Journal for Clinical Studies

JOURNAL FOR

Your Resource for Multisite Studies & Emerging MarketsCLINICAL STUDIESU

Drug-Drug Interactions Studies A Regulatory and Study Design Perspective

The Death of CNS Drug Development Overstatement or Omen?

Leveraging EthnobridgingTo Accelerate Global Drug Development

The Adoption of a Centralized Methodfor Significantly Improved Data Quality

Volume 3 - Issue 6

PEER REVIEWED

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www.jforcs.com Journal for Clinical Studies 1

FOREWORD

WATCh PAgES

8 Companion DiagnosticsIn today’s world the usage of companion diagnostics is becoming more common, as they allow for an increase personalisation of treatments by identifying the patients who are most likely to respond, or who are at lower or higher risk of a particular adverse event. By: Alejandra Muntañola, Project Manager at Thomson Reuters

10 Cardiovascular Safety Watch ColumnOff-target drug-induced blood pressure change, as a cardiovascular safety biomarker for non-cardiovascular drugs, is a topic discussed in this issue’s Cardiovascular Safety Watch page. This topic has been discussed at several scientific meetings during 2011, and most recently at the annual meeting of the Cardiac Safety Research Consortium. A summary of the recent discussion is presented by Rick Turner of Quintiles.

12 The Death of CNS Drug Development: Overstatement or Omen?The past year has been notable for several large pharmaceutical companies fundamentally abandoning or severely restricting their neuropsychiatric drug development efforts, citing costly and long drug development periods with disproportionately lower chances of successful central nervous system (CNS) drug applications. Henry Riordan and Neal Cutler of Worldwide Clinical Trials look into CNS drug development.

REguLATORy

16 Drug-Drug Interactions Studies: A Regulatory and Study Design PerspectiveTwo drugs can interact with each other pharmacokinetically and/or pharmacodynamically. Pharmacodynamic (PD) interactions lead to a change in drug response without any alterations in plasma concentrations. In this article, Dr Mario Tanguay and Jean-Francois Gagné of PharmaNet/i3 focus on issues such as regulatory framework and strategy, study design considerations, sample size and statistical considerations, and when to conduct DDI studies during drug development.

20 The Impending Sunshine Act: A Review for Clinical Trial SponsorsJessica Dolfi and Sondra Pepe of Medidata provide an enlightening review of the Sunshine Provision of the Patient Protection and Affordable Care Act (PPACA), which is one of the most highly anticipated changes in the clinical trial environment in recent years, requiring drug and device manufacturers to disclose all payments to physicians. The article points out that while some pharmaceutical, biotechnology and medical device companies are spending tremendous resources to comply with this legislation, many are unaware of the scope and detail of the impending legislation.

MANAgINg DIRECTOR Martin Wright

PuBLIShERMark A. Barker

MANAgINg EDITOR Mark A. Barker

EDITORIAL COORDINATORJaypreet Dhillon

EDITORIAL ASSISTANTSNick Love, Kevin Cross, Lanny McEnzie

DESIgN DIRECTOR Ricky Elizabeth

RESEARCh & CIRCuLATION MANAgERDorothy Brooks

BuSINESS DEVELOPMENT Lucy Beard

ADMINISTRATOR Barbara Lasco

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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.

Volume 3 Issue 6 December 2011 PHARMA PUBLICATIONS

JOURNAL FOR

Your Resource for Multisite Studies & Emerging Markets CLINICAL STUDIES U

Contents

Contents

Volume 3 Issue 62 Journal for Clinical Studies

MARkET REPORT

24 Clinical Trials Market in ukraine (Part 2)The history of clinical trials in Ukraine officially dates back to 1996, when the first regulatory permission to carry out multicentre international clinical trials was granted. This in-depth article by Mariya Dimova, Oleksii Gaydamak, Maxim Belotserkovsky and Tomasz Anyszek follows on from Part 1 (JCS September issue), and focuses on the important topics of who is already active in Ukraine, and evaluation of the potential of the Ukrainian clinical trials market - mutual benefits.

30 The Impact of Regional healthcare Variation on globalised Clinical Research – globalisation of Clinical Research: Benefits and RisksPetr Denisov, Paola Antonini and Michael Murphy, of Worldwide Clinical Trials, conclude that while the inclusion of emerging countries in global clinical research offers significant advantages, the case study they present appears to confirm how each trial must be considered in all particular features before endorsing the involvement of emerging regions and countries. This includes the trial’s targeted disease and its standard treatment, accessible patient population, and technology requirement for a proper execution. The case study looks at the feasibility of a cardiovascular trial in the Russian Federation.

34 Central and Eastern Europe: The Most Consistent Emerging Region for Clinical DevelopmentShaylyn Pike of Cutting Edge looks into opportunities in Central and Eastern Europe. For many companies looking to expand their marketing operations into emerging markets, the first step is often clinical development. Running a clinical trial in an emerging market allows a company to begin networking with regulatory officials and key opinion leaders. It also introduces the company to the cultural differences associated with these new markets without the must-sell-now pressure that jumping right into marketing would generate.

40 Leveraging Ethnobridging to Accelerate global Drug DevelopmentStanford Jhee of PAREXEL International explores the intense financial and competitive pressures on the biopharmaceutical industry, which make global drug development more important than ever. The imperative to quickly introduce products into as many countries as possible has increased dramatically in recent years as biopharmaceutical companies endeavour to maximise the commercial success of new therapies. In this demanding environment, Asian markets such as Japan, China and South Korea offer particularly attractive growth opportunities.

44 Resource for Multisite Studies and Emerging Markets – PolandFollowing European Union accession on 1 May 2004, Poland has implemented EU directives 2001/20 and 2005/28 and established a friendly environment for clinical trials. Tomasz Kowalczyk of Premier Research provides us a focus on Poland, and explores issues such as healthcare system characteristics, regulatory background, regulatory submissions, facts and myths about Poland, patient population, costs, quality, and IMP/laboratory logistic procedures.


Contents

ThERAPEuTICS

48 New Insight into the Impact and Treatment of MigraineDr James Sawyer, CEO, Prism Ideas, explores the recent developments in migraine. Migraine is one of the most commonly reported medical conditions in the world, and is associated with substantial personal and socio-economic impacts. The World Health Organization has ranked migraine as the 19th leading cause of disability worldwide, accounting for 1.4 per cent of all years of healthy life lost to disability.

52 Why ABPM Should Be Mandatory in All Trials of Blood Pressure-Lowering DrugsTraditionally, blood pressure (BP) has been assessed with the auscultatory technique introduced into clincal medicine at the end of the 19th century. Despite being inaccurate and misleading, this technique has survived largely unchanged for over 100 years. This article is by Eoin O’Brien, Professor of Molecular Pharmacology at the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, and covers issues such as advantages of ABPM, detection of white coat responders, absence of placebo response, reduction in patient numbers, and technological development of ABPM.

IT & LOgISTICS

56 Preserving Sample Integrity in Clinical Trials via use of Insulated Shippers JCS Speaks with ICON Central LaboratoriesIn this article, Andrew Roche and Caroline Brooks of ICON Plc detail the results of the most recent innovation at ICON Laboratories focused on continual enhancement of data quality. The innovation comprises an insulated ambient sample shipper which has been carefully selected to prolong maintenance of room-temperature conditions within the shipper and thus decrease the exposure of the contents of the shipper to the extreme seasonal conditions typically experienced in certain parts of the world.

60 The Adoption of a Centralised Method for Significantly Improved Data Quality and Substantial Time and Cost SavingsAmy Furlong of ERT states that, increasingly, the issue of cardiac safety is becoming a major concern for clinical trials sponsors. Cardiac safety is one of the most prominent causes of late phase delays, labelling changes, and product recalls of drugs entering the market. Problems such as these can lead to a variety of negative repercussions for a company, such as severe cost implications, loss of trust from consumers, and demise of company reputation as a result of product recalls. These factors can significantly impact a company’s revenue in the long run. The article concludes that the introduction of the centralised model has provided the industry with significant improvements to the traditional decentralised paper-based ECG methodologies.

62 JCS News

Journal for Clinical Studies 7www.jforcs.com

Foreword


The pharmaceutical industries of the US and Europe have been facing severe financial constraints over the past few years, which are expected to worsen in the coming years. With constraints such as the increasing cost of introducing new molecular entities (NMEs), tightening regulatory pressures resulting

in fewer FDA and other regulatory agency approvals, blockbuster drugs worth more than $100 billion experiencing patent expiry by 2014, and the drying developmental pipelines of the pharmaceutical industry, cost-cutting pressures are mounting on pharmaceutical companies, especially the big ones. These pressures are expected to drive these companies towards low-cost countries, for example for their R&D activities, which are one of their major expenses.

Offshoring to emerging markets and demand for late-stage development services will help to fuel cumulative growth of more than 50% in the worldwide market for clinical trials over the next five years, according to a report I read recently.

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

Over the next decade, full-service CROs will further benefit from multi-billion-dollar strategic alliances with big pharma companies, as outsourcing of drug development continues to provide access to strong therapeutic experience and significant cost savings.

At the same time, niche market players will be able to take advantage of increased demand for specialised clinical trial services, particularly in the fields of cancer and central nervous system disorders.

Revenue growth will also come from offshoring to emerging markets, especially India, China, Brazil and Russia, as well as other countries in Southeast Asia and Central and Eastern Europe.

Revenues from clinical trials in India and China will show compound annual growth of more than 20%, with China becoming the world’s second largest market for pharmaceutical clinical trial services by 2021.

Another market driver is expected to be demand for late-stage development services, which has outgrown demand for early-stage services in recent years. Pharmaceutical and biotechnology companies “are increasingly focusing on near-registration projects to combat the impending patent cliff”.

Journal for Clinical Studies was set up half a decade ago, with the ultimate objective of providing our readers within the clinical research industry, a definitive and clear understanding of these emerging regions, and gauging the potential and opportunities they can provide. In view of such a positive forecast relating to emerging markets, we are further motivated to continue to bring you a wide array of features, which will guide you progressively through these regions.

In this issue, the CNS Feature by Henry Riordan and Neal Cutler of Worldwide Clinical Trials is a hard-hitting analysis of the future of CNS drug development. Should the pharmaceutical companies do more?

In the Regulatory section, Dr Mario Tanguay and Jean-Francois Gagné of PharmaNet/i3 focus on when to conduct DDI studies during drug development, and Jessica Dolfi and Sondra Pepe of Medidata provide an enlightening review of the Sunshine Provision of the Patient Protection and Affordable Care Act (PPACA).

In the Market Report section, we have continued with an analysis of the Eastern European market, with key features on Poland and Ukraine. And in the upcoming issue of JCS for January 2012, we will be focussing on Asia, which will be an interesting read.

I take this opportunity to thank all our contributors for making Journal for Clinical Studies a continued success. I wish every one a Very Merry Christmas and a Wonderful New Year.

Mark BarkerPublisher

Editorial Advisory Board

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

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

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

In today’s world the usage of companion diagnostics is becoming more common, as they allow for an increase personalisation of treatments by identifying the patients who are most likely to respond, or who are at lower or higher risk of a particular adverse event. To assist sponsors who are planning to develop therapeutic products that are intended for use with IVD companion diagnostic devices, or IVD companion diagnostics themselves, the uS Food and Drug Administration published the Draft guidance for Industry on In Vitro Companion Diagnostic Devices (IVD Companion Diagnostic Device) in July 2011.

The FDA gives a definition of an “in vitro companion diagnostic device” as a “medical device that identifies/determines a condition of use for a therapeutic product and is important to ensure the safe and effective use of that product” meaning that if the safe and effective use of the therapeutic product requires a particular test result, then that test is a companion diagnostic.

Of chief focus in the draft guidance is the recommendation made by the FDA for novel therapeutic products, that the drug and the companion diagnostic should be approved contemporaneously (co-approval). The FDA will not approve one without the other. However, the guidance provides for exceptions to this statement in the following cases:a) When the therapeutic product is indicated for the

treatment of a serious or life-threatening condition, and,b) When the labelling for an already approved therapeutic

product must be revised to address a serious safety concern that can be addressed by using an unapproved IVD companion diagnostic device, the FDA will not delay approval of the changes to the labelling if the benefits from the use of the product with an unapproved IVD companion diagnostic device outweigh the risks from the lack of a cleared device.

Regarding labelling of a therapeutic product, the guidance refers the sponsors to the Code of Federal Regulations 21 CFR 201.56 and 57 for drugs and biologics respectively. Under these regulations, • If a drug or biological product has been shown to be safe

and effective only in a certain patient population identified by a diagnostic test, the Indications and Usage section must clearly define the patient population in whom the drug is approved.

• If a diagnostic test is essential for monitoring either therapeutic or toxic effects, the type of test should be identified under Warnings and Precautions.In addition, the guidance outlines that the labelling of the

therapeutic product must identify a type of device, rather than a manufacturer’s device. This action facilitates the approval of additional devices for use with the therapeutic product. Should the FDA approve a companion diagnostic device a posteriori, the sponsor should provide an update of the therapeutic product labelling. Labelling of an IVD companion diagnostic device needs to refer to the specific use (intended use/indication) of the device as per regulations

as well as to the therapeutic product or therapeutic class (when the test can be used within a class of products). The Guidance observes a labelling extension (PMA, 510(k) or PMA supplement) in the following cases: use in a new disease and use with a different therapeutic product.

Following the publication of the guidance document FDA approved two products in August 2011, each the result of co-development programmes in oncology: Xalkori® (Crizotinib)/Vysis ALK Break Apart FISH Probe (Pfizer/Abbott) and Zelboraf (vemurafenib)/cobas 4800 BRAF V600 Mutation Test (Genentech/Roche).

This Guidance is just another effort from FDA to facilitate the development of personalised medicines. Another agency intention is to develop internal procedures and policies to guarantee that the communication across different centres is effective, as well as the product review process. FDA encourages sponsors to solicit meetings with FDA review divisions.

References 1. Federal Register: July 14, 2011 (Volume 76, Number 135) (Pages

41506-41507)2. 21 cfr 809.10(a)(2)

Alejandra Muntañola, RPh, MS, Project Manager, Thomson Reuters. Alejandra Muntañola graduated as a pharmacist from Complutense University, Madrid and further specialised in European Regulatory Affairs. She has worked for the pharmaceutical industry in Regulatory

Affairs and is currently Senior Project Manager for the IDRAC United States (US) Module at Thomson Reuters.Email: [email protected].

Watch pages


Companion Diagnostics

Watch pages


It was noted in last month’s issue of the Journal that this column would provide a report on the 2nd DIA Cardiac Safety Conference in Japan (September 5th and 6th in Tokyo). However, given the amount of material presented there, and the relatively short length of these Cardiovascular Safety Watch columns, preparation of a full-length paper seemed more appropriate. This paper is therefore currently being prepared, and will be published early next year in the International Pharmaceutical Industry1. Accordingly, this column focuses on one particular topic discussed at several scientific meetings during 2011, most recently at the Annual Meeting of the Cardiac Safety Research Consortium on October 5th, i.e., off-target drug-induced blood pressure change as a cardiovascular safety biomarker for noncardiovascular drugs [see 2 for a more detailed discussion].

There is increasing scientific and regulatory interest in developing an appropriately informative assessment strategy for blood pressure alterations induced by noncardiovascular drugs (while increases may garner more attention, decreases of certain magnitudes are also undesirable, particularly in some patient populations). In contrast to the development of the ICH E14 Guideline addressing the evaluation of QT interval prolongation induced by non-antiarrhythmic drugs3 and the FDA and EMA guidance documents addressing the assessment of the cardiovascular safety of new antidiabetic drugs for type 2 diabetes mellitus4,5, several opportunities exist that lend themselves to facilitating regulatory guidance that has been beneficially influenced by various interested parties, including biopharmaceutical companies, contract research organisations, and specialised cardiovascular safety testing companies.

Several points of interest in this area include the following. First, the mechanism by which a noncardiovascular drug impacts blood pressure may not be of relevance. Arterial blood pressure is a manifestation of the interaction between the heart and the systemic vasculature. Mean arterial pressure (MAP) is the product, figuratively and mathematically, of cardiac output (CO, the amount of blood ejected per unit time) and total peripheral resistance of the systemic vasculature (TPR, the pressure against which the blood is ejected). It follows that a change in blood pressure can be the result of a change in CO, in TPR, or in both. There are many classes of antihypertensive drugs, all of which can lower blood pressure in certain patients via various mechanisms of action. It is likely that the actual mechanism of a drug that works well for an individual patient is less important than the fact it is of benefit. Using this logic for the off-target blood pressure changes of interest in this column, it can be reasonably argued that changes in blood pressure via any route are all equally undesirable, and hence the actual mechanism of action is not of central importance6.

Second, which blood parameter(s) -- systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP -- should be considered as the endpoint of primary interest? Related to this is, what degree of change(s) will elicit regulatory concern should a regulatory guidance document(s) be developed? That is, if the same approach to the prospective exclusion of unacceptable cardiovascular risk is taken here that was adopted for QT/QTc prolongation in general drug development and for MACE events in anti-diabetic drug development, where would the threshold(s) of regulatory concern be set? Clinical and regulatory science would be used to make this choice, and then statistical science used to identify instances when the threshold(s) has/have been breached. Another question therefore becomes: Does the wealth of blood pressure data collected across the last few decades make the choice of thresholds easier than were the choices of 10 msec and the relative risk ratios of 1.8 and 1.3, respectively?

It will be of considerable interest to many stakeholders to follow this area of cardiovascular safety as it unfolds over the coming months.

References1. Turner JR, Satin LZ, Japanese Cardiac Safety Requirements

(Part II): An Evolving Regulatory Landscape. In preparation for the International Pharmaceutical Industry.

2. Satin LZ, Turner JR, Drug-induced Blood Pressure Change as a Cardiovascular Safety Biomarker for Noncardiovascular Drugs: A Potential Future Regulatory Landscape. In preparation as an Expert Commentary for the Drug Information Journal.

3. ICH Guidance E14, 2005, The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.

4. FDA Guideline for Industry, 2008, Diabetes Mellitus—Evaluation of Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.

5. EMA Draft Guidance, 2011, 2nd version, “Guideline on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus.”

6. Comment made by Dr Norman Stockbridge (FDA) at the Cardiac Safety Research Consortium’s Annual Meeting, 5th October 2011.

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

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

Cardiovascular Safety Watch Column

Watch pages


Regrettably, the past year has been notable for several large pharmaceutical companies fundamentally abandoning or severely restricting their neuropsychiatric drug development efforts, citing costly and long drug development periods with disproportionately lower chances of successful central nervous system (CNS) drug applications. A recent report by the Tufts Center for the Study of Drug Development (Tufts CSDD)1 suggests that as little as 8.2% of CNS drug candidates ever become available for clinical use, compared with 15% of other drugs. It also takes more time to get regulatory approval—approximately 1.9 years for CNS drugs, compared with an average of 1.2 years for all other non-CNS drugs. In addition, Phase II and III development for CNS drugs takes an average of 8.1 years, more than two years longer than development for drugs in other therapeutic areas. Some CNS drugs take as long as 18 years from preclinical work to marketing, leaving little to no patent protection. Importantly, trial failures in CNS tend to occur later in the clinical development process, when resource demands and costs are at their highest. In fact, it was estimated that only 46% of CNS candidates succeed in Phase III trials, compared with 66% on average for all other drugs, making the cost of developing a CNS drug among the highest of any therapeutic area. Given this data, the risks associated with CNS drug development are currently weighed as being too great for many pharmaceutical companies, regardless of the continued need for treatment and an ever burgeoning market for many CNS drugs.

Even before the publication of the Tufts CSDD report, the development of CNS drugs has long been known to be fraught with innumerable complexities and obstacles (both genuine and perceived) compared to other therapeutic areas. Some of the more salient obstacles include a general bias regarding psychiatric illness and drugs, as well as a number of special concerns associated with CNS development that need to be successfully addressed during the course of the development process. Despite the advent and acceptance of biological psychiatry and the abundance of awareness campaigns regarding mental health issues, many lay people, and even healthcare providers, still inaccurately view CNS disorders as somehow less important than “real” diseases. This attitude belittles the value of CNS treatments, which are often seen as disparate from more “physical” ailments.

This bias can be seen when relatively more infectious disease and oncology therapies are being tested and approved compared to CNS therapies, reportedly due to their inherent “risk-benefit profile”, in which more risks (such as the side-effects and negative health consequences of a drug) are tolerated if the drug is also proven to be therapeutically efficacious. For many CNS indications this risk-benefit ratio is skewed, so that only negligible or no risk is acceptable.

For example, many CNS drugs are metabolised by P450 3A4 or 2D6 pathways, which are common substrates for innumerable CNS and non-CNS concomitant mediations, increasing the drug’s risk-to-benefit ratio via potential drug-drug interactions and greater side-effect profiles. This low to no acceptable risk level seems to apply especially to disorders that appear to treat “lifestyle”-type ailments such as depression, anxiety, and attention deficit disorder, which the general public (and even some healthcare providers) often misperceive as only impacting a person’s temperament and quality of life, while having little to no effect on their overall health. However, it is well known that the risks of not treating mood disorders include increased morbidity and mortality from related medical illnesses and suicide, as well as the worsening of other purely “physical” ailments due to stress interactions and treatment non-compliance2.

In fact, according to a global study by the World Health Organization (WHO), depression may well be the most disabling disease in the world, and people with chronic physical diseases such as angina, arthritis, asthma, and diabetes are far worse if they also suffer from depression3. Despite increasing and overwhelming evidence such as this, CNS disorders continue to be stigmatised. In one sense this bias can be inferred by the relative lack of press and general criticism following the announcements of several major pharmaceutical companies’ plan to abandon their CNS portfolios4. One cannot help speculating that if a similar renouncement occurred in areas such as cardiovascular (CV) disease, diabetes, or oncology, this would have been followed by a fierce uproar from patient advocacy groups, the general public, and the press.

Trial sample size has also been cited as another manifestation of bias in CNS drug development5. For example, as a rule CV trials are strikingly larger than psychiatric trials. While it would not be unusual to have 10,000 to 40,000 patients in a single CV study, most psychiatry studies have less than one-tenth that number (roughly 300-500 patients). Even the relatively large CNS trials sponsored by the National Institutes of Health (NIH) have no more than a few thousand patients each, resulting in a relative reduction in statistical power compared to CV trials. This may be an artifact of the pharmaceutical industry’s reluctance to invest in psychiatry trials, due not only to internal, methodological complexities but also to external pressures. The field of psychiatry is forced to deal with a strong and active “anti-psychiatry” movement made up of politicians, foundations, religious groups, and lay people who fundamentally do not believe in the benefits of psychiatric treatment. There appears to be no such interest groups for other disorders seen as purely “physical”.

The Death of CNS Drug Development: Overstatement or Omen?

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The bias against CNS drug development also manifests itself in approval trends by regulatory agencies, in which certain drugs are “fast-tracked” for approval due to perceived medical importance, such as those that can potentially treat serious or life-threatening illnesses, or those that address an unmet medical need. Researchers have reported that oncology drugs have a disproportionately higher share of FDA priority review ratings, orphan drug designations at approval, and drugs granted inclusion in at least one of the FDA’s expedited access programmes6.

CNS drugs often start off in a relatively poorer position than drugs in other indications, not just because they are viewed as a having a relatively higher risk and lower priority, but also because CNS drug developers are not routinely taking advantage of the regulatory tools available to them, such as Priority Review and Fast Track designation. There are innumerable CNS conditions that would be considered serious or life-threatening and therefore eligible for Fast Track designation. Given the lack of effective treatments, the growing number of treatment-refractory CNS patients, and the high degree of intolerable side-effects, many CNS development programmes would be considered to address an unmet medical need and be eligible for Fast Track designation.

The Fast Track designation enables early interaction with the FDA that can help to clarify elements of clinical study design whose deficiency or absence upon the submission of a new drug application (NDA) could delay approval decisions. Although the FDA makes similar interactions available to any sponsor who seeks consultation throughout the stages of drug development, these meetings are not always guaranteed. A unique option within the Fast Track designation is the opportunity to submit sections of an NDA to the FDA as they are ready, rather than the standard requirement to submit a complete application at one time. Thus, many CNS development programmes miss out on some of the essential advantages associated with this special designation. Regulators should encourage this approach and also endeavour to lower the regulatory “bar” for more traditional CNS programmes in cases where treatment need is greatest. This, as well as a simple extension of patent licences, could result in a major reduction in the apparent risk profile for many CNS compounds, and a subsequent increase in pharmaceutical investment in this area.

In addition to this bias there are existent intrinsic complexities in CNS drug development that have discouraged pharmaceutical and biotechnology companies. Although most companies enter into CNS development programmes fully aware of these complexities, they are often minimised or even ignored in favour of the potential payoff of a CNS drug approval, given the enormous and ever growing CNS customer base. In fact, the number of patients with CNS disorders far outstrips those with CV disorders. Given population trends in which those 85 years and older will quadruple by 2050, with accompanying increases in neurodegenerative disorders, this dominance is likely to intensify. The potential size of the untreated CNS markets is so great that the future growth of the global neuropharmaceutical market could outpace the growth in all other sectors of the pharmaceutical industry7.

Below are some of the more salient reasons that may make the design and conduct of CNS drug development programmes relatively more challenging and risky than other indications: • The relative lack of knowledge of fundamental biology and

pathophysiological underpinnings of many CNS disorders• The relatively poor predictive validity of preclinical

models, and lack of accepted biomarkers and surrogates by regulatory authorities and the scientific community

• The relatively high use of subjective investigator and patient-rated diagnostic scales and primary endpoints, ultimately resulting in heightened placebo response

• The relatively large number of failed trials (not just non-significant trials) in which an already approved active comparator fails to differentiate from placebo, resulting in more trials to secure two adequate and well-controlled studies

• The relatively lengthy and fluctuating treatment periods for chronic illnesses, resulting in tremendous variability in treatment response over time

• The relatively novel mechanisms of action for many CNS drugs that by definition are associated with a higher risk of failureArguably, all of these factors have made CNS drug

development comparatively more challenging for drug developers, resulting in poor CNS pipelines. Paradoxically, in an effort to respond to diminishing pipelines, many companies may have prematurely or inappropriately progressed CNS drugs into the Phase IIb/III setting based on marginal efficacy, inappropriate subgroup findings, inefficient data analyses, and specious conclusions from prior studies (especially in terms of dose selection). It also appears that many drug development teams have failed to truly benefit from proof-of-concept (POC) studies. POC studies should not habitually be designed and powered as potential back-up registration trials as they often are, but rather should take the form of a precise innovative experiment that specifically addresses one or two major objectives in a rigorous manner and often in enriched patients — the

www.jforcs.com Journal for Clinical Studies 15

Watch pages

results of which would inform eventual registration studies. Instead, gathering information regarding dose selection, exposure-response, and the means and variances of the primary outcome measure should be the goal of POC trials. Companies should also take advantage of regulatory input at the end of Phase IIa to help interpret POC data when designing registration studies.

The rush to Phase III and functional “silo”fication of big pharma departments has also resulted in tactical processes that can be antithetical to the strategic goal of drug development. Many companies segregate functions based on drug phase utilising disjointed functional teams. Lessons learned from one phase or team are often lost in the handoffs, with each team having its own goals, preconceptions, and biases that can be fundamentally at odds with each other. Long gone are the days when a well-seasoned singular drug development team with a unified goal and sense of ownership, equipped with unique knowledge of the drug’s attributes and pitfalls, and led by an expert product development champion/clinician could successfully usher a drug along the entire drug development pathway. It can be argued that not only are much needed information and a sense of responsibility lost in the handoffs, but also any chances of fortuitous, impromptu and unplanned explorations.

A recent meeting of the American College of Neuropsychopharmacology (ACNP) has concluded that it still may be premature to search “deductively” for psychiatric medications, reminding us of the important role that serendipity has historically played in neuropsychiatric drug development8. It was also suggested at this meeting that investigators should be alert to and note promising observations rather than simply discard outliers, and that they should initially utilise small pilot studies on the drug of interest. Further support was given for an open, dose-ranging trial followed by a move to a small sample, randomised clinical trial, all well before the move to Phase III. Furthermore, co-development of neuropsychiatric drugs with publically funded research institutions was also recommended to help to reduce the inherent risk involved in the CNS development process.

Unfortunately, the large amount of information gleaned from recent basic science innovations has had very little clinical relevance and, despite newly acquired knowledge gained on an almost daily basis, the past few years of CNS drug development have been characterised by relative stagnation. No matter the explanation for the lack of advancement of CNS drugs (whether bias, trial complexity, difficulty in study conduct, or some combination of many factors), most drug developers agree that there is an immense opportunity for expansion in the CNS marketplace. This fact alone should make CNS development attractive to the pharmaceutical and biotech sectors. Reducing patient suffering, prolonging life, and responding to very important public health concerns all demand greater efficiency in the clinical trial process resulting in an improved ability to secure approval for CNS drugs in a more timely and cost-effective manner.

Some of the recommendations above — such as a return to a singular clinical development team that ushers a drug

through the entire development process in a manner that maximises the possibility of serendipity and learning from prior studies; an increased utilisation of Priority Review or Fast Track designation with an accompanying decrease in regulatory burden; an increase in co-development or risk-sharing with publically funded institutions and the creation of networks of development partners; and increased attentiveness to the far-reaching effects of stigmatisation of CNS drugs and disorders — should all aid our shared goal of getting safe and effective CNS drugs to those most afflicted.

References:1. Kaitin KI, Milne CP. A Dearth of New Meds: Drugs to treat

neuropsychiatric disorders have become too risky for Big Pharma. Scientific American. 2011; 305: 16.

2. Agency for Health Care Policy and Research. Clinical Practice Guideline Number 5: Depression in Primary Care, 2: Treatment of Major Depression. 1993. Rockville, MD: Agency for Health Care Policy and Research, US Dept of Health and Human Services; AHCPR publication 93-0551.

3. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590): 851-858.

4. Kelland K. Analysis: Neuroscience under threat as Big Pharma backs off. 2011. Reuters. Feb 11. http://www.reuters.com/article/2011/02/11/us-neuroscience-pharma-idUSTRE71A2E120110211

5. Nemeroff C. Stigma in Psychiatry, Part 1 of 2 Medscape Psychiatry & Mental Health. 2008; ©2008 Medscape Posted 09/17/2008.

6. DiMasi JA, Grabowski HG. Economics of new oncology drug development. J Clin Oncol. 2007;25(2): 209-216.

7. Cutler NR, Sramek JJ, Murphy MF, Riordan H, Bieck P, Carta A. : Critical Pathways to Success in CNS Drug Development. 2010. John Wiley & Sons, Inc, Toronto

8. Klein DF, Gliock ID, Shader RI. Central nervous system drug development, basic, and clinical research: thinking outside the box. J Clin Psychopharmacol. 2011;31(5): 553-554.

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

Neal R. Cutler, MD is the CEO of Worldwide Clinical Trials. He is a board-certified psychiatrist who has authored over 250 publications, including nine books on CNS drug development. He has also been instrumental in the design and clinical development of nearly 200 compounds in numerous therapeutic areas and has particular expertise in central nervous system disorders.

Regulatory


Drug-Drug Interactions Studies: a Regulatory and Study Design Perspective

Drug-drug interactions (DDIs) are a significant public health concern that can lead to adverse drug reactions or therapeutic failure. Several products have been withdrawn from the market because of increased toxicity from the concomitant use of drugs (e.g., terfenadine, astemizole, cisapride). Therefore, the investigation of potential DDIs is a critical aspect of drug development.

Two drugs can interact with each other pharmacokinetically and/or pharmacodynamically. Pharmacodynamic (PD) interactions lead to a change in drug response without any alterations in plasma concentrations. A classic example would be the central nervous depression system resulting from the concomitant administration of opiates and benzodiazepines. Pharmacokinetic (PK) interactions would occur when the absorption, distribution, metabolism and elimination of a drug would be affected by the administration of another compound, which may in turn affect the clinical response. Most of the interactions are related to an effect on the metabolism of a drug involving the cytochrome P450 (CYP) family of enzymes (common CYP subfamilies include 1A2, 2C8, 2C9, 2C19, 2D6 and 3A). Other PK drug interactions may also be mediated by an effect on various cell membrane transporters. An example of these interactions is the inhibition or induction of P-glycoprotein. Displacement of drugs from plasma protein is another mechanism by which interactions may occur, even though these are rarely clinically significant.

The main focus of this article will be on the evaluation of metabolism-based DDI. An overview of the regulatory framework surrounding DDI studies and the various options for the study design will also be discussed.

Regulatory Framework and StrategyDrug development programmes should include early in vitro and preclinical evaluations of drug interactions, using experimental models such as human liver microsomes. The outcome of these evaluations is critical in order to determine the strategy related to DDI clinical assessment. In certain cases, early negative findings may clearly indicate the absence of a metabolic pathway, therefore eliminating the need for further clinical investigations. Positive in vitro findings would otherwise guide sponsors regarding the DDI clinical studies that would be required. In 2006, the US Food and Drug Administration (FDA) released draft guidance on drug interaction studies that provided detailed information on how in vitro data can be used to determine what clinical DDI studies should be conducted1. For example, if the new chemical entity is a substrate of a CYP enzyme and the contribution of this elimination pathway is major or unclear, clinical studies should be conducted with the use of the most potent CYP inhibitor and inducer. If the CYP enzyme identified in vitro is subject to functional genetic polymorphism (e.g., CYP2C9, 2C19, 2D6 and 3A5), a study comparing the PK of the drug in subjects with reduced metabolic enzyme activity (i.e., “poor” metabolisers) versus “extensive” metabolisers can be conducted in lieu of an interaction study with an inhibitor. If

in vitro findings suggest that the new chemical entity is a CYP inducer or inhibitor, then clinical studies using the most sensitive and specific substrates of the CYP enzyme(s) identified should be conducted. Table I lists some commonly used and recommended substrates, inhibitors, and inducers for DDI studies.

Adapted from the Food and Drug Administration Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and Labeling, September 2006.

DDI studies may be warranted even if the metabolic pathway of two compounds seems to differ. An example of this is when a new chemical entity is intended to be administered specifically with a commercially available compound (or therapeutic class) to exert a synergistic effect. This may also apply if an expected concomitant therapy would have a narrow therapeutic index. Other regulatory agencies, such as the European Medicines Agency (EMA) and Canadian Health Products Food Branch (HPFB), have also published guidance documents which cover similar aspects as the FDA guidance, and may provide useful information to determine when and which DDI studies should be performed during drug development2,3.

Study Design ConsiderationsDDI study designs will be based on the specific objectives of the study, on the need to assess inhibition or induction, and on the specific PK and PD characteristics of the substrate and interacting drug. As described above, a new chemical entity may be an inhibitor or inducer of a drug-metabolising enzyme. In such cases, the sponsor would be interested in investigating its effect as “perpetrator” on other drugs. The new drug candidate can otherwise be identified as a substrate of a drug-metabolising enzyme and would then be referred to as a potential “victim” of another drug. There are several options available to design a DDI study. For instance, one must consider single versus multiple dose administrations for each drug,

Table 1: Examples of recommended substrates, inhibitors, and inducers for drug interaction studies.

CyP/transporter Substrates Inhibitors* Inducers

P-gp Digoxin, fexofenadine, indinavir

Ritonavir, verapamil, ketoconazole

Rifampin

1A2 Theophylline, caffeine

Fluvoxamine Cigarette smoke

2C9 Warfarin Fluconazole, amiodarone

Rifampin

2C19 Omeprazole, esomeprazole, lansoprazole

Omeprazole, fluvoxamine, moclobemide

Rifampin

2D6 Desipramine, dextromethorphan,atomoxetine

Paroxetine, quinidine, fluoxetine

None identified

3A4/3A5 Midazolam, simvastatin, sildenafil

Ketoconazole, ritonavir, itraconazole

Rifampin, carbamazepine

Regulatory


randomised versus fixed-sequence design, adequate dosing regimen, and dose level, etc. Ultimately, the chosen design should maximise the potential for an interaction, without compromising safety, as most DDI studies are conducted in healthy volunteers.

In general, multiple-dose administration of the perpetrator (or inhibitor/inducer) is often preferred to ensure that the maximal potential interacting effect is being attained. This is especially justified when the drug candidate is expected to be a weak enzyme inhibitor or inducer. On the other hand, the victim (or substrate) can be administered as a single dose, as this would allow a proper assessment of the potential effect of the perpetrator on the PK of the victim drug. DDI studies should ideally be conducted using a randomised crossover design (e.g., subjects randomised to one of these two sequences: “A followed by A+B”, or “A+B followed by A”). In a crossover design, the washout period of the previous treatment should be sufficient to 1) allow complete elimination of the drugs before the beginning of the next period, and 2) allow enzymatic activity to return to normal after administration of an inhibitor or inducer. Figure 1a displays an example of crossover design where a perpetrator is administered under multiple-dose conditions and the victim is administered as a single-dose. When PD parameters are also evaluated, or when the new drug candidate is intended to be chronically administered, it may be preferable to administer multiple doses of both compounds to mimic clinical conditions as much as possible and maximise the PK and/or PD interaction, if any. Figure 1b provides an example of a DDI study where both the perpetrator and the victim are administered under multiple-dose conditions.

Under certain circumstances, it may be more appropriate to use a fixed sequence crossover design rather than a randomised design. This may be an interesting approach when the perpetrator has a very long half-life and/or must be administered for a prolonged period of time. Moreover, induction or inhibition of a metabolising enzyme may take a few weeks to return to normal activity, which would involve a long washout period between treatments. When the randomised study design involves a risk for carry-over effects to the next study period, a fixed-sequence design may be used. (See Figure 1a, Sequence 1.)

During drug development, it may be necessary to rule out any potential interaction between the drug candidate and another compound, even when neither compound is identified as an inhibitor or inducer. This is especially applicable when the new drug candidate is meant or likely to be administered with a concomitant treatment (e.g. HIV drugs, anti-cancer drugs). This approach is also routinely used during the development of a new fixed-combination product of two separate known entities. In such situations, a three-arm, single-dose, randomised, crossover study approach is often used. In these types of studies, the PK profile of both drugs under evaluation is characterised.The single-dose design is generally used when data from literature indicates that no interactions between the two drugs are expected. However, if such evidence is not available, it may be important to maximise the interacting effect by administering multiple doses of one or both compounds. One possible approach is to use a two-arm, mixed single/multiple-dose design, as shown in Figure 2.

Parent Versus Metabolite Data?When designing DDI studies, one must consider the PK and PD of both the parent and metabolite(s). In fact, if one or more metabolites have an interacting potential, it becomes necessary to evaluate the metabolites to the same extent as the parent compound, and to consider the half-life of the metabolite(s) for determination of the optimal washout period.

Cocktail ApproachThe cocktail approach consists in administering a mixture of CYP substrates in a single study to rapidly screen for the contribution of different CYP enzymes in the metabolic pathway of the drug under development. This may be of interest when in

Figure 1a: Example of a two-way crossover DDI study where subjects arerandomised to either sequence 1 or sequence 2. In this study, the effect of multiple administrations of a drug (perpetrator) on the single-dose PK of another drug (victim) is evaluated. SD, single-dose; MD, multiple-dose.

Figure 1b: Example of a two-way, multiple-dose, crossover DDI study where subjects are randomised to either sequence 1 or sequence 2. In this study, the effect of multiple administrations of a drug (perpetrator) on the multiple-dose PK of another drug (victim) is evaluated. SD, single-dose; MD, multiple-dose.

Figure 2: Example of a fixed-sequence crossover DDI study where the effect of multiple administrations of drug B on the single-dose PK of drug A is evaluated in Cohort A, while the effect of drug A on drug B would be evaluated for Cohort B. SD, single-dose; MD, multiple-dose.

vitro data is inconclusive or difficult to interpret. As pointed out in the FDA guidance, the various substrates should be specific for individual CYP enzymes, and there should be no known interactions among substrates.Negative results from a cocktail study may preclude further interaction studies, whereas positive results may dictate the need for further investigations on the interacting CYP enzyme1. Various cocktail strategies have been evaluated (from two- to six-drug cocktails), with a variety of substrate probe combinations4. The Pittsburgh’s cocktail, which consists of the following CYP substrates: caffeine (CYP1A2), flurbiprofen (CYP2C9), mephenytoin (CYP2C19), debrisoquine/dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and dapsone (CYP3A), is one example.

Sample Size and Statistical ConsiderationsAs the primary objective of DDI studies is to determine if there is an impact on the PK of a drug, a bioequivalence approach is often used. This approach requires 90% confidence intervals (CIs) for the ratios of AUC and Cmaxlie within 80% and 125% when comparing these PK parameters in the absence and presence of the interacting drug. However, a wider acceptance criterion could be justified (e.g., 70-143%), especially for the Cmax parameter, with proper PK/PD justification. If 90% CIs of the ratio of the PK parameters (Cmax, AUC) fall within the equivalence boundary, one can conclude that there is no clinically significant drug-drug interaction. The number of subjects (i.e., sample size) required will be dictated by the within-subject variability of the studied PK parameters (for cross-over trials) of the parent drug and its metabolites, when appropriate, the desired statistical power (usually 80%), and the acceptance criterion for the 90% CI limits. On the other hand, if an interaction is very highly suspected based on previous in vitro data, the study may not need to be powered to meet any specific acceptance criteria, and sample size should then include the minimum number of subjects that would be deemed acceptable to draw conclusions based on descriptive statistics (e.g., 24 subjects).

When to Conduct DDI Studies during Drug Development For obvious economic reasons, DDI studies are often conducted at later stages of the clinical development (e.g., during Phase III testing) once there is more evidence of a promising drug candidate. Appropriate in vitro metabolic studies should ideally be available before Phase II clinical studies3. A good knowledge of the metabolic pathways for a new chemical entity can be useful in Phase I clinical studies, where it may explain discordant PK observations, non-linear increases of plasma concentrations with increasing doses, unexpected PD effects, or an adverse events profile. There may be instances where DDI clinical studies should be performed early in the drug development programme and may be considered as a “go/no-go” milestone. It may be important to rule out a potential interaction that may represent a safety hazard in Phase II/III, and which may preclude further clinical development. It may also be required to perform DDI studies when the drug candidate will be administered in Phase II with a specific compound that may share a common metabolic pathway. Interactions identified early in the development programme may provide guidance for dose and population

selection for Phase II and III clinical studies, and possible dose adjustments for poor metabolisers or patients using concomitant therapy. Population PK assessment during clinical Phase III studies can subsequently provide opportunities to identify unexpected drug-drug interactions.

References1. Guidance for Industry: Drug Interactions Studies –

Study Design, Data Analysis, and implications for Dosing and Labeling (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072101.pdf)

2. Note for Guidance on the Investigation of Drug Interactions. EMEA, Committee for Proprietary Medicinal Products (CPMP), Dec 1997 http://www.emea.europa.eu/pdfs/human/ewp/056095en.pdf)

3. Drug-Drug Interactions: Studies In Vitro and In Vivo. Therapeutic Products Programme Guidance Document. Sept 21, 2000 (www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/drug_medi_int-eng.pdf)

4. Zhou et al. “Cocktail” Approaches and Strategies in Drug Development: Valuable Tool or Flawed Science? J Clin Pharmacol 2004;44:120-134

Dr Mario Tanguay, Vice President of Scientific and Regulatory Affairs, PharmaNet/i3, has more than 16 years of experience in the drug development industry, including 11 years with major contract research organisations, and five years at Wyeth-Ayerst Research and Pharmacia in the clinical research sector. Throughout his career, Dr Tanguay has served as co-investigator or clinical pharmacologist in over a thousand pharmacokinetic and Phase I trials, including bioavailability and bioequivalence, drug-drug interactions and first-in-human studies. Dr Tanguay holds a Bachelor’s Degree in Pharmacy and obtained an M.Sc. and a Ph.D. in Pharmacology from the University of Montreal. In addition to his current position at PharmaNet/i3, Dr Tanguay is a guest professor at the Faculty of Pharmacy of University of Montreal, being involved in their postgraduate programme on drug development. He has also worked as a community pharmacist for many years. Dr Tanguay has authored or co-authored over 50 articles and abstracts and has made numerous presentations at the national and international levels. Email: [email protected]

Jean-Francois Gagné, Manager of Clinical Research Scientists, Scientific and Regulatory Affairs, PharmaNet/i3,has nine years of experience in contract research organisations. He has provided guidance and participated in the elaboration of study protocols for hundreds of bioavailability and bioequivalence trials, drug-drug interactions, and first-in-human studies. He is also involved in the discussion of ethical issues related to the conduct of clinical trials. Mr Gagné holds an M.Sc. in Microbiology-Immunology from the Faculty of Medicine of Laval University. He is a lecturer for the Faculty of Nursing Sciences at the University of Quebec in Rimouski, and is a guest lecturer for the Laval University’s Pharmaceutical Product Development programme.

Regulatory


Regulatory


The Impending Sunshine Act: A Review for Clinical Trial Sponsors

The Sunshine provision of the Patient Protection and Affordable Care Act (PPACA) is one of the most highly anticipated changes in the clinical trial environment in recent years, requiring covered drug and device manufacturers to disclose all payments to physicians. As will be seen later in this article, while some pharmaceutical, biotechnology and medical device companies are spending tremendous resources to comply with this legislation, many are unaware of the scope and details of the impending legislation. In the face of technology challenges, legal interpretation hurdles and a general lack of consistent payment processes, most sponsors appear uninformed and unprepared for this business challenge.

Over the past decade, many state legislatures enacted reporting rules for physician payments and gifts. The existing state and federal laws are a public outcry to the status quo where, in 2008, $30 billion was spent on marketing activities alone, most of which were directed to physicians. A precipitating event was the outcry that arose when it became widely known that physicians were paid to enrol patients in seeding trials for Vioxx. While seeding trials are not illegal, their primary purpose of incenting a specific therapy or regimen for prescription by physicians does not sit well with the public. The Sunshine Act is meant to provide visibility for everyone, including patients — across all marketing, sales, consulting, education and research relationships — to identify the level of payments made by life science companies to physicians and teaching hospitals.

The Sunshine Act mandates the disclosure of payments made to all covered recipients by manufacturers of drugs, biologics, supplies and medical devices. A covered recipient is defined as a doctor of medicine or osteopathy, dentist, podiatrist, optometrist, chiropractor and teaching hospitals. The specific categories that require reporting include, but are not limited to: GiftsEntertainmentFoodTravel or trip expensesHonorariaResearchEducationCharitable contributionsConsulting feesCompensation for services other than consultingOwnership or investment interestRoyalties, licence fees Direct compensation for serving as faculty or speaker for medical educationand any other categories the Secretary of Health and Human Services deems appropriate

Failure to comply with reporting requirements results in financial penalty. Annual penalties are up to $10,000 for each payment not reported, not to exceed $150,000 annually. Any company that knowingly fails to report payments will be subject to more significant fines of up to $100,000 per offence, with an annual maximum of $1,000,000. The negative public view of companies withholding payment information would be potentially far more damaging than the financial penalties themselves.

The definition may seem clear, but the interpretation is proving to be hazy for most companies. At a webinar held by Medidata Solutions and the consulting firm of Deloitte in August 2011, a poll was conducted with attendees from life science companies. It produced startling evidence of the clinical research industry’s unawareness of this impending change in business practices.

In one question that gets to a very key issue for sponsors, sponsor participants were asked, “How is your company planning to report on clinical investigators for Sunshine?” A significant majority of 65% responded that they do not know how their company plans to report the payments to physicians. Some companies have plans defined, but they are not consistent across all parts of the company. Figure 1 illustrates the wide range of responses.

While sponsors will not have to transfer data to the Department of Health and Human Services (HHS) until March 31, 2013, the data collection to complete the report must begin January 1, 2012. Some companies have already started voluntarily reporting payments; others have begun reporting as the result of settlements with the federal government. The focus right now should be on: working with counsel to determine the level of detail reporting will include (e.g., PI, sub-PI, etc.); aggregating payment data across the organization; and improving payment decision processes to reduce the risk of unjustifiable payments.

Many Sunshine Act reporting categories include payments

Figure 1: How is your company planning to report on clinical investigators for Sunshine?

Regulatory


that are commonly made directly to physicians. The Sunshine Act clearly states that payments to physicians for clinical research must be included in reporting, but these payments add a unique layer of uncertainty that has not been clearly addressed to date. Many clinical research payments bundle physician reimbursements with pass-through costs such as lab and radiology costs. Most clinical research payments though are made through the physician’s employing institution; in the case of private practice physicians this is often a corporation. Further creating uncertainty, the rules have not yet been clearly defined to state whether payments should be disclosed for the physician acting as the principal investigator (PI) only, the PI and sub-investigator(s), and/or the institution itself. Some have even questioned equipment loaned to a site for study conduct; if not carefully managed to ensure that the property is returned to the sponsor, the equipment could be considered a “transfer of value” that would need to be reported. Clearly, sponsors must seek out expert counsel in interpreting and understanding how to comply with the law.

Some sponsors are investing in tying together disparate payment sources to aggregate the payment information required for reporting. The payment sources are found across the pharmaceutical and medical device landscape, including sales, marketing, medical affairs, continuing medical education and clinical research. With some sponsors these efforts began years ago, and they are still refining their alignment of payment-reporting processes with best practices. Some firms offer aggregate spend reporting solutions and can be a good resource. Within clinical research, a clinical trial management system (CTMS) with an integrated payment system is a best practice. Where these can generate automatic payments reports, much of the work of aggregating and assimilating the correct information is done. Without the right tools in place, getting to an automated report can be a complex and costly process.

This significant investment of time, money and human capital to meet the required changes creates an opportunity for sponsors to evaluate and improve upon all financial relationships with physicians. Commonly sponsors find that each internal department has very different methodologies for creating and negotiating financial relationships. Fair market value analysis is the best practice approach. Any work performed should be reasonable and necessary, and reimbursement should be based on the value of the work performed by a qualified individual. Figure 2 shows that

many companies do have processes in place that address fair market value determination.

Since payments to physicians comprise a significant portion of clinical trial costs, commercial databases of objective, third-party negotiated cost data are utilised by many sponsors to determine fair market value payments. Many sponsor companies also define payment rules for consulting activities, which may include service on advisory boards, protocol review and other work. Reimbursement should consider the value of the work and the qualifications of the individual. Evaluating each process against industry best practices is crucial. Even consistent methods only guarantee consistent results, and not necessarily correct or appropriate results.

Case Study: Consistency Creates Consistency, not AccuracyOne case study highlights the risk of assuming a consistent process is all that is needed. A large sponsor felt they had a reliable process in place whereby all initial offers for clinical trial payments began at Medicare reimbursement rates. The sponsor’s philosophy followed that since they were starting their negotiations at such typically low reimbursement rates they would never end up overpaying for services. As a result, negotiations were quite burdensome on sponsor employees since most physicians requested changes to the initial budget offer. The company’s compliance officer felt this resource expenditure was their trade-off for reducing the risk of inappropriate overpayment. The sponsor’s final physician reimbursements were compared against Medidata Grants Manager® Planning budgets for the same two studies, accessing Medidata’s proprietary PICAS® database of negotiated clinical trial investigator costs. The database is an aggregation of actual payments made in clinical trials collected from industry sources, creating an unbiased basis for measuring fair market value.

In the first study (see Figure 3) the sponsor’s negotiated cost per subject was significantly lower than even the 25th

Figure 2: Is there a process in place that is used to make sure all clinical trial services go through a fair market value (FMV) process?

Figure 3: Showing comparisons of sponsor’s payments vs. industry benchmark costs

percentile benchmark, leaving the company to question whether they were fairly compensating the research sites for their work. In the second study their negotiated cost per subject far outreached even the 75th percentile benchmark. Their compliance officer was startled. The sponsor’s standardised methodology created false security. Access to a third-party database of negotiated investigator costs informs reasonable initial offers and ongoing negotiations, ultimately saving sponsors both time and money.

Moving into the SunlightEmbracing the business change brought on by the Sunshine Act creates an opportunity for sponsors to improve their disparate and inconsistent payment processes across the organization. While plans and action must begin now, sponsors should avoid rushing to an unsatisfactory solution. As emphasised above, now is the opportunity to invest in processes that comprehensively and correctly deliver the compliance needed. Sponsors should apply their resources to reevaluate their processes and synthesise new ones worthy of the sunlight.

Jessica Dolfi, M.S. brings nearly a decade of experience working with dozens of global life science companies to increase efficiency and control costs for running clinical trials. At Medidata, she manages several client accounts. Jessica is responsible for

supporting and consulting with clients in the trial planning stages, particularly in dealing with benchmarking and pricing for investigative sites and contract research organizations (CROs). Email: [email protected]

Sondra Pepe is an experienced product manager and consultant to sponsors, helping with all aspects of their financial planning for clinical trials. She has worked with Medidata Grants Manager for over eight years and has assisted hundreds of clients in

improving the financial aspects and conduct of their domestic and international clinical trials. Sondra has also presented on the aspects of clinical trials at numerous industry conferences, focusing on investigative site needs and behaviors. Email: [email protected]

Market Report


Clinical Trials Market in ukraine (Part 2)The history of clinical trials in Ukraine officially dates back to 1996, when the first regulatory permission to carry out multi-centre international clinical trials was granted1. In 1996, a department for clinical trials affairs was established at the State Pharmacological Center of Ukraine2. Since then, there has been a trend of constant growth in the quantity of international multi-centre CTs. Growth was slow in the period from 1998 to 2002, when 20 to 55 multinational CTs were conducted in Ukraine a year, whereas since 2003, we have been experiencing a resurgence in growth – with 63 CTs held in 2006, 187 CTs in 20074 and 466 CTs in 20085 (Fig. 3). There has been a decrease

in the growth in the quantity of CTs in Ukraine as a result of the financial crisis, but the trend has not been completely halted. In 2008, Ukraine was mentioned as one of the countries most involved in clinical trials, with 150 approved IND trials. The majority of CTs in Ukraine are Phase III trials (66% of all CTs in Ukraine in 2006), with a smaller share of Phase II trials (30%) and Phase I and IV trials being in the minority (1% and 3% respectively)4. The majority of CTs in Ukraine are conducted in oncology – 23.87% (every fourth to fifth trial), followed by 20% in the cardiovascular field, with endocrine, nutritional, and metabolic diseases in third place (10.32%); and mental and behavioural disorders in fourth place (9.03%)5. The number of approved clinical bases in Ukraine, where CTs can be performed, has been growing steadily year-on-year, with a slight decrease in the rate of growth in recent years: for instance, there were 175 bases for CTs in Ukraine in 2001 compared to 1277 in 2007, 1300 in 2008 and 1308 in 20091,4 (Fig. 4). The majority of approved bases for CTs are located in the main cities of Ukraine with the highest population figures: Kiev (3.5 mln inhabitants), Kharkov (1.5 mln), Dnepropetrovsk (1 mln), Odessa (1 mln), Donetsk (<1 mln).

The performance of clinical studies in any country is based on three main criteria of feasibility: regulatory requirements, logistics and clinical feasibility8. The legislative and regulatory base for CTs in Ukraine is as follows: Ukrainian Law No. 783-XIV “On medicines” (1996), Orders of the Ministry of Health Nos. 281 and 347 (2000), No. 355 (2002), No. 66 (2006), No. 245 (2007), No. 43 (2007), and No. 690 (2009), as well as the Order of the Cabinet of Ministers of Ukraine No. 1419 (2004). In particular, Order No. 245 determines the “specialized medical and preventive treatment facilities in which clinical trials of

medicines can be carried out”; Nos. 43 and 1419 determine that, starting from 2009, clinical trials and the application of medicines should be carried out in accordance with standards of GCP for the sector1,2.

The State Pharmacological Center (SPC) of the Ministry of Health of Ukraine (pharma-center.kiev.ua) governs clinical trials in the country. To initiate a clinical trial in Ukraine, the sponsor company must submit a set of documents to the SPC and the Central Ethics Committee (CEC) of the Ukrainian Ministry of Health6. The documents to be submitted to the CEC are stipulated in Order No. 66 (2006). The documents can be submitted in parallel, and, if the documents have been previously submitted to the State Pharmacological Committee and it has already made its decision, the copy of the SPC’s decision should be submitted to the CEC. There are local ethics committees in many hospitals / institutions, but it is usually the Central Committee that grants approval for international multi-centre trials3. Table 1 (JCS Vol.3 Issue 5 P.54) provides a list of the basic documents to be submitted to the SPC and CEC for the initiation of CTs in Ukraine. The terms of approval for documents depend on each specific case, as further information may be required by either of the organizations. The approximate time necessary for approval is generally three to four months.

It is also important to be aware of the feasibility of logistics, such as possibilities, processes and timelines for organising import/export; customs procedures; the storage and distribution of clinical trial materials within a given country; and the local purchasing of clinical trial materials8. There are offices of international courier companies which provide a full set of services, including ambient and frozen sample shipments and temperature-controlled shipments of investigational products. A brief overview of the major logistics companies present in Ukraine and involved in the clinical trials market is provided below.

The Ukrainian office of TNT has a special department for clinical trials services and has been working in the CT market for over five years. It delivers biological samples to anywhere in Ukrainian territory, as well as to European central laboratories, and provides complete consultations for customs documents (tnt.ua). They also perform the express delivery of biosamples for the main clinics and laboratories in Ukraine. At present, TNT is involved in more than 230 CT projects.

Figure 3: Number of international multi-centre clinical trials in Ukraine, 1998-2009. Sources: State Pharmacological Center of Ukraine,5.

Figure 4: Overall number of approved clinical bases in Ukraine, 2001-2009. Source: SPC

Market Report


DHL Express started its operations in Ukraine in 1991 and currently has a network of 32 depots, serving more than 140 Ukrainian cities. The company provides its customers with a full range of worldwide medical express services, as well as all the necessary information and recommendations for the preparation of export customs documents and different packaging solutions for the safe and urgent delivery of time-sensitive clinical trials shipments. Certified packaging offers security, reliability and compliance with International Air Transport Association (IATA) regulations (dhl.com.ua).

However, it should be taken into consideration that even the best courier companies still have to go through customs procedures. In Ukraine, special permission from the regulatory authorities is necessary for any study-related import/export activity. Customs procedures, for both import and export, can take up to several days, and this should be taken into account when planning timeframes for drug or biological sample shipments3. Alternatively, the testing of samples can be organised in Ukraine, which makes it possible to automatically avoid all the customs procedures and costs, as well as the need for recourse to an international logistics service.

Storage and distribution of investigational medical products (IMP) and clinical trial materials, as well as the local purchasing of comparators, concomitant medications and materials, should also be closely considered before embarking upon a study in Ukraine. One option here is to hire an experienced CRO, which has a dedicated logistics department and its own pharmaceutical storage facilities, to be fully responsible for the study logistics service.

PSI is one such CRO that provides complete logistical support for clinical trials, including obtaining an import/export license, customs clearance, the local purchasing of medicines and materials, storage, distribution and the tracking of study drugs and materials; as well as the destruction of drugs and materials used in the study once the study is complete.

The availability of licensed storage facilities with variability of storage conditions, including the storage of deep-frozen samples at -70°C, allows PSI to keep the cost of shipment of biosamples to central laboratories down, as samples can be stored in Ukraine for the duration of the study and sent to the central laboratory in batches at the end of study or on an on-demand basis. There are also logistics companies in Ukraine whose main business is the storage and distribution of clinical trial materials. One such company is IMP Logistics, which operates in Russia, Ukraine and Belarus.

The clinical feasibility of a country can be measured according to two main parameters: the healthcare system, including local standards of medical care, and the performance of instrumental diagnostics and laboratory analyses. We have already looked at the first consideration above. However, it is worth mentioning that local standards of treatment should be clarified before the study starts, in order to avoid discrepancies between the study protocol requirements, accepted local practices and laws. For example, if a clinical trial protocol requires patients on cytotoxic chemotherapy and agranulocytosis not to be treated with antibacterial drugs until the development of infection or high-body temperature, the requirement may not be feasible in Ukraine, as local treatment guidelines recommend the prescription of prophylactic antibacterial therapy in cases of agranulocytosis.

Another example concerns previous treatment options given to patients. If not clearly described in the study protocol, the eligibility criteria for authorised previous lines of treatment described as standard without any additional specification may lead to a lack of homogeneity in the patient population entered for the trial. Besides, standard therapy as understood, for example, in the United States and in Ukraine may consist of different treatments and diagnostic approaches, and employ different groups of medicines.

The laboratories in most state hospitals (and such hospitals account for the majority in Ukraine) are already outdated and cannot always provide an appropriate level of elementary analyses. Moreover, they may not have been granted the necessary licenses. Although, over the past few years, many large hospitals in Ukraine have started to receive and install modern diagnostics equipment, there is still a shortage of diagnostics services. Diagnostics standards often differ significantly from what is accepted in Western European countries and the USA. For example, the current staging diagnostic protocol for NSCLC must include PET/CT in accordance with recent NCCN guidelines accepted in the US, whereas the only PET/CT scanner in Ukraine has just recently been installed in the country’s capital23. So, the only option is to go through the private laboratories which have opened over the last ten years in Ukraine. But such laboratories differ in terms of the list of performed analyses, equipment, location and own courier systems. For example, for a certain study, one such laboratory may have the necessary technical support to provide all the analyses except one or two. So the sponsor will be forced either to perform the remaining analyses in another laboratory (which means other equipment used, leading to a possible inconsistency in results, or another location, so additional logistical support required, etc.), or to ship the samples abroad (again additional logistical support required). In any case, it is inconvenient and does not make logical sense to divide analyses between laboratories for a whole host of obvious reasons – at the very least, the quality of the work performed will decrease. To have consistent laboratory data, the only possible solution is to use one laboratory for all study sites. Such a central Ukrainian lab may be a good option for clinical trials with many sites3. This lab has to be big enough, meaning that it must have the different departments (biochemistry, microbiology, etc.) necessary to offer the full range of clinical analyses that can be performed by modern medicine, provide well-organised logistical support, be compliant with international requirements (every multi-centre international clinical study is subject to audits) and have the necessary and valid certificates and licenses. Such laboratories do exist in Ukraine, and, at present, there are at least three companies in Ukraine which offer central lab services7. Clinical trials departments have been opened by each of these three private medical laboratories. Given that they perform analyses within Ukraine, it would perhaps be more appropriate to describe them as regional labs. The longest standing player on the clinical trials market – with 10 years’ experience – is the CT department of the first private Ukrainian medical laboratory, “Dila” (dila.com.ua). They were pioneers in the field in Ukraine and are considered to be the most experienced. For a few years, they had a monopoly on regional labs for the Ukrainian CT market. In 2006, the private clinic “Eurolab” also

Market Report


opened its own CT department (clinic.eurolab.ua). “Eurolab” is one of a small number of private clinics in Ukraine (private medicine is still not very highly-developed in Ukraine, as mentioned above), which offers a comprehensive range of medical services and stationary treatment, as well as having its own laboratory, which it uses as a basis to provide analyses for CT. Both laboratories – “Dila” and “Eurolab” – are located in Kiev. In 2008, a CT department was also opened by “Synevo”, a European private laboratory which has a network of laboratories throughout Europe, including in Ukraine. “Synevo” has the least amount of experience in CTs in Ukraine, but has 15 years’ experience in the European CT market, meaning that “Synevo” has the direct opportunity to apply its experience gained in Europe to the Ukrainian market. The entire network of “Synevo” CT departments operates under the name “Synevo Central Lab” and has representatives in Poland, Romania, Germany, Turkey and Belarus. In addition to a lab in Kiev, they also have a network of laboratories in Ukraine itself – located in five cities throughout the country, with the biggest lab being that in the capital. All three companies provide a full range of services such as data management, project management, logistics, laboratory service and QA.

Who is Already Active in ukraineThe best way to obtain direct information about the feasibility of clinical trials in Ukraine is to contact an experienced CRO which has dedicated feasibility study departments that collect, analyse and maintain information about local standards of medical care and hospital equipment. There are about 35 to 40 contract research organizations, active both globally and locally, with the capacity to provide potential clients with guidance on the CT market in Ukraine, such as PSI, Parexel, Quintiles, ClinStar, Evidence, SPRI, Chiltern, PharmaNet1,22. About 73-75% of clinical trials in Ukraine are managed through CROs 1,4. By way of comparison, in 2006, in Russia about 57% of all multinational international CTs were initiated by CROs, with others being initiated by the sponsor’s R&D department14. The work done by CROs is provided by high-level professionals, with many employees having a background in medical or pharmaceutical education. In addition, CROs provide internal GCP training courses9,10. In total, based on different sources, there are said to be about 30 to 140 CT sponsors with a presence in Ukraine, including GlaxoSmithKline, Pfizer, Boehringer Ingelheim Pharmaceuticals, Hoffmann-La Roche, Bayer, Nycomed and AstraZeneca5,22. Relationships between the main companies involved in the CT process are similar to those in other countries. Prior to the study, the sponsor or CRO (on the one hand) and the investigator and/or clinical base (on the other hand) sign the agreement. The content and form of the agreement are defined according to the Ukraine legislative base and the specific nature of the study. Third parties, such as insurance companies, site management organizations and central laboratories, can also be involved, if necessary (in which case additional agreements are signed)9.

Evaluation of the Potential of the ukrainian Clinical Trials Market: Mutual BenefitsAccording to statistical data, in 2006, there were 250 CTs approved in Bulgaria (for a population of 9 mln), 500 CTs in Poland (39 mln), 300 in the Baltic countries (7.2 mln) and 142

to 158 (according to different sources) in Ukraine (46 mln) 12,4. Now, according to different data, in Ukraine, the level of involvement of the Ukrainian population in clinical trials varies from 0.8 to 5.3% of the maximum registered in Europe, which is one of the lowest rates there is1. This means there is huge room for growth. American specialists, who participated in the 1st American-Ukrainian workshop of CT professionals in 2007, evaluated Ukraine to be a country of major interest in the field of CT9. Moreover, Ukraine is itself interested in the development of the clinical trials market. Clinical trials will provide an additional source of non-governmental income for the clinical bases; CTs also act as a form of “brain drain prevention mechanism”, giving physicians the opportunity to develop their specialist expertise whilst ensuring their services are retained; and, in general, they help to bring about an improvement in the standards of the healthcare system2,5.

Since 2006, the potential and evaluation of the Ukrainian CT market have been the subject of discussions as part an international conference on “Clinical trials of medicinal agents in Ukraine”, which is held in Kiev every two years. The third conference was organised from November 4-5, 2010. The event brought together CT specialists from different countries, with discussions touching on subjects such as the Ukrainian legislative base for the CT market, ethical questions in CT, studies of different group drugs, etc.. The conference is also an opportunity for the exchange of experience and up-to-date information in the field of clinical trials. The event is coordinated by the State Pharmacological Committee11,4,17.

The superior quality of clinical trial data produced in Ukraine has been confirmed by multiple audits and inspections. The reported advantages include, but are not limited to, strict compliance with the study protocol, with a low level of deviations from protocol and low patient drop-out rates; a low cost per completed case report form due to fewer days needed to recruit one patient, quality of recordings, as well as a low percentage of rejected recordings and a low number of queries per 100 CRF pages.

ConclusionsThe advantages and disadvantages of Ukraine on the CT market are summarised in Table 2. (JCS Vol.3 Issue 5 P.54) The advantages are obviously more prevalent, though, at the same time, the potential client has to be prepared for possible difficulties and be ready to take them into consideration. However, the key consideration here is the potential which is yet to be realised and the fact that, in the event of rational investment, the market has the potential to explode at any time. Ukraine is not a country where the CT market has to be built up from scratch; the foundations have already been laid. Everything that is necessary is already in place – clinical bases, investigators, patients in the necessary quantities and of the necessary quality, CROs, central labs, an approved legislative base, and, of course, lower costs. The next step is down to the investors.

Acknowledgements The authors would like to express their special thanks to the Special Services Department of TNT Ukraine and the National Customer Manager of DHL Express in Ukraine for the information provided about their companies and services.


Market Report

References1. Gornostai M., Mikheiev O. Ukraine: Promising prospects. European

Pharmaceutical Contractor (EPC), June 2010: 22-25. www.samedanltd.com/magazine/11/issue/131/article/2675

2. Starenkaya I. Clinical trials in Ukraine: past, present, future. Health of Ukraine, 2007, No. 18: 16-18 (in Russian) http://health-ua.com/articles/2071.html

3. Rudneva O. Ukraine Emerges as a Viable Location for Global Studies. Applied Clinical Trials (online), 2007: May 1. www.appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/CRO/Sponsor+Articles/Ukraine-Emerges-as-a-Viable-Location-for-Global-St/ArticleStandard/Article/detail/424919

4. State Pharmacological Center, www.pharma-center.kiev.ua 5. Gomenyuk L., Gornostai M. New Economic Perspectives. European

Pharmaceutical Contractor (EPC), December 2009: 40-42. http://www.samedanltd.com/magazine/11/issue/123/article/2544

6. Ministry of Public Health of Ukraine, www.moz.gov.ua 7. Rudneva O. GCLP: Recommendations for medical laboratories.

Apteka, 20/07/2009; No. 699 (28): 15-16. (in Russian) http://www.apteka.ua/article/9070

8. Ravdel A., Timofeeva S. Factoring in Feasibility. International Clinical Trials (ICT), February 2010: 32-37. http://www.samedanltd.com/magazine/13/issue/126/article/2591

9. Bugaichenko L. Clinical trials: how to train the investigator, monitor, inspector. Apteka, 16.04.2007; No. 586 (15). (in Russian) http://www.apteka.ua/article/4757

10. Rudneva O. Collaboration on the Clinical Trials market. Participation of Eastern European countries and Ukraine. Apteka, 29.10.2007; No. 613 (42). (in Russian) http://www.apteka.ua/article/5606

11. Gordienko S.M. International conference “Clinical trials of medicinal agents in Ukraine”. Health of Ukraine, 2006, No. 23-24. (in Russian) http://health-ua.com/articles/1539.html

12. Getz K. Global Clinical Trials Activity in the Details. Applied Clinical Trials (online), 2007: September 1. www.appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=453243

13. Vlasova I. Experimental money. Gazeta, 10/2007 (in Russian). www.cbio.ru/modules/news/article.php?storyid=2996

14. Stefanov I., Tverdokhleb P. Russia grows its CRO market. Applied Clinical Trials (online), 2008: April 1. appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=506846&pageID=1&sk=&date=

15. Ravdel A. Russia has all the required infrastructure and resources to conduct high-quality, accurate clinical trials. Journal of Clinical Studies, January 2010: 24-26. http://www.synrg-pharm.com/article107.htm

16. Rudneva O. Clinical study insurance – A necessary condition for its conduct. Apteka, 15/01/2007, 573 (2) (in Russian). http://www.apteka.ua/article/4255

17. Valkov A., Demidenok E., Yudin V. Second theoretical and practical conference with international participation: “Clinical trials of medicinal agents in Ukraine” (part 2). Apteka, 24/11/2008, No 667 (46) (in Russian). http://www.apteka.ua/article/7430

18. State Statistics Committee of Ukraine, www.ukrstat.gov.ua 19. Ukrainian Cancer Registry http://users.iptelecom.net.ua/~ucr/,

www.ucr.gs.com.ua/dovida7/index.htm20. www.health.unian.net/news/print.php?id=18795321. The Economist, www.economist.com 22. Sorokoletova O. How to earn money on drugs tests in Ukraine.

Delo, 01/02/2010. (in Russian) http://delo.ua/biznes/rynki/kak-v-

ukraine-na-testirovanii-136747/ 23. Belotserkovsky M. Clinical Trials worldwide and in Eastern European

countries or the peculiarities of the national mythology about clinical trials in the countries of former Eastern bloc. Ukrainian Journal of Nephrology and Dialysis, 2010, No 3 (27) (in Russian)

24. www.who.int/substance_abuse/publications/global_alcohol_report/msbgsreur.pdf

Mariya Dimova, PhD, Project Manager of Synevo Central Lab Ukraine & Belarus. Dr Dimova graduated from Kyiv National University, specialisation - microbiology and general immunology, and holds her PhD in Zabolotny Institute of Microbiology and Virology, Ukraine. She worked as Invited

Researcher in Strasbourg University, France in frame of her scientific projects. Her career in clinical trials she started in one of Ukrainian CRO and, hereafter, joined Synevo Central Lab team in June, 2010. Email: [email protected]

Oleksii Gaydamak, MD Country Manager, Synevo Central Lab Ukraine & Belarus Oleksii Gaidamak is responsible for Synevo Central Lab’s operations in Ukraine and Belarus since 2009. Oleksii Gaidamak got his degree in General Practice from Bogomolets National Medical University in Kiev, Ukraine. Dr.

Gaidamak got also Specialist Degree in Economy from Department of Economy, Education and Research Institute of Business, National University of Life and Environmental Sciences of Ukraine in Kiev, and Associate Specialist Degree in Laboratory Diagnostics from Department of Laboratory Diagnostics, First Kiev Medical College in Kiev, Ukraine. Prior to his carrier in Synevo Central Lab, he worked for 2 years as a Regional Director at Synevo Medical Laboratories in Ukraine. Email: [email protected]

Maxim Belotserkovsky, MD, PhD, Dr.Med.Sci.- Head of Medical Affairs Division, PSI CRO AG. Board-certification in Anesthesiology, Intensive Care, Rheumatology, and Internal Medicine. Associate-professor of Clinical Pathology. After 10 years of clinical practice worked for Merck Research Laboratories. With

PSI since 2001. Email: [email protected]

Tomasz Anyszek, MD, PhD is director of Synevo Central Laband, and is responsible for clinical trials operations in more than forty Synevo laboratories in Central and Eastern Europe. Dr. Anyszek started his career with Virtual Central Laboratory (Zeist, Netherlands). His experience also includes the coordination of activities of

sixteen regional Covance partner laboratories in Europe. During this period he performed more than 200 audits in clinical laboratories. Dr. Anyszek holds his PhD from Jagiellonian University (Krakow, Poland). Prior to his business career, he taught clinical biochemistry and laboratory medicine at the Jagiellonian University medical faculty. Dr. Anyszek has authored more than 20 scientific publications and co-authored several books and monographies in the clinical chemistry and laboratory medicine area. Email: [email protected]

Market Report


Clinical research represents today a cross-national and cross-cultural reality and the shift to emerging countries in the location of clinical trials is well documented. During the 20th century, clinical trials were predominantly conducted in patients in North America and Western Europe, largely related to the proximity of sponsoring research and development staff, influential regulatory authorities and principal markets. Since 2000, however, the number of trials taking place in the emerging economies has seen a substantial increase and the importance of globalisation within the development process for innovative therapy is unquestioned. In February 2009, the New England Journal of Medicine1 reported that approximately one-third of clinical trials are being conducted wholly outside the United States, with a majority of study sites (13,521 of 24,206) across all trials and therapeutic areas also outside the United States.

The geographic redistribution of clinical research activities, from more developed to less developed countries has been influenced by the benefits of conducting trials where patient access is relatively unencumbered. Many emerging countries offer environments that are highly conducive to enhanced and predictable study metrics due to a vertically integrated healthcare system for patient referral and investigator acumen, which together greatly facilitate the globalisation of the research process.

In 2006 the attractiveness of emerging countries was analysed by a specific study conducted by A.T. Kearney, which developed the Country Attractiveness Index for Clinical Trials2. The Index highlighted the evolving clinical trials landscape. It ranks attractiveness by evaluating five key areas: patient availability, cost efficiency, relevant expertise, regulatory conditions and national infrastructure. China, India and Russia emerged as the most favourable destinations (see Figure 1).

In a recent overview of clinical trials submitted in EMA marketing authorisation applications (MAA) during the 2005-

2009 periods, the contribution from Russia was particularly notable. Russian centres participated in more than 100 pivotal clinical trials enrolling 17,066 patients (contribution of 2.9%) and was third for patient recruitment in a list of nineteen (19) countries, after the United States and Canada3 (see Figure 2).

While these figures show the shift of clinical research to emerging countries, the globalisation of clinical trials raises concerns that are in direct proportion to those elements which incentivise global clinical research. These concerns include ethical and regulatory considerations4,5 but also encompass both medical and operational considerations which are mandatory for successful trial conduct. A feasibility assessment in Russia evaluating myocardial perfusion through serial quantitative Single Photon Emission Computed Tomography (SPECT) imaging is illustrative.

A Case Study: The Feasibility of a Cardiovascular Trial in the Russian FederationEnabling technologies for advanced cardiac imaging, which are readily accessible in traditional environments for research, can create daunting challenges when requested in emerging countries. Evaluating the feasibility of advanced imaging studies through the prism of Western research capabilities therefore provides an interesting contrast between the attractiveness of patient access versus the limitations of technology in developing regions.

The assessment investigated the possibility of engaging sites from Russia and other countries for a study already ongoing in the US. The proposed study therefore represented an ongoing trial for which additional centres in countries were requested due to faltering study metrics --- a common impetus for incorporation of additional centres from emerging countries given the exceptional patient access which can occur.

The Impact of Regional healthcare Variation on globalized Clinical Research – Focus on the Russian Federation

Figure 1:

Figure 2: Clinical trials submitted in marketing authorisation applications to the EMA. Overview of patient recruitment. Third countries with at least 0.5% of patients in the pivotal trials included in the MAA submitted to the EMA during the 2005-2009 period- EMA/INS/GCP/154352/2010

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Specific hypotheses revolved around the effects of an investigational product for myocardial perfusion, assessed by serial quantitative exercise SPECT MPI imaging, in patients with chronic coronary artery disease (CAD). Eleven (11)investigators in Russia were contacted. Domains evaluated included access to patients with chronic angina, standard of care, access to Myocardial Perfusion Imaging (SPECT MPI), and staffing patterns and other structural elements in the investigation that might impact study execution. The centres were preselected from a list of investigators that had participated in previous interventional studies in cardiovascular indications, although not all had participated in a trial mandating specific cardiac imaging requirements.

Access to Patients and Technology Five centres, out of the 11 contacted in the Russian Federation, were contributory to the survey, and confirmed access to Myocardial Perfusion Imaging technology (SPECT MPI). Collectively, the number of patients with chronic angina managed at each site per year ranged from 100 to 20,000, with differences in access reflecting differences in patient catchment areas and referral (Figure 3).

For example, a site in Russia reporting 20,000 patients represented a high capacity, cardiology specialised regional dispensary, covering a large geographical area (2,500,000 inhabitants). This type of site is not unusual in the centralised Russian healthcare system. In fact, each region in the country has a specialised cardiology dispensary providing specialised medical care for the majority of patients with cardiovascular disease.

However, large medical institutions even if well-equipped for routine clinical care, may report poor facilities and limited organization for early stage clinical research, especially when advanced diagnostic equipment is required. This situation is illustrated by this assessment where only one cardiology regional dispensary reported capabilities while many other regional institutions, also queried in the assessment, declined due to lack of access to SPECT MPI.

Private centres also included in the sample were largely non-contributory. Although these centres increasingly participate in post-marketing trials, contributions in a cardiac imaging protocol were limited by restricted patient access and an inability to provide requisite scanning services.

Even though Russian sites responding to this survey routinely perform SPECT MPI, further investigation suggested that due to high cost and limited access, SPECT MPI would not be a standard triage procedure for risk evaluation in patients with stable angina prior to revascularisation (the primary objective of the trial). The observation illustrates a frequent observation in many emerging countries regarding technology and innovative therapy: “available but not necessarily accessible”. Specifically, in many Russian centres stress echocardiograms are more frequently employed, and the use of a SPECT MPI would represent a significant departure from standard of care, obviating the relative advantages associated with a large patient referral base.Additionally, the technology required for SPECT MPI may not be adequate for clinical research purposes in many centres. As an example, one otherwise fully qualified investigator from Russia commented: “I’d like to read the list of requirements to the SPECT instrument, because our machinery is of 1995 year of issue and I doubt whether it’s suitable for the study.” Thus, in spite of considerable patient access, and good medical acumen, protocol requirements for imaging were significantly outside standards of care and capabilities of the available technology did not meet study requirements. Specifications of the SPECT instrument and other diagnostic interventions must be carefully evaluated as part of the site selection process, including site experience with the requested technique and the availability of both instrumentation and nuclear medicine (NM) specialists.

Our findings are in line with data reported in a recent article on the “state of the art” of nuclear medicine in Russia6. In Russia, there are 110 nuclear medicine departments, but only a percentage of these (≈30%) have modern fully functional equipment. Significant challenges also include a lack of central system technical support, resulting in service delays and high maintenance costs.

Ethical and Regulatory ConsiderationsA major concern is the ethical oversight of research involving human subjects in countries where wide disparities in education, economic and social standing and healthcare systems may jeopardise the rights of research participants to objectively weigh potential benefits and risks7. The concept of vulnerable population has been studied and emphasised when considering clinical trials in emerging countries. Seven areas of capacity, juristic (legal standing), deferential, social, situational and medical vulnerabilities have been identified as needing to be properly understood and addressed8.

In our case study we specifically inquired about the ethical approach to the study design. Because of the requirement of 4 SPECT MPI scans for the study in a relatively short period of time, WCT inquired whether it was acceptable to perform four serial SPECT MPI scans in a 1-2 month period for the proposed study. While surveyed sites from two countries in Western Europe indicated that the radiation dose would have been considered too high for acceptance by the ethical authorities, none of the sites in Russia had any concern in this respect.

Within the Russian Federation, all investigational studies are vetted through a system of review which includes both national regulatory authority and local ethics committees.


Figure 3

Market Report


However, in our experience, if Investigators do not detect any ethical concerns in trial design, the Russian ethical authorities are unlikely to offer a contrary opinion, especially when the study is approved in countries under European or US legislation. Utilisation of referent countries where the ethics of a clinical trial has been extensively vetted provides a very useful calibration in multinational trials when the Russian Federation is involved.

In accordance with this, it’s worth mentioning the “New Medicines Law”, Federal Law No. 61-FZ “On the Circulation of Medicines” recently issued in the Russian Federation (effective September 1, 2010). The new law has created a new regulatory environment, which now mirrors that of European Union countries in terms of agreement with accredited healthcare institutions, insurance requirements and qualification of principal investigators. In addition to similar regulatory requirements, these regulations facilitate monitoring of the quality of clinical trial data by various oversight bodies, an activity which, if underperformed, accentuates ethical and scientific concern for studies conducted in emerging countries which may lack the research pedigree characteristic of other geographic regions. Monitoring conventions in our case study fell well within the umbrella of that permitted by the current international regulatory environment.

ImplicationsOur case study in the Russian Federation appears to confirm an unparalleled patient access, within established ethical and regulatory guidance for international clinical research, with investigators showing acceptable clinical acumen. However, participation is limited by the requirement of a sophisticated technology infrastructure.

ConclusionsWhile the inclusion of emerging countries in global clinical research offers the significant advantages discussed in the introduction of this article, our case study appears to confirm how each trial must be considered in all particular features before endorsing the involvement of emerging regions and countries. This includes the trial’s targeted disease and its standard treatment, accessible patient population, and technology requirement for a proper execution.

Also the generic term “Emerging Countries” should be abandoned for more specific country/region considerations. In this respect the Russian Federation shows a well defined environment for clinical research, with an health system organization which provides ideal vetting for large size studies, with a regulatory environment which has introduced practical efforts to align itself with the Western standard, and a significant interest by investigators in contributing to the global clinical research, in the context of a great medical tradition in a culturally advanced country. However, in clinical trials where advanced sophisticated medical technology is required, the study may be less likely to find an enthusiastic reception in many centres in the Russian Federation, as our case study appears to confirm.

References 1 Glickman, S.W., McHutchison, J.G. et al. Ethical and Scientific

Implications of the Globalization of Clinical Research NEJM, 2009; 360:816-823

2 www.atkearney.com/images/global/pdf/EA_vol_IX_no_1.pdf3 Clinical trials submitted in marketing authorisation applications

to the EMA. Overview of patient recruitment and the geographical location of investigator sites EMA/INS/GCP/154352/2010

4 The European Medicines Agency Working Group on Third Country Clinical Trials Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted in third countries and submitted in marketing authorisation applications to the EMA. EMA/712397/2009

5 Schipper, I. Clinical trials in developing countries: How to protect people against unethical Practices? European Parliament; Directorate-General For External Policies Of The Union, 2009; http://www.europarl.europa.eu/activities/committees/studies)

6 Solodki, V.A. & Fomin, D.K. Current trends in nuclear medicine in the Russian Federation and in the world. Vopr Onkol. 2009;55(4):413-5.

7 Shapiro, H.T., Meslin, E.M. et al. Ethical issues in the design and conduct of clinical trials in developing countries. N Engl J Med 2001; 345:139-142

8 Ashcroft, R.E., Chadwick, D.W., Clark, S.R.L., Edwards, R.H.T., Frith, L. & Hutton, J.L. Implication of socio-cultural contexts for the ethics of clinical trials. Health Technology Assessment 1997 1(9): 65.

Petr Denisov, M.D., Ph.D., is Associate Director, Feasibility, for Worldwide Clinical Trials. Dr Denisov recieved his M.D. from Saint-Petersburg Medical State University n.a. acad. I.P.Pavlov (St-Petersburg, Russia). He has a Ph.D. in Normal Physiology. Dr Denisov has been playing a key role as the Global Feasibility

coordinator since 2006. Email: [email protected]

Paola Antonini, M.D., Ph.D., is Senior Vice President, Medical and Scientific Affairs for Worldwide Clinical Trials. Dr Antonini received her M.D. from the University of Rome “La Sapienza”. She has a Ph.D. in Clinical Pharmacology. In more than 20 years of experience in Big Pharma Industry Dr Antonini

has played a key role in many successful programs of drug development, capitalising on her scientific leadership and on-the-job experience in the designing, implementation and interpretation of clinical trial. Email: [email protected]

Michael F. Murphy, M.D., Ph.D., is the Chief Medical and Scientific Officer for Worldwide Clinical Trials. He is boarded in psychiatry, with a doctorate in pharmacology and is Research & Development Editor for American Health & Drug Benefits™ a publication which focuses upon issues of cost, quality and

access in the transition of novel diagnostic methods and therapeutics from discovery to commercialisation. As a faculty member within the Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, he has been a lecturer for over a decade on clinical trial methodology. Email: [email protected]

Market Report


Central and Eastern Europe: The Most Consistent Emerging Region for Clinical DevelopmentThe emerging markets offer hope to an industry struggling with patent cliffs, price cuts and an uncertain economy. Countries such as Brazil, Russia, India and China (BRIC) often headline the emerging markets discussion, though regions worldwide can benefit pharmaceutical companies’ bottom lines. For many companies looking to expand their marketing operations into emerging markets, the first step is often clinical development. Running a clinical trial in an emerging market allows a company to begin networking with regulatory officials and key opinion leaders. It also introduces the company to the cultural differences associated with these new markets without the must-sell-now pressure that jumping right into marketing would generate.

Running trials in emerging markets — from the often-discussed BRIC countries with hundreds of millions of people down to countries with less than 10 million inhabitants — is not easy, and few companies would claim to have conquered every challenge. Questions of quality, regulations, culture and cost plague clinical development teams, and attempting to differentiate scores of possible clinical trial locations produces reams of data and leaves these teams unsure of the best strategic locations for their trials. Even so, all emerging markets offer distinct clinical opportunities for companies interested in expanding beyond their borders, especially in terms of patient access.

Central/Eastern Europe (CEE), located next door to Western Europe, benefits from this proximity. Investigators and other clinical staff learn from their Western counterparts. For example, country managers in Germany may oversee trials running in Poland and the Baltic states, though Russia may require separate oversight. In the past few years, many of these countries have joined, or started an application to become part of, the EU, thus standardising clinical regulations and operations. Close proximity to Western Europe has resulted in the region’s longer history of clinical trials, as companies would look to neighbouring countries to fill trial enrolment. Its geographic closeness has helped the region advance further than other emerging regions in other areas as well, such as clinical knowledge, trial infrastructure, regulatory environment and supply chain management. In effect, CEE is one of the easiest regions in which to conduct trials.

The following sections highlight a few of the opportunities for pharmaceutical companies running trials in Central and Eastern European countries.

Opportunity 1: Access to PatientsWhen patient access numbers drive clinical executives to the emerging markets, most immediately think of India and China, and perhaps Brazil. But other countries and regions provide many of the same patient access benefits without as many intellectual property concerns as in India and China or

regulatory delays as in China and Brazil. Within the CEE region, specifically, pharmaceutical companies gain access to over 400 million patients, a population greater than that of the United States or the Big 5 in Western Europe. While no single country in CEE boasts a population rivalling those of India or China, most companies opt to select several countries with similar cultural, economic and political profiles for a larger overall patient population.

An added benefit of CEE markets is the large Caucasian population, which translates well for majority groups in Western Europe and the United States. As more research proves the difference in disease presentation, diagnosis and treatment among various ethnic groups, a largely untouched Caucasian population adds data integrity. When companies combine results from CEE sites with results from sites in India, China, Southeast Asia, Latin America and Africa, they can feel confident that the trial represents the global population. Payers and physicians can segment the results to those that match their clientele, giving them a much more relevant picture of how each drug or device will perform.

Cutting Edge Information spoke with clinical executives about their history of recruiting patients in CEE markets, and they expressed specific qualitative reasons for their positive experiences:• Slow access to life-saving medicines. Most patients technically

own access to care, but levels of access vary by social standing and sheer availability. For example, Russian citizens belong to a state-run insurance programme, but patients often must cover co-pays and often wait months before they see their medications. Trials offer immediate access to treatments at no cost to the patient. Many investigators, therefore, compile databases of patients awaiting treatment from which to recruit.

• Trusted patient/physician relationships. As in many emerging markets, physicians own a certain reverence from the community in CEE countries. For the most part, patients trust their physicians more than any other member of society because of the interest their physicians show in their care. For example, most patients enrolled at sites in Poland receive their physicians’ home phone number to call for questions or concerns. As a result, most investigators simply need to tell their patients that a trial could be beneficial, and that is often enough to meet enrolment needs. Following enrolment, this patient-physician relationship aids in retention. Because patients trust their physicians, they are less likely to discontinue a trial for minor side-effects, inconvenience or disinterest.

Overall, interviewed clinical executives associate Central/Eastern Europe with easy patient access and high retention rates, scoring these factors an average 8.3 and 8.0 out of 10,

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respectively. Though edged out by Asia, which is known for incredible patient access and retention, CEE countries boast high scores, proving that companies see high levels of patient access even in countries with much smaller populations.

Opportunity 2: high Quality ScoresThe most prevalent myth of emerging markets comes from industry professionals who have never visited or worked within these countries. Too often, these executives assume that these nations must be ‘backward’ — otherwise they would have already developed. According to interviewees, clinical knowledge is not one of these undeveloped areas. In fact, in CEE countries, for instance, most investigators attend university and postgraduate studies in the European Union and return home to practise medicine. Others benefit from the EU’s close proximity and learn from professors visiting from some of the EU’s finest universities. In short, investigators in CEE countries own the same medical knowledge and expertise as their counterparts in developed markets, and they are ready to prove it.

As the region has become more popular for clinical trials, the clinical knowledge base has grown substantially. The local CRO industry, especially, has evolved from a few CROs working with a large multinational CRO to dozens of specialised CROs focused on one or more of the CEE countries. Interviews with large pharmaceutical company executives reveal that most companies prefer to contract out their research to these local CROs because the larger CROs just cannot compete on the same local-market scale.

The influx of local CROs has aided in the development of other trial positions, such as CRAs and site staff, in effect building the CEE clinical industry from the ground up. Multinational pharma’s establishment of local headquarters has bolstered Eastern Europe’s clinical knowledge. It should be noted that compared to Poland or many of the Balkan countries, Russia performs at a lower level in every quality consideration, according to interviews with executives working in these countries. But this finding simply underlines the potential the industry sees in Russia. Russia owns significant resources to be a highly respected clinical market, but it has not yet reached that ideal. For other CEE countries, interviewees correlated investigators’ enthusiasm and high data quality. Sponsors find highly intelligent and respected physicians for investigators. These investigators understand the value of quality and its impact on the clinical trial industry in the region. As such, investigators pay close attention to the data collected, ensuring error-free documents.

Opportunity 3: Favourable Time and Cost EstimatesOf all trial considerations, cost garners the most attention in strategic planning sessions; in fact, every other consideration in the end reflects on the bottom line. Known for their cost-saving properties, the Central/Eastern European countries offer hope for the trial balance sheets. For direct costs (such as investigator fees and site management costs), interviewees estimate savings of 11–25% compared to developed markets. The region’s close connection to Western Europe has limited some of the cost savings, as costs such as investigator fees have come more in line with those of developed markets.

But not all trial expenses stem from actual expenditures. Other indirect expenses, namely timelines, also contribute significantly to overall trial cost. If Company X can launch its brand even

one month before Company Y, it could mean hundreds of millions of dollars of revenue annually. In clinical development, reducing time matters because the earlier the brand completes development, the longer it owns market exclusivity before its patents expire.

Unlike many of the other emerging regions, CEE does not usually cause longer trial timelines. Only one survey respondent, an executive working in Russia, reported that trials lasted longer than in developed countries. A combination of fast patient recruitment, high patient retention, and fairly developed

infrastructure and regulatory systems aids in reducing timelines. As such, many companies report double-digit percentage time savings. With all costs considered, most surveyed respondents anticipate total savings for CEE comparable to savings for the other emerging regions.

key Recommendations for Running Trials in CEEWith these benefits in mind, companies want to jump right in and start enrolling patients, but this response can be hasty, at best. Before starting the clinical trial, a company must understand the trial’s specific profile of needs and ensure that Central and Eastern European countries will adequately meet these requirements. For example, a company proactively considering the emerging markets may decide that the lower costs associated with trials in India more than make up for the longer trial timelines because they have the time, but a company already in the midst of a trial may look more favourably on countries in the CEE region precisely for the shorter timelines. Companies that charge in without the proper inward analysis risk additional challenges in their clinical trials, and often lay the blame for these difficulties on the emerging market, not on their own failures. But even if a company has conducted sufficient internal research and matched its needs to countries within Central and Eastern Europe, it should still keep a few things in mind to make clinical trials run more smoothly.Partner with a CRO/Vendor with Local Expertise…

However much talent and expertise pharma companies own in-house, they find that the emerging markets — even the countries next door in Eastern Europe — still present challenges. Companies need someone with knowledge and experience working in each aspect of clinical development for each individual country utilised in their trials. This ‘someone’ can be a local expert hired as a full-time employee by a company or a CRO, or one of several other possibilities. The goal is to find a person (or several) who understands how clinical development works in his or her specific country. When the company succeeds, the advantages are invaluable:• Smooth regulatory filing process. Each country owns a

different regulatory process, and in general, regulatory submissions are not the most clear-cut tasks. Having someone familiar with the country’s regulatory guidelines and contacts within the regulatory body can significantly decrease the challenge of regulations.

• Better communication between site staff and the sponsor company. This point person acts as a liaison, providing a step between the sponsor and everyone else working in the trial. Typically, this liaison also acts as the eyes and ears of the sponsor, managing the processes in place. As an added benefit, the liaison may communicate challenges or concerns more quickly than the site staff, helping to eliminate unnecessary delays.

• Clear understanding of the local culture. Lack of knowledge impairs relationships, which are crucial to clinical development. As discussed above, companies often enter markets without a clear understanding of the personnel they will be working with, causing distrust between trial staff and the sponsor. They can avoid this problem by using — and trusting the word of — the local expertise.

• An ‘in’ with respected key opinion leaders. Clinical trials rely

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on networking, balancing contacts within regulatory systems, academic institutions, CROs and other clinical functions, and investigators. As emerging markets become more popular, companies must build on the relationships they have or lose out on key resources to competitor trials.The benefits associated with local expertise suggest that

companies without it operate at a disadvantage within emerging markets — where no company wants to fall behind. The hunt for local expertise should be conducted calmly and thoroughly, though, as discussed in the following finding.…But Vet All CROs/Vendors Before Signing Any Contracts

Not all vendors — multinational or local — own the knowledge they claim. For US and 5 EU companies looking to expand into emerging regions, lack of experience can result in scamming by vendors promising expertise in the region. Sponsors should not blindly accept expertise statements from these companies because CROs and vendors may overemphasise skills in order to gain contracts.

One company gave an example: “We hired a Croatian IP import vendor, and they advised us wrong on the IP import processes at that time. That caused us to lose the study. We’re working back to where we were, but that’s my cost. I learned. Now, when looking for an IP import vendor in Bosnia-Herzegovina, we discovered that only one of four vendors knows the right processes, regulations and standards.”

Another executive narrated her experience working in Russia: “We hired a multinational CRO with an office in Russia. They gave us the impression that there was no opportunity to talk to Russian authorities to explain submissions. They told us the only thing we could do was keep writing responses to questions and resubmitting. We would have to sit and wait until they came back with a response, and then we would write more answers and send those. They claimed there was no opportunity for dialogue.”

The executive talked to her colleagues and discovered that the contact at the multinational CRO was misinformed. They directed her to a different multinational CRO with local regulatory experience. From that point forward, the trial ran smoothly.

A different interviewed executive cautioned that sponsors must ensure that the local people working on their trials also own local knowledge. “Just because they are Bulgarian does not mean that they have Bulgarian knowledge.” Sponsors’ best bets are vendors that employ a mix of local and Western-trained employees.

Companies should take time to thoroughly vet any CRO or vendor, regardless of size, location, or peers’ experiences. The following sections explain region-specific best practices to help in this process.

Ask Tricky QuestionsAccording to one interviewee, “You need to be really careful [in Eastern Europe] because people tend to tell you, ‘Don’t worry, everything is okay; we’ll arrange everything.’ You leave with a good feeling, but the services are never delivered. You need to ask the tricky questions to ensure that they really know the business.”These tricky questions fall in one of two areas:• Proof of process knowledge. Ask the vendor to describe each

step in the process instead of asking if they have knowledge

of the process. Detailed explanations are tougher to bluff through.

• Fact-checking. Research the most-concerning aspects of the process as the sponsor. Then ask pointed questions from a range of these areas to verify knowledge on all parts.

The first type of question is often less confrontational, while the latter can suggest ignorance on the part of the vendor. Many companies find success by combining aspects from both areas in an overall due diligence process.

Talk Face to FaceA US executive recommends finding contacts that “you can establish a personal connection with.” Even when investigating CROs in Russia, it is imperative that a company meets face to face with vendors. She travelled around the world to talk to potential vendors. “The personal connection may be intangible, but it is invaluable,” she stated. Particularly when working with different cultures in different regions, personal communication helps to clarify what knowledge the vendor owns. Email allows researched answers and more accurate English; being put on the spot, however, may be a truer barometer of language ability, regulatory knowledge, cultural differences, etc.

Look for a CRO Willing to Contradict a SponsorToo often, eagerness overrides competency in negotiations with CROs — on the part of both the CRO and the sponsor — in effect, hindering overall trial success. The sponsor may insist on ridiculous timelines or protocols that no CRO could meet, and CROs often exaggerate their abilities in an effort to close the contract. When this scenario happens, the CRO wins the contract, but the trial falters.

Companies should look for CROs that are willing to tell them when they are mistaken. Is the regulatory timeline realistic? Does the protocol reflect patients in the country? If not, good CROs will step in and provide insight based on their experience; as the knowledge experts, this is their responsibility. If a CRO cannot bluntly provide this insight, it should not be trusted with managing a sponsor’s trial.

*Note: All of this information comes from Cutting Edge Information’s Emerging Markets Clinical Trials library, which includes research on BRIC, Asia, Central/Eastern Europe, Latin America, and Africa. Each study resulted from surveys and interviews conducted with clinical development executives currently running trials in emerging countries. For more information, please visit www.cuttingedgeinfo.com/.

Since joining Cutting Edge Information’s research team in 2008, Shaylyn Pike has spearheaded CEI’s emerging markets series, a collection of reports focused on conducting clinical trials in emerging markets. In addition, she has led research on market-access related topics, including

health economics and pricing strategy, as well as autoimmune and diabetes pipeline analyses. Ms. Pike has been quoted as an industry expert in Outsourcing Pharma, Triangle Business Journal and MedAd News on CROs in emerging markets, the oncology pipeline, and branding strategies for autoimmune products. Email: [email protected]

Market Report


Including Asian patients in Phase I trials helps biopharmaceutical companies speed up product introductions for the rapidly expanding markets in Japan, China and South Korea.

The intense financial and competitive pressures on the biopharmaceutical industry make global drug development more important than ever. The imperative to quickly introduce products into as many countries as possible has increased dramatically in recent years as biopharmaceutical companies endeavour to maximise the commercial success of new therapies. In this demanding environment, Asian markets such as Japan, China and South Korea offer particularly attractive growth opportunities. Japan is the world’s second largest pharmaceutical market, and is growing at a faster rate than the markets in the US and the EU. China is poised to reach the fifth or sixth position in the near future, and some projections suggest that it could emerge as the leading biopharmaceutical market by the middle of the century.

Although the growth potential of the Asian market is significant, developing drugs for these countries presents substantial challenges for the biopharmaceutical industry. In addition to cultural issues and differences in medical practices, sponsors must deal with regulations that require the inclusion of clinical data from native populations – requirements that greatly increase the cost of developing products for these countries. This regulatory approach has also resulted in considerable delays in the introduction of vital new therapies for patients in need – especially in Japan, where new biopharmaceutical products have typically entered the market more than four years after their approval in the US or Europe.

In the last few years, however, changes in the Japanese regulatory environment – as well as the earlier adoption by the International Conference on Harmonization (ICH) of regulations covering the acceptance of clinical data between member nations – have created new opportunities for biopharmaceutical companies to incorporate Asian countries in the early stages of their drug development programmes and accelerate the introduction of their products into these important markets. In particular, the concept of “ethnobridging” – obtaining clinical data from native Asians living in other countries that can be scientifically linked to in-country populations – has allowed many sponsors to implement cost-effective, multi-ethnic approaches to their clinical trial programmes that reduce the time and cost of developing products for Asian markets.

To succeed in Asia, biopharmaceutical companies must understand the regulatory, cultural and historical difference of the region, and create multinational development programmes that support the global approval of their products. It is also vital to establish close relationships with the regulatory bodies in these countries to ensure

that the clinical approach for each product is appropriate. Equally importantly, sponsors need strategic partners that understand the complexities of the Asian market and have experience working with the regulatory agencies and leveraging ethnobridging to accelerate the development process.

The Evolution of the Japanese MarketplaceBecause Japan is the largest of the Asian biopharmaceutical markets, the changes that have taken place there in recent years are of great significance to the global biopharmaceutical industry. In the past, Japanese regulators required that clinical trials for potential new pharmaceutical products be conducted in Japan – even if successful trials and regulatory approvals had already taken place in other parts of the world. As a result of these policies and the high cost of conducting trials in Japan, many novel therapies are unavailable to Japanese patients, or become available long after they reach the market in other regions. This time-lag for innovative therapies created a serious public health concern in Japan.

The first major breakthrough on this issue came in 1998 with the ICH adoption of the “Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data” (E5), which established procedures under which clinical trial data gathered in one region could be used to fulfil certain regulatory requirements in other regions. The guideline included the concept “bridging” studies that might be used to demonstrate the applicability of one region’s clinical data to the population of another region.

In 2007, Japan’s Pharmaceutical and Medical Devices Agency (PMDA) issued a new guideline entitled “Basic Concepts for International Joint Clinical Trials.” This guideline makes it clear that the PMDA understands that Japan’s drug development regulations need to be more flexible, and it expands Japan’s criteria for allowing the inclusion of data from global trials involving non-Japanese patients. At the same time, the guideline states that companies conducting international trials across different geographic regions and populations must account for ethnic differences when gathering and submitting study data for drugs intended for sale in Japan. In addition, any clinical development plan must specifically assess the efficacy and safety of an investigational drug in Japanese subjects.

The guideline lists several other important conditions that global trials would be required to meet if their data is to be considered for inclusion in a Japanese regulatory filing, including:• All nations and institutions participating must conduct

trials under Good Clinical Practices (GCP) regulations as defined by the ICH

• All participants must accept onsite GCP inspections by

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Japan regulatory authorities• The study design, protocols, and analytical methods must

be acceptable to the PMDA

In all cases, the guideline advocates direct consultation with the Agency in the early stages of every clinical trial to discuss the study design and the criteria for including data from non-Japanese patients.

using Ethnobridging to Accelerate global Early-Phase Studies The PMDA guideline strongly recommends early clinical pharmacology studies involving healthy volunteers and patients from Japan to obtain pharmacodynamic (PD), pharmacokinetic (PK) and safety data. These studies have traditionally taken place in Japan, and thus do not require bridging. However, the high cost of conducting trials in Japan – combined with a shortage of available volunteers – has fostered an alternative approach: conducting the studies on Japanese citizens temporarily living outside of Japan. This alternative allows pharmaceutical companies to more efficiently conduct these early-phase studies, utilising volunteers recruited from the concentration of Japanese nationals in areas such as the western United States and the United Kingdom.

There are a number of compelling reasons for conducting these early-stage trials outside of Japan for drugs potentially targeting the Japanese market, including:• Lower costs• Shorter regulatory and trial implementation timelines• Access to experienced investigators and qualified trial

sites• Greater consistency in medical practices and data

collection• Ready availability of volunteers• Possibility of incorporating multiple ethnicities (Japanese,

Chinese, Korean) into a single Phase I trial for greater efficiency

• Availability of CROs with experience in Asian markets and existing relationships with regulators

• Fewer cultural and language barriers• Reduction in logistical issues such as travel costs and time-

zone differences• Faster completion of Phase I testing

The area around Los Angeles, California, provides excellent opportunities to recruit Asian patients outside their native countries. There are approximately 43,000 first generation Japanese passport holders in the area, and even larger populations of Chinese and Korean nationals – approximately 600,000 and 500,000 respectively. Other major cities, such as London in the UK, also have large populations of native Asians. In both of these cases, an infrastructure of CROs and other resources is already in place with capabilities and experience in conducting ethnobridging studies.

It is important to note, however, that these studies – and the volunteers – must meet strict “bridging” criteria. In order to be accepted by Japan’s regulatory authorities as representing the Japanese population, for example,

volunteers must be natives of Japan and must have been away from Japan for a relatively brief time – usually no more than five years. In addition, their lifestyle cannot have changed significantly since relocating, especially in terms of diet and other health-related factors. This requirement typically means that the volunteers must live in areas with large Japanese communities where they can more readily maintain their native lifestyle. The companies providing these ethnobridging services must also maintain ongoing relationships with Japanese regulators to ensure that their volunteers and data meet the bridging requirements for each study.

Sponsors targeting China in their global development programmes face similar questions about the acceptance of Phase I study data from Chinese patients located outside the country. There has been no official statement from China’s State Food and Drug Administration (SFDA) on this topic. However, the progress that had been made in Japan concerning the use of ethnobridging data offers reason for optimism for similar flexibility in China in the near future. Although China is not an ICH nation, its recent adoption of GCP guidelines was a significant step toward participation in global trials and cooperation with foreign researchers in

developing new medications for the Chinese market. South Korea, another significant market in the region,

has been more open to the inclusion of foreign data. It has also published its own GCP guidelines, and has essentially adopted ICH standards. More important, cooperation is increasing among Japan, China and South Korea concerning the mutual acceptance of clinical data.

While Japanese regulators still require that most pivotal Phase II/III trials be conducted in Japan, the ICH and PMDA guidelines allow for the possibility of including some clinical data from other populations if their equivalency to the Japanese population can be scientifically demonstrated by bridging studies. This flexibility offers the possibility that the growing inclusion of Asian-Pacific countries in global clinical trials could provide valuable data to support new drug applications in Japan. Countries such as China and South Korea that are considered ethnically similar to Japan could play an increasingly important role, providing a portion of Phase II/III data for Japanese regulatory filings – if the equivalency of those other populations to Japanese patients can be scientifically demonstrated. One such study would be a comparative pharmacokinetic study between Japanese, Chinese and Korean subjects. Perhaps most important, the recent PMDA guideline states that the Agency will evaluate proposals for joint trials and the inclusion of foreign data on a case-by-case basis, which could allow additional flexibility for orphan drugs or therapies that address serious unmet medical needs. This trend should continue to grow in the years ahead as Japan’s regulatory authorities gain experience – and confidence – with trial data from other populations.

Finding the Right PartnerHow do biopharmaceutical companies take advantage of this new opportunity to speed up their development efforts in Asia? The best approach is to establish a strategic partnership with a global CRO that has international clinical trial experience, as well as specific experience in conducting ethnobridging studies. The right partner would provide access to a wide range of resources and expertise that will help sponsors quickly and effectively expand their multinational clinical trial programmes to take advantage of these growing markets.

The capabilities of such a partner should include:• Offices and experienced personnel in Japan and other

major Asia-Pacific countries• Well-established ethnobridging capabilities and

infrastructure – including qualified investigators and study sites – in areas with large first-generation Asian populations, such as California in the US and London in the UK

• Experience working with regulatory authorities in Japan, China, South Korea and other Asian nations

• History of conducting successful ethnobridging studies• Wide range of therapeutic area expertise• Strong expertise and capabilities in clinical pharmacology

and early-stage trials

The key to these partnerships is access to global capabilities

combined with in-depth local knowledge and experience. With the many differences and challenges of drug development and approval in Asia, an experienced partner with strong resources in the Asia-Pacific region and an extensive background in ethnobridging offers the greatest chance of success in taking advantage of these market opportunities.

Speeding up Development in AsiaBoth the biopharmaceutical industry and the governments of these key Asian nations have a vital interest in accelerating and expanding the availability of novel therapies for their citizens. With the improving regulatory environment in Japan and elsewhere in the region, it is now feasible – and desirable – for biopharmaceutical companies to include these countries in their global development plans. The key success factors for faster product development in Asia are:• Incorporating Japanese and other Asian populations into

the earliest stages of development to support efficient global registration and marketing

• Establishing a broad ethnic base of patient data, and designing studies that can bridge the data between countries and regions

• Performing PK, PD, and other Phase I testing with multiple populations as early as possible to reduce the chances of ethnicity-based safety, PK and PD issues

• Working with regulators to ensure that study designs, protocols, analytical methods, and bridging strategies will meet their requirements

• Ensuring that all participating nations and institutions conduct trials under GCP regulations as defined by ICH

As the regulatory environment in Asia continues to evolve, the challenge for the global pharmaceutical industry is to find the right resources and best practices to take advantage of this new regulatory flexibility, while understanding the differences that continue to characterise the drug approval process in these countries. With the right approach, global companies can generate an increasing percentage of clinical data from Asian populations in other parts of the world and use that data to accelerate the approval of new compounds in these large and growing markets – saving time and money, maximising the value of new products, and bringing important new therapies to patients in this region more quickly.

Stanford Jhee, Pharm.D., is a Senior Director of Scientific Affairs, Early Phase, at PAREXEL International. For over eighteen years, Dr. Jhee has collaborated with pharmaceutical companies in the development of neurologic and psychiatric drugs. More recently, he has

extensively conducted Asian ethnobridging studies in support of global drug development with an emphasis on Asia. Dr. Jhee received his Doctor of Pharmacy degree from the University of Southern California and completed a pharmacy practice residency and a research fellowship from the same institution. He has authored over 45 scientific manuscripts and two books and is active in presenting at national and international scientific meetings. Email: [email protected]

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Following European Union accession on 1 May 2004, Poland has implemented EU directives 2001/20 and 2005/28 and established a friendly environment for clinical trials. Having 38 million citizens and a post-communistic centralised healthcare system makes it a very attractive country in which to conduct clinical studies, thus it is not a surprise that ClinicalTrial.gov shows 647 ongoing/starting studies in the country.1 Nevertheless the clinical site density in Poland per million population is only 30.8, compared to 76 Czech, 62 in Hungary and approximately 50 in Germany/France/Spain.2

According to a PwC (previously PricewaterhouseCooper) survey from November 2010, the clinical trials market in Poland is worth about 900 million Polish zloty (approx. 200 million euro) and continues to be the largest one in Central and Eastern Europe (CEE). Each year there are over 450 new clinical trials registered in Poland’s Regulatory Affair office. This number does not reflect observational studies, as those do not undergo RA submission. Another PwC survey confirms that the reasons for successful clinical trials growth in Poland are the accessible population allowing for efficient patient recruitment with the assurance of EU standards and high data quality. Sixty per cent of all studies in Poland are in the following therapeutic areas: oncology, rheumatology/immunology and cardiovascular trials.2

healthcare System Characteristics:The centralised healthcare system is obligatory and covers almost all citizens. It is paid and supervised by National Health Fund (NHF, Narodowy Fundusz Zdrowia3). The majority of patient treatment still occurs in public healthcare units. Official government data shows 995 public and 1260 non-public hospitals, whereas ambulatory units are about 4k in public sector and 20.5k private units.4 Of course, not all of these hospitals are suitable for conducting clinical trials. There has been a significant tendency seen to move clinical trials from public hospital facilities to private clinics in order to get a faster study start and a better financial ratio. 38% of clinical sites that Premier Research worked with in 2010 were private institutions.

The Polish healthcare system is characterised by poor accessibility of a patient to be seen by a medical specialist. A typical wait to meet with a neurologist, gastroenterologist or allergist can range from three months to one year. Clinical trials participation gives patients much quicker medical care access. Furthermore, Poland, similar to other developing European countries, has problems in assuring wide accessibility for the new medical therapies. These therapies are mostly grouped in special NHF programmes, not always accessible for every patient. For that reason clinical trials are often the only option for the patient to get new medical therapy access. Conversely, Polish healthcare units are unusually well equipped; they are able to perform CT or MRI assessments. The summation of these factors has led to excellent patient recruitment rates.

Regulatory Background: Polish law is a bit complicated for the inexperienced person as there are four main medical legal acts related to clinical trials conduct:1. The first, the Medical Profession Act (Dz.U. 1997 Nr 28 poz.

152), describes clinical studies as medical and scientific experiments.

2. The second, the Polish Pharmaceutical Law (Dz.U. 2001 Nr 126 poz. 1381), is applicable for clinical trials with medicinal products and is the main act of law in Poland covering clinical research.

3. The third is the Act on Medical Devices (Dz.U. 2010 Nr 107 poz. 679).

4. The fourth defines responsibilities of Polish Regulatory Affair Agency (Dz. U. 2011 Nr 82, poz. 451).

There are also several law orders including one that covers Good Clinical Practice (GCP) and Good Manufacturing Process (GMP). For these reasons, in 2009 the Ministry of Health started working on a separate Law Act on Clinical Trials; however the final launch is not expected before 2012. A pretty important aspect of the new Polish law is the requirement for investigator and sponsor compulsory third party liability insurance (not a ‘patient insurance’) for all interventional studies. These liability insurance values have been announced in a special decree, and depend on the amount of participants.

Regulatory Submissions:Considering the various law regulations, it is extremely important to have great regulatory know-how to guide sponsors though all these legal acts, which is in fact not so difficult. Currently, it takes approximately five to six months for the proper approvals in Poland.

Following the implementation of EU directives 2001/20 and 2005/28 into Polish Law, a parallel approval for studies with medicinal products from one central regulatory authority (RA) and one central ethics committee (EC) is required. For medical devices studies, EC approval must be obtained prior to regulatory submission. Observational studies (Phase IV and others), both interventional and non-interventional and with or without medical products, mostly require only one central EC approval. In May 2011, the Ministry of Health moved pharmaceutical registration responsibility to the Office for Registration Medical Products, Medical Devices and Bioacidal Products, and they became the only central regulatory affair body in Poland.5 This change should improve the regulatory submission process in the short term.

For the moment in Poland, an applicant needs 60 days in order to obtain RA approval; unfortunately the Polish Agency does not allow the Clinical Trial Application (CTA) to be submitted with the Voluntary Harmonisation Procedure (VHP). The Polish CTA application must support EudraCT. There is no need to translate the whole protocol into the

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local language, and there are no meeting dates or submission windows, thus the dossier may be submitted any working day. Prior to the agency starting the submission process, the agency will verify that the submitted documents are complete. It is extremely important to have suitable knowledge and submit a correct dossier, otherwise the agency may return in 30-40 days, noting that the submission was incomplete and that the submission process was not started. It is extremely important that the final executed contracts between sites/PIs be submitted before the submission timeline reaches day 60. Additionally, it is widely known that the submission process may be withdrawn at any time without any negative impact on the study in other participating countries. However, not widely known is the fact that the process may also be put on hold, without any negative impact, to provide missing signed contracts.

As mentioned previously, the EC approval process for medicinal product studies can be obtained in parallel with RA approval. It is important to note that there are different types of ECs in Poland. There are about 22 ECs located in regional medical chambers applicable for non-institute/non-university sites.6 Medical universities utilise their own ECs for university clinics, and other ECs are affiliated with most large clinical institutes.

Due to a change in the pharmaceutical law in 2004, the applicant must choose one of the PIs to take the role of the study country coordinator and use their associated EC to become the central EC voting on all sites participating in the clinical trial. This step is an important one, as the CEC also requires signed study contracts, thus the CEC selection must be connected with fast PI-coordinator contract execution. Although the CEC votes on the study on its own, it is obligated to contact regional ECs proper for other (than coordinator) sites in order to obtain information, for example if the site is eligible to participate in the multicentre clinical study. The applicant is not involved in this process, although the majority of local ECs will charge the applicant per each site’s assessment.

Contracting Issues - Facts and Myths about Poland: All individuals involved in clinical trial conduct in Poland have heard about issues connected to clinical trial agreements and the submission process. The fact is the signed clinical trial agreement must be executed prior to receiving EC and RA approval, and those bodies must receive an original or certified copy of the agreement. The myth is that this is ‘mission impossible’. The problem is that CROs and sponsors often use contract templates for hospital negotiations that often contradict Polish and sometimes even EU legislation. In Poland, the sponsor and investigator hold the biggest responsibility for study conduct. The hospital mostly provides facilities and allows the investigator to run the clinical study. Secondly, personal data protection is very strict in Poland. Thus having a 30-page hospital contract makes ‘mission impossible’. The Polish GCP association, together with the INFARMA association, have worked out a tripartite agreement template, which reflects all Polish and EU legal aspects and has all parties’ rights properly protected.7,8 Current contract execution problems are also caused by a control performed in 2009 and 2010 by the Supreme Audit Office in Polish clinical hospitals.9 It showed several

unintentional mistakes in hospitals connected with drug order procedure and clinical trials cost/benefit ratio procedure. These inadvertencies were not connected to clinical trial quality - most (if not all) hospitals have implemented suitable corrective actions and now the process is better. Still the best approach for contracting in Poland is working with someone that has experience with this area.

Patient Population: Although the start-up period in Poland is longer than other countries, the sites are able to achieve patient recruitment quickly. Assuming that it is not a very short study, Polish sites are well suited to contribute to patient enrolment. The success is mainly due to a relatively inefficient public healthcare system coupled with strong patient-physicians relationships. These trusted relationships, similar to other CEE countries, equate to higher patient retention and increased adherence in protocol procedures. The PwC Clinical Trials Report presents that oncology studies account for 34% of the overall clinical trial market in Poland, followed by 14% for cardiovascular and 12% for rheumatology. Endocrine/metabolic, CNS, infectious disease, urology, and some miscellaneous indications round out the remaining trials.2 Over-expression of oncology trials in Poland is due to the prior mentioned problematic accessibility for new medical therapies. Nevertheless, success in each study, regardless of the indication and complexity, is connected with proper feasibility data collection. Polish clinical trial units are mostly fluent in English and respond to feasibility questionnaires properly, although timelines must not be tight for proper response.

Costs: Conduct of a clinical study in Poland still costs roughly 20-30% less than countries in Western Europe (WE), although investigators’ fees are mostly similar to WE. Costs of medical procedures are now also similar to the west.

The RA application for clinical trials with medicinal products costs only 4,000 to 8,000 Polish zloty (approximately 1,000-2,000 Euro), and there is no amendment fee for medicinal products clinical studies. Regulatory fees have not changed for the past three years, thus it is probable that there will be an adjustment in the near future. EC costs have become more expensive due mostly to local EC assessment costs. CEC approval costs about 6,000 to 12,000 Polish zloty (1,500-5,000 Euro) per central application, plus 1,500 Polish zloty (approximately 380 Euro) per each local site assessment. An amendment fee is usually between 1,000 and 2,000 Polish zloty (260-520 Euro).

Due to often large distances for patients to travel to the sites, sponsors must take higher travel reimbursement costs into consideration. The best way to reimburse costs is to work with an external local company, as the tax and data protection law is very unclear in this area.

Quality:As mentioned earlier, Polish investigators are mostly fluent in English, and this reflects in proper communication and good study conduct.

Reviewing FDA data from 1994 to 2006, CEE countries had on average 0.85 findings per inspection versus 1.77 in

WE. There was only one administrative FDA sanction for CEE against 18 in WE.10 From 1997 to 2008, 38 FDA inspections were held in Poland and 23 (60%) provided no action required. Premier Research Poland has also participated in two FDA inspections, both in 2010, auditing two hematology units in Poland. Both showed excellent site performance with no action required for either the site or Premier Research. Recent calculations have shown that about 1,200 CRAs in Poland work for more than 50 CRO and pharmaceutical companies.2 The number of studies in Poland has been relatively stable over the last two to three years. It is also worth mentioning that almost all big pharma companies are present in Poland, with some having big clinical trial management centres located in Warsaw. Sponsors often give the role of the international principal investigator to Polish investigators.

IMP/Laboratory Logistic Procedures: Poland has been an EU member since May 2004, and in December 2008 Poland also joined the Schengen Agreement, which affords even better logistic and communication schemes. There is no import license requirement for EU-released IMPs. Also, other medical equipment needed for study conduct does not need import licenses, and export licenses for biological samples are not required. However, special requirements are in place for control substances and radiology active delivery.

Summary: Why to Run Studies in Poland? 1. Clinical trials have been conducted in Poland for more than

20 years. Thus, Polish investigators are highly experienced in clinical study procedures and are mostly fluent in English. The majority of physicians have undergone several GCP trainings.

2. While the regulatory approval process is not as short as in other EU countries, it is unified with the EU legislation and timelines are clear and predictable. Although contracting is a tough part of the submission process, it can be easily accomplished by thorough preparation using correct agreement templates. Furthermore there are huge efforts currently underway by the GCPpl and INFARMA associations in order to make the clinical trials business more transparent. They have worked out Rules for Conducting Clinical Trials in Poland, which intend to self-regulate the pharma and CRO industries in order to have the highest ethical standards in the clinical trials area.6 The key point is to work on better patient education (regarding rights, data protection, IMP characteristics and PI activities) when study-related documents are produced (for example informed consent forms) or study team trainings performed. The other important point of this transparency is principles related to financing (i.e. linking investigators’ remuneration with tasks, excluding double financing study procedures by both the sponsor and NHF, and having the clinical site study budget described only via the tripartite contracts in Poland).

3. IMP management and logistics is simple and does not vary form other EU countries. There are no import/export licenses needed for IMPs and laboratory samples sent from/to EU countries. Only controlled substances that are delivered via specialised pharmaceutical wholesalers need

an import license. 4. Private clinics, SMOs and private hospitals are a growing

part of the Polish healthcare system. These units provide an excellent environment for clinical trial conduct and give suitable competition for the public units. Nevertheless, each new study conduct must be considered carefully. A proper feasibility process must be in place, especially in highly developed areas like oncology, rheumatology and/or cardiology. Often it is worth utilising a less experienced site and making the effort to train them properly and providing greater attention during early enrolment to obtain higher recruitment figures.

5. The best recruitment results are obtained when the recruitment period is no shorter than nine months; shorter recruitment periods should be planned carefully. February to May and September to November are the most efficient recruiting months in Poland.

6. The main disadvantage is still the long regulatory timeline typically averaging closer to 90 days instead of the 60 days specified in the EU directive. Poland has yet to join the VHP registration procedure, but this should be positively solved in 2012. The biggest negative is still the administrative procedures connected to contract negotiations, and this is not only with regard to hospitals. Often CROs’ and sponsors’ procedures require several internal contract revisions, and this makes the contracting process longer. This is a result of the growing awareness of clinical trials risks and benefits, but this is a positive trend and should hopefully be improved by all parties in the short term.

References: 1. www.clinicaltrials.gov2. Clinical Trials in Poland – Key Challenges, report by PwC, Nov

2010; http://www.pwc.pl/pl/pl/biuro-prasowe/Clinical2010XI.pdf

3. www.nfz.gov.pl/new/index.php4. www.rejestrzoz.gov.pl, data as of 05 Nov 20115. Urzd Rejestracji Produktów Leczniczych, Wyrobów Medycznych

i Produktów Biobójczych , www.urpl.gov.pl6. www.infarma.pl/uploads/media/Rules_for_conducting_

clinical_trials.pdf7. www.gcppl.org.pl8. infarma.pl - Employers’ Union of Innovative Pharmaceutical

Companies INFARMA9. Supreme Chamber of Control, results of clinical trials control

(Polish version only) http://www.nik.gov.pl/plik/id,1862,vp,2203.pdf

10. Palaveev, R. European Pharmaceutical Contractor, Autumn 2007

Tomasz Kowalczyk, RPh Country Manager for Premier Research Poland. He graduated from the Pharmaceutical Department of Warsaw Medical University. Since 2004 he has held a Pharmacist License. Tomasz has over ten years’ experience in the pharmaceutical

and CRO industry. In Poland he participates in approx. 100 contracts negotiations a year. Additionally during his career he was directly involved in the submission of over 40 clinical trial applications. Tomasz is a member of the Polish GCP association and the Pharmaceutical Chamber in Warsaw. Email: [email protected]

Market Report


Therapeutics


Migraine is one of the most commonly reported medical conditions in the world, and is associated with substantial personal and socio-economic impacts. The World health Organization has ranked migraine as the 19th leading cause of disability worldwide, accounting for 1.4 per cent of all years of healthy life lost to disability.1 Migraine affects approximately three times as many women as men, and is estimated to affect >10 per cent of adults aged 18–65 each year, with the exception of Africa and the Eastern Mediterranean, where prevalence is lower.2

According to the second edition of the International Headache Classification3, migraine can be classified as either migraine with aura or migraine without aura. Of the two subtypes, migraine without aura is more frequent and is often more disabling.3 Several migraine triggers have been identified, including diet, lack of sleep, stress, alcohol intake, excessive caffeine consumption and hormonal factors.4

Non-Specific Migraine TreatmentFirst-line treatments for migraine attacks are usually analgesics, such as paracetamol, codeine, and non-steroidal anti-inflammatory drugs (NSAIDs; e.g. aspirin, ibruprofen, diclofenac, naproxen, tolfenamic acid, flurbiprofen), which are often combined with an anti-emetic (e.g. metaclopramide) to relieve nausea.

Migraine-Specific TreatmentErgotamine has been used to treat acute migraine since the mid-1920s, being the primary oral drug available for migraine relief prior to development of the triptans. While less expensive than the triptans, ergotamine is associated with significantly more severe adverse effects, including nausea, vomiting and muscular weakness and pain.5 Subsequently, the British National Formulary recommends that ergotamine is best avoided for the treatment of migraine, due to difficulties in absorption and its associated side-effects.6 Nevertheless, ergotamine remains the most widely available migraine-specific therapy worldwide, followed closely by the triptan drug sumatriptan.2

First developed in the 1990s, triptans are widely regarded as having revolutionised the treatment of chronic migraine. Seven triptans are currently marketed: sumatriptan (Imigran®), almotriptan (Almogran®), eletriptan (Relpax®), frovatriptan (Migard®), naratriptan (Naramig®), rizatriptan (Maxalt®, Maxalt Melt®), and zolmitriptan (Zomig®, Zomig Rapimelt®). While several modes of action have been indentified for triptans, the exact mechanism responsible for migraine relief remains unclear. Triptans are now available as subcutaneous injections, conventional oral tablets, orally disintegrating tablets, suppositories and nasal sprays. In addition, a transdermal patch is currently being developed for sumatriptan. While the high cost of triptans and concerns over associated cardiac side-effects have left some physicians reluctant to prescribe them, all seven triptans are now available as over-the-counter medications in different countries around the world.2

ProphylaxisIn addition to symptomatic migraine therapy, US Headache Consortium guidelines recommend the use of preventative therapies in cases where migraine significantly affects a patient’s daily routine, cases of treatment failure, contraindication or treatment-related side effects, overuse of acute medications, occurrence of >2 migraines a week, or in cases where attacks are increasing over time, resulting in an increased risk of rebound headache from repeated medication use.7 In comparison, guidelines by the European Federation of Neurological Societies (EFNS) recommend that migraine prophylaxis be considered when quality of life, business duties, or school attendance are severely impaired, when a patient is experiencing >2 attacks a month, where acute drug treatment is failing, or when frequent, very long, or uncomfortable auras are reported.8

The gold standard for prophylactic migraine treatment is a reduction in the frequency or severity of migraine attacks of at least 50 per cent. Several options for migraine prophylaxis are currently available, including beta-blockers (e.g. propranolol, timolol, atenolol, nadolol, metoprolol), anti-serotonergic drugs (e.g. cyproheptadine, pizotifen, methysergide), calcium channel blockers (e.g. amlodipine, verapamil, flunarizine, nimodipine, nifedipine, cyclandelate, nicardipine), NSAIDs (e.g. aspirin, naproxen, ibuprofen), anti-convulsants, (e.g. topiramate, divalproex) and tricyclic anti-depressants (e.g. amitriptyline, nortriptyline). To date, six medications have been approved by the US Food and Drug Administration for the prevention of migraine: methysergide, propranolol, timolol, divalproex, topiramate and (most recently) botulinum toxin type-A (approved for chronic migraine only). Methysergide has since been withdrawn from the market in the US; however, it is still available in Europe.

Current EFNS guidelines recommend several drugs for the prevention of migraine, including the beta-blockers metoprolol and propranolol, the calcium channel blocker flunarizine and the anti-convulsants valproic acid and topiramate. While European-wide licences are lacking for migraine prophylactics, a number of national licences have been granted. However, this has resulted in some discrepancy between European Union (EU) member states in the way migraine prophylactics can be used, as evidenced by recent efforts by the European Medicines Agency to synchronise the marketing authorisations for topiramate in the EU and the European Economic Area.

Measuring the Impact of MigraineAs poor patient-doctor communication can often delay diagnosis of migraine, a number of tools have been developed to aid the identification of migraine, by assessing the impact of headache and/or migraine on a patient’s life. Some of the most widely used assessment tools include the migraine-specific quality-of-life measure (MSQOL),9 the headache impact test (HIT and HIT-6),10 and the Migraine Disability Assessment (MIDAS).11,12 Of these tools, MIDAS was the

New Insight into the Impact and Treatment of Migraine


Therapeutics

first to advocate stratified treatment of migraine based on a patient’s migraine-related disability (Figure 1).

Step-wise versus Stratified CareThe Disability in Strategies for Care (DISC) study was the first large randomised controlled trial to evaluate stratified care in the treatment of acute migraine. In this study,13,14 adults with chronic migraine were randomised to one of three treatment strategies: step care across attacks (n=271), step care within attacks (n=285) and stratified care (n=279). Over 15 months (December 1997 to March 1999), each participant was treated for up to six moderate/severe migraine attacks with non-specific (aspirin, [800–1000 mg] plus metoclopramide [10 mg]) or migraine-specific therapy (zolmitriptan [2.5 mg]). In the step care across attacks cohort, patients were initially treated with non-specific therapy, and patients without a satisfactory headache response (i.e. a reduction in pain intensity from baseline to two hours post dose in at least two of the first three attacks) were switched to migraine-specific treatment for the remaining three attacks, while the remaining patients continued using aspirin plus metoclopramide.

In the step care within attacks cohort, all attacks were initially treated with non-specific therapy, and patients not responding to treatment after two hours were escalated to migraine-specific treatment. In contrast, initial therapy in the stratified-care cohort was chosen based on migraine-related disability, measured using MIDAS. Patients with a MIDAS score of two were treated with non-specific therapy, while patients with a MIDAS score of three or four were treated with migraine-specific therapy. Patients with MIDAS scores of one were not included in this study, as analgesics are considered best therapy for these patients.

The findings of this study revealed significantly greater headache response at two hours in the stratified-care cohort (52.7 per cent) than in either of the step-care cohorts (across attacks, 40.6 per cent; within attacks, 36.4 per cent; p<0.001 each). Disability time across all six migraine attacks was also significantly lower in the stratified-care cohort than in either of the step-care cohorts (p<0.001). This trial demonstrated for the first time that stratified care provides significantly better clinical outcomes and is more cost-effective than step-care strategies for migraine.13,14

Stratified Care in the Clinical SettingStratified care has now largely replaced step care as the migraine treatment approach of choice in the clinical setting. Current evidence-based best practice guidelines for migraine

Figure 1: MIDAS Questionnaire

INSTRuCTIONS Answer the following questions about ALL your headaches you have had over the last 3 months. If a single headache affects more than one area of your life (e.g., work and family life) it is counted more than once. Select zero if you did not have the activity in the last 3 months.1. On how many days in the last 3 months did you miss work or school because of

your headaches?2. How many days in the last 3 months was your productivity at work or school

reduced by half or more because of your headaches? (Do not include days you counted in question 1 where you missed work or school)

3. On how many days in the last 3 months did you not do household work (such as housework, home repairs and maintenance, shopping, caring for children and relatives) because of your headaches?

4. How many days in the last 3 months was your productivity in household work reduced by half of more because of your headaches? (Do not include days you counted in question 3 where you did not do household work)

5. On how many days in the last 3 months did you miss family, social or leisure activities because of your headaches?

SCORINg: Add the total number of days from questions 1–5MIDAS Score MIDAS grade Definition0–5 I Little or no disability6–10 II Mild disability11–20 III Moderate disability21+ IV Severe disability

Therapeutics

management in the US (US Headache Consortium),7 Canada (Canadian Headache Society),15 UK (Migraine in Primary Care Advisors guidelines),16 France (French Society for the Study of Migraine Headache),17 and internationally (EFNS and Headache Care for Practising Clinicians guidelines)8,18 have all adopted the stratified-care model. The MIDAS questionnaire is now one of the most widely used tools to assess migraine-related disability in order to implement appropriate stratified care, both in clinical practice and in more than 30 completed and ongoing clinical trials listed on the National Institutes of Health (www.clinicaltrials.gov) and International Standard Randomised Controlled Trial Number registers.

The Future of Migraine TreatmentA range of new and existing therapies are being investigated for migraine prevention. Those that have shown particular promise include anti-convulsants, anti-depressants, angiotensin II receptor antagonists, occipital nerve stimulation and dietary supplements. Examples of therapies being assessed for the symptomatic treatment of migraine include oral contraceptives, anti-convulsants, muscle relaxants, intranasal oxytocin, angiotensin-converting enzyme inhibitors, transient receptor potential cation channel antagonists, serotonin receptor agonists and neuronal nitric oxide synthase agonists. While calcitonin gene-related peptide (CGRP) antagonists have been described by some as representing a new era for migraine treatment, by providing migraine relief without direct vasoconstrictor activity associated with triptans,19 recent safety concerns of associated liver toxicity have led to development of some CGRP antagonists being terminated.

As well as evaluating new and existing treatments and combinations for migraine relief, predisposing genetic factors are also being investigated. For example, a polymorphism of the serotonin transporter gene has recently been shown to be associated with an increased risk of inconsistent response to triptans in migraine patients.20 While the field of pharmacogenomics is still in its infancy in migraine research, it has the potential to transform stratified care.

References1. World Health Organization: WHO Global burden of disease

2004 update. http://www.who.int/healthinfo/global_burden_disease/estimates_regional/en/index.html. 2004

2. World Health Organization: Atlas of headache disorders and resources in the world 2011: A collaborative project of World Health Organization and Lifting The Burden. 2011

3. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 Suppl 1:9-160, 2004

4. Fukui PT, Goncalves TR, Strabelli CG, et al.: Trigger factors in migraine patients. Arq Neuropsiquiatr 66:494-499, 2008

5. Tfelt-Hansen P, Saxena PR, Dahlof C, et al.: Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123 ( Pt 1):9-18, 2000

6. Joint Formulary Committee: British National Formulary. 61st Edition. ed. London: British Medical Association and Royal Pharmaceutical Society:2011

7. Silberstein SD: Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55:754-762, 2000

8. Evers S, Afra J, Frese A, et al.: EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force. Eur J Neurol 16:968-981, 2009

9. Wagner TH, Patrick DL, Galer BS, et al.: A new instrument to assess the long-term quality of life effects from migraine: development and psychometric testing of the MSQOL. Headache 36:484-492, 1996

10. Pryse-Phillips W: Evaluating migraine disability: the headache impact test instrument in context. Can J Neurol Sci 29 Suppl 2:S11-S15, 2002

11. Sawyer J, Edmeads J, Lipton RB et al.: Clinical utility of a new instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Neurology 501998 (abstr A433-A434)

12. Lipton RB, Stewart WF, Sawyer J, et al.: Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache 41:854-861, 2001

13. Lipton R, Stewart W, Stone A, et al.: Stratified care vs step strategies for migraine: The Disability in Strategies of Care (DISC) Study: A randomized trial. JAMA 284:2599-2605, 2000

14. Sculpher M, Millson D, Meddis D, et al.: Cost-effectiveness analysis of stratified versus stepped care strategies for acute treatment of migraine: The Disability in Strategies for Care (DISC) Study. Pharmacoeconomics 20:91-100, 2002

15. Pryse-Phillips WE, Dodick DW, Edmeads JG, et al.: Guidelines for the diagnosis and management of migraine in clinical practice. Canadian Headache Society. CMAJ 156:1273-1287, 1997

16. Dowson AJ, Lipscombe S, Sender J, et al.: New guidelines for the management of migraine in primary care. Curr Med Res Opin 18:414-439, 2002

17. Geraud G, Lanteri-Minet M, Lucas C, et al.: French guidelines for the diagnosis and management of migraine in adults and children. Clin Ther 26:1305-1318, 2004

18. Dowson AJ, Sender J, Lipscombe S, et al.: Establishing principles for migraine management in primary care. Int J Clin Pract 57:493-507, 2003

19. Schelstraete C, Paemeleire K: CGRP antagonists: hope for a new era in acute migraine treatment. Acta Neurol Belg 109:252-261, 2009

20. Terrazzino S, Viana M, Floriddia E, et al.: The serotonin transporter gene polymorphism STin2 VNTR confers an increased risk of inconsistent response to triptans in migraine patients. Eur J Pharmacol 641:82-87, 2010

Dr James Sawyer, CEO, Prism Ideas. Following a clinical career in general medicine and anaesthetics, James moved to the pharmaceutical industry in 1993, holding leadership positions in companies including Sanofi, AstraZeneca and Roche. James’s clinical development experience

spans all phases of clinical research and he has published widely across a variety of therapeutic areas. He has driven regulatory interactions for many compounds and is the author of several expert reports filed at European and North American agencies. James founded Prism Ideas in 2001. Email: [email protected]



INTRODuCTIONTraditionally, blood pressure (BP) has been assessed with the auscultatory technique introduced into clinical medicine at the end of the 19th century. Despite being inaccurate and misleading, this technique has survived largely unchanged for over 100 years. It is salutary to reflect that since Riva-Rocci and Korotkoff introduced the technique we have landed men on the moon, orbited Mars, invented the automobile and airplane, and, most importantly, revolutionised the technology of science with the microchip. Why, we might ask, has medicine ignored scientific evidence for so long and thereby perpetuated an inaccurate measurement technique in both clinical practice and hypertension research?1. The same sentiment has been expressed by Floras: “As a society, we are willing to contemplate widespread genomic or proteomic subject characterisation in pursuit of the concept of ‘individualised medicine.’ By contrast, blood pressure measurement is one of the few areas of medical practice where patients in the twenty-first century are assessed almost universally using a methodology developed in the nineteenth”2. Quite apart from the inaccuracy of the auscultatory technique, one of its major limitations is that it can only provide a snapshot of BP behaviour, usually under circumstances that may adversely affect the level of BP. To overcome these serious methodological shortcomings, the technique of ambulatory blood pressure measurement (ABPM) has been developed to provide automated profiles of BP behaviour over 24 hours. When we consider that the phenomena of white coat hypertension, nocturnal dipping, and morning surge cannot even be suspected with conventional BP measurement and that the technique can give no indication of the duration of antihypertensive drug effect, it is a matter of some wonderment that researchers can persist in using the technique. It is indeed worrying that the editors of scientific journals and their peer reviewers can give scientific credence to studies performed with a discredited technique. We must question also why the bodies that regulate the approval of antihypertensive drugs have not made BP measurement over 24 hours mandatory for studies of drug efficacy and why the pharmaceutical industry funds studies that do not provide ABPM3.

ADVANTAgES OF ABPMThere are several advantages of 24-hour ABPM over conventional BP measurements in demonstrating the efficacy of BP-lowering drugs, which include the following.

Detection of white coat respondersThe white coat effect, whereby the circumstance of measurement causes a temporary rise in BP, can cause a very significant rise in clinic BP, and a reduction in BP during a clinical trial can be attributed erroneously to drug efficacy rather than to attenuation of the white coat

effect4. Although a white coat effect may be evident in the first hour of ABPM (and possibly also in the last hour) when the patient is in the medical environment5, the average BP measurements during the daytime and night-time periods are devoid of the white coat influence. More than 20% of patients with borderline hypertension diagnosed by clinic BP measurement have normal daytime ABPM6. If patients with white coat hypertension are included in a pharmacological study, as is often the case when patients are recruited by clinic BP measurement, we might expect as many as one-fifth of these patients not to have sustained hypertension and to be unsuitable for the study7.

Absence of placebo responseUnlike clinic BP measurement, 24-hour ABPM is virtually devoid of a placebo effect3. The absence of a placebo effect with non-invasive ABPM allows the opportunity of simplifying the design and conduct of efficacy studies of antihypertensive drugs. For example, in randomised placebo-controlled trials, ABPM performed before and repeated at the end of the treatment period may suffice, making the crossover design with its risks of carryover effects and the need for prolonged placebo administration unnecessary. ABPM may also remove the need for a runin phase to exclude normotensive patients and detect truly hypertensive patients3. This significant advantage overcomes the ethical problem of keeping patients with hypertension off treatment for weeks or months3,8.

Reduction in patient numbersIt is becoming more difficult to recruit patients for pharmacological trials, especially for studies aimed at determining the efficacy of drugs in mild hypertension. The average BP over 24 hours is three times more reproducible than are clinic BP values, and this allows the number of patients needed in parallel and crossover design studies to be reduced without loss of statistical power3,9.

Provision of a 24-hour profileABPM provides a profile of BP behaviour over the 24-hour period rather than the snapshot provided by clinic BP. This profile allows assessment of the efficacy of antihypertensive drugs over not only the entire 24-hour period but also during windows of the 24-hour cycle10,11. For example, the 24-hour period can be divided into white coat, day-time, siesta, vesperal (evening), night-time, and matinal (early morning) windows. A number of patterns may be observed in these windows: white coat hypertension and white coat effect, siesta dip, dipping, Non-dipping, reverse dipping, excessive dipping, and morning surge in the nocturnal period. As the mechanisms involved in determining BP at different times may differ, not surprisingly drugs can have different effects on these different windows3,12.

Why ABPM Should Be Mandatory in All Trials of Blood Pressure – Lowering Drugs

Therapeutics

Assessment of blood pressure variabilityThe most important measures of circadian variation are the nocturnal dip and the morning surge13. Nocturnal hypertension (or a non-dipping pattern) is the most important finding associated with increased target organ involvement and increased cardiovascular morbidity and mortality. Recently, BP variability has been shown to be an important prognostic marker that is likely to become a target for antihypertensive drug treatment14,15. The prognostic impact of BP variability is largely dependent on the variability of BP over time, but the many measures of variability that may be obtained from ABPM make this an interesting alternative, especially for assessing the effect of antihypertensive medication on this parameter16.

Provision of derived measuresA number of indexes may be derived from ABPM. For example, the ambulatory arterial stiffness index, which is calculated from systolic and diastolic pressure over 24 hours, independently predicts stroke and cardiovascular fatality risk17. Analysis of hourly mean BPs and changes over 24 hours allows determination of the efficacy of a drug at half-hourly time points, thereby showing the optimal dosing regimens for a particular drug. Traditional trough-to peak ratio can be calculated as well as the more recent ABPM-derived smoothness index3,18.

Identification of drug induced hypotensionABPM allows ready identification of drug-induced hypotension, particularly in association with a postprandial fall in BP and during a siesta dip—phenomena that are particularly common in the elderly. Antihypertensive drugs with a prolonged duration of effect, or administered frequently, may cause a profound reduction in nocturnal BP in some patients, which may lead to myocardial ischemia and infarction3,19. Hypotension induced by excessive medication in patients with coronary arterial disease can induce episodes of overt and silent ischemia20.

Identification of adverse effects of drugs on BPThe increasing interest in the cardiovascular safety of drugs has tended to concentrate on the effects drugs may have in inducing adverse electrocardiographically detectable abnormalities21. However, the unwanted effects of drugs for general noncardiovascular use as well as those with specific cardiovascular indications can elevate or, more commonly, reduce BP, especially in the elderly and often in specific periods of the 24-hour profile, such as the postprandial (or siesta window) or the nocturnal period. Such phenomena can only be detected with ABPM.

TEChNOLOgICAL DEVELOPMENT OF ABPMABPM, which has been available in one form or another for some 30 years, has been advocated for studies of BP-lowering drugs for almost as long, but it has been slow to find acceptance22. Although assessing the BP-lowering efficacy of antihypertensive drugs over the 24-hour period is a logical scientific premise, the ability to do so has been dependent on technological developments. The first advance was the introduction of a direct intra-arterial technique

for the measurement of BP continuously over the 24-hour period3,23. The data on antihypertensive drug efficacy provided by studies using this system were particularly valuable because they provided continuous BP measurement over the 24-hour period, but use of the technique was limited by safety and ethical considerations3. Efforts were focused, therefore, on developing a device that would record ambulant BP noninvasively and, in the 1960s, the Remler device, which was capable of measuring BP intermittently during the daytime period, provided clinicians with a new technique for evaluating antihypertensive drugs3,24. This device yielded interesting information on drug efficacy but was limited by having to be operated by the patient, which precluded recording of nocturnal BP. The next technological advance was the introduction of fully automated devices that could measure BP intermittently at predetermined intervals over the 24-hour period25. This class of devices, among which the SpaceLabs series has been dominant, has allowed clinical scientists to assess not only the BP-lowering efficacy of drugs but also their influence on circadian patterns such as nocturnal BP and the morning surge3. The latest technological development has been the provision of a software system that can analyse the data from ABPM and provide not only statistical data on mean levels of BP throughout the 24-hour period but also indexes of BP and the relationship of drug effect to the time of ingestion and the association of drug level with BP lowering26.These developments in ABPM have brought a new dimension to the interpretation of studies of BP-lowering efficacy. By providing a profile of BP behaviour over demarcated windows of the 24-hour period, ABPM has demonstrated the deficiencies of clinic BP measurement. First, a number of studies have shown that ABPM can be in agreement with clinic BP measurements3. In such studies, where a clinic fall in BP was confirmed by ABPM, the latter also demonstrated what conventional BP measurement can never show, namely, the pattern of an antihypertensive effect over the dosing interval. Second, studies have demonstrated that clinic BP measurement can fail to detect the BP-lowering effect demonstrated by ABPM3. Third, it has been shown that whereas reductions in clinic BP may be significant, ABPM may be either non-confirmatory or show that the clinic BP reduction coincides only with a brief period of BP reduction on ABPM3. Finally, one of the major advantages of ABPM in studies of antihypertensive drug efficacy is that the degree of BP control achieved by an antihypertensive drug may be determined not only over the entire 24-hour period but also within windows of the circadian profile. For example, studies have shown that patients who appeared to have well-controlled BP on routine clinic measurement had uncontrolled BP during the early morning hours3. There are many studies showing that an elevated nocturnal BP or a diminished nocturnal fall in BP is associated with poor cardiovascular outcome both in populations and in patients with hypertension3,13. Isolated nocturnal hypertension, which may be present in 7% of patients with hypertension, can be diagnosed only with ABPM, and its presence in patients on antihypertensive drug trials could have an important influence on the assessment of 24-hour efficacy of BP-lowering drugs27.


Therapeutics


CuRRENT REguLATORy RECOMMENDATIONS IN CLINICAL TRIALSIt is abundantly evident from an extensive review of the literature3 that the scientific argument for using ABPM in all studies assessing the efficacy or long-term protective benefits of BP-lowering drugs is irrefutable and there can no longer be a case for performing such studies using clinic BP as the measure by which efficacy is judged. Indeed, the recommendations of the regulatory bodies on the use of ABPM in trials of antihypertensive drugs generally concur with this view, but there is nonetheless a certain ambivalence that is now scientifically unacceptable. The US Food and Drug Administration guidelines, which are still in draft form, state: “The effect of the drug over the duration of the dosing interval has generally been evaluated in recent years with ABPM studies (which can incorporate dose response elements and an active control), but studies that measure blood pressure at approximate peak and at trough (pre-dosing) blood levels can also be used”28,29. The document also suggests that ABPM is “perhaps” not subject to bias. The primary purpose of the guideline is to obtain values for the trough-to-peak ratio regardless of how BP is measured.

The current European Medicines Agency (EMA) guidelines unequivocally recommend ABPM in clinical trials: “As ambulatory blood pressure monitoring (ABPM) provides a better insight to blood pressure changes during everyday activities and is better standardised than casual readings, ABPM is required for the evaluation of new antihypertensive agents”30,31. However welcome scientifically this recommendation may be in principle, the requirements for ABPM stipulated by the EMA are nevertheless in need of considerable refinement.

FACILITATINg ThE uSE OF ABPM IN CLINICAL TRIALSThe use of ABPM in clinical practice and research has been hampered by both manufacturers and researchers having concentrated on the development and means of validating the accuracy of devices—the hardware—rather than directing attention to presentation and analysis of data—the software—so as to make the technique more user friendly and acceptable to clinicians and researchers. The Conway Institute, University College Dublin, in association with dabl Limited, has been endeavouring to redress this imbalance and has developed the dabl ABPM system to facilitate the wider use of ABPM in the clinical management of hypertension1,10,11,26,32,33. The use of this custom-designed software system for the analysis of ABPM has facilitated the application of ABPM in primary care by showing clearly on a standardised plot the windows of the 24-hour profile, the normal bands for systolic and diastolic BP, and the recorded levels of BP throughout the 24- hour period as well as a computer-generated interpretive report. Together with central hosting of data, the dabl ABPM system has provided valuable demographic information in research13,17,34 and it is now used in many centres internationally.

The analysis of ABPM data and the reported diagnoses by the dabl ABPM system have been shown to be more accurate than reporting of ABPM data by expert observers33.

A number of practical obstacles have militated against

the wider use of ABPM in pharmacological studies, especially in prospective multi-centre trials. These include lack of familiarity with the technique, the need for trained personnel, the need to standardise the methodology, the need for electronic collection and monitoring of data so as to be able to inform investigators in real time of the success or otherwise of ABPM recordings, and the cost of the procedure, which, though higher than conventional BP measurement, provides so much additional information that the benefits make the procedure very cost effective. Finally, the goal levels for reduction of both daytime and nighttime BPs need to be determined and real-time analysis and transmission to the investigators of the target ABPM levels achieved has to be feasible.

The dabl ABPM system has now been developed to incorporate the basic requirements that are needed for ABPM to be implemented in studies of antihypertensive drug efficacy. These include the capability of assimilating a number of parameters over the 24-hour period and also within the windows of the 24-hour period so as to provide a comprehensive analysis of clinic and ABPM parameters; provision of real-time analysis of ABPM data so as to be able to alert the investigator to the validity or otherwise of the ABPM; and organisation of ABPM data so as to permit ongoing analysis and flexibility of the system so that it can be adapted to accommodate studies of differing design.

CONCLuSIONConventional clinic BP measurement is influenced by many factors, which limit the applicability of this technique for research into drug efficacy. More importantly, clinic BP measurement cannot provide a comprehensive assessment of duration of effect, or of the effect of antihypertensive drugs on sleeping pressure. The benefits of ABPM in the assessment of the efficacy of drug treatment are now so well established that its use should be mandatory in all pharmacological trials of antihypertensive drug efficacy. From the scientific viewpoint, it is now time to utilise the technique to obtain a fuller understanding of the patterns of drug-induced lowering of BP than was ever possible with conventional clinic BP measurement. The following was written in 1991: “The time has surely come when antihypertensive drug efficacy studies that do not assess blood pressure over 24 hours should no longer be acceptable”35. That this plea has not become reality some 20 years later must be seen as an indictment of clinical science.

References

1. O’Brien E. Ambulatory blood pressure measurement: the case for

implementation in primary care. Hypertension. 2008;51;1435–

1441.

2. Floras JS. Ambulatory blood pressure: facilitating individualized

assessment of cardiovascular risk. J Hypertens. 2007;25:1565–1568.

3. O’Brien E. The value of 24-hour blood pressure monitoring to assess

the efficacy of antihypertensivedrug treatment. Hot Topics Hypertens.

2011;4:6–23.

4. Parati G, Ulian L, Sampieri L, et al., on behalf of the Study on

Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation

(SAMPLE) Study Group. Attenuation of the “whitecoat effect” by

antihypertensive treatment and regression of target organ damage.

Hypertension. 2000; 35:614–620.

Therapeutics

5. Owens P, Atkins N, O’Brien E. Diagnosis of white coat hypertension by

ambulatory blood pressure monitoring. Hypertension. 1999;34:267–272.

6. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh JH.

How common is white coat hypertension? JAMA. 1988;59:225–228.

7. Verdecchia P, Staessen JA, White WB, Imai Y, O’Brien ET. Properly

defining white coat hypertension.Eur Heart J. 2001;23:106–109.

8. Mancia G, Parati G. Office compared with ambulatory blood pressure

in assessing response to antihypertensive treatment: a meta-analysis.

J Hypertens. 2004;22:435–445.

9. Conway J. Ambulatory blood pressure and clinical trials. J Hypertens.

1991;9(suppl):S57–S60.

10. O’Brien E. The circadian nuances of hypertension: a reappraisal of

24-h ambulatory blood pressure measurement in clinical practice. Ir J

Med Sci. 2007;176:55–63.

11. O’Brien E. Ambulatory blood pressure monitoring: 24-hour blood

pressure control as a therapeutic goal for improving cardiovascular

prognosis. Medicographia. 2010;32:241–249.

12. Bilo G, Parati G. Temporal blood pressure patterns and cardiovascular

events: “good night” or “good morning”? J Hypertens. 2006;24:1703–

1705.

13. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over

clinic blood pressure measurementin predicting mortality. The Dublin

Outcome Study. Hypertension. 2005;46:156–161.

14. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of

visit-to-visit variability, maximum systolic blood pressure, and episodic

hypertension. Lancet. 2010;375: 895–905.

15. Rothwell PM, Howard SC, Dolan E, et al., on behalf of the ASCOT-BPLA

and MRC Trial Investigators. Effects of blockers and calcium-channel

blockers on within-individual variability in blood pressure and risk of

stroke. Lancet Neurol. 2010; 9:469–480.

16. Dolan E, O’Brien E. Blood pressure variability: clarity for clinical

practice. Hypertension. 2010; 56:179–181.

17. Dolan E, Thijs L, Li Y, et al. Ambulatory arterial stiffness index as

a predictor of cardiovascular mortality in the Dublin outcome study.

Hypertension. 2006;47:365–370.

18. Parati G, Schumacher H, Bilo G, Mancia G. Evaluating 24-h

antihypertensive efficacy by the smoothness index: a meta-analysis

of an ambulatory blood pressure monitoring database. J Hypertens.

2010;28:2177–2183.

19. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an

angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular

events in high risk patients: the Heart Outcomes Prevention Evaluation

Study Investigators. N Engl J Med. 2000;342:145–153.

20. Owens P, O’Brien ET. Hypotension in patients with coronary disease—

can profound hypotensive events cause myocardial ischaemic events?

Heart. 1999;82:477–481.

21. Min SS, Turner JR, Nada A, et al. Evaluation of ventricular arrhythmias

in early clinical pharmacology trials and potential consequences for

later development. Am Heart J. 2010;159:716–729.

22. O’Brien E, Cox J, O’Malley K. Ambulatory blood pressure measurement

in the evaluation of antihypertensive drug effect. In: O’Brien E,

O’Malley K, eds. Blood Pressure Measurement. In: Birkenhager

WH, Reid JL, eds. Handbook of Hypertension. Amsterdam: Elsevier;

1991:245–260.

23. Bevan AI, Honour AT, Stott FH. Direct arterial pressure recording in

unrestricted man. Clin Sci. 1969;36:329–344.

24. Kain HK, Hinman AT, Sokolow M. Arterial blood pressure measurements

with a portable recorder in hypertensive patients. I. Variability and

correlation with casual pressures. Circulation. 1964; 30:882–892.

25. O’Brien E, Fitzgerald D. The history of indirect blood pressure

measurement. In: O’Brien E, O’Malley K, eds. Blood Pressure

Measurement. In: Birkenhager WH, Reid JL, eds. Handbook of

Hypertension. Amsterdam: Elsevier; 1991:1–54.

26. O’Brien E, Atkins N. Can improved software facilitate the wider use

of ambulatory blood pressuremeasurement in clinical practice? Blood

Press Monit. 2004;9:237–241.

27. Fan HQ, Li Y, Thijs L, Hansen TW, et al., on behalf of the International

Database on Ambulatory blood pressure in relation to Cardiovascular

Outcomes (IDACO) Investigators. Prognostic value of isolated

nocturnal hypertension on ambulatory measurement in 8711

individuals from 10 populations. J Hypertens. 2010;28:2036–2045.

28. US Food and Drug Administration, International Conference

on Harmonization. Draft guidance:E12A principles for clinical

evaluation of new antihypertensive drugs. 2000. http://www.fda.gov/

RegulatoryInformation/Guidances/ucm129461 .htm and http://www.

fda.gov/downloads/Regula toryInformation/Guidances/ucm129462.

pdf (accessed October 4, 2010).

29. US Food and Drug Administration, International Conference on

Harmonization. Guidance on statistical principles for clinical trials;

availability. Fed Register. 1998;63:49583–49598. http://www .fda.

gov/downloads/RegulatoryInformation/ Guidances/UCM129505.pdf

(accessed October 4, 2010).

30. International Conference on Harmonization. Topic E12: principles for

clinical evaluation of new antihypertensive drugs. CPMP/ICH/541/

00. 2000.

31. European Medical Agency, Committee for Medicinal Products for

Human Use. Guideline on clinical investigation of medicinal products

in the treatment of hypertension. CPMP/EWP/238/ 95 Rev. 3 (Draft).

2009. http://www.ema.europa .eu/pdfs/human/ewp/023895endraft.

pdf (accessed October 4, 2010).

32. O’Brien E, Asmar R, Beilin L, et al., on behalf of the European Society

of Hypertension Working Group on Blood Pressure Monitoring.

European Society of Hypertension recommendations for conventional,

ambulatory and home blood pressure measurement. J Hypertens.

2003;21:821– 848.

33. McGowan N, Atkins N, O’Brien E, Padfield P. Computerised reporting

improves the clinical use of ambulatory blood pressure measurement.

Blood Press Monit. 2010;15:115–123.

34. Li Y, Wang J-G, Dolan E, et al. Ambulatory arterial stiffness index

derived from 24-hour ambulatory blood pressure monitoring.

Hypertension. 2006; 47:359–364.

35. O’Brien E, O’Malley K, Cox J, Stanton A. Ambulatory blood

pressure monitoring in the evaluation of drug efficacy. Am Heart J.

1991;121:999–1006.

The author has disclosed that he has contributed financially to the

development of the dabl ABPM software program for ambulatory blood

pressure measurement and that he is a member of the board of directors

of dabl Limited, Dublin, Ireland.

This Commentary was first published in the Drug Information Journal,

Vol. 45, pp. 233–239, 2011

Eoin O’Brien is Professor of Molecular

Pharmacology at the Conway Institute of

Biomolecular and Biomedical Research, University

College Dublin. He has published many scientific

papers on hypertension research, especially in the

areas of blood pressure measurement, ambulatory

monitoring and the management of hypertension

in the elderly. Email: [email protected]


Therapeutics

IT & Logistics


IntroductionLaboratory data, which comprises a significant proportion of all data collected during a clinical trial, is of central importance in enabling an accurate and efficient assessment of the safety and efficacy of a compound as it moves through the clinical development process. The integrity of samples directly impacts the quality of results and is therefore directly proportionate to the accuracy of the assessment. This publication details the results of the most recent innovation at ICON Laboratories (ICON) focused on continual enhancement of data quality. The innovation comprises an insulated ambient sample shipper which has been carefully selected to prolong maintenance of room-temperature conditions within the shipper and thus decrease the exposure of the contents of the shipper to the extreme seasonal conditions typically experienced in certain parts of the world. These conditions have long been suspected to damage the integrity of samples when they occur during transit from a clinical site to the laboratory during the course of a clinical trial. The results detailed within demonstrate the protective effect of the shipper as measured via a reduction in the occurrence of sample hemolysis and clotting which is most commonplace during winter months, as a result of extremes in cold.

The company has adopted a multi-factorial approach towards the continuous improvement of data quality. Firstly, the quality of data generated within each of the laboratories in our global network is ensured via utilisation of uniform instrumentation platforms, standard operating procedures, training programmes and regulatory certifications. This approach maximises the ability of each laboratory to produce analytically indistinguishable results from identical samples.

Secondly, we place considerable focus on sample collection at an investigator site in order to ensure the quality of the samples that arrive into our global network of laboratories. Interactions with clinical sites are a key aspect of this process and focus on the standardisation of technique, protocol training and study materials, and the collection, handling and storage of samples. These interactions have expanded over recent years as the global expansion and degree of complexity of clinical trials has evolved. In addition, we perform regular surveys with clinical sites (Graziosi, 2010), the results of which are used to continuously improve and advance our services. We believe this process has the ability to directly impact the quality of a sample leaving the clinical site, and thus the quality of the end result entering the study database.

While ICON and industry colleagues have extensive abilities to ensure quality of study data via the control of both in-house analytics and interactions with clinical sites, it is not possible to control the weather or other geographical incidents such as volcanic eruptions, which impact on samples during transit from the clinical site to the laboratory. This is particularly applicable for those samples that are shipped at ambient conditions during the course of a global study. Ambient temperatures, i.e., the temperatures of the surroundings,

will of course vary greatly depending on such factors as the time of year and geographical location. The question thus arises, how can one be sure that comparable samples leaving clinical sites from multiple diverse geographical locations will produce comparable results? It is clear that two comparable samples leaving on an early March afternoon, one from sunny southern California and the other from the sub-zero twilight of northern Siberia, will experience considerably different ambient conditions during their transit from clinical site to central laboratory. Numerous publications acknowledge the impact that such temperature extremes may have on sample integrity (Wegner et al., 1987; Wilding et al., 1977; Williamson et al., 1975). Yet the attainment of comparable results from comparable samples is critical to the creation of an accurate data set and the facilitation of an accurate assessment of safety and efficacy of the investigational drug.

The company has invested considerable focus over recent years on minimising the impact that ambient variations may have on samples during their transit from the clinical site to our laboratories. A publication (Brooks, 2010) from our team of global logistics experts highlights the importance of selecting and validating rapid transit corridors from the maze of options offered via the various courier organisations. This process has facilitated a reduction in transit time from clinical site to laboratory and thus a reduction in exposure to ambient variations. This current publication presents the next advancement by ICON towards the standardisation and delivery of quality samples to our central laboratories via minimisation of exposure to variable ambient conditions during transit from the clinical site to the laboratory.

The proposed solution is an insulated shipper designed to reduce the level of heat transfer between the inside and outside of the shipper, and thus prolong the time it takes samples inside to reach the potentially extreme ambient temperatures outside. As detailed within, this insulated shipper has shown substantial benefit in reducing the preanalytical occurrence of hemolysis, clotting of whole blood and clumping of platelets which would otherwise compromise the integrity of samples and hinder the creation of a complete analytical study data set.

InvestigationsAn insulated shipper was selected (please see Figure 1) in association with design input from scientific and logistical experts and reflected key requirements such as low cost of shipper supply, ease of use, minimised weight and volume to facilitate cost of transport from clinical site to central laboratory, and enhanced thermal insulation properties to minimise heat transfer between the interior and exterior of the shipper.

Upon selection, the shipper was subject to controlled investigations which demonstrated the ability of the shipper, in comparison to a standard shipper, to prolong the period of time it took for the interior of the shipper to reach those

Preserving Sample Integrity in Clinical Trials via use of Insulated Shippers JCS Speaks with ICON Central Laboratories

Therapeutics


temperatures external to the shipper. The shipper was then tested at a limited number of clinical sites to ensure ease of use (see Figure 1) at site, and ease of transport from site to central laboratory.

Upon confirmation of the ability of the shipper to meet the key design input criteria, the shipper was placed into service alongside standard non-insulated shippers in Ukraine and Russia, which are known to be subject to extremes in ambient temperatures during winter months. Thus a data set of approximately 4500 shipments was collected between October 1st 2010 and March 1st 2011. The occurrence of hemolysis, clotting and clumping in samples originating from both standard and insulated shippers was then compared as a means of assessing the value of the insulated shipper in reducing the occurrence of these specific commented results and thus enhancing the quality of the final data set.

Results A review of all shipments from Russia and Ukraine highlighted the average transit time to be 24-48 hours, with duration of transport being primarily dependent on the location of the clinical site. Transport durations were also impacted as a result of the extreme winter weather conditions that Europe was subjected to during November and December of 2010 (please see reference Eurocontrol A and Eurocontrol B). The extreme extent of these conditions created havoc across Europe and significantly impacted the ability of courier networks to transport samples from site to laboratory as transport hubs struggled to maintain standard levels of service. These conditions resulted in samples being exposed to greater extremes in ambient temperature and also longer transport times from clinical site to laboratory. Thus, the period of time selected fortuitously proved to be ideal for evaluation of the performance of the insulated shipper.

Trending of the occurrence of comments (hemolysis and clotting for whole blood samples and clumping of platelets) for all shipments, both standard and insulated, that took one, two and three days to reach the central laboratory from the clinical site was performed. Data reveals that the proportion of all comments increases with each additional day of transport (please see Table 1). Indeed, shipments arriving after three days of transport are almost twice as likely to have a comment associated with them as compared to shipments arriving after two. It should be noted that many shipments may be commented as a result of various preanalytical issues not attributable to transport, and it is expected that the comment rate for shipments received after one day is largely reflective of this.

That the rate of comments increase with each additional

day of transit from clinical site to laboratory is perhaps not unexpected in consideration of the extreme temperatures that samples would have been exposed to during their transit to the laboratory. The most frequent comment is that of whole

blood hemolysis, followed by clotting and platelet clumping. A comparison of the occurrence of shipments with commented results was then performed for both standard and insulated shippers. In total, 41% of all shipments were received in an insulated shipper. Results, as detailed in Table 2, confirmed the ability of the insulated shipper to substantially reduce the occurrence of commented results. The total occurrence of whole blood hemolysis was reduced by 114%, whole blood clotting by 64% and platelet clumping by 50%. Analysis of the occurrence of the hemolysed serum comment, a preanalytical issue not associated with transit in extreme weather conditions, showed, as expected, no significant differences between use of the insulated shipper compared to the standard shipper.

The trend in increase in the occurrence of comments with each day of transport was apparent for both insulated and standard shippers. Standard shippers demonstrated a particularly substantial increase in the occurrence of comments from between day 2 and 3 (please see Table 2) for whole blood hemolysis and platelet clumping. The number of samples received after three days of transport is however very small and represents a small percentage of total shipments. The distinction between shipments arriving after one and two days is not as substantial and, as previously discussed, the occurrence of comments in shipments received one day after departure from the clinical site are less likely to be associated with transport issues.

Overall, results clearly demonstrated the ability of the insulated shipper to reduce the occurrence of platelet clumping and whole blood hemolysis and clotting in comparison to the standard shipper. DiscussionThe value of a high quality data set is paramount to the facilitation of an efficient and accurate assessment of drug safety and efficacy. Missing data points as a result of compromised sample integrity hinders the creation of such datasets. Results detailed within demonstrate the latest innovation within ICON Laboratories towards the maximisation of data quality and demonstrate the ability of the insulated shipper to reduce the occurrence of missing data points, thus ensuring a more complete and higher quality data set.

The ability for the shipper to reduce the occurrence of missing data points also has substantial benefit at a subject level. The enhanced ability to protect the integrity of samples during transit to the laboratory maximises the ability to generate results that may be critical to the overall safety of

Figure 1: The insulated shipper and instructions for use.

Table 1: Impact of shipment duration from clinical site to laboratory on sample integrity as measured by the increase in occurrence of commented results from day 1 to 2 and day 2 to 3.

Travel duration between site Increase from day Increase from day and lab 1 to 2 (%) 2 to 3 (%)All comments 39% 93%Whole blood hemolysis 58% 124%Whole blood clotting -3% 62%Platelet clumping 158% 91%

IT & Logistics


each study subject. This is a key feature of the shipper that is expected to be of increased benefit to studies with, e.g., small sample sizes or those focusing on acutely ill populations.

Lost data points are frequently followed with a request for a redraw, while this is suitable for those analytes that are not subject to substantial fluctuations over short periods of time, e.g., HbA1C, it is not suitable for those analytes which are, e.g., PD markers. Similarly, studies with a need to keep the quantity and volume of blood draw to a minimum will also benefit. Again, the insulated shipper has the potential to maximise recovery of such results. Such maximisation also has the potential to improve clinical site morale and participation in the trial.

The value of the insulated shipper at a geographical level was clearly demonstrated via the reduction in the occurrence of comments in shipments coming from Russia and the Ukraine. While this region was selected as a result of the extreme winter conditions frequently experienced there, it was somewhat unexpected that the rest of Europe would prove to experience very similar extremes in weather during the same period of time. One would expect that routine use of the shipper during winter months (we recommend November through March with extension dependent on prevailing weather) would benefit all geographical regions likely to be exposed to such extremes.

The increase in the rate of comments with each additional day of transit from clinical site to laboratory was clearly demonstrated. This observation is especially pertinent in consideration of the recent logistical challenges that have been experienced across Europe and abroad as a result of the extreme weather conditions of late 2010 and also the air traffic restrictions that resulted from the Icelandic and Chilean ash clouds. While these situations cannot be anticipated in advance, selection of the insulated shipper may offer a form of protection against the full impact of shipment delays on sample integrity as a contingency plan. To this end, ICON has multiple global stock locations to facilitate rapid implementation of this product.

In summary, the insulated shipper has demonstrated clear ability to reduce the occurrence of compromised sample integrity. This has many benefits ranging from enhancement of the quality of a study data set and maximisation of protection of subject safety, to providing the ability to reduce the impact to study samples as a result of unexpected delays in sample shipment to lab. ICON Laboratories are delighted to present this latest innovation to their service portfolio and look forward to presenting further future innovations which will again enhance the quality of study data sets and maximise safety of subjects.

The authors would like to acknowledge the extensive contributions that Caroline MacKell (Managing Director,

Europe and Singapore) and Brian Carthy (Manager, Logistics) made to the studies detailed within.

References• Brooks, C. 2010. Shipment of Biological Samples and Clinical Trial

Supply in Emerging Markets. Journal for Clinical Studies, May, p.42

• Eurocontrol a. 2010. The air traffic day by day http://www.eurocontrol.int/news/air-traffic-day-day-3

• Eurocontrol b. 2010. First Look at Delays in December 2010 http://www.eurocontrol.int/coda/gallery/content/public/docs/coda_reports/2010/FLAD1210.pdf

• Graziosi, A. 2010. Investigator Site Survey. Supplement to Applied Clinical Trials, p 30.

• Wegner, G., et al. 1987. Deformability of human red blood cells stored for different periods at subzero temperatures. Biomed Biochim Acta 46:599-603

• Wilding, P., Zilva, J.F., Wilde, C.E. 1977. Transport of specimens for clinical chemistry analysis. Ann Clin Biochem 14(6) p.301-306

• Williamson, J.R., Shanahan, M.O., Hochmuth, R.M. 1975. The influence of temperature on red cell deformability. Blood 46:611-624

• Andrew Roche, Ph.D. Associate Director, Scientific Affairs, ICON Central Laboratories

Andrew Roche Ph.D. has worked within the pharmaceutical industry for over 15 years. Since completing a Ph.D. in Medical Microbiology, Andrew has held various positions within the industry including those which have focused on the identification and validation of drug targets for large molecule

anti-infective therapeutics, the creation of novel diagnostic products and the custom design, development and validation of methods for analysis of biomarkers and biopharmaceuticals. Andrew joined the Scientific Affairs department of ICON in 2009 and aids internal departments and customers via the provision of scientific expertise. Email: [email protected]

Caroline Brooks has worked within the pharmaceutical industry for over 20 years. Having gained a BSc in Medical Laboratory Sciences she worked in a teaching hospital in the UK before joining one of the first dedicated Clinical Trial laboratories in London. In 2001 she moved into the

specialist courier business to apply her experience in supporting the supply chain for Clinical Trials and in 2008 returned to the central laboratory arena at ICON to manage the movement of outbound lab kits and inbound patient samples to their global lab locations. Email: [email protected]

Table 2: Increase in rate of occurrence of the respective comments with each additional day of transport from clinical site to laboratory for both standard and insulated shippers. The per cent reduction in respective comment occurrence for insulated shipments received across the combined three days, as compared to the standard shipper, is also shown.

Variation in comment occurrence from Day 1 to 2 (%) Day 2 to 3 (%) % Reduction with insulated shippersComment type Standard Insulated Standard Insulated across the combined three daysWhole blood hemolysis 126% * 944% ** 114%Whole blood clotting -5.2% 53% 54% 120% 64%Platelet clumping 83% 34% 578% 152% 50%Serum hemolysis 9.3% -14% -11% ** 2.0%* No hemolysis observed in samples arriving on day one of transport **No hemolysis observed for samples arriving on day three of transport

IT & Logistics

Increasingly, the issue of cardiac safety is becoming a major concern for clinical trials sponsors. Cardiac safety is one of the most prominent causes of late phase delays, labelling changes, and product recalls of drugs entering the market. Problems such as these can lead to a variety of negative repercussions for a company, such as severe cost implications, loss of trust from consumers, and demise of company reputation as a result of product recalls. These factors can significantly impact a company’s revenue in the long run. In order to exhaustively assess their impact on the cardiac health of patients and ensure public safety, all new drugs must undergo comprehensive clinical testing before they are released to the market. Accurate collection, analysis and interpretation of ECG data are therefore essential. As a result of this ever-growing concern around the importance of cardiac safety, regulatory scrutiny of the potential effect of all new compounds on the heart has become increasingly prominent in the industry.

In October 2005, the ICH E14 industry document was issued. This provides guidance to sponsors on a number of issues concerning the design, contact, analysis and interpretation of clinical studies to assess the cardiac safety of a drug. The document was adopted by the FDA (Food and Drug Administration), EMEA, Health Canada and the Japanese Ministry of Health, and recommends that a thorough ECG trial (TET) should be performed. Phase II trials will also require more robust or intense ECG collection. The guidance also stipulates the use of centralisation in cases where cardiac safety concerns are raised. In line with this, many other regulatory agencies are now demanding a standardised output of research data.

The adoption of centralised cardiac safety laboratories is one area where momentum is significantly increasing, however this activity is primarily undertaken due to regulatory requirements. Sponsors are often unaware that the benefits of using centralised ECG go beyond the sole advantage of compliance. Sponsors who adopt a centralised model can benefit from time and cost savings, dramatically improved data quality and accuracy, access to cutting edge technologies, and improved efficiency of processes. These benefits are now prompting, the pharmaceutical industry to fully recognise the advantages and substantial return on investment of centralisation.

Cutting the Cost Although the recognition of the benefits of centralisation have recently been made increasingly clear, many sponsors are still discouraged from using this model due to the false apprehension that it incurs greater costs than a localised method. This misapprehension mainly stems from the

hardware distribution associated with a centralised method. When a centralised model is employed, the majority of collection, transcription, cleaning and interpretation of ECG data is conducted by a core laboratory. With a decentralised method, this work is split between the existing sponsor and the individual monitoring site, and carried out using local ECG machines. As a result of this, many companies working within the industry perceive the core laboratory in a centralised system as an unnecessary added expense. However, research has shown that a centralised approach does in fact save costs.

Using a decentralised approach can often incur significant costs as sponsors must pay a considerable ECG acquisition fee, which includes charges for both technician time and the use of ECG machines at the investigator site. Contracting with a core lab reduces fees paid to each site for technical support and ECG reading (often by unskilled readers). Additionally, by eliminating errors in collections and transcription of ECG data, sponsors can minimise the amount of re-testing that must be carried out.

In a recent study of investigative sites by the Tufts Center for the Study of Drug Development (CSDD)1, it was found that despite initial financial concerns, there has been a shift in the opinion of a centralised approach. 70% of respondents identified the costs of using an ECG core lab as less than, or equal to, the costs of using paper. These cost savings are not only attributed to the work done at the time of study conduct, but also to the reduction of discrepancies and queries due to inconsistent interpretation during the statistical analysis and medical review phase. In the very rare case that centralised ECG providers do prove more expensive, most users often continue to implement the processes because pros such as improved data quality and accuracy far outweigh the cons, and justify the costs.

Enhanced Data Quality & Significant Time Savings Along with substantial cost savings, the use of a centralised model can also accelerate analysis time, leading to significant improvements relating to the reliability and accuracy of the data. This increases the chance of cardiac risk being detected earlier, reducing the risk of wasted time and cost expenditure planning for a potential drug compound that is ultimately not viable. High quality data is imperative; however, it cannot always be offered by a fragmented collection of local providers. The employment of a decentralised model means that ECG studies are carried out across multiple investigator sites, using local ECG machines. Consequently, inconsistent results often occur due to the variation of instrument models used across the different sites. This is a result of different types of instruments using varying algorithms

The Adoption of a Centralised Method for Significantly Improved Data Quality and Substantial Time and Cost Savings


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for calculations, and various interpretation guidelines and methods utilised by the local investigator or their contracted specialists. Moreover, this paper-based approach can lead to the occurrence of unexpected and unreliable results due to the manual transcription process and the site investigator’s individual interpretation of the results. These inconsistencies pose a significant challenge for sponsors, who require reliable data in order to accurately assess the cardiac safety of Phase I compounds.

The use of consistent and validated systems in a centralised approach means that the issue of inconsistency can easily be overcome. This method allows high quality data to be collected digitally in a standardised format for assessment Every ECG is evaluated by a qualified cardiologist who is trained to follow standardised procedures, whilst all interval duration measurements (IDMs) are assessed by qualified individuals. For added security, the processes are continually validated through a quality control programme. Additionally, many core laboratories also employ systems that are able to automatically check for missing visits or changes in demography. These standardised processes can result in sponsors benefitting not only from increased speed of analysis, but also much cleaner and more reliable data. The Tufts report showed that 97% of respondents rated the central lab as more accurate, and 90% viewed central labs as more efficient. Looking to the future, as a result of the more accurate and standardised data produced by ECG centralisation, 89% of respondents expected the use of centralised ECG to increase across the next five years.

Implementation of Innovative TechnologiesIt is becoming more and more important that pharmaceutical companies keep up with current trends, and invest wisely in new innovation and technology to ensure continued company success. The adoption of a centralised method allows clinical trials sponsors to gain access to a range of innovative technologies which will ultimately lead to more reliable, efficient and accurate results. Emergent technologies, such as lightweight and compact ECG machines, are made available through the use of core labs. These devices have a significantly smaller footprint than existing systems and remove the challenges raised by more traditional heavy and expensive instrumentation.

Additionally, these innovative ECG devices are much easier to manoeuvre and less costly to ship and store, making the centralised method far more accessible. Their compact size means that the cutting-edge instruments also offer an improved service on a technical level, effortlessly integrating with computer systems through a web application whilst also offering more consistency and improved accuracy.

The pharmaceutical industry is increasingly seeing the fast adoption of these new highly compact instruments in a bid to overcome the issues of using larger ECG equipment.

Making the Change Increasingly, sponsors are making the wise choice to look beyond the issue of regulatory compliance and recognise the value and advantages of ECG centralisation. As indicated by the Tufts report, irrespective of regulations becoming more or less stringent, ECG centralisation is progressively being recognised as a more accurate cost-effective and preferable method for conducting cardiac safety reporting within a trial. The application of the centralised model holds a myriad of benefits for the industry in a number of important areas and significantly reduces overall costs. The model enables data quality and data capture to be significantly improved, as well as dramatically reducing the workload for sponsors and the investigator site.

The introduction of the centralised model has provided the industry with significant improvements to the traditional decentralised paper-based ECG methodologies, which are associated with a number of clear shortcomings. The centralised method can result in improved patient safety, increased productivity, enhanced service, greater satisfaction and potential dramatic cost savings. These countless benefits beyond just compliance lead to the prediction that in coming years, more and more companies will adopt a centralised method in their clinical studies to provide a more effective and reliable way to analyse and manage the cardiac safety profile of a compound.

References1. Mapping Adoption of Centralized Cardiac Safety Assessment

Study Report, Tufts Center for the Study of Drug Development (Tufts CSDD) March 2010

Amy Furlong, Executive Vice President, Chief Operations Officer - Amy has been Executive Vice President of Cardiac Safety at ERT since December 2005 and previously served as Senior Vice President of Regulatory Compliance. She holds a Bachelor of Science degree in Biology and

a Master of Science degree in Quality Assurance and Regulatory Affairs from Temple University’s School of Pharmacy. Amy has more than 15 years of clinical research experience specialising in regulatory compliance and computer system validation.Email: [email protected]


IT & Logistics

Matching Patients with Biomarker-Driven Cancer Trials - genetic Sequencing Might helpCancer researchers are developing a catalog of potential targets for novel treatments while they continue to identify genetic mutations powering different cancer subtypes.

Recently, the University of Michigan Comprehensive Cancer Center and Michigan Center for Translational Pathology (MCTP) completed a pilot investigation. The goal of the study was to solve the practical challenges researchers face in quickly and systematically sequencing genetic material from individuals suffering with advanced or treatment-resistant cancer so that they can be matched with existing clinical trials based on the biomarkers identified. Findings from the exploratory investigation, known as the Michigan Oncology Sequencing Project (MI-ONCOSEQ) are published in Science Translational Medicine.

Co-lead investigator Dr. Dan Robinson, a post-doctoral fellow at MCTP, explains:

“We’re talking about more than just examining a few genes where mutations are known to occur, or even about a hundred genes. We’re talking about the ability to sequence more than 20,000 genes and look not just for individual genetic mutations, but at combinations of mutations.”

The researchers discovered that identifying an individual’s “mutational landscape” offers a promising technique for determining which trials could help a patient the best. Source: University of Michigan

Coffee Emerges As Protective Against Cancer and Other DiseasesStarbucks fans around the world can rejoice that their tipple gets the thumbs up yet again. Already shown to protect against a number of diseases, a recent study in the Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, shows coffee drinkers who consume more than four cups a day have a 25% lower risk of developing Endometrial Cancer. It is thought that the antioxidant properties in coffee may be a part of the mechanism.

Edward Giovannucci, M.D., Sc.D., professor of nutrition and epidemiology at the Harvard School of Public Health, and a senior researcher on the study, said coffee is starting to be proven as a protective agent in cancers that are linked to obesity, estrogen and insulin.Source: Medical News Today

Vaccine Targeting Latent TB Enters Clinical TestingStatens Serum Institut and Aeras today announce the initiation of the first Phase I clinical trial of a new candidate TB vaccine designed to protect people latently infected with TB from developing active TB disease. The trial is being conducted by the South African Tuberculosis Vaccine Initiative (SATVI) at its

field site in Worcester, in the Western Cape province of South Africa. Dr. Hassan Mahomed is the principal investigator.

“Two billion men, women and children live with latent TB infection,” said Jim Connolly, President and Chief Executive Officer of Aeras. “It’s daunting to comprehend that there is a vast reservoir of people with a 5-10% lifetime risk of becoming sick with TB. A vaccine that prevents TB disease in this population could save millions of lives, and this trial is a first step in assessing a vaccine candidate designed for this purpose.”

The candidate TB vaccine (SSI H56-IC31) is a subunit vaccine containing recombinant TB proteins formulated in a proprietary adjuvant IC31® from Intercell. It is being developed under a consortium of researchers led by Peter Andersen at the Statens Serum Institut (SSI) based in Copenhagen. The consortium is supported as part of the Grand Challenges in Global Health, an initiative that fosters scientific breakthroughs needed to prevent, treat and cure diseases of the developing world.


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SSI H56-IC31 is being developed for both adolescent and adult populations. The trial has been approved by the Medicines Control Council of South Africa. Preliminary results of this trial are expected at the end of 2012. Source: by JCS Staff Reporter, Jaypreet Dhillon

European Commission launches framework for research and innovationEFPIA, the voice of the research-based pharmaceutical industry in Europe, welcomes the launch of the European Commission’s new Framework for Research and Innovation: Horizon 2020.

“The European Commission should be commended for their intention to further develop public-private partnerships (PPP). There is shared understanding that private companies and public bodies must collaborate more and to think about new business models which allow us to work much more quickly to meet unmet needs,” said Richard Bergström, director general of EFPIA.

He added: “EFPIA confirms industry interest in continuing

public private collaborations which will enable game changing biopharmaceutical research projects that address scientific and technological bottlenecks in areas with grand societal challenges, such as antimicrobial resistance. Such PPPs in life sciences will clearly contribute to the three cornerstones of the Commission proposal: excellent science, industrial leadership and tackling societal challenges.”

Horizon 2020 will be the EU’s funding instrument to implement the Innovation Union. This framework is part of the European Commission’s proposed European Union budget for the period 2014 to 2020. Horizon 2020 is designed to last until the end of this decadeSource: Center Watch News

Bristol-Myers and Johnson & Johnson to Study Combination Therapy for hepatitis C

Bristol-Myers Squibb Co. will collaborate with a unit of Johnson & Johnson to study a potential combination therapy for chronic hepatitis C. The companies will test the potentially positive effects of combining Johnson & Johnson’s drug TMC435 with Bristol-Myers Squibb’s daclatasvir. The clinical trials will begin in the first half of 2012 and will include a combination of the two drugs, the drugs plus pegylated interferon and ribavirin, and the drugs plus ribavirin.

The terms of their partnership were not disclosed.Source: by Dr. Trupti Shirole, JCS India

“No decision about me, without me”It’s one of the latest political catchphrases in relation to the health service, and describes a vision of healthcare where the patient is – if not an equal partner – then certainly an active participant in treatment decisions

It’s one of the latest political catchphrases in relation to the health service, and describes a vision of healthcare where the patient is – if not an equal partner – then certainly an active participant in treatment decisions. In the field of clinical research the concept is already taking hold, with patients and their carers starting to play a greater role in determining the research agenda.

Articulate, energetic, and with a passion for putting something back into the NHS, Rosemary Humphreys is one of a growing number of “lay” consultants: patients and carers who are helping to shape what research is done in our surgeries and hospitals, and the way it is carried out. In common with fellow non-clinical advisers, she believes strongly in the value of research to the NHS – but feels that the patient role should extend beyond simple participation in a trial.

“At one point I was sceptical about the value of involving patients,” he admits, “but now I am an enthusiast. Patients bring a fresh perspective to research. They add value from the development of the hypothesis right through to dissemination of the results.”Source: Mark Barker, JCS – Pharma Publications



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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 the DIA Cardiovascular Safety meeting in Japan. Chrysanthemum is the National Flower of Japan, which features on the Front Cover. I hope this journal guides you progressively, through the maze of activities and changes taking place in these Emerging Countries.

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