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Volume 3 - Issue 2

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

FDA’s Efforts on Improving Access to Therapies for Rare Diseases The Role of Amyloid Biomarkers in Accelerating Alzheimer’s Disease Drug Development Unprecedented Growth in Clinical Trial Collaboration and Korea as the New Destination Managing ePRO Patient Compliance in Emerging Markets




Watch Pages

Your Resource for Multisite Studies & Emerging Markets



FDA’s Efforts on Improving Access to Therapies for Rare Diseases The FDA is currently engaged in several collaborative efforts to improve the outlook for available therapeutics for rare diseases. To address the lack of treatments for rare conditions and to stimulate the approval process, the FDA held several public meetings in 2010 to focus attention on improving the review process for therapeutics. By: Regina Ballinger of Thomson Reuters


Cardiovascular Safety Watch Column Oncology pharmacotherapy illustrates benefit-risk balances in different circumstances. Cardiotoxicity following cancer chemotherapy and thoracic radiotherapy is therefore a special situation that remains a significant problem in long-term survivors. By: Rick J. Turner of Quintiles


The Role of Amyloid Biomarkers in Accelerating Alzheimer’s Disease Drug Development The European Medicines Evaluation Agency (EMEA) released its first Qualification Opinion of Alzheimer’s Disease Novel Methodologies/biomarkers for BMS-708163 for public opinion. This CNS watch will summarise this opinion, as well as the utility of amyloid-targeting drugs and biomarkers in AD drug development. By: Henry Riordan of World Wide Clinical Trials


Improving Patient Retention and Compliance by Investing in Proven Solutions Patient non-compliance is a growing issue that requires tailored, cost-effective solutions. To address these challenges, it is essential to proactively employ strategies that ensure patient compliance in order to avoid compromised data, complete trial failure, or heavy financial losses Successful retention and subject compliance are essential to the completion of a successful trial. By: Tim Davis of Excointouch


Quality Gaps in China’s CRO Sector China’s domestic clinical research outsourcing has also grown quickly at 25% annually, compared to the global value of 22%. The United States and Europe are still dominant in the global CRO industry, accounting for 88% of market share. Yet the Chinese domestic market for CRO services has reached 50 billion Yuan, with Beijing, Shanghai, Tianjin, and Chengdu initiating strong pull factors for foreign investors, with the multinational pharmaceutical companies gradually starting to develop business in China. By: Jacky Cheng & May Lan of The Scott Partnership China


A Trial in Tunisia In Tunisia, health-related services are considered a growth window and a key engine for economic and social development, and the number of clinical trials conducted in Tunisia increased dramatically as soon as regulation was implemented in early 1990. By: Meriem Melaouhia of Amilcar International & Habib Ghedira, MD and Professor at the Medical Faculty of Tunis

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 Samantha J. Stevenson 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: 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

Publisher’s Keynote

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Contents Regulatory 18


Clinical Evaluation of Medical Devices: How to Negotiate the Maze of Regulations around the World The requirements for the demonstration of clinical safety and performance of Medical Devices are steadily increasing. Georg A. Mathis, Annick Toggenburger, and Rolf Marugg, of Appletree AG, discuss how the industry faces the double challenge of meeting the ever-increasing demands on documentation and data quality, not least for clinical evaluation, and of satisfying the diverse regulatory standards. Argentina has Established a New Regulation for Pharmacological Clinical Trials The pharmacological regulatory authority in Argentina is the ANMAT. ANMAT Provision 5330/97 was the directive that regulated pharmacological investigation in Argentina for 13 years. Recently, as from November 8th 2010, a new regulation that repeals the Provision 5330/97 has come into force. Ezequiel Klimovsky of QUID Consulting explains how this new regulation substantially modifies the requirements for the conduct of clinical trials. Market Review





Unprecedented Growth in Clinical Trial Collaboration and Korea as the New Destination Dr Cho, director of KHIDI USA, looks into issues of clinical trials in Korea. The G20 summit, hosted and chaired by Korea last year, came up with one solution - “work together to promote global sustainable growth.” As expressed in the G20 summit Joint Statement, the threats of the pharmaceutical industry can be overcome through collaboration with Korea. Six Steps to Streamlined Contracting of Sites for Clinical Studies Keyur (Kevin) Shroff of Medidata Solutions explains the six streamlining steps: Pre-Approve and Reuse Contractual Components; Create a Budget Hierarchy; Use Benchmarks to Competitively Price; Use Multiple Touchpoints for Faster Response; Streamline the Workflow; and Unify Data and Workflow in a Single Application. All of these steps are imperative in increasing transparency and site satisfaction while decreasing the amount of time it takes to reach contract agreements. Effective Utilisation of India for Global Clinical Trials Challenges with clinical trial subject recruitment in Western countries and the growing track record of emerging countries have resulted in a universal acceptance of the imperative to include at least one emerging country in product registration Phase II-III clinical trials. India is becoming the most attractive member of this group. Nermeen Varawalla of ECCRO evaluates why selecting India could well be a very good choice. The Increasing Costs of Post Marketing Research and Meeting the Objectives of Multiple Stakeholders Post Marketing Research (PMR) has been described as the fastest growing area of clinical research. Partly, this growth can be attributed to the fact that regulatory agencies are

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increasingly requiring additional safety and efficacy data from the PMR environment. Michael Holdsworth of African Clinical Research discusses the other factors which are contributing to the growth. Therapeutics 40 Drug Phototoxicity – a Burning Issue in Drug Development? Phototoxic drug events over the past decade have fuelled the increasing safety expectations of patients and regulators. It is as a result of these events that photosafety guidance for drug development has emerged from both the EMEA and FDA. James Ferguson, Head of the Academic Department of Dermatology, University of Dundee, Ninewells Hospital and Dr Brian Sanderson of Chiltern Early Phase Ltd discuss the importance of assessment of drug phototoxicity. 46 Centralised Endpoint Adjudication in Cardiovascular Outcomes Studies Composite Endpoints, Risk Ratios, and Clinical Endpoint Committees Cardiovascular outcomes studies typically require the recruitment of subjects at a large number of investigational sites located in many countries. Accordingly, there is a considerable degree of variability in the ‘identification’ of cardiovascular clinical endpoints. J. Rick Turner, Ransi Somaratne, Christopher H. Cabell & Catherine A. Tyner of Quintiles identify why regulatory agencies are increasingly expecting, and in some cases requiring, the centralised adjudication of these clinical endpoints. 50 Major Depressive Disorder (MDD): Uncovering Patients’ Perceptions Behavioural Aspects of Participating in a Clinical Trial Competitive patient recruitment in major depressive disorders requires a fundamental understanding of patients, in order to develop patient recruitment strategies that resonate with them and their families, regarding clinical trial participation. This issue is here examined by Liz Moench of MediciGlobal. IT & Logistics 54 ePRO: Managing ePRO Patient Compliance in Emerging Markets It is important that electronic patient reported outcome (ePRO) technology and services meet the needs of clinical trials conducted in emerging markets. This article by Kai Langel, Rohini Beavon and Deepankar Arora of CRF Health outlines some practical considerations regarding ePRO technology and services, which are pertinent to studies conducted in the emerging markets. 60 Utilising a CTMS to Create a Development Edge John Humphreys of CTMS Perceptive Informatics examines issues such as using a CTMS to Create a Development Edge, the CTMS Role in Patient Recruitment and Site Management, the Advantage of CTMS Integration with Other eClinical Systems, CTMS Support for Monitoring, ROI with CTMS, and Reducing Time to Market with CTMS.

Volume 3 Issue 2

Keynote In an effort to improve treatment and one day find a cure for pancreatic cancer, the TGen Foundation has joined with key donors and community leaders to announce the creation of globalCure. The backbone of globalCure is an alliance between TGen and the Pancreatic Cancer Research Team (PCRT), which includes leading pancreatic cancer scientists, physicians and researchers, armed with the most technologically advanced tools and resources, at 46 institutions worldwide. Pancreatic cancer claims the lives of more than 42,000 Americans and more than 235,000 people worldwide annually, making it the fourth-leading cause of cancer death. Funds generated through globalCure will enable an international team of physicians to move quickly on promising new clinical therapies. Specifically, the funds will enable globalCure supported scientists and clinicians to: identify biomarkers of diagnostic value, as well as those that constitute new drug targets in pancreatic cancer; identify and optimize new agents that affect the activity of those targets; and evaluate new agents and take the most promising ones to clinical trials for patients in advanced stages of the disease. In this issue the Watch Pages highlight important developments from Regina Ballinger of Thomson Reuters who looks into the FDA’s efforts on improving access to therapies for rare diseases, to Rick Turner the Senior Director of Cardiovascular Safety at Quintiles, who updates us on Oncology pharmacotherapy. Watching the role of Amyloid Biomarkers in accelerating Alzheimer’s disease drug development is Henry Riordan the Senior Vice President of Medical and Scientific Affairs at Worldwide Clinical Trials. Tim Davis of Exco Intouch investigates the issues relating to improving patient retention and compliance. Jacky Cheng and May Jan of the Scott Partnership look into the quality gaps in China’s CRO sector while Meriem Melaouhia focuses on regulations related to trials in Tunisia. Rolf Marugg and Annick Toggenburger of Appletree AG, a Swiss CRO

specialised in ophthalmology and medical devices, give us a view on how to negotiate the maze of regulations around the world. Meanwhile over in Argentina, Ezequiel Klimovsky explains that Argentina has established a new regulation for pharmacological clinical trials. JCS Market reports are a useful and informative tool, and in this issue focus is on the unprecedented growth in clinical trial collaboration and Korea as the new destination. Do Hyun Cho, the director of KHIDI USA, provides an insider’s view. While Keyur (Kevin) Shroff of MDSOL provide us with six steps to streamlined contracting of sites for clinical studies. Other regional markets covered are India with a focus on effective utilisation of India for global clinical trials. Professor James Ferguson and Dr Brian Sanderson cover the hot therapeutics topic of drug phototoxicity, while the topic of centralised endpoint adjudication in cardiovascular outcomes is detailed by Rick Turner. Major Depressive Disorder (MDD) is an interesting subject, uncovering patients’ perceptions covered in this issue of JCS by Liz Moench of Medici Global. IT & Logistics has always been a strong section in JCS, and in this issue managing ePRO patient, compliance in emerging markets is covered in detail by Kai Langel, Rohini Beavon and Deepankar Arora. Other topics covered are utilising a CT MS to create a development edge by John Humphreys of Perceptive. JCS looks forward to the 2nd Oncology Clinical Trials in Emerging Regions. Conference, co-located with the Cardiovascular Clinical Trials in Emerging Regions Conference. The meeting will be held at the Radisson Edwardian Hotel, Heathrow, London, UK on the 9th & 10th May 2011. Another very well attended and important conference is the cardiac & cardiovascular safety conference, the DIA’s conference entitled “Cardiovascular Safety in Drug Development: State-of the-Art Assessments”, will be held in Washington DC, US, on 14-15th April 2011. I hope you enjoy the varied source of articles in this issue, and hope to see you all the DIA Euro Meeting. Mark A Barker

Editorial Advisory Board

World Health Organization (WHO) Expert in ethics

Andrew King, Managing Director, Biocair International.

Georg Mathis Founder and Managing Director, Appletree AG

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

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH

Nermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation Patricia Lobo, Managing Director, Life Sciences Business Consulting Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories Rabinder Buttar – President & Chief Executive Officer of ClinTec International

Janet Jones, Senior Director, ICON Clinical Research

Catherine Lund, Vice Chairman, OnQ Consulting

Jerry Boxall, Managing Director, ACM Global Central Laboratory

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

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

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

Rob Nichols, Director of Commercial Development, PHASE Forward

Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma.

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

Charles Horth – Senior Life Sciences Consultant

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

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

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB

Elizabeth Moench, President and CEO of Medici Global

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a

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

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company

Steve Heath, Head of EMEA - Medidata Solutions, Inc

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T S Jaishankar, Managing Director, QUEST Life Sciences

Volume 3 Issue 2

Watch pages

FDA’s Efforts on Improving Access to Therapies for Rare Diseases The development of therapies and diagnostics for people with rare conditions presents economic and scientific challenges. Rare diseases are sometimes referred to as “tropical diseases” or “neglected diseases”, and include diseases such as tuberculosis (TB), malaria, hookworm infection, and leprosy. Neglected diseases affect more than one billion people around the world.1 Since the 1983 passage of (and subsequent amendments to) the Orphan Drug Act (ODA), more than 350 drugs and biological products with orphan designation have received US Food and Drug Administration (FDA) marketing approval. Prior to that time, only 12 new drugs for rare diseases received FDA approval between 1973 and 1982. This was largely due to the high development cost for therapies targeting few patients that often was seen as a prohibitive economic barrier. In support of device development, the Humanitarian Use Device (HUD) programme provides a regulatory approval pathway for devices intended for patients with a disease or condition that affects fewer than 4000 individuals in the US per year. In order to obtain HUD designation, the applicant must provide authoritative references to demonstrate that the device meets the definition described in 21 CFR 814.3(n).2 In February 2010, the FDA created the position of Associate Director for Rare Diseases in the FDA Center for Drug Evaluation and Research (CDER). The Associate Director for Rare Diseases, along with the Office of Orphan Products Development (OOPD), supports collaboration among scientists and clinicians throughout the FDA to facilitate timely development and approval of new treatments for adult and pediatric patients with rare diseases. The FDA is currently engaged in several collaborative efforts to improve the outlook for available therapeutics for rare diseases. To address the lack of treatments for rare conditions and to stimulate the approval process, the FDA held several public meetings in 2010 to focus attention on improving the review process for therapeutics. A committee of FDA employees established under the requirements of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law 111–80, section 740) is tasked with investigating ways to optimise the FDA’s review of the data from non-clinical studies and clinical trials, as well as the agency’s marketing authorisation process and post-marketing surveillance for products intended to treat rare disease populations. The “section 740 committee”, which was established in March 2010, collected public comments at the June 2010 public meeting. The transcripts for these meetings are available on the FDA’s website. Section 1102 of the Food and Drug Administration Amendments Act (FDAAA) created a new section 524 of the Federal Food, Drug, and Cosmetic Act (the Act) that authorises FDA to award priority review status vouchers to sponsors of certain tropical disease product applications that meet certain criteria specified by the Act. An awarded priority review voucher may be used by the sponsor who originally obtains it or may be transferred or sold to an alternate sponsor to obtain priority review status for a different drug product application.3 6 Journal for Clinical Studies

FDA is also participating in cross-agency initiatives with the National Institutes of Health (NIH) and the Centers for Disease Control (CDC) to improve access to treatments for rare diseases, and has directed financial assistance to these Critical Path Partnerships.4 The FDA is also collaborating with the World Health Organization (WHO) on developing vaccines for rare diseases through the WHO vaccine pre-qualification programme.5 The FDA Center for Biologics Evaluation and Research (CBER) provides support to several WHO regional vaccine networks to enhance scientific and regulatory capacity needed to assure the development of high quality vaccines. The FDA is planning several public meetings in 2011 that support the initiatives on rare tropical diseases. Topics for these meetings include consideration of the process used by the FDA to grant an orphan drug designation for drug products intended to treat rare diseases, and clinical pharmacology issues related to facilitate efficient and informative drug development for drugs for rare diseases.6,7 References: 1) Testimony of Jesse L. Goodman, MD, MPH, Chief Scientist and Deputy Commissioner for Science and Public Health FDA, US Department of Health and Human Services before the Subcommittee on Agriculture, Rural Development, FDA, and Related Agencies Committee on Appropriations on the topic of Rare and Neglected Diseases, U.S. Senate. 111th Cong. (2010). Food and Drug Administration Website: Testimony/ucm216991.htm#_ftn1. 2) Designating Humanitarian Use Devices (HUD). Food and Drug Administration Website: www. DesignatingHumanitarianUseDevicesHUDS/default.htm. 3) Food and DrugAdministrationDraftGuidanceforIndustry:TropicalDiseasePriority Review Vouchers. Food and Drug Administration Website: www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM080599.pdf. 4) FDA Critical Path 2010 Update. Food and Drug Administration Website: SpecialTopics/CriticalPathInitiative/ucm204289.htm#WhatCPI 5) Prequalification of vaccines. World Health Organization website: en/index.html. 6) Fourth FDA orphan drug designation workshop scheduled for February 28 - March 1, 2011 [press release]. Washington, DC: Food and Drug Administration. ForIndustry/DevelopingProductsforRareDiseasesConditions/ UCM215487.pdf 7) Advisory Committee for Pharmaceutical Science and Clinical Pharmacology; Notice of Meeting, 76 Federal Register 3912-3913 (2011) Regina M. Ballinger, has been with Thomson Reuters for eight years, specialising in pharmaceutical regulatory affairs. She manages US regulatory content for the IDRAC database and publication of IDRAC’s AdComm Bulletin. She has been employed in the healthcare industry for over 15 years. Email: Volume 3 Issue 2

Watch pages

Cardiovascular Safety Watch Column Oncology pharmacotherapy illustrates benefit-risk balances in different circumstances. Imagine a scenario in which an individual patient’s diagnosis is that his or her cancer is likely to be terminal in several months. Some patients may decide that they are willing to take a considerable risk in an attempt to prolong their lives by a relatively short, but personally meaningful, amount of time, and/or to improve their quality of life (and the quality of life of their caretakers) for their remaining time. In this scenario, the risk of druginduced cardiotoxicity several years in the future from a therapeutic agent that will achieve these benefits may not seem of particular concern, since their life is likely to end much sooner. However, a paradox has arisen in this therapeutic area. Pharmacotherapy, sometimes in conjunction with surgery and/ or radiation therapy, has proved very successful in many cases. Many disease states have gone into remission, with patients living for considerable lengths of time following intervention. While the prolongation of life can be considered a great success, an unfortunate consequence in some cases is that drug-induced cardiotoxicity can be experienced several years following the cessation of the intervention. Cardiotoxicity following cancer chemotherapy and thoracic radiotherapy is therefore a special situation that remains a significant problem in long-term survivors. At therapeutic doses, some cytotoxic cancer agents, particularly the anthracyclines, can produce myocardial damage by direct damage to subcellular systems within cardiomyocytes. Cardiovascular manifestations of damage include heart failure, cardiomyopathy, pericardial/pleural effusion, arterial hypoand hypertension, myocarditis, and thromboembolism. An additional complication is that various cardiotoxicities can differ considerably in their timelines following chemotherapy and radiotherapy. Some acute concerns can arise immediately

after a single dose of an anthracyclines, others can develop in the 12-48 month timeframe, and others can surface 10 years following radiation and/or multiple chemotherapies. Monitoring cardiotoxicity non-invasively is of considerable interest. In addition to ECG and myocardial perfusion imaging (ischemic complications) and 24-hour continuous Holter monitoring (dysrhythmias), Doppler echocardiography is a useful technique. This was discussed at the Cardiac Safety Research Consortium’s 2010 Annual Meeting last December (a conference that was discussed in the previous column). Dr Bonnie Ky (University of Pennsylvania School of Medicine) discussed the use of echocardiography in the evaluation of cardiotoxicity during clinical development programmes. Echocardiography is non-invasive, widely available in many countries, relatively inexpensive, and portable. Measurements include left ventricular ejection fraction, systolic and diastolic dimension, and endocardial fraction shortening. Indices of diastolic function include early peak mitral inflow velocity (represented as E), atrial peak mitral inflow velocity (A), and the E/A ratio. It also provides information on left and right ventricular function, and assesses both structure and function, including cardiac remodelling. Inter-rater correlations for trained sonographers are relatively high: nonetheless, for large multisite trials, standardisation is very important. The use of a core echo lab is extremely valuable (for similar reasons that a core ECG lab is valuable when assessing drug-induced QT interval prolongation and other ECG characteristics). For a particular study, the core echo lab can help in many ways. These include: creating rigorous personnel training plans, measurement collection strategies, and quality assurance (QA) tools; establishing standard image transfer methodology and secure data storage; performing regular data QA (e.g., range limit checks, data double-entry); and performing regular quality control measures to decrease inter- and intrareader variability. Changing gear now to look forward to another important cardiac & cardiovascular safety conference, the DIA’s conference entitled “Cardiovascular Safety in Drug Development: State-ofthe-Art Assessments”, will be held in Washington DC, US, on 1415th April 20111. This is a very well attended conference, notable for the strong participation of individuals from regulatory agencies from many countries. This column will provide a report in an upcoming issue of the journal. Reference 1. EducationalOffering.aspx?productID=24928&eventType=Meetin g (accessed 28th February 2011) 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:

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Volume 3 Issue 2

Watch pages

The Role of Amyloid Biomarkers in Accelerating Alzheimer’s Disease Drug Development Shortly after the last issue of CNS Watch (Volume 3 Issue 1) which reviewed the recent FDA guidance on biomarker and patient reported outcome qualification, the European Medicines Evaluation Agency (EMEA) released its first Qualification Opinion of Alzheimer’s Disease Novel Methodologies/biomarkers for BMS-708163 for public opinion. This opinion addresses whether the use of two cerebral spinal fluids (CSF) related biomarkers (AB1-42 and total tau) are qualified in selecting subjects for trials in early Alzheimer’s disease (AD). This CNS watch will summarise this opinion, as well as the utility of amyloid targeting drugs and biomarkers in AD drug development, including the possible use of amyloid-based surrogate biomarkers as primary efficacy variables to accelerate AD drug development. The EMEA biomarker qualification team carefully considered whether the positive signature of CSF biomarkers was qualified to predict the evolution to dementia in patients diagnosed with Mild Cognitive Impairment (MCI) by reviewing publically available data submitted by Bristol Myers Squibb. Analyses were restricted to prospective longitudinal studies that evaluated the sensitivity and specificity of these CSF biomarkers over a long term (>1 year) period. Despite variable entry criteria, all of the prospective longitudinal studies that informed the accuracy of CSF biomarkers were performed in populations defined by the Petersen criteria (which are less specific than the more recent Dubois criteria, as the latter are based on a very specific episodic memory measure). BMS expressly requested qualification of these amyloid biomarkers as related to the application of the Dubois criteria for prodromal AD1,2. The qualification team concluded that overall studies were supportive of the concept that a positive CSF signature predicts the evolution to dementia, and the Committee for Medicinal Products for Human Use (CHMP) qualification opinion stated that “In patients with MCI a positive CSF biomarker signature based on a low AB1-42 and a high T-tau is predictive of evolution to AD-dementia type. This is based on the results of a metaanalysis which showed that the sensitivity of the combination AB1-42+total tau to predict AD type dementia was 0.87, 95% CI 0.80-0.95, the specificity 0.70, 95% CI 0.57-0.83 and the positive predictive value of 0.65, 95% CI 0.53-0.77. Overall the accuracy is considered sufficient to provide the desirable population enrichment of patients at risk of developing AD dementia. In fact the biomarker signature of low AB1-42 and high Tau has a relatively high sensitivity that allows the exclusion of subjects with a low likelihood of developing dementia when it is not present.” ( library/Regulatory_and_procedural_guideline/2011/02/ WC500102018.pdf). This is the first opinion released by either the EMEA or the FDA 10 Journal for Clinical Studies

on biomarker qualification. Representing a major step forward in the quest for relevant biomarkers for use in AD clinical trials, it may even assist the pursuit of a claim for disease modification (DM) in AD. The main focus of this qualification was to provide a valid and reliable technique to enable accurate categorisation or selection of patients in the prodromal stages of AD. As such it would be seen largely as a predictive biomarker rather than a pharmacodynamic biomarker to be used as a surrogate for efficacy. Having a qualified biomarker may enable more accurate evaluation of AD drugs that were developed to inhibit the production or aggregation of beta amyloid or to enhance its clearance, ultimately increasing the chances of marketing approval. Unfortunately, to date the numerous drugs and vaccines (>20) developed targeting amyloid (to treat symptoms of AD or modify the course of AD based on the amyloid cascade hypothesis) have largely failed, causing some researchers to question even the validity of the approach. These failed trials along with various amyloid-based approaches to AD drug treatment were recently reviewed at the 7th annual scientific meeting of the International Society of CNS Clinical Trials and Methodology (ISCTM) in Washington DC Although somewhat debatable, it was generally agreed upon that most amyloid-targeting drugs/vaccines have mechanistically been able to impact their intended targets in the predicted manner, they have not proven to be clinically efficacious, and in some cases are even deleterious. This may be due to a variety of methodological and design flaws which include underpowering, poorly chosen outcome measures, short timeframes, and inappropriate subgroup analyses. However, the most salient factor contributing to these failed trials has been subject inclusion criteria, as it was determined that these various amyloid-based interventions may have all been administered much too late in the course of AD illness. The general sentiment was that some good drug candidates were simply applied at the wrong stage of illness. Therefore, investigating amyloid agents in patients who are in the prodromal or even “preprodomal” phases of illness would be more advantageous when assessing efficacy. While it was also suggested that the presence of a measurable biomarker implied that it was far too late to significantly improve the disease state, nevertheless it is accepted that having qualified biomarkers in the arsenal of CNS drug development tools is beneficial. The session also summarised the circumstances under which a biomarker/unvalidated surrogate measure could be adopted as a primary efficacy variable, with accounts provided from representatives of both US and EU regulatory agencies. These represented personal views and not those of their respective agencies. A “surrogate marker” can be defined as “...a laboratory Volume 3 Issue 2

Watch pages measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy”3. The FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials, establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit. They may also grant approval on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity 4 . Obviously, there is no accepted definition or clear threshold of evidence supporting the term “reasonably likely” which is subjective and open to interpretation. As such, surrogate markers remain insufficiently understood, and none to date are validated for use as sole primary measures of effectiveness in definitive trials of CNS investigational drugs. Surrogates are sought after as they have the potential to significantly decrease both the duration and size of studies, shorten development timelines, save money, and accelerate approval. Surrogates are also particularly useful when the clinical benefit of the drug is likely to be well in the future and when there are no other therapies. Surrogates may be less useful when clinical effects are easily measured in a reasonable timeframe. Therefore surrogates are often proposed as a more realistic way to support a claim for slowing down disease progression in AD5 which remains an ambitious goal for any CNS drug development company. US regulatory authorities have implied that the disappointing AD trial results to date fail to lend credence to the utility of amyloid-targeted surrogates in AD trials, suggesting that the preferable but as yet undefined indication for testing an amyloidbased unvalidated surrogate would be in the setting of the very early stage of AD. In this case subjects would be included in trials ,even though they are essentially asymptomatic, but may be at high risk of AD at a later time, based on some combination of risk factors, including, but not limited to, family history, apolipoprotein E, genotype status, medical history, etc. In this trial setting, the assessment of traditional AD outcome measures such as the ADAS-Cog or CGIC/CBIC would be impossible, or at best irrelevant. Instead, a correlation between the effects on a surrogate marker and an appropriate clinical outcome (such as cognition either as a single scale or domain) could be considered for a disease modification claim in AD, in which a slowing of progression, not prevention, is evidenced. In these very early patient populations a defined change in a biomarker and cognition, even with no global measure provided, may be adequate for approval, pending an advisory meeting to support the validation of the biomarker5. European regulators also identified the need for a link or plausible correlation between a biomarker (such as a PET ligand that labels beta amyloid plaque in the brain) and a desired clinical outcome. To facilitate this, they have essentially proposed a two-step approach which shows a delay of progression based on initial signs and symptoms and followed by a correlation with biomarker data to support a disease modification claim in AD6. Because a “disease modifying effect cannot be established conclusively based on clinical outcome data alone, such a clinical effect must be accompanied by strong supportive evidence from a biomarker programme. As this is difficult to achieve without

an adequately qualified and validated biomarker, a two-step approach may be more suitable. If in a first step, delay in the natural course of disease progression can be established based on clinical signs and symptoms of the dementia condition, this may be acceptable for a limited claim, e.g. delay of disability. If these results are supported by a convincing package of biological and/or neuroimaging data, e.g. showing delay in the progression of brain atrophy, a full claim for disease modification could be considered” ( library/Scientific_guideline/2009/09/WC500003562.pdf). Of note, on January 20th, the FDA’s Peripheral and Central Nervous System Advisory committee failed to recommend approval of florbetapir, a PET ligand-targeting B-amyloid, but unofficially sanctioned florbetapir if the company (Avid, purchased by Lilly) were to step up educational initiatives for training programmes to ensure accuracy and consistency of imaging readers, bringing this two-stage approach closer to realisation ( AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ UCM244441.pdf). References 1. Petersen RC, Parisi JE, Dickson DW, et al., Neuropathologic features of amnestic mild cognitive 349 impairment. Arch Neuro 2006; 63:665-72. 2. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: 327 revising the NINCDSADRDA criteria. Lancet Neurol. 2007 Aug; 6(8):734-46. 3. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282:790–795, 1999. 4. Katz, R. Biomarkers and Surrogate Markers: An FDA Perspective. NeuroRx. 2004 April; 1(2): 189–195. 5. Katz, R. Under what circumstances would a biomarker/ surrogate measure be accepted as a primary efficacy variable? Session presented at the 7th annual scientific meeting of the International Society of CNS Clinical Trials and Methodology (ISCTM) in Washington, DC Feb 21-23, 2011. 6. Broich K. What is required to accept a biomarker as a primary outcomes measure – an EU regulatory perspective? Session presented at the 7th annual scientific meeting of the International Society of CNS Clinical Trials and Methodology (ISCTM) in Washington, DC Feb 21-23, 2011. 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:

Journal for Clinical Studies 11

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Improving Patient Retention and Compliance by Investing in Proven Solutions With heightened regulatory standards and the increasing trial complexity and duration of clinical studies, patient non-compliance is a growing issue that requires tailored, cost-effective solutions. To address these challenges, it is essential to proactively employ strategies that ensure patient compliance in order to avoid compromised data, complete trial failure, or heavy financial losses (through replacement patients and lost revenue days). Successful retention and subject compliance are essential to the completion of a successful trial. Statistically, over 85% of clinical trials fail to retain enough patients, with the typical patient drop-out rate across all clinical trials surveyed at 30%. Of 50,000 clinical trials in the US alone, 80% are delayed by one month or more due to unfulfilled enrolment. Without supportive reminders, patients are likely to forget medication regimens, clinic visits, fasting procedures, blood draw preparation and diary reporting, with detrimental effects on the accuracy and quality of trial data. Through a lack of planning, the risk of patient dropout is extremely high, and will only increase as trials become more complex and lengthy while simultaneously regulatory standards become more stringent. Depending on the therapeutic area, patient discontinuation rates can be as high as 40%, with the process of replacing lost patients impacting significantly on the cost and timeline of studies, in addition to decreasing data quality. Patient compliance can be improved by targeted patient recruitment and the use of reminders and motivational or educational messages throughout the study, which communicate the required activity and themes of appreciation/motivation directly to patients. Companies often do not plan or budget adequately for

patient recruitment or compliance, even though it is recognised as a bottleneck in the clinical trial process. Almost half of all trial delays are caused by patient recruitment problems, and we are all acutely aware of the massive impact of these delays in hundreds of thousands of dollars in lost revenue. By proactively factoring in retention solutions from the outset of a trial, it has been proven that 20% of the typical 30% of patients that drop out can be avoided. Budgets are tighter than ever, but in the long run, the cost of investing in retention solutions far outweighs the high costs incurred by patient noncompliance, both to a trial’s budget, and to overall accuracy and quality. Rather than ‘Can we afford to include a retention strategy?’, the question for the sponsor becomes, ‘Can we afford not to?’. To summarise: take care of your patients, and the data will take care of itself. Exco In Touch provides cost-effective and innovative retention and compliance solutions to engage with patients through customised communication, reducing early withdrawals and improving overall data quality. InTouch Clinical software has revolutionised clinical trial communication, using short message service (SMS) to send automated, scheduled, actiondriven and motivational or educational text messages directly to the mobile phone user, enhancing volunteer relationship management and compliance to the requirements of the protocol design. Successful patient compliance begins with targeted recruitment. InTouch Clinical is designed to improve subject recruitment, by targeting, identifying, and prescreening volunteers and relevant patient populations, and matching them to their nearest recruiting site. With many countries enjoying 100% adoption rates for cell phones, and it being the major means of communication in others, the majority of people now consider their cell phone to be as indispensable as their wallet and keys; as such, SMS solutions have been proven to improve patient retention by over 40%. Tim Davis. Tim has Dual Honours in Biotechnology and Microbiology from University of Sheffield, 1996. He has held various positions including Data Manager at Parexel International and managing the European technical support group at Procter & Gamble pharmaceuticals. This role involved the first pilot EDC trial through to progressive scale up of EDC throughout the organization.In 2004 Tim co-founded Exco InTouch Ltd, an interactive mobile messaging company delivering innovative solutions for patient recruitment, compliance and real-time data collection. Tim has published several articles and regularly speaks and chairs at conferences specializing in EDC, e-PRO, new technology implementation and electronic source data. Email:

12 Journal for Clinical Studies

Volume 3 Issue 2

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Quality Gaps in China’s CRO Sector Currently drug discovery and development outsourcing is growing rapidly worldwide, with the CRO market valued at $163 billion. China’s own domestic clinical research outsourcing has also grown quickly at 25% annually, compared to the global value of 22%. The United States and Europe are still dominant in the global CRO industry, accounting for 88% of market share. Yet the Chinese domestic market for CRO services has reached 50 billion Yuan, with Beijing, Shanghai, Tianjin, and Chengdu initiating strong pull factors for foreign investors, with the multinational pharmaceutical companies gradually starting to develop business in China. However, although the CRO industry’s rise in China is an indisputable fact, it is also clear that it has lagged behind in quality control and that its development has been hampered by lack of standardisation. In this context, the domestic CRO industry’s first focus should be on international standards. Gong Yan Hua, Secretary-General CROU (Clinical Research Organizations Union) said, “I believe that standards will enhance the domestic CRO drug clinical trials enterprise operations management and service management to improve China’s CRO business competitiveness in the international arena.” In light of the international financial crisis, domestic and foreign pharmaceutical companies have decreased R&D funding to different degrees, affecting all countries involved in the pharmaceutical outsourcing services industry, and due to differing accreditation standards and international differences, many Chinese CRO companies face greater challenges. “Lack of professional teams, small scale operations, brief organisational history and a lack of international experience lead to the quality systems not being perfect, especially when staff turnover is high. The domestic CRO industry also faces other threats: the rapid development of international CROs in China [and] other emerging markets such as India’s rapidly growing CRO sectors,” said Xu Jun, the Shanghai Clinical Research Centre senior vice president. He believes that the future of China’s CRO industry must lie in improved management and the conducting of more frequent mergers and acquisitions. An overhaul of the Chinese CRO industry is apparently imminent; to speed up the CRO industry’s standardisation, CROU has initially established a quality management standard Technical Working Group and Academic Advisory Group. It is understood that CRO members of the CRO Technical Working Group are from major domestic and foreign enterprises such as Shanghai Nisshin, Kai Weisi, Quintiles, PharmaNet Development Group and so on. The Advisory Group members are mainly from Novartis, Bayer, AstraZeneca, and other multinational pharmaceutical giants such as China and North Pharmaceutical Group. In conjunction with the Technical Working Group, the SFDA plans to make several reforms to China’s Good Clinical Practice (GCP) content, in order to enact and promote the following 14 Journal for Clinical Studies

points. Firstly, to strengthen the pharmaceutical production and quality management systems, with a substantial increase in the quality of enterprise management software requirements. Secondly, to improve the overall quality of the workforce by increasing the quality of management personnel engaged in drug production and quality requirements of the terms and content to further clarify responsibilities; for example, clear definition of responsibilities among pharmaceutical manufacturing personnel. Thirdly, to refine the operational procedures, production records and other document regulations, guidelines, and increased manoeuvrability. These steps may go towards addressing concerns of individuals such as the Ministry of Health Beijing Hospital, Department of Research Clinical Trials Director, Liu Yong, who also identifies three specific performance gaps: firstly, the lack of standardised training; secondly, the quality of drug management, clinical trial implementation for discretion; and thirdly, the lack of audit inspection. A measure that is already being put in place is to have local CROs ISO 9001 certified, such as in January, 2010, when RUNDO-CRONOVA International Pharmaceuticals Research & Development Co., Ltd became the first domestic CRO to receive ISO 9001 quality system accreditation, as well as the international quality certification union (IQNet) Certification and a CROU evaluation certificate. ISO may well provide a platform on which further standardisation efforts will be based. The CROU member FangYuan Group has already co-developed two documents, the “CRO Standard Management Norms” and “Application of ISO 9001 to the CRO Sector. However, whether these measures will prove successful still remains to be seen. 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: May Lan joined The Scott Partnership as a Senior Account Executive in October 2010. May has a double MSc degree in Bioinformatics from The University of Edinburgh and in Information Technology from The University of Abertay Dundee. She also has a background in pharmacy. Prior to joining The Scott Partnership, May worked in public relations for the chemical and pharmaceutical industries. Email: Volume 3 Issue 2

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A Trial in Tunisia In Tunisia, health-related services are considered a growth window and a key engine for economic and social development1, and the number of clinical trials conducted in Tunisia increased dramatically2 as soon as regulation was implemented in early 1990. Clinical Trials Regulation: The Law Aware of the need to site clinical research in the country, legislators enacted a decree in early 1990, the main intent of which was that clinical trials must be performed in accordance with international conventions, human rights statements and deontology. With respect to ethics, clinical trials would only involve volunteers over the legal age, and would not involve pregnant or breastfeeding women. In Tunisia, Phase III and IV clinical trials are permitted for most known pathologies, and Phase II if no effective treatment is available for a specific disease. A new bill currently under preparation will broaden the field of clinical trials. Tunisian Good Clinical Practice The Ministry of Public Health (MOPH) developed a list of specifications for clinical trials which summarises ICH Good Clinical Practice E6 (3). As part of the requirements to participate in a clinical study, the list of specifications needs to be signed by the sponsor and the investigator-coordinator, attesting that they understand the clinical trial law and requirements. Ethics of Clinical Trials Unless referred by the MOPH, clinical trial ethical issues are not reviewed by the National Committee of Medical Ethics of Tunisia, but must be directly proposed for review by the IRB/IEC of each public hospital where a trial is conducted. The IRB/IECs in Tunisia consist of at least five members, two of whom are not in the medical field, with at least one of the two not being a scientist, and fulfilling the requirement specified by the ICH3. Clinical Trials Resources, Services and Facilities: Services Today, clinical trials can be supervised and monitored by Tunisian CROs. Tunisian CROs usually consist of highly educated CRAs and project managers with medical and pharmacy degrees. Furthermore, local transport companies are now including specialised services to manage investigational products (IP) and materials specifically for clinical trials. Phone communication coverage is comprehensive, with availability of broadband connections and 3G networks, and conducting clinical trials entirely online is a full operative option in Tunisia. IP Management Facilities A central warehousing facility is usually made available in the pharmacy department of a public hospital, and from there IP can be supplied to sites as required. The pharmacy departments are well equipped to manage IP, and many pharmacists are now trained for that. Custom IP release offers no difficulty, with a short delay and adequate storage when needed. If the IP is an investigational new drug (IND), the MOPH may require a biochemical and bacteriological analysis report by the Drug Control Lab, which is an independent agency. 16 Journal for Clinical Studies

Investigation Sites In Tunisia, the organisational chart for trial investigation includes an investigator-coordinator for the country, one principal investigator (PI) per site, and one or more co-investigators per site. The investigator-coordinator signs the MOPH’s list of specifications on behalf of all the investigators, but each PI is responsible for the patients’ welfare at each site, how the trial is conducted at their site, compliance to GCP and clinical trial laws, following the protocol, and effectively managing any serious adverse events (SAEs). Keys to Success Sustainable development of clinical trials in Tunisia is due to the high education level of investigators, usually university professors, with patients who still rely totally on their doctors. This relationship favours compliance and patient inclusion, and the government and health authority are willing to promote clinical trials as part of healthcare and services development. All these elements contribute to the high inclusion rate, and the low number of patient withdrawal that is observed in most trials conducted in Tunisia. Evaluation of Costs The overall cost of clinical trials is reduced by 30 to 40% compared to trials conducted in Europe. While investigators’ fees are usually similar to those given to European investigators, no or minimal fees are required for IRB/IEC approvals, hospital sites, regulatory approvals, and customs release fees. Additionally, CRO and other services’ costs are significantly less compared to similar quality services in Europe or the USA. References: 1. Marc Lautier. Les exportations de services de santé des pays en développement: le cas tunisien. Agence Française de développement; Notes et Documents N°25; 2005. 2. Clinical Trials Database - Accessed on Dec 20, 2010. 3. Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf Meriem Melaouhia is a MD and was hired in 2005 as a CRA by Amilcar International, a Tunisia-based CRO. She is ensuring trial management since 2007. She managed several international trials and has special skills for Regulatory submission and monitoring supervision. Her main job is to supervise Tunisian sites for international sponsors (Sanofi-Aventis, BoehringerIngelheim, Novartis) Email: Habib Ghedira is MD and a Professor in the Medical Faculty of Tunis. He is head of a respiratory department in Thoracic Hospital of and Principal Investigator and Investigator Coordinator in Tunisia of many studies like Endorse, Cobra and Lifenox sponsored by Sanofi-Aventis, Tiospir sponsored by Boehringer-Ingelheim. He has a huge experience in Asthma, COPD, Lung Cancer and Respiratory infections. Volume 3 Issue 2


Clinical evaluation of medical devices: how to negotiate the maze of regulations around the world A medical device is commonly and internationally understood as a therapeutic or diagnostic principle for use in human beings, which fulfils its purpose by physical rather than biological action (see Box 1 for a more detailed definition). As opposed to pharmaceuticals, the standards, data requirements and procedures for marketing authorisation of medical devices vary greatly between different legislations despite the fact that a Global Harmonization Task Force (GHTF) has been active for almost 20 years1. In addition, the escalating technological progress results in the development of novel medical device applications at a pace the regulators struggle to match. As one of the consequences, the requirements for the demonstration of clinical safety and performance are steadily increasing. The industry faces the double challenge of meeting the everincreasing demands on documentation and data quality, not least for clinical evaluation, and of satisfying the diverse regulatory standards. Not only is the regulatory environment around the world rather confusing, in a number of countries the regulation for medical devices is only being established and difficult to come by. In this paper we will review the different regulatory environments in Europe, the USA and Japan, as well as in selected emerging markets, such as India, China or Brazil, with a focus on clinical evaluation and investigation. For a regulatory overview consult Table I. Medical Device Classification Systems In order get an understanding of the different regulatory requirements, one first has to comprehend the policy of classifying medical devices. Devices are very diverse, ranging from simple and well-known tools, such as surgical instruments or gloves, to highly sophisticated implantable devices, such as cardiac pacemakers or artificial bone implants. It would be inadequate to subject all devices to the same stringency of regulation. Therefore, as a general rule, all countries classify the devices into different classes depending on their risk of application. For each class different rules and regulations for placing on the market and, notably, for the requirement of clinical studies, apply. To discuss all existing classification systems would be far beyond the scope of this paper. We will thus focus on the basics of the European and US classification systems. As a rule, many of the other classification systems are patterned after the European or US template. In Europe, there are four risk classes of devices2: • Class I, e.g. most non-invasive devices • Class II a, e.g. some invasive devices in body orifices • Class II b, e.g. some surgically invasive devices • Class III, e.g. all active implantable medical devices (AIMD). 18 Journal for Clinical Studies

The US system classifies medical devices into the classes I, II and III, with the risk of application increasing from class I to III. Regulatory control is highest with class III devices. The FDA in addition recognises de novo medical devices, which are device types that have not been on the US market before, as well as devices for orphan diseases, which are regulated by the Humanitarian Device Exemption (HDE) act3. Principle Differences in Regulatory Approach Among the regulatory procedures, the unique European principle of market authorisation by self-certification by the manufacturer stands out. This is not an “easy” option; rather it places the emphasis including all regulatory and legal responsibility with the manufacturer. E.g. simple devices (mostly class I) can be certified and thus marketed by the manufacturer in its own right, while in the certification of other devices the so-called Notified Bodies are involved to a greater or lesser extent. A Notified Body is an independent, often privately-owned testing or certification organisation that has been recognised by the concerned regulatory authority as able to perform one or more conformity assessment procedures. The respective national regulatory authorities, or “Competent Authorities” (CAs) as the European term reads, supervise the entire certification process. This is a very different concept when compared to the procedures in most other countries, notably the US, which for most devices require a more or less extensive process of authorisation by regulatory authorities. European Legislation In order for a medical device to be “placed on the market” (i.e. offered for sale) and “put into service” (i.e. sold, given away, leased or similar) in Europe it must bear the CE mark. Europe in this context includes all 27 European Union (EU) member states, all EFTA countries (i.e. Switzerland, Liechtenstein, Iceland and Norway) plus Turkey (“CE area”). CE marking by selfcertification of conformity allows for market entry in the entire CE area. The minimal requirement for self-certification is the establishment of a quality management system according to EN ISO 13485(2003). The relevant EU legislation addressing clinical evaluation of medical devices are the Medical Device Directive 93/42/EEC, as amended (21 March 2010; MDD, mandatory since 13.06.1998) and the Active Implantable Medical Device Directive 90/385/EEC, as amended (21 March 2010; AIMDD, mandatory since 01.01.1995). This legislation has been transposed into the national law of all concerned countries. Both directives being New Approach Directives, they depend on supporting external standards. A number of European countries have imposed additional requirements for market entry of medical devices (see Box 2). Volume 3 Issue 2

Regulatory The MMD explicitly does not apply to: • Human cells and their derivatives • Transplants, tissues or cells of animal origin (unless tissue or derived tissue products are non-viable) • Transplants, tissues or cells of human origin and products derived thereof On the other hand, products derived from human blood or human plasma are covered by the MDD. Importantly, in these cases the conformity assessment route is unique and very different from the one applicable for other medical devices in that the European Medicines Agency must assess them in a manner similar to pharmaceuticals Both the MDD and AIMDD require clinical evaluation for the CE marking of any medical device. Clinical evaluation may either be • a critical evaluation of the relevant scientific literature, • a critical evaluation of the results of all clinical investigations made or • a combination thereof. Clinical investigations are called for if the available data are not sufficient to demonstrate safety and performance of the device within the scope of the intended use, regardless of the class of the device. For implantable devices and devices in class III “clinical investigations shall be performed unless it is duly justified to rely on existing data”. The clinical evaluation must be documented and integrated in the technical file or the design dossier, respectively, of the device. The applicable standard for clinical investigation is (EN) ISO 14155(2011)5, which has very recently (1 February 2011) come into effect. The standard replaces the former EN ISO 14155 -1/2 (2003). The European legislation explicitly requires adherence to the Declaration of Helsinki6, which defines the ethical principles to be respected when performing investigations on human subjects. Further guidance on clinical evaluation of medical devices is given by the EU guidance document MEDDEV 2.7.1 Rev. 3. In addition other regulations may be applicable to medical device investigations (see Box 2). Other than for pharmaceuticals, the European legislation does not define requirements for the qualification of persons responsible for medical devices, such as for persons involved in medical device release or vigilance / incident reporting. No equivalent to the “Qualified Person” in the pharmaceutical industry has been defined. A European registry for all medical devices including in-vitro diagnostic devices is being established (EUDAMED). It shall contain data on: • Manufacturers • Devices • Certificates issued, modified, supplemented, suspended, withdrawn or refused • Device vigilance The entries must be made using an internationally-recognised nomenclature such as the Global Medical Device Nomenclature (GMDN)7. The database is accessible to all CAs for all medical device categories. EUDAMED shall be fully implemented by 5 September 2012, but the member states must use it by 1 May 20 Journal for Clinical Studies

2011. Devices which were on the market prior to 1 May 2011 must have a summarising entry by 30 April 2012. US Legislation At the US Food and Drug Agency (FDA) the Center for Devices and Radiological Health (CDRH)8 deals with medical devices. As opposed to the European regulatory process, authorisation by the FDA for most medical devices is required before a medical device can be marketed. The two principle routes of authorisation are premarket notification using form 510(k) or premarket application (PMA). The main applicable laws are the Federal Food, Drug and Cosmetic Act (FD&C) as well as Title 21 of the Code of Federal Regulations (21 CFR). The classification of the device defines the course needed to obtain FDA approval for marketing: • Class I devices are under so-called General Controls and are mostly exempt from premarket notification • Class II devices are under so-called Special Controls and need premarket notification • Class III devices require premarket application The FDA system knows many exemptions from the concept described above. E.g. certain class II devices are exempt from 510(k) notification; whereas some class I devices may need one. The FDA has classified approximately 1700 different types of devices and listed them in a database, together with the corresponding regulations that apply9. The designation 510(k) refers to section 510(k) of the 1976 Medical Device Amendment Act. A 510(k) procedure is a premarketing submission made to the FDA to demonstrate that the device to be marketed is safe and effective, as well as substantially equivalent to a device which is already on the US market. The submission of a 510(k) is described in 21 CFR 807. A premarket application has the objective to demonstrate that there is enough scientific evidence to show that a device is safe and effective within its intended use. It has to be based on valid scientific evidence, including data gained in nonclinical laboratory testing, animal studies and clinical experience in humans. For some 510(k) submissions and most PMA applications, clinical performance data are required. In these cases the clinical trial must be conducted in accordance with FDA’s Investigational Device Exemption (IDE) regulation, as outlined in 21 CFR 812. The IDE allows investigational devices to be used in clinical studies to support PMA and 510(k) notification. It describes the procedures for the conduct of a clinical study with a medical device in a manner essentially similar to the ICHGCP guidelines used for pharmaceutical development. Under an IDE a clinical study needs IRB approval and FDA approval, if a high-risk class is involved. As in Europe the clinical studies have to follow the principles of the declaration of Helsinki. Clinical evidence gathered outside of the US is only accepted when the respective studies were conducted in compliance with the declaration of Helsinki and the applicable national laws and regulations guaranteeing safety and wellbeing of trial subjects. In the past few years the 510(k) process has been criticised as being unpredictable and lengthy. Therefore, the FDA has announced changes to come into force in 2011, making the process more transparent, but also more adequate for novel technologies10. Volume 3 Issue 2

Regulatory Box 1: Definition of “Medical Device”

Box 2: Additional regulatory requirements in selected European countries

A medical device is any product (instrument, appliance, apparatus, software, material, article, contrivance, implant, or similar) that is intended for use with human subjects and which does not usually contain a pharmacologically active substance. The device is intended for: • diagnosis, prevention, monitoring, treatment or alleviation of diseases • diagnosis, monitoring, treatment, alleviation of or compensation for an injury • investigation, replacement or modification of the anatomy or of a physiological process, • control of conception Note: This definition is not meant to include every detail.

• Spain: national registration of device with the Ministry of Health. • Italy: national registration of the device with the Ministry of Health. • France: review of devices containing animals tissue by Viral Safety Expert Group; notification of high potential risk devices (classes IIb, III and AIMD) to the Competent Authority

The most important definitions are described in: • European Directive 93/42/EEC • US FD&C Act U.S.C. 321 (includes use in animals) • Global Harmonization Task Force GHTF (includes in vitro reagents, calibrators, apparatus for disinfection of medical devices)

Box 3: O  ther relevant European directives, which may be partially or fully applicable to medical devices • Product liability (85/374/ /EEC & 99/34/EC) • Processing and transmission of personal data by EC bodies and institutions (95/46/EC) • Packaging and packaging waste 94/68/EEC) • Medicinal products / MEDDEV2.4/1 rev 8. July 2001(2001/83/EC) • Machinery (89/392/EEC) • Personal protective equipment (89/686/EC) • Low Voltage (73/23/EEC)

Table 1: Applicable Legislation for Medical Device Marketing Authorisation in Selected Legislations Country /ies

Regulatory Authority /ies




Quality Management Requirements

Acceptance of foreign assessments

EU/EFTA/ Turkey (CE area)

Competent Authorities (=National Regulatory Authorities) Notified Bodies

93/42/EEC (MDD) 90/385/EEC (AIMDD) MEDDEV Guidelines

- Establishing quality control system - Consulting with / certification by Notified Body (depending on device class) - Conformity declaration by self declaration (CE marking) - Registration with EUDAMED - Supervision by national Competent Authority

I, IIa, IIb, III

ISO 13485:2003

Conformity declaration in accordance with the legislation is generally universally accepted in the CE area.


Food and Drug Administration FDA

Federal Food, Drug and Cosmetic Act (FD&C) Title 21 Code of Federal Regulations (21 CFR-800 ff)

- Registration of manufacturer - Annual Device Listing of manufacturer - 510(k) for substantially equivalent devices - PMA Pre-Market Approval for high risk devices - IDE investigational device exemption for investigational devices (clinical study)


FDA 21 CFR 820 QSR

Clinical evidence from outside of the US is only accepted when the study was conducted in compliance with the declaration of Helsinki and the national laws and regulations guaranteeing safety and well-being of trial subjects


Ministry of Health, Labour and Welfare MHLW Review by: Pharmaceuticals and Medical Devices Agency, Japan PMDA

Japan’s Pharmaceutical Affairs Law (PAL), Ordinance #169 for Quality Management

- License for Manufacturer - Accreditation of foreign Manufacturers by PMDA (QMS-Audit) - Market Authorisation Holder (MAH) as legal representative responsible for submission - Pre-market submission required for classes II, III, IV in STED format

I, II, III, IV (III and IV are both highly controlled)

Ordinance #169

CE-marking and assessment by European bodies or FDA not accepted, but aids the registration process Foreign clinical study data will be accepted if they fulfil the Japanese standards, specific QMS requirements

People’s Republic of China

State Food and Drug Administration SFDA division of Ministry of Health (MoH)

Regulations for the Supervision and Administration of Medical Devices from April 01, 2000

- Import Medical Device Registration Certificate to be applied from SFDA, Local Legal Agent required - Clinical trials are mandatory for the registration of class III devices and usually required for class II - Data from clinical trials conducted in China necessary for class III - CCC Mark (China Compulsory Certificate) required for some product categories - Accredited institutions test the medical device


YY/T02872003 similar to 13485:2003

QMS according to FDA or ISO 13485:2003 will be accepted Foreign clinical data for low risk devices accepted


Central Drugs Standard Control Organization CDSCO

Drugs and Cosmetics Act and Rules , Rule 24A, Form 40

- Regulatory procedures unclear at the moment. - Until new law comes into force, some medical devices are defined as drugs, these must be registered with the Ministry of Health and need an import licence to be sold in India.

A, B, C, D according to GHTF (proposed only)

ISO 13485 / CE cert mentioned in drafts

For Applications FDA, JPN, EU authorisation-dossiers can be submitted.

Links to English Web-pages of Competent Authorities EU European Commission Medical Device Reference Documents: http://ec.europa. eu/consumers/sectors/medical-devices/ documents/index_en.htm last visited on 10 February 2010

USA Main page: default.htm last visited on 10 February 201. 21 CRF Code of Federal Regulations Title 21: cfdocs/cfCFR/CFRSearch.cfm last visited on 10 February 2011. Guidance Documents for Medical Devices: DeviceRegulationandGuidance/ GuidanceDocuments/ucm2005753.htm last visited on 10 February 2011

Japan Main page: html last visited on 10 February 2011. Medical Device Regulation: index_e.html last visited on 10 February 2011

India Main page: last visited on 10 February 2011. Medical Device Regulation: division.htm last visited on 10 February 2011

China Main page: last visited on 10. February 2011. Medical Device Regulation: webportal/W45649038/A48335998.html last visited on 10 February 2011

Brazil Main page: htm last visited on 10 February 2011. Medical Device Regulation: medical_devices/index.htm last visited on 10 February 2011

Journal for Clinical Studies 21

Regulatory Japanese Legislation In Japan, the review for marketing approval of medical devices is conducted by the Office of Medical Devices, a department of the Pharmaceutical and Medical Devices Agency (PMDA). The PMDA is an independent administrative organisation, which was established in April 2004 to rationalise approval processes. Final responsibility for approval lies with the Ministry of Health, Labour and Welfare. Premarket submission is required for all but the lowest risk devices, namely device classes II, III and IV. The legal basis for obtaining market authorisation is the Japanese Pharmaceutical Affairs Law (PAL) and Ordinance #169, which specifies the necessity of a quality management system similar to ISO 13485(2003), but with additional requirements. The approval process for market entry usually takes longer in Japan when compared to the CE area or the US. European or US market authorisation is not sufficient for Japanese marketing authorisation. However, the documentation for European or US marketing authorisation may be used supportively. The applicable medical device classification system is based on Japanese Medical Device Nomenclature codes, and differs significantly from the classifications in the EU or US. If Japanese law requires clinical data for marketing approval, foreign clinical data will be accepted as long as the studies meet the Japanese standards. Otherwise clinical studies must be conducted in Japan. Foreign manufacturers need to be accredited by PMDA. The marketing authorisation holder must be a resident of Japan. Legislation in Emerging Markets India. India has been in the process of implementing a medical device-specific regulation since 2006. The latest drafts were recently published on the Indian Central Drugs Standard Control Organization (CDSCO) homepage. These drafts are very close to the recommendations by the Global Harmonization Task Force, GHTF. Until the new law comes into force, specified medical devices, such as orthopaedic implants, heart valves and i.v. cannulae, are defined as drugs. These must be registered with and authorised by the Ministry of Health, and need an import licence to be sold in India. Clinical safety and performance need to be demonstrated by clinical studies in accordance with the accepted standard for pharmaceuticals in India, i.e. in principle the ICH-GCP standard. If meeting the Indian requirements, foreign studies will be accepted. Clinical trials performed in India must be registered with the Indian Clinical Trial Registry11. Medical devices not defined as drugs, but having a market authorisation in another country, only require an import licence. For medical devices not falling in any of the two aforementioned categories, the regulatory pathway is not (yet) defined and should be discussed upfront with the authorities. The Indian regulation also relies on a risk-based classification system for medical devices based on the GHTF recommendations. Notably, the process to obtain regulatory approval for clinical investigations is seemingly independent of the device classification, but rather follows the arguments outlined above. As the Indian regulatory process for medical devices is still in development, it is advisable to periodically check the actual regulatory requirements when planning the marketing authorisation of a medical device in India12. 22 Journal for Clinical Studies

China: Medical devices need to be registered with the State Food and Drug Administration (SFDA) before being introduced to the Chinese market. They must meet Chinese product standards. Changes in indication or intended use, design or technical changes or new manufacturing locations also need explicit approval. Existing registrations can in some cases be amended, e.g. for formal issues like name or trade-issues. Third-party review by another country is not accepted by the Chinese authorities: each device needs an approval by the SFDA for marketing in China. The classification system and the corresponding regulation differs from the US or EU systems. E.g. a class I (lowest risk) device also requires SFDA approval. Sample testing must be conducted in any case in China by SFDA-certified testing centres. High-risk devices may require additional clinical data obtained in China, also when foreign country approvals and clinical data are in evidence. Brazil Before marketing a medical device in Brazil, it must be registered with ANVISA, the Brazilian National Health Surveillance Agency. The legal basis is the Brazilian resolution RDC185/1, which is similar to European Directive 93/42/EEC. Devices are classified in classes I, II, III and IV, largely corresponding to the European classes, whereby the Brazilian classes II and III correspond to the European classes IIa and IIb, respectively. Brazil has established a specific Brazilian GMP standard (B-GMP), which foreign manufacturers will have to comply with. It is similar to the FDA Quality Systems Regulation. The ISO Norm 14971(2007) on risk management is an additional requirement for all implants, intrauterine devices and blood bags. Conclusion The need for harmonisation of the standards for the regulations of medical devices around the world is obvious and has been widely acknowledged. Attempts to implement the recommendations of the Global Harmonization Task Force are evident, such as in the new standard ISO 14155 (2011), which is likely to be more universally accepted than its predecessor. However progress is slow, and harmonisation lags far behind the global harmonisation achieved for marketing authorisation requirements of pharmaceuticals. An example is the Global Medical Device Nomenclature system, which was created in order to have a universal standard for exchanging medical device information. It has however not yet been universally accepted, and its implementation is, among other things, pending translation of the English original version into national languages. Device classification is another issue lacking international transparency. All classification systems have in common that they are risk-based, with the consequence of higher regulatory control with higher risk classes. In contrast, risk assessment procedures and philosophy differ widely between legislations, potentially resulting in varying classifications of the same device in different countries and thus different regulatory requirements. As a consequence, in different legislations clinical evaluation or clinical investigations of a medical device may or may not be required for market entry or may need to address different questions. In the next paper of this three-part series on medical devices Volume 3 Issue 2

of medical devices in major legislations. We will address the options for meeting as many standards as possible in one clinical study, which may be desirable in the context of a global development programme. References 1. GHTF created 1992 by European Union, European Free Trade Association, Turkey, Australia, USA, Canada, Japan; www.ghtf. org/documents/sg1/sg1n29r162005.pdf 2. MDD 93/42/EEC Annex IX: further explained in MEDDEV2.4/1 rev 9. June 2010 3. 21 CFR 814 Subpart H - Humanitarian Use Devices 4. none 5. ISO 14155(2011), “Clinical investigation of medical devices for human subject – Good clinical practice”, published on 1 February 2011, 6. MDD, Annex X, § 2.2; AIMD, Annex 7, §2.2; ISO14155 (2011) § 4.1, Annex A, §A.12 a) 7. 8., visited 10 February 2011 9. Overview/ClassifyYourDevice/UCM051530#regs 10. w CDRHReports/UCM239450.pdf 11. 12. w Georg Mathis is a doctor of veterinary medicine with a PhD in pharmacology. He has obtained an MBA from the State University of New York at Albany and the GSBA Zurich in Switzerland. After medical practice, he spent ten years in medical research. The last 20 years he was active in various sectors of the health care industry, mostly in executive positions. He was Medical Adviser at Ciba Vision Ophthalmics, Managing Director of Sana Care, a Swiss HMO and CEO of Sucampo Pharma. In 2002 he founded his own boutique CRO, Appletree Ltd, in Switzerland, with a subsidiary in the EU, Luxembourg; which is specialised in clinical research in ophthalmology and medical devices and is predominantly active in the United Kingdom, Northern, Central and Eastern Europe. Email: Rolf Marugg has a BSc in Information Sciences. As Head Drug Regulatory Affairs working with Appletree since 2009 he has experience with Regulatory Authorities and Ethics Committees submission and reporting for studies with Drugs and Medical Device Investigations in UK, Central and Eastern Europe. Annick Toggenburger is a biology graduate with a PhD in technical sciences. She has more than ten years experience in clinical trials in the Medical Device area as well as in the Pharmaceutical area. In 2009, she joined Appletree AG, a Swiss CRO specialised in ophthalmology and medical devices, where she continues to manage clinical trials in addition to her role as Medical Writer. Email:


Argentina has Established a New Regulation for Pharmacological Clinical Trials The pharmacological regulatory authority in Argentina is the ANMAT (National Administration of Drugs, Food and Medical Technology). ANMAT Provision 5330/97 was the directive that regulated the pharmacological investigation in Argentina for 13 years. Although during that period the regulation has been complemented and has undergone certain changes (for instance, in the year 2005, Provision 690/05 modified the procedure for inspections; in 2005 and 2008 some amendments to the safety aspects were introduced; in 2008 the documentation requirements for the initial filing were tightened), the core of the regulation continued to be the same Provision. Recently, as from November 8th 2010, a new regulation that repeals the Provision 5330/97 has come into force. This new regulation substantially modifies the requirements for the conduct of clinical trials. The spirit of the new regulation is to come into closer alignment with the international guidelines (incorporating some ethical provisions conveyed in the Helsinki Declaration that were not specified in the previous regulation, and adjusting the requirements and the text so as to make them more similar to those of the ICH-GCPs and the Document of the Americas), as well as to smooth the process for the submission of documentation in order to make the approval faster and more efficient. In this article, we will describe the changes that we consider more significant. Analysis of the regulation: As regards the formal aspect, the regulation is divided into six sections, from A through F, namely: General Aspects, Documentation, GCP Guideline itself, Inspections, Glossary and Forms. Each section contains different chapters. Main General Aspects: 1. A  s regards the scope of the Provision, it specifies that the only studies that must be authorised by the Agency are pharmacological studies with the aim of registration or regulation. This is why, in the case of drugs already in the market, it includes those studies that are sponsored by the pharmaceutical industry with the purpose of requesting a new indication or a new pharmaceutical form; but it excludes those studies performed by physicians with the aim of improving the medical attention of their patients, with no registration purposes. This is no news, as it has been the Agency’s idea for years, but it had not been explicitly stated in the regulations. 2. P  rovision 5330/97 required two approvals – that of the Independent Ethics Committee (IEC) and that of the Research and Teaching Committee (RTC) – for the scientific aspects of the studies. The new regulation incorporates a chapter of 24 Journal for Clinical Studies

requisites from the IEC (section C4) that were not specified before, and no longer require the approval of the RTC. 3. The new regulation specifies in a much more detailed way than before the contents of the Informed Consent. The same happens in the case of the Investigator’s Brochure. 4. There are new chapters that cover monitoring, auditing, inspections, essential documents of the study and source documents, including electronic documents. What is new is the incorporation of inspections of the sponsor that, although mentioned in the glossary of Provision 5330/97, had never been implemented. It is expected that, with this new regulation, there will be inspections of the sponsor in the future. 5. In addition, there is a new chapter on Protection of the Subject in which it is specified that the use of placebo must always be properly justified in the protocol, and demands that the IEC evaluate the need for post-trial access to the study medication, other alternative interventions or other appropriate benefits. It also includes a paragraph in connection to women of fertile age and their protection. 6. The consent process is much more detailed, specifying how it must be obtained (for instance, verifying the subject’s understanding) and what needs to be documented in the source documents (for example, the starting hour of the process). One of the most important changes in this respect is that, before, the Argentine regulation was binding on the witness in all cases. With the new regulation, and similarly to the ICH-GCPs, a witness is required only in cases of socially, educationally or economically vulnerable subjects, making the investigator responsible for the decision regarding the existence of such vulnerability, although it enables the IEC of an institution to demand a witness in all cases if it considers that all of the population of the study is vulnerable. 7. Another novel aspect in the process of informed consent is that it permits the application of an abbreviated consent in the case of studies in acute situations, in which case the presence of a witness is mandatory. Modifications in the area of documents: 1. Format of the documents: before this regulation, the request for approval was submitted on Form ECLIN 1.0.1, which included all the information regarding both the clinical trial and the site. Now, the documents are divided into forms EFCA1 for the clinical trial, and EFCA2 for the site. This will permit in future the submission of the protocol without the need for previous approval of the site by the IEC, and the possibility of submitting the presentations to the ANMAT and the IEC simultaneously, reducing the start-up time. 2. For the initial approval, it is required that there is a local Volume 3 Issue 2

Regulatory sponsor with an address in the country, and with accredited legal status. Also, it requires the original sworn statement of compliance with GMP of the product under investigation and a copy of the product’s label. This is a new requirement that incorporates some of the specifications included in Annex 13 of the European Directive. The investigator is required to provide documentation that certifies that he can practise his medical profession, as well as documenting his experience and/or training in clinical trials, and his experience in the speciality or in the disease under study (for clinical trials Phase II and III). 3. T  he investigator must submit to the IEC the insurance policy, the contract model and the subjects’ recruiting methods, and must also declare any potential financial conflict of interest. 4. P  eriodic reports: previously, the ANMAT required a periodic report every six months if the study lasted more than a year. Under the new regulation, and in order to bring it closer to the ICH-GCPs, the reports are required at least once a year, and not every six months. 5. S  USARs (Suspected Unexpected Serious Adverse Reactions): also following the ICH-GCPs, the new regulation requires that the sponsor report the SUSARs related to a product under investigation to every investigator of every study in process related to the product, within 14 days of having learned of them. The investigators must inform the corresponding IEC within the terms established by the same. Also, the sponsor must report the SUSARs to the ANMAT, and other security

information related to a product, within 10 working days from having been informed of them. Apart from this, the sponsor must submit on a semi-annual basis, and by each product under investigation, a single summary of all the SUSARs which occurred in any of the centres during the corresponding period. 6. D  eviations: with this new regulation, the ANMAT requires that the sponsor informs the Agency of any major deviation from the protocol that may have affected the rights or safety of the participants, and of any minor deviations that were repeated in spite of having been warned to the investigator, within 10 working days of having learned about them. We consider that this regulation represents a significant progress towards making pharmacological investigation in Argentina more efficient and more protective of the investigation subjects. The Spanish version of the regulation can be found at: Dispo_6677-10.pdf

Ezequiel Klimovsky who is currently the Associate Director of QUID Consulting and Secretary of FECICLA (Ethics and Quality in Clinical Research in LATAM Foundation). Email:

Market Report

Korea as the New Destination November 18th, 2008, a 27-year-old American patient living in Japan was lying in Osaka General Hospital, having been given only days to live. Every therapy applied to him had failed, and cancer had spread all over his body, including his brain. His doctor contacted Professor Hiroyuki Mano of Jichi Medical University to evaluate him. Dr Mano, who researched molecular biological analyses to look for novel signalling molecules involved in the growth mechanism of hematopoietic cells, found out that samples of three responders of the patient’s cancer cells were analysed for ALK (Anaplastic Lymphoma Kinase)-EMLK4 and all responders had ALK-EML4 mutations. Dr Mano transferred the patient to Dr Yung-Jue Bang, the professor of Seoul National University who was the principal investigator for the ‘first in human’ studies in Asia for the ALK inhibitor developed by Pfizer, and the patient enrolled in Dr Bang’s Korea study. One month later, the patient was back in Tokyo, shopping. This short story exemplifies the clinical trial collaboration model of the modern day. Clinical trials benefit patients by offering them immediate access to innovative treatments. More importantly, however, this case speaks to the advanced state and current position of clinical studies in Korea. Thanks to its excellent infrastructure for clinical research, South Korea is rapidly emerging as a global hub of clinical trials for multinational pharmaceutical companies. In 2000, Korea adopted ICH-GCP guidelines that enabled the nation to conduct global clinical trials. Over the last decade, Korea has experienced dramatic growth in the clinical trial field through solid partnerships with the government, academia, and hospitals. In 2009, the Korea Food and Drug Administration (KFDA) approved 400 clinical trials, 202 of which were multinational. In the first half of the year 2010, KFDA approved 202 clinical trials, an approximately 20 per cent increase from 169 approved cases in the same period a year previously. This sharp increase demonstrates the high degree of professionalism and efficiency prevalent in Korea’s leading clinical trial centres, where the majority of the nation’s clinical trials are undertaken. Another important feature of multinational clinical trials is a significant shift to earlier phase trials. Korea’s involvement in multinational clinical trials from an earlier phase of global development programmes indicates the competent and efficient nature of the country’s infrastructure for R&D. What makes Korea a competitive setting to conduct global clinical trials? Here, I would like to focus on four major benefits of conducting clinical trials in Korea. First, Korea possesses magnificent medical infrastructure. Korea’s world-class researchers and medical professionals show high expertise and passion in advancing the nation’s medical science field. Korean clinical trial sites may be the best equipped hospitals in all of Asia, if not in the world. Currently, the Government is designated to grant 14 regional clinical trial centres, with most holding more than 1000 beds. Second, Korea maintains an efficient manner of recruiting patients, a difficult undertaking for all sites across the globe. In the US, 62 per cent of all clinical sites recruit less than five patients each. As one of the largest metropolitan cities in Asia, Seoul’s investigator sites recruit patients in a very speedy 26 Journal for Clinical Studies

and efficient manner. This is in part attributable to the highly dense population, as well as to people’s attitudes towards and perception of clinical trial participation. In 2006, about 282,000 people participated in clinical trials in Korea. According to a survey conducted by the Yonsei University Hospital, a top Korean medical centre, more than 18.5 per cent of the 1500 survey participants claimed to be willing to participate in clinical trials. Of those with diseased family members, about 40 per cent reacted positively to clinical trial participation. Such data illustrate the public’s trust in Korea’s advanced medical technology. Third, less time-consumption and affordability make Korea an efficient place to conduct clinical trials. The procedures required to commence a clinical study in Korea require very little time and occur in a fast manner. The KFDA takes less than two months to approve the launch of a trial. The IRB (Institutional Review Board) process happens in parallel with the KFDA review process, saving even more time for sponsors. Customs clearance, which enables drugs to be released and imported following KFDA approval, takes about a month or so. In terms of price, clinical trials in Korea cost only 25 per cent of those in the United States and the European Union (EU). Advanced information technology (IT), paired with an excellent computer system, enables Korea to design clinical trials at a lower cost. In the US, each trial costs over $30,000 to set up and $2000 per day to monitor. Lastly, the government’s conscious effort to cultivate the health industry partly explains Korea’s excellent infrastructure for clinical trials. By 2010, the Korean Government had invested 60 million USD in enhancing the competitiveness of regional clinical trial centres. In 2007, the Government established the Korea National Enterprise for Clinical Trials (KoNECT), an entity that enhances the quality and efficiency of clinical trials conducted in Korea. Through strong government support and active industry participation, the number of clinical trials conducted in Korea rose by about 10 times from the last decade. In a world facing various challenges like the economic crisis, the competitive devaluation of currencies, and global trade imbalances, how do we go about addressing and improving upon such an uncertain environment? The G20 summit, hosted and chaired by Korea last year, came up with one solution - “work together to promote global sustainable growth.” As in other industries, the pharmaceutical industry currently faces huge threats. To name a few, these threats include patent expiration of blockbuster drugs, declining R&D productivity, and price and regulation pressures. As expressed in the G20 summit Joint Statement, the threats of the pharmaceutical industry can be overcome through collaboration with Korea. For the previously stated reasons, in the year 2011, I anticipate a further growth in the number of clinical trials to be conducted in Korea. Do Hyun Cho, PhD. Dr Cho is currently the director of KHIDI USA. His responsibilities include establishing Korea-International collaboration programmes and attracting multiregional clinical trials to Korea. Email: Volume 3 Issue 2

Market Report

Six Steps to Streamlined Contracting of Sites for Clinical Studies Postponed study starts in clinical research can translate into delays in bringing new drugs to market, with potentially significant revenue loss for research sponsors and longer waits for patients in need of innovative treatments. The implications are huge for everyone involved, regardless of the metrics chosen to measure them. According to a 2009 Thompson CenterWatch survey of 950 sites, 49% of sites attributed enrolment delays to holdups in contract and budget negotiations and approvals – more than any other reason. On average, over 80% of sites surveyed were enrolled one or more month/s later than planned. These delays are influenced by numerous variables within the site contracting process. Many doctors and nurses do not have sufficient knowledge of the financial techniques that are needed to properly analyse a study budget. The varying operating procedures across sponsors and a lack of standards force sites to understand and follow different contracts and budget structures each time they participate in a study by a different organisation. Additionally, there is often a lack of transparency and trust between the two parties. In some cases, sponsors have the additional challenge of consolidating data from multiple, disparate systems when contracts and budget processes are spread across several applications. All of these factors result in extremely inefficient contracting processes that are prone to significant and unanticipated delays. Fortunately, there are some key areas that sponsors, contract research organisations (CROs) and investigative sites can focus on to reduce the time and effort wasted in grant budgeting and approval. In the next few paragraphs, we explore some ideas to compress the cycle time, as well as reduce the total number of cycles required to contract with a site. The mutual goal for both the parties is to engage in a quick and transparent process to reach a financial agreement. Implementing the following six steps will make the contracting process much more efficient.

2. Create a Budget Hierarchy Before communicating grant proposals to sites, ideally the sponsors and CROs should create a well-defined master study budget from benchmarked cost data that accounts for different site types, geographies, trial types, subject populations and trial complexity. Properly analysing these factors and applying business objectives will result in a better positioned reimbursement and fewer site objections. This master budget can then be used to create a few different versions of site budgets. Deriving site budget versions from the master budget allows flexibility to further customise costs based on attributes such as overhead variance and previous site performance with reduced effort. Grouping sites in a few categories based on common attributes such that one version of the site budget can be distributed to the entire site group further streamlines the process. Having fewer site categories and fewer versions of site budgets minimises administrative work.

1. Pre-Approve and Reuse Contractual Components Since both sponsors and sites have to protect their legal, financial and regulatory interests, the teams working on contract language usually have very stringent acceptability guidelines. An increasing level of contractual complexity has resulted in extensive review periods in the last few years. To shorten this review period, sponsors’ legal teams can preapprove multiple versions of clauses for commonly negotiated terms, such as indemnification, intellectual property and publication empowerment. This allows non-legal personnel to draft much of the contract, without constantly consulting the legal team. If the sponsor and site have worked together in the past, they can standardise and reuse previously agreed terms in new contracts. This enables a sponsor to start from a point that was previously acceptable to both parties.

4. Use Multiple Touchpoints for Faster Response After sending a budget draft to a site for consideration, the sponsor or CRO should quickly follow up with a phone call or an email to express the urgency. Waiting to contact the site only after a few days of unresponsiveness can waste precious time in each cycle. Staying in close contact during the review process reduces the cycle time, and including a soft deadline in the communication sets correct expectations. In general, using multiple touchpoints (online, phone, fax, email) to communicate and engage with a site has been shown to work well. Sponsors should foster an environment where both parties can continuously communicate. Sites should proactively communicate legitimate issues to allow for better planning. If a site is consistently unresponsive during the negotiation process, there is a high probability that

28 Journal for Clinical Studies

3. Use Benchmarks to Competitvely Price Analysing previously approved budgets as a point of reference provides a basis to start from and reduces the number of cycles for sites that commonly request changes. If time is critical, then the cost numbers may need to be higher than the prior threshold to cut the number of budget cycles. Otherwise the numbers can start lower and adjustments can be made with every cycle until both parties are satisfied. Sponsors conducting studies in emerging markets such as India and China should know that procedure and professional fees are up to 75% lower compared to those in the United States. However, the costs are gradually increasing and these markets are highly price-sensitive. Sponsors without accurate cost benchmarking data may be offering disproportionately high reimbursements. Hence, it is imperative to understand grant costs negotiated by competing sponsors in these emerging markets.

Volume 3 Issue 2

Market Report the site will be just as slow during every stage of the study. Sites that have slow administrative procedures may not be optimal for a study, and ignoring this early sign is risky. 5. Streamline the Workflow Budget approval processes typically involve legal, clinical operations, and other departments that review the documents. Each node in the decision-making process can be a source of additional delay, so keeping the overall workflow lean is a good idea. Efforts should be made in parallel wherever possible. It is important to identify all of the critical nodes that are required to create, review, modify and approve the budget or contract, and focus efforts to reduce the time it takes to review and transfer documents internally. Individuals on the critical path should have a predetermined backup in case of an emergency. 6. Unify Data and Workflow in a Single Application Using multiple tools or applications, such as email in conjunction with spreadsheets and a clinical trial management system (CTMS), to negotiate and budget ultimately requires consolidation of fragmented information from various sources. This also increases the chance of human error, especially transcription errors if the tools are not tightly integrated. According to Manhattan Research, 86% of physicians in the United States used the internet in 2009, and the usage is steadily increasing. Communication, exchange and consolidation of

contracting information using a unified web-based application, accessible in real-time to sites and study budgeting team simultaneously, is now an extremely viable alternative. Adoption of online applications can also help standardise the contracting and budgeting process across multiple sponsors and multiple geographies. In summary, automation and use of online applications can help streamline the negotiation process and reduce errors. Simplifying the contract language can lower the number of cycles, whereas having multiple touchpoints can dramatically shorten the contracting cycle. Having fewer versions of site budgets and streamlining the process can reduce the amount of administration. All of these steps are imperative in increasing transparency and site satisfaction while decreasing the amount of time it takes to reach contract agreements. Keyur (Kevin) Shroff manages web applications such as Grants Manager Contracting at Medidata Soultions. He has excellent management skills and has developed various innovative web applications in both the pharmaceutical and social networking space. Previously he co-founded GlobalLinker LLC and co-authored a technology patent. He is currently pursuing his MBA at Rutgers University. Email:

Market Report

Effective Utilisation of India for Global Clinical Trials Challenges with clinical trial subject recruitment in Western countries, and the growing track record of emerging countries, have resulted in a universal acceptance of the imperative to include at least one emerging country in product registration Phase II-III clinical trials. India is becoming the most attractive member of this group, for reasons shown in Figure 1. The Indian clinical trials sector is enjoying brisk, even exponential growth, albeit from a low baseline. The number of international clinical trials conducted in India has increased by 30% per annum for the past three years. Global clinical trials that include India have increased from 1366 to 1533, an increase of 11%, in the six-month period ending 15th February 2011 (www. More than half of these were Phase III trials. Oncology, infectious disease, diabetes and cardio-respiratory disease are the commonest therapeutic areas being trialled in India. Presently only 1.5% of the world’s ongoing clinical trials include India, as compared to 52% that include the US. Key Growth Drivers of India’s Clinical Trial Sector The most compelling reason for sponsors to include India in their global clinical trials is the access to clinical trial subjects that India offers. India has 16% of the global population, but 20% of the global disease burden. In addition to widely prevalent infectious and tropical diseases, rapid and extensive urbanisation has resulted in disease prevalence similar to that found in developed countries. There are approximately 3 million patients with cancer in India, with about 1 million new cases detected every year. India has the largest number of individuals in the world with a combination of insulin resistance, hyperlipidemia and obesity. There are 60 million diagnosed cases of Type II diabetes mellitus, 80 million individuals suffer from cardiovascular disease, and there are 50 million asthmatics. A mixture of private and state-subsidised healthcare exists in India. Healthcare insurance coverage is low; hence there exists

Figure 1. Emerging countries are essential for Phase lll-lV clinical trails and India is the most attractive of them

a huge unmet medical need. Healthcare is centralised and hospital-centric, with patients travelling to centralised hospitals for healthcare. It is the large population, high disease burden and unmet medical need that collectively contribute to the large numbers of potential, willing clinical trial subjects in India. This, combined with the centralised, hospital-centric healthcare delivery system, gives Indian hospitals the potential to be amongst the world’s most productive clinical trial sites. Clinical trial conduct costs in India can be as low as 60% as compared to the West. This is a result of lower diagnostic and therapeutic costs, relatively lower investigator grants and the potential, although not always realised, of working with productive, cost-effective clinical trial sites. High site productivity with elimination of the wastefulness in clinical trial conduct that has become so prevalent in the West could be the most important contributor to the cost savings that India offers. India has 10,000 GCP-trained clinical research professionals, and 1500 GCP-trained investigative sites. English is the language for clinical research, healthcare & business, although informed consent documents and patient literature need to be made available in a selection of India’s 14 languages. There exists a robust IT infrastructure with an IT-savvy workforce, making the universal adoption of electronic data capture (EDC) relatively straightforward. Over the past five years, clinical data from India contributing towards pivotal global clinical trials has been accepted by the FDA and EMEA on numerous occasions. Data submissions from India in the recent past have been part of 13 successful NDA submissions. The increasing volumes of data from India being submitted to the FDA prompted its first audit in India in 2005. There have been 14 FDA inspections in India since 2005 with no “Official Action Indicated” verdicts. Hence India has developed a proven track record of being able to deliver data to meet international regulatory submission standards. Given India’s well developed generics pharmaceutical industry and pharmaceutical price control, although the domestic pharmaceutical market is the fourth largest in the world by volume it is only 13th in rank by value. However the 12% annual growth in domestic pharmaceutical sales makes India one of the world’s fastest-growing pharmaceutical markets. Clinical Trial Regulatory Environment India’s regulatory environment for clinical trials is stable, progressive and evolving to meet the needs of India’s international clinical research sector. The regulations balance the need to be industry-friendly with the requirement to ensure subject protection. First in human, Phase I clinical trials for investigational products discovered in a foreign country are not allowed in India. In view of the limited experience with the conduct of first in man trials in India and the lack of any real advantages as compared to Western countries, India’s

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Volume 3 Issue 2

Market Report attractiveness for first in man trials is limited. Phase II – IV clinical trials can be conducted by any hospital in India and every application is considered on a case by case basis. A Clinical Trial Application and Application to Import Clinical Trial Supplies must be made to the Drugs Controller General of India (DCGI) and may be done so only by a company with a legal basis in India. The application dossier is usually complemented by a formal presentation to the DCGI by the sponsor or the appointed clinical research organisation (CRO). Applications whose protocols have already been approved by one of the USA, UK, Switzerland, Australia, Canada, Germany, South Africa or Japan are more likely to obtain a prompt clinical trial approval in India. This is because the regulatory authorities of these countries are deemed to be more experienced, hence their approval of applications signals that the protocol satisfies the requirements of a sophisticated clinical trial regulatory environment. In these instances the first response or approval from the DCGI office can be expected within 45 days. The license to import the clinical trial supplies and investigational product takes another 15 days. Factors that expedite and support timely regulatory approval are a well collated, complete application dossier supported with a justification of why India has been included in the study. A description of how the study drug might address an important healthcare issue in India is also of value. The regulator obtains reassurance if the study is already initiated in other countries and already has a number of subjects enrolled. Most major clinical institutions and hospitals have ethics committees (ECs) that comply with the ICH Good Clinical Practice (GCP) guidelines. India does not have a central ethics committee. Hence, all the approvals are given by individual ECs who approve all study protocols prior to study commencement. ECs customarily meet once a month. Approvals generally take up to 60 days but are occasionally granted in four weeks. The investigator submits the documents for EC approval and may need to make a presentation on the study to the committee prior to its decision. EC approvals are processed in parallel with regulatory approval. Notice of EC approval should be given to the DCGI prior to initiation of a clinical trial. The trial may be initiated at a site only after obtaining approval from that site’s ethics committee. Sites without an EC can accept the approval granted to the protocol by the EC of another site or an independent EC. Protocol Feasibility Assessment Protocol feasibility assessment from the medical, operational and regulatory perspective is the first crucial step for successful clinical trial conduct in India. Drawing on local experience, knowledge and relationships, it is advisable to obtain an accurate feasibility assessment as early in the trial planning phase as possible. Figure 2 summarises the key components of a correctly performed feasibility assessment. It is important to ascertain the feasibility of the trial protocol within India’s healthcare environment. This includes consideration of the standard of care for that particular disease state. Even though there is uniformity in healthcare standards across the world with a universal recognition for what is deemed to be best practice, in the under-resourced Indian healthcare environment, there remain substantial differences in standard of care. These differences are perhaps most heightened in 32 Journal for Clinical Studies

oncology, where there remains a discrepancy in the number and aggressiveness of the lines of treatment provided. Understanding these differences in standard of care will not only prevent inappropriate protocol design, but also enable an appreciation of disease profiles in India and provide opportunities to conduct certain, challenging trial designs. Factors such as diet, alcohol intake, co-prevalent disease, use of supplementary non-allopathic medications and pain threshold modify disease behaviour and response to pharmaceutical intervention. The impact of these factors, if any, needs to be ascertained when selecting India for inclusion in a global clinical trial. It may be possible to compensate for the effect of any such factors by minor modifications in the protocol. It is also essential to ensure that there is access to the prescribed diagnostic and therapeutic interventions. It may be necessary to import comparator treatments or additional diagnostic kits, and ascertaining this at an early stage is clearly good practice. India’s healthcare systems and patient follow-up processes may not be conducive for long-term subject follow-up. In such situations, special arrangements must be made or a decision taken not to include India. Similarly, if successful trial conduct requires access to comprehensive patient registries, databases and quality medical records, it would be prudent to carefully assess the suitability of India. Protocol feasibility assessment must address the abovementioned medical and clinical issues and not focus only on estimating subject enrolment rates. If there are issues related to protocol feasibility, at an early planning stage, an informed decision must be made about whether to modify the protocol so as to make it conducive for India. If such modifications could jeopardise the overall trial objectives, it would be best to abandon plans to conduct the trial in India. Such a timely decision could result in substantial time and resource savings. Site & Vendor Selection Clinical trial sites in India have the potential to be amongst the most productive in the world; however this potential can only be realised with careful site selection and site support. The large number of potential sites and the substantial variation between their capabilities makes careful site selection very important. Local knowledge is valuable to judiciously select clinical trial sites and investigators that will be capable of delivering quality clinical data. Often these sites are located within

Figure 2. P rotocol feasibility assessment from the medical, operational and regulatory persepective is the first, crucial step

Volume 3 Issue 2

Market Report smaller, second-tier cities, still large by most standards, with populations of around two million. Select second-tier cities have well developed healthcare facilities that also serve populations from surrounding rural and semi-rural areas, and motivated investigators keen to participate in international clinical trials. However the investigator at a typical Indian clinical trial site faces a number of challenges, namely to balance resources between patient care and clinical research; to ensure that relatively low levels of patient education, literacy and financial status do not compromise the principles of GCP; and to guard against allowing the sponsor’s requirements for rapid patient enrolment to compromise quality standards. Hence site support in the form of well trained site managers able to facilitate the conduct of clinical trials at the site is essential if Indian sites are to deliver evaluable subjects with no compromise of data quality or subject protection. Vendor selection is critical to access the clinical trial opportunities that India offers with mitigation of the associated risks. Apart from the CRO, it may be necessary to select central laboratory, imaging and EDC vendors in India, depending on how the overall global programme has been structured. There are a number of quality vendors able to provide these services at competitive prices. The advantage of working with local CROs is that they offer cheaper prices, thereby enabling the sponsor to maximise the cost savings that India offers. This is because local CROs do not have the expensive overheads of global structures, processes and systems. Global CROs offer the advantage of a “one-stop shop” as they are able to execute trials in a number of countries. Global CROs seek to address the subject recruitment challenge by continually increasing the number of countries with its associated risks and costs. Specialist CROs have the contrary strategy, which is to focus on select clinical trial sites and achieve enhanced performance by leveraging their regional expertise, knowledge and relationships. Sponsors may select one of these strategies or indeed, as they recognise the value of utilising specialist local CROs, they could opt for a combination of global and local clinical trial service providers. India’s Contribution to the Global Trial To fulfill international regulatory requirements and meet commercial imperatives, a proportion of the subjects in most global clinical trials should be enrolled from North America and / or Western Europe. The remaining subjects could be recruited from one or more emerging countries in order to gain the advantages of speed and cost-effectiveness that they so clearly offer. India could be selected to be one of the high recruiting countries, able to contribute between 30 and 80 per cent of trial participants. The exact proportion would depend on the protocol, study objectives and commercial imperatives. The effort of including India for fewer than 30% of patients would need careful evaluation, because it might not be worth the effort to negotiate the regulatory process and the challenges of a new geography. On the other hand, pivotal data submissions to international regulatory authorities with over 80% of subjects from India would be inadvisable unless there were strong, protocol-specific reasons to do so. This is because although neither the FDA nor the EMEA have categorically stated their views on the proportion of evaluable subjects that may be enrolled from emerging countries, prevalent industry wisdom is that including a fair representation of subjects from the US and 34 Journal for Clinical Studies

Western Europe is essential so as to present a subject population that includes representation from the largest commercial markets. Further, the Indian regulator, the DCGI, continues to look to these more experienced regulatory agencies when making decisions about both marketing authorisations and clinical trial approvals. Given that the essential attraction of all emerging countries is cost-effective patient access, a case may be made for including only one emerging country to serve this objective. The advantage of including more than one emerging country is to build in a contingency solution from the outset should a regulatory or unforeseen operational hurdle develop. The cost of multiple emerging countries is a loss of focus, increased complexity, additional resources and escalated costs. If there are concerns that the selected emerging country might be unable to deliver as expected, then there is a case for more than one emerging country, such that the other could “step up” and take over the patient recruitment allocation of its counterpart. On the other hand, if a thorough feasibility assessment is performed that addresses medical, clinical and regulatory issues, the risks of the selected country not performing are negligible. Hence, a strong case could be made for selecting, albeit carefully, only one emerging country – and India could well be a very good choice. Dr. Nermeen Y. Varawalla, MD, DPhil (Oxon). MBA, President & CEO, ECCRO. Dr. Nermeen is the founder and CEO of ECCRO, a specialist CRO focused on international clinical trials in India. Nermeen has been involved with the conduct of clinical trials in emerging countries for the past decade. Initially whilst at Accenture’s Business Consulting Practice. She then founded PerinClinical, a specialist CRO that was acquired by PRA International; a leading global player. Nermeen was a Vice President at PRA for five years, during which time she established PRA’s operation in India. Nermeen received her medical training at the KEM group of hospitals, Mumbai, India. she was awarded the Rhodes Research Fellowship to the University of Oxford to conduct her doctoral research in Molecular Genetics. Nermeen practised as a specialist at two of the UK’s leading NHS Hospitals. she then obtained her MBA at INSEAD. Nermeen is a frequent invited speaker at industry conferences and is also the Life Sciences and Healthcare Sector Specialist covering India for UK Trade and Investment. Email:

This article is co-authored by

Dr Rajesh Jain, MBBS, CCRA, PGDGM, General Manager and Head of Operations

Mr David Stern, MBA, Vice President International Business Delivery

Volume 3 Issue 2

Not everything in life is black and white... Specialising in medical and pharmaceutical translation in all language combinations, we are able to meet all your requirements from a single drug label to a complete multi-lingual marketing authorisation application. With a team of experienced and qualified in-country translators at our disposal, we ensure that projects are completed on time, every time – and you have added peace of mind, secure in the knowledge that you are dealing with an ISO accredited company that can provide declarations guaranteeing all translations. To find out more about how we can help you, please contact Jill Wright: Tel +44 (0) 1462 429714

Market Report

The Increasing Costs of Post Marketing Research and Meeting the Objectives of Multiple Stakeholders Post Marketing Research (PMR) has been described as the fastest growing area of clinical research. Partly, I believe, this growth can be attributed to the fact that regulatory agencies are increasingly requiring additional safety and efficacy data from the PMR environment. However, partly, as discussed in greater detail later in this article, there are also other factors which are contributing to the growth; like marketing departments requiring additional data to help them understand an increasingly complex marketplace. This increased demand, from various stakeholders, for data means that PMR costs are increasing dramatically. Post Marketing Research (PMR) refers to several types of studies that are conducted after a drug or biologic has been registered and marketed. There are also Post Registration Studies, which are studies that are conducted after a product is registered, but before a product is marketed. Post Submission Studies, on the other hand, refer to studies that are conducted after submitting a regulatory application but before the product is registered (or approved) and before the product is marketed. For the sake of this article, I am only concentrating on Post Marketing Research (PMR) and the several types of studies that fall within this category. To a large extent, the terminology which refers to these types of studies is misunderstood and misused. For example, I have sat in marketing meetings where the terms “Phase IV” and “Post Marketing Surveillance” study are used interchangeably. However, the Association of the British Pharmaceutical Industry (ABPI) clearly differentiates between these two types of studies. The ABPI defines them thus: A Phase IV trial is interventional and is carried out using a licensed formulation within the terms of its product license. It is conducted either in general practice or hospital, primarily to extend the efficacy database, although collection of safety data will form an essential part of such a study. In most instances an active comparator will be employed, and all clinical trial materials are supplied by the sponsor1. A Post Marketing Surveillance study (similar to a post marketing registry) is observational and non-interventional, and is conducted primarily to monitor safety when a medicine (which is generally newly introduced) is prescribed in everyday clinical practice. Simple measures of efficacy may be included in order that risk/benefit judgments may be made. Observation on a comparator drug may also be incorporated into the design of a Post Marketing Surveillance study1. You can see from the above two ABPI definitions that the differences between a Phase IV trial and a Post Marketing Surveillance study are significant. Yet, both of these study types, one interventional and the other observational, fall within the 36 Journal for Clinical Studies

umbrella category of Post Marketing Research. Later in this article I will also briefly talk about Real World Research, which also falls within the category of Post Marketing Research. The face of Post Marketing Research (PMR) has changed dramatically in recent years5. PMR has also been described as the fastest growing area of clinical research. This change and growth is driven, I believe, by the following interrelated factors: • The arthritis medication rofecoxib (marketed as Vioxx) was on the market for over five years before Merck voluntarily withdrew the product due to safety concerns. An estimated 88,000 Americans had heart attacks while taking Vioxx, 38,000 of whom died. The drug was withdrawn in 2004; by 2006 over 13,000 lawsuits involving Vioxx had been filed against Merck2. The Vioxx debacle (and this is just one example of a number of high profile drug withdrawals) triggered a Congressional inquiry into drug safety and the structure of the FDA. In 2007, Congress passed the FDA Administrative Amendments (FDAAA), giving the FDA broad powers to require post marketing studies for any drug or biologic for which “new safety information” becomes available3. Increasingly, other regulatory agencies are requiring additional safety and efficacy data from the “real world” environment of PMR. • Biopharmaceutical marketing departments have always had an interest in using PMR data to support their promotional and marketing needs. However, in the last 10 years, the landscape has changed significantly for marketing departments. The costs of building a brand among increasingly demanding consumers (who have multiple purchasing options) has rocketed. Marketing departments, consequently, are increasingly interested in product marketplace data, like: reimbursement data, healthcare system access data, healthcare system utilisation data, physician experience, patient reported outcomes, patient satisfaction, compliance and burden of illness data4. This product marketplace data helps marketers to understand the marketplace and make important decisions. • Consumers of biopharmaceutical products have become more discerning. As mentioned in the previous bullet point, consumers increasingly have multiple purchasing options which allow them to choose between competing products5. The Vioxx debacle together with some of the other high profile drug withdrawals had the added effect of sensitising consumers to the fact that registered and marketed products are not always as effective and safe as they would like to believe. Volume 3 Issue 2

Market Report In short, regulatory agencies are being legally empowered to require additional safety and efficacy data from the PMR environment. Marketing departments also require additional data to help them understand an increasingly complex marketplace and to help them understand and reassure increasingly discerning consumers. This increased demand for data, of course, means that PMR costs are increasing dramatically. The ABPI definitions of a Phase IV trial and a Post Marketing Surveillance study, you will notice, include the scientific objectives of PMR, but do not include the marketing objectives. As mentioned in a previous paragraph, biopharmaceutical marketing departments increasingly are interested in product marketplace data4, like: • Medical Aid reimbursement data • Healthcare system access and utilisation data • Physician experience data • Patient reported outcomes • Patient satisfaction data • Compliance data • Burden of illness data Real World Research (RWR) is a fairly new term which refers to Post Marketing Observational studies which are conducted in real world settings in order to measure a product’s effectiveness, and to help us validate whether the safety and efficacy results, as originally seen in the clinical trial setting, translate into everyday ‘real world’ practice. However, RWR also refers to research that not only meets scientific objectives, but also meets marketing objectives. Marketing departments need to answer questions, make decisions and understand an increasingly complex marketplace. RWR recognises that the success of a Post Marketing Observational study is not only determined by the quality of the scientific methodology employed, but also by its ability to meet the needs of the patients, the payers, the prescribers, the marketers and the regulators4. RWR is not ashamed of the fact that research also has commercial objectives. Instead it balances the needs of the scientists with those of the marketers to ensure that both scientific and marketing objectives are met. RWR often takes the form of Patient Registries, and has been criticised for not being adequately controlled to offer useful information. It is true that the ‘real world’ environment is often uncontrolled, but if these studies are properly managed, following a scientific methodology, then they can produce a wealth of valuable data. While following scientific methodology, RWR should not try to mirror the controls and rigours of Phase I, II, III and IV research. For one thing, RWR needs to be more cost-effective than traditional clinical trials, and secondly, recent drug recalls have made it clear that the rigorous scientific and epidemiological methods utilised by traditional drug trials are no guarantee of safety and effectiveness4. In summary, the face of PMR is changing. There are now multiple stakeholders, like regulatory agencies and marketing departments, who demand more data (and different types of data) from the PMR environment. This increasing demand for data means that the costs of PMR are also dramatically increasing. 38 Journal for Clinical Studies

ACRO The African Clinical Research Organisation (ACRO) helps local and international companies develop their healthcare products in order to bring them to market as economically and as quickly as possible. Based in South Africa, the company’s multi-skilled and experienced team offers clinical trial services tailored to client needs across the African continent. The company recognises the importance of Real World Research (RWR). In a Post Marketing Research climate where costs are increasing, ACRO recognises the need to design Real World Studies that simultaneously meet the needs of the regulators, the marketers, the patients, the payers and the prescribers. Using its experience and expertise, ACRO has carefully designed Real World Standard Operating Procedures (SOPs) that allow better and more effective planning and implementation, and manage Real World Studies according to sound scientific methodology, but at the same time achieving cost-effectiveness compared to traditional clinical trials. We meet the needs of the multiple stakeholders and help in achieving cost-effectiveness by using affordable technological solutions which, to some extent, lack the bells and whistles of vendor-supplied technology, but also does not have to bear the burden of expensive annual license costs. Our technology and procedures have all been designed to incorporate Quality Management practices and have multiple Quality Control points and multiple layers of Quality Assurance. All of this allows us to produce quality and timely data that meet the needs of the client. References 1.The Association of the British Pharmaceutical Industry. Guidelines for Phase IV Clinical Trials. September 1993. 2. Resnik, D. Drug Design, Development and Therapy 2007:1. 3. Mahn, T. Life Sciences Litigation Review 2009:2. 4. Polygenis, D. Canadian Pharmaceutical Marketing. September 2005. 41-43. 5. Polygenis, D. Radulescu, G. Bioscienceworld. October 2010.

Michael Holdsworth is a Senior Data Manager working for African Clinical Research (ACRO). Michael has previous experience in teaching, IT and programming. For the past 9 years, he has worked as a clinical data manager and as a departmental head for both local and international companies. Michael has a wealth of knowledge and experience in this specialised field. Email:

Volume 3 Issue 2


Drug Phototoxicity – a Burning Issue in Drug Development? Phototoxic drug events over the past decade have fuelled the increasing safety expectations of patients and regulators. It is as a result of these events that photosafety guidance for drug development has emerged from both the EMEA and FDA1,2. In addition, the assessment of drug phototoxicity has been further highlighted in the current version of ICH M33. One interesting feature of the past decade is the finding that this type of toxicity is no longer confined to certain drug classes, such as the fluoroquinolone antibiotics. More recently we have evaluated a much wider range of small molecules in different therapeutic areas. Of particular concern are those drugs for chronic usage where over time the opportunities for phototoxic damage to the skin may be significant. As a consequence of these factors, a range of laboratory and clinical methodologies is now available to address the issue of phototoxicity prior to drug regulatory approval and marketing. So why is this a burning issue?

of skin in normal sunlight exposure conditions. There is also concern with some photomutagenic drugs (which may also be photoimmunosuppressive) that this skin sensitisation, in the long term, may increase the risk of skin cancer.

What is Drug Phototoxicity? The working definition of drug phototoxicity is that it is a nonimmunological mediated skin reaction which will arise in any individual providing there is enough drug and appropriate irradiation. It is seen in photoactive molecules and/or metabolites where UVA, UVB or visible wavelengths interact, forming free radicals and other species which in turn manifest as a toxicity (see Figure 1 below), which on occasion may have a therapeutic role, e.g. photochemotherapy. In the context of this article, phototoxicity is a direct photo-irritation rather than an immune-mediated skin or eye phenomenon.

Clinical Presentation From a clinical service perspective, the Photobiology Unit (PBU) based in Ninewells Hospital, Dundee, Scotland, has reviewed the cases of drug-induced photosensitivity seen since 1980. A summary of the causative drugs is presented below in Figure 2. Most of these drugs are well known and span different therapeutic areas. It is reasonable to expect such a diverse spread to continue into the future. Most of our experience with drugs under development, inducing photosensitivity, has been with the fluroquinolone antibiotic class. When these new molecules were assessed using a randomised controlled trial methodology in the 1980s and 1990s, the photosensitivity seen involved UVA wavelengths with a transient nature (lasting < 48h from last dose) and were dose-related. A varied degree of response has been observed, from none to profound (for example BAY 3118). Figures 3 and 4 illustrate the clinical picture of fluroquinolone phototoxicity as seen with Naladixic acid (the â&#x20AC;&#x153;mother drugâ&#x20AC;? of the quinolone class), and BAY- 3118, a fluroquinolone, the development of which was discontinued4.

Figure Figure 1: 1: Mechanisms Mechanismsof ofDrug DrugPhototoxicity Phototoxicity

Figure PBU 1980 - 2010 Figure 2: 2: Summary Summary of of Drugs Drugscausing causingPhototoxicity: Phototoxicity:Ninewells Ninewells PBU 1980 - 2010

Figure 3: Nalidixic Acid Phototoxicity

This process produces increased skin sensitivity to terrestrial sunlight, resulting in a range of symptomatic, erythema, urticaria, blistering, milia, dermatitis and pigmentation changes. The clinical manifestations of acute skin sensitisation can be severe, painful and debilitating to patients; not unlike having marked sunburn with itching and blistering of exposed areas 40 Journal for Clinical Studies

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Therapeutics Figure 4: BAY- 3118 phototoxicity

How Should a New Drug be Investigated for Phototoxicity? 1,2,3. This falls into three general categories: 1. Preclinical testing 2. In vivo testing in healthy volunteers 3. Surveillance during late phase development for photo-induced dermatoses Preclinical testing For years, the mainstay of laboratory assessment has been the Neutral Red uptake assay (3T3 assay). This compares the cytotoxicity of a drug candidate when tested in the presence and absence of a non-cytotoxic dose of UVA, visible light or solar simulator simulated light. Neutral red dye is taken up by the cells, and this process requires intact cell membranes and active cell metabolism. If this is disrupted, as a result of phototoxicity, then the uptake of the dye is reduced as shown in an example of the test in Figure 5 below. Figure 5: Neutral red Uptake assay Example

The 3T3 assay has been accepted as the validated in vitro method of choice by the EMEA and is also cited in FDA guidelines along with other preclinical tests, including photo-irritation models in rabbits, mice and swine. Of course, there are agreed limitations of these preclinical models. While useful, they are not performed in the target species i.e. man - in which differences in drug distribution, tissue and protein binding, differences in (photo) active metabolites and the actual dose of drug used, can influence whether the preclinical data is relevant. In vivo testing in healthy volunteers The EMEA and FDA photosafety guidelines issues in 2002 and 2003 respectively1,2 do detail that photoirritation risk needs to be assessed in molecules which absorb UVA, UVB or visible light,

are significantly distributed to eye or skin, and are positive in photo-irritation testing such as the 3T3 assay. In such cases, the recommendation is to communicate the risk to users of the drug in that patients should avoid sun exposure whilst taking the drug. This uncertainty, based on preclinical assessments, is difficult to translate into a clinical setting. How much sun exposure should be avoided? What are the likely effects and clinical presentations if not avoided? Is there the potential for retinal toxicity in man (this can occur when the drug in question demonstrates phototoxicity in the visible light spectrum and not in the UVA and UVB spectrum)? How long is the period of risk “off drug” in man? Case Study 1 below illustrates what can happen when this risk assessment is based on inadequate clinical testing. Drug Development Case History 1: Fluroquinolone Antibiotic The Problem: Drug absorbed in UVB/A with 3T3 positive Significant drug distribution to skin and eye Phototoxicity study in volunteers was negative: conducted elsewhere During launch in spring, 300 patients suffered severe phototoxicity events over a fourmonth period Approximately 20 required hospitalisation The Solution: Clinically serious phototoxicity could have been detected using a more robust and validated clinical study method. This would have avoided patient injury.

Current guidelines do look at a stepwise risk-based approach. The recent update to ICH M3 guidelines now includes guidance on photosafety testing, which recommends an initial assessment based on a drug’s photochemical properties and class. If this assessment indicates the potential for significant human phototoxicity risk, then appropriate protective measures should be taken during outpatient clinical studies. Further drug distribution work to look at skin and eye exposure should be completed, then further evaluation (either non-clinical or clinical) of phototoxic exposure should be undertaken prior to Phase III. Alternatively, a stepwise approach of direct phototoxic potential can be taken in a clinical or non-clinical study. If this is negative, an assessment of skin and eye distribution is not called for. This is where our healthy volunteer in vivo clinical model comes in. Over a period of 25 years, Spectratox and Chiltern Early Phase have worked collaboratively in this area, using an approved and regulatory accepted in vivo human method for assessing drug phototoxicity, and have multiple publications of this work in peer-reviewed journals5,15. The success story of this methodology is not just measured by publication; it is measured in helping new drugs continue their developmental journey for areas of therapeutic need, such as thrombocytopenia, diabetes, Hepatitis C, neurodegenerative disease and severe infections. The timing of such a trial invariably is prior to the step into full development in Phase III. The results help to: • Fully assess the phototoxicity risk (if any) in man • I f present – is this clinically relevant in terms of severity and causative wavelengths • Assess the likelihood of retinal phototoxicity •F  rom the above, provide advice on protective measures for future development Our established methodology involves a parallel group, placebo and positive controlled randomised controlled trial design, involving healthy male and female volunteers. The treatment Journal for Clinical Studies 41

Therapeutics arms are: • Test drug – normally recommend studying two doses of the test drug; the lowest at the therapeutic dose for development and the 2nd at a higher but previously tolerated dose in man • Negative control – placebo (for test drug) • Positive control – drug that is a known mild/moderate photosensitiser- Ciprofloxacin 500 mg twice daily for example Subjects undergo pre-randomisation baseline photo testing using both a monochromator and a solar simulator during the screening period, which is typically performed up to 21 days prior to randomisation. The subjects are then admitted to the Chiltern CPU, and are dosed until plasma steady state is achieved. Subjects are housed in the Chiltern CPU for the duration of dosing and until they return to baseline readings, if they are found to be photosensitive. The Chiltern CPU is a photo-protective environment which assures safety and quality control and compliance. Further phototesting evaluation similar to that performed at baseline is performed on drug. Each subject acts as his/her own control, since the skin of the back is used – one side for pre-drug testing and the other for on drug testing. The equipment used involves both an irradiation monochromator (IM) and a solar simulator (SS). The IM is an instrument that disperses light into its constituent wavelengths using a finely etched diffraction grating and focuses this into a collimated beam. The SS is an instrument that attempts to produce a spectrum of light that is similar to that of sunlight at ground level and midday on mid-summer days at the Equator. Whilst some may think that the use of the SS alone is enough to assess likely clinically relevant phototoxicity, given what this instrument is designed to reproduce, our experience as published15 has taught us that the IM is a more useful detector of problems arising from UVA and visible wavelengths. Combining the two instruments effectively reduces the chance of missing the relatively narrow UVA-dominated phototoxicity. The photosensitising potential of the test drug (positive and negative control) are assessed by evaluating the subject’s cutaneous responses to controlled light exposures. Subjects are exposed to wavebands that represent the ultraviolet (UV) and visible light spectra to detect the presence of an immediate photosensitivity response (e.g., transient oedema with or without flare) and a delayed erythema response at 24 and 48 hours post-irradiation. Phototoxicity measurements are performed at the seven wavebands that represent UVB (295±5 nm, 300±5 nm, and 305±5 nm), UVA (335±30 nm and 365±30 nm), visible light (400±30 nm and 430±30 nm), spectra and solar simulator. These are biologically important wavebands since UVB is mainly responsible for sunburn reactions, UVA is commonly but not exclusively involved in drug-induced phototoxicity, and the visible spectrum holds wavebands to which subjects are commonly exposed on a daily basis. The best parameter for assessing photosensitivity potential is the Phototoxicity Index (PI) at 24h and 48h post-irradiation, derived by division of the baseline Minimal Erythema Dose (MED) by the postdose MED at a given waveband. The MED is the energy of light required to produce the first signs of reddening (erythema)

42 Journal for Clinical Studies

on the skin. By evaluating the MED of each waveband, the study assesses the wavelength dependency of the drug’s photosensitising potential. Figure 6 shows the test area on the back of a subject who demonstrates the MED response and Figure 7 outlines a categorical assessment of PI with some examples of drugs that fit into these categories. Figure 6: Back of a Test Subject

Figure 7: PI by Category

By this method, clinically relevant data can be obtained within a few weeks, and at relatively low cost, in man, compared to the alternative, which is to perform surveillance in Phase III trials by use of a questionnaire designed to detect for photo-induced skin events. With such a method, the concerns are: 1. The clinical investigator may not have the diagnostic experience to detect such reactions 2. The application of photoprotection restrictions may prevent the emergence of the true phototoxic picture In addition, there is the question of compliance with these procedures. Signals would be detected very late and the regulatory authorities may then ask for more direct formal quantification of this. In fact, this was the case approximately 10-15 years ago when many of the drugs we studied were prior to marketing authorisation, and the regulatory authorities delayed their registration until our method was applied to answer this question. New Developments in Volunteer Testing Recently we have introduced new study designs to act as initial “screening” in man for drugs with potential phototoxicity. These methodologies have evolved in response to the growing demand to assess this earlier in clinical drug development - even after the First Time in Man study (FTIM). The new studies employ fewer

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Therapeutics subjects and single dose with either a crossover or parallel group design, and can be a “bolt on” to an FTIM programme. Thus they are quicker and less expensive than the full study whilst remaining scientifically robust. They indicate the possibility of phototoxicity in man before the crucial “go/no-go decision” prior to Phase III. An example of a crossover design is presented below in Figure 8. Figure 8: Example of a randomised crossover “screening phototest study” design in N = 6 volunteers

2a/3 where more patients would be exposed with fewer photoprotective restrictions. See Case History 2 below. Drug Development Case History 2 The Problem: Molecule showed absorption in UVB and UVA range Distributed to eye and skin 3T3 phototoxic fibroblast model positive Animal phototoxicity study (not conducted) Phase 2 development – six out of 200 patients experienced summer month photosensitivity The Solution: Volunteer Testing Single dose phototoxic “look-see” type study – negative Full regulatory study with placebo vs. Ciprofloxacin vs. higher dose of drug Placebo and Ciprofloxacin negative for immediate erythema Ciprofloxacin positive for delayed erythema Drug in question – negative; placebo – negative Conclusion: Drug clear of phototoxicity at dosage tested Conclusions So is drug phototoxicity a “burning issue” in drug development?

In some cases, sponsors have opted for or required a combined approach; that is, the single dose screening study and a traditional regulatory study to answer safety issues that have emerged early in development. This staged approach resulted in a “stepwise” derisking of the drug, which allowed it to progress into late phase in

Our experience would indicate that it is with both regulators1,2,3 and pharmaceutical companies becoming increasingly aware of this through recent regulatory guidance and amendments to the ICH M3 guidelines. Drug phototoxicity is complex both in its mechanisms and presentations, and as we have seen in Case History 1, if not addressed can lead to serious safety issues. Not all drugs that are found to be phototoxic need to be discontinued. Our methodology quantifies the risk in the target species, thus

Therapeutics helping maintain the development of that molecule. The recent development of human volunteer screening study designs can help provide a rapid risk assessment early in drug development. Randomised controlled trial human volunteer testing early on in clinical development can quantify drug phototoxicity so it no longer becomes a “burning issue”. References 1. CPMP/SWP/398/01: Notes for Guidance on Photosafety testing; EMEA; June 2002 2. Guidance for Industry; Photosafety Testing; US Dept of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); May 2003 3. ICH Topic M3 (R2); Note for Guidance on non-Clinical Safety studies for the Conduct of Human Clinical trials and Marketing Authorisation for Pharmaceuticals (CPMP/ICH/286/95); EMEA; December 2009 4. Man I, Traynor NJ, Ferguson J. Recent developments in fluoroquinolone phototoxicity. Photoderm Photoimmunol Photomed 1999; 15: 32-33. 5. Bowen CJ, Lobb KM, Park JW, Sanderson B, Ferguson J. Eltrombopag (75 mg) does not induce photosensitivity: results of a clinical pharmacology trial. Photoderm Photoimmunol Photomed 2010; 26: 243-249. 6. Dawe RS, Ibbotson SH, Sanderson JB, Thomson EM, Ferguson J. A randomised controlled trial (volunteer study) of sitafloxacin, enoxacin, levofloxacin and sparfloxacin phototoxicity. Br J Dermatol 2003; 149: 1232-1241. 7. Ferguson J, McEwen J, Al-Ajmi H, Purkins L, Colman PJ, Willavize SA. A comparison of the photosensitizing potential of trovafloxacin with that of other quinolones in healthy subjects. J Antimicrob Chemother 2000; 45: 503-509. 8. Man I, Murphy J, Ferguson J. Fluoroquinolone phototoxicity: a comparison of moxifloxacin and lomefloxacin in normal volunteers. J Antimicrob Chemother 1999; 43, Suppl. B: 77-82. 9. Man I, Traynor NJ, Ferguson J. Recent developments in fluoroquinolone phototoxicity. Photoderm Photoimmunol Photomed 1999; 15: 32-33. 10. Vousden M, Ferguson J, Richards J, Bird N, Allen A. Evaluation of phototoxic potential of gemifloxacin in healthy volunteers compared with ciprofloxacin. Chemotherapy 1999; 45: 512-520. 11. F erguson J, McEwen J, Gohler K, Mignot A, Watson D. Phototoxic potential of gatifloxacin, a new fluoroquinolone antimicrobial. Drugs 1999; 58, Suppl: 397-399 12. F erguson J, Dawe R. Phototoxicity in quinolones: comparison of ciprofloxacin and grepafloxacin. J Antimicrob Chemother 1997; 40, Suppl. A: 93-98. 13. F erguson J. Fluoroquinolone photosensitization: a review of clinical and laboratory studies. Photochem Photobiol 1995; 62: 954-958. 14. F erguson J, Johnson BE. Clinical and laboratory studies of the photosensitizing potential of norfloxacin, a 4-quinolone broad spectrum antibiotic. Br J Dermatol 1993; 128: 285-295. 15. F erguson J, Johnson BE. Ciprofloxacin-induced photosensitivity: in vitro and in vivo studies. Br J Dermatol 1990; 123: 9-20. 16. M  oseley H, Ferguson J. Which light source should be used for the investigation of clinical phototoxicity: monochromator or solar simulator? Photoderm Photoimmunol Photomed 2010; 26: 3-6.

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Professor James Ferguson, MD, FRCP. James Ferguson, Head of the Academic Department of Dermatology, University of Dundee, Ninewells Hospital, has the responsibility for the Scottish Photodiagnostic/Therapy Unit. His MD thesis was on the topic of drug-induced phototoxicity, an area of active research and service to regulatory authorities and the pharmaceutical industry. Other research areas include photodynamic therapy and increasingly the efficiency and safety of various forms of phototherapy. During his career he has published 250 peer-reviewed articles as well as editing the text “An Introduction to Photodermatology”. His research interests lie within the area of the biological effects of ultraviolet and visible radiation. The Photobiology Unit in Dundee has in the region of 25 clinical and scientific staff, of whom approximately half are directly employed in clinical research. He is Director of Spectratox Ltd (, a charity-owned company which serves industry in the area of drug-induced phototoxicity. Ambicare Ltd. is a lighting-based medical device technology company of which he is a founder director. Email: 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. He then joined Drug Development Solutions (then DDS Medicines Research) in 1998 as Deputy Medical Director, and in February 2002 was promoted to CEO & Medical Director. He led the management buyout of DDS Medicines Research to form Drug Development Solutions Limited in September 2005 prior to the acquisition of DDS by Chiltern in February 2008. 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 I studies and is an Author of over 60 Phase I study reports. Brian holds the Diploma in Clinical Pharmacology, is a member of the American College of Clinical Pharmacology and 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:

Volume 3 Issue 2


Centralised Endpoint Adjudication in Cardiovascular Outcomes Studies Composite Endpoints, Risk Ratios, and Clinical Endpoint Committees Cardiovascular outcomes studies typically require the recruitment of subjects at a large number of investigational sites located in many countries. Accordingly, there is a considerable degree of variability in the ‘identification’ of cardiovascular clinical endpoints. Regulatory agencies are increasingly expecting, and in some cases requiring, the centralised adjudication of these clinical endpoints to control for the impact of this variability and to produce data for use in statistical analyses that are as standardised as possible 1,2. The centralised adjudication process can be applied to both efficacy and safety endpoints. In efficacy studies, conducted for cardiovascular drugs, the objective is to evaluate whether there is compelling statistical evidence that fewer events occur in the test drug treatment group than in the control group, i.e., that the test drug is effective. In safety studies, conducted for non-cardiovascular drugs, the objective is to evaluate whether the number of events occurring in the test drug treatment group is statistically significantly greater than the number in the control group: if there is compelling evidence that the drug leads to more events than the control drug, there is evidence of a cardiovascular safety concern, and potentially evidence of unacceptable cardiovascular risk. In both cases, the validity and integrity of the study’s results and interpretation are enhanced by the acquisition of optimal quality endpoint data and robust, centrally adjudicated cardiovascular outcomes. A clinical endpoint committee (CEC) is an essential component of this process. A CEC is a panel of independent experts charged with centrally reviewing and classifying suspected efficacy and/or safety endpoints in a blinded and unbiased manner, ascertaining whether they meet protocol definitions (endpoint criteria), and providing standardised endpoint outcomes for statistical analysis. This paper discusses the benefit of employing composite clinical endpoints in cardiovascular outcomes studies, provides examples of composite endpoints reported in the literature, and explains the statistical methodology employed to investigate the occurrence of statistically significant decreases (efficacy domain) or increases (safety domain) in cardiovascular events of interest. It then provides an overview of the complex operational considerations necessary for successful implementation of the centralised adjudication process, and a reference to more detailed discussions. Composite Endpoints in Cardiovascular Outcomes Studies Cardiovascular outcomes studies are large clinical trials performed relatively late in a drug’s clinical development programme, and also in postmarketing settings. Endpoints of interest include the Major Adverse Cardiac Events (MACE) composite endpoint, comprised of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. This is often used as the primary endpoint in cardiovascular outcomes studies, for efficacy and safety purposes. Once a subject experiences one of these 46 Journal for Clinical Studies

individual events, and the event is confirmed through centralised adjudication to meet protocol endpoint criteria, their endpoint data are included in analyses of the number of occurrences of the composite endpoint for the respective treatment group. The usefulness of composite endpoints arises since the occurrence of cardiovascular events of interest is often low, particularly when such events are positioned as safety endpoints. A large number of subjects is therefore needed to provide the power necessary to identify a statistically significant difference between treatment groups in the rates of occurrence of an event. One way to increase the likelihood of finding a difference between the treatment groups (if one truly exists) is to use a composite endpoint. This approach reduces the required size of the study in two ways. First, the numbers of events in the treatment groups compared are larger, since they comprise occurrences of any of the individual components of the endpoint. Second, if the three individual components of the MACE composite endpoint were compared separately between treatment groups, not only would the numbers of events in each case be lower, but a statistical correction would need to be made to address the issue of multiplicity: As more comparisons are made, the chances of ‘finding’ a statistically significant difference that does not in fact exist (committing a Type I error) increases. To counter this possibility, the a-level (typically 0.05 for a single comparison) used for each of the multiple comparisons must be lowered3. Using a composite endpoint therefore helps reduce the number of statistical comparisons of primary interest. If a trial’s investigators are intent upon exploring a large range of endpoints, all the other endpoints should be declared as secondary endpoints. It is common for statistical comparisons to be made for these secondary endpoints, but the degree of confidence that can be put in any individual ‘finding’ of a statistically significant difference between treatment groups is decreased. Such a ‘finding’ should be thought of as exploratory, and can then be legitimately investigated in further trials in which it is the primary endpoint3. Employment of Risk Ratios in the Determination of Efficacy and Unacceptable Risk The numbers of specified cardiovascular events of concern in each treatment group can be compared in terms of relative risk, defined as the occurrence of the adverse event in the drug treatment group divided by its occurrence in the comparator treatment group. Hence: Relative risk = Number of events in the drug treatment group Number of events in the comparator group If the test treatment and the comparator treatment were truly equal in terms of the risk of an event, the risk ratio would be unity, written here as 1.00. A risk ratio higher than 1.00 means that the event occurs more frequently in the drug treatment Volume 3 Issue 2

Therapeutics group than in the comparator treatment group, and a ratio interest between the test drug and the control drug (in this case, lower than 1.00 means that the event occurs less frequently in the test drug being associated with a greater cardiovascular the drug treatment group than in the comparator treatment risk), clinical and regulatory considerations are again pertinent. In this context, the question becomes: Is the identified increase group. Evaluation of statistically significant differences in occurrence in risk sufficient to deem it unacceptable? In the case of new of events is achieved via the employment of confidence intervals antidiabetic drugs to treat Type 2 diabetes mellitus (T2DM), (CIs). A point estimate of the risk ratio is obtained, and CIs are the FDA has employed a three-component model to answer then placed around this point estimate. If the test treatment this question in terms of prospectively excluding unacceptable and the comparator were truly equal in terms of the risk of risk1. This model involves clinical, regulatory, and statistical an event, the ‘perfect scenario’ of obtaining a risk ratio of considerations11. A ‘threshold of regulatory concern’ of 1.3 precisely 1.00 would not realistically be seen. Rather, the point is presented. If the upper limit of the CI falls below 1.3, an estimate would be close to 1.00, with the upper limit of the CI increase in risk, even if statistically significant (the lower limit lying above 1.00 and the lower limit lying below Table 1: Examples of Individual Events and Composite Endpoints 1.00. Such an occurrence would indicate that the Events and Endpoints numbers of events in the two treatment groups, Trial >Primary endpoint: a composite of death though actually different, are not different to a The Japanese Primary Prevention Project (JPPP)4 from cardiovascular causes (including fatal statistically significant degree. myocardial infarction [MI], fatal stroke, and Consider first a scenario where the risk ratio other cardiovascular death), non-fatal stroke (ischaemic or haemorrhagic), and non-fatal MI. point estimate is 0.90, and the lower and upper >Key secondary endpoints include a composite limits of the CI are 0.85 and 0.97. Given that unity of cardiovascular death, non-fatal stroke, nonis not encompassed by the lower and upper limits fatal MI, transient ischaemic attack, angina pectoris, or arteriosclerotic disease requiring (the upper limit lies below 1.00), there is evidence surgery or intervention; each component of that the event occurs statistically significantly the primary endpoint; non-cerebrovascular and less often in the test drug treatment group than non-cardiovascular death; and extracranial haemorrhage requiring transfusion or the control treatment group. We can go one step hospitalisation. further and state the following: the data from this Primary outcome: The occurrence of any stroke, Carotid Revascularization Endarterectomy vs. single study are compatible with as much as a Stenting Trial (CREST)5 myocardial infarction, or death during a 30-day 15% decrease and as little as a 3% decrease in peri-procedural period, and ipsilateral stroke during follow-up of up to four years. risk of the adverse event in the general population, Secondary outcomes include restenosis and and our best estimate is a decrease in risk of 10%. health-related quality of life. In an efficacy outcomes study, this result would Perindopril Protection Against Recurrent Stroke (ischaemic), stroke (haemorrhagic), stroke provide statistically compelling evidence for a Stroke Study (PROGRESS)6 (unknown). cardiovascular benefit of the drug. ACTION (A Coronary disease Trial Prespecified events included acute or procedural However, this result is not necessarily the Investigating Outcome with Nifedipine)7 MI, refractory angina, heart failure, and debilitating stroke. end of the story. Both clinical and regulatory 30-day composite of death, MI (CEC considerations are also pertinent. While our best PARAGON-B trial. Second Platelet IIb/ IIIa Antagonist for the Reduction of adjudicated), or ischaemia-driven intervention. estimate is a decrease in cardiovascular risk of Acute Coronary Syndrome Events in a 10%, the evidence from this one clinical trial Global Organization Network Trial.8 is also consistent with a decrease in risk of 3%. Effects of Clopidogrel in Addition to Aspirin Primary outcome: a composite of death from cardiovascular causes, non-fatal myocardial While any decrease is theoretically positive, the in Patients with Acute Coronary Syndromes infarction, or stroke. actual therapeutic usefulness of the drug will without ST-segment Elevation (CURE).9 Primary efficacy endpoint: composite of depend on other factors, including the number and Enoxaparin Prevents Death and Cardiac Ischemic Events in Unstable Angina/ all-cause mortality, recurrent MI, or urgent degree of side-effects present, and the availability Non–Q-Wave Myocardial Infarction revascularisation. (or otherwise) of other drugs for the disease or Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial.10 condition for which the drug is being developed. Now consider a scenario in which the risk ratio point estimate is 1.10, and the lower and upper limits lies above unity), is not deemed unacceptable should the drug of the CI are 1.03 and 1.18, respectively. Given that unity is have a beneficial therapeutic effect on what is certainly a serious not encompassed by the lower and upper limits (the lower disease. limit lies above 1.00), there is evidence that the event occurs At the time of writing, cardiovascular outcomes study for statistically significantly more often in the test drug treatment assessment of cardiovascular safety have not been mandated group than the control treatment group. We can go one step in other therapeutic areas, but such occurrences are certainly further and state the following: the data from this single study possible. Regulators’ thinking in the T2DM area is likely are compatible with as little as a 3% increase and as much representative of their approach in other therapeutic areas, as an 18% increase in risk of the adverse event in the general should additional guidances be released. population, and our best estimate is an increase in risk of 10%. In a safety outcomes study, this result would provide compelling Clinical Endpoint Committees: Generation of Optimum evidence for a potential cardiovascular safety concern. Quality Data However, while there is again statistically compelling evidence Optimum quality results and interpretations from clinical of a differential occurrence of the cardiovascular events of trials require optimum quality study design and operational

Journal for Clinical Studies 47

Therapeutics execution to generate optimum quality data for analysis12. In cardiovascular outcomes trials, the occurrence (or not) of cardiovascular events of interest is best judged by CECs. A CEC is a panel of independent experts charged with centrally reviewing and classifying suspected efficacy and/or safety endpoints, ascertaining whether they meet protocol definitions (endpoint criteria), and providing standardised endpoint outcomes for statistical analysis. CECs review overall subject data, as well as endpoint-specific data, applying complex medical definitions to determine these adjudicated outcomes. CECs should be blinded to treatment when performing centralised adjudication, regardless of whether the trial is conducted in a blinded manner13, Table 2: Key Characteristics of CECs and their Operation Primary Objectives of Centralised Adjudication • Ensuring complete and accurate capture of all suspected endpoints within the established endpoint categories requiring adjudication; • Collecting optimum quality descriptive supporting documentation of each suspected endpoint for CEC review; • Obtaining expert standardised study endpoint classifications (adjudicated outcomes) from the CEC. Clinical Trial Decision-making Processes involving CEC-adjudicated Endpoints • Sample size (power) estimations; • Periodic safety reviews by data monitoring committees (DMCs); • Sample size re-estimation and other interim analyses: • Next stage progress for adaptive design trials; • Study completion for event-driven trials; • Overall results for efficacy and safety analyses. Critical Components of CEC Establishment and Operation • CEC composition; • CEC charter development; • Endpoint data capture; • Endpoint management; • Integration of the centralised adjudication process within the overall trial. Requirements for Study Designs incorporating Centralised Adjudication • A well-defined integrated data capture strategy to ensure complete and accurate capture of all suspected endpoints for adjudication; • A clearly-defined tactical plan for effective endpoint case management; • A CEC adjudication process that is structured to deliver consistent, reliable, and accurate results.

and the centralised adjudication process should be designed to both preserve the independence of the CEC and prevent any undue bias that could impact its decision-making processes. CECs are employed when a protocol contains clinical events that will be assessed as key efficacy or safety endpoints. Since classification of such clinical events as study endpoints is a partially subjective process based on application of a complex set of medical endpoint criteria to an often complex clinical event, investigator classifications can vary considerably due to differences in individual medical training and application of clinical judgment. The dual purposes behind the implementation of centralised adjudication by a CEC are to limit the number of individuals providing classifications of study endpoints to control for this variability, and to employ experts to provide these classifications to achieve greater precision in the final classification of study endpoints. Differences between initial classifications by trial investigators and final CEC-adjudicated outcomes should not be seen as a ‘failure’, but rather a success: this is the expected result of any centralised adjudication process. CEC-adjudicated outcomes typically either validate, negate, upgrade, downgrade, or otherwise modify initial classifications of suspected endpoints. CEC adjudicators can also identify new, previously unreported suspected endpoints for investigation and follow-up. Final CECadjudicated outcomes are not provided to investigators, since 48 Journal for Clinical Studies

they have the potential to unduly bias investigator reporting of suspected endpoints, and their intended use is for the purposes of performing uniform analysis of key clinical efficacy and safety variables. CEC-adjudicated outcomes are not intended or suited for patient treatment. Final CEC-adjudicated outcomes do not replace initial classifications, but they are the outcomes that are used to assess key efficacy and safety variables in primary and secondary endpoint analyses. Standardising the Standardisation Process It is of note that, for a process that is ultimately intended to achieve standardisation of key clinical efficacy and safety variables, the implementation of centralised adjudication is remarkably non-standard and unregulated across the biopharmaceutical industry. The overall effectiveness of centralised adjudication in achieving its three primary objectives, presented in Table 2, can either be enhanced or diminished by the manner in which various available process components are assembled into a complete CEC model for a specific study. A guidance document on the establishment and operation of CECs would shape overall understanding of the primary objectives of centralised adjudication across the industry, and outline the advantages and disadvantages of common approaches and models in use, providing sponsors with the necessary context and background to make informed decisions regarding endpoint project design. Such a guidance would enable sponsors to achieve maximal benefit of centralised adjudication at the protocol or programme level. In addition, the guidance would drive an industry-wide, standardised approach to CEC implementation, enabling sponsors to work from a set of clearly outlined, robust processes that govern the most critical components of the establishment and operation of a CEC (see Table 2). In this spirit, Tyner et al14 recently published a best practice White Paper discussing these topics in detail that is available to all readers upon request. References 1. Caveney E, Turner JR, 2010, Regulatory landscapes for future antidiabetic drug development (Part I): FDA guidance on assessment of cardiovascular risks. Journal for Clinical Studies, January issue, 34-36. 2. Turner JR, Caveney S, 2010, Regulatory landscapes for future antidiabetic drug development (Part II): EMA guidance on assessment of cardiovascular risks, Journal for Clinical Studies, March issue, 38-40. 3.Turner JR, Reeve R, 2010, Multiple comparisons in drug development, Part I. International Pharmaceutical Industry, in press. 4. Teramoto T, Shimada K, Uchiyama S, et al, 2010, Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP), a randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events. American Heart Journal, 159:361-369. 5. Sheffet AJ, Roubin G, Howard G, et al, 2010, Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST). International Journal of Stroke, 5:40-46. 6. Ninomiya T, Donnan G, Anderson N, et al; PROGRESS Collaborative Group, 2009, Effects of the end point adjudication process on the results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). Stroke, 40:2111-2115. 7. Kirwan BA, Lubsen J, de Brouwer S, et al: ACTION (A Coronary disease Volume 3 Issue 2

Therapeutics Trial Investigating Outcome with Nifedipine GITS) investigators, 2007, Diagnostic criteria and adjudication process both determine published event-rates: The ACTION trial experience. Contemporary Clinical Trials, 28:720-729. 8. Mahaffey KW, Roe MT, Dyke CK, et al, 2002, Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. American Heart Journal, 143:242-248. 9. Yusuf S, Zhao F, Mehta SR, et al for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators, 2001, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine, 345:494-502. 10. Armstrong PW, 1999, Pursuing progress in acute coronary syndromes. Circulation, 100:1586-1589. 11. Turner JR, 2010, Integrated cardiovascular safety: Employing a three-component risk exclusion model in the assessment of investigational drugs. Applied Clinical Trials, June issue, 76-79. 12. Turner JR, 2010, New Drug Development: An Introduction to Clinical Trials, 2nd Edition. New York: Springer. 13. FDA Guidance for Clinical Trial Sponsors. Establishment and Operation of Clinical Trial Data Monitoring Committees. March Guidances/ucm127073.pdf (Accessed 2nd November 2010). 14. Tyner CA, Somaratne R, Cabell CH, Turner JR, 2010, Quintiles White Paper. Centralized Endpoint Adjudication in Cardiovascular

Outcomes Trials: Best Practice for Implementation across the Biopharmaceutical Industry. Available at cecwhitepaper J. Rick Turner, PhD Senior Scientific Director, Cardiac Safety Services, Quintiles Email:

Ransi Somaratne, MD, MBA, FACC Director, Medical and Scientific Services Email:

Christopher H. Cabell, MD, MHS, FACC Senior Vice President, Global Head, Therapeutic Delivery Email:

Catherine A. Tyner, MA, MFA, ABD Senior Director & Global Unit Head Clinical Safety & Oversight Group (CEVA) Solutions Lifecycle Safety, Quintiles Email:


Major Depressive Disorder (MDD): Uncovering Patients’ Perceptions Behavioural Aspects of Participating in a Clinical Trial Background Competitive patient recruitment in major depressive disorders requires a fundamental understanding of patients, in order to develop patient recruitment strategies that resonate with them and their families, regarding clinical trial participation. This is achieved by talking with patients through market surveys, focus groups or interviews. This patient-centric approach to recruitment planning provides important clues to developing and implementing patient recruitment and retention programmes customised to each clinical trial. Before patient interviews were conducted with MDD patients, motivations and concerns were sourced in peer-reviewed publications expanded upon by primary market research. The summation below highlights findings from an online market research survey of over 100 people living with Major Depressive Disorder (MDD). This survey specifically examined the patients’ perceptions and factors influencing decisions when contemplating their disease and possible participation in a clinical trial. Objective The survey sought to identify issues and concerns related to clinical trial participation, specifically of those living with MDD, and how these findings might influence patients’ willingness to participate in a clinical trial. The survey was also aimed at exploring issues and concerns that would need to be addressed in the design and implementation of a patient recruitment and retention programme, as well as preparation of study sites. Background methods Methods An online market research survey was disseminated to various depression communities with postings in mental health and MDD chat rooms and social networking sites, inviting people with MDD to take the survey. Over 120 individuals took the survey, of which 74 completed all questions. Responses to questions were analysed and tabulated. Open-ended question responses were evaluated using a ‘word cloud’ analysis to reflect the level of important issues raised by respondents based on how many times such words were used. Methods Summary of findings 1. Demographics Based on the responses to profile questions, the majority of 50 Journal for Clinical Studies

survey respondents appeared to meet the criteria for MDD. More than 72% of respondents were women, of which 50% were clustered in the 25 to 49 year age group. Just over half (53%) acknowledged suffering from repeat depressive episodes lasting more than 12 weeks and beginning more than five years ago. 2. Behavioural Aspects Most respondents (89%) reported “fatigue/lack of energy” and “feelings of worthlessness and/or guilt”; 50% of the respondents believe their depression was caused by “stress and trauma”, compared to 35% who viewed “family history” or “a pessimistic outlook” to blame. 3. Approach to Finding Treatment Options While 42% of respondents reported online sources and their psychiatrists as their most trusted resources for treatment information and guidance, 41% reported they “do not know where to start to get help”. This may be due to physical and psychological fatigues, as well as the limited availability of accessible information. 4. Perceptions of Clinical Trials The majority of survey respondents (80%) acknowledged access to expert care as the most important incentive in the decision-making process to participate in a clinical trial. Almost 68% of the respondents found “access to quality care at no cost” and “expert attention” as very valuable considerations when making a decision. 5. Adherence to the Protocol The majority of respondents (66%) believed they would have no difficulty in following study directives, including being asked detailed questions about their depressive episodes. Over 50% were willing to take only the study drug(s), but 68% were very unwilling to participate if the study protocol involved the possibility of receiving placebo. Compensation for time and travel was reported as another valid reason to consider participation and raised the willingness-to-participate quotient to 63%. 6. Benefits vs. Concerns of Participating in a Clinical Trial As illustrated by the word cloud, “Medication”, “Money” and “Symptoms”, were ranked as highly important, based on their word frequency, when respondents were asked to consider the benefits of participating in a clinical trial. Similarily “Medication”, “Depression” and “Side-Effects” ranked as the three highest concerns. “Medication” was the most significant Volume 3 Issue 2

Therapeutics benefit as well as concern regarding study participation. This might be due to patientsâ&#x20AC;&#x2122; feeling conflicted about receiving the benefits of medication at no cost while having concerns about possible side-effects. Universally, MDD patients perceived access to experts in depression and quality care at no cost as important motivating factors when deciding whether or not to participate in a clinical trial. They consistently defined quality care as less wait time, faster medical attention, close monitoring by medical professionals and assistance with medical referrals for other medical conditions. Discussion Based on the responses to questions about depressive symptoms, the majority of survey respondents appeared to meet criteria for MDD based on the DSM-IVR behavioural symptom criteria for Major Depressive Disorder (fatigue, feeling worthless/ guilt, irregular sleep pattern, lack of focus). However it should be noted that the presence of other mental health conditions, both diagnosed and undiagnosed, could have a significant impact on the data acquired from the survey. The demographic data show that the majority of survey respondents were females suffering from MDD, and this is consistent with epidemiology data that reports MDD more frequently in women, starting from the teenage years into the late 40s. The increased presence of MDD in females, together with the prevalence of women searching for health-related information online, may further account for the increased survey response from females. MDD patients expressed access to experts, money and attention as their three highest priorities when considering participation in a clinical trial. Specifically, they felt access to psychiatrists with expertise in depression and gaining access to knowledge about their disorder to be of very high value. This may be driven by a desire to better understand and manage their disorder in order to take control of their lives, rather than being dependent upon the care of others. This may be surmised from the fact that almost 90% of respondents expressed feelings of guilt and worthlessness as a result of their medical condition, and many expressed the desire to avoid a financial burden on their families. This latter point was further confirmed by 52 Journal for Clinical Studies

Volume 3 Issue 2


their high levels of willingness to receive the study drug and study- related medical treatment at no cost. In general, willingness to participate in a clinical trial was low. The most negative aspect of clinical trial participation was the possibility of receiving placebo. Most patients were willing to answer detailed questions about their depressive episodes and follow study directives, but 29% expressed an unwillingness to attend weekly clinic visits. Compensation for time and travel was seen as “very important” and seems to be another motivating factor in the decision-making process. With a high level of fatigue, sense of worthlessness and guilt, the majority of MDD patients turn their attention toward internet websites or their psychiatrists for solutions. These activities may also be indicative of a strong desire for privacy about their medical condition, coupled with their lack of physical and psychological strength to seek information by other means. Conclusion MDD patients are willing to participate in clinical trials when their needs and concerns are addressed. In their fatigued state, the effort to return frequently for study visits appears to be overwhelming. Yet they are open to information and e-marketing tools, including social media, blogs, and online videos, that simply and effectively engage them in providing answers to their questions and address their concerns can encourage them to consider participating in an MDD clinical trial. In order to improve patient retention and patients’ experiences with clinical sites, the study sites must employ staff that are attentive, and allow MDD patients to feel they are being heard. Delivering what patients perceive as high quality care, as well as access to medical professionals who are knowledgeable in treating depression, creates strong

incentives for patients to return. There is a fine line in delivering care that makes patients feel better at study visits that may confound patient reporting on assessment scales, but timely attention and demonstrating knowledge about depression are the qualities of site staff that MDD patients will be assessing. Incorporating the voice of MDD patients into study planning is essential for patient recruitment to be effectively implemented. When patients’ concerns and motivations are well defined and addressed, recruitment materials can be designed to be on target. Patient-centric planning and well executed recruitment/retention plans are at the heart of what we do. Liz Moench is the President, CEO, and founder of MediciGlobal®, the global leader in marketing clinical trials directly to patients. Liz pioneered the first DTC advertising campaign in pharmaceutical history and utilising her extensive background in direct-topatient marketing, she and her team are leading the industry in developing award-winning global marketing activities that are accelerating clinical trials globally; bringing new drugs to market faster. Recognised for over 17 years of high quality performance with outstanding results, MediciGlobal® is a world leader serving the global Life Sciences industry and a preferred provider to many biotech and pharmaceutical companies around the globe. Email:

Journal for Clinical Studies 53

IT & Logistics

Managing ePRO Patient Compliance in Emerging Markets There is an increasing trend for pharmaceutical companies (sponsors) and clinical research organisations (CROs) to conduct clinical trials in the emerging markets, such as Asia (in particular India and China) and Eastern Europe, to the extent that many companies now have an established presence in these countries. Studies in these regions range from small early phase studies to establish the safety profile of a drug, to large late phase studies required for licensure of a drug in the country where the study is conducted or as part of a global, multinational study. Running clinical trials in these markets offers many benefits over the more traditional and established areas in Western Europe and North America. These include: access to a larger population of potential study patients with the disease being targeted, resulting in faster patient recruitment; a reduced cost of conducting the trials; and, compared to the European Medicines Agency and US Food and Drug Administration, fewer perceived regulatory constraints. It is therefore important that electronic patient reported outcome (ePRO) technology and services meet the needs of clinical trials conducted in these emerging markets from the perspective of the trial patients, investigators, CROs, sponsors and regulatory agencies. This article outlines some practical considerations regarding ePRO technology and services, which are pertinent to studies conducted in the emerging markets. Compliance Matters For sponsors, ensuring compliance with a study protocol is very important in clinical trials, as this has an impact on the evaluable subjects at the end of a clinical trial to determine the safety and effectiveness of a drug. Study teams take care to ensure that the protocols are designed to meet the study endpoints, follow good clinical practices, and adhere to applicable regulatory agency requirements. These protocols are reviewed internally by the sponsor and externally by ethics committees. Similarly, study teams plan and design ePRO systems with close reference to the protocol and conduct multiple reviews and testing rounds to ensure that appropriate outcomes can be captured with minimal site and subject burden. The study medication itself often has a specific mechanism of action, and it’s important that the patients follow the specific instructions they’re given regarding when and how much medication they should be taking. Study medication intake and the actual collection of ePRO data is often done by the patient in an unsupervised environment. Therefore when a protocol calls for patient reported outcome measures and strict adherence to a medication schedule, an ePRO system plays an important role in ensuring a high level of compliance with the collection of data related to these activities. ePRO Systems for Patient Compliance Management ePRO systems can be set up for effective compliance management in a clinical trial. However, this requires careful planning by the sponsor, the CRO and the ePRO vendor. Here are the main components of an effective compliance management 54 Journal for Clinical Studies

process: 1) The patient eDiary Subjects participate in clinical trials because they are motivated by the potential benefit the research might have for them or the wider community. They are usually quite good at doing what is asked of them, provided they have been given clear instructions in a language they understand, and tools that are easy to use. Patients are not research professionals; to get the best results, there are a few things to keep in mind. First, keep it simple for the patients. Don’t expect them to remember what they need to do during the different phases of the trial. The eDiary can help them by acting like a personal digital assistant and actively guiding them throughout the trial. Some features that are useful here are alarms, real-time edit checks and conditional questionnaire navigation. Instead of asking the patient to make a choice, the eDiary can simply direct them: “It is time to complete your weekly questionnaire today. Click ‘Continue’ to proceed”. Essential in emerging markets is the provision of an ePRO tool that has instructions and questions in the most frequently used local languages. Care needs to be taken to ensure translations are accurate and questions can be interpreted in the same way in each language, especially for global studies. ePRO tools must be simple to use so that training is not perceived as burdensome by the study investigators. Again, the eDiary can assist the site staff with the administrative procedures: “Subject setup is now complete. Please select ‘Continue’ to proceed with the subject training”. A training module should be made available to the patients so that they can be trained and become familiar with the ePRO device and study questions. Simple instructions for the sites and patients in the form of a single-page quick reference guide, aimed at the local culture, can make the process easier. Questions for data collection purposes in the ePRO system also need to be short and simple, and should retain the meaning of the question in all languages. When forming the questions to pose, sponsors, CROs and ePRO vendors need to take into account the fact that many languages are inherently much longer than English, which often extends the length of the ePRO question on the device screen. Use of characters rather than Roman text usually requires a larger font size to ensure these more complex characters are easily readable. As often as possible, the ePRO systems should have closeended questions in order to avoid collection of ambiguous data. Ongoing encouragement to patients can be given through an effective, but underutilized, method of simply giving them regular feedback on how they are performing during a study. For example, in an eDiary to be completed by pediatric patients, a weekly cartoon can be displayed to motivate them to improve on their compliance or to congratulate them on a job well done. Of course, these kinds of motivational tools must be appropriate for the population and culture for which they’re being used.

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IT & Logistics 2) Reporting system for study sites Remote monitoring tools for use by investigator sites are an important part of the process to ensure patient compliance with ePRO data collection. This is especially important in studies where patients must fulfill a critical procedure at home, such as completing a particular questionnaire within a specified timeframe or collecting drug-related safety data. These remote monitoring tools allow the sites to proactively manage their patients. The sites can have access to reports that show the compliance for each of their patients. In addition, they can be automatically notified by the ePRO system via email or a report of poor or non-compliant patients, before they become protocol violators. Figure 2: Example automatic notification of poor compliance

Another method that can be very effective is to encourage competition between the sites or countries participating in the study by highlighting sites whose patients have high compliance rates. Sites that are not on the list might make an extra effort to make the list, and sites on the list will do their best to stay there. This kind of report works really well if there is some reward involved, such as recognition in the study newsletter. Figure 3: Example report to show investigator site compliance performance

However, having compliance measurement and reporting tools in place doesn’t accomplish anything by itself. Effective trial management is essential, and this usually starts at the site level with an investigator contract. To encourage good oversight of ePRO data by investigator sites, the investigator contract should include requirements for sites to review critical ePRO report(s) online at specified timepoints in the study. There should also be a requirement for the investigator site to make a phone call to potential non-compliant patients who are about to miss an important ePRO assessment at home. Once the investigators’ ePRO responsibilities are defined, the reporting system should be designed to measure site performance in real time. In addition, the reliable support of a 24-hour helpdesk will assist the study subjects with any issues they may have related to the ePRO system. 3) Reporting system for monitoring and study teams The monitoring clinical research associate (CRA) is crucial to ensuring ePRO compliance within a clinical trial, as they build a relationship with investigator site staff, train them in all aspects of the study, and act as the liaison between the investigator site and the study team. In emerging market countries, the CRA will also be aware of the cultural sensitivities and local understanding of a study. It is therefore essential that ePRO vendors, CROs and sponsors include CRAs from each country 56 Journal for Clinical Studies

in the user acceptance testing of the ePRO system, train the CRAs on all aspects of the study-specific ePRO system, and have ePRO tools designed to assist them in the monitoring of sites. This will ensure that they can provide additional support to the investigator sites as needed, and consequently this will improve compliance. Some ePRO systems support reports where the CRA can see whether or not the site staff has reviewed a particular report according to the investigator contracts. This makes it easy for the CRAs to monitor the sites and provide additional support for sites to improve their adherence to the agreed ePRO responsibilities. Figure 4: Site compliance report highlighting sites that have non-compliant patients and are NOT using the compliance reports

Study Region Impact on Compliance While there are no hard rules for compliance expectations for different countries, there are certainly cultural differences and trends that can be observed from global compliance data.

Figure 5: Global compliance metrics by region based on compliance metrics collected by CRF Health’s ePRO system

Figure 5, taken from CRF Health internal data, shows that the Asia Pacific region tops the charts in terms of compliance, but quite surprisingly, Western and Eastern Europe are not far behind. Southern Europe was separated into its own category because of the clear differences in compliance compared to the rest of Europe. This data shows a difference between some of the regions, but it doesn’t necessarily reflect a cultural difference. There is much more variation between different therapeutic areas than there is between different countries. For example, average compliance in vaccine studies conducted by CRF Health is 93.3%, while oncology has an average compliance of 87.2%. Part of the difference may be explained by the seriousness of the patient’s condition; vaccine studies typically use a healthy population. The complexity of the protocol also plays a big part, as oncology studies often have long duration and more complex measures, while vaccine studies typically collect simple safety data in the form of injection site reactions and other systemic effects over a much shorter time period. The good news for the pharmaceutical industry is that Volume 3 Issue 2

IT & Logistics some of these countries. The European Union and various trade agreements between countries in the west have made logistical matters quite trivial; the situation is completely different in Asia and some Eastern European countries, particularly Russia. Once a study is up and running, the users will need support in terms of a helpdesk. Here again, subjects and investigator sites must be served in their local language or they will simply not use the helpdesk and their issues will not be solved in a timely manner. Providing reliable support in many languages across all time zones is a challenge that only the most well-established and reliable ePRO vendors can accomplish. It is important to choose an ePRO vendor that routinely collects and monitors helpdesk metrics to ensure the very best in service. Conclusion In summary, the provision of ePRO solutions for clinical trials in emerging markets is a great opportunity for companies to use advances in technology to ensure the highest complianceto-protocol for the collection of their ePRO data. Sponsors, CROs and ePRO vendors need to provide a solution for studies in emerging markets that: a) Meets the logistical needs of the country, so that the devices can get into the country in time for study start and work reliably after deployment b) Employs a device that is simple to use - allowing for effective training and simplified data collection by patients c) Has questions that are simple to understand and answer, in local languages and with edit checks to ensure error-free data d) Provides suitable reports and alerts that will allow sites, CRAs and study teams to track compliance in real time – ensuring that small issues are caught before they become larger problems One thing is certain: ePRO systems and technologies will evolve further in the future, but attention to these basic elements will help ensure improved compliance.

some of the regions with the most compliant patients are also regions that are the most cost-effective in which to run clinical trials. However, deploying ePRO in these regions requires some consideration in terms of scalability and support. The ePRO vendors must be able to handle localisation of their software into various complex languages. For example, India alone has 21 official languages, and many of the Asian languages use complex scripts (fonts) that are not supported by all technology platforms. Logistical considerations are another issue. Choice of device must take into account local communication networks (i.e. landline or wireless of a mixture of both) so that patients can reliably send their data in an efficient manner. In addition, companies not only have to deal with large distances and different time zones, but also must be able to deal with differing customs regulations in order to be able to import their technology into

Rohini Beavon, PhD is Director of R Beavon Solutions Limited in the UK and is currently a freelance clinical research professional to the pharmaceutical industry. She has worked in the pharmaceutical industry for 12 years, most recently for Pfizer (formerly Wyeth) as a Clinical Project Manager and Clinical Scientist and was educated at the University of Liverpool and the University of Surrey. Email: Kai Langel has worked with CRF Health since the company’s inception in 2000 and is one of the pioneers in the ePRO industry. During this time, Kai has been involved in all aspects of ePRO operations from system design to deployment and support. Kai spent 5 years in the United States where he was responsible for building CRF Health’s technical delivery team. He is currently based in Europe in a consultative role providing advice and guidance to both customers and CRF Health’s internal teams on technical, operational and regulatory issues. Kai is a true global ePRO expert, having worked both in the United States, Europe and more recently in Japan and Asia. Contributor: Deepankar Arora, Manager, Clinical Operations at GVK Biosciences Pvt. Ltd. Journal for Clinical Studies 57

IT & Logistics

Utilising a CTMS to Create a Development Edge As clinical trials become more globalised and complex, there is an increased need for investigators in all regions of the world, as well as for treatment-naïve patients. The industry faces demanding regulatory needs, as well as the complexities of innovative treatment combinations and adaptive trials, against the backdrop of needing to find new cost and time efficiencies. Many challenges associated with this changing landscape, including administering, planning, monitoring and controlling clinical trials, can be addressed through the effective use of a CTMS (Clinical Trial Management System). Most companies adopt such a system as a means of providing a central database for all non-clinical and some clinical data, as well as providing all the tools for entering and reporting this information. Yet it is within the effective use of a CTMS that a development “edge” can be achieved. This article will consider four different aspects of the clinical trial process that illuminate this point.

The CTMS Role in Patient Recruitment and Site Management The definition of a successful study starts and ends with recruiting enough evaluable subjects. Yet even with the best patient recruitment web pages, a greater need yet is for wellqualified, enthusiastic, effective sites. It is difficult to argue with the assertion that picking the best sites matters more than anything else in achieving trial success. As was recently reported in CenterWatch, ‘On any given clinical trial, half of all sites under-enroll or fail to enroll a single patient, while 30 percent of sites provide 70 percent of all evaluable subjects…’. (Advocacy groups use Internet to target patients for disease-specific Recruitment, CenterWatch Monthly, November 2010). The critical questions then remain: How can the “30 per cent” become the majority? How might the failure rate be reduced? Worse still, sites that only enroll one subject can impose even more workload burden than those that fail to recruit at all. To make headway, there is a need for effective tools to assess a site’s suitability. A well-designed trial management system can positively impact the success of patient recruitment and site management. It will store information gleaned from mailshots and CRA interviews, providing a first indication of who should be approached to participate. A data mining tool in the CTMS facilitates the process, allowing one to focus on those people who responded a certain way to a given question or questions – as an example, if the sites were asked “How many new asthma patients do you see each month?”, an initial screen could seek to retrieve those doctors and those sites who responded with ‘5 or more’. This list of names could then be further filtered using a geographical or specialist/key opinion leader search with the potential to narrow it down even further to those in a given city, province or country, and to those with appropriate certification or experience. This can be a useful first step, but self-reported information can only go so far. Objective, retrospective data obtainable from a CTMS, as it is used year on year, will offer an extraordinarily rigorous method for finding the very best investigators. Examples of key metrics to consider include: • When they were recruited before, did they hit or exceed their planned number of patients? • Was their dropout rate lower than average? • Did they avoid protocol deviations? • Were they ahead of the curve in their speed of startup - in getting all the documents together, obtaining ethics approval and recruiting their first patient? And these quality measures can be combined with other criteria, such as: • Promptness at resolving issues • Correct follow-up of all serious adverse events

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IT & Logistics • Performance in overall per-patient and per-site costs Note that all of these measures are objective, avoiding the trap of evaluating a site’s suitability on the basis of personal preference, or on their availability for preliminary investigator meetings. This methodology instead relies on their proven track record. The Advantage of CTMS Integration with Other eClinical Systems Once the sites have been selected - using all of these intelligent assessment methods - it will be necessary to further qualify sites using on-site or telephone assessments. Their regulatory documents will need to be collated and the necessary ethics approvals obtained. A final step before enrolment can start will often be the setting up of the sites’ EDC (electronic data capture) and RTSM (randomisation and trial supply management) accounts. It is important not to activate these accounts too soon – before trial supplies are delivered and the staff are trained. A winning approach is to have the CTMS signal to the other systems that the site is ready: a combination of ‘all personnel are trained’, ‘drug supplies are available’, and ‘ethics approval is obtained’. A clinical trials management system is, after all, the primary source of site statuses; therefore, it is clearly the system to rely on. This is just one facet of the eClinical approach, linking all critical pharmaceutical software components together. The most effective CTMS has the latest enrolment data funneled into it from all the electronic data capture tools in use; that is, the data from one or more RTSM systems and an EDC system are fed into the CTMS. This helps to avoid over-enrolment, equating to cost overruns, and also keeps the trial manager alert to failing sites and countries. CTMS Support for Monitoring The “100% SDV” pendulum has swung back and forth over the last two decades. A monitor may – or may not – need to visit his or her sites every month: a large Phase IIIb or Phase IV study would be a challenge to monitor that closely. This does not mean, however, that the sponsor or their CRO are free of their GCP responsibilities. Instead, there is a trend towards virtual site management, that is, a flexible combination of EDC, some site monitoring, and skilled company personnel reaching out to the site by telephone. The clinical trials management system can guide the office-based CRA or administrator by displaying which sites have not been contacted recently, which sites have recruited new patients and which ones are falling behind compared with their planned enrolment. This allows the users to know whom to contact first. The CTMS will show them the best time to call the site and their preferred method of contact. The caller will be able to perform a variety of activities including discussing any issues the site may be having, following up on any expiring or missing documents, covering any recruitment or supplies difficulties, and dealing with inquiries concerning payments. This will be possible as the CTMS will have all of this information on one screen. ROI with CTMS Whenever “return on investment” for a CTMS is discussed, one consistent message is the ability of the best systems to

automatically calculate and generate investigator payments. Any study involving more than a few investigative sites brings with it the headache of ensuring accurate and prompt reimbursement to the site. It would be sufficiently complicated to be paying on a patient visit by patient visit basis, together with a percentage holdback until all data are certified as ‘clean’. There is, however, an additional wrinkle in certain regions of the world in the form of multiple contracts, all paying on a visit-by-visit basis, but paying different amounts to different payees – the sub-investigators, the PI (principal investigator), the institution and even the pharmacy and the laboratory. This represents a quantum leap in complexity, and it is the most stringent test of any clinical software system to achieve precise payments in this scenario - especially if the programme involves several dozen sites like this. The most efficient way is to have a CTMS capable of storing all the contract payment rules and updated with the exact details of each patient visit as it is recorded. This might mean an EDC link, or simply very diligent monitoring of the centre. Reducing Time to Market with CTMS “It does not matter what innovation or technology is being discussed, it always promises faster time-to-market!” This was the exasperated cry of a clinical executive recently. Can a clinical trials management system really make any difference? If the most effective, i.e. ‘best’, sites are chosen, as discussed, then it will result in studies starting more rapidly, studies completing sooner and submissions filing earlier. It is clear that the best available systems can help with this. However, shouldn’t a company use a tailored system, one exquisitely shaped for their needs? Where is the competitive advantage if a “configurable off-the-shelf system” is used? When this question is posed, I tend to respond that it is a company’s drugs that will make it competitive. The CTMS will help with a lot of things, but it cannot fill a development pipeline. Although it may seem ideal for a company to build a system that precisely matches their processes, as regulations and departmental priorities change, so must the system. It can often be the case that home-grown systems become a heavy IT burden to maintain and keep up-to-date. Conclusion As we discussed in the previous section, software per se must not be considered as a clinical research panacea. Yet the intelligent application of a CTMS will substantially increase the chances of a successful drug programme, particularly when linked with all the other tools we have at our disposal: safety systems, EDC, and RTSM. With this approach we really can know what is going on, know where we are going and know how to do better next time. John Humphreys has worked with Clinical Trial Management Systems for the last 14 years and is currently responsible for the strategic direction of Perceptive’s CTMS products in an overall eClinical framework. Trained as a biochemist, he worked in the pharmaceutical industry in sales and clinical research before switching to pharmaceutical software. Email: Journal for Clinical Studies 61

Exhibitions & Conferences

Event to Attend Oncology Dr Nermeen Varawalla, MD, DPhil(Oxon), MBA CEO and Founder, ECCRO The 2nd Oncology Clinical Trials in Emerging Regions Conference, co-located with the Cardiovascular Clinical Trials in Emerging Regions Conference, will be held at the Radisson Edwardian Hotel, Heathrow, London, UK on the 9th & 10th May 2011. This event, which is gaining much interest from sponsors and CROs active in emerging country clinical trial conduct will take a fresh look at the latest developments in oncology and cardiovascular clinical trials in Asia Pacific, India, the Middle East, Central & Eastern Europe and Latin America, using case studies, keynote presentations and panel discussions. Participants will understand the cost/benefit ratio of outsourcing oncology clinical trials to emerging regions, learn how best to recruit patients in these regions, get an update on the regulatory landscape, and appreciate the pros and cons of partnering with a local vs global CRO. Speakers include credible experts from sponsor organisations, academia and CROs. Confirmed speakers in the oncology event include Martine George, Vice President Global Medical Affairs, Oncology, Pfizer, who will share the clinical and commercial issues facing large pharmaceutical companies when making emerging country clinical trial outsourcing decisions. Dr Jorge

Otero, Vice President Clinical Development & Medical Affairs, Emerging Markets, GlaxoSmithKline, will discuss some of their early considerations before commencing Clinical Trials in Emerging Regions. Ridwaan Jetham, Global Clinical Operations Head, Oncology Senior Director, Johnson & Johnson, will describe how to engage with CROs and the advantages of utilising local expert CROs over their global counterparts. The cardiovascular conference speakers include Rob Scott, Vice President and Head of Global Cardiovascular Development, Amgen, and Jorge Enrique Saenz, Regional Medical Director Cardiovascular and Metabolic Disease, Pfizer Latin America, who will share their respective emerging country perspectives. Professor Colin Baigent, Clinical Trial Service Unit, Oxford University, will draw on the Study of Heart and Renal Protection (SHARP) to discuss the preparation and design of multi-national clinical studies. Both conferences have provisions for one-to-one meetings, a panel discussion with audience participation, and networking receptions. For further information and to register, contact Steve Hambrook, Conference Director (email: steve@globalengage. or visit

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The Role of Amyloid Biomarkers in Accelerating Alzheimer’s Disease Drug Development Unprecedented Growth in Clinical Trial Collaboration and Korea as the New Destination Managing ePRO Patient Compliance in Emerging Markets

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Ever wondered , why we choose flowers as the front cover of JCS? Each of the flowers we feature on the cover, represent the national flower of one of the emerging country we highlight in that particular issue. eg. In this issue we have featured a report on South Korea. Rose of Sharon or Rose of Althea is the National Flower of South Korea, which features on the front cover.

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Journal for Clinical Studies - Your Resource for Multisite Studies & Emerging Markets