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FDA Raises the BarIn Bioanalytical Method Validation

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The Elements Requiring Particular Attention While Conducting Clinical Trials in a Paediatric Population

Going Native? Deciding the optimal app approach for smartphone eCOA

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THE DOMINO EFFECT When the Patient Recruitment Leader MediciGlobal is not Involved

Wouldn’t it have been easier just to call MediciGlobal?

BECAUSE MediciGlobal wasn’t involved in recruiting for the trial, there were not enough patients.

BECAUSE the trial did not have enough patients, the trial fell behind schedule.

BECAUSE the trial fell behind schedule, the pipeline was changed.

BECAUSE the pipeline was changed, revenue targets were missed.

BECAUSE revenue targets were missed, investors lost faith.

BECAUSE investors lost faith, the stock price plummeted.

BECAUSE the stock price plummeted, the board issued a statement.

BECAUSE the board issued a statement, “the CEO is cleaning out his desk”.

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Contents

Journal for Clinical Studies 1www.jforcs.com

04 FOREWORD

WATCH PAGES06 Action Plan to Address Demographic Subgroup Data in FDA Product Applications

The Food and Drug Administration Safety and Innovation Act, directed the US Food and Drug Administration (FDA) to report on the extent to which demographic subgroups participate in clinical trials in marketing applications for drugs, biologics, and devices. Regina Ballinger of Thomson Reuters discusses the Action Plan which follows the publication of this report.

08 The Cardiac Safety Research Consortium “Think Tank” for CV Outcome Studies: February 19, 2014

The Cardiac Safety Research Consortium was organised “to advance scientific knowledge on cardiac safety for new and existing medical products.” In February 2014, the CSRC sponsored an “Outcomes Think Tank” where the value of cardiovascular outcome studies for both cardiovascular and non-cardiovascular therapies was discussed. L. Allen Kindman and Philip Galtry of Quintiles report on this conference.

10 Dementia, Cognitive Impairment, and Arterial StiffnessVascular cognitive impairment (VCI) and its more severe manifestations such as Alzheimer’s disease are debilitating conditions which have a significant impact on the patients themselves, as well as their families and caregivers. Bobby Stutz and Dr Winter of Atcor Medical Inc. describe how the evidence accrued to date strongly suggests that evaluation of arterial stiffness and management of central BP could play a useful role in reducing the decline in cognitive function.

12 Logistics in Emerging Markets Column: Singapore Investing in the Future of Life Sciences

More than a decade ago, the Singaporean government decided to invest heavily in the infrastructure needed to smooth the transit of pharmaceuticals - including clinical trial supplies, and subsequently target the life sciences industry. Sue Lee of World Courier explores how their decision to do so is now reaping rewards.

14 ADHD: Then and NowSymptoms of Attention Deficit/Hyperactivity Disorder (ADHD) have been documented in medical literature since the late 1700s, but were not serendipitously treated until 1937, when Benzedrine was observed to improve the behaviour and school performance of children with severe headaches. Craig Earl of INC Research examines how symptoms and treatments have developed, and describes how the remaining challenges continue to be the proper diagnosis and treatment of adults with ADHD.

REGULATORY16 Risk-based Monitoring: Roundtable Discussion

A risk-based monitoring (RBM) approach has opened a pathway to the enhanced quality conduct and reporting of clinical study that the industry has been seeking for many years. Ashok Ghone of MakroCare, Sandra Sather of Clinical Pathways LLC, Sue Fitzpatrick of Redtree People, and Jane Tucker discuss some of the key aspects of RBM-like risk assessment, including: risk management, monitoring plan, centralised monitoring, and technology.

MANAGING DIRECTOR Martin Wright

PUBLISHERMark A. Barker

EDITOR Cecilia Stroe

EDITORIAL MANAGERHolly Barnes

DESIGNER Fiona Cleland

RESEARCH & CIRCULATION MANAGEROrsolya Balogh

BUSINESS DEVELOPMENTRichard Goodard

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PUBLISHED BY Pharma PublicationsUnit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DGTel: +44 0207 237 2036Fax: +0014802475316Email: info@pharmapubs.comwww.jforcs.com

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

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 6 Issue 3 May 2014 PHARMA PUBLICATIONS

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20 FDA Raises the Bar in Bioanalytical Method ValidationFor many years, the FDA guidance on bioanalytical method validation (BMV), issued by the CDER in 2001, has been the Holy Grail for laboratories which deal with the pharmacokinetic analysis of drugs and their metabolites in clinical trials. A revised version has been expected since the EMA issued its guideline on BMV in 2012. Stephan Wnendt of MLM Medical Labs GmbH summarises the new FDA draft guidance, and considers its implications for clinical studies.

MARKET REPORT24 Advantages and Challenges Facing Clinical Research in South Africa

Clinical research has a long history in South Africa and dates back as far as the 1960s. Over the past two to three decades, as pharmaceutical research has proliferated and the need for investigator sites has grown, medical doctors - have established their own research units to fulfil this need. Dr Gavin W Leong and Karen Mallalieu of Criterium Inc. explain the advantages and challenges of conducting clinical trials in South Africa.

28 Mauritius: An Emerging Centre for R&D in Biotechnology and the Life Sciences

The economy of Mauritius has been successfully transitioned from a monocrop to a diversified innovation-driven and knowledge-based economy. Emerging sectors such as healthcare and life sciences are presenting some niche areas for the taking, and the enabling environment is being put in place to make it happen. Dr Géraldine Jauffret and Claire Blazy Jauzac of CIDP (Centre International de Développement Pharmaceutique) discuss the transformation of Mauritius into a medical hub.

30 Setting the Standard for Central Labs in Asia Pacific and China

For more than two decades, central laboratories have played an important part in running global and large multi-regional clinical trials in Europe and the United States. With the rapid increase in the number of global clinical trials in China and the Asia Pacific region, trial sponsors should understand how to choose central labs in those regions. Dr Chiew Yan Lee and Jerry Boxall of ACM Global Central Laboratory explain why trial sponsors will continue to require a separate central lab in China, and how these labs should be set up.

THERAPEUTICS36 The Elements Requiring Particular Attention while Conducting Clinical Trials in a Paediatric Population

Children account for 20-40% of the global population depending on the region, but only a third of all medications are officially approved to treat children. Maxim Belotserkovsky, Iryna Teslenko and Maxim Kosov of PSI CRO AG outline and review the elements to which particular attention should be paid when planning and conducting paediatric clinical trials.

42 Implications of Paediatric Asthma in Clinical TrialsAsthma bronchiale is the most common and most frequent chronic illness in childhood. The global prevalence of paediatric asthma has continuously increased over the past few decades across many different countries. Andrea Banfi of Auxiliis’ “Svábhegy” Health Service Ltd states

that the most important factor in cost reduction of paediatric asthma treatment is improving asthma control; and explains how carefully planned asthma management programmes can reduce the burden.

44 Paediatric Clinical Trials in Central and Eastern Europe: Here and Now

Paediatric trials are a core part of clinical development. Not only is there a commercial incentive to develop paediatric treatments, but there is also a moral imperative. Dr Malgorzata Szerszeniewska of EastHORN describes how, every month, new precedents are set and regulations clarified for the practical purpose of attracting high-quality paediatric clinical research in Eastern Europe.

IT & LOGISTICS48 Going Native? Deciding the Optimal App Approach for Smartphone eCOA

It is estimated that over half of the global population owns a mobile phone, and with 680 million active mobile users of Facebook each month and 120 million using Twitter on their mobile phones, the opportunity to reach the patient is huge. Bill Byrom of Parexel Informatics explores the different ways in which functionality can be delivered to mobile devices, and the benefits and limitations of each when applied to the collection of eCOA in clinical trials.

54 Mobile App Development for Clinical TrialsMobile devices and apps are set to become an essential part of clinical trials. Their connectivity, along with high processing speeds, high-quality visual displays, and ability to interface with other devices via protocols, make smartphones an ideal choice for capturing participant data in clinical research. Justin Johnson of FirstApp examines these issues, which range from sourcing and development methodologies, to validation and deployment strategies. performed in the 1980s.

58 The Changing Face of Healthcare: Medical Apps & Crowdtesting

Because doctors and patients rely on the information and tools around cure, ensuring quality and safety are of paramount importance in gaining their trust in medical apps. Crowdtesting subjects medical apps to an exhaustive battery of tests performed under real-world conditions on a variety of devices. Dieter Speidel and Mithun Sridharan of PASS Group describe how many of the challenges facing mHealth apps can be thoroughly addressed through crowdsourcing testing and evaluation.

62 JCS Interviews Tim Davis of Exco InTouch on the Use of Mobile Technology in Clinical Trials

The growth of mobile technology is now recognised by the pharmaceutical industry as an opportunity to change the way we interact with patients during clinical trials. JCS sat down with Tim Davis of Exco InTouch to find out why he believes taking a mobile approach can enhance clinical research for patients and sponsors alike.

Contents

Volume 6 Issue 32 Journal for Clinical Studies

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The JCS May issue brings to your attention the so-called “minefield” of paedriatic research, arguably one of the most challenging areas from an ethical, medical and regulatory point of view. There is a moral imperative to develop paedriatic treatments that goes beyond the commercial incentive, thinks Dr Malgorzata Szerszeniewska of EastHORN, who provides in-depth insight into running paedriatic trials in countries from Central and Eastern Europe. It seems that, although this market is not yet mature, it is rapidly catching up: with the right partners able to negotiate the “hurdles and pitfalls”, sites in this region can easily enroll more significant numbers of patients faster than their more “sophisticated” Western European and North American counterparts.

“Children are not small adults.” Andrea Banfi of Auxiliis’ “Svábhegy” Health Service Ltd explains why this saying is particularly true when it comes to asthma bronchiale, the most common and frequent chronic illness in children, with a global prevalence that

has relentlessly escalated over the past decades. Clinical trials may help to elucidate the actual causes and hopefully establish new therapeutic strategies.

To outline the critical issues that need to be addressed when planning and conducting paedriatic clinical trials, Maxim Belotserkovsky, Iryna Teslenko, and Maxim Kosov of PSI CRO AG analysed the results of clinical studies involving over 1400 patients aged between 1 and 18 years old. Get the hang of the regulatory “sticks and carrots” and find out how to raise the chances of success of a clinical trial in a paedriatic population.

In the IT & Logistics section, we pursue our series on the opportunities and challenges of “m-health”. Bill Byron of Parexel Informatics talks about “going native” and deciding the optimal app approach for smartphone and eCOA. There is little doubt, he argues, that mobile solutions offer tremendous opportunities to interact with the patient throughout the course of a clinical trial.

As Justin Johnson of FirstApp explains, mobile apps are set to play a significant role in ePRO clinical trial participant data capture. It all comes from the key feature of mobile devices – the ability to be “always connected”. And it is this connectivity, along with high processing speeds, high quality visual displays, and the ability to interface with other devices via protocols such as Bluetooth, that makes smartphones the tool of choice for capturing participant data in clinical trials.

Dieter Speidel and Mithun Sridharan of Pass Group believe the adoption of mobile technology happened at “breakneck speed” and has transformed the healthcare industry, creating an area of innovation (mHealth) fuelled by numerous mobile applications developed and released by companies and developers alike for general use by lifestyle consumers, patients and healthcare professionals. But medical apps are tricky tools placed in the hands of doctors and patients, having the power to significantly impact healthcare outcomes. Apparently, even though “crowdtesting” delivers tremendous benefits to medical app development companies, navigating the murky waters of regulatory bodies, software engineering, the healthcare ecosystem, consumer psychology, etc. is a major venture in itself.

Well, the good news is that medical app development companies and entrepreneurs do not have to sail these waters on their own. As always, it comes down to finding a trusted partner to help them glide across the murky waters.

You`ll find out from JCS’s Q&A with Tim Davis of Exco InTouch, that within clinical trials, the use of mobile technology is revolving around maintaining the relationship and the contact, and ensuring the patient feels valued. It’s about integrating remote monitoring and data collection into the patient’s everyday life, but also having the ability to correlate subjective personal analysis from a patient with objective data from a medical device that is connected to their mobile phone. This gives enormous value to the data construct for that particular clinical trial, providing a better, quicker and more accurate model. What everyone has been striving for in clinical research for decades!

Cecilia StroeEditor

Foreword

Editorial Advisory Board

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

Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA

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

Cellia K. Habita, President & CEO, Arianne Corporation

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

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

Elizabeth Moench, President and CEO of MediciGlobal

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, MD, 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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

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

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

Volume 6 Issue 34 Journal for Clinical Studies

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Volume 6 Issue 36 Journal for Clinical Studies

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Action Plan to Address Demographic Subgroup Data in FDA Product Applications

The Food and Drug Administration Safety and Innovation Act (Pub. L. 112-144) (FDASIA), in Section 907, directed the US Food and Drug Administration (FDA) to report on the extent to which demographic subgroups (sex, age, race, and ethnicity) participate in clinical trials in marketing applications for drugs, biologics, and devices1. This assessment report, issued in August 2013, provides a review of information derived from sponsor applications, FDA reviews, and product labelling on the status of this data in product applications. Section 907 also requires that FDA develop an action plan no later than one year following publication of the report. The legislation directs that the content of the action plan includes recommendations as appropriate for different product types on the following topics/issues/concerns:

• Ways to improve the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data, and in labelling

• The inclusion of demographic subgroup data, or the lack of availability of such data, in labelling

• Improve the public availability of subpopulation data to patients, healthcare providers, and researchers.

At a public meeting on April 1, 20142, various stakeholders presented their comments to an FDA panel. The FDA framed the meeting by asking several questions pertaining to issues and challenges associated with the collection, analysis, and availability of demographic subgroup data in applications for approval of FDA-regulated human medical products. The comments and discussions, in addition to comments to the public docket, will be used to assist in developing the action plan mandated by FDASIA. These regulatory activities are a likely precursor to more stringent requirements regarding the inclusion of demographic subgroup analysis in product applications.

The overwhelming recommendation made at the public meeting focused on the need for the FDA to initiate mandated requirements for product sponsors regarding the inclusion of appropriate demographic subgroups in clinical trials, and the information on any related analysis. Further, stakeholders recommended that the FDA develop and maintain a formal system to monitor compliance, track clinical trials, and make the results of studies of demographic subgroups readily available to the public. The stakeholder recommendations for mandating requirements were cross-cutting, extending to devices as well as drugs and biologic products. Many presenters also recommended an incentive plan, either similar to other expedited review pathways (i.e., fast track) or with some sort of “conditional approval” elements applied.

The stakeholders presenting at the meeting also urged the FDA to complete guidance on recommendations for providing subgroup information and analysis in clinical studies. There are some general FDA guidance documents to direct sponsors on providing demographic subgroup information, but in many instances these documents have not been recently updated or finalised. Many of these are listed in the FDA’s August 2013 report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products3.

One of the more recent guidances - the 2011 Draft Guidance for Industry and Food and Drug Administration Staff, Evaluation of Sex Differences in Medical Device Clinical Studies4 - targets device applicants. Another guidance document - the Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials5

- issued in 2005, describes the FDA’s recommendations for sponsors of new drug applications (NDAs) on presenting a summary of safety and effectiveness data by demographic subgroups (age, gender, race), as well as an analysis of whether modifications of dose or dosage intervals are needed for specific subgroups.

The public also made recommendations on ways to improve the available data on demographic subgroups, and on communicating information to the public. Comments on the latter point often focused on

information in product labelling. Many participants recommended that the FDA establish standardised requirements in labelling for medical products that would detail subgroup demographic information and analysis. Such labelling information would also include a statement that noted whether or not the population studied could support efficacy and safety. Alternatives to labelling were also offered as recommendations. These included using experts on public communication to make recommendations, use of internet-based tools, and possibly a “demographic guide” that would provide information to patients on the use of products for specific subgroups. Additional public comments on this topic are available at regulations.gov by accessing the FDA docket: FDA-2013-N-0745-0022.

References1. Food and Drug Administration Safety and

Innovation Act (Pub. L. 112-144) (FDASIA) http://www.fda.gov/RegulatoryInformation/Legislation/F e d e r a l F o o d D r u g a n d C o s m e t i c A c t F D C A c t /S i g n i f i c a n t A m e n d m e n t s t o t h e F D C A c t / F DA S I A /default.htm. Accessed April 15, 2014.

2. Federal Register: Action Plan for the Collection, Analysis and Availability of Demographic Subgroup Data in Applications for Approval of Food and Drug Administration-Regulated Medical Products; Notice of Public Hearing; Request for comments (Notification of public hearing; request for comments), March 4, 2014 (Volume 79, Number 42) (Pages 12134 – 12135).

3. Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products. FDA Website. http://www.

f d a . g o v / d o w n l o a d s / r e g u l a t o r y i n f o r m a t i o n /legislation/federalfooddrugandcosmeticactfdcact/s i g n i f i c a n t a m e n d m e n t s t o t h e f d c a c t / f d a s i a /ucm365544.pdf August 2013. Accessed April 14, 2014

4. Guidance for Industry and Food and Drug Administration Staff, Evaluation of Sex Differences in Medical Device Clinical Studies (draft). FDA Web site. http://www.fda.gov/Medica lDevices/DeviceRegulat ionandGuidance/GuidanceDocuments/ucm283453.htm December 2011. Accessed April 14, 2014.

5. Guidance for Industry, Collection of Race and Ethnicity Data in Clinical Trials for FDA Regulated Products. FDA Web site. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126396.pdf September 2005. Accessed April 14, 201

Regina Ballinger is a Senior Manager of Regulatory Intelligence with Thomson Reuters. She has been employed by Thomson Reuters for 11 years and currently manages US regulatory content for the Cortellis Regulatory Intelligence database (formerly IDRAC), and is the executive editor of the AdComm Bulletin. Ms. Ballinger has been employed in the health care industry

for over 20 years with specialized experience in public health, pharmaceutical regulatory affairs, health communications, nursing, and occupational safety and health. She has had numerous articles published on topics related to new drug approvals and drug regulatory issues. Ms. Ballinger was educated at the University of Maryland in law and nursing. She holds an MS degree in Healthcare Systems Management.Email: regina.ballinger@thomsonreuters.com

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Journal for Clinical Studies 7www.jforcs.com

8 Journal for Clinical Studies Volume 6 Issue 3

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The Cardiac Safety Research Consortium “Think Tank” for CV Outcome Studies: February 19, 2014The Cardiac Safety Research Consortium was organised in 2006 by the Duke Clinical Research Institute, FDA, and stakeholders from the pharmaceutical and device industries, “To advance scientific knowledge on cardiac safety for new and existing medical products by building a collaborative environment based upon the principles of the FDA’s Critical Path Initiative as well as other public health priorities”. The CSRC organises meetings of interested stakeholders on specific topics. In February, the CSRC sponsored an “Outcomes Think Tank”. The value of cardiovascular outcome studies for both cardiovascular and non-cardiovascular therapies was discussed. The panel included representatives from the FDA, academia, and industry. A synopsis of the meeting has been released (https://www.cardiac-safety.org/think-tanks/february-2014) and a thorough review of the conference is in preparation.

Over the past 20 years, several high-profile market restrictions and withdrawals have increased awareness by the public, legislators and regulators of the potential cardiovascular risk associated with new medicines. Risk associated with prolongation of the cardiac QT interval has been largely mitigated by the promulgation of the Thorough QT study, as outlined by both the FDA and the EMA. As noted by Dr Robert Temple, it is not likely we will be confronting the issue of unexpected QT prolongation and resultant torsade de pointes again.

Cardiac risk broadly falls into three categories: Risk accompanying medicines designed to treat cardiovascular conditions in patients with cardiovascular disease, risk of medicines prescribed for management of non-cardiovascular conditions in otherwise healthy patients, and risk associated with medicines used to treat non-cardiac conditions in patients vulnerable to cardiac disease. The conference focused on several high-profile case studies of excess cardiovascular risk; what signals, if any, were present in the pre-NDA studies; and how subsequent post-approval safety studies lead to re-assurance, or restriction or even withdrawal from the marketplace. A general consensus was reached on several points:

1. Cardiovascular outcome trials are not practical for all drugs, indications, or types of patient. Vulnerable patients and indications do deserve particular attention, if even small safety signals are noted pre-NDA, particularly if plausible mechanisms leading to harm could be inferred.

2. Biomarkers can serve an important role as an indicator of potential hazard. In the absence of a significant signal of a well-validated biomarker such as blood pressure, additional study may not be necessary.

3. Meta-analyses should be considered hypothesis-generating only. Since there are many ways to perform these studies, at relatively little expense, it is incumbent upon the scientific community to develop more standardised method approaches which will minimise bias and risk of multiple measures.

4. Sponsors should proactively and aggressively adjudicate cardiovascular events using standard definitions for revascularisation, myocardial infarction, cardiac death, and stroke. It was also pointed out that the definition of major adverse cardiac events should probably be broadened to include acute heart failure and other vascular events.

5. Very well-designed and carefully controlled registry and post-marketing outcome studies can contribute high-quality data. As real-time clinical data become more readily available through

the integration of electronic health records into post-marketing surveillance programmes, even more data will be available. The FDA discussed its efforts using the MINI-SENTINAL system (WWW.MINI-SENTINAL.ORG). In some cases, pre-existing registries, such as those sponsored by the National Cardiovascular Data Registry, may have already collected relevant and useful data (WWW.NCDR.COM). Representatives from NCDR were very quick to point out that the registry is unusual, and other fields or specialities have not made the same investment in infrastructure needed to create a similar database. In reality, even the NCDR is limited in its scope, and there are practical limits to the amount and quality of data that can be collected prospectively. Thus new questions require supplemental databases, and added expense. And missing data will still need to be obtained in the usual way.

6. Finally, all agreed that concern about the cost of increasingly large trials is driving development decision-making and might be preventing needed medicines from reaching patients.

While the Thorough QT study, and a much better molecular understanding of the ion channels driving malignant arrhythmias, have mitigated the arrhythmic risk of new molecular entities, aside from blood pressure, LDL cholesterol, and hemoglobin A1C, there is as yet little consensus regarding surrogate markers predicting other cardiovascular events. So for the foreseeable future, cardiovascular outcome trials will continue to be needed.

L. Allen Kindman MD, FACC is Medical Director, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. He is also a Clinical Professor of Medicine at the University of North Carolina, Chapel Hill. Until recently, he was an interventional and non-invasive cardiologist. Email: allen.kindman@quintiles.com

Philip Galtry is Vice President and Cardiovascular Therapeutic Strategy Head, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. Philip holds an Honours degree in Biochemistry from the University of Bristol, UK, and has worked in the management of cardiovascular studies for almost 25 years. Email: philip.galtry@quintiles.com

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10 Journal for Clinical Studies Volume 6 Issue 3

Dementia, Cognitive Impairment, and Arterial Stiffness

Vascular cognitive impairment (VCI) and its more severe manifestations such as Alzheimer’s disease are debilitating conditions having significant impacts on the patients themselves, and their families and caregivers. The primary risk factor for cognitive dysfunction is age1 and, with life expectancy increasing, the burden of cognitive impairment is becoming significant. Gaining a better understanding of the pathophysiology associated with cognitive dysfunction may provide insight into potential mechanisms for prevention of accelerated cognitive decline and dementia. Traditional risk factors for cardiovascular disease such as hypertension, diabetes mellitus, and hypercholesterolemia may also be risk markers for VCI and Alzheimer’s disease. Recently, the American Heart Association and the American Stroke Association released a joint scientific statement reviewing the vascular contributions to cognitive impairment and dementia, identifying arterial stiffness as a potential risk marker for VCI2. Before discussing how arterial stiffness may contribute to accelerated cognitive decline, it is important to understand the basic functions of the arteries.

With each heartbeat, blood is ejected in spurts, during systole, from the left ventricle into the aorta. The function of the aorta and the rest of the arterial tree is then twofold: to serve as a cushion and a conduit. Its elastic components expand to absorb the pulsatile pressure and flow generated by the heart and, for most organs, deliver it in an almost steady-state manner to peripheral arterioles and capillaries as the vessel slowly recoils. The brain is unique, however, in that it is one of only a few organs that does not have the ability to regulate the amount of pulsatile phenomena to which it is exposed, thus making it susceptible to increased fluctuations of pressure and flow3.

Progressive stiffening occurs in the central elastic arteries, i.e. the aorta, with advancing age. This stiffening can also be accelerated under certain pathophysiological conditions. As a consequence of increased arterial stiffness, both the amplitude of the central blood pressure wave (the central pulse pressure, CPP) and the speed at which it propagates through the vessels (pulse wave velocity, PWV) are increased. These increased pulsations are transmitted into the microvasculature of the brain, predisposing it to rupture of the arterial walls and microhemorrhages, with resultant microinfarcts, and a predisposition to dementia4.

Considering that blood pressure (BP) in the aorta differs from that in the periphery, the change in CPP cannot always be reliably appreciated from conventional brachial cuff sphygmomanometric values – the values traditionally used in clinical practice. For example, in normal aging, the brachial pulse pressure may increase from 40 mmHg at age 20 to 65 mmHg at age 80, or 63%, while CPP may increase from 22 to 65 mmHg - a gain of 200%, over the same timeframe5. This is believed to partially explain why central BP values and waveform characteristics have been demonstrated to be more strongly predictive of future cardiovascular events than brachial BP6. Additionally, the measurement of aortic PWV is considered to be a direct measurement of aortic stiffness, and has also been shown to improve risk prediction when added to traditional cardiovascular risk assessment models7.

Research has shown an association between microvascular brain lesions and cognitive decline. A recent review by Singer et al. examined the associations between arterial stiffness and structural change in the brain, specifically lacunar infarction and white matter hyperintensities as markers of small vessel disease, and found a consistent association between PWV and hyperintensities and infarcts8. In another study not included in the review, Hughes et al. have expanded on these findings demonstrating that an increase in aortic PWV over two years was associated with an increase in β-amyloid plaque deposition, a pathologic feature of Alzheimer’s disease9.

Singer et al. also examined the associations between arterial stiffness and cognitive decline. Cross-sectional studies provided highly consistent evidence of arterial stiffness being associated with cognitive decline, while longitudinal examinations found PWV to be predictive of declining cognitive function. In one of the studies reviewed, Hanon et al. found higher aortic PWV to be significantly associated with cognitive function (Figure 2), with aortic stiffness appearing to be an independent determinant of Alzheimer’s disease10. Another investigation found aortic stiffness to be the single strongest predictor of cognitive decline11. Several large prospective studies have since published similar findings12,13, but there have been some inconsistencies14.

Finally, Pase et al. recently demonstrated that central systolic BP, CPP, and pulse pressure amplification (the relative increase in pulse pressure as it travels from the central to the peripheral arteries) were sensitive predictors of cognitive aging. These aspects of cognitive function were not associated with changes in brachial BP15.

Clinical strategies need to be developed to mitigate the risk of

Figure 1: Schematic diagram of pulsatile peripheral flow in a young (top) and old subject (bottom). In a young person (top), as the arteries are distensible, the cushioning function of the arteries absorbs most of the pulsatility. In the older subject, however, stiffening of the arteries causes loss of their ability to cushion pulsatility of the blood flow, thus this will extend further into highly perfused organs such as brain and kidneys. Flow through normally perfused vascular beds is represented at the right of each model, and is nonpulsatile. Flow to highly perfused vascular beds such as brain and kidneys is represented at left. Perfusion of these beds becomes highly pulsatile when arteries are stiff (bottom left).

Figure 2: Relationship between PWV and cognitive status

accelerated cognitive decline and progression to VCI or Alzheimer’s disease, and likely requires a multifaceted approach. The evidence accrued to date strongly suggests that evaluation of arterial stiffness and management of central BP could play a useful role in reducing the decline in cognitive function.

References1. Mayo Clinic Staff. (2012). Mild Cognitive Impairment [online].

Available: http://www.mayoclinic.org/diseases-conditions/mild-cognitive-impairment/basics/risk-factors/con-20026392 [2014, March 26].

2. Gorelick Philip B. et al. (2011, Sept). Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 42 (9), 2672-713.

3. O’Rourke MF and Safar ME (2005, July). Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension, 46 (1), 200-4.

4. Adji A et al. (2011, Jan). Arterial stiffness, its assessment, prognostic value, and implications for treatment. Am J Hypertens, 24 (1), 5-17.

5. O’Rourke MF. (2007, Nov). Arterial aging: pathophysiological principles. Vasc Med, 12 (4), 329-41.

6. Roman M et al. (2009). High central pulse pressure is independently associated with adverse cardiovascular outcomes the strong heart study. J Am Coll Cardiol, 54 (18), 1730-4.

7. Ben-Shlomo Y et al. (2014, Feb 25). Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol, 63 (7), 636-46.

8. Singer et al. (2014, May). Arterial stiffness, the brain and cognition: a systematic review. Ageing Research Reviews, 15, 16-27.

9. Hughes et al. (2014, Mar 31). Arterial stiffness and β-amyloid progression in nondemented elderly adults. JAMA Neurol, in press.

10. Hanon O et al. (2005, Oct). Relationship between arterial stiffness and cognitive function in elderly subjects with complaints of memory loss. Stroke, 36 (10), 2193-7.

11. Scuteri A et al. (2007, May). Arterial stiffness as an independent

predictor of longitudinal changes in cognitive function in the older individual. J Hypertens, 25 (5), 1035-40.

12. Waldstein SR et al. (2008, Jan). Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore longitudinal study of aging. Hypertension, 51 (1), 99-104.

13. Zeki Al Hazzouri A et al. (2013, Feb). Pulse wave velocity and cognitive decline in elders: the health, aging and body composition study. Stroke, 44 (2), 388-93.

14. Poels MM et al. (2007, Mar). Arterial stiffness, cognitive decline, and risk of dementia: the Rotterdam study. Stroke, 38 (3), 888-92.

15. Pase MP et al. (2013, Nov 1). Blood Pressure and Cognitive Function: The Role of Central Aortic and Brachial Pressures. Psychol Sci, 24 (11), 2173-81.

Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. He has spent the last seven years in the medical device industry and prior to that earned his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C.Email: b.stutz@atcormedical.com

Dr. Winter is currently Vice-President of Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial tonometry. He is an internationally recognized expert in physiological fluid mechanics, biomechanics and medical

device development. Email: d.winter@atcormedical.com

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Journal for Clinical Studies 11www.jforcs.com

Singapore was once an Asian Tiger together with Hong Kong, South Korea and Taiwan. They are all high income, high investment countries, with education high on their agenda. Each country specialises in different areas. Singapore and Hong Kong have been known as financial centres, and South Korea and Taiwan are hubs for manufacturing. They are all used as centres for clinical trials. At the present time, Hong Kong is running 928, Singapore - 1235, Taiwan - 3428 and South Korea - 5234i.

The Singaporean government decided more than a decade ago to target the life sciences industry. They focus not only on local manufacturing but also on research and clinical trials, and aim to be the first-choice logistics centre in Asia Pacific, and the first choice for regional distribution of pharmaceutical products.

Heavy investment in infrastructure, including regulation, has been made to ensure that Singapore is the regional hub for trials and research. For example, the country boasts seven research institutes and five research consortia in a country with a population of just 5.3 million (around the same size as the Washington DC metropolitan area). The government also encourages international companies to set up their regional offices in the country. Many international companies have invested in Singapore to build their storage and distribution centres, using the most up-to-date supply models to allow just-in-time deliveries of clinical trials supplies to investigator sites. Singapore works with companies that fit their requirements to bring in high-end investment and the possibility of knowledge transfer. Their aim is for quality, not quantity.

Shipping into SingaporeIf materials are ultimately delivered within Singapore then they must be completely cleared and subjected to 7% GST tax. They are exempt from duty. Shipments may be tax free if the importer is registered with the tax department for tax exemption status. A licence may be required, and this includes when shipping samples for testing. Drugs for local use require the relevant licence, applied for by the CRO, which takes around a week to be issued. The importer of record must apply for an import licence, which is a controlled document. In addition to this, all importers must be registered with Singapore Customs in order for the Customs Permit to be applied for via trade net by the transport company. Once registered, companies are issued with the importers’ UEN (Unique Entity Number) which is used across the clearance paperwork, and a customs clearance permit (CCP) must be issued which can be applied for before the flight from the origin point arrives. This requires a master airwaybill, a house airwaybill, and a copy of the invoice to be submitted with the relevant forms. The invoice must be identified as an invoice or commercial invoice. “Proforma invoices” are not acceptable to Singapore customs.

Importation requirements have been simplified for supplies when they are being sent to a storage location in Singapore to then be forwarded into other parts of Asia Pacific. They are subject to a redistribution licence which must be applied for by the local depot. It is normally immediately approved. Items undergo a limited clearance, but must be re-exported from Singapore for the short flights into countries such as Vietnam, South Korea and Cambodia. This allows companies to ship bulk trial drugs into the depot and have them in physical proximity, ready to make deliveries once

patients are enrolled at a particular clinical site, without having to be concerned about a full clearance and full re-exportation.

Regulatory & Facility ConsiderationsThe Health Sciences Authority works within PIC/S (Pharmaceutical Inspection Co-operation Scheme) - an international body for the appropriate standards of GMP and GDP. Additionally, they operate a voluntary certification scheme for interested companies to seek official certification. A GDP Certificate is issued when the company’s quality system has been audited and found to comply with HSA’s GDP Standard. All companies importing material into Singapore should conform to the PIC/S GMP and GDP standards. Practical information and guidance is available on the HSA’s websiteii. The HSA is closed at the weekends so no approvals can be given at those times. Clearance can take place at the weekends if everything else is in place, and all the details are arranged during business hours on the Friday.

Singapore Changi Airport has a perishables handling centre, situated within the free trade zone, with the areas available ranging from -28°C through 2-8°C, to +18°C. This is located at Airfreight Terminal 2. The facility allows for shipments to be accessed to replenish refrigerant (add ice, change gel packs, change batteries etc.) while still under Customs control, and when under the control of the airline authority. This allows for the maximum flexibility in controlling temperature whilst undergoing clearance.

Singapore chose to invest heavily in the infrastructure needed to smooth the transit of pharmaceuticals - including clinical trial supplies. Their decision to do so is now reaping rewards with all the significant players in the market setting up facilities, and bringing knowledge, trade, and international investment into the region.

Referencesi. http://clinicaltrial.gov/ii. http://www.hsa.gov.sg/publish/hsaportal/en/health_

products_regulation/GMP/gmp_gdp_standard.html

Volume 6 Issue 312 Journal for Clinical Studies

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Singapore Investing in the Future of Life Sciences

Sue Lee, Technical Portfolio Manager, World Courier Management has worked for World Courier for 25 years. During this time, she has experienced a variety of customer service and operational functions including the setting up of numerous multi-national clinical sites for the transportation of biological samples. She has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations,

and each presenting their own obstacles and dilemmas. Email: slee@worldcourier.co.uk

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Volume 6 Issue 314 Journal for Clinical Studies

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ADHD: Then and Now

Symptoms of Attention Deficit/Hyperactivity Disorder (ADHD) have been documented in medical literature since the late 1700s1, but were not serendipitously treated until 1937, when Benzedrine was observed to improve the behaviour and school performance of children with severe headaches2. In 1963, the first study on the effects of Ritalin (methylphenidate) on ‘emotionally disturbed children’ was published3; and in 1969 the first ADHD rating scales for children were developed4. In the 1970s, research on the effectiveness of stimulant medications in children with ADHD symptoms continued, but so did the criticism that school-aged children were being over-medicated unnecessarily. In 1975, several books were published to support the belief that ADHD isn’t a real diagnosis, but was created by drug companies to make money, or that hyperactivity is caused by food allergies and additives.

There has been an exponential growth in ADHD articles in the literature between 1980 and 2005, with 5269 articles published on the epidemiology, diagnosis and treatment (2325 drug-related articles) of ADHD across the lifespan of the patient population5. The diagnosis of ADHD has been fine-tuned and refined periodically by panels of experts, especially in the adult population. In addition, many of the previous myths regarding the causes of ADHD have been proven to be incorrect. Neuroimaging studies have shown that subjects with ADHD have smaller, less active, less developed brain regions compared with controls6. Reduced brain volumes in the range of 3-10% have been observed in five brain regions, including the prefrontal cortex, and the smaller the regions the more severe the ADHD symptoms; particularly inhibition. A 2-3 year lag in brain development, and frequently a 4-5 year delay in emotional development, were observed in ADHD subjects. These developmental delays eventually catch up with the norm by early adulthood, but problems with inattention and impulse control often persist.

ADHD occurs in 7-8% of school-aged children and 4-5% of adults. It is found in all countries around the world with rates similar to or higher than those observed in North America. However, adult ADHD is only recognised and treated in 18 European countries. Predominately males are diagnosed with ADHD as children, but more females are being identified and diagnosed in adulthood. Symptoms of inattention, impulsivity and hyperactivity are well characterised in children with ADHD, but symptoms are different and more subtle in adulthood, which can often result in misdiagnosis.

Successful treatment of ADHD symptoms may result in only modest functional improvement in their daily lives due to the frequent occurrence of comorbidities. At least one comorbid condition is observed in 65% of children and 75% of adults with ADHD. In ADHD children, the comorbid conditions include oppositional defiant and conduct disorder, anxiety and mood disorders, tics or Tourette’s disorder, and learning and pervasive developmental disorders. In ADHD adults, who have an average of three psychiatric comorbidities, including mood, anxiety, sleep, personality, and substance use disorders; gambling and

other addictions are very common. In a study of 112 children with ADHD who were followed for 10 years, it was observed that stimulant treatment decreases the risk for subsequent comorbid psychiatric disorders and academic failure7.

Pharmacotherapy, especially stimulant medications, remains the mainstay of treatment for ADHD. New formulations (isomers, immediate-release, and extended-release) and delivery systems (liquid, sprinkle, tablet, capsule, and patch) have made it possible to tailor the individual patient’s treatment to the duration of efficacy required, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant medications to treat ADHD have emerged in the past few years, and though not as efficacious, provide a better safety profile and reduced concerns of abuse and addiction. Currently, several ‘triple reuptake inhibitors’, with varying affinities for dopamine, norepinephrine and serotonin receptors, are being developed to treat adult ADHD. In addition to treating symptoms of ADHD and having a low abuse potential, these new agents may potentially be effective on the comorbid mood disorders.

Remaining challenges continue to be the proper diagnosis and treatment of adults with ADHD. Though an increasing number of adults are being diagnosed with ADHD, an additional pool of adults has gone undiagnosed or is being ineffectively treated for alternative disorders. As with most chronic conditions, newly-diagnosed subjects fail to remain compliant with their prescribed medication for greater than two months. The average amount of time that an ADHD adult remains compliant with their initial ADHD therapy is 49.5 days8. Therefore, new long-acting, non-stimulant medications that are more tolerable and efficacious are needed for the long-term treatment of ADHD.

References1. Barkley RA, Peters H. The earliest reference to ADHD in the medical literature?

Melchior Adam Weikard’s description in 1775 of “attention deficit” (Mangel der Aufmerksamkeit, AttentioVolubilis). J AttenDisord. 2012 Nov;16(8):623-30.

2. Bradley C: The behavior of children receiving benzedrine. Am J Psychiatry 1937; 94:577–585

3. Conners CK, Eisenberg L. The effects of methylphenidate on symptomology and learning in disturbed children. Am J Psychiatry 1963;120:458-464.

4. Conners CK. A Teacher Rating Scale for use in drug studies with children. Am J Psychiatry 1969;126:884-888.

5. Lopez-Munoz F. A bibliometric study of international scientific productivity in attention-deficit hyperactivity disorder covering the period 1980-2005. Eur Child Adolesc Psychiatry. 2008 Sep;17(6):381-91.

6. Castellanos FX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002; 288(14): 1740-1748

7. BiedermanJ, et al. Do Stimulants Protect Against Psychiatric Disorders in Youth With ADHD? A 10-Year Follow-up Study. Pediatrics 2009; 124(1): 71-8.

8. Perwien AR, et.al. Stimulant treatment patterns and compliance in children and adults with newly treated attention-deficit/hyperactivity disorder. J. Manag Care

Pharm. 2004; 10(2): 122-29.

Craig Earl, Ph.D. is Vice President of CNS Clinical Development

at INC Research. He has more than 25 years of experience in the

pharmaceutical industry, primarily in CNS clinical development.

His clinical areas of expertise include protocol design (adult

and pediatric, Phases I to IV), study conduct oversight, NDA

submissions, regulatory agency responses, and key opinion leader

and investigator interactions. His therapeutic areas of expertise

include ADHD, psychiatry, pain, sleep disorders, and neurology.

Email: craig.earl@incresearch.com

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Volume 6 Issue 316 Journal for Clinical Studies

Regulatory

Risk-Based Monitoring: Roundtable Discussion

Aggressive financial targets and reduced R&D budget are building tremendous pressures on life science companies to develop new drugs/devices in a cost-efficient and timely manner. Moreover, the complexity of clinical trials has been increased significantly in the last few years, and therefore it is becoming more challenging for drug/device development companies to achieve high data quality to meet the requirements of a successful regulatory submission within a given budget. As far as expensive clinical trial management is concerned, frequent monitoring visits to investigational sites and 100% source data verification do not necessarily result in higher data quality, better patient safety, or in understanding the critical issues early on. Therefore, it is imperative to look into alternative and smarter ways to achieve improved data quality and patient safety in a cost-efficient manner. A risk-based monitoring (RBM) approach has opened a pathway to enhanced quality conduct and reporting of clinical study that the industry has been seeking for many years. Moreover, the EMA quality risk management reflection paper, ‘MHRA risk-adapted approaches’, and the FDA RBM guidance document encourage the industry to adopt an RBM approach. Sometimes RBM is referred to by different names such as “intelligent monitoring”, “targeted monitoring” or “triggered monitoring”, but it is definitely an evolution in clinical trial management processes to achieve better quality data in a smarter way. At the same time, we need to understand that RBM is a set of methods and processes that requires the correct resources and technology to be in place, so that when employed right from study planning, through conduct, to close-out, will bring greater results with regard to data integrity, quality, patient safety and cost-optimisation.

Ashok Ghone, Ph.D., VP-Global Services at MakroCare, talked with the other thought leaders in this area to put the opinions together in the form of a discussion. The other experts that contributed to this discussion are: Jane Tucker - Independent Trainer and Risk Management Consultant; Sue Fitzpatrick - former Head of Education and Training at the Institute of Clinical Research; and Sandra (Sam) Sather - Vice President at Clinical Pathways, LLC.

As the industry is actively looking into adopting a RBM approach and some of the sponsors/CROs are already running pilots to standardise the process, this discussion is designed to focus on some of the key aspects of RBM-like risk assessment, risk management, monitoring plan, centralised monitoring and technology.

Ashok: We all know that the clinical trial management process is evolving to achieve better cost-efficiencies with improved data quality and safety of patients. RBM offers a paradigm shift from traditional planning and execution of clinical trials and therefore, a right implementation of RBM is essential to maximise its benefits and ensure better outcomes. Risk assessment and risk management are the two important aspects of RBM. The first step in successful implementation of an RBM approach is to have a study-specific holistic approach to identify all potential risks and evaluate those risks to assess the impacts. Effective risk action planning involves effective risk identification and proactive root cause analysis (RCA) as part of risk mitigation. Therefore, it is necessary to thoroughly identify sources of all potential risks and root causes to improve action planning. Sam,

would you like to opine on this process of risk identification and root cause analysis?

Sam: Root cause analysis (RCA) is an important process that is not inherent and involves scientific principles. Tools used to perform RCA (e.g. 5 Whys, fishbone diagrams, cause mapping, force field analysis, etc.) do not teach an individual how to perform RCA. RCA, instead, must be taught and practised. RCA is a process that is part of performance management. In order to determine the cause of performance gaps, you should assess the primary environmental and individual performance factors (also known as system and project level) that must be in place to support any performance for any project where you are depending on others to perform critical functions for you, such as a clinical study. Interventions assigned to address deficiencies must be based on the root cause(s) (i.e. at least one root cause for each intervention or set of interventions), in order to be effective and prevent issues from occurring or recurring. It is imperative to include evaluation design in the interventions so that performance can be measured, and assess whether RCA was performed well. RCA also focuses on addressing the systems level factors - again to promote improvement. RCA analysis within clinical trials is primarily formally used when implementing CAPAs internally or externally linked to other stakeholders (i.e. sponsor to investigator, sponsor to CRO). But with the industry focus on building better clinical quality systems that include risk management, the use of proactive RCA at all levels of performance management in clinical trials is essential (e.g. during risk assessment).

There are many opportunities where root cause analysis (RCA) can be used in running clinical trials, but not just for non-compliance root cause assessment. Another important opportunity to use root cause analysis is in an anticipatory environment. Here, RCA can support the conciliatory effort of sponsor and/or investigational site cross-functional teams to identify why something could go wrong within a study, and link interventions directly to the root cause(s) to better mitigate risks, especially those linked to risks to human subject protection, quality data and project milestones (e.g. RCA used during early project planning, study start-up risk assessment and action planning to develop study plans). The use of RCA is also crucial in determining the essence of change, and what it will take to support it (e.g. integrating clinical quality risk management in GCP). Additionally, RCA can help to develop both the workforce and the strategy involved in future state goals (e.g. risk management skills within a GCP environment, reorganisation of a clinical research department function, in support of a product development plan). Instead of being primarily reactive and trying again and again to fix similar problems, it is critical to put the RCA at the front end with risk assessment and action planning. It is important to recognise the role of RCA in good clinical practice (GCP) and RBM today.

Ashok: Jane, once we identify, analyse, and prioritise risks, what would be the next steps with regard to risk management/action planning?

Jane: The responses should be planned appropriately for the significant risks, and those responses could be one of four different types: Avoid, Transfer, Accept or Mitigate.

2013 022 VC adv A4.indd 1 20-06-2013 12:56:33

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Regulatory

If there are any real show-stopper risks it may be necessary to opt for an Avoid Response. This may mean that the current plan for the project or clinical trial should be reviewed and changed substantially in order to eliminate the root cause of the show-stopper risk. For example, with regard to a clinical trial planned to involve a new technology, if there is a risk that the regulatory authorities may not accept the relevant data being incorporated into a submission, it will be necessary to delay any further activity until a regulatory opinion has been obtained; and if necessary, identify alternative acceptable data collection options.

If any potential risk response is outside of the sphere of influence of the team involved, it may be necessary to identify an alternative group to whom the risk could be transferred for action or decision-making. For example, if there have been issues identified by previous (or ongoing) clinical trial teams with the formulation of Investigational Medicinal Product, it may be necessary to pass risks related to IMP back to the Drug Development Team or Manufacturing department for action. It is vital for the alternative team to agree to take on responding to the transferred risk.The Accept response option may need to be utilised for risks such as ‘Regulatory Authorities may announce a change to regulations which will affect the outcome of the trial’; since there is no way the trial team (or sponsor company) can influence the regulators the trial team will need to accept the risk and move on. The Accept response is also relevant for any risks that will have minimal effect if they do occur.

Mitigate is the response type with which most people are familiar. Definition of mitigation actions should start with the most significant risks first, and then progress down the risk list once the top risks are being managed. Mitigation actions may have one of three different objectives: minimise the impact of the risk, reduce the likelihood of the risk occurring, or increase the chances of the risk being detected if it should occur. Mitigation actions should be allocated to a named person (the one who will actually take the action – not the project leader) with a defined first review date and a measure of success. It is quite likely that one risk may need more than one mitigation action, but also that one mitigation action may mitigate more than one risk. Taking for example some of the clinical monitoring activities of a study - such as if we have an inexperienced investigational site on the study - as a part of risk mitigation we may increase our monitoring depth for this site as a part of centralised and on-site monitoring to ensure there are no quality or patient safety issues arising from the site. It is vital that risk documentation should include the details of all agreed risk responses and, where mitigation actions are defined, that those actions are followed up until the risk is closed or no longer relevant, e.g. recruitment risks once recruitment is closed.

Ashok: Regarding clinical monitoring aspects, once we identify risks related to clinical investigation conduct and reporting, the next key step is to design a comprehensive monitoring plan. The monitoring plan for a RBM approach is different than the traditional monitoring plan as it will include both components of on-site and centralised monitoring, and is a “dynamic” plan too. As a part of risk assessment, once we identify various risks and categorise them as high, medium and low, the monitoring plan should define how we would be tracking, controlling and mitigating these risks through on-site and centralised monitoring. The monitoring plan should outline what would be monitored through centralised and remote monitoring, and which triggers will be used to identify risks, data or procedures that should be

monitored by on-site monitoring. On-site monitoring should be utilised effectively for review of high/critical risks data and procedures which are very important for the validity of study conduct and reporting, e.g. ICF documentation/procedure, data related to eligibility criteria, or data and procedures related to primary and secondary efficacy and safety end points. Again, the monitoring plan is dynamic, as monitoring activities will vary based on the quality of data coming in from different sites, and the performance of various sites, e.g. the sites that are not performing well or are having more quality issues will receive more attention or on-site visits than the sites which are performing as, or better than, expected. The monitoring plan should also define the threshold of risk signals or key risk indicators which will trigger immediate site contact (telephonic or visit) based on centralised monitoring findings. We all know that the FDA guidance document encourages use of centralised monitoring techniques for certain monitoring activities in place of, or to complement, traditional monitoring techniques. Sue, what are your thoughts on centralised monitoring and its importance in RBM?

Sue: Centralised monitoring is a remote evaluation carried out by sponsor personnel or representatives (e.g. data management personnel, statistical or clinical monitors) at a location other than the site(s) at which the clinical investigation is being conducted.

The idea of centralised monitoring is not new. The 1997 ICH GCP E6 guidelines clearly state, “In general there is a need for on-site monitoring before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance, can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.”

Centralised monitoring has been widely used by non-commercial sponsors. However, more and more commercial organisations and sponsors are adopting a centralised approach as part of their monitoring strategy, moving away from the traditional way of monitoring trials where on-site visits are made 4- to 6-weekly, irrespective of site performance and quality. The reason centralised monitoring has become increasingly important is that it is a feature of risk-based monitoring. The FDA guidance for industry “Oversight of Clinical Investigations – A risk based approach to monitoring”, finalised in August 2013, focuses on critical data and advocates the use of a number of monitoring activities, but encourages greater reliance on centralised monitoring practices where appropriate. This view is echoed by the EMA and the Competent Authorities in Europe.

With the advent of eCRFs (electronic case record forms) and other eDCT (electronic data capture tools) it is easy to check things centrally or remotely from the site. Remote CRF review can be used to monitor performance at the site (data not being recorded in a timely manner), to identify missing data, and check inclusion/exclusion criteria to ensure only eligible patients are entered in real time.

Using reports from databases or statistical sampling methods, centralised monitoring can be used for validation checks of data and help identify triggers or signals that may highlight areas of non-compliance. Centralised monitoring could allow a direct comparison across sites, and show trends in data or outliers that

may not be identified by a monitor using a traditional approach.

In order to implement a centralised monitoring system, there are prerequisites: robust and validated computer systems are required, and very well-defined criteria or triggers for high-risk sites and data have to be identified and justified in the monitoring plans. Statistical techniques and modelling to identify patterns or trends may be used. This technique can pick up incorrect or implausible data. For example, it may compare the number of adverse events at sites and identify outliers, odd distributions, or unusual variability in the data. It is acknowledged that not all current monitoring tasks may be performed centrally and a “one size fits all” approach is not the answer. Trials that use a hybrid approach can be a means of directing visits to sites when required, therefore making best use of the resource available without compromising patient safety or data integrity.

Ideally, centralised monitoring should be used for data validation checks and the more expensive face-to-face monitoring for sites or data that are critical, or when issues have been identified. As with all processes, once the monitoring strategy has been determined, it should be documented and must be followed. Evidence of central monitoring activities should be retained, for example: reports generated from interrogating the database, documents received from investigator sites, and evidence of review, as well as records of decisions or escalation in activities.Centralised monitoring methodology and its evaluation are still developing, and key processes such as data collection, cleaning, and monitoring need to be integrated, but how this is to be achieved is not yet fixed. There is no validation of effectiveness of approaches, but it is acknowledged that the traditional approach has its failures.

Ashok: While the industry is struggling with the increased complexity of clinical trials and the high cost of clinical development, the risk-based monitoring approach is a better alternative to efficient quality management, high data integrity, enhanced patient safety, and reduced on-site monitoring visits. Comprehensive risk identification, assessment, understanding study-specific high risks data, procedures and designing a well-defined monitoring plan are the key steps in planning a RBM approach. Controlling and mitigating risks through trigger-based, dynamic monitoring is the core of RBM execution. This new process offers a proactive approach to ensure better quality of data, and to understand issues earlier than the reactive traditional monitoring approach. The successful implementation of RBM requires effective planning, process restructuring, cross-functional expertise alignment, and right technology with analytics tool. As the industry is moving forward with the process standardisation and optimisation, with the introduction of centralised monitoring the role of some of the key resources like CRAs will continue to evolve.

The use of right technology - especially collaborative and analytics tools - to pull in the right data from different sources such as EDC, CTMS, IVRS, and safety system on a real-time basis, and provide a customised analytics dashboard to facilitate centralised monitoring and observe site performance metrics, data trending, and data outlier will make the RBM process more efficient and reliable. The monitoring of the metrics during study management using a RBM approach related to quality, safety, timelines and budget will help understand the benefits and potential of RBM, and will give more confidence to the industry to adopt an RBM approach.

Regulatory

Journal for Clinical Studies 19www.jforcs.com

Sandra “SAM” Sather is an industry-leading consultant whose mission is to promote clinical quality systems for Sponsors/CROs and Investigators/Research Institutions. She has over 25 years of clinical experience, with a Bachelor of Science in Nursing and a Master of Science in Education with a Specialization in Training and Performance Improvement. SAM is the vice-president of Clinical Pathways, LLC. SAM is dual certified by the Association for

Clinical Research Professionals (ACRP) for over 10 years (CCRA and CCRC) and a current member of the ACRP Academy Board of Trustees and Regulatory Affairs Committee (RAC). SAM has authored dozens of courses for clinical research in various functional areas (e.g., risk management, monitoring, safety, HIPAA, and vendor management). Email : samsather@clinicalpathwaysresearch.com

Jane Tucker has more than 25 years pharmaceutical industry experience across the disciplines of data management, computer system validation, training, data quality management and quality risk management. Jane was a founder member, and for 8 years co-leader, of Clinical Research Computer Systems Validation working party and lead the publication of ‘Computerised Systems Validation in Clinical Research – a practical

guide’. Jane now operates as an independent Trainer and Risk Management Consultant. Email: janetucker7@gmail.com

Ashok Ghone, Ph.D. is Vice-President, Global Services at MakroCare USA. He has around 20 years of experience in pharmaceutical and clinical research industry. He carries good knowledge & understanding of global clinical research with hands-on experience in clinical operations, project management, process development, site management and patient recruitment activities. He has led various cross functional teams successfully by providing

strategic direction, guidance for accomplishment of local, regional and global projects involving early & late phase clinical studies in various therapeutic areas. Email: ashok.ghone@makrocare.com

Sue Fitzpatrick joined the Pharmaceutical Industry in 1980. She has been responsible for the management and audit of CRAs and clinical trials in a wide range of therapeutic areas. As former Head of Education and Training at the Institute of Clinical Research she was responsible for the provision of training courses for the industry and postgraduate courses in collaboration with several UK Universities. Sue is an accredited teacher with Cranfield

Universitys and continues her collaboration with Universities and Industry as an independent trainer currently providing courses and master classes in risk based monitoring. Sue is also a Director of Redtree people working on employability skills to help new entrants enter the sector. She has authored many articles and books on clinical research and career development topics. Sue is currently working on a book in Clinical and Healthcare Research for publication with the Oxford University Press. Email: sue.fitzpatrick@redtreepeople.com

Regulatory

Volume 6 Issue 320 Journal for Clinical Studies

FDA Raises the Bar in Bioanalytical Method Validation

For many years, the FDA guidance on bioanalytical method validation (BMV) issued by the CDER in 20011, has been the Holy Grail for laboratories which deal with the pharmacokinetic analysis of drugs and their metabolites in clinical trials. A revised version has been expected at least since the EMA issued its guideline on BMV in 20122, which is much more explicit and detailed in its requirements compared to the FDA guidance from 2001. The new FDA draft guidance is summarised in this editorial, and its implications for clinical studies are discussed.

The basic objective of method validation is to assess the performance of an analytical method before clinical trial samples with unknown concentrations of specific analytes are going to be measured. The core parameters of method validation are accuracy, precision, selectivity, sensitivity, reproducibility and sample stability. Further aspects are standard curve/response function, interference by other substances, specificity etc. These performance parameters have to be tested by each laboratory offering a specific method used for bioanalytical assessment of clinical trial samples, and summarised in a validation report. Bioanalysis, in its original sense, is focused on the analysis of drugs or drug candidates and their metabolites in plasma and urine, or other biological matrices. While the FDA guidance from 2001 was primarily written for chromatographic methods (especially LC-MS/MS), the EMA guideline also provided guidance for immunoassays like ELISAs and other ligand binding assays. Interestingly, the EMA has taken a very unambiguous position regarding the validation of biomarker assays for the assessment of pharmacodynamic endpoints as it is defined in the scope of the guideline: ‘Methods used for determining quantitative concentrations of biomarkers used in assessing pharmacodynamic endpoints are out of the scope of this guideline.’ Therefore there is still a lack of regulatory guidance regarding the design of validation studies for biomarker assays under European regulation – it is basically not defined how to validate biomarker assays under current EMA guidelines.

However, the new draft guidance on bioanalytical method validation released by the FDA in September 20133 is taking a clear position on biomarkers. The FDA states, even in the first paragraph, that the principles of bioanalytical method validation are not only applicable to the methods used in pharmacokinetic studies, but also for the assessment of biomarkers. In the section ‘Additional Issues, Biomarkers’, the draft guideline explains: ‘Biomarkers can be used for a wide variety of purposes during drug development; therefore, a fit-for-purpose approach should be used when evaluating the extent of method validation that is appropriate. When biomarker data will be used to support a regulatory action, such as the pivotal determination of safety and/or effectiveness or to support labeled dosing instructions,

the assay should be fully validated.’ This clear statement confers some clarity to sponsors and central laboratories since neither the EMA guideline nor the FDA guidance from 2001 have claimed any applicability beyond the area of pharmacokinetics. With the new draft guidance, it is now clear that basically all methods used for the assessment of safety, efficacy and pharmacokinetics should be validated according to the same standards - provided that this guidance will come into force. For biomarkers that are primarily studied to better understand mode of action or other aspects of supportive information, a fit-for-purpose validation approach is obviously acceptable. However, there are two aspects that need further clarification:-

1. Does this need to fully validate methods used for pivotal biomarkers apply to classical clinical chemistry parameters, such as amino-transferases for monitoring liver toxicity, or creatinine for kidney function, as well? Examples for efficacy parameters might be LDL-cholesterol for monitoring the pharmacodynamic effect of statins, or ostase for controlling the effect of osteoporosis drugs. It remains to be seen whether the FDA also regards such classical clinical chemistry parameters as safety or pharmacodynamic biomarkers. Since these parameters can be of crucial importance for certain drugs and drug candidates, it should be expected that the FDA will recommend to validate these methods according to the new BMV guidance, as soon the revised version supersedes the guidance from 2001. On the contrary, one could argue that such parameters are sufficiently well-covered by proficiency testing and extensive experience with these frequently-assessed parameters, and therefore a partial validation might be sufficient. It has to be seen how the final version of the BMV guidance will deal with this question.

2. Is it appropriate to request the same performance in terms of accuracy and precision for biomarker assays as for bioanalytical assays? The FDA requests a maximal imprecision of 15% (CV < 15%) and a relative error of less than 15% (RE < 15%) for all chromatographic methods. These limits can both be expanded towards 20% CV and 20% RE for ligand binding assays. This is feasible for many assays, but there are situations where – especially at low concentrations – precision and accuracy will only reach CV and RE values of 30%. In such situations, it is sometimes not possible to choose a different method because these are often parameters for which only a few vendors offer reagents or kits. Like the EMA guideline, the FDA also points out that commercial assays (‘kits’) need to be validated to the same standards as methods that have been developed by the laboratory which will conduct the analysis of clinical trial samples. Here it would be desirable if the FDA guidance would finally leave an option for using other means to obtain

26272-RQA-Clinical Research_GCP_Advertisement__AW(P).indd 1 26/04/2013 13:21

biomarker data that can be used in clinical studies. One approach is the analysis of all samples of one subject in one analytical campaign to avoid inter-assay variability.

Another important requirement relates to the so-called ISR, incurred sample reanalysis: 5-7% of the totally analysed samples need to be re-analysed to test reliability of the reported concentrations after storage. This applies not only to pharmacokinetic assays, but also to biomarker assays - a requirement that is not self-evident since the stability of biomarkers in their respective matrix, even after repeated freeze-thaw-cycles, is generally tested during validation studies. It has been requested by the EMA in the 2012 validation guideline as well, but was limited to bioanalytical applications. In combination with the generally relative wide acceptance criteria for ISR, and the fact that biomarkers are generally endogenous compounds, it might be questioned whether the reanalysis of biomarker samples is indeed increasing the reliability of biomarker data in clinical trials.

One difficulty scientists are facing when it comes to the assessment of accuracy and lower limit of quantification (LLOQ) for an endogenous biomolecule used as a biomarker, is the fact that this molecule is endogenously present in the clinical matrix. Therefore, it is not possible to assess the LLOQ by spiking known concentrations of the biomolecule to the analyte-free matrix as for xenobiotic compounds. The FDA does not generally recommend using artificial matrices for endogenous substances, but accepts such matrices if no other options are available. Furthermore, quality control samples can be prepared in clinically-relevant matrices by spiking known concentrations of the endogenous molecule to well-characterised samples of these matrices with known concentration levels of the same molecule. These suggestions are certainly helpful to address this issue.

Comparing the new draft guidance to the FDA guidance on BMV from 2001, the revision has led to a regulatory paper that is similar to the EMA BMV guideline from 2012

in many aspects. A detailed comparison between the FDA draft guidance and the EMA guideline from 2012 has recently been published4. The fact that the FDA BMV draft guidance requests to validate biomarker assays according to the same principles as pharmacokinetic methods, will most likely have the biggest impact on the conduct of clinical trials, and will endorse the role of specialised central labs for clinical trials in the assessment of such parameters.

References1. Guidance for Industry, Bioanalytical Method Validation,

U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), May 2001

2. EMEA/CHMP/EWP/192217/2009, Committee for Medicinal Products for Human Use (CHMP), Guideline on bioanalytical method validation

3. Guidance for Industry, Bioanalytical Method Validation, DRAFT GUIDANCE, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), September 2013

4. Zimmer D, New US FDA draft guidance on bioanalytical method validation versus current FDA and EMA guidelines: chromatographic methods and ISR; Bioanalysis (2014) 6, 13–19

Regulatory

Prof. Dr. Stephan Wnendt, biochemist, has held senior positions in pharmaceutical industry, medtech and biotech in Germany before joining MLM Medical Labs GmbH in January 2008. Dr. Wnendt is honorary professor at the University of Technology in Aachen, Germany, and CEO of MLM Medical Labs, a central lab fully dedicated to clinical trials based in Germany. Email: swnendt@mlm-labs.com

Volume 6 Issue 322 Journal for Clinical Studies

Market Report

Volume 6 Issue 324 Journal for Clinical Studies

Advantages and Challenges Facing Clinical

Research in South Africa

IntroductionClinical research has a long history in South Africa and dates back as far as the 1960s. During the early years, clinical research was primarily confined to the academic university research units based at the major medical schools in the major cities of South Africa. Over the past two to three decades, as pharmaceutical research has proliferated and the need for investigator sites has grown, medical doctors - having been exposed to clinical research during their early careers - have established their own research units to fulfil this need.

South African Healthcare SystemThe South African healthcare system consists of public healthcare, which is financed and managed by the South African government, and private healthcare, which is primarily funded by health insurance and private direct fee for service payments. Private healthcare consumes more than 50% of total healthcare spending in South Africa, but only services about 20% of the population able to afford health insurance or direct funding of their healthcare needs.

Attraction of South Africa as Clinical Research DestinationSouth Africa is classified internationally as a developing country and is often viewed by the less-informed as a poorly-developed African country. This is far from the truth.

As mentioned in the introduction above, South Africa has a long history of conducting clinical research; this translates to interest of the medical profession in furthering their knowledge and remaining at the cutting edge of medical development. This is a good indication of the pool of experienced clinical research staff available for research, which is growing and developing as the research environment changes over the years. Clinical research experience is of paramount importance in the South African research environment: it is a regulatory requirement that investigators may only participate as principal investigator after having participated in at least two different clinical trials as a sub-investigator. A major attraction of running clinical trials in South Africa is the commitment and dedication of the majority of doctors and medical support staff conducting research in the country. Rarely are target numbers for eligible patients not provided for different trials. This has often resulted in many large studies with poor recruitment in first world countries seeking services provided in South Africa.

South Africa has a dual regulatory process in that any clinical trial requires both regulatory authority (Medicines Control Council) and relevant ethics approval prior to the commencement of the trial. This applies to all clinical trials using consumed investigational products. Strict guidelines for conducting clinical research are outlined in the South African National Health Act 2003. The Department of Health

has published good clinical practice (GCP) guidelines to assist clinical research staff in performing research ethically, and to ensure the safety of clinical trial participants. It is a requirement that all research staff are fully trained in GCP, and updated certification is needed every three years. Ethics committee approval is also required before clinical trials can commence. There is a choice of use of central ethics committee or institutional ethics committee. The general rule of thumb is that the university/academic sites generally require the institutional ethics committee to review and approve the trial being performed at their facilities. To ensure all ethics committees adhere to specific standards, the National Health Research Ethics Council (NHREC) was established in 2005 to regulate the standards of all ethics committees in the country.

South Africa has a sophisticated infrastructure and clinical trial support system available. Laboratory support to process and analyse blood and tissue samples is readily available in all the large metropolitan cities in South Africa. Most, if not all, of the major laboratories have a clinical trial division that specifically caters for the clinical trial environment, and usually have some partnership/working relationship with the large multinational analytical laboratories. All the clinical laboratories are audited and accredited by SANAS. These facilities meet all of the international standard requirements.

As South Africa is located quite a distance from the major manufacturing facilities in the USA, Europe and Asia, investigational product depots are often used to import and distribute clinical trial products to site. These facilities adhere to all international packaging and manufacturing (GMP) and clinical trial requirements (GCP). As they generally receive, store, and distribute clinical trial investigational product for a number of different studies and companies, they have very strict control mechanisms in place to ensure confidentiality and safety of clinical trial product. They are able to manage all types of investigational product at all temperature ranges.

As South Africa is a relatively small country in terms of size, travel distances by air and road are on the short side. All the major multinational courier services have a direct presence or partnership with local services. Once a study is approved by MCC and Ethics, the MCC approval letter serves as the import licence for the investigational product. The accompaniment of proforma invoice and transport documentation makes for relatively smooth importation of clinical trial product. The courier services have the facilities to handle temperature-sensitive investigational product without compromising the integrity of the product.

Challenges of Clinical Research in South AfricaThere are many challenges that are constantly faced when doing clinical trials in South Africa. Some are not unique to South Africa.

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Volume 6 Issue 326 Journal for Clinical Studies

Market Report

Patient recruitment is probably the biggest risk factor for conducting clinical trials in any country or region, and is influenced by a number of factors. South Africa is a developing country with a large proportion of the population unemployed and with limited access to best medical care available. Their primary source of healthcare is via the public health system. The public health system services 80% of the population with 50% of the total annual healthcare expenditure. The system is overworked, understaffed, and poorly managed due to the bureaucratic red tape needed to get anything accomplished. Patient recruitment from the poorly serviced, impoverished, and often poorly educated group does, at times, result in further scrutiny due to the inherent risks of being exploited by researchers. The challenge of balancing the benefits of the patients being exposed to fewer currently marketed medications, willingness to participate due to limited treatment options, and options of receiving some form of treatment not freely available to them; versus exploitation, capturing valid data from often complicated tools from, at times, poorly educated patients, and patient compliance due to work commitments, is something that constantly needs to be reviewed and addressed with all studies undertaken in the country.

Recruiting and retaining of participants is a major challenge, specifically for long-term studies. Slow recruitment leads to longer time to market, which in turn, leads to revenue loss. Poor retention also negatively impacts on the overall evaluable data for regulatory submissions. Dropped participants must be replaced, which incurs further expenditures and time delays. Subject dropout rates are estimated to range between 15 and 40% of enrolled participants in clinical trials2.

Despite the largest proportion of patients being serviced in the public health system, the majority of all clinical research conducted in South Africa is done by private health investigators. The public health service patients participating in research primarily come through academic institutions. Unfortunately, due to the overworking and understaffing

of the system, clinical research is confined to the major metropolitan centres, larger academic hospitals and dedicated academic research centres. Efforts to address this by the MCC have included requesting a portion of sites participating in studies to be public health sites. This has resulted in a few new public health sites with poorly set-up sites. A lot of time and effort is then spent by monitoring CROs or sponsor companies to ensure these inexperienced sites are able to deliver quality data. In essence, some cross-subsidisation of training is being done for these sites.

Community leaders play an integral part in the lives of, particularly, the lower socio-economic and poorly educated population groups in South Africa. These community leaders can determine the success of any patient recruitment/education drive in these communities. This has been of particular importance in the many HIV/AIDS clinical trials and education programmes. Many clinical trials that did not get the support of local community leaders were unsuccessful, and vice versa. This brings up a very pertinent point, that engaging the community and considering different cultural backgrounds is important in ensuring successful research projects. This can be achieved in many ways - from grass roots interaction of the community through the community leaders, to interactive theatre/role play presentations, community radio broadcasts, meetings, and events.

Clinical trial participants are often very eager to partake in a trial, but compliance to the many required visits could potentially become an issue without considering the following points mentioned below. This is often due to1:

• Monetary burden:- Often participants have to travel a distance (using their own finances to pay for transport) or take time off work (unpaid leave) to attend follow-up visits. This issue can be overcome by offering compensation for travel and time spent for visits. Compensation for patients may typically include some combination of medical treatment and cash compensation, intended to provide for reimbursement of expenses (travel, telephone usage, missed work, babysitter, lunch etc.) but not to be so large that it would be considered perverse incentives. All medical costs that are covered by the clinical trial should be discussed in detail with the participants: this will allow the participant to see which cost is for their own, or medical aid’s, account.

Being treated with respect and kept informed will help to make the overall experience of trial participation positive for all participants2.

• Discouragement of family members, community and disease progression:- Family members and the community might discourage participants from going to sites for visit, and would rather they go to traditional healers in the area for assistance. If the disease progresses and the participant doesn’t have a positive outcome from the visits, the other participants might become despondent and subsequently not return

to the site. Therefore, the participant needs to diligently inform of the possible outcome of their disease.

• Commute:-Transport compensation is of particular importance for participants who depend on public transport. Sufficient funds should be made available to cover the full fare for participant and caregiver if needed. Weather can also have an impact on participant compliance.

• Lack of information:-Adequate information about the treatment risks and advice on how to make the trial more comfortable and convenient need to be discussed with the participants2.

South Africa and other Southern African countries do have a high incidence of HIV/AIDS. The challenge of determining the impact this disease may have on the study data, integrity of the study, and effect on study participants is almost always a topic of discussion during health authority and ethics committee discussions.

The highly regulated nature of clinical research and the importance of proper and fully-informed consent prior to participation in clinical trials has presented some interesting challenges in patient recruitment. This, compounded by the increased complexity of clinical trials being presented by the pharmaceutical industry, has turned the patient information leaflet and informed consent form (ICF) into a daunting document. The ICF is usually drafted by highly-educated research staff, yet the information needs to be presented in a format that can be easily understood by non-scientific participants.

Health surveillance and epidemiological data collection is poor - primarily due to a lack of sufficient staff, and poor reporting by the clinical staff to the data collection centres. The submission of incomplete and incorrect data further hampers accurate interpretation of data. Apart from major epidemic infections of HIV/AIDS and tuberculosis, the prevalence, morbidity and mortality rates are rough estimates made from data received from private disease associations/societies/support groups, along with private sector hospital data. Due to the heavy workload of the public health sector and poor record-keeping systems, data from this sector is incomplete, inconsistent, and unreliable. As this represents a larger proportion of the population, this unreliable information has the potential to give a skewed picture of the actual disease risks facing South Africa. This could have potentially dire consequences for conducting clinical trials in inappropriate locations.

Time is always the enemy of clinical research, and the MCC approval cycle is at least three months from the time of submission to approval of the study. It is always a challenge during this process to ensure all documents, questions, and regulatory requirements are addressed to ensure approval of the study. This is not always smooth sailing. The most common issues are overload of clinical trials for review at each cycle, the limited amount of time available to discuss specific trial concerns, lack of sufficiently experienced reviewers for trials, lack of sufficient staff at the MCC to prepare trials for review,

poor follow-through communication between the MCC and the rest of the industry. The biggest challenge regarding this issue is that there is no assurance that if the trial meets all requirements that approval will be granted within the three-month cycle. This is of particular importance in seasonal studies such as vaccine studies, CAP studies etc.

A challenge facing the long-term clinical trials for chronic disease conditions is the continued use of successful treatments after completion of the trial, and before the treatment is registered in the country for use.

In conclusion, despite the many challenges encountered, these are not insurmountable, and solutions to all problems can be found. Without clinical research and the voluntary participation of ordinary people, the advances in medical treatment would not have reached where it is today. That being said, improving on past success must always be one of the goals.

References1. Journal of Oncology Practice – Barriers to Recruitment of

Rural Participants in Cancer Clinical Trials: Shamsuddin Virani, MB, BS, Lola Burke, MSIV, Scot C. Remick, MD, and Jame Abraham, MD

2. Pharmanet - Customizing patient retention strategies in clinical trials: Andrea Vondrášková, MD, MSc, MICR

3. Health in South Africa: changes and challenges since 2009, Bongani M Mayosi, et Al, www.thelancet.com

4. The ethics of clinical research in developing countries, Nuffield Council of Bioethics 1999.

5. The clinical trials industry in South Africa: Ethics, Rules and Realities. Wemos July 2013.

Karen Mallalieu started her career in the Clinical Research in 1999 at Quintiles Clindepharm as a Clinical Trial Administrator (CTA). In 2001 she joined Pharmacia South Africa as a CTA, Monitor, EDC Liaison Officer and Clinical Trial Finance Administrator. Pharmacia was acquired by Pfizer laboratories in 2003. Karen joined Criterium Inc South Africa in 2004 as a CTA and is currently Senior CRA and assistant project manager. She gained extensive experience in all aspects

of clinical Research including data capture and management at Criterium headquarters in Saratoga Springs, USA. Email: kmallalieu@criteriuminc.com

Journal for Clinical Studies 27www.jforcs.com

Dr Gavin Leong completed his medical degree at University of Witwatersrand Medical School in Johannesburg in 1993. Clinical experience is gained in various specialities with 6 years in anaesthesiology. Dr Leong has been involved in Clinical Research since 2001 in various capacities, namely CRA, Medical Monitor and Medical Advisor for number of different companies. He joined Criterium Inc, South Africa in 2003. Dr Leong is currently the Clinical Operations Manager for Criterium South Africa

with added role of Medical Monitor for designated studies.Email: g_leong@criteriuminc.com or headtt@telkomsa.net

Market Report

Market Report

Volume 6 Issue 328 Journal for Clinical Studies

Mauritius Island – An Emerging Centre for R & D in

Biotechnology and the Life Sciences

Mauritius, the tropical island situated in the Indian Ocean and known worldwide for its beautiful beaches, is also internationally recognised for its rule of law, and political and social stability. Over the past few years, the economy has been successfully transitioned from a monocrop to a diversified innovation-driven and knowledge-based economy, resting on agribusiness, export-oriented manufacturing, tourism, financial services, property development and real estate, ICT-BPO, the seafood industry, a free port, logistics and a nascent ocean economy. Emerging sectors such as healthcare and life sciences are presenting some niche areas for the taking, and the enabling environment is being put in place to make it happen - especially in the light of sustained growth within pharmaceutical, medical device, and clinical research.

Important international players are already in operation locally as the country has established the appropriate legal and regulatory frameworks based on international norms, for the development of a strong biomedical research sector.

Emergence of Pharmaceutical and Clinical Research Sectors While endowed with a small but increasingly affluent local population, Mauritius has secured preferential access to markets worth several hundreds of millions of consumers. With the EU, through the Cotonou agreement; with the US, under the AGOA (Africa Growth and Opportunity Act); with Eastern and Southern Africa, through the COMESA (Common Market for Eastern and Southern Africa) and SADC (Southern African Development Community). The business relationship that Mauritius shares with these countries is an appealing factor for pharmaceutical companies.

To date, one emerging sector is the environment-friendly manufacture of medical disposables, which includes surgical equipment such as syringes, gloves, blades, clamps, gauze sponges, sterile packaging, bandages, disinfecting materials, test strips, stents, disposable dishes, and many others. It is worth pointing out that leading medical devices manufacturers from Europe have set up their manufacturing units in Mauritius, which now accounts for 5% of the world’s catheters for angioplasty, as well as silicone implants, dental crowns, electrotherapeutic and ophthalmic devices, among others. The industry is gaining momentum as further development in the sector is expected in the coming years.

Another vision of the Mauritian government is to transform Mauritius into a medical hub. Thus, the medical research sector is poised to become an important component in the gradual transformation towards the knowledge and innovation-based economy. The promulgation of the Clinical Trials Act in 2011 has paved the way for contract research organisations (CROs) to carry out clinical trials activities in Mauritius. The pending enactment of the Preclinical Research Bill will no doubt boost

R & D within the pharmaceutical research value chain. The Clinical Trials Act has already enabled applied

biomedical research to be carried out as per international norms. Three main committees act as regulatory bodies for clinical trials, namely the Clinical Research Regulatory Committee, the Ethics Committee and the Pharmacovigilance Committee.

CROs are showing a growing interest in using Mauritius as a platform for conducting clinical trials with the Ministry of Health and Quality of Life overseeing these activities. Only one CRO is presently active in the Mauritian territory and fully benefits from a wide panel of multi-ethnic volunteers spanning a wide range of pathologies. Sixty-eight per cent (68%) of the Mauritian population is of Indian descent, 33 % of African origin, 3% Sino-Mauritian and 2% have European roots.

In Mauritius, the main clinical development areas are:• Diabetes and cardiovascular diseases: there is currently

a high prevalence of metabolic, cardiovascular and lifestyle-related diseases - a survey performed in 2009 indicated that approximately 23.6 % Mauritians suffer from diabetes.

• Orphan diseases such as palmoplantar Keratoderma and Lamellar Ichthyosis.

• Dermatology diseases: Mauritius, with diverse population groups, presents a variety of chronic skin conditions such as acne or psoriasis, as well as pigmentation disorders such as melasma or vitiligo.

• Infectious diseases: Mauritius offers an ideal platform for the study of emerging tropical diseases. One such spate included Chikungunya and Dengue, for example.

Journal for Clinical Studies 29www.jforcs.com

Market Report

The evaluation of the cytotoxicity of new ingredients and finished products during their development is a critical point for the industry. Risk assessment is mandatory for chemicals registrations (e.g. under REACH) and for clinical testing. Following the European Union regulatory deadline (7th Amendment to the Cosmetics Directive) and ethical considerations, animal and human testing is now replaced by alternative techniques including in vitro assays and chemical testing.

Mauritius also benefits from a unique eco-region of the Mascarene islands in close proximity to the African continent, which constitutes one of the global biodiversity hotspots. It is blessed with rich and diverse traditional practices.

Recognising the demand for novel ingredients for the cosmetic, pharmaceutical and neutraceutical sectors, centres for phytotherapy research have been set up to cater for this niche area. They propose to bring to the world novel aromas, cosmetics, drugs and therapies from the locally-used medicinal plants. By using their expertise to add value to ancestral traditional knowledge on locally-used and lesser-known plants, they promote the sustainable use of biodiversity and provide leads for the above-mentioned sectors. Mauritius’ objective is to validate the rich biodiversity in this unique eco-region, and to propose comprehensive portfolios for the above-mentioned sectors, and help promote the development of innovative products.

Way ForwardIn light of the state-of-the-art facilities and highly-qualified personnel providing comprehensive high-end medical care in Mauritius, the Board of Investment (BoI) - which is the local national investment promotion agency - is now actively

positioning Mauritius as a platform for biomedical research. In this vein, BoI regularly organizes major conferences (IOR-ARC 2013, Bio Africa 2014) to showcase the opportunities that the Mauritian biotechnology sector has to offer.

Dr. Géraldine Jauffret, born Escher, graduated with a B.Sc. in Organic Chemistry and a M.Sc. in Biomolecular Chemistry from the University of Montpellier II (France). She pursued her doctoral studies at the University of Edinburgh in Biological Chemistry on the design, synthesis and in vitro analysis of peptoid based cellular carriers. Dr. Jauffret worked at Altrika Ltd as scientific researcher for the project “Cell labelling for in vivo and in-process quality control” before joining CIDP (Centre

International de Développement Pharmaceutique) as head of the Preclinical department. Email: g.jauffret@cidp-cro.com

Claire BLAZY JAUZAC, Managing Director of the CIDP group, holds a Pharm. D from the Toulouse University and an MBA from the ESSEC business school. Following several years of service within the SANOFI AVENTIS group in France, she moved in Mauritius in 2004 and co-founded the CIDP group, a private and independent Contract Research Organisation (CRO). At present, she is involved in the strategic development and management of activities across the different affiliates in the

world namely Mauritius (Ebène), India (Delhi), Romania (Bucharest) and Brazil (Rio). Email: c.blazy@cidp-cro.com

Market Report

Volume 6 Issue 330 Journal for Clinical Studies

Setting the Standard for Central Labs

in Asia Pacific and China

For more than two decades, central laboratories have been an important part of running global and large multi-regional clinical trials in Europe and the United States. With the rapid increase in the number of global clinical trials in China and the Asia Pacific region, trial sponsors should understand how to choose central labs in those regions, and the reasons for those choices. This article focuses on Singapore and China. Although Singapore has emerged as the hub for central labs in the Asia Pacific region, trial sponsors will continue to need a separate central lab in China, and must understand how these labs need to be set up there.

Historical Perspective: The Development of Central Labs in the West and the Growth of Clinical TrialsThe concept of the central laboratory originated in the United States, and was related to the hospital diagnostics business when Metropolitan Pathology Laboratories was founded in 1967. The company changed its name to MetPath in 1969, was acquired by Dow Corning in 1986, and spun off as Quest Diagnostics in 1997. Improved automation in the laboratory along with better IT systems enabled the central lab concept to develop, and the model was adopted in Europe in the 1980s and in the Far East in the 1990s to support clinical trials analysis.

The MetPath concept entailed the analysis of large quantities of samples in strategically placed locations near to communications hubs. This enabled transport of samples to central locations within short sample stability timelines. The business was driven by the private United States health sector and coincided with the development of improved air transport infrastructures led by FedEx, and better IT capabilities enabling rapid results delivery and flexible reporting capabilities. The outcome was economy of scale and lower cost.

The central laboratory concept in the diagnostic world was then adapted for clinical trials. In this model, samples from each continent and all the laboratories in the network are consolidated, and data is entered into a single database. This is possible because these data came from similar instrument platforms, meaning that they can be harmonised. Before the central laboratory industry was established, local laboratories near to trial centres, or laboratories preferred by sponsors or investigators would be used.

The challenges of handling multiple reference ranges, variable quality standards and the management of large numbers of laboratories became nearly impossible for large Phase III trials. Improvements in global availability of the same instrumentation, better harmonisation of methods, and the expansion of airport networks made it possible for central laboratories to support global trials.

The Establishment and Operation of Central Labs in Asia PacificAs more pharmaceutical companies have been expanding their research activity in Asia Pacific, the clinical trial support network in the region has improved. While the number of clinical trials conducted in the United States declined 12 per cent from 2009 to 2012, the number of clinical trials increased 24 per cent in developed Asia Pacific nations, and 18 per cent of developing Asia Pacific nations during the same time period. During that same time period, the number of clinical trials in the Asia Pacific region, excluding Japan and India, grew from 250 to 475. In the United States, growth was slower, with 6656 trials in 2007 compared to 7616 in 2012 1.

Just as the expansion of clinical trials in the United States drove the development of the central labs industry, the increase in the number of global trials in Asia Pacific has spurred the establishment of central labs in the region. Throughout Asia Pacific, many central labs have been set up as wholly-owned entities, rather than as partnerships or independent subsidiaries, as this structure allows for the

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use of consistent operations standards around the world. Singapore has emerged as the chosen hub for central labs in the region.

A hybrid central lab business model also emerged. This model provided central laboratories with their own facilities in the United States and Europe to use third-party laboratories in the rest of the world to procure global multi-centre trials. In addition, there are CROs or organisations without their own labs, but who partner with third-party labs globally. All types of global central laboratory strategies have their advantages and disadvantages. Historically, central labs initially partner with a regional lab when entering a foreign market until sufficient business warrants the investment to build their own lab facilities. This wholly-owned central lab model provides advantages that include data integrity, homogenous data integration, and functional controls. Even with the advantages a central lab offers over other models, there still may be the need to partner with regional labs to outsource esoteric tests. Other aspects to consider in retaining partnerships with regional labs are expertise regarding logistics, and navigation of regulatory guidelines.

The operational hybrid approach allows sponsors to take advantage of established, regional central labs while benefiting from advanced data management systems for the centralisation and harmonisation of test data.

In addition to the global central labs, there are local diagnostic laboratories that play various pivotal roles in clinical trials. They are involved in almost all the Phase I and IV testing, and some speciality testing. Up until the early 2000s, local diagnostic labs in Singapore conducted at least 60 per cent of clinical trial testing, according to local experts active in the industry at that time. Though these local labs provide very high-quality results, they cannot provide services such as logistics and project management. Today, more than 80 per cent of clinical trials in Singapore are coordinated through central labs, these local experts report. Although local diagnostic laboratories still play a minor role, they are conducting some of the esoteric, low-volume but high-margin testing. Additionally, most non-time-critical esoteric tests can be consolidated in Singapore and shipped to the United States, a European parent laboratory, or specialised laboratories.

Considerations for Selecting a Global Central Lab Partner for Asia Pacific TrialsAll central laboratories are able to provide testing, specimen management, data management, project management, logistics management, and kit production. For trial sponsors, the critical factors in deciding which central lab to use are competitive price, a broad test menu that includes speciality testing, global reach, logistics management, flexibility, proactive communication, an extensive customer base, and industry reputation. Other considerations for choosing a central lab in the region are an expert staff with extensive clinical trials experience, local knowledge of regulatory requirements and country-specific logistics, and familiarity with local customs and languages.

The competitive advantages that large central labs often have over smaller labs are economies of scale, such as having a broader test menu and more expertise. Pricing of a test and construction of a full-service proposal can be done in many ways, however sponsors may not be able to compare services directly on a like-for-like basis.

The same applies for logistics costs, where pricing can vary based on whether the transportation company considers a city to be primary, secondary, or tertiary in its network. The logistics costs in Asia Pacific can be two to five times more expensive than the United States. Additionally, the primary logistics service providers in the region are not the same companies as those found in the United States, which means having to establish trusted relationships with new vendors. However, FedEx is expanding biomedical logistics capabilities into Asia Pacific. This concern is not specific to central labs in Asia Pacific, and can also be found in Europe and South America. Ultimately, the effective selection and management of couriers is a key requirement of the central laboratory, and global logistics experts are a very important asset to the central laboratory team.

Even though the considerations of logistics and other expenses can be daunting, trial sponsors must have access to an Asia Pacific central lab. This need is driven by facts such as the number of registered interventional studies in Asia, which have grown at an average rate of 8 per cent over the past five years. The number of similar studies in North America fell by 2 per cent. During the same period, the number of investigators in Asia grew by an average annual rate of 14 per cent, compared with 9 per cent in North America2.

Singapore has become a favoured hub for central labs because of its strong transportation system, and having an airport that is within a seven-hour flight of all countries in the region. Another consideration in choosing Singapore for a central labs operation is the highly-educated local population, where English has been established as the official second language for education3.

Development and Operation of Central Labs in ChinaWith its large, treatment-naïve population, China has become an important centre for pharmaceutical development. In 2007, there were 954 clinical trials being conducted in China. As of 2012, there were 2442 1.

In China, local diagnostic laboratories, which are government-owned and based in public hospitals, played a pivotal role in many trials in the early days in the absence of multi-national central labs. As in the West, a shift in business has occurred to private laboratories such as Kingmed, Adicon, Wuxi Apptec, Di-an and other smaller private laboratories. Tigermed CRO is the most recent example. Tigermed is the largest China-owned CRO in China and its central lab, located in Guangzhou, was given accreditation by the College of American Pathologists (CAP) in 2013. This made Guangzhou Tigermed Central Lab the first CRO central lab in mainland China.

The market segment in China’s central labs consists of

standard safety; data management; logistics and courier management; kit production; project management; integrated database management; IT reporting and flexibility; and speciality test(s). Although China is late to start offering central lab services, the industry is expected to significantly grow in all areas of clinical trials testing, ranging from PK/PD analysis, to specialised testing such as pharmacogenetic or pharmacogenomic testing. Genostratification could be the pattern of the near future, as the pharmaceutical industry is moving more towards personalised medicine, especially in oncology. This is a very important development for labs serving the domestic Chinese market, as there are proven ethnic differences in biomarkers such as epidermal growth factor receptor (EFGR) distribution in comparison to Caucasians, particularly in non-small cell lung cancer and gastric cancer. Many large central labs already have these capabilities in their Western labs and may well consider developing them further in China.

According to ChinaBio LLC, the number of ongoing global clinical trials in China nearly tripled between 2007 and 2012 to 564 4. However, one of the current main hurdles that could slow the rate of increase of new clinical trials is the approval time required by the China Food and Drug Administration (CFDA), which was previously the SFDA. It is critical for sponsors to start the clinical trial application process as early as possible to avoid undue delays.

Most local laboratories will take on local trials testing, and

a couple of the global multi-national central laboratories are also participating. In these cases, sponsors will find that the pricing is low, compared with pricing of similar labs outside of China. However, in China, there are progressively more principaI investigator-initiated trials, with the testing price comparable to a global trial.

Multi-national central laboratories have established their presence in China. The question is whether the reverse will happen. Currently, there are no Chinese central labs that have a presence outside China. It is possible in the future that this could change.

Although China does not allow for the import or export of biological samples – meaning that all central labs in the country support the domestic market – one company has found a way to serve outside markets. WuXi AppTec is located in Shanghai Waigaoqiao Free Trade Zone at Pudong Airport, the first free trade zone to be established in China. Because the company is not technically located in China, it can receive, and has been receiving, PK samples from outside China, as a single testing location, processing samples from the United States and Europe. Recently WuXi AppTec has also set up a central safety laboratory, also within the trade zone, which means that it can handle samples from global clinical trials outside China.

Gap Analysis of Central Laboratories in ChinaAs China’s regulations prevent the export of biological samples for testing, all samples need to be tested in China. Global central laboratories in China must therefore either outsource or perform testing in-house, depending on the anticipated return on investment. Harmonisation is always an issue and can lead to the need to import materials such as reagents. Chemicals such as these might not be available in China, either because the manufacturer has not yet filed an application for the medical device to the CFDA, or because there is no distributor in China. Either way, the difficulties of needing to import and access needed chemicals and equipment could lead to higher costs, which is passed on to the sponsor. Even if a central lab is used, trial sponsors must take into account the management and oversight needed for the lab and these requirements can be considerable.

Most pharmaceutical companies recognise CAP Accreditation as a sign of compliance to quality standards. To be accredited, one has to run the proficiency survey material supplied by CAP. Import of CAP material into China is not without its problems. There have been delays in receiving time-sensitive reagents and other testing materials. As a result, CAP now has a strategic alliance with Becton Dickinson, set up in July 2013 to handle the import of CAP-approved material5. This is just one example of a gap, and can apply to most material that needs to be imported into China. Earlier identification of testing needs is important if delays are to be avoided.

Another factor that has to be taken into account is that to date, local operating companies still prefer to choose local diagnostic laboratories for specialised testing related to

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anatomic pathology. This is related to the availability of local experts and the inability to export samples.

One of the most important considerations in evaluating a central lab is the knowledge and experience of its personnel. Sponsors must make sure that the central lab owner has a strong local team in China that can navigate the regulatory and cultural landscape, and can train personnel to work according to the standards of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP). Because of these considerations, the inherent costs of doing business in China are relatively high.

When it comes to the talent pool, in 2008, 51 per cent of Chinese bachelor’s degrees were awarded in the science and engineering fields compared with 31 per cent in the United States6. In 2009 alone, more than 108,000 overseas students returned to China, an annual increase of 56.2 per cent compared with 20087. This, in addition to the investment by global companies in training, will reduce any gap in the talent pool in China.

Another way to evaluate a central lab in China is the quality of the data provided and how the lab handles combining data from local labs in different geographical locations. The basic requisite is to use the same instrumentation and materials. Correlation is done in real time so that sample stability is no longer an issue. Different labs use different tools, but with the same objectives and outcomes.

Many pharmaceutical companies use preferred provider status as a right to tender, and for the selection of a central laboratory in the competitive tendering of projects. There is still an exception to this in China.

ConclusionThe dominant service providers in both the United States and Europe are the private central labs, and these are also emerging as the main players in the Asia Pacific region, followed by China.

With the improvement in ICH-GCP training and compliance, more trials will be conducted in Asia Pacific and China to speed up drug development. Most large multi-national central labs are already dominating the Asia Pacific region and China. This could help to improve the overall quality of trial data coming out of the region. In addition, due to biological sample export restriction, Chinese labs that are wholly owned by CROs will need to conduct more esoteric tests to be self-sufficient. This means Chinese central labs will be creating broader menus than central labs located in Singapore or other Asia Pacific countries, and Chinese central labs could become comparable to their parent companies. However, more China-owned private diagnostic labs could enter the clinical trial lab testing business.

There are still hurdles to overcome in establishing central labs in China but these can be addressed by putting together an experienced, local team to run these operations. For the

rest of the Asia Pacific region, particularly Singapore, the major concern is the cost of logistics, as logistics companies, such as FedEx, have not expanded into Singapore. Effective courier selection and management is a key requirement of the central laboratory and global logistics experts are a very important asset to the central laboratory team.

References1. www.clinicaltrials.gov, visited on 20 Apr 20142. Anderson, A., & Korieth, K. New Growth and Decline in

Asia Clinical Trials The CenterWatch Monthly Vol. 20 Issue 10, 1-6 (2014)

3. Dixon, Quentin L. The Bilingual Education Policy in Singapore: Implications for Second Language Acquisition Proceedings of the 4th International Symposium on Bilingualism Cascadilla Press (2005)

4. China Clinical Trials 2013: Open to the World - Analysis of IND and NDA Applications in China 2009-2013 ChinaBio LLC (2013)

5. BD and the College of American Pathologists Announce Strategic Alliance to Support Laboratory Quality and Performance in India and China, PRNewswire, July 2013 http://www.prnewswire.com/news-releases/bd-and-the-college-of-american-pathologists-announce-strategic-alliance-to-support-laboratory-quality-and-performance-in-india-and-china-217618231.html

6. https://nms.org/Education/TheSTEMCrisis.aspx, visited 30 April 2014

7. http://en.ccg.org.cn/_d276009973.htm visited 30 April 2014

Jerry Boxall is a trained biomedical scientist with more than 30 years of experience in the field. For the past 20 years, he has held senior central laboratory posts both in the UK and in Europe. Mr. Boxall has been heavily involved in the establishment of both European and global central laboratory networks and has been responsible for central laboratories in Germany, France, Denmark, The Netherlands, and the United Kingdom. He joined the

ACM team from CRL-Medinet in June 2000 as Head of European Operations, and took over as Managing Director, Europe, in January 2005. Email: jboxall@acmgloballab.co.uk.

Dr. Lee is a seasoned professional in the laboratory field with a depth of clinical trial experience and knowledge gained over more than 20 years in both the United Kingdom and the Asia-Pacific region. Dr. Lee holds a PhD in chemical pathology and is a Fellow of the Royal College of Pathologists (UK). Her career in Asia Pacific extends back to 1988 and includes experience in Singapore and Malaysia with both health service institutions and central

laboratory facilities. Dr. Lee founded the highly regarded Phoenix Pharma Central Services (S) Pte Ltd in 2001 having previously played a pivotal role in the establishment of the central laboratory services for Covance (Asia) Pte Limited. Email: cylee@acmgloballab.com.

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The Elements Requiring Particular Attention while Conducting Clinical Trials in a Paediatric PopulationIntroductionChildren account for 20-40% of the global population depending on the region1, but only a third of all medications are officially approved to treat children2. A significant amount of medications are used in children off-label, which leads to the development of adverse reactions3, 4. Only 7.4% of clinical trials for medications are conducted in paediatric populations5. The development, research and approval of the use of new medications in children are significantly behind the current need.

Based on our experience, we would like to outline and review the elements to which particular attention should be paid when planning and conducting paediatric clinical trials.

When writing this article, we analysed the results of paediatric clinical studies involving over 1400 patients. The indications for these studies included complicated and non-complicated community-acquired pneumonia, preventing post-operative nausea and vomiting, preventing chemotherapy-induced nausea and vomiting, preventing neutropenia in patients with rabdomyosarcoma and solid tumours, etc. The age of patients, depending on the study, was between 1-18 years old.

We have identified several elements which require our special attention when planning and conducting these clinical trials:-

1. Obtaining approvals from regulatory and ethics bodies. Clinical trials in a paediatric patient population are closely monitored by the ethics and regulatory bodies which justly apply strict requirements to clinical trial protocols. Obviously, it is most difficult to obtain the approval of a clinical trial using placebo as a comparator, or if the new medication is being studied in children and it is a first-in-human study and not enough data has been accumulated on its safety.

From an ethical point of view, placebo is justified in situations for particular indications with no proven effective treatment where an investigational drug may potentially have a significant therapeutic effect. If the drug is being researched first-in-human and there is not enough data on its safety, we recommend involving leading specialists in a particular therapeutic area to prepare independent expert opinions and append these opinions to the regulatory/ethics submission package. It is preferable to address the key opinion leaders in each particular country in which the study is planned to be conducted. At the same time, it should be taken into consideration that the expert providing an independent opinion must not participate in the study himself, and preferably, should not represent an institution expected to participate in the study. He/she must not be a consulting

expert of the sponsoring company. It must be noted that the provision of a positive independent expert opinion does not guarantee the approval of the study, but may help the experts to get a more detailed concept on whether the study is feasible and appropriate in a particular country.

A regulatory submission in each particular country should be prepared separately and thoroughly. We would like to draw your attention to the fact that regulatory and ethics bodies in each particular country act independently of each other, and obtaining approvals in certain countries may not be a sufficient ground to obtain such approvals in other countries.

We have encountered a situation where a study approved in the USA and other countries of Western and Eastern Europe is not approved in Russia, Serbia, Bulgaria or France. At the same time, it is obvious that the opinion of a local key opinion leader, according to our experience, is always favourably taken into consideration.

2. Informed Consent Process.Parent(s) must provide consent for their child to take part in a clinical study. At the same time, many countries require the consent of both parents - if they are married (Russia), or sometimes even if parents are divorced (Argentina). We do not doubt the legal status of these requirements, since both parents have equal rights in decisions related to their child. However, the necessity to obtain the informed consent of both parents may complicate the procedure of patient enrolment, and decrease the number of patients - especially in cases when a study takes place in an “acute clinical situation”, and a decision on enrolment must be made immediately: within 24 hours or shorter time frames. It is obvious that in such cases, the number of signed informed consent forms is influenced not only by the non-willingness of one of the parents to sign the consent, but also by logistical reasons, i.e. the absence of one of the parents at the time of informed consent signing, and the impossibility to speedily get in touch with him/her.

For example, in a clinical trial of an antibiotic for the treatment of pneumonia in hospitalised patients, not more than four hours should have passed from the moment a patient was diagnosed with pneumonia until the beginning of antibacterial treatment, in accordance with the international treatment guidelines6. This period of time was often not sufficient to establish communication with the second parent of a child, if the child was admitted to hospital accompanied by only one of the parents.

On the other hand, when conducting a study of a medication for preventing chemotherapy-induced nausea and vomiting in children, investigators had sufficient time, because there is always a time slot of a few days between the diagnosis of cancer in a child and the start of treatment.

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These few days are used for required diagnostic procedures and both parents have time to visit the clinic, discuss the study, and make a decision.

This is why, when selecting countries for clinical trials where screening procedures are allotted a short period of time, local legislation regulating the process of obtaining informed consent and possible complications should be taken into consideration.

3. Choice of comparator.Standard therapy is most commonly used as a comparator in clinical trials. The likelihood of the comparator medication being administered in children “off-label” must be taken into account. This is the matter of how appropriate it is to compare the effectiveness of the study drug with a medication which is being used in children, but has no proven effectiveness in this particular indication in a paediatric population. In addition, every particular country may have approvals only for specific formulations and dosages of a certain comparator.

For example, in treating acute hematogenous osteomyelitis in children, depending on the epidemiological situation, it is recommended to use the following medications: nafcillin, first generation cephalosporins (cefalexin), vancomycin or clindamycin7. However, nafcillin is not approved in Europe; cefalexin is not approved in Austria, Latvia, Lithuania and Estonia. In Serbia it is approved for use only in children older than five years of age, and in Croatia in children older than seven years of age. Clindamycin is approved in Russia in children older than eight years of age, and in Serbia in children weighing more than 10 kg, i.e. older than one year of age. Linezolide is not approved to treat children in the countries of the European Union, while it is approved for use in children older than 12 years of age in Russia (but not in children with osteomyelitis).

This simple example shows the difficulties that may be encountered when planning a clinical trial in children with acute hematogenous osteomyelitis, which undoubtedly is a serious problem in paediatric practice. As a practical recommendation, it is possible to either choose countries where one and the same medication may be used as standard treatment, or allow to compare the study drug in each country vs. its local treatment standard, which will simplify patient enrolment but will subsequently complicate statistical management of the study results.

Using placebo as a comparator in children is significantly limited. There is no doubt that prescribing placebo is not equal to the absence of treatment, because as a rule, standard treatment is prescribed along with placebo. However, it is the very word “placebo” that produces a negative attitude in parents and doctors, being associated with the absence of treatment.

For example, in a planned clinical trial of an antiviral medication for the treatment of respiratory syncytial virus in children, placebo was to be used as a comparator due to the fact that there was and still is no commonly accepted

standard effective treatment of this medical condition. However, it would be more reasonable to propose a study design where commonly accepted maintenance therapy was used vs. the study drug. Such a study design would simplify both receiving study approval by ethics and regulatory bodies and obtaining informed consent from parents, because even if their child would not receive the study drug, he/she would receive maintenance therapy, which in a parent’s opinion is always better than placebo.

4. Study procedures and schedule of visits.Study procedures should be most convenient and safe for a patient.

Main points to take into consideration:a. Invasive procedures should be minimised, and if they are

unavoidable, local anesthesia should be used (e.g. local anesthetic cream).

b. Number of blood draws and the volume of blood samples must be limited. If possible, protocol-specific tests must be combined with routine tests. According to the EMA guidelines, blood loss related to clinical trials must not exceed 3% of the circulating blood volume in four weeks and/or 1% of circulating blood volume at any given moment8. For example, circulating blood volume in children less than one year of age is 80 ml/kg, i.e. in a six-month-old child weighing 8.5 kg, it will be 680 ml, and 3% of this volume is 20.4 ml. To minimise blood loss, the minimal blood volume required for a clinical study must be defined at the stage of planning a study, and blood tests for different parameters must be combined and dry blood spot samples must be used where possible.

c. In case of repeated blood draws from a vein, it is preferable to use a peripheral catheter instead of repeated venous puncture.

d. Schedule of visits and study procedures must be most convenient for the child and his family. For example, in small children, the time of an afternoon nap must be taken into consideration. Times in class must be taken into account for children attending school.

e. Every age group has its behavioural and social particularities, which should be considered when planning a study. For example, teenage girls may be psychologically non-accepting of a pregnancy test that is part of screening procedures.

The study protocol of a paediatric clinical trial must be written with the paediatric population specifics in mind, instead of taking an adult protocol and adapting it to a study in children9.

5. Difficulties of diagnostics.It is common knowledge that it is more difficult to diagnose many medical conditions in children than in adults. The difficulties of diagnostics are related firstly to the physiological specifics of being a child, i.e. immaturity of organs and systems, fast generalisation of a pathological process because of the immaturity of the immune system, and vagueness of symptoms and objective signs of disease. Secondly, to the psycho-emotional age characteristics of a

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child which complicate a subjective assessment of a patient. It is often necessary to use additional methods of diagnostics and laboratory tests. Unfortunately, if the time of screening is limited, diagnostic errors may take place.

For example, in the aforementioned clinical trial of a new antimicrobial drug for the treatment of community-acquired pneumonia, the period of screening would inevitably amount to only three to four hours and after it elapsed, treatment had to be started. As a result, several patients after the start of study treatment were diagnosed with other diseases: Kawasaki disease, mycoplasma pneumonia, and/or legionella infection. The clinical picture of these diseases at earlier stages is almost the same as that of a typical bacterial pneumonia, and the short screening period did not allow for a fully-fledged differential diagnostics. Even though very undesirable, this is a normal clinical situation when empirical treatment was started based on a preliminary diagnosis and the final diagnosis was established after a period of time, based on, among other factors, the response to treatment. When changing a diagnosis, treatment would need to be corrected. In clinical trials, however, this situation was regarded under a special angle. When establishing a different diagnosis, such patients were withdrawn from a study and from per protocol analysis, since they did not appear to have the studied disease. Considering that the number of patients enrolled in a paediatric clinical study (sample size) was usually smaller than the sample size of adult studies, withdrawing two to three patients from the analysis could compromise the statistical power and consequently the credibility of the study results. To avoid such a situation in paediatric trials, we can recommend using the principle of patient “substitution” more frequently.

6. Serious adverse events.According to our experience, the frequency of serious adverse events in children is higher than in adults. This is due to more frequent hospitalisation of children because of the necessity to perform in-depth diagnostics when a clinical picture is vague, due to the inclination to generalise the pathological process and more complicated clinical course of the disease, as well as due to social reasons, i.e. young age and impossibility to provide adequate medical monitoring at home or the complexity of performing medical procedures in an outpatient setting. These factors must be taken into account both by investigators and study sponsors when planning the workload of an investigational team.

ConclusionIn recent times, there has been a tendency to increase the number of clinical studies in the paediatric population, which is also influenced by the “sticks and carrots” FDA and EMA policies. As the number of studies increases, however, the success of each particular trial depends not only on the necessity to conduct it, and on the administrative pressure by regulatory bodies such as the FDA and EMA, but also on the professional approach of the investigators and clinical research professionals who plan and conduct a study. We think that the considerations of the factors that we described in this article will increase the chances of success of clinical

trials in a paediatric population.

References

1. http://www.euro.who.int/__data/assets/pdf_file/0012/97599/E91713R.pdf

2. Choonara, I., Conroy, S. Unlicensed and Off-label Drug Use in Children:

Implications for Safety. Drug Saf. 25 (1), 1-5 (2002)

3. Neubert, A., Dormann, H., Weiss, J. et al. The Impact of Unlicensed and Off-

label Drug Use on Adverse Drug reactions in Paediatric Patients. Drug Saf. 27

(13), 1059-1067 (2004)

4. Pandolfini, C., Bonati, M. A Literature Review on Off-label Drug Use in Children.

Eur J Pediatr. 164(9), 552-558 (2005)

5. Pasquali, S.K., Lam, W.K., Chiswell K. et al. Status of the Pediatric Clinical Trials

Enterprise: an Analysis of the US ClinicalTrials.gov Registry. Pediatrics. 130,

e1269-1277 (2012)

6. Bradley, J.S., Byington, C.L., Shah, S.S. et al. The Management of Community-

Acquired Pneumonia in Infants and Children Older Than 3 Months of Age:

Clinical Practice guidelines by the Pediatric Infectious Diseases Society and

the Infectious Diseases Society of America. Clinical Infectious Diseases. 53

(7), e25-e76 (2011)

7. Harik, N.S., Smeltzer, M.S. Management of acute hematogenous osteomyelitis

in children. Expert Rev Infect Ther. 8 (2), 175-181 (2010)

8. Ethical Considerations for Clinical trials on Medicinal Products Conducted with

the Paediatric population. Ad hoc group for the development of implementing

guidelines for Directive 2001/20/EC relating to good clinical practice in

the conduct of clinical trials on medicinal products for human use. http://

ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf.

9. FDA. Best Pharmaceuticals for Children Act.

Available at: www. FDA.gov/RegulatoryInformation/

L e g i s l a t i o n / F e d e r a l F o o d D r u g a n d C o s m e t i c A c t F D C A c t /

SignificantAmendmentstotheFDCAct/ucm148011.htm

Iryna Teslenko, MD, MSc, MBA is Director of Medical Monitoring & Consulting at PSI CRO AG. She is a board-certified physician and holds a Master of Science degree in Radiology Diagnostics. She has more than 10 years of experience in clinical research as a clinical research professional. She is also the author/co-author of more than 20 publications. E-mail: iryna.teslenko@psi-cro.com

Maxim Belotserkovsky, MD, PhD, MBA is Head of Medical Affairs at PSI CRO AG. He is a board-certified physician in Internal Medicine, Rheumatology, Anesthesiology and Intensive Care, and Hemodialysis, a Certified Associate Professor of Pathological Physiology. He has more than 20 years of experience in clinical research as an investigator and clinical research professional. He is also the author/co-

author of more than 130 publications. E-mail: maxim.belotserkovsky@psi-cro.com

Maxim Kosov, MD, PhD, Medical Affairs Manager at PSI CRO AG is a board-certified physician in Neonatology and Anesthesiology. Before joining PSI he worked in Ott Research Institute of Obstetrics & Gynecology and Paediatric Medical Academy. He has 30 articles. E-mail: maxim.kosov@psi-cro.com

Oncology

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Volume 6 Issue 342 Journal for Clinical Studies

Therapeutics

Implications of Paediatric Asthma

in Clinical Trials

Asthma bronchiale is the most common and most frequent chronic illness in childhood. The International Study of Asthma and Allergy in Childhood (ISAAC), as the largest international epidemiologic study so far, confirmed that the global prevalence of paediatric asthma has continuously increased over the past decades across many different countries, causing a surge in money spent on resolving asthma-related symptoms (figure 1). The most important factor in cost reduction (medical, non-medical) of paediatric asthma treatment is improving asthma control: carefully planned asthma management programmes can reduce the burden on both individual patients and society as a whole.

Figure 1. Prevalence of asthma in children aged 6-7 years and 13-14 years ISAAC Phase Three 1999-2004

Source: Prevalence of asthma and allergies in children. The prevalence

rates of asthma symptoms and allergic rhinoconjunctivitis in children

aged 6-7 years and 13-14 years, WHO, Europe Fact sheet No 3.1, May,

2007, Code RPG3_Air_E1

In terms of asthma, the often cited statement, “Children are not small adults”, is particularly true in view of the illness and asthma-related clinical trials. The childhood asthma disease spectrum is well recognised, however subgroups (phenotypes) are challenging to identify, define, and use as a base for therapeutic considerations. There is no doubt that the pathophysiologic base of the illness is a chronic inflammation-related exacerbation, but the actual causes are heterogeneous in different ages of childhood (figure 2).

Looking at the paediatric asthma guidelines – GINA (Global Initiative for Asthma, 2012) and PRACTALL (Diagnosis and Treatment of Asthma in childhood: a PRACTALL consensus report, 2008) - completed ARIA (Allergic Rhinitis and its

Impact on Asthma, 2012) and EPOS (European Position Paper on Rhinosinusitis and Nasal Polyps 2012), it shows that the guidelines are underlying current asthma therapy in everyday practice. From the point of view of creating and updating paediatric guidelines, paediatric clinical trials are essential, since results of the trials can give evidence which serves as a basis for the therapeutic concepts of paediatric asthma. However, paediatricians also have to consider that every patient is an individual, every case is unique, and physicians have to examine and treat the whole organism including related diseases (e.g. allergic rhinitis, eczema), not only asthma. Furthermore, in evaluation of asthma symptoms, differential diagnostic approaches are necessary as well.

Treatment of paediatric asthma has not changed substantially in recent decades; mainstream therapy consists mostly of inhaled corticosteroids in combination with beta agonists. Montelukast has a role in treating viral-induced wheeze in younger children and in preventing exercise-induced asthma. New therapeutic approaches in order to reach better asthma control and quality of life in children suffering from asthma, are necessary. That means not only adapting the “old” asthma therapy for children, but also examining the innovative asthma medicines and primary prevention strategies.

There are some paediatric specialities which have to be considered in terms of design and implementation in paediatric clinical asthma trials.

Figure 2. Asthma phenotypes in children aged > 2 yrs of age. Source: Diagnosis and treatment of asthma in childhood: A PRACTALL

consensus report, L.B: Bacharier et al. (Europen Paediatric Asthma Group),

Allergy 2008: 63: 5-34

First of all, there is heterogeneity between children of different ages suffering from asthma and heterogeneity in the natural history of the illness. In paediatric asthma, age and triggers can be used to define different phenotypes of disease. They do not represent separate disease entities, and are rather part of the “asthma syndrome”.

Additionally, the viral and bacterial infections may play an important role in asthma exacerbations (AE), however, evaluation of asthma exacerbation can sometimes be subjective because it is interpreted by parents.

Successful spirometry tests demand good cooperation from children. The implementation of tests can sometimes be difficult for children because they are not able to pay enough attention to test-related instructions. Evaluation of forced manoeuvres is frequently restricted in children because the six-second forced expiration is not always feasible in these patients. Repeated spirometry tests (usually during the randomisation visit) can be stressful for children, too. This situation may cause the most significant difficulties in the enrolment of paediatric asthma patients in trials. Forced oscillation procedures (FOT) and interrupter resistance (RINT) can be applied in children from three years of age to measure airways resistance.

Our experience in paediatric studies shows that the use of electronic diaries, which are sometimes combined with peak expiratory flow measuring devices, are highly recommendable. Use of pictorial symptom diaries may allow self-completion by the child. For pre-school children, diary completion by parents rather than child may result in more complete data, but may introduce bias at the same time.

Assessment of asthma control in children by means of an Asthma Control Test (ACT) is usually based on parents’ reports. The reliability of symptom assessment by questionnaires may be influenced by poor symptom perception, and also by the reporter’s personality (child or parent). Since the decision to administer a rescue bronchodilator is often made by the parents, this indicator may not assess asthma control accurately in young children. Some age-specific paediatric versions of commonly used control questionnaires, translated to different languages, are becoming available for clinical studies (ACT, C-ACT). However, their potential application in paediatric clinical practice needs yet to be evaluated carefully.

Measurements of biomarkers might be useful in asthmatic children. However, successful sputum induction in children is limited, and serial assessment of sputum may be problematic since many children are unwilling to undergo repeated sputum inductions during follow-up visits. FENO (Exhaled Nitric Oxide) measurement is an acceptable evaluation of biomarkers in children with asthma, and may be helpful in monitoring medication effects. Reliable measurement of FENO is limited to children of five years and older.

Estimating unscheduled healthcare consultations for asthma in children is usually complicated by infection-related non-specific airway symptoms. Determination of healthcare utilisation and non-medical costs in paediatric

and adolescent clinical trials is based more upon the reports of parents or caregivers than on reports of patients. Child-completed quality of life (QOL) questionnaires are useful in asthma studies if investigators are taking into consideration the child’s reading capabilities. Children under 12 years of age may have difficulty in reading and/or understanding a questionnaire without assistance. When children are assisted by their parents in completing a questionnaire, though, their responses change. Therefore, child-completed questionnaires should either be completed by the child alone or with the assistance of professional staff.

Asthma-related clinical trials in paediatric patients play a very important role in asthma research. These processes require paediatric and respiratory medical expertise from the investigators, and also thorough understanding of factors biasing study results. Clinical trials may help to establish new therapeutic strategies and evidence. These studies can only be carried out successfully by investigators with excellent communication, patience, and professional humility.

Andrea Banfi MD, Ph.D. is a paediatrician, pulmonologist and bronchologist. She is a medical officer of Auxiliis’ “Svábhegy” Health Service Ltd, Budapest; and chief physician of University of Szeged, Faculty of Medicine Department of Paediatrics. Her research area is the investigation of airway inflammation and asthma. She is a member of the European Respiratory Society (ERS), and the World Association for Bronchology and Interventional

Pulmonology (WABIP). She is a board member of the Hungarian Bronchological Society and Hungarian Paediatric Respiratory Society. Email: andrea.banfi@svabhegy.eu

Journal for Clinical Studies 43www.jforcs.com

Therapeutics

Therapeutics

Volume 6 Issue 344 Journal for Clinical Studies

Paediatric Clinical Trials in Central and Eastern Europe – Here and NowTraditionally, emerging markets have lagged behind more-developed countries when it comes to paediatric trials and have, on occasion, demonstrated a reluctance to perform research on children. This comes from well-documented challenges relating to paediatric trials, such as:

• The characteristics of the study population: intrinsically more vulnerable than adults; cognitively immature; dependent on adults

• Lack of comprehensive regulations protecting children while on study

• Ethical concerns relating to some study procedures that are common for all countries

• Bad press and media activities focused on any form of child abuse in developing countries, particularly during pharmaceutical development.

Although Central and Eastern Europe has a long history of running paediatric clinical trials, particularly in those countries that are EU members such as Poland, Hungary, and the Czech Republic, the total number is still some way behind the Western world (see Table 1).

Table 1Paediatric trials statistic based on www.clinicaltrials.gov.comNumber of ongoing trials in selected countries on April 10th 2014*Clinicaltrials.gov data includes all trials in the US, but does

not necessarily capture all ex-US studies. The US number should therefore be considered an outlier. However, relative to CEE countries, Western countries (excluding the US) are still performing vastly more paediatric trials.

CEE countries’ regulations relating to paediatric trials are not always sufficiently robust to address the most challenging aspects of trials, such as:

1. type of study/protocol into which children are permitted to be enrolled

2. early stage projects (Phase I, Phase I/II)3. subject consenting process4. protection of children’s rights while in the study

Published regulations and their interpretations vary from country to country. The variance is mostly in the detail, but in general they lack clear answers for many hypothetical situations in which a paediatric patient might find themselves while in a clinical study. Moreover, due to lack of experience in this field, some countries’ regulatory bodies have not had the opportunity to adjust their regulations or create comprehensive guidelines to meet the practical requirements. This problem is mostly related to countries that are non-EU members like Serbia, Russia, Ukraine, Georgia, and Belarus.

In countries like Poland, Hungary and the Czech Republic, there are situations in which the final decision on how to handle the paediatric subject in unusual circumstances, e.g. emergency care, is determined by the hospital local ethics committee on an “as needed” basis due to a lack of general guidelines and rules.

Not every CEE country is right for every paediatric study, and very thorough regulatory feasibility research has to be done before determining the optimal country for the project.

1. Type of clinical study with paediatric patientsEU countries have implemented regulations stating that, in general, only trials with potential therapeutic or preventive benefits are allowed. Testing of flavour, palatability or overall acceptability is not permitted.

Issues with regulatory approval arise when there is insufficient data relating to the IMP derived from adult studies. How should one define “sufficient data“? This is individual to each regulatory body and varies from country to country, but the strictest country in the region is the Czech Republic and their regulatory authority: SUKL. Sponsors should be prepared for a very long list of questions before approval is granted. There are some indications like congenital and metabolic diseases specific to the paediatric population for which adult data is not available, but for those studies, sufficient documentation has to be presented to the regulatory bodies. While doing feasibility research for such a project, it is recommended to

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check whether a similar study design was approved in the past and if other factors would recommend that country.

A paediatric investigational plan (PIP) is of great benefit at this stage. It is a specific requirement of the EMA, but a robust PIP can also be reviewed very favourably by non-EU countries in the region. The following is an extract from the EMA’s own guidelines:-

‘A paediatric investigation plan (PIP) is a development plan aimed at ensuring that the necessary data are obtained through studies in children, when it is safe to do so, to support the authorisation of a medicine for children. Pharmaceutical companies submit proposals for PIPs to the European Medicines Agency’s Paediatric Committee (PDCO). This Committee is responsible for agreeing or refusing the plan.The Paediatric Regulation requires PIPs to be submitted to the Agency early, wherever possible.

The normal development of a medicine requires that various studies be performed to ensure its quality, safety and efficacy. PIPs:

• include a description of the studies and of the measures to adapt the medicine’s formulation to make its use more acceptable in children, such as use of a liquid formulation rather than large tablets;

• cover the needs of all age groups of children, from birth to adolescence;

• define the timing of studies in children compared to adults.

The development plan for a medicine can be modified at a later stage as knowledge increases. Modifications can also be made if the applicant encounters such difficulties with the implementation of a PIP, which render it unworkable or no longer appropriate.’

Another significant challenge is placebo-controlled research in paediatric populations. In some branches of medicine this cannot be avoided. In general, approval for pure placebo studies is granted only in exceptional cases. There have been examples in Hungary, Poland, Slovakia, and Romania. The strictest country in the region is often the Czech Republic. In addition, the Russian MOH rarely allows paediatric placebo trials. In order to avoid regulatory refusal which may impact approval in other countries, it is recommended to ask for a scientific hearing from the EMA or the respective local regulatory bodies. If placebo trials allow the standard treatment on top of IMP and all patients receive the standard care, then even the Czech authority can grant approval.

There is a very country-specific approach which often correlates to a country’s economic standing. In Georgia, for example, if the IMP or comparator used during the study contains expensive treatment registered for a specific disease that otherwise would not be affordable and is not reimbursed, such a study may be welcomed by regulatory bodies.

Trials involving critical care of children who require emergency procedures are extremely difficult to conduct in CEE countries. For example, in Poland, which is one of the most experienced countries in paediatric trials, it is practically impossible to conduct a project with a drug that is not already registered within the EU or is planned to be administered other than for the registered indication. If the drug is registered for the studied indication, the study is possible and is considered as life-saving treatment in this particular case.

Also, protocol design and procedures have to be adjusted not only to scientific needs but also to the limitations of the paediatric patients, e.g. in terms of frequency of injection and volume of blood taken during sampling. Also, other procedures have to consider the age of children involved in the study and differentiate between those younger than 12 years and those older, or even redesign the procedures for each age group. Experience shows that the regulatory authority in the Czech Republic may require a country-specific amendment with more strict inclusion/exclusion criteria for younger children. It may also be the case that a regulatory authority gives approval for one age group only and requests that the protocol is modified for others.

2. Early-stage Projects (Phase I, Phase I/II)Early stage trials have always been a challenge due to much greater risk to the subjects, and less provable medical benefits. For Phase I, there must be a robust rationale as to why a particular study cannot be run in an 18-65-year-old population. Typically, such a Phase I study can be proposed if the study disease is not present in the adult population, e.g. genetically-driven diseases and abnormalities. There are no strict regulations prohibiting Phase I trials in paediatric populations, but in some countries, e.g. Russia, a sponsor must prove with supporting materials that there is a clinical need for the study to be conducted in Russia. In reality, it is rare that the MOH is satisfied with these proposals.

Moreover, CEE countries do not have many qualified and certified sites that can perform Phase I trials in paediatric populations. The most advanced country is Hungary, with an established network of centres specialising in early-stage clinical trials. Examples are FUTURENEST, as well as the Phase I unit at Semmelweis University in Budapest.

Phase I trials by definition allow subject remuneration for their time spent on the trial, and this is obviously a very controversial issue when it comes to children: • Should we pay money to parents for children‘s

participation? If so, they might be motivated financially to offer their children for trials.

• Should we offer children some non-monetary rewards? If so, what would be most appropriate? Are sweets or toys commonly considered to be pleasant for children and are they truly valuable to them?

• Should we compensate parents for their time while assisting their child at the hospital during the study?

All these dilemmas lead to common conclusions that it is better not to offer any reimbursement for participation

Therapeutics

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in Phase I except for travel, generous meal costs and usually parents‘ accommodation costs to assist children in hospital. If any other material is going to be offered to support participation in clinical trials (e.g. a small backpack for carrying medication with substantial volume), this has to have a low commercial value for the subject and be approved by the relevant ethics commitee.

3. Paediatric Study Subject Consenting ProcessThe consenting process restrictions are the most significant factors impacting patient recruitment, and have become increasingly important during the last 25 years of cultural change in the region.

The paediatric study subject consenting process has been addressed well in the majority of CEE countries, but as always there are differences between EU countries and non-EU countries. Russia, Ukraine, Georgia, and Belarus have relatively straightforward processes in comparison to those of EU countries. Hungary and Georgia allow a one-parent signature. This is considered a significant advantage and may explain the high interest in placing paediatric trials in Hungary. Nevertheless, the majority of countries require both parents‘ signatures on the informed consent for their children. The law usually says that in special cases when the second parent is not available for formal reasons, one parent is sufficient. In practice, a lot of certificates and documents are required to prove the formal status of the second parent, and many people would rather give up participation in the trial than endure this bureaucratic burden, often associated with a variety of domestic problems.

To assess the impact of the single-parent factor on recruitment, we need to know the regulatory requirements as well as the prevalence of single-parent status. Analysing data from the last five years, single-parent status is highest in Russia with over 50% of marriages ending in divorce, followed by Hungary and the Czech Republic with over 30%, but less than 20% in Poland.

Although in Russia both parents are required to sign the consent, there are various ways to avoid the need for both parents to be present. It is sufficient if one parent authorises another person to represent him/her at the consenting process. In Russia, the consent is taken with the presence of a witness who also has to sign and date the PIC as well. Parents are crucial for children‘s participation in clinical trials; for example, in Russia and Ukraine it is legally impossible for children that are deprived of parental care, adopted, fostered or orphaned, to participate in clinical trials. Advertising for paediatric patients is strictly prohibited in Russia.

Informed consent text has to be adjusted to the appropriate age level, and in Russia, Ukraine and Georgia, usually two age groups are specified – below 14 years and above 14 years. EU members have more comprehensive requirements, and the exact requirements vary from country to country with regard to age limits. Assent form requirements are not always formally stated in the local regulations, but there are usually specific recommendations. For example, in

Poland it is advisable to have the following assents: below 11 years, 12-14 years, and 15-17 years; while in the Czech Republic: 6-7 years (maximum two pages, big letters, pictures as well as text), 12-14 years (maximum four pages), and 15-17 years (similar to adults‘ ICF, including information about contraception). The assent forms have to be adjusted according to the protocol design, and there are no specific regulations relating to this. The child‘s consent is always an issue as there is no strict age barrier when the child is considered capable of taking decisions about their participation in the study. It is defined that children above 12 years are able to take the relevant decision, but individual assessment by a psychologist regarding a child‘s cognitive abilities might be needed in the case of some specific diseases. Adolescents (>12 years) have the right to withdraw from the study whenever they wish.

Paediatric trials are a core part of clinical development. Not only is there a commercial incentive to develop paediatric treatments, but there is also a moral imperative. As discussed above, the environment for conducting paediatric research in Central and Eastern European countries is not yet as sophisticated as that of Western Europe and North America. However, they are catching up fast. Every month, new precedents are set and regulations clarified for the practical purpose of attracting high-quality clinical research.

Of course, the fact that the market for paediatric trials is not yet mature means that there are fewer competitive trials, and there remain large untapped patient populations. It is vital that detailed feasibility research is performed in advance of choosing countries. This requires investigation, not just of the epidemiology of a disease and the associated standards of care, but also the regulatory environment, precedence of similar studies and the cultural issues associated with paediatric trials. With the right partner, with the relevant experience and local expertise and the ability to negotiate the hurdles and pitfalls, sites in this region can easily enroll larger numbers of patients over shorter periods of time than their equivalents in the West. Overall, it is expected that this region will continue to make very efficient and significant contributions to paediatric research.

Dr. Szerszeniewska is CEO of EastHORN, a leading CRO operating in Central and Eastern Europe (CEE).Previously, she was president of AbCRO, Inc. Prior to that Dr. Szerszeniewska spent more than 10 years at Covance, where she held various positions including Regional Resource Manager, Project Manager, Director of Strategic Development and Clinical Operations in CEE, and was responsible for development of the company’s

Clinical Development Services in the CEE region. Before joining the CRO industry, she worked as an Anesthesiology and Intensive Care Specialist at Warsaw University Hospital. Dr. Szerszeniewska’s therapeutic experience includes paediatrics, oncology, neurology, cardiovascular, psychiatry and gastrointestinal medicine. Dr. Szerszeniewska received her Medical Diploma from the Warsaw Medical University.Email: malgorzata.szerszeniewska@easthorn.eu

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IT & Logistics

Volume 6 Issue 348 Journal for Clinical Studies

Going Native? Deciding the Optimal App Approach for Smartphone eCOA

IntroductionGlobal mobile penetration has enabled a great opportunity for interacting with consumers of all types in different ways. The app phenomenon underlines the impact of mobiles on the consumer market. The free game, Flappy Bird, for example, was downloaded by over 50 million Android users in only a few months, and topped the Apple download charts at the start of this year, before being withdrawn as it was felt too addictive1. Ninety-one per cent of American adults own a mobile phone, with 55 per cent having a smartphone2. Eighty-one per cent of American mobile phone users regularly use them to send or receive SMS text messages, 60% to access the internet, 52% to send or receive email, 50% to download apps, and 49% to get directions or information based on location3. It is also estimated that over half of the global population owns a mobile phone4. The percentage of SIM card registrations per total population exceeds 100 per cent in most regions (many people have more than one device), including Europe, North America, Russia, Latin America and the Middle East; with 87 per cent and 73 per cent penetration in Asia Pacific and Africa respectively4. There are 680 million active mobile users of Facebook each month, and 120 million using Twitter on their mobile phones4. Considering the high level of mobile use and penetration, the opportunity to touch the patient in healthcare and clinical research is large.

This article will explore different ways in which functionality can be delivered to mobile devices, and the benefits and limitations of each when applied to the collection of eCOA (electronic clinical outcomes assessments) in clinical trials.To frame the discussion, we will define the following terms: native app, web app and mobile website.

Native AppsA native app is a software application that is downloaded and

installed to run on the mobile phone’s operating system. It is usually accessed via an icon on the device home screen, and once downloaded can be used without requiring a mobile or internet connection.

Mobile WebsitesA mobile website is a website that has been optimised for use on a device with a smaller screen such as a smartphone or tablet. A mobile website displays information for a user to read and browse, but doesn’t typically provide functionality for a user to “do” something.

Web AppsWeb apps are websites that look and feel like native apps. They are accessed via a browser, and contain functionality for users to perform tasks or activities, as opposed to only accessing information. Examples include games or apps to access and manage email. Home screen shortcuts can be used as a convenient way of launching mobile apps. For the purposes of this article, we will consider only native and web apps. Because they can look and feel very similar, we will explore some basic app properties and the advantages and limitations of each approach.

1. Using Native Smartphone FunctionalityWeb apps are increasingly able to access certain mobile-

specific functions, such as click-to-call, SMS and integrated GPS. However, web apps are unable to access many other native smartphone or tablet features, such as the in-built camera and the ability to connect with remote devices using short-range radio technology such as Bluetooth. Popular apps, such as barcode readers, utilise the smartphone’s camera feature and are difficult to deliver without a native app approach. Devices such as activity trackers (e.g. Fitbit) can use Bluetooth to download and synchronise activity data

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collected with a native smartphone app, which can provide tracking interfaces for the user. In general, if an application requires access to any native phone or tablet feature, it will need to be developed as a downloadable native app.

2. Universal AccessibilityWhen you compare Apple and Android app stores, you will see that some apps are available in one and not the other, and within a store certain apps require a minimum version of the corresponding operating system to run (e.g. Honeycomb (3.2), Ice Cream Sandwich (4.0), Jelly Bean (4.1-4.3) or KitKat (4.4) on Android). This adds a level of complexity for native app development to be used across multiple platforms and devices. A web app does not need to download and be made compatible with multiple operating systems, as it is accessed simply via the browser within the mobile device but runs remotely. Web apps may provide greater speed to market when operation across multiple device types is needed.

3. Sending and Receiving High Quantities of DataA native app will generally work faster than a web app as it does not rely as heavily on internet connectivity speed to serve up and process information. If an app is required to take in and process a lot of data – perhaps performing complex calculations, or producing charts and reports (such as banking or investment apps) – the performance may be superior using a native app. The same is true for gaming apps, such as Angry Birds, which are highly interactive and present rich graphical content. These are much better suited to using the device’s processing power as a native app than relying on internet connectivity and network speed as a web app. That said, many apps do not require complex graphics or large amounts of data. As a result, there should not be a significant difference between approaches.

4. Frequent UpdatesNative apps require additional downloads to implement

software updates. Whilst these are straightforward technically, commercial app developers have additional hurdles, such as receiving app store approval before updates can be made available. Web apps enable updates to be implemented rapidly across the user base without additional downloads or activity. When a live app requires frequent updates, it is simpler to manage via a web app.

5. Offline UsageFor apps to work offline without a mobile connection, they must be developed as native apps. These apps can work in full without a mobile connection. Where they are used to collect information, data can be stored locally within the app until the device establishes a connection, at which point the information can be transmitted. Traditionally, web apps have been available only when a mobile connection is in place. The new HTML5, however, has the ability to cache and retain updated local copies of a web application so that the app can be used without a web connection. HTML5 has not been on the market long enough to fully assess these capabilities and evaluate the security of information held in this way.

6. SecurityThere has been considerable recent discussion about

native app security, particularly as it relates to the collection of personal and health-related data. Kevin Johnson, CEO of network security consulting firm Secure Ideas, has stated that native app security is a concern when these apps contain personal health information5. His concern is that many native apps will not encrypt data to prevent any local data store from being accessed through a backend route. In addition, if not developed with adequate encryption and security, apps may not prevent other apps from accessing the data they contain. As we consider eCOA, these are important considerations. These issues are not limitations with the native app approach, but app developers need to ensure security and encryption features are addressed in the way their apps are developed

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and configured. This is particularly important in the “bring your own device” (BYOD) area, as eCOA providers have less control over the devices being used.

Application to eCOAConsidering the six properties listed above, we can explore how these might affect app methodology choice for delivery of clinical assessments in clinical trials and peri-approval studies (Table 1).

While both approaches are typically considered to be satisfactory, there are a few specific instances where one approach is preferable. In studies where we wish to use some native phone features, whether the patient’s own phone or one provided for the study, a locally-installed native app is required. Most commonly, this would include the use of Bluetooth connectivity when the patient is also collecting data using peripheral devices such as spirometers, glucose meters, activity meters and the like. Bodies such as the Continua Health Alliance are helping to define important standards to improve the interoperability of sensors and devices used in healthcare. If we wish to combine the objective assessment data collected with these sorts of devices along with additional patient-reported outcomes (PROs), then the solution must be developed as a native app.

In addition, native apps would be favoured if the study is being conducted in geographies where mobile connectivity may be unreliable. In this case, a native app would be expected to store data locally until a connection is made to enable secure data transfer. Native apps will need to maintain sufficient capacity on the device to ensure eCOA data can always be stored when needed. This applies particularly in a BYOD setting.

Web apps, however, offer ease of universal accessibility across multiple devices and operating systems, that is important if the patient’s own device is to be used in the study. As described above, whilst native apps can be developed for BYOD settings, it is easier to develop a web app because there is no requirement to produce multiple app versions to operate on different platforms and their operating systems, such as iOS, Android and Windows Mobile platforms. As we consider BYOD in ePRO, we also need to be aware of current regulatory thinking and guidance around PRO validation6. Validation requirements for installed software are different to those for software accessed via a browser. Alan Yeomans of the Pharma Consulting Group describes this in his recent article 7. Software installed on multiple devices and operating systems will likely need to be validated on each type of device / operating system to ensure correct operation. For web apps, the validation question becomes largely a display validation question, as opposed to device validation. Can the instrument or diary be displayed in a way that will not affect patient understanding or response across multiple devices? In his discussion, Yeomans proposes some principles for effective BYOD implementation for web apps, including:

1. Use devices with comparable capabilities – for example, similar screen sizes, graphics resolutions and colour

palettes. (Implicit in this requirement is the ability to prohibit access from incompatible devices.)

2. Deliver the PRO instrument using a common graphical denominator that makes it appear the same on all devices – e.g. all answer choices are shown without the need to scroll. Larger screens, such as tablets / phablets would utilise the same limited display area as a smartphone – ensuring comparability in appearance of the diary or instrument across devices.

More specifically, by designing to a minimum device specification (screen size, screen resolution, colour palette, graphical capabilities, browser type and version) it should be technically possible to ensure that instruments used are displayed identically across devices of that screen size and higher. If ePRO assessments are delivered in this manner, then it would seem logically only a small step to provide the level of comfort that different devices are not affecting patient responses. When using different screen sizes in the way described above, there may be no difference in appearance, instructions, layout or font size. Alternatively, moving between screen sizes may reflect a “minor” change in appearance as specified by the ISPOR recommendations for ePRO validation8.

Implementing in this manner will require the ability to exert some controls over the way a web app is displayed, as opposed to allowing the device to pick its perceived optimal display. BYOD will also require mobile platforms to be able to detect device characteristics, specifications and orientations so that devices not meeting minimum technical requirements can be blocked.

eCOA solutions must also adhere to the level of security expected with any solution recording personal and health-related data. Whilst web app entry usually means that a secure log-in exists, passwords can be checked and data is entered over a secure connection straight into the database; native apps require certain properties to be built in to ensure they comply with data security requirements. In his blog,9 Dale Jessop, Chief Technology Officer at Exco InTouch, explains how native apps can be developed to ensure a level of security appropriate for clinical trials and the collection of patient outcomes data. Specifically:

• Apps should explicitly set the privileges of data files so they are all private to the app, ensuring that other apps installed on the device can’t access or modify them.

• The contents of an app’s data files should be encrypted to prevent their access or via rooting (gaining privileged access to the system).

• Data transmission via HTPPS ensuring the data is secure in transit between the app and the main server.

• Standard two-token authentication (username and password) to gain access to the app (as required for eCOA web apps).

Whilst this is not a limitation for the use of native apps in eCOA, it is important that they are developed to ensure the above requirements are met.

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ConclusionsThere is little doubt that mobile solutions offer tremendous opportunity to interact with the patient throughout the course of a clinical trial. Aside from special cases (e.g. Bluetooth connectivity needed), the choice between native and web apps is not enormously important.

Perhaps one deciding factor is around the ability to use the instrument without connectivity for certain geographies. This will undoubtedly change as we become more comfortable with the reliability of mobile data networks globally.

Reflecting on the phases that EDC has gone through within our industry, we recall that initially, many systems were developed as hybrid (online/offline) systems to ensure that data could be captured if web connections were not available. Now, we trust internet availability, and all EDC systems are deployed in a pure-web mode in which the system is accessed exclusively over the internet. We see the same changes in mobile networks and connectivity. Soon our level of comfort with network availability will lead to fewer concerns about developing native apps simply to enable offline use. As described above, HTML5 may also accelerate this with its ability to store web apps for local use, although the security of data stored in this way will need to adhere to the same requirements described for the development of native apps.Mobile is an enduring phenomenon, and the pharmaceutical industry is beginning to leverage its power within the strict regulations that exist, to improve clinical trials, ultimately making them more efficient and easier for all participants involved.

References1. http://www.bbc.co.uk/news/technology-26114364,

visited on 5 Mar 2014.

2. http : / /www.pewinternet .org/fact -sheets/mobi le -technology-fact-sheet/, visited on 5 Mar 2014.

3. http://www.pewinternet.org/2013/09/19/cell-phone-activities-2013/, visited on 5 Mar 2014.

4. http://www.gsmamobileeconomy.com/GSMA%20Mobile%20Economy%202013.pdf, visited on 5 Mar 2014.

5. http://m.healthcareitnews.com/news/ethical-hacker-calls-byod-a-security-nightmare, visited on 5 Mar 2014.

6. FDA. Guidance for industry. Patient reported outcome measures: use in medical product development to support labelling claims (1999).

7. h t t p : / / w w w . a p p l i e d c l i n i c a l t r i a l s o n l i n e . c o m /appliedclinicaltrials/Online+Extras/The-Future-of-ePRO-Platforms/ArticleStandard/Article/detail/833920?contextCategoryId=47497), visited on 5 Mar 2014.

8. Coons S.J. et al. Recommendations on Evidence Needed to Support Measurement Equivalence between Electronic and Paper-Based Patient-Reported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report. Value in Health.12, 419-29 (2009).

9. http://www.excointouch.com/news/blog/exco-intouch-blog/2013/10/03/the-security-leek, visited on 5 Mar 2014.

Bill Byrom, Ph.D., is Senior Director of Product Strategy at PAREXEL Informatics, where he helps to set direction for a number of the company’s technology products and services. Bill has extensive clinical development experience, having worked in a variety of roles within pharma, including statistics, trial monitoring and direction, and international marketing, before joining PAREXEL in 2000. Email: bill.byrom@parexel.com.

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Mobile App Development for Clinical Trials

Mobile devices and apps are set to become an essential part of clinical trials. While adoption in trials is currently underway, there are still many questions and issues regarding the use of mobile devices and apps in this field. The issues range from sourcing and development methodologies, to validation and deployment strategies. One thing is for sure: the adoption of mobile devices by the general populace is undeniable. More than half of the US population owns a smartphone (57% according to a Pew study – see Figure 1) and Americans are spending an average of two hours per day on their mobile devices. There are an estimated 1.4 billion smartphone devices in existence. That’s one in seven people worldwide.

Figure 1. Smartphone adoption figures according to Pew study.

The ‘smartphone’ nomenclature in use today is somewhat misleading. Mobile phones have in fact evolved to become highly portable personal computing devices. The audio phone capability of the modern mobile device is just one amongst a wide variety of communication possibilities provided. Audio telephony provided by the mobile network operating companies is another way of facilitating two-way transmission of ones and zeros in the same way that Wi-Fi and Bluetooth are. Modern mobile devices are also extremely powerful. For comparison, a modern mobile device is more than 15 times faster than the Cray-1 supercomputer circa 1979 and is, of course, substantially smaller.

A key feature of modern mobile devices is their connectivity to the internet as a default operating state. This ‘always connected’ capability allows mobile devices to hold two-way data communication with any server in the world. This connectivity, along with high processing speeds, high quality visual displays, and the ability to interface with other devices via protocols such as Bluetooth, make smartphones an ideal choice for capturing participant data in clinical trials.

Application and DeploymentThe smartphone’s ubiquity brings with it a number of key benefits for clinical trial participant engagement. Firstly, it is likely that the participant will already know how to operate a mobile device and, providing the data capture app adheres to known mobile platform user interface paradigms, will quickly learn how to use the app. Secondly, mobile devices are portable and people generally carry them wherever they go. This gives them a great advantage over desktop or even laptop computers because it means they can be accessed at any time and in any place. Thirdly, mobile devices are always connected to the mobile network operating service and the internet. This permanent connectivity capability is a distinct advantage for mobile ePRO data capture as it allows messages to be pushed to the mobile device in the form of SMS messages, or push notifications via either Google or Apple notification services. These benefits combined give mobile device ePRO data capture an advantage over ePRO data capture on desktop or laptop computers, leading to increased participant engagement and adherence. Interfacing with a mobile device is more convenient.

It is clear that mobile offers many advantages in clinical trials ePRO data capture. How then should a mobile app be developed and deployed to the participants? First, it has to be decided which platform the mobile app should be developed for. Today, mobile deployment will be on either Apple or Android devices. Apple offers a clear advantage in terms of minimising device variety because they carefully control the range of hardware that they manufacture. Apple’s operating system, iOS, only runs on Apple hardware, leading to a reduction in compatibility issues. They also have firm policies on operating system upgrades, which leads to less market fragmentation. Google adopted a completely different strategy with their operating system, Android. Android is made available to a large number of hardware manufacturers. As a result, it is available on a bewildering range of hardware devices of varying capabilities. These hardware manufacturers have also occasionally taken it upon themselves to modify the user interface and features - leading to a much more fragmented market both in terms of capabilities offered and robustness. Top-end Android HTC and Samsung devices compete aggressively with iPhone, but there is a huge array of cheaper Android devices of varying capabilities and operating system versions. This makes Android a much more challenging platform to develop for.

For some clinical trials, it is possible to pre-select the mobile hardware and deploy these to the participants. This is by far the safest approach because there is total control over the hardware. Unfortunately, it is also the most expensive option - particularly with Phase III trials where the number of trial participants can run into the thousands.

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The alternative is BYOD (bring your own device). Here, the participant is allowed to use their own mobile device, which means there are no upfront costs associated with buying and deploying dedicated mobile devices. The trade-off is a necessary increase in the technical support required. There are literally thousands of different mobile devices in the market that the app will need to operate with. It becomes particularly problematic with Android devices which are fragmented both in hardware specifications, and operating system versions.

Implementation StrategyBeyond the choice of deployment platform, there are a number of other decisions that must be made regarding app software development strategy. The default de-facto way of developing apps is using the native development tools and languages provided by the platforms. For Apple devices, this means developing in Objective-C using Apple’s XCode IDE (Integrated Development Environment), while for Android this means developing in Java using the Eclipse IDE and Google’s Dalvik Java Virtual Machine. Native development allows total access to the device’s capabilities and delivers the smoothest user interface experience. It comes at a cost, however. Objective-C and Java are very different languages, and XCode and Eclipse are radically different development environments. Developing natively for Apple and Android devices is a duplication of effort, which has an impact on cost, resources, and time.

Another option is to leverage web technologies to produce web apps. All mobile devices ship with feature rich browsers supporting HTML5, Javascript and advanced CSS styling. The idea with web apps is to utilise these technologies to produce web pages that look and behave like an app. This solution is particularly attractive to developers that come from a web development background as it uses familiar web-based solutions. There are a number of downsides to this approach, however. The device must be online in order to load the web page containing the app, and web apps are confined to using browser user interface controls or custom controls created with HTML5 and CSS styling, rather than the mobile devices native user interface controls. This leads to an app that doesn’t quite feel or function the same way that native apps do. Web apps cannot be listed in the platform app stores. Instead, a link is provided that starts the browser and loads the web page that contains the HTML5 code for the app. This link can be placed on the mobile device apps’ home pages, but it is another aspect that serves to separate web apps from native apps, as there is a clear visual distinction between an app and a web page link. A noteworthy restriction on web apps is that you are confined to the browser environment. This is fine as long as a given project does not require deeper level access to the mobile device’s hardware, for example accessing Bluetooth to communicate with medical devices.

The situation can be improved by using a web app wrapping technology such as PhoneGap. These services take a web app and embed it into a generic app chassis that can then be deployed to the platform stores. This means that the web app is now behaving more like a native app – at least from a

deployment perspective. Unfortunately, other problems now arise. The browser access provided for embedded web apps has a myriad of issues and idiosyncrasies. Speed of execution is compromised as the Javascript code for such apps is not compiled “on the fly” using a JIT (Just In Time) compiler, but is interpreted instead.

Other pitfalls include cross-platform visual rendering speed and glitch issues, the need to capture mobile-specific events, and implementing workarounds for certain user interactions. Web apps wrapped with PhoneGap have a 300-millisecond latency on element user interactions, leading to an annoyingly sluggish feel with the apps’ user interface.

Given that native development can be expensive and require more resources, whilst web apps do not give the much-coveted native feel or deeper access to mobile device hardware features, is there another solution that provides

native look and feel and hardware access capabilities, combined with the cross-platform development benefits mentioned above? Indeed there is. There are a number of different middleware technologies that produce native apps but allow development in a common language, such as Javascript, with a library that provides access to native controls. The Javascript is often compiled to native code. This is potentially the best of both worlds: a common language and set of libraries that map to either platform’s native user interface elements, whilst producing a fast native app for deployment. As an additional benefit, such middleware provides the ability to include external libraries as plug-ins, allowing access to mobile hardware if required.

One particular middleware that has been used to achieve this is called Titanium Pro, part of Appcelerator’s middleware offering. It includes an Eclipse-based IDE that is used to develop Javascript code for deployment to Apple and Android

mobile devices. There are, as usual, a number of things to watch out for. The APIs for Titanium can often change to adapt to alterations or fixes in mobile platform operating systems, which can lead to minor incompatibility issues that, nevertheless, need to be resolved. There still needs to be some code that is platform-specific because, although the majority of user interface elements have a common abstraction for each platform, there are some differences in paradigms. Most notably, the user interface for tabs is different between iOS and Android.

Even with the issues stated above, in our experience mobile app development time can be cut by up to a third by using middleware like Titanium, so it is a solution that is often overlooked, yet well worth consideration given the right project.

Figure 2. Anatomy of a mobile ePRO system Connectivity

ConnectivityInterfacing smartphones with biosensors and medical devices is becoming more commonplace in mHealth and clinical trial apps. For example, a clinical trial based on treatment for respiratory problems such as asthma or COPD may utilise a smartphone that pairs with Bluetooth-enabled respirators and spirometers. There are many sensor devices that utilise Bluetooth for tracking biometrics such as temperature, heart rate, blood glucose and blood pressure. Figure 2 highlights some of the implementation and connectivity options available to mobile ePRO apps.

Such device pairing allows the objective collection of usage and biometric data which can then be transmitted to back-end servers for analysis and reporting. This data, when paired with the usual ePRO diary data, provides a compelling and detailed record of how a participant is progressing within the trial.

Persistent Bluetooth connectivity comes at a cost with regard to power consumption, however. To alleviate this issue, a low-energy version of Bluetooth was developed, called Bluetooth LE (low energy). Bluetooth LE uses the same 2.4 Ghz radio frequencies as Classic Bluetooth, but uses

a much simpler modulation system and a different set of channels. Most new mobile devices support Bluetooth LE, but not all smartphones currently present in the market do. The Bluetooth Special Interest Group (SIG) predicts that more than 90 per cent of Bluetooth-enabled smartphones will support the low energy standard by 2018. In the meantime, this is a consideration for trials that utilise BYOD, particularly on Android, where Bluetooth LE isn’t supported on Android operating system versions below 4.3.

Any deployment scenario where the app requires an interface to a Bluetooth device will rule out a pure HTML5 approach, because standard out-of-the-box web technologies have no means to support Bluetooth at all. HTML5 app deployments can utilise wrappers such as PhoneGap that allow access to native plugins and therefore can provide a library for interfacing with Bluetooth. A similar plugin approach can be taken when using middleware such as Titanium Pro, but the easiest way to interface with Bluetooth and other specialised mobile device features is by developing natively.

Mobile apps are set to play a major role in ePRO clinical trial participant data capture. There are a number of trade-offs to take into consideration regarding development and deployment. More mobile ePRO cases will emerge that need to interface with Bluetooth LE-capable medical class devices as part of their data collection capability, which will reflect on which development and deployment strategies to choose.

Justin Johnson is Chief Executive Officer at FirstApp. He has over 20 years experience in the software industry and is the co-founder of several technology companies ranging from clinical trial software development to virtual environments and merchandising in the games and entertainments industry. In recent years his primary focus has been on user data capture using mobile devices combined with big data processing and analytics. His latest company,

FirstApp, specializes in mobile software for mHealth and clinical trials. Email: justin.johnson@firstapp.com

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The Changing Face of Healthcare – Medical Apps & Crowdtesting

For generations, innovations that created direct impact and value were personified by lone geniuses, the likes of Thomas Edison and Steve Jobs toiling away in their laboratories. Today’s reality, however, paints a different picture; the confluence of political, economic, social, and technological forces forges a diverse and often complex ecosystem that shapes, fosters and demands innovation. The medical technology field, especially in developed economies, has long profited from the convergence of forces that spurred innovations such as prosthetic limbs, hearing aids, imaging technologies and less-invasive cardiovascular procedures, which have reduced recovery times and greatly improved healthcare outcomes.

However, according to PwC’s report titled, “Operating performance in the Medtech industry: Trends and imperatives”, research and development (R&D) activities are not generating as much value and growth as they historically did. PwC’s study of 56 global medical technology companies revealed that the impact of R&D on revenue growth declined at an average annual rate of 10% between 2005 and 2011. These companies compensated for this decline through cost-cutting measures and by increasing operational efficiencies.

The most significant challenge faced by the medical device industry is that the fundamental nature of innovation has changed dramatically. It was a world built on incremental innovations with hardware focus. The notion that the players could demand price premiums for these innovations is slowly disintegrating. This phenomenon is accelerated by the emergence of modular systems that complement hardware ubiquitously available among healthcare stakeholders, and by a shift to software-centricity.

The adoption of mobile technology at breakneck speed has also transformed the healthcare industry, creating an area of innovation - mobile healthcare (mHealth), fuelled by numerous mobile applications developed and released by companies and developers alike for general use by lifestyle consumers, patients and healthcare professionals. In 2012, the number of medical application users reached 247 million and the global revenue from mHealth apps grew to USD 1.3 billion, and it continues to grow on an upward trending curve.

With mobile applications, regular smartphones could be easily converted into an effective healthcare platform that patients come to rely on. Disease symptoms and medication side-effects can be easily and progressively tracked, logged and electronically shared with healthcare practitioners. Gathering diagnostic data, such as blood pressure, heartbeat rate, and even much more complex kinds of diagnostics, e.g. for antibiotic resistance and eye diseases, can be automated. Appointments with healthcare specialists can be scheduled with a single click, and these meetings improve in quality as

patients could systematically record and share their concerns with these experts before a physical visit. In case of physical discomfort, sickness or diseases, patients could browse through a comprehensive FAQ database through a mobile device to see available medications and options before physically consulting a practitioner. In extreme scenarios, as in cancer, patients could gain access to a community, where they could discuss their problems, ask questions, derive inspiration from success stories, participate in information exchanges, gain moral support, and stay positive - knowing that they are not alone in their battle for a cure. Healthcare organisations could curate knowledge from diverse information sources and provide structured access to healthcare consumers where and when they need it. Pharmaceutical companies could use mobile channels to disseminate information, organise webinars, work directly with patients, and so on. The possibilities are boundless.

Surveys reveal that mobile applications have become increasingly important to both patients and doctors alike. Research conducted by Dutch physicians showed that over 60% of doctors use medical apps on their mobile devices. 83% of them use mobile apps to find information, 47% utilise them for reference purposes, and about 40% use them for support during consultations.

However, another study published by the Department of Neurology in the Academic Medical Center, University of Amsterdam, also discusses the dangers and lack of regulation, and proposes quality assurance guidelines for mobile healthcare apps. The authors of the study agree that medical apps have tremendous potential, but also underline the alarming lack of knowledge about risks that these apps pose. Regulation and guidance are urgently required.

Furthermore, medical apps should be peer-reviewed by healthcare experts, and quality control measures should be streamlined to safeguard the quality of care. Because doctors and patients rely on the information and tools around cure, ensuring quality and safety are of paramount importance in gaining their trust in medical apps. Awareness among medical professionals is absolutely required, so that they can make informed choices about the apps they use in clinical care, knowing that some apps may contain unreliable, non-peer-reviewed content.

Hence, it is easy to recognise that mHealth is a very complex and diverse ecosystem - mHealth applications require the highest degree of accuracy from both device and software. The medical app frontier is an entirely new development for established regulatory bodies like the US Food and Drug Administration (FDA). In July 2011 in its “Draft Guidance for Industry and Food and Drug Administration Staff: Mobile Medical Applications”, the

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FDA proposed that certain types of mobile apps targeted for medical use be considered medical devices and placed under its scrutiny before they can be released for public use.

However, the FDA clearance processes for medical apps do not require comprehensive clinical testing to ensure safety and quality as do the procedures for drugs and medications. With the increasing complexity of software systems, the possibility of failure through software defects increases exponentially, reinforcing the need for stringent quality assurance measures. Even though the FDA’s guidelines on medical apps have been finalized, it only addresses a subset of the entire medical app space.

According to a study, “Medical apps for smartphones: lack of evidence undermines quality and safety”, and although no harm caused by medical apps has been reported, without app quality assurance and safety standards it is only a matter of time before some medical errors happen and unintended harm to the patient occurs. To ensure quality of medical apps, the authors of the study suggest:

1. Official certification marks that guarantee quality2. Peer-review system implemented by physicians’

associations or patient organisations3. Making high quality apps more findable by adding them

to hospital or library collections.

Presently, the feedback and ranking mechanism in place at app stores, while good for games and less critical apps, is highly inadequate for medical apps. The medical community, app store operators, regulatory bodies, auditors, patients, and other stakeholders need to get more involved in evaluating medical apps, at least on the following aspects:-

1. Validation and certification of software quality that endorses apps’ fitness for purpose and use

2. Peer-reviews by diverse stakeholders – physicians, medical associations, patients, regulatory agencies, subject matter experts, etc.

3. Continuous monitoring of user feedback, complaints through establishment of vigilance systems.

The responsibility of addressing the aforementioned requirements falls on the medical app development companies: they are required to validate the apps they develop – a responsibility requiring a spectrum of expertise and experience. Many medical app development companies have neither the bandwidth nor the resources to handle comprehensive quality assurance and validation. Though several journals now include app reviews by doctors and healthcare practitioners, evaluating the apps from a 360-degree perspective requires cross-functional skills and knowledge.

For example, medical app design is an area of paramount importance when developing mobile medical apps. Medical apps are intricate tools placed in the hands of doctors and patients, which can significantly influence healthcare outcomes. Hence, these apps must be designed and developed

with usability in mind, and address human factors including user errors that result from unintuitive design. In an article titled, “Developing a Mobile Medical App? Don’t Forget Human Factors!”, it is suggested that medical app developers should consider at least the following human factors:

1. Preliminary analyses (such as hazard analyses, contextual inquiries, task analyses, heuristic analyses, and human factors expert reviews)

2. Exploratory human factors research3. Formative human factors usability testing4. Human factors validation testing.

The FDA guidance also recommends app manufacturers follow the human factors guidelines, even when their apps are not subject to regulation. This strategy is perceived to be the best way to both mitigate risks and encourage adoption, while simultaneously avoiding the high costs associated with unnecessary redesigns and product recalls.

From a software engineering perspective, even small changes in software could dramatically change the way a mobile medical app works. These changes may stem from requirement changes, design modifications, or amendments required by regulatory agencies. Ensuring the continued quality, accuracy and safety of mobile medical apps requires that any software modifications undergo a life cycle of software quality assurance and validation process. Regression testing should be as comprehensive as possible to demonstrate that the changes were implemented correctly, and did not adversely impact other parts of the product.

The FDA’s final guidance addresses these perspectives required of mHealth apps, and states that regulating mobile medical apps will be a high priority from 2013. The ramifications of this decision imply that medical app development companies are forced to implement rigorous testing procedures to ensure compliance – a development that is perceived to be associated with high costs, complexity, and scope. Raising the bars might improve the overall healthcare outcomes, but may simultaneously deter aspiring developers and entrepreneurs from developing healthcare IT solutions.

Complex challenges such as these often spur innovative, creative and simple solutions, but in the case of mHealth apps these challenges can be thoroughly addressed using the help of professional communities and users, in other words, through crowdsourcing testing and evaluation.

Crowdtesting, a variant of outsourced software testing, undertaken with a community comprising of subject matter experts, professional testers, legal consultants, software engineers, healthcare professionals, patients, usability experts, etc. easily scales the scope and support required by a medical app development company to ensure that their solutions have been evaluated at all angles and comprehensively tested. The concept of crowdtesting, traditionally used to ensure quality of general purpose web and mobile apps, subjects the medical app to an exhaustive battery of tests performed under real-world conditions on a variety of devices with a group of

professionals plus an identified target users group, before the medical app is released to the marketplace. Crowdtesting encompasses the rigour of traditional, formal software testing methods and complements these formal methodologies by emulating real-world conditions - a development that many medical app companies haven’t had access to before.

The fundamental concept of crowdtesting is the idea of distributing a specific quality assurance problem among a community of experts specifically curated to solve the task. These experts are inherently motivated to solve the challenges for either monetary or non-monetary rewards. Medical app development companies could avail crowdtesting services ranging from fully-managed testing services to a self-service concept, where the company only seeks access to the testing platform and the expert community when needed.

In addition, the company could save on associated overheads, such as hardware and software costs, because the community already owns various combinations of different device types, operating systems and language versions – a situation that is almost impossible to simulate in an internal lab. Crowdtesting opens a large pool of software testers and domain experts to medical app companies, so selection of target groups could be achieved at different levels of granularity.

As the crowdtesting process is fast and flexible by design, it could easily be integrated into existing software release cycles and delivery models, so that the shortcomings could be identified and corrected immediately before the software is released. Crowdtesting also permits testing at different stages of software development - from the prototype evaluation to a final check at the end of the beta stage. The ability to leverage real medical app users and devices helps achieve a substantial cost reduction during the development and maintenance phases of the medical app life cycle. Furthermore, human factors enumerated by the FDA could be progressively validated through the various stages of software development through post-deployment and maintenance. As a result, the software quality increases exponentially while simultaneously relieving the app development company of important domain considerations beyond their area of expertise and freeing up their internal resources to focus on core operations.

In closing, crowdtesting delivers tremendous benefits to medical app development companies. Navigating the murky waters of regulatory bodies, software engineering, healthcare ecosystem, consumer psychology, etc. is an exhaustive endeavour in itself. Medical app development companies and entrepreneurs do not have to steer the waters alone. A trusted crowdtesting partner with extensive healthcare domain expertise could help cruise these muddy waters by complementing core skills available in-house and providing valuable mission-critical feedback from a broad and diverse panel of medical app users, healthcare practitioners and stakeholders, who have much to gain from innovations in the healthcare vertical.

References1. Operating performance in the Medtech industry: Trends

and imperatives – A PwC case study2. Draft Guidance for Industry and Food and Drug

Administration Staff: Mobile Medical Applications by Food and Drug Administration (FDA), the USA

3. US$ 1.3 billion: The market for mHealth applications in 2012 by http://research2guidance.com

4. Mobile Health Market Report 2011-2016 by http://research2guidance.com

5. Mobile Medical Apps – Where is the Evidence? PUBMed Link: http://www.ncbi.nlm.nih.gov/pubmed/22923708

6. Medical apps for smartphones: lack of evidence undermines quality and safety. PubMed PMID: 22923708

7. Developing a Mobile Medical App? Don’t Forget Human Factors: http://www.mddionline.com/article/developing-mobile-medical-app-don’t-forget-human-factors

8. Mobile Apps, Healthcare and Crowd Testing. Wired Innovation Insights: http://insights.wired.com/profiles/blogs/mobile-apps-healthcare-and-crowd-testing

9. Mobile Technologies Heralding Innovations in Healthcare Industry. Passbrains: http://www.passbrains.com/blog/mobile-technologies-heralding-innovations-in-healthcare-industry/

10. Testing Applications for the Real World: Can the Crowd Deliver “Better, Faster, Cheaper” Testing for a Software-Driven World? Passbrains: http://www.passbrains.com/blog/passbrains-presents-at-sig-global-sourcing-summit-spring-2013

Mithun Sridharan is a Business Development Manager with Passbrains, based in Eschborn, Germany. He brings over ten years of international experience in Business Development, Marketing, Global Delivery and Consulting. He holds a Master of Business Administration (MBA) and Master of Science (M.Sc). He is a Project Management Professional (PMP) and a Certified Information Systems Auditor (CISA). He also serves as the

Communication Chair for the German Outsourcing Association.Email: mithun.sridharan@pass.ch

Dieter Speidel is founder & CEO of PASS Group, one of Europe’s most dominant providers of on-demand software and system testing services with offices in Germany, Switzerland, Serbia, the U.S. and India. PASS Group owns and operates passbrains.com, the leading global platform for on-demand crowdtesting services. An entrepreneur in the Software Development and Testing domain since more than 30 years with strong focus

areas within the Healthcare & Life Sciences industry, Dieter Speidel founded and successfully expanded PASS Group, offering managed QA and testing services through global delivery, including near-/offshoring and crowdsourcing. In 2011 he built the passbrains business unit and developed a fully integrated SaaS platform for enterprise crowdtesting and a global community with thousands of software testers in more than 100 countries. Email: dieter.speidel@pass.ch

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JCS Interviews Tim Davis of Exco InTouch on the Use of Mobile Technology in Clinical Trials

The growth of mobile technology is now recognised by the pharmaceutical industry as an opportunity to change the way we interact with patients during clinical trials. We sat down with Tim Davis, CEO and co-founder of Exco InTouch to find out why he set out on this path almost ten years ago, and how he believes taking a mobile approach can enhance clinical research for patients and sponsors alike.

You are a pioneer in the use of mobile in clinical trials. What gave you the inspiration to improve patient experience and bring the technology into the clinical research arena?

Back in 2004, I had been working in the clinical trial technology field for some time, and it was clear that the patient experience left quite a lot to be desired. Even back then, mobile technology was quite well adopted, and my co-founder and I realised this would be a fantastic way to reach patients. We found that using the patient’s mobile to provide motivation and support through the trials was incredibly effective, but quickly realised that mobiles were also an ideal means to collect data as well, and we ran the first ePRO study with a mobile phone back in 2005. Now, almost ten years later, you can see that mobile phones are well-established and part of everyday life for pretty much everyone in the world. The tremendous developments in technology have given us the opportunity to improve the patient’s experience, not just in clinical trials, but also in the field of general healthcare.

The use of mobile technology in clinical research seems to be the topic of much conversation at the moment. Why do you think that is?

I think there are two driving forces, actually; firstly, mobiles are an everyday part of everybody’s life; regardless of who they are, what they do, or where in the world they live, chances are they use a mobile phone to manage part of their life - whether that’s just talking to their kids, checking bus timetables, or something more involved like mobile banking. So, therefore, when participating in a clinical trial, which obviously takes up a lot of time and has a lot of obligations, this kind of service makes a lot of sense. In addition, the cost of bringing new drugs to market is phenomenal - according to Forbes, when you take into account all the failures along the way, the average cost of bringing a new product to market is now almost $6bn. In clinical trials it’s difficult to find patients, it’s difficult to retain them, and therefore this kind of service that maintains the relationship with the patient when they’re not in front of their doctor can only be of benefit.

Interesting. So how does the use of mobile technology benefit clinical trials?

Within clinical trials the use of mobile is really around

maintaining the relationship, maintaining the contact, and ensuring patients feel valued, because at the end of the day they are doing this for the greater good - for people who have similar diseases and similar conditions. It is built around integrating remote monitoring and data collection into the patient’s everyday life, and of course having the ability to correlate subjective personal analysis from a patient on how they feel they are doing with objective data from a medical device that is connected to their mobile phone. This gives enormous value to the data construct for that particular clinical trial and, because it is mobile, the data is available, providing the better, quicker, and more accurate model that we’ve been striving for in clinical research for decades.

Taking ePRO (electronic patient-reported outcomes) as an example, the traditional model has been to provide patients with a fixed device to capture their data. This not only presents issues with lack of familiarity with the user-interface, but having a separate device also means patients have to remember to get them out of the drawer and complete their assessments. Now that people have personal access to mobile technology, it makes sense to utilise that to communicate with them and collect their data, so there is a move towards delivering this technology on the patient’s own device – termed “bring your own device (BYOD).”

But, of course, this is not just about a single technology, it’s not just about mobile, it could be on tablets, it could be internet TV and a whole range of other devices that connect to these. Medical devices are obviously key, but we’ll see more

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and more other kinds of devices being included in the future, I think; for example, consumer products such as wearable devices have already been included to supplement more traditional assessments and approaches.

Will clinical trials adopt this ‘bring your own device’ (BYOD) approach?

BYOD is already being used in clinical trials; we actually first used BYOD to capture data from patients back in 2008. Initially this approach was in late phase trials and vaccination studies, where large dispersed patient populations presented particular challenges for data capture. However, as the concept has been proven, we are now seeing BYOD being used both pre- and post-approval. That not only means more clinical trials can gain the advantages of electronic data capture, it also means that, for all of those studies, it’s reducing the costs for sponsors. When patients use their own device it means less hardware to provision, less of a burden for the sites, and it reduces the logistical challenges which, in the past, seriously plagued traditional ePRO provision.

Are there important considerations when implementing BYOD?

The key lies in understanding how to implement a BYOD approach as well as having the underlying systems in place to deploy that effectively and securely. A BYOD approach should be inclusive, not exclusive, in order to reach the maximum patient population. We have developed a device-independent platform that enables us to identify the device in use and optimise configuration accordingly. As well as developing this platform to comply with data protection regulations (Safe Harbor, HIPAA, EU data protection), we have built in the capability to block devices which do not meet display specifications set for each study. This means that through running equivalence studies and setting display specifications, we are now able to include validated instruments in BYOD studies.

How do regulators view this approach?

I’ve always believed that regulators are open to the use of mobile to collect outcomes data during clinical trials, as long as systems are in place to ensure traceability, just as you would do for any other form of data capture. It was great to hear this confirmed publicly by the FDA recently, when they took part in a panel discussion at the MCT-Congress, an event organised to discuss the use of mobile in clinical trials.

The FDA actively promotes electronic data capture through eSource, PRO, and 21CFR Part11 guidance. The three FDA representatives clarified that they view mobile devices as wireless computers; therefore as long as data can be shown to be accurate and attributable, in the same way as data collected through a traditional computer, there are “no barriers to adoption”. The panellists also discussed the use of mobile technology to deliver validated instruments, again supporting the approach to maintain a consistent form factor and design layout. As an industry, we are typically very

risk-averse when it comes to regulatory approval, so it was excellent to hear the myths that have arisen around mobile data capture being dispelled so clearly by the FDA. For me, their comment that we are “at the threshold of a revolution in clinical studies” sums it up wonderfully!

So what’s next for mobile technology in clinical trials?

One of the most exciting areas is real-world health programs; what we term ‘mHealth’. Pharma companies are seeking to expand their role from that of simply drug manufacturer to provide support for patients long term, commonly known as ‘Beyond the Pill’. We’re building some truly unique platforms for these customers, bringing together all the elements of health support – data collection, alerts, rewards, content etc – into an intelligent system that can analyse and display information in personalised portals. By this I mean personalised for the stakeholder in question, but also we’re able to adapt these portals for individual users, not simply according to their personal preferences; we are actually able to adapt the information according to their responses and the status of their condition. So, for example, we can flag to a healthcare professional that a patient has recorded concerning results and may be close to hospitalisation, and at the same time provide additional support to the patient, targeted advice, and more frequent data collection to help them get their condition under control. On the other hand, a patient showing their condition is under control would see very different information: perhaps how lifestyle changes could further help improve their health, or flagging how close they are to achieving a personal goal.

As a result, we are able to feed innovations from these mHealth programs back into clinical trials. We are certainly seeing clients beginning to take elements from these commercial programs back into their trials in the same therapeutic area, so in the future you could reasonably expect these products to be launched with the support of an mHealth program, and ultimately becoming a continuum of technology following the patient through clinical research into a broad healthcare setting.

Tim Davis is CEO and co-founder of Exco InTouch, the leading provider of mobile and digital patient engagement solutions to support the Clinical, Late Phase and mHealth industry. Having worked in the clinical research technology industry for over 17 years, Tim is passionate about leveraging everyday technology to simplify the process of clinical data capture, both for the pharmaceutical industry and for the patients themselves. As

a subject matter expert in the clinical technology arena Tim was recently recognized as one of the PharmaVOICE 100 for his vision in utilizing mobile technology to engage patients throughout the clinical trial and healthcare process.Email: info@excointouch.com

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