventual benefit from treatment. Importantly, if biomarkers are measured using some type of device, the review of this device and authorisation for its marketing represent an entirely separate process from DDT qualification. A PRO is defined as a means of capturing patient reported outcome data used to assess the impact of treatment as an objective of a clinical trial, which can be in the form of a rating scale composed of a subjective rating scale, or a questionnaire plus the information and documentation that support its use. PROs are widely used across a variety of psychiatric investigations, along with clinician-based measures, but are relied on almost exclusively in analgesia studies. PROs can be used as the basis for medical product approval and labelling claims if the measures are deemed to be a well-defined and reliable assessment of the study objectives, if findings are supported by appropriately designed investigations, and if the instrument measures the concept represented by the claim. Separate guidance for PRO use in medical product development can be found at www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM193282.pdf. The DDT draft guidance supplies ample information regarding the qualification process, whose goal is to reach a conclusion regarding the adequacy of the submitted data to support the DDT’s qualification and context of use. The process commences with an initial stage of regulatory consultation and advice, with a subsequent stage of review for qualification determination. The consultation stage may involve multiple information-gathering and data assessment steps. The process enters the review stage only if data are thought to be sufficiently complete and adequate to allow for substantial review. It is in this stage that CDER will perform a full review of the complete data package and render a qualification decision. If a DDT is qualified, its context of use may become modified or expanded over time as additional data are collected, or even withdrawn if the growing body of scientific evidence no longer supports the context of use. The guidance lays out a very clear process beginning with a letter of intent requesting specific context of use and a summary of studies planned to provide supporting data. This is followed by submission of a DDT briefing package. Appendices IV and V of the guidance define the contents and structure of the briefing package for biomarkers and PROs, respectively. If accepted January 2011


Watch pages this leads to the formation of a Qualification Review team (QRT) composed of CDER review staff from various relevant disciplines with expertise to review of the submission. The QRT provides advice at an initial meeting, as well as continuing advice to the submitter regarding the evidence needed for qualification. Data identified during this meeting must then be acquired through DDT investigation and development, in which the submitter acquires any additional data identified during the meeting. When the submitter believes the data are satisfactorily complete (the DDT is qualified for a specific context of use) and the CDER agrees that any identified critical knowledge gaps have been addressed and official data review is warranted, a formal qualification package is submitted. If the review and decision-making process results in a CDER decision to qualify the DDT, a Statement of Qualification summarising the CDER’s qualification determination will be issued as draft guidance and posted on the FDA website for comment. Although this qualification process is very thorough, there are several areas which require further clarification, including but not limited to: data required to qualify PROs versus biomarkers; some distinction between various characterisations of biomarkers and the qualifying authority (e.g., FDA vs. EMEA); distinction between PROs (including ePROs/automated tests) and clinical rating scales which are treated like PROs in this draft guidance; the extent and type of proof needed to support qualification; the investigation and development

standards of DDTs along with minimal qualifications for DDT development; the degree of generalisability of a qualified DDT across indications; the demand for proprietary versus collaborative DDTs; the involvement of other agencies and the public; and finally some notion of the anticipated timeframes and costs associated with this qualification process. Industry members, and especially CNS researchers who frequently utilise biomarkers and PROs in drug development programmes, and are looking forward to using these across programmes, should make every effort to review this draft guidance as it applies to their particular circumstances, and provide comments, questions and concerns to the FDA. Although comments can be made at any time, those received before January 24th will be given full consideration. 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: henry.riordan@wwctrials.com


Regulatory

Steps Towards Effective Pharmaceutical Product Safety Risk Management System The term risk management plan (RMP) is not unique to drug safety. It can be applicable to any industry or project. There are several definitions of this term in the literature. Wikipedia describes RMP as a document prepared by a project manager to foresee risks, to estimate the effectiveness, and to create response plans to mitigate them. It consists of the risk assessment matrix. A risk is an uncertain event or condition that, if it occurs, has a positive or negative effect on a project’s objectives. Risk is inherent with any project, and project managers should assess risks continually and develop plans to address them. The risk management plan contains an analysis of likely risks with both high and low impact, as well as mitigation. Risk management plans should be periodically reviewed by the project team in order to avoid having the analysis become stale and not reflective of actual potential project risks. Most critically, risk management plans include a risk strategy. Broadly, there are four potential strategies, with numerous variations. Projects may choose to: accept risk, simply taking the chance that the negative impact will be incurred; avoid risk, changing plans in order to prevent the problem from arising; mitigate risk, lessening its impact through intermediate steps; transfer risk, outsourcing risk to a capable third party that can manage the outcome. Rob Holliday, a former pilot and Head of Safety Services for Virgin Atlantic Airways, explained the fundamental importance of risk management in the airline industry at a symposium organised by the British Association of Pharmaceutical Physicians in March 2010. The whole company or organisation needs to have a sound safety culture based on safety risk management which needs to be proactive, he said. It should facilitate identification of hazards and development of risk controls prior to the occurrence of an event. If you think everything is going well, you should be thinking ‘What have I missed?’ In the guidance document on risk management systems for medicinal products for human use, the European medicines Agency (EMA) describes a risk management system as a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions. A risk management system can be presented to competent authorities in the form of a Risk Management Plan. Risk management is a continuing process throughout the lifetime of a medicinal product. However, the activities used for risk management may be changed by technical, scientific and legislative developments, as well as by the information available, the perceived risks and their estimated public health impact, and where a product is in its lifecycle. All these factors should be taken into account when formulating risk management plans in the EU. The FDA guidelines define risk management as an iterative 14 Journal for Clinical Studies

process of: assessing a product’s benefit-risk balance; developing and implementing tools to minimise its risks while preserving its benefits; evaluating tool effectiveness; and reassessing the benefit-risk balance, and making adjustments, as appropriate, to the risk minimisation tools to further improve the benefit-risk balance. This four-part process should be continuous throughout a product’s lifecycle, with the results of risk assessment informing the sponsor’s decisions regarding risk minimisation. For the majority of products, routine risk minimisation measures are sufficient to minimise risks and preserve benefits. Only a few products are likely to merit consideration for additional risk minimisation efforts. When planning risk assessment and risk minimisation activities, sponsors should consider input from healthcare participants likely to be affected by these activities (e.g., from consumers, pharmacists and pharmacies, physicians, nurses, and third party payers). Risk Management Steps The management of a single risk consists of four steps: – risk detection – risk assessment – risk minimisation – risk communication A typical individual medicinal product will have multiple risks attached to it, and individual risks will vary in terms of severity, and individual patient and public health impact. Therefore, the concept of risk management must also consider the combination of information on multiple risks with the aim of ensuring that the benefits exceed the risks by the greatest possible margin both for the individual patient and at the population level. Measures Necessary for an Effective Risk Management System • Effective risk assessment during clinical development – Adequate assessment in terms of quantity (ensuring that enough patients are studied) and quality (the appropriateness of the assessments performed, the appropriateness and breadth of the patient populations studied, and how results are analysed). – Good clinical risk assessment in the later stages of drug development should be guided by the results of comprehensive preclinical safety assessments and a rigorous, thoughtful clinical pharmacology programme (including elucidation of metabolic pathways, identification of possible drug-drug interactions, and determination of any effects from hepatic and/or renal impairment). •D  evelopment of effective risk minimisation plans to manage risks identified in clinical development – Risk minimisation activities can be divided into those where a reduction in risk is achieved primarily through the provision of January 2011


Regulatory information and education, and those which seek to control the use of the medicine. – When it is obvious that a risk minimisation activity will be needed post-authorisation, consideration should be given to piloting the activity during the development phase to see the effectiveness and suitability. • Signal detection, assessment and investigation, risk confirmation, risk communication, review and update of risk minimisation plans post-authorisation – It is impossible to identify all safety concerns during clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical products. – Therefore, postmarketing safety data collection and risk assessment based on observational data are critical for evaluating and characterising a product’s risk profile and for making informed decisions on risk minimisation. • Key staff responsible for product safety should be experienced in safety assessment in clinical trials and post-authorisation. The supporting safety team should have relevant skills and experience. This will ensure effective safety monitoring and assessment from study design, through to protocol writing, data reviews and clinical study report writing, compiling RMP

documents and product labelling. • Good company standard operating procedures on the RMP process - planning, writing, review and approval process. • Involving all the relevant functions at all stages. References – Guideline on Risk Management Systems for Medicinal Products for Human Use; EMEA/CHMP/96268/2005 – Guidance for Industry Premarketing Risk Assessment; FDA March 2005 – Guidance for Industry Development and Use of Risk Minimization Action Plans; FDA March 2005 – Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment; FDA March 2005 Joy Chukwujindu, MD, DTM&H, MPH, DipPharmMed, FFPM, MBA. Dr Joy is Managing Director of Crown Drug Safety and Crown Consultants (Lon) Ltd. She has over 20 years experience in Drug Safety. Crown Drug Safety specialises in the provision of safety processing, evaluation and reporting services in clinical trials and post-marketing. Email: joy@crown-consultants.com


Regulatory

Clinical Trials in Children Challenge Central Laboratories It is standard medical practice to treat children with drugs that have been approved for use in adults only. In the past, clinical trials did not include children, and children were not considered to be a target population when planning clinical trials. Unfortunately, we should be aware that children are not just small adults. This therapeutical approach followed thus far may cause a number of problems, such as a possible lack of efficacy due to underdosing, toxic effects due to overdosing, or just no therapeutic effect at all. To improve the health of children, both the US FDA (BPCA Best Pharmaceuticals for Children Act and PREA Paediatric Research Equity Act) and the European Parliament have implemented appropriate regulations in 2002 and 2007, respectively. The authorities’ goal was, and still is, to increase the involvement of children when developing new medications. Interestingly, the logistics involved in collecting and handling blood samples in paediatric trials significantly differs from the standards used in “adult” studies. Necessity of Paediatric Clinical Trials As children significantly differ from adults in their metabolism patterns, they consequently should not be treated with drugs simply by extrapolating dosing information developed for adults. With regard to health risks associated with over- or underdosing, off-label use of drugs in the paediatric environment should be avoided. Regulatory authorities in the USA as well as in the EU are in agreement that there is a clear need to conduct clinical trials in children to increase the knowledge about potential health risks, inappropriate drug dosage, or galenic formulations. Running studies involving children is a challenging and complex enterprise. In addition to strong ethical considerations, study compliance by both parents and children, and a childfriendly environment at the sites, there are special needs for blood sampling equipment as well as analytical methods in order to face the need to handle small blood volumes. Children are Different from Adults When talking about children we should keep in mind that “children” do not just form a homogenous population, as shown in Table 1. The various age groups significantly differ in their organ maturity and metabolic patterns, and therefore will unequally respond to drug treatment depending on the organ functions affected by the drug’s pharmacokinetic and dynamic effects. When planning study protocols and study drug production, the galenic formulation of the study medication plays a significant role. In summary, paediatric trials require a more individualised approach to study planning and performance when compared to studies in the adult population.

Regulatory Scenario – a Comparative Overview between the USA and Europe In the United States legislation regulating paediatric data 16 Journal for Clinical Studies

in drug labelling has been in place since 1997 via the Drug Modernization Act (FDAMA). It was only in January 2007 when a similar legislation (Paediatric Medicinal Product Regulation by the European Medicine Agency EMA, formerly EMEA) was introduced in the European Union. Table 2 shows a comparison of regulations for studies in paediatric patients in the USA and the European Union. In addition, in 2002 and 2003 two acts were enforced in the USA with the objective of promoting the performance of paediatric studies. The Best Pharmaceuticals for Children Act (BPCA, 2002) grants a six-month marketing exclusivity if paediatric clinical trials are registered and performed. The Paediatric Research Equity Act (PREA, 2003) legitimates the FDA to oblige pharmaceutical manufacturers to conduct paediatric studies. The new paediatric medicines regulation released by the EMA has the objective of improving the health of children in Europe by: – facilitating the development and availability of medicines for children aged 0-17 years – ensuring that medicines for use in children are of high quality, ethically researched, and appropriately authorised – improving the availability of information on the use of medicines for children without: – subjecting children to unnecessary trials, or – delaying the authorisation of medicines for use in adults A Paediatric Investigation Plan (PIP) has to be submitted by drug manufacturers to the Paediatric Committee (PDCO) of the EMA, which evaluates the PIPs and forwards an opinion to the EMA. The requirement to submit a PIP shall be waived for specific medicinal products or classes of medicinal products that: – are likely to be ineffective or unsafe in one or more paediatric age groups – are intended for conditions that occur only in the adult population (the EMA homepage lists “class waivers”, e.g. conditions that only occur in the adult population. All classes of medicinal products intended to treat these conditions will therefore be exempt from the requirement for a PIP) – do not present a significant therapeutic benefit to paediatric patients compared to existing therapies. The PDCO may grant a deferral in cases where it might be more appropriate to conduct first studies in adults prior to initiating studies in the paediatric population, or when studies in the paediatric population would take longer than studies in adults (e.g. no adequate formulation for use in children is given, or no sufficient safety data is available). Similar to the US regulation, the European paediatric regulation implemented in 2007 also grants a patent extension January 2011


Regulatory of six months in return of paediatric clinical data. The Paediatric Use Marketing Authorization (PUMA) was implemented under this law, which gives a specific market protection for medicinal products developed for exclusive use in children. Therefore the European Paediatric Regulation specified that PIPs must address all paediatric age groups, and Marketing Authorization Applications (MAA) must contain data for use of products in each of these different paediatric age groups unless waived or deferred. The FDA and EMA are committed to developing a framework to harmonise the worldwide regulations and requirements that surround clinical studies in children from a regulatory perspective, and to avoid the unnecessary duplication of studies in children. Raising Public Awareness In 2007 the EUCROF (European Federation of Contract Research Organisations) created the Paediatric Working Group (PWG), which consists of a group of seven clinical research professionals representing the Czech Republic, France, Germany, Spain and The Netherlands. One of the goals of this working group is to raise public awareness of the need to conduct paediatric studies in order to achieve safer and more effective drugs for our children, to increase the knowledge about the methodology of clinical trials in children, and to train investigators in European countries. Refraining from treating children because there are no medication data available for use in this population is not

really a protection. The PWG published two surveys, in 2009 and 2010. The first survey addressed the historical situation from 2005 to 2007 in the EU, Russia and Ukraine, and showed that the number of ongoing paediatric studies during that period was very low. The second survey evaluated the situation in 2008 to determine the main difficulties and constraints in clinical research with children experienced by the organisations involved, and to collect additional and more comprehensive information about paediatric clinical trials in Europe. Paediatric Clinical Trials: Challenges from the View of the Central Laboratory As shown in Table 1, children have to be allocated to specific age groups due to the development of their organic functions. The most challenging aspect of running clinical trials in children below two years of age is their overall reduced total blood volume. Consequently, when treating children, blood cannot be drawn in the same quantities or using the same type of tubes as used for adults. It is therefore critical to identify appropriate sampling techniques. The critical questions are a) how much blood can be collected, and b) which sampling techniques are available. Interestingly, the Code of Federal Regulations of the FDA merely states that blood withdrawal should be done with minimal risk to children (21 CFR 50.51 and 21 CFR 50.53). But what does this mean for practical purposes? How much blood


Regulatory can be withdrawn with minimal risk to children? How is minimal risk defined? Institutional review boards (IRBs) or ethical review committees (ERCs) tend to consider a single blood draw equivalent to 1 to 2% of the child’s total blood volume as minimal risk. But one blood draw is generally not sufficient when running a clinical trial. Therefore, other experts define it as safe if the cumulative blood volume collected over an eight-week period does not exceed ten percent of the child’s total blood volume. Unfortunately literature about this item is not consistent. Most publications recommend the total blood volume to be drawn in a 24-hour period to be below 3-5% of the total blood volume. This would mean approximately 10ml blood for a newborn child with an average weight of 3kg and a total blood volume of 270ml, or approximately 3ml in the case of a premature baby with less than 1kg body weight and a total blood volume of up to 90ml. Back in 2005 Michael Cole et al. published a retrospective review describing the impact of the blood volume withdrawn for research purposes on the health of paediatric subjects (8). They found that the frequently-quoted safe limits of 3-5% of total blood volume taken on any one study day are not based on published data, and may not be tolerable for all patients. Actually, the individual medical situation should be taken into account. Collection Techniques when Treating Children Table 3 lists some equipment available for collecting blood in children. The low blood volumes collected via these devices actually mean an additional challenge to those laboratories involved. There might be a need to adapt established instrumentation and methods to allow determination from diluted samples. Also, existing methods might need to undergo a validation to enable them to operate with reduced sample volumes. An alternative sampling method to the conventional blood withdrawal is Dried Blood Spot (DBS) (9). DBS offers significant practical advantages over traditional sampling methods, as the samples are easy to obtain from finger, earlobe or heel-prick. Suitable commercial sampling papers absorb the blood sample, which is distributed evenly through the paper to leave a spot of blood which is allowed to dry in situ. Using the DBS technology, a typical sample size is approximately 15µl. Thus, this method could help to overcome the challenge of collecting multiple samples to perform pharmacokinetic and pharmacodynamic evaluations, which are also required in paediatric studies. With its well-characterised advantage of low sample volume and its relatively non-invasive nature, the DBS sampling method could be ideally suited for this type of clinical trial. Challenges for the Laboratories Involved in Paediatric Trials Due to the low volume of blood received at the laboratory, there might be a need to adapt established instrumentation and methods to allow determination from diluted samples. Also, existing methods might need to undergo validation to enable them to operate with reduced sample volumes. One side of the coin is collecting low blood volumes; the other side is finding a laboratory able to handle such minimal blood volumes. This is of special interest, because most automatic analysers have a so-called “dead volume” which 18 Journal for Clinical Studies

Table1: Different age classes due to ICH Guidance E11 Paediatric Age Classes < 37th weeks of gestation Premature baby 0 to 27 days Neonate 28 days to 23 months Baby and small child 2 to 11 years Child 12 to 16-18 Teenager

Table 2: Regulations and initiatives USA versus EU 1997: FDAMA (Food and Drug Modernisation Act); required data in labelling for medicinal products 2002: BPCA (Best Pharmaceuticals for Children Act); voluntary incentive for drug manufacturers to acquire an additional six months of marketing exclusivity if they conduct studies 2003: PREA (Paediatric Research Equity Act); legal right for FDA (Food and Drug Administration) to ask for drug research in children 2006: Dec. (EC) No. 1901/2006 EMA (European Medicine Agency) release of new paediatric medicines regulation: for all new products and line extensions for existing products; manufacturer has to submit a PIP (Paediatric Investigation Plan); additional six months marketing exclusivity 2007: Jan.EMA: Paediatric medicinal products regulation took effect 2007: PUMA (Paediatric Use Marketing Authorization): 10 years of market protection for conducting clinical trials in patients for products approved under a PUMA 2007: PWG (Paediatric Working Group) of EUCROF (European CRO Federation); two surveys on the current status of paediatric research in Europe, published in 2009 and 2010

USA

EU

Table 3: Supplies for blood withdrawal in paediatric use Micro-Sampling Equipment • Blood withdrawal – Safety lancets for puncture and incision e.g. QuickHeel – Safety-Multiflies e.g. 23G, 25G • Sampling – Microtainer vials for capillary blood withdrawal – Micro Vacutainer for venous blood withdrawal – Capillary ESR (erythrocyte sedimentation rate) – Vials with microvolume inserts • Alternative samples – DBS (Dry Blood Spot)

Table 4: Low-volume techniques Methods for Low-Volume Analysis Method adaption for diluted samples and validation for small volumes e.g. HPLC-MS/MS. Method Special devices with possibilities for small volumes e.g. Roche Modular/Integra Semi-automatic devices e.g. Liaison/Diasorin ELISA devices (runs with several pre-dilutions, manually) Capillary blood from newborns DBS (Dry Blood Spots) Gyrolab for quantitative assays Luminex

Parameter e.g. Ferritin, TSH and clinical chemistry e.g. TPA, 12-Hydroxy Vit. D3, Bone marker, Renin and Thymidinkinase e.g. Diphtherie, Tetanus, EBV and CMV e.g. Homocystein e.g. Amino acid and Acylcarnitin Macromolecules Multiplexing techniques

Table 5: Advantages of a central laboratory in paediatric trials What Denotes a Good Central Lab? I. Assistance while compiling the PIP II. Provision of micro-sampling techniques III. Visit-specific kits and study-specific manuals IV. Specific analysers for low-volume testing V. Shipping logistics, extended frozen storage VI. Project support VII. One single, consistent and clean database

January 2011


Regulatory means that the vial which is inserted into the analyser has to contain more fluid than actually needed for the determination itself. Therefore before planning a paediatric clinical trial, an appropriate laboratory should be found which is able not only to run the methods needed, but also to show sufficient expertise in supporting paediatric studies and in handling very small blood volumes. High sensitivity assays such as LC-MS/MS allow analytics with very low blood volumes. Automation via microplate techniques with extraction is also becoming common in many laboratories. There are a number of techniques that can offer significant reductions in the volumes of biological fluids required for each analysis, e.g. multiplexing techniques such as Luminex. This method not only reduces the sample volume required, but also improves the efficiency when compared to single analyte methods. This technique allows performing analysis of a large number of analytes on extremely small volumes of approximately 50µl per sample. Another assay using nanotechnology for quantitative assays of macromolecules is Gyrolab. Up to five assays can be run simultaneously on Gyrolab on the same sample. Sample size for this method is as little as 10µl. Table 4 shows an assortment of some low-volume techniques for use in paediatric studies. How can a Central Lab Assist during a Paediatric Trial? In view of the specific requirements when running paediatric studies, and due to the fact that each blood sample collected is very, very valuable as it cannot simply be reproduced, involving a centralised laboratory rather than using local laboratories should be evaluated. A central laboratory experienced in supporting paediatric clinical trials will smooth the initiation process e.g. by providing study-specific instructions, by producing visit-specific kits with the appropriate micro-sampling materials, by using low-volume analysers, or by providing the logistical support to ensure fast and reliable sample transportation and storage. In addition to such operational advantages, a central laboratory will avoid investigators having to transfer lab results into their CRFs (case record forms) as they will receive standardised lab reports from the central laboratory. The sponsor will have access to a single, consistent and clean database with all lab data for all sites involved. All processes at a central laboratory should follow GCP standards, which generally is not the case in local laboratories. Table 5 shows some advantages when using a centralised laboratory dedicated to supporting paediatric trials. Conclusion Regulatory authorities and pharmaceutical manufacturers have found agreement in the need to run paediatric studies to reduce the “off-label” use of drugs in children. Paediatric clinical trials are demanding as they represent significant challenges to the authorities, ethical review committees, sponsors, laboratories and, last but not least, to the children involved and their parents. Involving experienced professionals in the investigational sites and in the laboratory sector, e.g. by selecting a central laboratory, may contribute to a successful completion of each paediatric study. Children are not simply small adults, and their blood volume is very scarce and hence very valuable. www.jforcs.com

References 1. P. Smit-Marshall. “Paediatric Trials: A Worldview.” Applied Clinical Trials, 32-38 (January 2010) 2. S. Conroy, I. Choonara, P. Impicciatore et al. “Survey of Unlicensed and Off-Label Drug Use in Wards in European Countries.” British Medical Journal, 320, 79-82 (2000) 3. M. Dehlinger-Kremer, C. Kreutz, A. Cournot, A. Alemany, K.P. Saalbach, J. Schaefer, P. Smit-Marshall. “Testing medicines for children in Europe.” Good Clinical Practice Journal, 10-15 (July 2009) 4. A. Svobodnik, A. Alemany, A. Cournot, J. Schaefer, M. DehlingerKremer, M. Mas, M. Levy, P. Smit-Marshall. “How to improve Children`s Research.” Applied Clinical Trials, 46-53 (Feb. 2010) 5. S. Hannam, J. Allinson, R. Briggs. “Minimising Volume, Maximising Returns.” European Biopharmaceutical Review, 4648 (April 2010) 6. M. Cole, A. V. Boddy, P. Kearns, K.H. Teh, L. Price, A. Parry, A.D.J. Pearson, G.J. Veal. “Potential impact of taking multiple samples for research studies in oncology: How much do we really know?” Paediatric Blood & Cancer 46 (7), 723-727 (2005) 7. Regulation EC No 1901/2006 on Medicinal Products for Paediatric Use: http://ec.europa.eu/enterprise/pharmaceuticals/ eudralex/vol-1/reg_2006_1901_en.pdf 8. Amending Regulation EC No 1902/2006 on Medicinal Products for Paediatric Use: http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/reg_2006_1902_en.pdf 9. ICH Guidance E11: “Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population” (CPMP/ICH/2711/99) www.ema.europa.eu/pdfs/human/ ich/271199en.pdf 10. H. Schulz. “Successfully involving central laboratories: How to avoid fundamental errors.” International Pharmaceutical Industry IPI: 74-77, Autumn 2009 Dr. Katja Neuer-Etscheidt. Prior to joining INTERLAB as Business Development Manager in 2008, Dr Katja NeuerEtscheidt worked as a research associate for Analytical Organic Chemistry at the Institute for Physics, University of Augsburg. She was a postdoctoral research fellow at the Institute of Ecological Chemistry at the Helmholtz Institute (formerly GSF), Neuherberg. In the past, Katja has been invited to talk about paediatric studies at scientific conferences. Email: Katja.Neuer@interlab.de Dr. Hermann Schulz. Before founding INTERLAB in Munich in 1994, Dr Hermann Schulz held senior R&D positions in the pharmaceutical industry (Merck & Co, AstraZeneca/ICI and UCB/Schwarz) during 12 years. As a visiting professor, Hermann is head lecturer for applied clinical pharmacology in the postgraduate course “Pharmaceutical Medicine” at the University Duisburg-Essen (formerly WittenHerdecke). He has written more than 35 scientific publications and is invited as speaker to international conferences such as DIA and IIR. Email: CEO.Schulz@interlab.de

Journal for Clinical Studies 19


Market Report

Delivering Top Performance across Cultures Clinical research is conducted on a global scale. Many studies are not just international but intercontinental. Pharmaceutical, biotech companies and CROs need to be able to operate worldwide and yet have local knowledge and expertise. Consequently many organisations have offices and field-based staff scattered throughout the areas of the world where clinical trials are conducted. These staff need to perform effectively and efficiently, and be managed and appraised fairly and consistently. Staff performance is dependent on a number of factors including staff selection procedures, access to learning and development opportunities, measurement against performance standards, appraisals, good management and career planning. Let us imagine that an organisation has in place very precise and detailed policies and procedures for training staff and appraising them. These methods have been developed in the organisation’s main offices at their headquarters. The intention is to implement these procedures globally. This seems a reasonable expectation, given that the company wants to build a strong and fair corporate culture. However, trying to implement a very rigid management framework globally will fail if local factors such as culture, business practice and law are not taken into account. Cultural differences between countries are well known. There are many excellent books and references on how to manage cultural diversity. However, some of the differences are very subtle. Simply the feeling of having a corporate culture imposed from a head office in another country can easily foster an attitude of “you don’t understand how things work here”. There are national cultural differences in work-life balance, attitude to time, the relationship between a manager and subordinate, how meetings are conducted, and how decisions are made. Sometimes differences in local infrastructure need to be accounted for. I remember being in a meeting to discuss an organisation’s travel policy, and a huge row erupted about what was reasonable travel time. What was considered to be a realistic amount of time for a road journey in the location of the company’s head office was out of the question in several eastern European countries. Cultural differences not only exist between nations, but there can be variations between different offices even in the same country. This may depend on historical reasons. Perhaps a new office has been acquired as Table 1 KPI Title Employee turnover

KPI Definition

Method of Measurement The total number of HR department will employees who resign, provide monthly plus the number of reports (graphs) to employees terminated department heads for performance reasons. That total is then divided by the number of employees at the start of the year (1st January)

20 Journal for Clinical Studies

Target Reduction of 7% by year end (31st December)

the result of a merger, and there is still the legacy of the original organisation’s culture. Other differences may be due to the size of the office or the profile of the staff who work there. I often find this when working with companies that have a number of offices in the same country. Just from waiting to be met in the foyer and observing the staff arriving for work, I have picked up differences in office culture from the way staff greet each other, their attitude to the receptionists, and how people dress. When running training courses, some of the cultural differences become even more apparent in how the staff apply and conduct themselves. Coffee and lunch breaks also provide a useful insight into individual office rituals. Both company and office culture can be influenced by very powerful individuals, such as owner/managers or very senior staff. One of the companies I used to work for was micromanaged by the owner. He had very strong, and in some cases unusual, views on how a company should operate. We were not allowed any personal effects on our desks, and the only pictures permitted on the office walls were chosen personally by him. This was no small undertaking, as we had offices in seven different countries on three continents. Another quirk of his was that no one was allowed to choose a white-coloured company car. Unfortunately he ruled with a culture of fear, and this pervaded itself throughout the whole company. No one felt empowered to make a decision without referring first to the owner, and this led to a rather rigid and unresponsive organisation that was often seen by its clients as inflexible, impersonal and arrogant. As well as cultural factors, each country’s own legal system will have an influence on how staff are hired, appraised and when necessary – disciplined or dismissed. Regional market forces in pay and reward schemes are critical, and need to be taken into account. Local expectations of how employees expect to be treated by their company will play a part. When I was working for an international organisation, employees in most countries claimed travel expenses directly. At that time in Sweden, each employee was given a monthly allowance for expenses. What they didn’t spend they could keep, and that was seen as part of their remuneration package, a concept which was alien in other countries. The same company introduced a global share options scheme for employees, which was a very virtuous idea. Unfortunately it proved very complicated and cumbersome to implement in different countries because of legal and tax implications, and not all employees were able to reap the benefits. The access that staff have to managers will vary in different locations, and can be due to diverse workplaces, ranging from lone workers operating from home to large offices which may have hundreds of employees. Some managers may have their whole team made up of field-based people from different countries. How do international organisations cope with these major challenges when trying to achieve global consistency in staff performance? One solution is to use key performance indicators (KPIs). KPIs help organisations define and measure January 2011


Market Report

progress towards business goals. They must be quantifiable and related to activities that are critical to the success of the whole organisation. KPIs can also be used as a performance management tool by focusing employees on achieving the business goals. The trick is to allow flexibility in how these goals are reached locally. In some cases it may be sensible to set local targets too. KPIs should be straightforward and uncomplicated. It is very important that all employees understand them and can appreciate their relevance to business success. Each KPI should be realistic, and yet provide a target that will stretch and develop the organisation’s business. KPIs must also be able to be influenced by staff performance. They should be measured regularly, and the results reported to the workforce. This allows everyone to share the same picture and reflect on their individual contribution. Think of KPIs as the vital few parameters that need to be tracked, reported and acted upon. How might this work in practice? A global CRO may decide that staff turnover is one of its KPIs. There is a critical business reason for this, as many pharmaceutical companies that use CROs are concerned about frequent changes in their personnel and the subsequent disruption that can bring to the successful completion of clinical trials. A CRO that can reduce its staff turnover and maintain it at acceptable levels will have a competitive advantage over its rivals. Pharmaceutical companies may have corporate KPIs, such as the number of regulatory approvals obtained annually, as well as the usual financial drivers. Their clinical development department may have their own KPIs, for example time from last patient completed to database lock. The first step is to describe the KPI by the following features. It should have a title, a definition, a method of measurement, and a target. For the example of staff turnover, the details may be described in a table. In some cases in might be prudent to set local targets, particularly if there is a specific problem in retaining staff www.jforcs.com

in some regions. Once the KPIs have been defined, the staff performance standards that can influence them can be identified. However, methods by which the KPI targets can be reached may vary locally. Companies may have global job descriptions, competencies and procedures for training and appraising staff, and these should be written in such a way as to allow for reasonable regional flexibility. If we take the example of staff turnover, as well as staff remuneration and benefits, other factors which affect this KPI include how well staff are selected for hire, and how skilfully they are managed and appraised with respect to both their current job and their future career aspirations. How these aspects are managed will vary regionally depending on national cultures, laws and market forces. Pay and benefits schemes will need to be decided locally. The human resources representative in each country should have a key role in providing the relevant information, so that an attractive and fair package can be created for each country. Managers have a key role along with human resources specialists in ensuring that the right people are hired. Staff turnover can be high because of poor selection and interview techniques, and the subsequent round pegs in square holes rarely stay long in a job for which they are ill-fitted. Having a targeted selection scheme using situational interviewing is generally considered the most reliable method for hiring the right people. Even though there might be a corporate scheme in place, the local office should have input into the targeted questions used so that they are relevant for their candidates. The relationship between manager and subordinate is often one of the most variable factors in different cultures. This relationship is often one of the major reasons that people cite when they make a decision to stay with or leave an organisation. In some countries the relationship is casual and relatively informal, whereas in other cultures a more rigid and visible hierarchy exists. People from different cultures will have varied expectations about how they expect to manage or be managed, and these should be respected. Sometimes a manager will be supervising staff in other countries, and both parties should take time to learn about each others’ cultures and agree a framework for how the relationship should work. Even though it is important for companies to have a ‘corporate culture’ which includes global values, standards and procedures, successful organisations will ensure that there is enough flexibility to account for cultural and national differences. Staff must be empowered to find their own local solutions and methods to support the business and influence the KPIs. This will result in a committed and motivated workforce that is striving for both individual and collective performance excellence. Martin Robinson is a Director of Dovetail Clinical, and has over 15 years’ international experience in training and organisational development. He joined Dovetail from the Institute of Clinical Research, where he managed the Institute’s programme of training courses. Martin’s skills include project management coaching and training, helping organisations identify and meet the learning needs of their staff, and facilitating process improvement. Email: mrobinson@dovetailclinical.com Journal for Clinical Studies 21


Market Report

Clinical Trials in Russia 3rd Quarter 2010 Executive Summary The new law “On circulation of medicines” became effective on 1st September 2010. According to this law the right to issue licences for performing clinical research was transferred from The Federal Service on Surveillance in Healthcare and Social Development of the Russian Federation (alias RosZdravNadzor, RZN) to the Ministry of Healthcare and Social Development. Due to this transition, the issue of licences was temporarily suspended in September. In our opinion it caused a decrease in the main indicators of the clinical research market compared to the corresponding period of last year. RZN approved 134 new clinical trials of all types, including local and bioequivalence studies, during the third quarter of 2010, demonstrating a 12% decrease compared to the previous year’s figure. The main contribution to the total number of studies is still made by multinational multi-centre clinical trials, even though the number of these studies fell by one-third over Q3 2009, and stood at 60 new studies in Q3 2010. The number of local clinical trials conducted in Russia by domestic and foreign sponsors demonstrated a 7% increase, and stood at 42 trials. Although most clinical trials in Russia are still being sponsored by foreign companies (57%), the ratio between foreign and domestic companies changed significantly: in Q3 2009 their shares were 67% and 33% respectively, while in Q3 2010 the share of trials sponsored by domestic companies increased to 43%. Clinical trials initiated in Q3 2010 were sponsored by manufacturers from 17 countries. The greatest number of trials was initiated by Russian sponsors, American sponsors took the runner-up place, followed by German and Swiss sponsors, and the top six is concluded by French, Belgian and Belarusian sponsors, each with four new studies. Twelve new Phase I clinical trials were launched in the third quarter of 2010; three trials more than in the corresponding quarter of last year. The number of Phase II trials decreased significantly, from 47 trials in the third quarter of 2009, to 18 in the third quarter of 2010. The number of Phase III trials also demonstrated a decrease over the last year’s number, down from 86 to 61 studies, while the number of Phase IV studies remained almost unchanged at 10 new trials. The number of patients planned to be enrolled in the Phase II-IV trials launched in the third quarter of 2010 stood at 11,758 – a little less than the last year’s number. The number of Phase III subjects increased by 24% from last year’s figure. The Swiss giant Novartis, sponsoring seven new studies, is on the top of the heap in the third quarter of 2010. The German Boehringer Ingelheim, with five new trials in Q3 2010, took the runner-up place. It is followed by the British Pantheon and GlaxoSmithKline, each sponsoring five new studies. The top five is concluded by the French sanofi-aventis, having four new studies in Q3 2010. The Russian pharmaceutical company ZAO Rafarma, sponsoring five new clinical trials, ranked number one among 22 Journal for Clinical Studies

domestic pharmaceutical manufacturers by the number of new studies in the third quarter 2010. They are followed by NIOPIK and ZAO Pharm-sintez, with three new trials each, and ZAO Firn M with two new trials. ZAO Vector-Medica and OOO Niarmedik, with one new study each and the same number of patients and sites, conclude the top six. 62 per cent of the new studies in Q3 2010 were conducted in the five leading therapeutic areas. The greatest number of trials (20) was initiated in oncology; 13 clinical trials in neurology; 10 new studies in infectious diseases; nine in respiratory diseases, and eight new endocrinology studies were initiated in Q3 2010. According to the FDA data as of November 12 2010, there were two FDA inspections conducted at the Russian investigative sites during Q3 2010. Both were performed at investigative sites in Saint-Petersburg and concluded with NAI – No Actions Indicated. Clinical Trials by Type and Manufacturing Country The RZN approved 134 new clinical trials of all types, including local and bioequivalence studies, during the third quarter of 2010, demonstrating a 12% decrease compared to the corresponding period of last year. As shown in Figure 1, the main contribution to the total number of studies is still made by multinational multi-centre clinical trials (presented as MMCT in Figure 1), even though the number of these studies fell by one-third over Q3 2009, and stood at 60 new studies in Q3 2010. The number of local clinical trials conducted in Russia by domestic and foreign sponsors (the CT(R) bar in Figure 1) insignificantly increased from 39 to 42 clinical trials, demonstrating a 7% increase over the same point in 2009. The number of bioequivalence studies (BE in Figure 1) initiated in the third quarter of 2010 stood at 32 new trials, eleven studies up over last year’s figure. The proportions between different study types (multinational multi-centre clinical trials, local studies and bioequivalence trials) changed significantly over the same point in 2009. Along with the decrease in the number of studies, the share of multinational multi-centre clinical trials significantly fell from last year’s figure, and stood at 45% of the total number of clinical trials approved by RZN in the third quarter of 2010. The shares of the local trials and bioequivalence studies in Q3 2010 stood at 31% and Figure 1. Clinical trials approved by RZN in Q3 2010 153 134 93 60 39

42

32

21

Total

MMCT Q3 2009

CT(R)

BE

Q3 2010

January 2011


For more information, please contact Anna Ravdel (ravdel@synrg-pharm.com), or visit www.synrg-pharm.com


Market Report 24% of the total number of studies, respectively, while they accounted for 25% and 14% in Q3 2009. Although most clinical trials in Russia are still being sponsored by foreign companies (57%), the ratio between foreign and domestic companies changed significantly compared to the same period of the last year. Thus, shares of trials sponsored by foreign and domestic companies were 67% and 33% respectively in Q3 2009, while in Q3 2010 the share of trials sponsored by domestic companies increased to 43%. Clinical trials in Russia in Q3 2010 were sponsored by companies from 17 countries. Figure 4 demonstrates the input of the leading countries of sponsor’s origin into the total number of clinical trials. The highest number of trials (58) was initiated by Russian sponsors, while American sponsors, with 20 studies, took the runner-up place, followed by German sponsors with 14 trials. 11 new trials were instigated by Swiss manufacturers, and the top six is concluded by French, Belgian and Belarusian sponsors, each with four new studies in Q3 2010. Canada, the United Kingdom, Israel, Sweden, Japan, Austria, Dania, Poland, Portugal and Croatia are represented among others. Clinical trials by Phase Twelve new Phase I clinical trials were launched in the third quarter of 2010; three trials more than in the corresponding quarter of last year. The number of Phase II trials decreased from 47 trials in the third quarter of 2009, to 18 in the third quarter of 2010. The number of Phase III trials also demonstrated a decrease over last year’s number, down from 86 to 61 studies. The number of Phase IV trials remained almost unchanged at 10 trials in this period. As shown in Figure 6, the share of Phase III trials in Q3 2010 stood at almost 60% of the total number of studies, the share of Phase II trials accounted at 18%, Phase IV trials stood at ten per cent, and the share of Phase I studies amounted to twelve per cent. The number of patients planned to be enrolled in the Phase II-IV trials launched in the third quarter of 2010 stood at 11,758, a little less than the last year’s number (11,956). The number of Phase III subjects increased by 24% from last year’s figure. Three hundred and sixty-five subjects will be recruited in Phase I trials; 1,220 patients in Phase II trials; 7,973 subjects in Phase III studies, and 2,200 patients will be enrolled in Phase IV studies. The minimal number of subjects in a single study is twentyfour, and the maximum number is 1,050. The proportion of the number of patients between different Phases is shown in Figure 7. The duration of the shortest trial is three months, while the longest one will last almost nine-and-a-half years Rating of International Sponsors The Swiss Novartis, sponsoring seven new studies, is again on top of the heap in the third quarter of 2010. The German Boehringer Ingelheim, with five new trials in Q3 2010, took the runner-up place. It is followed by the British Pantheon and GlaxoSmithKline, each sponsoring five new studies. The top five is concluded by the French sanofi-aventis, having four new studies in Q3 2010. The top five international sponsors by the number of new studies in Q3 2010 is presented in Table 1. 24 Journal for Clinical Studies

Figure 2. Clinical trials by type in Q3 2010

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

14%

24%

25%

31%

61%

45%

Q3 2009

Q3 2010 BE

CT(R) Figure 3. Russian and international sponsors in Q3 2010

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

57%

67%

43%

33% Q3 2009

Q3 2010

Russian sponsors

International sponsors

Figure 4. Countries represented in the Russian clinical trials market in Q3 2010 USA 15%

Russia 43%

Germany 11% Switzerland 11% France 3% Belgium 3% Belarus 3%

other 14%

Figure 5. Clinical trials in Russia in Q3 2010 by Phase 86 61 47

18

12

9

Phase 1

Phase 2 Q3 2009

11

Phase 3

10 Phase 4

Q3 2010

Figure 6. The proportions between study phases in Russia in Q3 2010

Phase II 18% Phase I 12%

Phase III 60%

Phase IV 10%

January 2011


Market Report Rating of Russian Sponsors The Russian pharmaceutical company ZAO Rafarma, sponsoring five new clinical trials enrolling 260 patients in five sites, ranked number one among domestic pharmaceutical manufacturers by the number of new studies in the third quarter of 2010. NIOPIK, with three new trials and 170 subjects in eight sites, took the runner-up place. It is followed by ZAO Pharm-sintez, with three new trials but fewer patients, and ZAO Firn M with two new studies. The top six is concluded by ZAO Vector-Medica and OOO Niarmedik, with one new study each and the same number of patients and sites. Therapeutic Areas of Clinical Trials in Russia in Q3 2010 Sixty-two per cent of the new studies in Q3 2010 were conducted in the five leading therapeutic areas. The highest number of trials (20) was initiated in oncology; 13 clinical trials in neurology; 10 new studies in infectious diseases; nine in respiratory diseases, and eight new endocrinology studies were initiated in Q3 2010. The proportions between different therapeutic areas are shown in Figure 8.

Figure 7. The number of patients in Q3 2010 by study Phase

Phase IV 19% Phase III 68%

Phase II 10% Phase III 3%

Table 1. Top five international study sponsors in Q3 2010 No

Sponsor

No. of trials

No. of patients

No. of sites

1

Novartis

7

1051

70

2

Boehringer Ingelheim 5

1192

78

3

Pantheon

5

462

49

4

GlaxoSmithKline

5

310

24

5

sanofi-aventis

4

1098

62

Table 2. Top five Russian study sponsors in Q3 2010

Clinical Trials Results The Center for Drug Evaluation and Research (CDER) of the FDA approved 22 new drugs during Q3 2010; only three of them are new molecular entities (NME); others are new dosages, manufacturers or indications of already-marketed drugs. Table 3 represents the three which were tested in clinical trials in Russia. No negative opinion was adopted for any of the drugs which had been approved earlier. Seven of the drugs which received positive opinions from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMEA) were (or are being) tested in clinical trials in Russia (see Table 4).

No

Sponsor

No. of trials

No. of patients

No. of sites

1

Rafarma

5

260

5

2

NIOPIK

3

170

8

3

Pharm-sintez

3

148

6

4

Firn M

2

160

3

5

Vector-Medica

1

200

2

6

Niarmedik

1

200

2

Figure 8. Clinical trials in Russia in Q3 2010 by therapeutic area Infectious disease 8% Endocrine and metabolic disease 8%

FDA Inspections According to the FDA data as of November 12 2010, there were two FDA inspections conducted at the Russian investigative sites during Q3 2010. Both were performed at investigative sites in Saint-Petersburg, which concluded with NAI â&#x20AC;&#x201C; no actions indicated. Igor Stefanov, MBA. General Manager â&#x20AC;&#x201C; Synergy Research Group. After an engineer degree at the Moscow Aviation Institute in 1989 Mr. Stefanov joined the leading Russian defense R&D Institute as the Firstclass Engineer for Battle Aircraft Design and Efficiency Evaluation. After an MBA in Economics at the Moscow International University in 1993 he went into the business consulting area developing and implementing localization strategies for the Fortune 500 companies in Russia comprising General Motors, 3M, Unilever, Kodak and Shell, to name but a few. Prior to joining SynRG in January 2007, Igor was General Manager of Smartlock, the Russian hi-tech biometric company and was recognized as an entrepreneur of the month by the Russian edition of Forbes magazine in 2005. With in-depth macro- and microeconomics knowledge, strong management skills and solid local expertise Mr. Stefanov has been providing various consulting services to large multi-national companies in Russia since 1993, and there are a number of Big Pharma representatives on the list including Pfizer, J&J, GlaxoSmithKline, Roche and others.

26 Journal for Clinical Studies

Respiratory dieseases 9%

Other 38%

Oncology 21%

Neurology 14%

Table 3. New drugs approved by the FDA in Q3 2009 and tested in Russian sites Approval date

Drug

Manufacturer

07/23/2010

Aricept (Donepezil Hydrochloride)

Eisai Inc

08/13/2010

Ella (Ulipristal Acetate )

Lab HRA Pharma

08/19/2010

Atazanavir Sulfate

Emcure Pharms

Source: CDER FDA http://www.fda.gov/cder Table 4. New Drugs approved by EMEA in Q3 2010 and tested in Russian sites Approval date

Drug

29/07/10

Twynsta (telmisartran/amlodipine)

Manufacturer Boehringer Ingelheim

International GmbH

29/07/10

Arixtra (fondaparinux sodium)

Glaxo Group Ltd

29/07/10

M-M-RVAXPRO (measles, mumps

Sanofi Pasteur MSD

and rubella vaccine live)

29/07/10

Viread (tenofovir disoproxil)

Gilead Sciences International Ltd

01/10/10

Mabthera (rituximab)

Roche Registration Ltd

01/10/10

Tasigna (nilotinib)

Novartis Europharm Ltd

01/10/10

Invega (paliperidone)

Janssen-Cilag International N.V.

Source: CHMP EMEA http://www.emea.europa.eu/index/indexh1.htm

January 2011


Therapeutic

Chemotherapy Combination Programmes Bevacizumab in the Treatment of Disseminated Colorectal Cancer Objectives of the Study To study the efficacy and toxicity of bevacizumab in combination with two chemotherapy programmes in patients with metastatic colorectal cancers. Study Design Advances in drug treatment of disseminated colorectal cancer orbital are largely determined by the development and introduction into clinical practice of new anticancer drugs and more rational modes of administration of cytostatics. Since 2006 in the treatment of disseminated forms of colorectal cancer has used the anti-angiogenic agent bevacizumab in State Institution of Healthcare “Regional Clinical Cancer Center”. Two groups of patients received treatment for the following programmes. The first group received oxaliplatin 100mg/m2 intravenously on day 1, leucovorin 20mg/m2 + 5-fluorouracil 500mg/m2 intravenously from days 1 to 5, with an interval between courses of three weeks. 22 subjects were treated using this programme. The second group (24 patients) received a treatment programme with oxaliplatin 50mg/m2 intravenously on days 1, 8 and 15, and capecitabine 2000 mg/ m2 intravenously within 14 days. The interval between courses was two weeks. All patients received bevacizumab at a dose of 5mg/kg on days 1 and 15 of the course.

Inclusion / Exclusion Criteria Thus, during the reporting period, 46 patients aged 28-73 years with metastatic colon cancer were treated, of whom 30 were male and 16 were female. Characteristics of patients and their tumors are presented in Table 1. Violation of the general condition of the patients is rated on the Eastern Cooperative Oncology Group (ECOG) scale. In all patients the diagnosis was confirmed histologically. Characteristics of preferential localization of metastases before treatment show significant frequency of metastatic liver, lungs and pleura at least, with local recurrence of metastasis to retroperitoneal lymph nodes and ovaries. The Results of Treatment Efficacy of treatment was evaluated according to WHO criteria in all 46 patients who received at least four courses of treatment. The overall effectiveness of the programme OXA/5-FU/LV/BEV was 40.91 ± 8.6%, of which 4.54 ± 5.1% completed responses. The overall effect of therapy in OXA /CAP/ BEV was 45.83 ± 8.6% (11 patients), including complete regression achieved in four patients, which amounted to 16.66 ± 5.6%. The median time to progression in the first group of patients was 8.3 months, and in the second, 9.8 months. Under OXA / CAP/ BEV, three out of five patients with isolated liver metastases were operated on after three months of treatment in this treatment scheme, resulting in patients’ post-operative complications not associated with a prior bevacizumab.

Table1: Characteristics of patients and tumors Parameter Gender: Male Female Average age, years ECOG Status: 0 1 2 3

| | | | | /5-FU/LV/BEV

| | | | | /| | | | | /BEV Number of subjects / %

14/63.64 8/36.36 57.8 years 7/31.82 8/36.36 5/22.72 2/9.10

16/66.67 8/33.33 53.2 years 8/33.33 9/37.50 5/20.83 2/8.34

Previous surgery: -Radical surgery -Palliative surgery -Not done Prevalence of tumour process:

7/31.82 7/31.82 8/36.36

5/20.83 4/16.67 15/62.50

8/36.36 9/40.90 2/9.10

6/25.00 8/33.33 4/16.67 3/12.50 1/4.17 4/16.67

-liver metastases -metastasised to the lung / pleura metastases in the retroperitoneal-l / nodes -dissemination of the peritoneum -metastases in the ovaries -local recurrence Total number of patients

28 Journal for Clinical Studies

1/4.54 5/22.72

22

24

January 2011


Therapeutic

The high importance of clinical improvement for this severe category of patients should be emphasised. In the course of treatment, the subjective effect of my treatment scheme of chemotherapy was studied. The subjective effect was assessed by an increase in physical activity (change of status on an objective scale ECOG), to ease the pain of a change in body weight. The dynamics of the general status of patients are presented in Table 3. After the end of chemotherapy on the submitted treatment scheme, the decreases in patients’ ECOG status scores were established, generally showing a change in status of two or three degrees. Before the start of chemotherapy there were no violations in the objective status of 15 patients (32.62%), while after chemotherapy, this group had increased to 23 patients (50.0%). Toxicity of Therapy The toxicity of the treatment scheme was studied using the CTCNCIC scale in all 46 patients, and this is presented in Table 4. The frequency of adverse reactions was calculated by the total number of courses. Toxic manifestations during chemotherapy plus bevacizumab in combination with capecitabine and oxaliplatin, as well as in combination with 5-fluorouracil and leucovorin, were very diverse, but were generally infrequent, of moderate severity, and associated mainly with exposure to cytostatics. Clinically significant complications requiring cessation of therapy were recorded.

Conclusion Thus, the outpatient use of bevacizumab in combination with different chemotherapy regimens in patients with metastatic colorectal cancer is followed by the low risk of complications, and increases the time to progression, which gives hope for improved long-term results of treatment of this patient group. List of authors O.V. Zharkova1, E.B. Mironova3, V. Karaseva2, V.A. Haylenko2, O.D. Kadnikova3, P.S. Feoktistova4, A.V. Sizintsev1, J.M. Kolesnikov1, N.A. Safronova5 1. State Institution of Healthcare “Regional Clinical Cancer Center”, Kemerovo, Russia 2. Medical University, Moscow, Russia 3. Clinical Hospital No81 FMBA Seversk, Russia, 4. Oncology dispenser , city Nizhnevartovsk 5. SRC, Moscow, Russia Natalia Safronova is graduated from Moscow Medical Academy and the University of Helsinki, pharmaceutical faculty. Natalia has worked for GSK in CNS group during 5 years. Email: nsafronova@src-pharm.com

Table 2: Effectiveness of chemotherapy in combination with bevacizumab Direct effect Complete regression Partial regression Stabilisation Progression Total number of patients

| | | | | /5-FU/LV/BEV 1/4.55 8/36.36 9/40.91 4/18.18 22/100

| | | | | /| | | | | /BEV Number of subjects / % 4/16.66 7/29.17 10/41.67 3/12.50 24/100

Table 3: Changing of objective status of the patients ECOG Status 0 1 2 3 Total number of patients

Before treatment Number of subjects / % 15/32.62 17/36.96 10/21.73 4/8.69 46/100

After treatment Number of subjects / % 23/50.00 15/32.62 6/13.04 2/4.34 46/100

| | | | | /5-FU/LV/BEV

| | | | | /| | | | | /BEV Number of subjects / %

24/27.27 6/6.82 4/4.54 2/2.27

22/23.91 3/3.26 2/2.17 4/4.35

23/26.14 4/4.54 6/6.82 2/2.27

26/28.26 4/4.35 4/4.35 2/2.17

21/23.86

26/28.26

3/3.40 88

16/17.39 92

Table 4: Side-effects of chemotherapy Side-effects and their grades Hematological: -neutropenia I-II -neutropenia III -trombocytopenia II -anaemia II Gastrointestinal: -nausea/vomiting II -diarrhoea II -stomatitis I-II -abdominal pain II Neurological: -limb paresthesia I-II Skin: -hand-foot syndrome Total number of courses

www.jforcs.com

Journal for Clinical Studies 29


Therapeutic

Phase I: Adding Value in Drug Development? For many working in the industry, Phase I studies are viewed as a stage in the drug development cycle that must be done, and is not necessarily considered to “add value” to a drug’s portfolio. More companies are looking to move into patients earlier for answers. This has led to new strategies and terms, proof of concept (POC) being one, and microdosing another. The attraction of the latter is that companies can move into man quicker with an abbreviated preclinical package, thus claiming to “be in man” with their compound, which helps satisfy business metrics, company performance statistics and shareholders. There is no doubt that these new studies have their place, though the more traditional Phase I studies have evolved over the years, with new thinking being applied along with a wealth of expertise available, which add value. Not Just Phase I Some use the term Phase I to mean clinical pharmacology and vice versa. However, these terms are not interchangeable. Phase I is a specific area of clinical pharmacology focusing on the first administration in man of new chemical and biological entities. Primarily, this involves administration to healthy volunteers, except in the case of specific therapies such as cytotoxic drugs where the risk:benefit ratio does not allow healthy subjects to be involved. A significant amount of clinical pharmacology work occurs in new chemical entities (NCEs) during the drug development lifecycle. Drug/drug interaction studies, which study the effects (usually pharmacokinetic, though sometimes pharmacodynamic) of one drug on another, are performed in all stages of clinical drug development, even when a drug is in Phase III. These are determined by the pharmacology of the drug, in particular the route of drug metabolism and transportation in the liver and the gastro-intestinal tract. This is an area of advancing scientific knowledge and of increasing regulatory concern, due to the increase in poly-pharmacy that comes with an ageing population with associated multiple pathology. This is one area where clinical pharmacology in healthy volunteers has direct relevance to prescribers. At the first-in-man or Phase I stage, the new chemical entity formulation is usually crude (often a simple oral solution, made with bulk drug). Considering that up to 40% of NCEs fail in Phase I due to inappropriate pharmacokinetics1, companies do not want to invest large sums of money in a drug which may still fail. The counter-argument to this is that the crude formulation may be the reason for the inappropriate pharmacokinetic profile, while a refined formulation might demonstrate a more appropriate profile. Again, clinical pharmacology has a pivotal role here in demonstrating that refined “market image” formulations have appropriate pharmacokinetics for successful self-administration by patients that will allow the drug to achieve a marketing authorisation. Bioavailability (BA) 30 Journal for Clinical Studies

and bioequivalence (BE) studies, both as initial formulation pilot pharmacokinetic studies and subsequent regulatory BA/ BE crossover studies, can provide this information. In the case of a molecule that may have several formulations, small pilot pharmacokinetic studies (sometimes as part of the initial firstin-man study) are used to ascertain the optimal one for full development. The effects of disease on drug pharmacokinetics, and hence pharmacodynamics, can affect both safety and efficacy. This information is required for the SPC or drug label. Most small molecule drugs undergo hepatic metabolism and clearance and/or renal clearance. Therefore, disease states of these organs can affect drug exposure, leading to toxicity. Renal function as measured by creatinine clearance can start to decline in the fourth decade of life at a rate of 8mL/min/1.73m2/decade in approximately two-thirds of elderly persons2. Drug utilisation in this age group is also high, with a high incidence of chronic illness requiring long-term therapy. Thus, knowledge of any dose adjustments in those with end organ compromise is important to aid compliance and to assure long-term safety. Such dose adjustments can usually be calculated from simple single-dose pharmacokinetic studies comparing the PK in those with renal and hepatic impairment compared to those with age-sex matched healthy volunteers3,4. First-in-Man (FIM) Some are of the opinion that not much has changed in Phase I dose escalation studies. A recent review5 which looked at 105 published studies from 1995 to 2004 concluded that there was little consensus in the design of such trials. The average trial was placebo-controlled, double-blind and included 32 subjects at five dose levels, yet with great variation in cohort size (Figure 1). The parallel single-dose design was the most common and the most conservative. The use of the crossover designs, both grouped and alternating, were considered more novel approaches. Since these designs allow the drug to be administered more than once to each subject, they allow more information to be obtained from fewer subjects and importantly, enable intra-subject comparability at the different dose levels. The use of these crossover designs coincides with the drive by the industry to achieve more out of such studies. There has been an emergence of multi-functional protocols or “umbrella protocols”, particularly in Phase I. These involve the combination in a single study of the traditional single ascending dose study with the first-in-man multiple-dose tolerance study. Food effect crossover legs have been added as well. The advantages are that such studies require only one regulatory approval and ethical review, there is consistency in the inclusion/exclusion criteria, and they are quicker to perform. In addition, all parts of the study can be managed by the same project manager and team, and be conducted by the same January 2011


Therapeutic centre and the same investigator, thus promoting operational efficiencies and saving time. However, these studies require control mechanisms to be in place to assure participant safety when moving from the single-dose to the multiple-dose section of the study; specifically, what data will be available to select the dose regimen for the multiple dose, what decision criteria will be applied, who will apply these criteria, and how will this data be assured to be accurate? The key is to be as flexible as possible and use algorithms to clearly define the different possible scenarios. Traditionally, such dynamic changes during a Phase I study were handled by protocol amendments, though the approval of these can restrict the speed of research. With the use of predefined algorithms detailed in the protocol, changes in dose levels and sampling numbers, for example, can be instituted without further regulatory review. Of course, this must all be explained in clear terms to the study participants in the information sheet and consent form, which can result in large and sometimes “user-unfriendly” documents that require a high level of explanation from research staff in order to ensure that proper informed consent is achieved. Using pre-approved consent updates during the study to cover the pre-planned changes described by the protocol algorithms is a technique that has to be employed in order to ensure that informed consent is maintained throughout the study. “Healthy” patients in Phase I? In recent times there has been the emergence of the use of certain groups of patients in what were traditionally the firstin-man studies (excluding cytotoxics). These are usually patient groups who are otherwise healthy, with minimal end organ dysfunction caused by their disease; Hepatitis C patients for example. Some of these patients chronically infected with the Hepatitis C virus have no symptoms or signs; all that might be present is a mild derangement in serum ALT and positive viral serology. In these patients, liver and renal function are normal, and thus any new chemical entity is likely to be handled in the same way as in normal healthy subjects. Their viral serology can be used to assess any potential benefit of new anti-viral molecules and thus give very early proof of concept as well as safety in the target population. Such studies can have a key role to play in taking the decision to move into Phase II and full development. For small companies, such data allows them to out-license the drug to a partner. In this respect, clinical pharmacology is being used to assist in business and development decisions, rather than solely for regulatory requirements. As the example in Figure 2 above demonstrates, patients can be included as part of the first-in-man healthy volunteer study as a sub-group, once a safe dose that demonstrates appropriate drug exposure has been established in healthy volunteers. However, this does rely on having a biomarker that will be affected by a relative short duration of dosing, such as viral load in Hepatitis C. Translational / Experimental Medicine Another area that has grown in interest in the past few years is that of translational medicine or experimental medicine. Both terms have been used frequently to mean the same area. This involves the use of innovative measurements (referred to as biomarkers), models and designs in studying human subjects for establishing proof of mechanism and concept for new 32 Journal for Clinical Studies

drugs. It also can be used to explore the market differentiation for successful drug candidates, and for terminating the development of unsuccessful ones6. Biomarkers The biomarker chosen must be valid and meaningful for the target therapeutic area. Biomarkers can be as simple as measuring blood glucose and serum insulin in response to new anti-diabetic agents, measuring routine coagulation parameters in healthy subjects in response to new anti-coagulants targeted for thombo-embolic disease, and the use of bacterial lipopolysaccharide ex vivo to “spike” human blood to demonstrate a reduction in TNF response when comparing certain antiinflammatory agents to placebo in healthy subjects. Others are more complicated. Examples include the use of forearm blood flow measurements to assess vascular response to endothelin antagonists and euglycaemic hyperinsulinaemic clamp studies for assessment of anti-diabetic agents. Newer challenge agent models have been developed to look at anti-inflammatory effects in the skin; for example, the use of urate crystals intradermally to recruit neutrophil infiltration of the skin with an inflammatory response which can be assessed by laser Doppler and local biopsy. Skin blisters are formed using a vacuum chamber, are de-roofed, and urate crystals are applied to the skin to provoke the inflammatory response. Comparisons can be made between responses seen with active drug versus placebo7. Microdosing Microdosing is another relatively new development which has been put forward by many as a potential way of reducing development time, gaining early proof of concept and reducing the traditional attrition rate seen in early drug development. Essentially, microdosing is a human ADME (Absorption, Distribution, Metabolism and Excretion) study performed before a new drug candidate moves into Phase I (sometimes referred to as a “Phase 0” study). The drug is administered in a sub-pharmacologically active dose, and the study utilises ultra-sensitive analytical techniques, such as accelerator mass spectroscopy (AMS) and positron emission tomography (PET), in order to assess the pharmacokinetics and the potential pharmacodynamic responses. PET scanning is an exciting new development which can be used to demonstrate receptor occupancy of a new drug, for example dopamine and 5-HT receptors7. It can detect the displacement of labelled receptor ligand by the ’cold‘ new molecule, thus demonstrating receptor interaction. The use of AMS allows the pharmacokinetics of the microdose to be assessed to show potential appropriate human ADME8. The word “potential” is used here because the technique relies on the compound having linear kinetics in the pharmacologically active range. Can Phase I Studies Add Value in Drug Development Today? Absolutely – but you need to move away from the traditional paradigm. Adding value starts even before the study actually begins. Phase I is a discipline in its own right. As in other areas, there are experts in clinical pharmacology/Phase I who can help a sponsor plan, implement and interpret data that provide answers for a drug; even if that answer demonstrates that the January 2011


Therapeutic benefits of hospital-based CPUs, which apply not only to FIM studies, but to other clinical pharmacology studies as well. These benefits include: • Ease of access to specialised diagnostic techniques and experts within the hospital itself for some of the biomarker assessments previously mentioned. • Teaching hospitals have senior medics who are key opinionleaders in therapeutic areas, and are able to collaborate with the Phase I CPU in helping refer in small number for patients for proof of concept studies, which are becoming a part of the Phase I programme rather than Phase 2. • Access to hospital labs with their array of assays and experts can help the CPU medics interpret results from studies, and help give the sponsor guidance on any findings. • Referral into the hospital for “non-emergency“ adverse events; for example, having a dermatologist consult to give an opinion on possible drug-related skin rashes can be achieved more quickly if the CPU is hospital-based.

drug in question or its current formulation could not be moved into full development. In the majority of cases this is due to inappropriate or variable human pharmacokinetics. Getting these answers quickly and reliably is where having a good Phase I project team and project manager pays dividends. They coordinate all the elements that make up a Phase I trial: protocol and informed consent production, regulatory and ethics submissions, start up, recruitment and screening, coordination of clinical scheduling and activities (in conjunction with the medical and nursing staff within the clinical pharmacology unit (CPU)), data collection and management, as well as report production. Not to mention coordination with other possible external parties such as laboratory, monitors, drug supply and other study-specific suppliers. An experienced investigator is also required. He/she can often help prevent issues during the study by using their experience to advise the client how to maximise the benefits they can get from such studies, and to avoid potential pitfalls. This is in addition to their traditional role as being the person responsible for subject safety during the study. Location for Phase I studies is a factor as well. There has been a move to conduct more FIM studies in hospital-based CPUs, primarily because of safety concerns and to ensure rapid access to emergency medical services in the case of serious adverse events (SAEs). Access to a hospital crash team who can assist the CPU medical team manage ill subjects in the unit has become a prerequisite for many pharmaceutical companies placing work in CPUs. However, there are other non-emergency

Timelines are always critical in early phase studies. The conduct of Phase I studies is a global activity, with different countries having different approval timescales. In the UK, for example, we are fortunate to benefit not only from years of experience with Phase I studies following the growth of CPUs in the 1980s, but also to enjoy a favourable ethics and regulatory climate. This means that there can be a parallel submission for both ethics and regulatory approval, in which valid submissions are reviewed and approved within a 14-21-day timeframe in most

Figure 1: Summary of Phase I dose escalation designs (Boen et al) A

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January 2011


Therapeutic cases. Data published by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the period April 2008 to August 2009 demonstrated that the average time for application review for Phase I healthy volunteer studies, including FIM but excluding those required by the Expert Advisory Group (since they were considered to be of “higher risk”) ranged from 9.8 days to 15 days9. Looking at all of this together, one can see that Phase I or clinical pharmacology is not like other stages of clinical drug development. More so than ever before, there are developments in this area with new approaches and study designs coming to the fore. Out-of-the-box thinking is needed by pharmaceutical companies and CROs alike to help deliver maximum value to drug development pipelines in order to ascertain at the earliest possible opportunity whether any drug is suitable for full development or not. Key to this is innovation, planning careful site selection and good project management. These buzz-words have become more associated with the new trends of POC, microdosing and biomarker studies, yet they equally apply to the more traditional phase study. These will produce added value if planned and managed by the right CPU with an experienced team and in the right location. References 1. Dimasi JA (2001): “Risks in new drug development: approval success rates for investigational drugs”, Clinical Pharmacology and Therapeutics 69, pp297-301 2. The Merck Manual of Geriatrics, Ch 97, Ageing and the Kidney: www.merck.com/mkgr/mmg/sec12/ch97/ch97b.jsp 3. EMEA Committee for Human Medical Products (CHMP) (2004): “Notes for guidance on the evaluation of the pharmacokinetics

of medicinal products in patients with impaired renal function: CHMP/EWP/225/02”. Available via www.emea.europa.eu/pdfs/ human/ewp/022502en.pdf [Accessed January 10th 2007] 4. US Department of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and Research (2003): “Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic function: Study Design, Data Analysis and Impact on Dosing and Labeling”. Available via http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm072123.pdf 5. B  uoen C, Bjerrum OJ & Thomsen MS (2005): “How First-TimeIn-Human Studies are being performed: A survey of Phase 1 Dose-Escalation Trials in Healthy Volunteers Published between 1995 and 2004” J Clin Pharmacol 45:1123-36 6. Littman BH & Williams SA (2005): “The ultimate model organism: progress in experimental medicine”, Nature Reviews 4(8) p613-8 7. Newbold P (2004): “Challenge Agents and Microdosing”, Presentation at the Insitutute of Clinical research conference “From Concept to Reality” 8. Wilding I (2005): “The art of the possible”, Scrip Magazine 146 p19 9. w w w . m h r a . g o v . u k / H o w w e r e g u l a t e / M e d i c i n e s / Licensingofmedicines/ Clinicaltrials/UKclinicaltrialauthorisation assessmentperformance/index.htm

Figure 2: Schematic of an example of a multi-functional or “umbrella” type protocol Combination products Dose level (mg)

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Dr Brian Sanderson MBChB, MRCGP, MFPM (Dis), DCPSA, Medical Director Chiltern Early Phase Ltd Brian graduated from the University of Dundee in 1986 and pursued a career in General Practice (Member of the Royal College of General Practitioners) before commencing his career in pharmaceutical medicine with Inveresk in 1994. Brian has developed an interest in first into man administration and biomarker measurements in healthy volunteer trials. He has been Principal Investigator or Co-Investigator on over 350 Phase 1 studies and is an Author of over 60 Phase 1 study reports. Brian holds the Diploma in Clinical Pharmacology, is a member of the American College of Clinical Pharmacology, the Institute of Clinical Research Clinical Pharmacology Special Interest Group and is a regional Fellow of the Royal Society of Medicine. He has also achieved Membership by Distinction of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians for whom he acts as an Educational Supervisor for Higher Medical Training in Pharmaceutical Medicine and is a Fellow of the Royal Society of Medicine. Brian’s combined GP and clinical research background has gained him practical experience in project planning and implementation. Email: brian.sanderson@chiltern.com.

Journal for Clinical Studies 35


IT & Logistics

ABPM in Clinical Trials: Logistics In the last issue, the importance of using ambulatory blood pressure measurements (ABPM) in clinical trials for antihypertensive drugs and as a safety biomarker was discussed. Given the advantages of ABPM, one must examine why it is so rarely used in clinical trials. This article discusses the issues involved in conducting trials using ABPM and demonstrates why a centralised ABPM system is necessary to overcome these. Data Collection Conventional blood pressure measurements (CBPM) are easy to record on a standard clinical research form. This is not as straightforward for ABPM, as consideration must be given to the devices and software used, the number of measurements and their validation according to the study protocol. ABPM device selection ABPM devices are for professional use and, while about twothirds of them are validated in accordance with a recognised international protocol and recommended for use1, they tend to be somewhat more expensive than office BP devices. Ideally, a single model would be used for all ABPMs in a clinical trial. While reasonable for Phase I and Phase II trials, this is impractical for Phase III trials and most Phase IV trials. Furthermore, device malfunction planning is problematic as the use of a backup device per centre is prohibitively expensive whereas, with a replacement system, there is a risk of patients missing an optimal time for an ABPM while the centre is awaiting the replacement. A more practical approach is to allow investigation centres to use their existing validated devices regardless of the models. However, though validated, each device model has a small error when compared to a â&#x20AC;&#x153;gold standardâ&#x20AC;? which can become significant when compared to that of another model. For example, one device may tend to overestimate a pressure while another might tend to underestimate it. If these devices were used on the same patient during a clinical trial, those device differences would seriously compromise the ability to measure the treatment effects. Therefore, a method of ensuring that the same model is used on the same patient throughout the trial is essential. A centralised ABPM system, such as dabl2, overcomes this problem by linking to a number of validated devices. Furthermore, they provide controls to ensure that the same make and model are used on the same patient throughout the study. ABPM validation ABPMs for clinical trials have stricter and more complex validation requirements than those required for routine ABPMs. For instance, they usually have to start within a standard and rather short timeframe and they must cover the full period between drug intakes on both the start and return days. Few missing measurements are permitted and, depending on the target efficacy of the drug, there may be particular emphasis on sufficient measurements during certain periods, such as nocturnal and matinal hours, which are themselves governed by 36 Journal for Clinical Studies

drug intake times, bed times and rising times. Further complexity may be added where chronotherapeutic (timing of dosing) effects are part of the trial. This validation must be performed as soon as the data is loaded from the device. Where an ABPM fails the validation test, a repeat ABPM may be required as soon as possible. ABPM initialisation, uploading and storage A clinical trial will usually require ABPM devices to be initialised with requirements that may differ from those used for routine ABPMs. While various types of proprietary software will permit this, the methods used will differ greatly and require manual selection of the correct routine with the consequential room for human error. When loading the ABPMs, it will be necessary to ensure that study ABPMs are separated from other groups of ABPMs. For example, the dabl ABPM system for clinical trials is specifically designed to accommodate this2. Data storage formats differ between proprietary software. This not only complicates the validation analysis, but also the later requirements to standardise them before analysis. A method of transferring the ABPMs securely to the data centre also needs to be devised. Study Progress Where CBPMs are used, entry requirements, drug titration, other changes and alerts are usually based on the level of BP measured. Where ABPM is used, these requirements can be more complex. Software analysis for the next step Clinical trials can have several designs3,4 but each involves several visits, some of which require standard changes (for example at the start of treatment or on a change of regimen in crossover trials) and some of which require change dependent on the results of the ABPM (for example drug titration or the addition of further drugs). These changes should be determined by the software, as they may be based on a set of ABPM-derived statistics with which investigators may be unfamiliar. Similarly, the optimal date of the next visit can be calculated and appointment diary facilities provided in order to optimise protocol adherence. Where ABPM is used as a cardiovascular safety biomarker, alerts may be dependent not only on the results of the most recently loaded ABPM, but also on changes between that ABPM and a previous one. Regardless of the situation, ideally a system should provide an investigator with clear instructions as to the next step. Blinding of measurements The goal of blinding medication arms of a clinical trial from investigators is quite difficult to achieve in practice. A major step, recommended by the FDA, is, where possible, to blind the test results3. Where the software provides all of the information required for the next step, there is no reason to show the actual measurements either to the investigators or to the monitors. This greatly improves the quality of the blinding. In a centralised January 2011


IT & Logistics system, values need only be visible to a supervisor to review specific ABPMs. Transparency and auditing It is essential that the integrity of the data can be proven. Therefore, at every stage in the process, a full audit must be recorded of what was done, so that all transactions are transparent and the full sequence of events can be followed. All changes must be reversible and all data must be backed up. Contingency plans must be in place in case of loss of access to the system. All export files must be electronically signed to guarantee their integrity. Solutions While Phase I and Phase II trials using ABPM may be conducted with difficulty using proprietary software, the amount of manual input required increases the risk of mistakes and the loss of patients to the trial. However, it is not reasonably possible to conduct Phase III clinical trials in this way. Proprietary software by manufacturers cannot be expected to provide the facilities necessary to run a clinical trial using ABPM. They are designed as day-to-day management tools, and the increase in complexity that would be needed to make them suitable for the management of clinical trials would be neither cost-effective nor reasonable for the majority of users. In order for a clinical trial to use ABPM, a centralised system with the following facilities is mandatory: • Standardised initialisation and reading of validated ABPM devices, regardless of the make or model. • Assurance that the same make and model of device is used on the same patient throughout the study. • Standardised recording and presentation of data. • Validation of ABPMs immediately after uploading the ABPM data. • Next step instructions for investigators including completion of missing data with impossible and unlikely combinations handled appropriately. • Safety alerts provided where necessary. • Withdrawal of patients as necessary. • In multi-centre trials, investigators, monitors, supervisors and data managers should access data according to their needs and requirements. • The provision of reports for monitors. • An export, in electronically signed files, of raw and calculated parameters as required for the study analysis. Conclusion While regulatory authorities have been slow to recognise the benefits of ABPM in clinical trials, and pharmaceutical companies have been slow to recognise their potential for the development of new types of drugs and regimens, the hitherto logistical problem of conducting such a trial has been a major obstacle behind the reluctance to either use it or demand it. Recently, however, a number of companies have been pioneering software for such clinical trials. This is very important both from a safety perspective, and in determining the unique attributes of a new or improved drug. The EMA adopted its guidelines on 22 December 2010, in which “ABPM is strongly recommended for the evaluation of new antihypertensive agents”.5 In the USA, research on behalf of the 38 Journal for Clinical Studies

Cardiac Safety Research Consortium is showing the importance of ABPM as a cardiovascular safety biomarker in clinical trials, and a paper is in preparation for publication this year.6 With the provision of clinical trial systems, such as that provided by dabl2, the recognition by the EMA5 of its importance, and the research in the USA6, the final barriers to the use of ABPM in clinical trials have been overcome. Different forms of hypertension and blood pressure irregularities have been described since ABPM began over 30 years ago but, to date, specific treatment of these conditions has been largely ignored. The door is open to assessing new drugs and new chronotherapeutic regimens or formulations. Furthermore, the use of ABPM as a cardiovascular safety biomarker will lead to safer drugs where more side-effects and better BP-derived markers can be assessed. The benefits for patients, and the opportunities and financial benefits for pharmaceutical companies, are enormous. Perhaps, as a result, this decade will see a revolution in the treatment of cardiovascular diseases and the elimination of unacceptable cardiovascular safety risks. References 1w  ww.dableducational.org/sphygmomanometers/devices_3_ abpm.html (Accessed 10 January 2011) 2 www.dablresearch.com (Accessed 10 January 2011) 3U  S Food and Drug Administration, International Conference on Harmonization (ICH). Guidance on Statistical Principles for Clinical Trials; Availability. Federal Register 1998;63(179):4958398. Available from URL: www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM129505.pdf (Accessed 10 January 2011) 4U  S Food and Drug Administration, International Conference on Harmonization (ICH). Draft Guidance: E12A Principles for Clinical Evaluation of New Antihypertensive Drugs. 2000. Available from URLs: www.fda.gov/RegulatoryInformation/ Guidances/ucm129461.htm and www.fda.gov/downloads/ RegulatoryInformation/Guidances/ucm129462.pdf (Accessed 10 January 2011) 5 E uropean Medical Agency, Committee for Medicinal Products for Human Use. Guideline on Clinical Investigation of Medicinal Products in the Treatment of Hypertension. EMA/238/1995/ Rev. 3. 2010. Available from URL: http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2010/12/ WC500100191.pdf (Accessed 06 January 2010) 6H  eilbraun J on behalf of the Cardiac Safety Research Consortium. Points to consider for thorough blood pressure evaluation. (In progress) Available with membership from URL: https://www. cardiac-safety.org/papers/in-process/points-to-consider-forthorough-blood-pressure-evaluations (Accessed 10 January 2011) Neil Atkins a director of dabl Ltd and statistician, has 25 years of research experience in hypertension and blood pressure measurement. He is an author of the BHS and ESH-IP validation protocols and is recognised as a leading expert in blood pressure device validation. Email: neil.atkins@dabl.eu

January 2011


IT & Logistics

Efficient and Cost-Effective Monitoring for Observational Studies The success of new biopharmaceutical products no longer depends on simply obtaining approval from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) or other regulatory bodies. While such approvals allow companies to market their products, there is no guarantee that products will achieve acceptance in the global marketplace. Stakeholders such as reimbursement agencies, managed care organisations and patient-advocacy groups now demand more data than results obtained just from pre-approval clinical trials, which typically involve relatively small numbers of patients, are narrowly-focused by stringent eligibility criteria to ensure uniformity, and are evaluated by highly-trained research investigators. Today’s new products must demonstrate efficacy in a controlled environment, and “effectiveness” in a real world setting that embraces patients having multiple co-morbidities being treated by physicians according to standard of care, rather than a rigid protocol developed by the product’s manufacturer. Given the significant side-effects that have been demonstrated for several new products (albeit at a relatively low incidence), such effectiveness assessments also require many more patients than were evaluated for pre-approval clinical trials in order to assess the product’s true safety profile.

The evolving drug development environment described above has ushered in an era in which observational studies -including long-term registries, retrospective analyses and various approaches to collecting patient-reported outcomes -- are now widely employed to obtain critical information regarding the appropriate use of newly approved products. Such studies – which are non-interventional in the sense that no study drug is administered – seek to evaluate patients in a natural setting. As such, these studies typically employ few if any patient inclusion/ exclusion criteria, involve no protocol-driven visit or sampling requirements, and are often conducted by physicians who have little or no experience with clinical research. This latter study design element – reliance on medical personnel with little resemblance to the investigational sites typically employed for randomised clinical trials (RCTs) – creates obvious challenges. These include ensuring that physicians and their staff are adhering to even very modest requirements for observational study, and that data is collected and entered in a timely and credible manner. This article describes various approaches to monitoring the performance of sites participating in observational studies, as well as the advantages and limitations of each approach. Monitoring Site Performance for Observational Studies – Potential Options The range of monitoring options for observational studies varies from the same intense approach used for RCTs, to dispensing with monitoring altogether. As will be seen, there is no approach that will work for every type of observational study. Each option must be considered within the context of the study’s objective and the purpose for which the resulting data will be used. Option No. 1 – Intense On-Site Monitoring: The most effective method to monitor site performance for any clinical research study is the approach taken with RCTs, namely sending contract research associates (CRAs) to inspect the physicians and their staff at six- to eight-week intervals. The CRAs will then spend an entire day on-site scrutinising all aspects of patient enrolment and treatment, auditing study drug inventory and reconciliation logs, and evaluating procedures for data collection and case report form (CRF) completion. However, some registries can last ten years or more and may involve 20 or more countries and 1000 or more sites. Using such an approach is impractical as the travel costs for the inspectors alone would be millions of dollars. Employing an RCT-type monitoring approach is also unnecessary for observational studies. For example, the medications patients receive are all commercially available, eliminating the need to inventory and reconcile study drug logs. The wide use of electronic data capture (EDC) for observational studies also generally removes the need for CRF review.

40 Journal for Clinical Studies

January 2011


IT & Logistics Option No. 2 – Limited On-Site Monitoring: To address the cost of monitoring for lengthy observational studies, many sponsors simply choose to reduce the frequency of on-site visits from every six to eight weeks, to every six to twelve months. While such an approach certainly results in a more palatable budget, the lack of interaction with CRAs typically leads to a deterioration of site performance, both in terms of patient enrolment and data collection and entry. The reason is obvious: given their limited experience with clinical research, physicians and staff involved with observational studies need frequent contact to reinforce appropriate performance. Without repetitive contact they quickly revert to their routine behaviours. Another approach is to eliminate monitoring completely and simply collect patient-related information electronically, or have sites submit data via fax or expedited delivery. This option is effective for observational studies in which retrospective information is simply collected from a managed care database. It is also widely employed for studies involving abstraction of information from medical charts, since inspectors are typically precluded from examining patient records due to privacy restrictions. However, such an approach for prospective observational studies has obvious limitations and would call into question not only the credibility of patient enrolment information, but also the data that was collected.

patients, ensuring identification of all potential safety-related events and quickly triaging potential problems. Figure 1 illustrates the variety of observational study tasks that can be successfully handled by a Remote Monitor managing their sites via phone. Figure 2 is a standard approach to monitoring sites participating in a long-term observational study such as a registry, via a combination of monthly remote monitoring and annual on-site visits. The combined approach provides an effective means for ensuring that source documents, informed consent forms and regulatory documents can be audited (via yearly on-site visits) and that sites have ample opportunity to “bond” with their primary monitor via frequent interactions on the phone. The key to ensuring that the model works as designed is as follows: 1) the Remote Monitor must be an experienced Figure 1: The variety of site management tasks that can be successfully managed by a remote monitor engaging with their sites via phone, acting in a similar capacity as an air traffic controller monitoring the status of aircraft circling a control tower

Remote monitor

Assist/motivate sites: recruitment and regulatory

Ensure timely CRF completion and query resolution

Option No. 3 – A Balanced Approach to Monitoring: An Triage issues to project Identify potential alternative to providing too much or too little monitoring is to team and facilitate impediments to quality resolution performance and engage with sites remotely via telephone. Such an approach propose solutions Assist with collection is frequently confused with call centres, where individuals safety information Maintain site with a minimal amount of clinical training assist with patient communication log Track compliance recruitment, market access tracking and similar activities. Retrain if needed Share ‘best practices’ In contrast, Remote Monitors for observational studies are Primary point Distribute newsletters / Identify potential of contractor site experienced CRAs who play a critical role in managing day-tosite correspondence requiring an on-site visit Physicians and day site performance. Much like an air traffic controller, who does staff not need to be physically in the cockpit of an airplane to know whether the plane and crew are performing as expected. Figure 2: A standard approach to monitoring sites participating in a long-term observational study such as a registry, via a combination of monthly remote monitoring and annual on-site visits. Remote Monitors can ascertain whether sites are meeting expectations by checking indicators such as Remote monitor the time required to complete On-site monitor study start-up documents, the need for repeated training of study procedures and the amount and quality of data entered via electronic data Site capture (EDC) (to which the Remote Monitors typically have access). Remote On-site On-site On-site monitoring obviously cannot monitoring monitoring monitoring visit visit visit be employed for source document verification and Year 1 Year 2 Year 3 other tasks that require an onsite visit. However, frequent contact with sites via phone, even if only for a short period of time, is a very effective way to reinforce desired Remote monitoring calls behaviours such as enrolling 42 Journal for Clinical Studies

January 2011


IT & Logistics CRA who is adept at identifying early warning Figure 3: An example of how frequent interactions between the Remote Monitor and sites can reveal information regarding “safety signals” that might not otherwise be reported to the Sponsor’s Safety Department, and how this signs of potential problems; 2) an effective information is triaged triage system must be established to ensure that appropriate actions can be taken in response to early warning signs; and 3) a “pool” of additional Sponsor on-site monitoring visits should be included in safety dept the budget to make out-of-cycle visits to sites that may be experiencing difficulty meeting their Ensuring all ‘safety signals’ are identified study obligations. Typically this pool can be as and addressed small as an additional 10%, and is used on an as4 1. Upon prompting by needed basis for under- or over-performing sites, remote monitor, site recalls unusual response or for cause. of patient during last visit Although this approach appears to break the Site 2. Remote monitor contacts most important commandment of monitoring medical affairs to discuss Site Medical – that all sites have a single point of contact – medical affairs indicates Site affairs response was likely an that is not the case. For observational studies, the SAE Remote Monitor is always designated as the site’s Site 3. Remote monitor contacts single point of contact, given the infrequency with site and works with them to ensure event which the on-site monitor visits the site. is forwarded to sponsor 2 As mentioned before, one of the primary safety department 1 3 responsibilities for a Remote Monitor is triaging 4. Site forwards safety information to sponsor unexpected developments to identify potential using standard procedure problems quickly and achieve prompt resolution. One of the best examples of this responsibility is Remote monitor the early identification of possible safety-related events. Many observational studies are conducted to monitor the long-term occurrence of serious These changing patterns have focused attention on the need adverse events (SAEs) in the real world of standard clinical practice. However, despite the extensive training typically to carefully evaluate the methods employed for monitoring provided by sponsors regarding the importance of reporting observational studies. This ensures not only that costs are potential SAEs, sites involved with observational studies often minimised, but also that the approaches employed yield reliable over- or under-report such events. This can be due to their lack results that will satisfy all stakeholders involved, including of experience with clinical research, their unfamiliarity with regulators, reimbursement agencies, physicians and patients. One such method is the use of frequent remote monitoring by products new to their practices, and/or their limited contact with an experienced CRA to provide sustained engagement with sites the sponsor or monitor. This challenge could be addressed by instituting a rigorous throughout the long duration of a registry. When appropriately RCT-type approach to frequent on-site monitoring, or by using staffed and managed, remote monitoring can provide an a full-time Medical Monitor to engage with sites and field effective means to assess site performance, triage problems questions from them. Both of these approaches are expensive and maintain motivation. When linked with limited on-site and generally unnecessary. A better method is illustrated in visits to audit proper documentation of events and outcomes Figure 3, which shows how frequent interactions between the and the appropriate completion of regulatory documents, the Remote Monitor and sites can reveal information regarding combination provides an effective and cost-efficient approach “safety signals” that might not otherwise have been reported to for monitoring observational studies. the Sponsor’s Safety Department. In this example, the Remote Monitor uses probing questions to learn about an “episode” that Dr. Ronald E. Weishaar is Executive may or may not have been an SAE, then discusses the episode Director, Observational Research, for with an appropriate physician in Medical Affairs to ascertain its PharmaNet’s Phase IV Development Group. potential importance. If the episode is deemed to be a potential Dr. Weishaar has global responsibility SAE it is reported to the sponsor’s safety department for further for the design and implementation of review. The Remote Monitor then questions other sites regarding non-interventional studies and has the occurrence of similar episodes and, if warranted, initiates extensive experience with safety registries, supplemental training to ensure that this safety signal is being efforts to evaluate standard of care for different conditions and uniformly reported to the sponsor. studies with combined clinical/scientific and commercial/strategic objectives. He has also coordinated Phase IV projects involving Conclusion The growing importance of evaluating products in the real at-risk patient populations, with a particular emphasis on research world has led to an increase in the conduct of registries and in seniors. He holds a BS and MA in Chemistry and a PhD in other types of observational studies and greater emphasis on Pharmacology and has held previous positions with the Huntington the overall effectiveness and long term safety of new products. Institute, Parke-Davis and Coromed/Omnicare Clinical Research. This has resulted in larger and lengthier post-approval studies. Email: rweishaar@pharmanet.com. 44 Journal for Clinical Studies

January 2011


IT & Logistics

Leveraging Clinical Logistics to Improve Trial Efficiency Taking a coordinated approach to clinical logistics services ensures that supplies reach the right locations in the right conditions at the right time – reducing costs and avoiding trial delays In today’s competitive biopharmaceutical environment, no one can afford delays in critical trial milestones because of problems with clinical supplies and logistics. As trials become more global and complex, however, sponsors are finding it increasingly difficult to arrange reliable delivery of trialrelated supplies to multiple locations around the world. One recent survey reported that only 23 percent of sponsors rated their clinical supply chain as effective, and just 13 percent said their clinical supplies usually arrive on time and complete. In another survey, 41 percent of European clinical sites ranked “availability of study drug” as their most frequent cause of study delays. To improve logistics performance while also reducing costs, many sponsors are turning to outside companies for comprehensive clinical logistics services (CLS). A typical CLS partner would provide centralised coordination of all clinical trial supplies and logistics, related inventory data management services, and quality monitoring, as well as overseeing subcontracting relationships such as lab services and couriers. The two major components of clinical logistics are: – Clinical Supply Chain Management, including: – Clinical Trial Supplies – Coordinating drug supply from wholesalers and manufacturers, managing import/export requirements, labelling, warehousing and inventory control, distribution of drug supply to trial sites, and return and destruction of unused medication – Ancillary Supplies – Distributing testing and diagnostic equipment, maintaining lab supplies, and providing CRFs, diaries, investigator brochures, patient retention material and other site documents • Lab Services, including selection of analytical laboratories, organising a centralised lab system/process, supplying forms and kits for patient visits, overseeing transportation logistics for lab samples, managing/cleaning lab results, and long term sample storage. A centralised approach to CLS eliminates costly delays by coordinating all three components and integrating them into the overall clinical trial process. The key for sponsors is to find a CLS partner with the knowledge and experience to effectively manage worldwide clinical trial logistics, as well as the required depth of resources, including: a global distribution infrastructure that can properly handle expensive study supplies; local expertise in import/export regulations; and sophisticated technology systems to track shipments, inventory levels and lab results. In short, a sponsor’s CLS partner must be able to globally deliver the right products to the right locations in the right condition at the right time – an accomplishment that will 46 Journal for Clinical Studies

help accelerate site readiness, improve lead times, reduce study costs and increase compliance. Establishing the Role of Clinical Logistics Leader One of the most important best practices to create a strong, efficient clinical logistics system is to have a manager in place to specifically oversee and coordinate all logistical operations – a position that has come to be known as a “clinical logistics leader.” What do clinical logistics leaders do? It is their responsibility to oversee all aspects of the clinical trial materials related to a study, including: • Defining and deploying a clinical logistics strategy in concert with a sponsor and other relevant stakeholders • Taking an active liaison role between clinical managers, the sponsor, and third parties involved in supplying materials • Managing the overall logistics plan and resources in a coordinated fashion to maximise the efficiency of: – Wholesalers – Manufacturing providers – Drug depots – Ancillary supplies – Printing companies – Device and other medical equipment providers – Central laboratories – Courier providers • Leveraging appropriate technology solutions to improve efficiency and maintain quality. Most important, a clinical logistics leader ensures that logistical planning is integrated into the trial process – beginning with study start-up planning – so the supply system will mesh seamlessly with trial requirements and timelines. This close coordination of logistics will accelerate site readiness, minimise supply and distribution issues, and reduce the risk of delays – improvements that save time and money. Efficiently Managing Clinical Trial Supplies With the high cost and stringent handling requirements of many biopharmaceutical products, the logistics of clinical trial supplies are more critical than ever. The value of some study drugs can reach tens of millions of dollars, so it is essential to avoid overproduction, oversupply, and inventory expiration issues. The key functions for managing clinical trial supplies include: • Developing cost-efficient clinical supply strategies and forecasts, supported by sophisticated computer simulations • Size optimisation of shipment containers, and shipment consolidation across trials to depots and sites • Ensuring that appropriate import/export requirements are met January 2011


IT & Logistics

• Actively managing the labelling process for drug supplies • Managing GMP vendors, including work order management and complaint management • Providing investigators and depot partners with documents to support staff training • Defining, executing and controlling a suitable drug storage and distribution system • Closely monitoring supply couriers to maintain schedules and performance • Day-to-day monitoring of inventory stocks along the entire supply chain – from the manufacturers to local depots and investigational sites • Continually evaluating logistics and supply data to strengthen and refine strategies • Ensuring a suitable return and destruction system, including managing the collection of all relevant documentation to minimise patient and sponsor risks. Trial supply functions increasingly require specialised knowledge and infrastructure that may not be available from typical GMP or drug distribution providers – especially when trials include hundreds of sites in multiple countries. An experienced CLS partner can help ensure regulatory compliance for far-flung logistics activities, as well as implement integrated global solutions that support consistent, high-quality processes across all trial sites. For multinational trials, global regulatory experience is also vital. Improving Supply Forecasts Forecasting has grown into one of the most important aspects of effective clinical supply management. Sophisticated simulations are essential to provide answers for key study supply questions, such as: • What quantity of supplies does the study require? • What are optimal dispensing unit/kit sizes? • What lead times are expected for local importation, and what is the implication for patient recruitment? • What if recruitment is faster or slower than anticipated? • What is the impact of initiating additional sites, or opening sites in additional countries? • When should additional production runs be scheduled? www.jforcs.com

• How do medication expiry dates affect the study schedule? Obtaining the right answers to these questions can substantially reduce expenditure for a sponsor by avoiding overproduction, overstocking and supply shortages. As many as 30 variables might have to be considered, weighing factors such a drug cost, number of patients, number of sites, recruitment success rates, number of depots, product expiration dates, and the size of production batches. Given this multiplicity of variables, robust forecasting and simulation software – plus experience in using the software in complex trials – is required to achieve the appropriate balance of total drugs needed, stock levels per depot, and shipment frequency for each study. Coordinating Ancillary Supplies Ancillary supplies are an important element of clinical supply chain management. Clinical trials require a wide variety of ancillary supplies in addition to the trial drug, such as diagnostic and testing equipment, medical devices, refrigerators, centrifuges, ECG machines, test strips, and disposable products, as well as computer equipment such as instructional DVDs, CDs and tapes. Every site must also be supplied with numerous trial documents, including site reference manuals, investigator brochures, CRFs, diaries and trial protocols. The growing complexity of many trials has increased both the volume of these ancillary supplies and the number of vendors needed to produce them. As a result, global trials require centralised management of all ancillary materials to ensure that essential supplies reach every site in a cost-efficient manner to save sponsors time and money. By coordinating its efforts with clinical resources, a centralised ancillary supplies team can determine what supplies are needed for a specific trial, and then ensure that the required material reaches the sites to meet study timelines. Transporting these supplies requires country-by-country knowledge of import/export rules, such as the fact that some countries ban the importation of certain diagnostic and testing equipment. Key capabilities for efficient, centralised ancillary supply services include: • Accurate supply forecasts • Well-established material ordering processes Journal for Clinical Studies 47


IT & Logistics • Full inventory transparency, including location data – a critical feature for recall support • System control and facilitation of manufacturing processes (e.g., kit assembly) • Barcode usage for all relevant system applications • Inventory and expiry-date management, including re-supplies (e.g. test strips) • Automatic, real-time proof of delivery • Sophisticated reporting on expiry dates and shipment status Centralising Lab Services As clinical trials address increasingly complex diseases, the lab services required to process the samples must also be more sophisticated. With biomarkers, genetic sampling, and other new types of testing becoming commonplace, selecting reliable lab resources and managing time-sensitive shipments between multiple sites and various specialised labs is a substantial logistical challenge. Sample analysis can represent as much as 80 percent of study data, making it critical to study success. Providing reliable lab services and consistent, robust data requires meticulous planning of sample handling, transport, analysis and reporting. Sponsors are increasingly turning to CLS providers that can centralise the provision of lab services and manage lab-service logistics. A qualified lab/logistics partner must provide safe and reliable handling of sample collection and shipments around the world, with services that typically include: • A centralised network of highly qualified labs that have been pre-screened for ICH-GCP compliance, quality, data security, and reliability • Lab vendor management, including performance and quality oversight • Global import/export management • Delivery of kits and lab supplies to the trial sites • Transportation and tracking of lab samples • Data tracking and integration services • Real-time lab data cleaning and security • Regulatory compliance Integrating Lab Information Integrated lab information systems and databases are also key success factors for centralised lab services. A consolidated database that brings together CRF or eCRF and lab request forms – as well as results and clinically relevant checks – improves accuracy, avoids duplicate data entry, clarifies the primary data source, and harmonises query procedures. The result is a reduction in the number of queries, avoidance of late-stage data issues, and faster database lock. A robust lab information system is essential to maximise efficiency throughout the lab sampling and analysis process. A system that is integrated with EDC simplifies the data capture process, and allows the clinical logistics, clinical operations, and data management staff to use the same tool for query resolution and safety review for both the trial sites and labs. The characteristics of a robust lab information system should include: • Real-time data cleaning capabilities • Ability to track shipments and samples • Automated sample recognition system, such as barcodes 48 Journal for Clinical Studies

• Flexible flagging and blinding capabilities • Multiple options for reporting (e.g. fax, e-mail, hard copy) according to site preferences • FDA 21CFR Part 11 compliance • Electronic data import from all the connected analysers • Support for CDISC-based data export • Daily data integration into EDC solutions • Clinical significance management via EDC Equally important, the data gathering processes must fit into the normal routine of study investigators. Investigators and other study personnel are not lab physicians, so they need easy-to-follow documentation and procedures, and minimal data entry requirements (such as using barcodes) to make the data entry process as simple as possible without compromising data quality. Meeting the Logistics Challenges of Today – and Tomorrow Complex global trials require centralised, end-to-end management of clinical logistics to meet drug development timelines, reduce costs, improve compliance, and increase efficiency in every aspect of clinical trial supplies, ancillary supplies and lab services. To meet that challenge, sponsors must select a CLS partner that can take a holistic approach to logistics by leveraging global experience, integrated solutions, and a multinational infrastructure. A clinical logistics leader plays a crucial role in the drive to greater logistics efficiency by coordinating and integrating logistics into study processes, and ensuring that the right resources, technology, and expertise are applied to the full spectrum of the clinical supply chain. By strategically selecting the right CLS partner, a sponsor can reduce total drug development costs, improve regulatory compliance, optimise the flow of costly study drugs, enhance data management, reduce overhead costs, and – most importantly – increase patients’ safety in every clinical trial. Sponsors can also achieve greater piece of mind – knowing that the right supplies are in the right places, in the right condition, at the right time, so they can avoid costly trial delays and reduce risks to their patients around the world. References Bio IT World, March 2008 CenterWatch 2006 (European Clinical Sites Survey) Jens Mattuschka, Director, Clinical Logistics Services Worldwide, PAREXEL International. As Director of Clinical Logistics Services Worldwide at PAREXEL, Jens Mattuschka oversees a global team focused on providing biopharmaceutical companies with high quality, centralized coordination of clinical trial supplies, ancillary supplies, and central lab services. During his tenure at PAREXEL, Mr. Mattuschka has served in several senior roles in the areas of project and data management supporting a variety of international clinical trials. Previously, he worked in clinical research at Charité university hospital in Berlin . Mr. Mattuschka is Clinical Data Management Trainer for the PAREXEL Academy , and a teacher of the Academy’s Clinical Research Study Program with the University of Wales. Email: Jens.Mattuschka@PAREXEL.com January 2011


Africa subsection

Clinical Trials South Africa 2010 – Regulatory Perspective The South African clinical trial regulatory landscape in 2010 can best be described as one of change and collaborative efforts. External consultancy to assist the Medicines Regulatory Authority (MRA) with the backlog of clinical trial and medicines registration applications was continued. Revisions were proposed to the current legislation to increase the application review fee, and to facilitate the formation of the South African Health Products Regulatory Authority (SAHPRA). The Department of Health moved to Civitas Building, two blocks from its previous offices at Hallmark Building in July 2010. This was a tumultuous period for both applicants and MRA staff plagued by infrastructural problems. Although this hampered the already burdened clinical trial approval timelines, estimated at 5-6 months, all remaining 2010 submission and review meeting dates were maintained. The focus on the initial application reviews, however, resulted in delays to the approval timelines for protocol amendments and new investigators. Seven submission dates have been allocated for initial clinical trial application dates for 2011. The application approval timelines will be monitored during 2011 with a planned constructive feedback process to the MRA as well as to the clinical trial applicants. The Industry Task Group (ITG), made up of a collaboration of trade and professional associations, engaged positively with the MRA to address issues that affected the health products industry. Some milestone achievements in the ITG collaboration with the MRA were the consultation and agreement of proposed application review fees, initiation of training for submission of electronic applications for medicines registration, initiation of the review and revision of clinical trial application documents, and continued dialogue on managing application review delays. PIASA (Pharmaceutical Industry Association of South Africa) and SACRA (South African Clinical Research Association) collaborated to conduct a survey amongst industry professionals on their perceptions of regulatory barriers experienced by their organisations in the execution of clinical trials in South Africa, as well as their recommendations for improvement. The results of this survey will be shared with government stakeholders to increase the awareness of these barriers and strategise a means of removing these barriers to improve the clinical trials environment in South Africa. Changes and collaborative efforts took place not only on the regulatory front, but also in the ethics arena. The National Health Research Ethics Council, a body that was formed to regulate matters of research ethics in South Africa, initiated training and capacity building of ethics committees in South Africa. This is part of the process toward accrediting ethics committees to meet the stringent requirements as described in the Ethics in Health Research: Principles, Structures and Processes guidelines. Due to varied quality levels of good clinical practice (GCP) training and concerns raised by local ethics committees, industry proposed the need for standardisation of GCP training curricula in 2009. Minimum requirements were proposed during 2009 and finalised in 2010 for the training curricula, facilitation and review 50 Journal for Clinical Studies

of all GCP training providers in South Africa. These minimum requirements stipulated the incorporation of South African GCP guidelines as well as international guidelines in the curriculum development. Training on GCP was to be conducted by trained and experienced facilitators. The process was spearheaded by the GCP subcommittee of industry stakeholders. The subcommittee consulted with and applied to the Health Professions Council of South Africa (HPCSA) to govern the review process through its approved accreditors. HPCSA is an Educations and Training Qualification Authority (ETQA) of the South African Qualifications Authority (SAQA), and therefore a fitting independent body to govern this process. In October 2010 the HPCSA approved the application. In future GCP training providers will be required to submit applications for approval to the approved HPCSA accreditors annually. The review process will be two-fold – firstly to allocate continued professional development (CPD) points for the course, and secondly to confirm that the training provider meets the industry-set minimum requirements. The seeds of change and growth have been sown – with continued collaboration and positive efforts we can look forward to further milestone achievements in 2011 toward improving the clinical trial environment in South Africa. Savi Chetty-Tulsee, is currently the Managing Director SCT Consulting, Managing Director AGCP, Chair SACRA, Chair CRA Unit Standards Working Group, Chair GCP Sub Committee of industry stakeholders, ITG committee member, SAHPRA working group member. She has over 14 years of experience focused on clinical research operations, quality assurance and training; providing clinical research consulting services and training to industry on the foundational element of service excellence. She is committed to capacity building and effecting positive change in the local clinical research environment, has been an active member of SACRA and served on the executive committee of SACRA since 2003. Email: savi.sct@mweb.co.za January 2011


Africa subsection

The Transformation of the Nigerian Clinical Trial Sector The Emergence of the AGCPN Organisation The Association for Good Clinical Practice in Nigeria (AGCPN) is a non-profit organisation founded in 2005 to address the professional development, educational and networking needs of clinical research professionals and others who support the work of clinical investigations. The organisation is dedicated to the development and promotion of good clinical research practices. The emergence of AGCPN in Nigeria led to the recognition of clinical research as a distinctive and valuable profession, and created a forum for clinical research practitioners to exchange ideas and encourage best practices on responsible conduct of human research. Recognising the importance of sound government R&D policies towards the growth and health of the clinical research industry, AGCPN constantly lobbies for improvements in the laws and policies that govern health research. AGCPN presently has over 200 members, drawn from Nigerians in the pharmaceutical and healthcare sectors both within and outside Nigeria. The membership is wide, and represents a broad array of professionals in the health, and biomedical research scientists from academia and the biotechnology and pharmaceutical industries. AGCPN has both an international and local advisory board, and partners with like-minded organisations. AGCPN is equipped to provide professional training for investigators, potential IRB members, monitors and auditors, and to provide the necessary certification that qualifies the trainee to render services as a clinical research professional (CRP) in Africa. Positive Milestones In its five years, AGCPN has been an organ of promotion of GCP, ethics and bioethics, with an emphasis on responsible conduct of human research, and on protection of human participants. Some of the key achievements include: • Increasing the pool of trained CT professionals: AGCPN has trained over 250 individuals and certified them. The training curriculum is robust, and was developed with input from international advisors and CROs. It is designed to provide adequate knowledge for the conduct of clinical trials with the highest ethical standards to ensure the scientific integrity of data. Remarkably, all AGCPN training has been conducted in collaboration with Nigeria’s regulatory body, the National Agency for Food, Drug Administration and Control (NAFDAC). •C  ITI training: Recognising the resourcefulness of the internet and the busy schedule of many clinical research professionals, AGCPN has subscribed to a web-based training course. This was created in partnership with CITI (Collaborative Institutional Training Initiative) and is designed for professionals who want to obtain clinical research training to help advance their career, but have no time to participate in one of the national or regional training events. • Train-the-Trainer programme: In recognition of the need for sustainability and enhancing the local capacity for expanding AGCPN training activities, we have set up a training and mentorship programme to create a local faculty 52 Journal for Clinical Studies

and a pool of trainers. So far, we have created a faculty of 30 who are currently under internship, and are being prepared to serve as trainers in subsequent training. • Accreditation as a trainer of ethics committees: AGCPN has received accreditation from the National Health Research Ethics Committee (NHREC), and has been registered as a trainer for members of the institutional research ethics committees. Mobilising Stakeholders towards a Common Objective We knew from the outset that our success will depend on our ability to bring all stakeholders together for a common purpose, and for the harmonisation of strategies geared towards the transformation of the Nigerian CT arena. To this end, we have partnered with many groups, both private and public agencies. Examples of some of these collaborative initiatives include: • Advocacy to government agencies such as the Federal Ministry of Health (FMOH), the regulatory agency in Nigeria, NAFDAC, and the legislative arm of our government (the Senate and the House of Representatives). Also we established collaboration with key research institutions in Nigeria, notably the Nigerian Institute for Pharmaceutical Research and Development (NIPRD) and the Nigerian Institute for Medical Research (NIMR). • AGCPN collaborated with a Nigerian CRO, Clintriad Pharma Services, and the European-based Good Clinical Practice Alliance (GCPA), to conduct a workshop in London in May 2008, entitled ‘Clinical Trials in Africa: Strategies for the Last Frontier’ as part of the Conference organised by Informa Life Sciences on ‘Conducting Clinical Trials in Emerging Economies’. This was an important effort geared towards showcasing Nigeria as a credible clinical trial destination. Influencing Policy through Advocacy: AGCPN believes that its advocacy and lobbying activities described above helped create the fertile environment for some of the positive policy changes in the Nigerian CT arena. Some of these policies include: • Recent efforts to revise the Nigerian CT regulations and enhance NAFDAC’s regulatory capacity. • The establishment of a National Health Research Ethics Committee (NHREC) with the responsibility to regulate and provide oversight over the Institutional Health Research Ethics Committee (IHREC) – the Nigerian equivalent of the IRB. NHREC’s National Code of Conduct guiding Human Research in Nigeria provides a comprehensive manifesto for the ethical conduct of human research in Nigeria (see http://www.nhrec.net/nhrec/). • Community involvement in decisions pertaining to participants’ rights and compliance have been achieved through assisting with education of potential participants and the media. Emergence of CROs: AGCPN believes that these activities have helped encourage the emergence of CROs in Nigeria. Two US-based CROs (Clintriad – www.clintriad.com & Caligeo - www.caligeoclinical.com) and one January 2011


Africa subsection UK-based CRO (Pharmedas Clinical Research - www.pharmedascr. com) are currently collaborating with AGCPN in clinical research professional training and certification. These three are also fully operational as indigenous CROs in Nigeria. Emergence of a Molecular Pathology Laboratory • I n the spirit of private-public partnership being promoted by the Federal Government of Nigeria to promote services in the country, a private laboratory - the Safety Molecular Pathology Laboratory - has just been set up in our university campus. It is manned by an expert clinical laboratory scientist, and the laboratory is capable of running a wide array of molecular diagnostic services. The website of this molecular laboratory facility in the UNN Enugu campus is: http://www.safetybiomedical.org/index.html, www. safetybiomedical.org/assay_catalogue/assay_catalogue.html. NAFDAC Capacity-Building Initiative Perhaps AGCPN’s most important achievement to date is the current capacity-building initiative for NAFDAC. As many have acknowledged, the ability of the clinical trial enterprise of any nation to produce the desired benefits for the public health needs of the society depends on the robustness of its regulatory body. Specifically, in order for NAFDAC to evolve into an agency that is well equipped to help our nation realise the benefits of great advances in biomedical research, and an agency that helps put those advances at the bedside where they are needed, we need to develop a comprehensive and robust regulatory infrastructure that is adaptable to the changing global environment. It was thus a great honour for AGCPN to embrace, with a sense of humility as well as with great excitement, the mandate provided by NAFDAC to, amongst other things: •T  ake stock of the current status of clinical trials in Nigeria. • I dentify gaps and deficiencies within the Nigerian clinical trial regulatory process. •E  xamine cutting edge clinical trial regulatory practices. • Share best practices and experiences from other parts of the world. • Highlight the key steps that must be taken to enhance clinical trials and clinical trialregulation in Nigeria. • Set new targets for Nigerian clinical trial regulations, and the entire clinical trial industry, and create a new regulatory framework for the nation. To deliver on this mandate, AGCPN set up the AGCPN Clinical Trial Task Force, made up of key regulatory technocrats and experienced clinical trial experts based in Europe, the USA and Nigeria who have worked in pharmaceutical industries, government regulatory agencies and clinical research organisations. Dr Anthony Ikeme, President & CEO of Clintriad Pharma Services, was appointed Chairman. The Task Force concluded that the best way to kick off this effort was to have a joint NAFDAC/AGCPN Workshop, which subsequently became the four-day NAFDAC CapacityBuilding Workshop, with a town hall event for key policy-makers and stakeholders in the Nigerian pharmaceutical and clinical trial sectors as the concluding event on the last day. The Firm Commitment of Nafdac to Transform the Nigerian CT Sector NAFDAC has set itself the task of transforming the Nigerian clinical trial sector, and creating a new clinical trial regulation that is in 54 Journal for Clinical Studies

alignment with both ICH guidelines and Nigeria’s overall drug development and healthcare objectives. To this end, the NAFDAC Capacity-Building Workshop for NAFDAC regulatory staff was organised by NAFDAC in collaboration with AGCPN. This workshop was held at the Transcorp Hilton Hotel, Abuja, Nigeria, from 26th29th April 2010. The theme of the workshop was “Towards the Transformation of the Nigerian Clinical Trial Sector”. Participants in this highly-acclaimed event were drawn from North America, Europe and Nigeria, and included experts from FMOH, NIPRD, the US FDA, Health Canada, the Bill and Melinda Gates Foundation, major global pharmaceutical companies, contract research organisations (CROs), the Nigerian Association of Pharmacists and Pharmaceutical Scientists (NAPPSA), the Nigerian Clinical Trial Network (NCTN) and African Technology & Policy Studies (ATPS). In a very insightful and visionary keynote address, Dr Paul Orhii, the NAFDAC Director-General, recognised the vital role clinical trials play in pharmaceutical innovation and healthcare delivery in Nigeria. He submitted that the objectives of setting up the healthcare system in Nigeria cannot be met if Nigeria is precluded from the global clinical trial enterprise, which is designed to develop the drugs that address global health priorities and new knowledge for healthcare delivery. Workshop Goals The key goals of the workshop included: 1. Take stock of the current status of clinical trials in Nigeria. 2. Identify gaps and deficiencies within the Nigerian clinical trial regulatory process. 3. Examine cutting edge clinical trial regulatory practices. 4. Distil best practices and experiences from other parts of the world. 5. Highlight the key steps that must be taken to enhance clinical trials and clinical trial regulation in Nigeria. 6. S  et new targets for Nigerian clinical trial regulations and the entire clinical trial industry. MOVING FORWARD NAFDAC Taking Active role in Global Regulatory Affairs Nigeria has key attributes and features, such as huge human and natural resources that could potentially enable her to become a major player in the global clinical trial enterprise. The pool of talented and experienced professionals in pharmaceuticals, within and outside Nigeria, can create a path for the emergence of Nigeria as a leading outsourcing destination for clinical trials, similar to what has been achieved in India, Brazil and Korea. We are glad that NAFDAC is already taking a more active role in global regulatory affairs to enhance its visibility and reputation as a credible and competent regulatory authority in Africa, and indeed throughout the world. NAFDAC has been working on partnerships with leading regulatory agencies such as the US FDA, Health Canada, and MHRA for instance. NAFDAC is already playing a visible leadership role in WADRA. Other platforms exist with major NGOs, like WHO and non-profit sponsors of clinical trials in diseases of the developing world. AGCPN Clinical Trial Task Force is set to submit the reviewed recommended CT regulations in this first quarter of 2011. More Training It is our desire to ensure that the AGCPN training is made available across the country. To this end, AGCPN plans to complement the web-based training with annual on-site training workshops in the six geopolitical zones, as well as holding annual conferences. January 2011


Africa subsection Mandatory Certification for Clinical Research Professionals One of the greatest drawbacks to clinical trials and the most important cause of trial failures is the use of untrained or poorly trained clinical research practitioners in the conduct of clinical trials. In order to honour the efforts that have been invested in creating platforms for the development of the Nigerian clinical trial industry, and to protect the success we have achieved so far, we propose the enactment of a policy that would require all clinical research professionals to obtain certification before they can be allowed to conduct clinical trials in Nigeria. Such a policy would also go a long way to help preserve public trust. Africa-wide Collaboration In the long term, AGCPN hopes to work with other African/northern partners to establish visible footprints all over Africa. We hope to have the financial backing of government, global pharmaceuticals, medical devices companies and CROs to make this happen. We plan to push for adoption of the AGCPN model by other African GCP to achieve the following: •D  evelop general capacity for clinical trials - by which we mean; developing capacity specifically for clinical trials in the general relevant population, thus creating a pool of stringently trained investigators, monitors and auditors within African nations. •S  ustained networking and education of investigators in good clinical practice in order to safeguard and keep the highest standards in clinical research. • Create a pool of trained investigators, potential IRB members, and other professionals who are qualified to render services as Clinical Research Professionals (CRPs) in Africa • Sustained public/media enlightenment on issues of ethical conduct of human research. More Closely Harmonised CT Regulations Across Africa AGCPN is an advocate for a Pan-African group that: •w  ould be the driver for all countries in Africa to leverage their RCT industry quickly • will provide a platform for collaboration of all African nations to share safety and efficacy data • should aim at moving African CT regulators to be ready to be part of the one global regulatory system by 2020, i.e. lead Africa toward international regulatory cooperation •w  ill forge the common interest of African nations, through advocacy to all national African governments, to understand the project aim and be committed to its sustainability and implementation • e ach participating nation should showcase their commitment by contributing towards a common fund that should be used for driving the Afroguide enterprise Regional CT Regulations: AGCPN is proud to be part of the initiative for the harmonisation of CT regulations among national and regional regulators in Africa via the Afroguide (Developing Guidelines for Health Research in Africa) project by the UN Economic Commission for Africa (UNECA). This initiative hopes to create a unified platform for effective regulation of clinical trials across the region. The report of the committee with ideas for Developing Guidelines for Health Research in Africa has been submitted to the committee leaders for approval. Appreciating the importance of developing African GCP standards for improving ethical review and human subject’s www.jforcs.com

protection, AGCPN is a core partner with the Afroguide project and COPAB (Pan African Bioethics Congress), as well as with PABIN (Pan-African Bioethics Initiative). These African bioethics/ GCP groups should work together to ensure an action plan that would include the formation of regional harmonisation groups in West, East, North and South Africa to represent the subregions in ICH. If a consensus umbrella organisation cannot be functionally implementable, Nigeria could take the lead in West Africa through NAFDAC’s role in WADRA to facilitate the development of region-specific ICH guidelines in order to achieve GCP. Within the last five years, Nigeria has made giant strides in capacity-building for CTs, especially GCP advocacy and education, through the activities of AGCPN, Nigeria HIV Vaccine and Microbicides Advocacy Group (NHVMAG), NIBIN, WABIN and a couple of others. We could assist in aiding similar processes in other African countries by sharing Nigeria’s experiences, challenges and breakthroughs in: •p  romotion of GxPs and the quality assurance profession in Nigeria • s trengthening of national IRBs •p  ackaging and administration of world-class online bioethics, GxP, RCR and HSP training through the CITI programme Conclusion The introduction of improved facilities, a multidisciplinary professional infrastructure, new good clinical practice standards which would protect participants in clinical trials, and CT regulation that is robust and rigorous without being hostile to the country’s ability to attract CT from global pharma/medical equipment companies, would transform how Nigeria can make significant improvements in participating in development of new medicines/medical devices and of indigenous medicines, and would ultimately help to relieve the overwhelming burden of disease facing the nation. Africa has much to gain from properly conducted, industry-sponsored, clinical trials. To that end, the policy-makers need to understand that: – Without ethics, there is no public trust! – Without public trust, research cannot flourish! – Without research, public health is substandard. – Without health, there can be no meaningful economic development. ACKNOWLEDGEMENT The author wishes to thank Anthony C. Ikeme, PhD, President & CEO of Clintriad Pharma Services. And Francis P. Crawley, Executive Director, Good Clinical Practice Alliance – Europe for their contribution to this article. Professor Ifeoma Okoye is a Professor of Radiology at the College of Medicine, Enugu Campus of the University of Nigeria, A medical practitioner for 29 years, she has authored over 60 scientific papers and 6 books. She is the founder and chair of; the Association for Good Clinical Practice in Nigeria (AGCPN – www.agcpn.org) – for promoting responsible conduct of clinical trials in Nigeria, and Breast Without Spot Initiative (BWS – www.breastwithoutspot.org/) – a nationwide cancer prevention initiative. Email: okoyeij2002@yahoo.co.uk Journal for Clinical Studies 55


Africa subsection

Destination: South Africa South Africa has always delivered substantial contributions to medical innovation. An example of this radical pioneering work is most aptly illustrated by Dr Christiaan Barnard, who was the first surgeon to perform a human heart transplant on 3rd December, 1967. A lesser-known fact, but just as important, is that Barnard also developed a system of post-operative intensive care that greatly influenced the survival rates of all critically ill patients. Barnard is also credited with developing a new design for artificial heart valves, performing heart transplants on animals, and correcting the problem of the blood supply to the foetus during pregnancy. 1,2 Career-long dedication in the field of clinical research is not unknown in South Africa, with numerous internationally renowned professionals devoting a substantial part of their careers towards promoting the South African industry through their efforts. South Africa certainly has a wealth of clinical trials experience. There is an ever-increasing number of dedicated, focused individuals who on an ongoing and daily basis are contributing to the development of medicine and the improvement of patient care in the country. This is well illustrated by another team from Groote Schuur, who, 40 years later, pioneered a technique to transplant kidneys between HIV-positive donors and recipients. Dr Elmi Muller, a surgeon at the University of Cape Town’s (UCT) Department of Surgery in the Faculty of Health Sciences, performed the first such kidney transplant in September 2008.20 South Africa is the leading economy in Africa and a major gateway into the rest of the continent. What makes this even more impressive is that its geographic area is 1,219,090km2, slightly less than twice the size of Texas or twice the size of France. It has a stable political environment, allowing it to be an influential member of major political and economic African associations, e.g. OAU and SADC. Almost 50% of the members of the American Chamber of Commerce in South Africa are Fortune 500 companies; over 90% operate beyond South Africa’s borders in southern Africa and across the continent. Its GDP of $489.7 billion (2008 estimate), supports its ranking of 32nd out of 181 countries on the World Bank Ease of Doing Business index, and 2nd of 46 countries in sub-Saharan Africa. It is also ranked joint 9th (with the UK) of 181 in Investor Protection.7,22 Something that makes South Africa attractive to international drug development companies is the fact that the regulatory environment is very conducive to clinical trials. The regulatory authority, the Medicines Control Council, was established in 1965. It reviews over 400 clinical trial applications per annum and has approved over 20,000 medicines. The National Health Research Ethics Committee oversees and accredits all ethics committees, whether they are academic (affiliated to medical schools) or private (for private sector physicians). South Africa has an estimated population of 49 million, 56 Journal for Clinical Studies

of which nearly 11% (5.2 million) is living with HIV. The agestandardised death rate indicator shows that HIV/AIDS, and TB among HIV-positive as well as -negative people, are the leading causes of death. However, non-communicable diseases, cardiovascular diseases, cancer and injuries are also contributing heavily to the mortality rate. Shockingly, though not surprisingly, the causes of death among children under five years of age are neonatal causes, HIV/AIDS, diarrhoeal diseases, measles, pneumonia and injuries. This substantiates the concept that South Africa has a distribution of First and Third World diseases. Also, the rich cultural diversity of the population makes it the ideal destination for inter-ethnic studies. An added advantage is the reverse seasons from the Northern Hemisphere, essentially allowing more time for recruitment on global studies.6,7,8 There are five major cities where clinical trials are focused, although they are certainly not limited to these cities alone. These cities are Johannesburg (population circa 3 million), Pretoria (1.6 million), Cape Town (2.4 million), Durban (2.1 million), Bloemfontein (0.35 million), with Port Elizabeth (0.75 million) and George (0.094 million) also contributing to a slightly lesser extent due to the smaller population, although they have a bigger catchment area per site.6,9 Clinical trial sites are located in the public and private sector. There are academic sites associated with government hospitals, in addition to clinics, which are the first entry point into the health system. The private healthcare network consists of major groups such as Netcare and Life, as well as other smaller, independent institutions and individuals. The Netcare Group comprises 57 hospitals, 8713 registered beds, 319 operating theatres and 87 retail and hospital pharmacies countrywide. Their Primary Care Division operates medical and dental provider services through Medicross, as well as a managed care organisation, Prime Cure Medicentre, which focuses on the low-income market. This includes a national network of 108 Medicross and Prime Cure Medicentres, with 41 retail pharmacies and 12 day-theatres. Furthermore, a group of 590 independent doctors and dentists provide comprehensive primary health services to about 3.5 million patients. Prime Cure manages a designated provider network of more than 10,000 health service providers, which includes 3877 contracted doctors and dentists.10 Life Healthcare’s extensive hospital network includes 63 hospitals, 7776 registered beds – including 664 ICU and 316 high care beds, 308 theatres, 12 cardiac units, four renal dialysis facilities, and 41 accident and emergency units providing a range of healthcare services throughout South Africa. The group has hospitals in seven of the country’s nine provinces, and in the country’s most populous metropolitan areas, including Johannesburg, Pretoria, Cape Town, Durban, Port Elizabeth, East London and Bloemfontein. Life Healthcare operates a range of facilities adapted to meet the local demand in the various regions of the country, including high technology, multidisciplinary hospitals, community hospitals and specialised stand-alone facilities to provide the appropriate scope of healthcare services.11 The main differences between the public and private January 2011


ACRO as a partner is the embodiment of a Client driven, Reliable, Accountable CRO with One mission – to promote access to innovative medical products, services and technologies throughout Africa. We do this through combining our experience in the multinational environment with in-depth knowledge of local languages, peoples, and country infrastructures, employing performance-driven staff, customising programs to provide quality solutions, building sustainable partnerships and developing local research capacity. We are fast becoming the Clinical Research Organisation of choice in Africa, showing exponential growth and an increasing demand for our vast knowledge and experience, our quick and cost-effective mobilisation, our trade mark customised services – tailor-made to the client’s exact needs and specifications. Innovative from the beginning, ACRO is the first South African full-service, BEE Clinical Research Organisation to manage phase I-IV clinical trials in the region. Pioneering industry public-private partnerships, it was formed out of an initiative set up throtugh collaboration between LIFElab, the commercial arm of the East Coast Biotechnology Innovation Centre, now incorporated into the Technology Innovation Agency (TIA) (a 3a Public Entity of the South African Government’s Department of Science and Technology), and Batswadi Pharmaceuticals, a black-empowered company with a focus on biotechnology. With this unique inception, ACRO services the biotechnology sector, donor-funded organisations, non-governmental organisations, research institutions, pharmaceutical and medical device companies, and the government as a full service CRO. Our track record shows client driven flexibility - some clients have required assistance with just one or two aspects of their product development, some have required assistance with charting the route from early-stage research right through to the clinic and the market. We work closely with each of our clients, to tailor the solutions we offer to their special and particular needs. ACRO strongly emphasises the ethical conduct of business and research; a client-centered approach; respect for research volunteers and meticulous safeguarding of their welfare; and capacity building, both within and outside the organisation.

But it is really the ACRO team that cements the principles into our daily activities, making it the enviable organisation it is. Each and every contact with ACRO creates an awareness of: Client focus - all projects are equally important. There is a sense of pride about satisfying each client’s particular needs and expectations. Community Awareness - we strive to be worthy of the trust placed in us by members of the community, and we recognize the central role of volunteers in the research we conduct. Empowerment - we are committed to living BEE principles, advancing employees and the greater society. Workplace Harmony - every team member leads by example, decision-making is an inclusive process, and we work together as a supportive team. ACRO is organised into five departments: 1. Clinical Trial Management and Monitoring; 2. Regulatory Affairs; 3. Medical Affairs; 4. Data Management Services and; 5. Training. These departments work together to ensure our clients receive an integrated service tailored to their needs. Services we offer include: 1. Clinical study management, monitoring, and evaluation 2. Regulatory consulting and submissions 3. Medical monitoring 4. Medical and scientific writing and consulting 5. Data management and statistical support services 6. Management, monitoring, and evaluation of epidemiology and health surveys 7. Training • Clinical Research Associate training • GCP training • Data Management • Biostatistics 8. Clinical trial site development (including site identification, establishment of site administrative and physical infrastructure, and GCP training of site staff) For all your clinical trial requirements in Africa and the Middle East, contact: Mary-Ann Richardson, Managing Director Email: mary-ann.richardson@acro.co.za Tel: +27(0)11 267-2250 www.acro.co.za


Africa subsection hospitals are that the public hospitals normally have academic affiliations and fall within the remit of a specific university and its corresponding research ethics committee. Private hospitals fall within the remit of central research ethics committees and individual hospital review boards. Also, the public hospitals are mainly used by government-subsidised, mostly lower income patients, while the private hospitals are mostly frequented by patients with privately (self) paid medical insurance. That said, there is an increasing implementation of hybrid models, as demonstrated by the Netcare Group and Charlotte Maxexe Johannesburg Hospital, servicing both private and public sector patients. A prime example of a public hospital is the Chris Hani Baragwanath Hospital, in Soweto, Johannesburg. With its 2964 beds, it is the largest acute hospital in the world. The hospital grounds cover an area of 173 acres, consisting of 429 buildings with a total floor area of 233,785.19m2. It is the only public hospital serving approximately 3.5 million people, and it provides half of all the hospital services in Southern Gauteng. Being a specialist hospital, referrals for specialist treatment are received from all over the country, as well as surrounding African states. Chris Hani is one of 40 provincial hospitals in the Gauteng Province, financed and run by the Gauteng provincial health authorities. The hospital has a staff establishment of nearly 5000, of which 600 are doctors and 2000 are nurses. The greater part of the teaching and clinical research for the Faculty of Health Sciences of the University of the Witwatersrand takes place at this hospital.12 Of course, we cannot fail to mention the site of the first heart transplant - Groote Schuur Hospital. It is a central hospital which forms part of the Western Cape Provincial Department of Health. In addition to specialised and super-specialised care for patients, it serves as a world-class academic training site for interns and residents. This is supplemented by the fact that it is still, as it was in 1967, a world-renowned research hospital. The hospital has 3663 staff, who accommodate 560,000 referrals and inpatient admissions per year.12 South Africa has many internationally recognised research units actively contributing to the advancement in the fight against HIV/AIDS and tuberculosis. As a point of interest, South Africa participated in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) study, designed to determine the optimal time to initiate antiretroviral therapy in patients with HIV and tuberculosis co-infection, who were receiving tuberculosis therapy. Based on the results of this study, the World Health Organization guidelines for treatment of TB and HIV co-infection were revised in late 2009, and on World AIDS Day in 2009, President Zuma of South Africa announced the new policy, to provide ART to all TB patients with HIV infection and CD4 counts below 350 cells per cubic millimetre.14 The results from the microbicide study conducted in 889 South African women and completed in 2010, showed that Tenofovir Vaginal Gel reduces the HIV transmission risk by 39%. This was commented on by the CDC at the XVIIIth International AIDS Conference, and published by AVAC. What makes it extraordinary is that the gel was designed in South Africa.16,17,18,19 Throughout the public hospital and private hospital groups 58 Journal for Clinical Studies

there are experienced clinical trial sites, as well as independent, private sites successfully executing clinical trials from Phase I â&#x20AC;&#x201C; III in infectious diseases and chronic lifestyle diseases, in fields such as cardiovascular, respiratory, gastroenterology, endocrinology, oncology, central nervous system, gynaecology and obstetrics, haematology, nephrology, orthopaedics, pain and urology. South Africa boasts five major units specialising in early phase development, located in Pretoria, Bloemfontein, George and Port Elizabeth. These units have experience in conducting difficult Phase I first-in-man studies, and have the global support and expertise to support them. Indicating that all this translates into an environment optimum for the conduct of clinical trials, a large number of international CROs and pharmaceutical companies have a presence in South Africa, including PPD, Quintiles, Parexel, ICON, AstraZeneca, Pfizer, Novartis, and Sanofi-Aventis, to name but a few. There are also a number of local CROs, as well as generic companies such as Adcock Ingram and Aspen, occupying most of the market share. In summary, bringing Destination South Africa to bear on clinical trials from a truly South African perspective: South Africa ranks 10th in terms of contribution to clinical trials in the world, while maintaining high standards of clinical practice, as demonstrated by the fact that the pass rate of site audits by multinational companies and FDA in South Africa is high. Guidelines for clinical trials in South Africa are stringent, and comply with both ICH and local health regulatory and ethical review policies. All investigators are trained in good clinical practices (GCP) as it is a requirement by the regulatory authority before participating in clinical trials. In the sciences, English is the preferred language in South Africa. The value of clinical research in South Africa was estimated at US $265 million (approx. ZAR2.2 billion) in 2008.15,21 In conclusion, carrying forward the good work of Professor Barnard and others, South Africa and its clinical trials industry remains focused on maintaining exceptional standards,

January 2011


innovation and patient care, not only in the southernmost part of Africa, but also around the globe. This is Destination, South Africa. References 1. www.heart-transplant.co.uk/barnard.html, visited on 07 January 2011. 2. http://zar.co.za/barnard.htm, visited on 07 January 2011. 3. http://fullstopcom.com/index.php?option=com_content&task= view&id=99&Itemid=28, visited on 07 January 2011. 4. h ttp://www.sapharmacol.co.za/SASBCP_Site/aspx_pages/ About/2-04.aspx, visited on 07 January 2011. 5. h ttp://www.cmf.org.za/cgi-bin/giga.cgi?cmd=cause_dir_ leader&leader_id=3402&cause_id=975, visited on 07 January 2011. 6. http://www.statssa.gov.za/publications/populationstats.asp, visited on 07 January 2011. 7. https://www.cia.gov/library/publications/the-world-factbook/ geos/sf.html, visited on 08 January 2011. 8. http://www.who.int/whosis/whostat2006.pdf, visited on 08 January 2011. 9. http://www.citypopulation.de/SouthAfrica-UA.html, visited on 08 January 2011. 10. h  ttp://www.netcare.co.za/live/netcare_content.php?Category_ ID=2390, visited on 08 January 2011. 11. h  ttp://www.lifehealthcare.co.za/Company/Hospitals.aspx, visited on 09 January 2011. 12. w  ww.doh.gov.za, visited on 11 January 2011. 13. h  ttp://www.phru.co.za, visited on 12 January 2011. 14. h  ttp://www.caprisa.org/joomla/index.php/researchtraining/ research-sites, visited on 12 January 2011. 15. h  ttp://www.synexus.com/go/global_reach/south_africa/, visited on 23 August 2010 16. h  ttp://www.cdc.gov/nchhstp/newsroom/ CAPRISAMediaStatement.html, July 19, 2010. 17. h  ttp://blog.msh.org/index.php/2010/07/23/aids-2010update-results-of-caprisa-microbicide-gel-trial-an-exciting-hivprevention-tool-for-women/, 23 July 2010. 18. h  ttp://www.avac.org/ht/d/sp/i/28226/pid/28226, visited on 14 January 2010. 19. h  ttp://www.hivandhepatitis.com/2010_conference/ AIDS2010/docs/0720f_2010.html, visited on 14 January 2010. 20. S A first to do HIV kidney transplants, Published: 6 July 2010 at www.sagoodnews.co.za 21. h  ttp://sacraza.com/members-menu/ 22. w  ww.doingbusiness.org Mr van Wyk has been in the Pharmaceutical Research Industry since 1998, working as Clinical Research Associate, Operations Manager and Global and Local Project Manager for various Contract Research Organisations and Pharmaceutical Companies. He was Country Manager for two of these companies. He was also instrumental in building and managing a Phase I unit. He brings strategic vision to a team, combined with a drive and a passion for accountability. Currently he is a consultant to the Pharmaceutical Industry. Email: enquiries@acro.co.za www.jforcs.com


Africa subsection

Cradle to Grave or Cradle to Cradle… Banking for the Continuity of Life Operating in Africa, BioAnalytical Research Corporation (BARC) is mindful of the significance of maintaining viable stored clinical trial samples if Africa is to maximise the health benefits offered by an increase in clinical trial registration, and thereby improve the health of its people. Viability or ‘capacity for survival’ of the cells and tissues is sought through the proper cold chain management of samples and through their storage at low temperatures. In 2007, two significant pieces of research contributed to the improvement of understanding of critical points in storage and movement of samples that may compromise sample viability. Bull et al, working at the HIV Vaccine Trial Unit (HVTN), looked at parameters involved in blood collection, processing and shipping, and how they influence immunological function. They demonstrated that immunological function of cells that are cryo-preserved is affected critically by cryo-preservation procedures, and showed that peripheral blood mononuclear cells (PBMCs) must be processed and frozen within eight hours from the time of blood draw to maintain maximum function of the cells in immune-monitoring assays. These assays require PBMCs that have been isolated and cryo-preserved under strictly defined conditions to ensure optimal recovery, viability, and functionality1. Bull described three cold shipping methods that maintain immunological function in appropriately cryo-preserved PBMCs, and demonstrated that shipping PBMCs in liquid nitrogen (LN2) showed slightly better results than shipment of PBMCs on dry ice. She also noted that shifting PBMCs to higher temperatures once they are stored in LN2 should be avoided at all costs, as immunological function would be impaired1. A Centre for HIV-AIDS Vaccine Immunology (CHAVI) study in 2007 contributed to our understanding of how time and temperature relate in this regard. It showed that the maximum acceptable time for a cryovial taken from a liquid nitrogen transfer pan to be kept safely at room temperature (17.4°C) is 15 seconds2. These insights enabled informed improvements in BARC South Africa’s cold chain management systems, and ensured our investment as a world class, African first, biobanking facility, In late 2009, BARC South Africa added a biobanking repository to its clinical trials laboratory facility. The specialised repository facility is designed to support clinical trial science research through the archiving of biological samples. It has capacity to store more than 2 million clinical trial samples in -80°C ultralow-temperature freezer storage, and 1 million samples in liquid nitrogen vapour phase tanks. By providing high volume, long-term storage facility for samples from clinical trials in Africa, future scientists may, with the aid and development of new biomarkers or assays that may not have been discovered when the original trials were started, find solutions to ongoing disease problems. In these cases, stored samples maintained continually at the correct temperatures will be extremely beneficial for re-analysis, and future research phases may be developed which offer an opportunity either in 60 Journal for Clinical Studies

a scientific breakthrough towards improved disease treatment and management of the patient, or as a time-saver by designing better prospective trials in the future. As science evolves and new forms of scientific testing are developed in new diagnostic assay techniques or biological markers, new forms of analysis and testing of function may therefore be applied to existing stored samples. Total cold chain management standards and the integrity of samples are maintained throughout all business and storage processes within BARC. The best practice storage conditions available are upheld and controlled, giving sponsors assurance that all samples are maintained intact and fully viable on arrival from the various research centres, and all processes are documented, ensuring a complete chain of custody from the time the samples arrive up to the time of shipment out of the facility. Shipments are couriered only by approved courier companies with expertise in cold chain logistics and management. Samples are shipped in cryo-shippers by IATA trained personnel. These shippers have a static holding time of 18 days and a field working time of 11 days. Only standardised approved packaging containers and validated materials are used so as to ensure sample integrity throughout the cold chain process. Effective packing techniques protect samples during transit and allow for unexpected delays during shipment. Stringent monitoring of samples received at the unit is conducted to assess the adequacy of the storage container and size used. Proper packaging is essential to maintaining sample integrity; the physical size of dry ice and quantities used will all impact critically on fitness / viability of the samples prior to long-term storage. Continual real-time temperature monitoring of samples held in storage further ensures that no critical temperature threshold limits or violations are reached. It is the aim of the BARC biobanking repository to ensure the viability of all samples. Different samples require different temperatures. In order for optimal viability to be maintained, plasma and serum samples are best kept below -70°C, whereas the stability of frozen cells cannot be assured unless the material is maintained below -130°C as an absolute maximum, with below -150°C being ideal. Every time a frozen vial is exposed to a warmer environment, however briefly, it experiences a change in temperature which can affect the viability of the sample, thus closing the window of opportunity available, and impacting negatively on the scientific research. To avoid this, all samples in liquid nitrogen are handled in temperature-monitored and regulated liquid nitrogen baths. This ensures that the glass transition phase (GTP), the critical temperature point above which samples are impaired and rendered useless for further study, is not breached. The quality of samples is maintained throughout their stay at BARC and they are kept well below the GTP. The BARC biobanking facility is notably the most sophisticated of its kind in the world. The sophistication is evident from various features including its information technology (IT) and laboratory information management systems (LIMS). The facility uses the January 2011


Africa subsection Meditech® LIMS system as well as the Laboratory Database Management System (LDMS) for sample handling, management and shipping. All LIMS systems are backed up offsite in order to ensure disaster management control. An FDA-approved cold chain monitoring system has been set up to ensure real-time continual monitoring of the temperature, equipment electronic systems, liquid detection monitors, oxygen levels and related equipment failures within the facility. All instrumentation monitoring is electronically documented, and any critical changes result in a text message via two independent service providers to standby staff members. Risk assessments have been performed in all the critical areas, and the assessors are assured that the backup systems in place are more than adequate, and will cover the risk of any loss of power to any of the areas. Standard operating procedures for all areas are in place with fully trained and certified staff. Water-cooled -80oC ultra-low-temperature freezers have been installed, allowing for direct heat exchange transfer from the condenser via the reticulation system to the cooling towers. This is the most efficient means of heat exchange mechanism available, and a number of back-up operational systems to ensure continual operational functionality have been incorporated through additional water supply options and reservoirs. The water cooling system results in a direct electrical consumption saving of up to 40% less electricity compared with other facilities of equal size. Energy conservation is critical, as the ambient temperature is over 20oC for most of the year, making heat extraction critical for functionality of the freezers and for staff safety. Carbon dioxide (CO2) cylinders are linked to each freezer and are continually monitored by real-time monitoring. Should freezer temperature be compromised due to power loss, the CO2 gas will maintain the temperatures required for up to 24 hours. This will enable the movement of samples to backup freezers that are always kept primed. Large, fully automated, microprocessor-controlled, archival liquid nitrogen refrigerators with the highest available level of sample security, including safe, efficient isothermal properties and dependable operational mechanisms, have been installed. Typical liquid nitrogen consumption of these refrigerators is less than nine litres per day, as opposed to the average consumption in excess of 20 litres per day, thereby minimising wastage of LN2. In the vapour phase storage, temperatures throughout the archive refrigerator typically vary less than 8°C with dependable temperature stability at -187°C. A vapour guard is provided to guarantee that liquid can never come into contact with any samples. BARC has ensured continuity of LN2 supply through multiple supplier arrangements. Health and safety is a fundamental concern at the BARC biobanking repository. The management team at BARC has ensured that all staff members are fully trained in the use of the safety equipment as well as in safety procedures before they are allowed to enter the environment, thereby ensuring personal safety at all levels. Accredited atmospheric monitoring and extraction systems are in place in order to assure constant monitoring of oxygen levels within the facility – this is to detect the slightest increase in the levels of the inert gas, nitrogen, as this could result in asphyxiation. (Asphyxiation is caused by high levels of this gas and can occur without warning as the gas is odourless, colourless and tasteless). Extraction and ventilation systems are optimised 62 Journal for Clinical Studies

to be continually operational throughout the facility; should the oxygen levels fall below the acceptable limits, extraction fans are automatically activated, enabling total air replacement within three minutes. Systems are all alarmed, ensuring that warnings of deviations will allow an efficient return to normality within the shortest time period, affording staff and sponsors confidence in the safety of the environment3,4. The reputation of the BARC biobanking unit rests on placing stringent ethical requirements on our clinical trial partners. BARC ensures all the proper consent is obtained and where consent is found to be lacking, the samples can be destroyed5,6. BARC South Africa is an experienced clinical trials laboratory. Its latest addition is the biobanking repository, a sophisticated, world class archiving facility. It maintains samples from clinical trials to be held safe for new tests and assays that are developed in the future. It preserves Africa’s health challenges today for tomorrow’s solutions with the prospect that as the cycle of life is recreated it brings with it the promise of better health. References 1. Bull, M., Lee, D., Stucky, J., Chiu, Y.L., Rubin, A., Horton, H., McElrath, M.J. Defining blood processing parameters for optimal detection of cryo-preserved antigen-specific responses for HIV vaccine trials. Journal of Immunological Methods. 30, 322 (1-2): 57-69 (2007). 2. Ferrari, G., Long, K. & Cumming, M.J. Time dependence of temperature change when cryovials frozen in liquid nitrogen are exposed to room temperature. CHAVI central QAU, CHAVI study plan. 1, 04 (2007). 3. Arrieta, A., et al. Hazards of inert gases and oxygen depletion. European Industrial Gases Association - IGC Document. 44/09/E (2009). 4. Statebourne Cryogenics. -190°C Vapour Safe Cryobiology. Statebourne Cryogenics Booklet. (2009). 5. Nicol, Prof. D., Otlowski, Prof. M., Stranger, Dr M. Consent Challenges for biobank and tissue bank facilities. Clinical Research Advisor. 268, 4-5 (2010). 6. Hansson, M.G. Building on relationships of trust in biobank research. Journal of Medical Ethics. 31, 415-418 (2005). Dr Jessica Trusler is Medical Director of BARC SA. A Clinical Pathologist, Dr. Trusler has been involved in clinical trials across Africa for more than 10 years. Highly recognized in academic circles, Dr. Trusler served as a registrar for the SAIMR at Chris Hani Baragwanath & Johannesburg Hospitals and thereafter as a consultant for the NHLS in the Chemical Pathology Department at the University of the Witwatersrand. A keen student, Dr. Trusler continues to invest in training & personal development to ensure that she and her staff remain at the cutting edge in the role of pathology in clinical research, effective laboratory and disease management. Dr. Trusler holds a MBChB (UCT), DCH (SA), DTM&H (WITS), FC(PATH) CLIN (SA), MMED Clinical Pathology (WITS). She is currently a member of SACRA, SAMA, IDDSA, SEMSDA, and SAAP. Her day to day activities involve management of the organization; planning for growth; monitoring of and adherence to Quality Assurance Programs and GLP & GCLP; tendering for quotes and liaison with clients and colleagues. Email: truslerj@lancet.co.za January 2011


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ACRO (African Clinical research Organisation) 57 Almac Group Ampath Clinical Trials BARC South Africa (PTY) Ltd. Centrical Global Ltd. Central Lab Logistics Chiltern International Ltd Dora Wirth (Languages) Ltd. DIA EuroMeeting Geneva 2011 ERT ExCard Research GmbH Giga Medical INTERLAB â&#x20AC;&#x201C; central lab services â&#x20AC;&#x201C; worldwide GmbH KENDLE MediciGlobal Medilingua BV PAREXEL Partnership in Clinical Trials USA PDP Couriers Polaris BioPharma Consulting SCA Cool Logistics Synergy Research Group SynCon International Temmler Werke GmbH Triclinium Clinical Trials Project Management (PTY Ltd) World Courier

Ever wondered , why we choose flowers as the front cover of JCS? Each of the flowers we feature on the cover, represent the national flower of one of the emerging country we highlight in that particular issue. eg. In this issue we have featured a dedicated subsection on AFRICA (Nigeria & South Africa) Coctu Spectabilis is the representative flower of Nigeria (Yellow Trumpet) which features on the front cover.

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I hope this journal guides you progressively, through the maze of activities and changes taking place in these Emerging Countries. JCS has also launched a Weekly News Letter. Please visit www.jforcs.com and sign in to receive the very informative weekly news letter.

January 2011


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