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Volume 8 - Issue 6

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U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

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Clinical Research Association A Leading Civil Society Organisation in Turkey eSource Optimising the Sponsor, Site, and CRO Experience Cardiovascular Safety Sub-Section Part 2 Cardio-Oncology: Safeguarding the Cardiovascular Safety of Anti-cancer Therapies The Comprehensive in Vitro Proarrhythmia Assay. Which Protocol Should I use: The Standard ICH E14 Thorough QT/QTc Study or Concentration-Effect Modeling?

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06 FOREWORD

Your Resource for Multisite Studies & Emerging Markets

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MANAGING DIRECTOR Martin Wright

08 Why the Intranasal Influenza Vaccine is Not Recommended this Season

U CLINICAL STUDIES

PUBLISHER Mark A. Barker

EDITOR Orsolya Balogh EDITORIAL ASSISTANT Emoke Karasz emi@pharmapubs.com DESIGNER Fiona Cleland RESEARCH & CIRCULATION MANAGER Evelyn Rogers info@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER © istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.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 8 Issue 6 November 2016 PHARMA PUBLICATIONS

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Each year, as autumn is well underway, seasonal influenza vaccinations become a topic of conversation for everyone in general and for those with children in particular. At this year’s meeting of the CDC’s Advisory Committee on Immunization Practices (ACIP), citing preliminary data regarding the vaccine effectiveness of the vaccines in use during the 2015-2016 seasons, the committee noted that the downward efficacy trend had continued. Walter Chalkley, Senior Editorial Project Manager for Cortellis Regulatory Intelligence, discusses how CDC is working not only with the manufacturer, but also with the US Food and Drug Administration, the US Department of Defense, and other public health organisations to determine the cause. 10 India, Once Again the Jewel in the Clinical Trial Crown India is the seventh largest country in the world by total area, with the second highest population at 1.2 billion, and is bordered by the countries of Bangladesh, Bhutan, Burma, China, Nepal, and Pakistan. Healthcare issues and diseases include tuberculosis, malaria, HIV, vascular diseases, cancers, and diabetes. The India government invested significantly in the early 2000s in order to encourage foreign investment and clinical trials. The money was used to create systems and to recruit and train personnel to process applications, conduct ethics reviews. Sue Lee at World Courier explains how India has returned to the fold of clinical trial countries which, with the additional safeguards in place can only be a positive step for all concerned – sponsors, patients and CROs alike. 12 Drug Development in Systemic Lupus Erythematosus – Can it be Successful? Systemic lupus erythematosus (SLE) is an autoimmune disease that causes the immune system to produce several types of antibodies, particularly against cell nuclei. This disease is extremely heterogeneous in how it manifests, which leads to significant problems and delays in diagnosis. SLE is probably one of the most challenging indications for drug development. Without understanding its challenges, as well as ways of addressing them, it is very hard to execute a successful trial, even with a drug that may be successful. Marcin Ernst, MD, Vice President, Clinical Development at INC Research, explains how the lessons learned from past challenges will allow sponsors to successfully bring new therapies to the market. 14 Sponsors and CROs: Closing the Technological Gap in Clinical Trials Engagement has recently been established as a key concept within clinical trials. This trend has delivered a multitude of benefits for participants, who, rather than being unconnected from the trial between site visits, now engage in a continual technology-enabled dialogue with their study. However, the industry has overlooked the potential for engagement technologies to benefit two other key stakeholders: sponsors Journal for Clinical Studies 1


Contents time and cost burdens of current quality management practices. 22 Medical Management in Clinical Trials: A Roadmap to Operational Excellence (Part 4 – Close-out Phase) Being the final feature of this four-part series of medical management of clinical trials, Mohamed El Malt, MD,PhD, Vijayanand Rajendran, MD and Kelechi K. Olu MD, MSc. At Europital in this article will focus on the medical activities during the close-out phase of a clinical study. The close-out phase here refers to the period from last patient out (LPO) till the issuing of the final clinical study report (CSR). As the study conduct operations come towards a conclusion, the routine medical monitoring activities give way to the intense data cleaning, data review and reports development phase. MARKET REPORT 26 Clinical Research Association: A Leading Civil Society Organisation in Turkey

and CROs. Chris Watson at Exco InTouch explains how technological framework has the potential to end the uneven distribution of benefits unlocked by clinical trial engagement technologies. REGULATORY 16 Serving on an FDA Advisory Committee: One Member’s Point of View The Federal Food, Drug, and Cosmetic Act (FD&C Act) is a federal law enacted by Congress. Along with other federal laws, it establishes the legal framework within which FDA operates. The FD&C Act can be found in the United States Code beginning at 21 U.S.C. 301. The FDA develops regulations based on the laws set forth in the FD&C Act or other laws under which FDA operates. Dr Jennifer Higgins details her experience as an AADPAC committee member and offers her views relating to issues affecting consumers. 18 Risk-based Quality Management: Improving Trials Data through Minimalism There is no doubt about the importance of maintaining quality standards throughout clinical research processes, but in recent years the regulatory bodies have begun to question the industry’s approach to quality management. This has led to an addendum to the good clinical practice guidelines that advocate rethinking of current quality management practice during clinical trials. Gunnar Danielsson, Senior Regulatory Advisor, PCG Clinical Services, considers the new way of thinking, which promises to allow more focused and costeffective trials that could reduce considerably the enormous 2 Journal for Clinical Studies

As can be seen in all areas, civil society organisations and initiatives are of key importance in clinical research. In order to translate the ideas and requirements raised by any stakeholder into structured and constructive policy initiatives, societies, through non-profit organisations and associations, are actively involved in activities in clinical research in the world. In Turkey, the Clinical Research Association (Klinik Arastirmalar Dernegi – KAD) is an important initiative which serves to improve the clinical trials in Turkey. Duygu Koyuncu Irmak, Associate Director in INC Research Turkey, explains how the Clinical Research Association is the first and unique civil society organisation in Turkey, and has become a multidisciplinary contributor to improve clinical trials. 32 How Emerging Companies Can Make Being Small a Strategic Advantage Small- to mid-sized (aka “emerging”) firms bring fewer resources to bear on the same drug development problems as large pharmaceutical companies. All developers face rising regulatory requirements. But, on top of these common challenges and risks, emerging companies face unique pressures. They have relatively smaller finances. They rely on funding from increasingly skeptical and sophisticated investors who are conducting more rigorous due diligence than in the past, and are turning to outcomes-based financing models. Ubavka DeNoble, MD, Corporate Vice President, PAREXEL, explains how emerging companies can succeed by concentrating on science, filling in expertise or resource gaps when needed and pivoting agilely – all tactics that may be harder for their big pharma counterparts to execute. 36 Boldly Going Where Few Have Gone before: Key Considerations for ‘Siteless’ Clinical Trials Advancements in technology are impacting many aspects of clinical research, opening doors to innovative study designs and clinical operations that may not have been possible even five years ago. This is especially true when evaluating the potential of emerging technology for home-based assessments, as a component of observational or interventional research. Michael F Murphy MD PhD, chief medical and scientific Volume 8 Issue 6


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Contents officer at Worldwide Clinical Trials, explores the implications of ‘siteless’ clinical trials for patients and researchers, the range of potential clinical assessments within these studies, and key considerations for exploiting this emerging opportunity. 40 Outcomes of International Trials Can Be Affected by Poor- quality Translations Quality in translation is important. Everybody knows that. In this piece, Simon Andriesen, founder and CEO of MediLingua, will show you how to stay away from US court rooms, and also how to prevent a nightmare scenario such as described below. While an error in an instruction guide for a microwave is simply annoying, an error in a medical document can injure or kill a patient, and in the worst case it can put you in front of a US jury sympathetic to a grieving widow. In the translation world some terrible stories go around about injury and death due to translation errors in medical instruction text. THERAPEUTICS 44 Mitigating Risks of Block-enrolled Ophthalmology Studies The use of block enrolment in ophthalmology trials helps enrolment keep up with the speed of these studies. However, the challenges inherent in their successful execution are numerous. Some studies complete enrolment in a single day, while others enroll in “blocks” over consecutive days or weeks to take advantage of this accelerated recruitment. These aggressive timelines create risks in the logistics of successful study completion. Simon Chandler, PhD, Senior Director of EU Clinical and Regulatory Operations and Jocelyn Wise Director of Monitoring at ORA, Inc., discusses effective practices to mitigate these risks. TECHNOLOGY 48 New Approaches to Measuring Health Outcomes – Leveraging a Gaming Platform Clinical trials employ a variety of approaches to measure the health status of patients and changes in their health due to treatment. In many therapy areas, subjective ratings made by the patient or by a clinician are used to measure status or change over time. Patient-reported outcomes measures, such as a daily symptom diary or a quality of life questionnaire, importantly measure the perspective of the patient regarding the effects of treatment, and in some cases (e.g. pain assessment) may be the only way to assess outcomes. Bill Byrom, Darragh Walsh and Willie Muehlhausen of ICON Clinical Research discuss a further clinical outcome assessment, which is the performance outcome (PerfO), in this article. 52 eSource: Optimising the Sponsor, Site, and CRO Experience The clinical research industry has long hungered for a nextlevel innovation to make paper all but obsolete in clinical research. In eSource, that innovation has finally arrived. After all, while EDC has brought significant gains to clinical research in terms of speed and data integrity, it has not eliminated paper entirely. eSource enables researchers to finish the job, and may constitute the most significant cutting out of the middle man in the history of the industry. Mike Novotny and 4 Journal for Clinical Studies

Nick O’Brien, at Medrio, explain the benefits and beneficiaries of eSource. 58 Going All In on eCOA Significant growth opportunities in the ePRO field mean the industry is calling out for solutions, advice and guidance that can help deliver on its promises. JCS talks to nine experts from organisations across the sector to share their insights into some of the industry’s most pressing questions surrounding this expanding market. JCS talks to nine experts from organisations across the sector to share their insights into some of the industry’s most pressing questions surrounding this expanding market. SPECIAL FEATURE - CARDIOVASCULAR SAFETY PART 2 66 Cardio-oncology: Safeguarding the Cardiovascular Safety of Anti-cancer Therapies The ratification of the E14 guideline in May 2005 by the ICH steering committee presented the first major safety guidance adopted by a global regulatory body. However, this landmark regulation, appropriately for its time, focused on only one aspect of drug-induced cardiotoxicity – QT prolongation and pro-arrhythmia. Boaz Mendzelevski, MD at Cardiac Safety Consultants Ltd, explains how the emerging field of oncology drug-induced cardiovascular toxicity, also known as ‘cardio-oncology’ (CO), expanded the boundaries of the current cardiac safety model beyond QT prolongation and proarrhythmia, to include all forms of drug-induced cardiovascular toxicities. 72 The Comprehensive in Vitro Proarrhythmia Assay The focus of the comprehensive in vitro proarrhythmia assay (CiPA) is on delayed repolarisation and Torsades de Pointes (TdP) proarrhythmia, a rare but potentially lethal drug-induced arrhythmia that can lead to ventricular fibrillation and death. To address limitations with the present approaches, the goal of CiPA is to provide a new in vitro-based paradigm that provides a more accurate and comprehensive mechanisticbased assessment of proarrhythmic liability of evolving drugs. Gary Gintant, of AbbVie, explains how CiPA is intended to replace the cumbersome (and expensive) TQT study typically conducted late in drug development with earlier, mechanisticbased studies that will include robust preclinical and clinical assessments. 76 Which Protocol Should I Use: The Standard ICH E14 Thorough QT/QTc Study or Concentration-effect Modelling? We now have two methods to fulfill the regulatory requirement to thoroughly evaluate ECG effects of new drugs. Superficially, the CEM approach may seem preferable because it gives early answers at a lower cost and with considerable time savings. However, there are many factors that must be considered in making the choice between the CEM and the standard TQTS approach. The purpose of this article by Jay W. Mason, MD, Chief Medical Officer, Spaulding Clinical Research and Professor of Medicine, University of Utah, is to help pharmaceutical sponsors decide between the two accepted methods for assessing ECG liability of new drugs.

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Foreword Government health agencies are cracking down on sluggish reporting of clinical trial results. Health and Human Services (HHS) announced an expansion of an existing law, which will require the results of all but Phase I studies to be posted on clinicaltrials.gov within one year of the trial ending. Previously, only trials related to approve treatments were subject to the rule. “I think a lot of major universities just miss the point that if you do an experiment on a person and get consent, you really have the obligation to make the results known,” Robert Califf, US Food and Drug Administration (FDA) commissioner, said. “This is fundamentally an ethical issue.” Simultaneously, the National Institutes of Health (NIH) declared that all agency-funded trials will be required to follow HHS’s rules. Although a federal law requiring transparent reporting of human clinical trial data has been in place since 2007, many study sponsors are non-compliant, and there are substantial loopholes. NIH Director, Francis Collins, said his agency might withhold funding if researchers don’t obey the rules. “We are serious about this,” Collins said. “It’s hard to herd cats, but you can move their food, or take their food away.” Califf stated that the government will not be adding staff to enforce the law. Ben Goldacre, a fellow at the University of Oxford and co-founder of the COMPare project and Alltrials.net, said not doing so is “a big problem.” Alongside reporting results, study organisers will be required to post their protocols and statistical analyses. For privacy concerns, individual patient data will not be required. Ida Sim, a leader in clinical trial registry policy based at the University of California, San Francisco, supports this decision. “I think this is an appropriate scope at this moment,” she stated. The rules go into effect January 18, 2017. This is the last issue of 2016 and what an eventful year it has been. The year 2016 saw dementia overtaking cardiovascular as a primary cause of death in the UK. I believe that more investment and research will be done in this field. We have a fantastic array of articles in this issue. We feature Part II of the Cardiovascular Safety Series. In the article entitled Cardio-Oncology: Safeguarding the Cardiovascular Safety of Anti-cancer Therapies, Boaz Mendzelevski, MD at Cardiac Safety Consultants Ltd explains the emerging field of oncology drug-induced cardiovascular toxicity. Gary Gintant of AbbVie explains how CiPA is intended to replace the cumbersome (and expensive) TQT study typically conducted late in drug development with earlier, mechanistic-based studies that will include robust preclinical and clinical assessments, and Jay W. Mason, MD, Chief Medical Officer, Spaulding Clinical Research and Professor of Medicine, University of Utah, writes on Which Protocol to Use; The Standard ICH E14 Thorough QT/QTc Study or Concentration-Effect Modelling? In the Technology Section, we have featured a very interesting Q&A on the topic of ePRO and patient engagement. Michelle Valentine of Discovery PR talks to nine experts from organisations across the sector to share their insights on some of the industry’s most pressing questions surrounding this expanding market. Bill Byrom, Darragh Walsh and Willie Muehlhause of ICON Clinical Research discuss a further clinical outcome assessment, which is the performance outcome (PerfO). In the Therapeutics Section, Simon Chandler, Ph.D., Senior Director of EU Clinical and Regulatory Operations and Jocelyn Wise, Director of Monitoring at ORA, Inc., discuss how to Mitigate Risks of Block-Enrolled Ophthalmology Studies. Our country focus for this issue is on Turkey. Duygu Koyuncu Irmak, Associate Director in INC Research Turkey, explains how the Clinical Research Association is the first and unique civil society organisation in Turkey, and has become a multidisciplinary contribution to improve the clinical trials. I hope you all enjoy this issue of JCS. My team and I wish you all a Very Merry Christmas and a Wonderful New Year. See you in 2017. Orsolya Balogh Editor

As you have all noticed, we have brought back flowers as the front cover picture for JCS. Are you still wondering why we feature flowers on the front cover? Each of the flowers to feature on the front cover represents the national flower of one of the countries to be highlighted in that issue. In this issue we have featured a report on Turkey, so the cover image is of an Ottoman Tulip, the national flower of Turkey. I hope this journal guides you through the maze of activities and changes taking place in the clinical research industry worldwide.

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

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

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

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

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

Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Georg Mathis, Founder and Managing Director, Appletree AG

Catherine Lund, Vice Chairman, OnQ Consulting

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

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

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

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

Cellia K. Habita, President & CEO, Arianne Corporation Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global

Janet Jones, Senior Director, ICON Clinical Research

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

Jerry Boxall, Managing Director, ACM Global Central Laboratory

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

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

Elizabeth Moench, President and CEO of MediciGlobal

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

Eileen Harvey, Senior VP/General Partner, PRA International

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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Watch Pages Why the Intranasal Influenza Vaccine is not Recommended this Season Each year, as autumn is well underway, seasonal influenza vaccinations become a topic of conversation for everyone in general and for those with children in particular. And with good reason. Depending on the circulating strains of influenza and the native immunity within any given community, the percentage of people in the United States who contract the flu annually can be between 5% and 20%, with an average of more than 200,000 patients hospitalised every year. The number of flu-related deaths can be even more staggering, ranging from as few as 3349 (1986-1987) to as many as 48,614 (2003-2004). While these numbers vary year to year, and are subject to interpretation, there is little doubt that even at the lowest end of this range, the number is often surprisingly large. For this reason, the Centers for Disease Control and Prevention (CDC) has recommended a seasonal influenza vaccine prior to each season. Sometimes this vaccine matches the circulating strains, sometimes it does not (the

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strains are chosen in February for a flu season that begins about 10 months later). The formulations, traditionally a three-virus strain “cocktail,” have recently added a fourth strain to increase the potential virus match of the annual vaccine. Even when the vaccine content is a match for the circulating strains, the efficacy of the vaccine can fluctuate due to several factors, ranging from the recipient’s metabolism to which type of vaccine is used. Most vaccines are inactivated vaccines, that is, the virus within has been killed or taken apart so that only pieces remain. These pieces stimulate the immune system and potentially yield the desired immunity result. A notable exception to the inactivated influenza vaccines is FluMist (in the US, Fluenz in Europe), which is different for not only containing live — though weakened — virus in the vaccine, but is also delivered intranasally.

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Watch Pages This delivery method was popular with recipients who did not like needles (or pain) and was particularly favoured by paediatric patients. The intranasal vaccine, a live attenuated influenza vaccine (LAIV), was determined to be as effective as injectable influenza vaccines and approved in 2003, but only in patients aged 5-49 years. It was approved later in the age group 2-5 years. The vaccine was popular with the paediatric population and data continued to appear to reflect comparable (or better) efficacy against the circulating strains of influenza as the injected inactivated vaccine.

This loss of a popular formulation of the seasonal influenza vaccine had the potential to strain the supplies of other injectable vaccines. However, it is believed that the CDC acted soon enough to allow suppliers to increase production of recommended, still quite effective, vaccines. It was also hoped that this early action assisted doctors who had pre-ordered the intranasal vaccine in amending their supplies in order to be able to offer the injectable vaccine.

However, starting three seasons ago, during the 20132014 season, there began a noticeable downward trend in vaccine effectiveness for the LAIV. That season’s data showed no measurable efficacy against the H1N1 influenza A strain in the paediatric population, whereas the inactivated vaccine had a 60% effectiveness midpoint estimate. This difference was statistically significant against the predominant virus that season, which was the same strain that caused the 2009 pandemic.

The CDC has noted that the reasons behind the reduction in efficacy of the LAIV vaccine in children are not understood and that the study data are being reviewed to aid in determining the cause. Current theories suggest that perhaps the virus strains in the vaccine are less effective in stimulating an immune response when administered nasally, or perhaps the target population has developed some resistance to the immunity reaction. Still, these theories are in the early stages of research and run counter to the previous data that had demonstrated improved effectiveness of the LAIV vaccine in children against the H1N1 pandemic strain in prior years relative to the inactivated injection.

These data were echoed the following year against the prevailing virus strain (H3N2), though it was acknowledged that neither the LAIV nor the inactivated vaccine worked particularly well against that virus. However, the inactivated vaccines showed a 15% midpoint vaccine effectiveness estimate while the same data point for the LAIV vaccine was -23%. Neither are great efficacy numbers, but one is markedly worse than the other.

As a result, the CDC is working not only with the manufacturer, but also with the US Food and Drug Administration, the US Department of Defense, and other public health organisations to determine the cause. In the meantime, the CDC has stressed that inactivated injectable vaccines have, for whatever reason, remained effective and recommends that everyone over six months of age, even those who dislike needles, get an influenza vaccination for the 2016-2017 season.

Ultimately, at this year’s meeting of the CDC’s Advisory Committee on Immunization Practices (ACIP), citing preliminary data regarding the vaccine effectiveness of the vaccines in use during the 2015-2016 season, the committee noted that the downward efficacy trend had continued. The data appeared to show that the LAIV effectiveness in recipients aged 2-17 years was only 3%, while the injected inactivated vaccine had an effectiveness estimate of 63%. The 3% estimate (with a confidence interval of -49% to 37%) for the LAIV meant that the vaccine imparted no measurable protective benefit. For this reason, the ACIP recommended that the intranasal LAIV not be used for the 2016-2017 influenza season. The committee still maintained its recommendation that everyone aged six months and older receive an inactivated or recombinant influenza injected vaccine. Two months after the ACIP’s recommendation, the CDC made the recommendation official CDC policy. The American Academy of Pediatrics followed suit soon thereafter, noting in its announcement that children who received the LAIV intranasal vaccine were 2.5 times more likely to contract the flu than those children who received an injected vaccine. www.jforcs.com

Walter Chalkley is a senior editorial project manager for Cortellis Regulatory Intelligence, a regulatory affairs information database and part of Clarivate Analytics, formerly the IP & Science business of Thomson Reuters. His education was completed primarily at Virginia Commonwealth University in Richmond, Virginia. He achieved his Regulatory Affairs Certification (RAC) and his regulatory interests are primarily focused on biologics, specifically vaccines. Email: walter.chalkley@thomsonreuters.com Journal for Clinical Studies 9


Watch Pages India, Once Again the Jewel in the Clinical Trial Crown India is the seventh largest country in the world by total area, with the second highest population at 1.2 billion, and is bordered by the countries of Bangladesh, Bhutan, Burma, China, Nepal, and Pakistan. India has the largest postal network in the world, with over 1.5 million post offices, and the name ‘India’ is derived from the River Indus, the valleys around which were the home to the early settlers. According to the census of India of 2001, India has 122 major languages and 1599 other languages, of which 30 are spoken by more than a million native speakers. Generally Hindi and English are used for administrative, government and business purposes. The Healthcare Environment Healthcare issues and diseases include tuberculosis, malaria, HIV, vascular diseases, cancers, and diabetes. Childhood mortality is high and the WHO estimated total diarrhoeal deaths in India among children aged 0-6 years to be 158,209 in 2013. Infant mortality stood at 39 per 1000 live births as of 2013. Clearly there are significant challenges to be faced. India is home to more than 17 per cent of the world’s population and around one fifth of the global burden of disease. According to the 2012 WHO report, non-communicable diseases (NCDs) are responsible for two‐thirds of the total morbidity burden and 53% per cent of total deaths in India. Due to financial constraints, the sick and the suffering poor have restricted access to healthcare.

Clinical Trial Infrastructure The Indian government invested significantly in the early 2000s in order to encourage foreign investment and clinical trials. The money was used to create systems and to recruit and train personnel to process applications, conduct ethics reviews, etc.; this proved a serious draw for pharmaceutical companies. Global share of CTs in India grew from 0.9 per cent in 2008 to 5 per cent in 2013. Issues were reported between 2011 and 2013, culminating in the Supreme Court of India requiring information from the Health Ministry concerning etiquette and ethical conduct for clinical trials. The government responded to the issues by enacting a series of amendments to the clinical trial regulations under the Drugs and Cosmetics Rules (Third Amendment) in February 2013. The objective was to improve patient safety, reporting timeliness of serious adverse events including deaths during clinical trials, and the payment of compensation to patients. These amendments led to many multinational companies choosing to withdraw their clinical studies from India, and a suspension across all clinical areas and phases.

Government expenditure on health and provision of state-funded facilities has fallen over the years, standing at approximately 4.7% of GDP. This has led to a rise in the private healthcare sector, which successfully services the higher levels of society. Most healthcare in India is conducted through private health provision, with expenses paid direct by patients and their families, rather than through any system of insurance. Public healthcare is free for those below the poverty line, but there is just one hospital bed per thousand persons. The total number of registered doctors in the country was 936,488 as of December 31, 2014. Average life expectancy is 68.45 years, which is 167 th on the global league tables. Private insurance is available in India, as are various government-sponsored health insurance schemes. According to the World Bank, about 25% of India’s population had some form of health insurance in 2010. A 2014 Indian government study found this to be an over-estimate, and claimed that only about 17% of India’s population was insured. Insurance generally does not cover consultations or medication. Over 35% of poor Indian households have incurred catastrophic health expenditure (CHE) which can be defined as health expenditure that threatens a household’s capacity to maintain a basic standard of living.

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Watch Pages Resolution was reached following the formation of subject expert committees (SEC), and additional safeguards for each therapeutic area and studies have resumed. The responsibility of reporting serious adverse events has been moved by the licensing authority from the sponsor to the investigator and must happen within 14 days. There are currently 440 open clinical trials in India as per Clinicaltrial.gov, a major upturn over the last two years.

to arrive on Sunday then pre-clearance documents need to be received by midday Saturday (midday Friday for every second Saturday of the month). Caution should be taken around monsoon season to avoid spoilage of goods if the warehouses are full. Shrink wrapping should always be used to reduce water ingress. Simple pack outs are recommended in case customs decide to remove and count each component in a shipment. Temperature monitors should always be declared on the invoice.

The Import Process It takes about 180 days to get clinical trials approved in India. Reviewing and approval timelines for all types of applications must occur in consultation with the SEC. Only institutional ethics committees can review and grant approval for the conduct of clinical studies at any site.

The Future for India in the Global Landscape So India has returned to the fold of clinical trial countries which, with the additional safeguards in place can only be a positive step for all concerned – sponsors, patients and CROs alike. Looking forwards, given the ability of Indian pharmaceutical companies to routinely reengineer processes for manufacturing generic drugs to make medication available at much lower costs (which is a result of Indian patent law which only protects formulation rather than composition of a drug), it would be foolhardy to exclude them. Biosimilars and generic drugs are big business in India and they typically become available very quickly once patent protections expire. This will be the way forward for this exciting subcontinent, which once again is taking its place in the global pharmaceutical marketplace.

The Drugs Controller General of India (DCGI) issues an approval letter to conduct a clinical trial, to an accredited principal investigator of the trial and the ethics committee of the institute. This is needed for clearance together with an import license which the consignee needs to apply for after getting a no objection certificate from the DCGI. The permit usually takes 12-14 weeks and requires the importer of record to complete extensive amounts of documentation. Customs also require an IEC number (import export code number) and an invoice for clearance, which generally takes 24-48 hours. The invoice must be original, on shipper’s official letterhead, and should clearly state: • Importer of record if different from consignee • Reference to protocol or study ID • The name of the drug must match the “Name of the Drugs” on the import licence • The ‘mg’ or ‘ml’ of the drug unit (capsule or vial) must match the stated unit amount on the import licence • Customs must be able to easily tally the exact amount of drugs that the invoice represents in order to debit the correct amount from the tally section of the licence • Value must be provided at a unit (per tablet, capsule) level in addition to the total • Value of the shipment, which is a definite number and not a value for customs • Incoterms • Manufacturing date, expiry date and batch number. These must be identical on invoice, packing list and product label • A value evidence certificate (VEC) for customs is required, stating that the invoice value is true & correct. This should be on company letterhead of the shipper, in duplicate. Facilities En Route and Logistic Needs Major ports like Delhi, Mumbai, Bangalore & Hyderabad have temperature control facilities at the airports for storage during customs clearance. The second Saturday of each month is a customs holiday; if a shipment is due www.jforcs.com

Sue Lee 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 in her capacity as Head of the Major Clinical Trial Unit. Sue 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. More recently in her role as Regional Quality Manager, Sue has been auditing and developing procedures and systems for regulatory compliance, package and vehicle testing, as well as temperature control and mapping. Currently, Sue’s role includes delivering pertinent, technical information and updates on latest industry developments via technical presentations, articles and white papers, workshops, association and discussion group involvement and direct links with other industry professionals. This also includes direct involvement delivering and maintaining World Courier’s online presence. Email: slee@worldcourier.co.uk Journal for Clinical Studies 11


Watch Pages

Drug Development in Systemic Lupus Erythematosus – Can it be Successful? Introduction to SLE Systemic lupus erythematosus (SLE) is an autoimmune disease that causes the immune system to produce several types of antibodies, particularly against cell nuclei. This disease is extremely heterogeneous in how it manifests, which leads to significant problems and delays in diagnosis. The condition most frequently affects the skin, joints and muscles, but can also disrupt other organs and systems, like the kidneys, heart, central nervous systems and others. The prevalence of lupus is approximately 50 patients per 100,000 in the United States. There are significant differences in the disease prevalence among different races. For example, Eastern Asians (excluding Japanese), African Americans and Hispanics are affected more frequently by the disease than other races. In addition, the prevalence of SLE is higher among women (up to nine times) than men.

Definition of Population It starts with defining in protocol the patient population that should be enrolled in the trial. As mentioned earlier, SLE is a disease with very heterogeneous manifestations that make it difficult to diagnose. In addition, there is not a single test that can either confirm or exclude SLE, and there are several diagnosis criteria, which do not necessarily completely overlap with each other (ACR, SLICC). Serology tests (like anti-nuclear antibodies or anti-DNA) play a role in diagnosis, but they may become negative during the course of the disease. A requirement for positive ANA and anti-DNA will increase the probability of enrolled patients to actually have SLE (possibly increasing the difference between active treatment and placebo). This can lead to significant increases in the screening failure rate, thereby reducing the enrolment rate in an already difficult-to-enroll indication.

History of Drug Development in SLE Despite the disease prevalence, there is no effective treatment for SLE. Since the approval of aspirin in 1948, Drug Development in Systemic Lupus Erythematosus – Can it be Successful? and then hydroxychloroquine and steroids in 1955, there By Marcin Ernst, MD, Vice President, Clinical Development, INC Research in 2011 — that has been only one drug – Belimumab, Introduction to SLE was approved by FDA. Before and after Belimumab, a significant number drugsdisease have failed at system different Systemic lupus erythematosus (SLE) is of an autoimmune that causes the immune to produce several types of antibodies, particularly against cell nuclei. This disease is extremely stages of development. heterogeneous in how it manifests, which leads to significant problems and delays in diagnosis. The

Disease activity at baseline in protocols is usually defined using two indices – Systemic Lupus Erythematosus Disease Index (SLEDAI) together with its many variations and British Isle Lupus Assessment (BILAG). Defining a higher SLEDAI score at baseline (or requiring more BILAG A or BILAG B scores) will result in patients with higher disease activity. It is easier to demonstrate decrease in disease activity in such patients. Such populations should have a lower placebo response rate (assuming other factors affecting placebo response rate are the same) than a group of patients with lower baseline disease activity. However, setting the required SLEDAI or BILAG at the higher level leads to more challenges in enrolment. Similar to serology requirements, a balance needs to be achieved to increase the probability of success, in both results and enrolment.

Drug Rituximab

Year 2009

Number of patients 257

Outcome No difference in efficacy between placebo and active treatment. Abatacept 2010 118 No difference in efficacy between placebo and active treatment. Epratuzumab 2016 786 No difference in efficacy between placebo and active treatment. Tabalumab 2016 2288 No difference in efficacy between placebo and active treatment. PF-04236921 2016 183 No difference in efficacy between placebo and active treatment. Drug development for SLE has suffered many setbacks, especially in the last few years.

Drug development for SLE has suffered many setbacks, Placebo Response Rate especially inarise the last few years. Common issues that during SLE trials include high placebo response rates and the relatively small difference between active treatment and placebo arms. Even trials that Response met efficacy endpoints — such as Belimumab registration trials — still faced similar Placebo Rate challenges. What this demonstrates is a multifaceted challenge, which all studies need to address in Common issues that arise during SLE trials include high order to be successful. placebo response rates and the relatively small difference between active treatment and placebo arms.

Even trials that met efficacy endpoints — such as Belimumab registration trials — still faced similar challenges. What this demonstrates is a multifaceted challenge, which all studies need to address in order to be successful.

12 Journal for Clinical Studies

Concomitant Medication Patients with active SLE will have different therapies aimed at decreasing disease activities – steroids and immunosuppressants. However, reducing or washing out these therapies prior to the study is not feasible. Aside from ethical concerns, there would be an increased risk of patients experiencing disease flares, making them unsuitable for a clinical study. On the other hand, these therapies have the potential to affect efficacy outcomes, which will likely increase the placebo response rate. Steroids present another special challenge due to the frequency of their use, and because they are efficacious in this indication (their safety profile is the reason they are not considered to be a long-term solution). The majority of protocols mandate steroid tapering during the study (providing a patient’s clinical status allows it) to address the issue. This is not an easy process, though, as there is no standard guideline for steroid tapering and different physicians follow various protocols. In addition, they have different thresholds as well as different time Volume 8 Issue 6


Watch Pages points to start tapering steroids. All of these factors create challenges and affect outcomes of SLE trials. 3.

Efficacy Endpoints We already discussed different indices to measure disease activity at entry. The endpoints used in efficacy SLE trials are even more complex. There are mainly two types of endpoints – Systemic Lupus Erythematosus Responder Index (SRI-4 or SRI-5) and BILAG-Based Composite Lupus Assessment (BICLA). The first one is based more on the SLEDAI index, the second one more on BILAG. SRI-4   

At least 4 point decreases in SELENA SLEDAI score from baseline (5 point decrease for SRI-5) No worsening of the physician global estimate (≤10%) No new BILAG A or two BILAG B scores

BICLA  Improvement of all BILAG A to B, C or D or all BILAG B to C or D  No worsening of the physician global estimate (≤10%)  No new BILAG A or no more than one new BILAG B  No worsening of SLEDAI score from baseline  No initiation of non-protocol treatment

Peng, M. Kinaszczuk and P. Nash. The Efficacy and Safety of Abatacept in Patients With Non–Life-Threatening Manifestations of Systemic Lupus Erythematosus. Arthritis & Rheumatism 2010; 62: 3077–3087 Megan E. B. Clowse, Daniel J. Wallace, Richard A. Furie, Michelle A. Petri, Marilyn C. Pike, Piotr Leszczyński, C. MichaelNeuwelt, Kathryn Hobbs, Mauro Keiserman, Liliana Duca, Kenneth C. Kalunian, Catrinel Galateanu, Sabine Bongardt, Christian Stach, Carolyn Beaudot, Brian Kilgallen, Caroline Gordon. Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results from the Phase 3, Randomized, Double-blind, Placebo-controlled Trials, EMBODY™ 1 and EMBODY™ 2. ‘Accepted Article’, doi: 10.1002/art.39856

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D. A. Isenberg, M. Petri, K. Kalunian, Y. Tanaka, M. B. Urowitz, R. W. Hoffman, M. Morgan-Cox, N. Iikuni, M. Silk, D. J. Wallace. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:323–331

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J. T. Merrill, R. F. van Vollenhoven, J. P. Buyon, R. A. Furie, W. Stohl, M. Morgan-Cox, C. Dickson, P. W. Anderson, C. Lee, P.-Y. Berclaz, T. Dörner. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:332–340. Daniel J. Wallace, Vibeke Strand, Joan T. Merrill, Serghei Popa, Alberto J. Spindler, Alicia Eimon, Michelle Petri, Josef S. Smolen, Joseph Wajdula, Jared Christensen, Cheryl Li, Annette Diehl, Michael S. Vincent, Jean Beebe, Paul Healey, Sudhakar Sridharan. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomized controlled trial. Ann Rheum Dis Published Online First: September 26, 2016 doi:10.1136/ annrheumdis-2016-209668.

Both these endpoints are highly subjective in nature. Both of theseof endpoints are highly subjective in nature. This translates into inter-rater variability and additional “noise” in the data, whichinter-rater cannot be fully eliminated. Placebo response rateadditional and overall This translates into variability and additional variability coming from this contributes to failures in many lupus studies. “noise” in the data, which cannot be fully eliminated. One mitigation to the risks of incorrectly diagnosed patients being enrolled, and variability in endpoints Placebo response rate and overall additional variability assessments, is to implement an additional review of patients’ eligibility and of endpoints. This is done in different waysfrom on SLE studies. ideal, and also the most process, requires a group of lupus peers coming thisThecontributes todetailed failures in many who are thoroughly familiar both with SLEDAI and BILAG scoring as well as lupus trials. Before being studies. randomised, each patient is reviewed by this team and differences are discussed with investigators. The

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same process is applied to review each patient’s data for endpoint assessments. This review allows for increased consistency and the early identification of incorrectly enrolled patients, as well as possible needs for training.

7.

Larissa Lisnevskaia, Grainne Murphy, David Isenberg. Systemic lupus erythematosus. Lancet 2014; 384: 1878–88

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Chee-Seng Yee, Vernon Farewell, David A. Isenberg, Anisur Rahman, LeeSuan Teh, Bridget Griffiths, Ian N. Bruce, Yasmeen Ahmad, Athiveeraramapandian Prabu, Mohammed Akil, Neil McHugh, David D’Cruz, Munther A. Khamashta, Peter Maddison and Caroline Gordon. British Isles Lupus Assessment Group 2004 Index Is Valid for Assessment of Disease Activity in Systemic Lupus Erythematosus. Arthritis & Rheumatism 2007; 56: 4113–4119 I. Castrejón, C. Tani, M. Jolly, A. Huang, M. Mosca. Indices to assess patients with systemic lupus erythematosus in clinical trials, long-term observational studies, and clinical care. Clin Exp Rheumatol 2014; 32 (Suppl. 85): S85-S95.

One mitigation to the risks of incorrectly diagnosed patients being enrolled, and variability in endpoints Summary assessments, is to implement an additional review of SLE is probably one of the most challenging indications for drug development. Without understanding its patients’ eligibility and endpoints. This trial, is even done challenges, as well as ways of addressing them,of it is very hard to execute a successful with a in drug that may beways successful.on It is also difficult to replicate Phase II results in largerand trials, where the the different SLE studies. The ideal, also issues described above are enhanced. There are some promising drugs currently in different stages of most detailed process, requires group ofsponsors peers development for SLE. Hopefully the lessons learned from past a challenges will allow to who successfully bring new therapies to the market.both with SLEDAI and BILAG are thoroughly familiar scoring as well as lupus trials. Before being randomised, each patient reviewed by this has team and differences are Marcin Ernst, MD, Viceis President, Clinical Development, more than 15 years of experience in clinical research, including nine years working in various positions with a contract research organisation (CRO). discussed with investigators. The same process is applied Ernst also has four years’ experience working as a general and cardiac surgeon in a hospital setting, as towellreview each patient’s data endpoint assessments. as three years in pharma, where he managed studiesfor exclusively in rheumatology. For the last five years, Ernst has been leading the Immunology and Inflammation group at INC Research, where he is This review allows for increased consistency and the early identification of incorrectly enrolled patients, as well as possible needs for training. Summary SLE is probably one of the most challenging indications for drug development. Without understanding its challenges, as well as ways of addressing them, it is very hard to execute a successful trial, even with a drug that may be successful. It is also difficult to replicate Phase II results in larger trials, where the issues described above are enhanced. There are some promising drugs currently in different stages of development for SLE. Hopefully the lessons learned from past challenges will allow sponsors to successfully bring new therapies to the market. References 1.

Joan T. Merrill, C. Michael Neuwelt, Daniel J. Wallace, Joseph C. Shanahan, Kevin M. Latinis, James C. Oates, Tammy O. Utset, Caroline Gordon, David A. Isenberg, Hsin-Ju Hsieh, David Zhang and Paul G. Brunetta. Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus. Arthritis & Rheumatism 2010; 62: 222–233

2.

J. T. Merrill, R. Burgos-Vargas, R. Westhovens, A. Chalmers, D. D’Cruz, D. J. Wallace, S. C. Bae, L. Sigal, J.-C. Becker, S. Kelly, K. Raghupathi, T. Li, Y.

www.jforcs.com

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10. Marilyn C. Pike and Lexy Kelley. Data Quality Challenges in Systemic Lupus Erythematosus Trials: How Can This Be Optimized? Curr Rheumatol Rep (2012) 14:324–333 11. Aikaterini Thanou, Eliza Chakravarty, Judith A. James, Joan T. Merrill. Which outcome measures in SLE clinical trials best reflect medical judgment? Lupus Science & Medicine 2014;1:e000005. doi:10.1136/ lupus-2013-000005

Marcin Ernst, MD, Vice President, Clinical Development, has more than 15 years of experience in clinical research, including nine years working in various positions with a contract research organisation (CRO). Ernst also has four years’ experience working as a general and cardiac surgeon in a hospital setting, as well as three years in pharma, where he managed studies exclusively in rheumatology. For the last five years, Ernst has been leading the Immunology and Inflammation group at INC Research, where he is responsible for global delivery of all projects in this therapeutic area. He has been responsible for a large portfolio of studies in indications like rheumatoid arthritis, systemic lupus erythematosus, psoriasis and gout. He also has experience in orphan indications. Email: marcin.ernst@incresearch.com. Website: www. incresearch.com. Journal for Clinical Studies 13


Watch Pages

Sponsors and CROs: Closing the Technological Gap in Clinical Trials Engagement has recently been established as a key concept within clinical trials. This trend has delivered a multitude of benefits for participants, who, rather than being unconnected from the trial between site visits, now engage in a continual technology-enabled dialogue with their study. However, the industry has overlooked the potential for engagement technologies to benefit two other key stakeholders: sponsors and CROs. These stakeholders have first-hand experience of the value of these technologies. Previously, interactions were limited to occasional site visits, with patients receiving varying levels of support or encouragement in between. Even well-intentioned patients forget to take their medication, and drop out of studies because of a failure to maintain the enthusiasm that initially drives them to enrol. However, the rise of SMS text messaging – and subsequently in-app notifications – has enabled continual dialogue, and mobile devices have enabled sponsors and CROs to oversee a transformation in the relationship between clinical trials and participants. Conversely, the use of these technologies has meant that the amount of data these other stakeholders need to manage has increased – data which are potentially very valuable and can yield insights that improve the performance of an active trial and show where improvements might lie.

permission level, unauthorised access to data would be prevented. This would also allow users to access data relevant to their jobs. Moreover, a well-designed system would issue targeted alerts whenever data, analyses and reports are available. How Sponsors can Benefit Patients already benefit from systems which alert them to information relevant to the study they’re participating in. The specifics of how to extend these types of benefits to sponsors are tied to their position within the trial process. Sites oversee patients; CROs oversee sites; and sponsors oversee everything, meaning sponsors need a macro-level view of a trial’s, or multiple trials’, performance. Specifically, sponsors need quick, straightforward ways of monitoring their clinical research programmes. Currently, clinical trials are generating these data but technological shortcomings are rendering the insights they contain inaccessible to sponsors. Opening up the data will yield multiple benefits. If a sponsor can pull up data on enrolment and compliance and compare them to targets they will have more productive progress reviews with CROs.

Breaking Down Silos, Creating Insights Organisations in every sector are tracking a wider range of metrics than ever before, so what is needed are technologies that can intelligently connect and handle large datasets. Currently, the ability of CROs to derive insights that improve the performance of an active trial is hindered by the fact that data are siloed within each module of a study, making overall performance monitoring difficult. Technologies must pull down unnecessary silos, making it possible for each type of organisation to access all of the data it is permitted to see. This new type of system would remove barriers that obstruct data-toinsight workflow, and provide sponsors and CROs with the tools that can sort and package information in a meaningful way. The next generation of clinical trial tools must handle information in a way that yields easyto-understand insights through real-time data. Clinical trials are complex operations, and each end user needs access to different information. Sometimes access to details is limited by regulation, making things even more complex. An ideal system would differentiate between types of data and user, adjusting its response and output accordingly. By tailoring the display to a user’s 14 Journal for Clinical Studies

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This workflow is underpinned by access to real-time data analyses on the status of a clinical trial. The system must pull in data as they are generated and very quickly analyse and package information in a meaningful way. Without such a rapid system, sponsors will struggle to respond to issues quickly enough to have an impact on the running of clinical trials.

The Value of Integrated Engagement This technological framework has the potential to end the uneven distribution of benefits unlocked by clinical trial engagement technologies. Lately, patients have rightly been the focus of trial engagement initiatives with the use of mobile devices leading to studies becoming evermore attuned to patient needs.

What CROs Stand to Gain Granular data are more useful to CROs than macro-level overviews. It is normally CROs that contract with sites. As such, CROs need easily-digestible data on how a clinical trial is performing on a site-by-site basis. Real-time access to these data can determine whether or not a study falls behind.

Like patients, sponsors, CROs and sites can all benefit from these advances. Information already exists – what was lacking was a way to organise and analyse data that met the unique needs of organisations. This technological gap has now been addressed and soon the current system will appear as outmoded as the pre-patient engagement era appears to us today.

For CROs, the criticality of the data derives from their ability to support performance-altering decisions. If a CRO can identify which sites are struggling to enrol patients early on, it can initiate support actions to bring centres up to speed. A CRO can also spot high-performing sites, learn what’s working there, and transfer the lessons accordingly. These immediate, targeted benefits are complemented by longer-term gains. Technology can also provide an overview of multiple clinical trials, giving a snapshot of the overall health of the activities being overseen by a CRO. Retrospective analyses of these activities can uncover learnings that enable CROs to improve the design of future trials. This can save time and reduce the risk of problems arising once a trial is live. www.jforcs.com

Chris Watson has a PhD in behavioural neuropharmacology and is an experienced product strategist with over 16 years’ experience in the delivery of business- and consumer-based solutions, the last six of which have been focused in the clinical technology industry. He has an extensive knowledge of product and software development processes and is responsible for implementing mobile product strategy at Exco InTouch. Journal for Clinical Studies 15


Regulatory

Serving on an FDA Advisory Committee: One Member’s Point of View I have served as a member of the FDA anesthetic and analgesic drug products advisory committee (AADPAC) since March 2014. AADPAC reviews and evaluates available data concerning the safety and effectiveness of marketed and investigational human drug products for use in anesthesiology, analgesia, and surgery and makes appropriate recommendations to the Commissioner of Food and Drugs. It is important to note that this brief article provides the views of the author only and does not in any way reflect the views of the Food and Drug Administration. The Federal Food, Drug, and Cosmetic Act (FD&C Act) is a federal law enacted by Congress. Along with other federal laws, it establishes the legal framework within which FDA operates. The FD&C Act can be found in the United States Code beginning at 21 U.S.C. 301. FDA develops regulations based on the laws set forth in the FD&C Act or other laws under which FDA operates. FDA follows the procedures required by the Administrative Procedure Act, another federal law, to issue FDA regulations. This typically involves a process known as “notice and comment rulemaking” that allows for public input on a proposed regulation before FDA issues a final regulation. FDA regulations are also federal laws, but they are not part of the FD&C Act. FDA regulations can be found in Title 21 of the Code of Federal Regulations (CFR). FDA follows the procedures required by its “Good Guidance Practice” regulation to issue FDA guidance. This guidance describes the FDA’s current thinking on a regulatory issue. Guidance is not legally binding on the public or the FDA. The Good Guidance Practice regulation can be found in the U.S. Code of Federal Regulations at 21 CFR 10.115 (http://www.fda.gov/AboutFDA/Transparency/Basics/ ucm194909.htm).

research initiatives due to the fact that it is risky to include them, given increased sensitivity to drug products and the complicating health factors older adults often have, including the regular need to use a variety of contraindicated drug products. I am forever advocating for the inclusion of older adults in clinical trials, so that the unique health conditions of this population and the effects of medications on them can be better understood. This is especially important given the demographic imperative that relates to the aging of the baby boomer population. Another recommendation I often make to sponsors is the inclusion of an extended and more diverse patient population in their clinical trial samples. I am a firm believer in the need to be able to better generalise statistically to the broader population what effects drug products can have. Of particular significance to my FDA advisory committee work is the review of opioid and opioid abusedeterrent drug products. I have gained intimate knowledge of these products and learned from the general public that presents at our meetings how the products have affected them, both negatively and positively. It is important to me to be able to represent the thoughts and experiences conveyed by the general public and consumers of these products. I am grateful for the contributions of the general public. As background, opioids are a class of drugs that include the illicit drug heroin, as well as the licit prescription painrelievers oxycodone, hydrocodone, codeine, morphine, fentanyl and others. Opioids interact with opioid receptors

My experience as an AADPAC committee member is from the perspective of the consumer. As a longtime clinical researcher and patient recruiter in the fields of neurology and psychiatry, I have a unique perspective to offer as it relates to issues affecting consumers. For instance, I am keenly aware of how drug products and their applications address the needs of consumers, especially vulnerable populations such as children and older adults. As a trained gerontologist, I am always interested in learning what ways the research used to support drug product applications has included older adults in the populations studied. It is common knowledge that vulnerable populations are often excluded from clinical 16 Journal for Clinical Studies

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Regulatory on nerve cells in the brain and central nervous system to produce pleasurable effects as well as relieve pain. Addiction is a primary, chronic and relapsing brain disease characterised by an individual pathologically pursuing reward and/or relief by substance use. Of the 21.5 million Americans 12 or older that had a substance use disorder in 2014, 1.9 million had a substance use disorder involving prescription pain relievers and 586,000 had a substance use disorder involving heroin. It is estimated that 23% of individuals who use heroin develop opioid addiction. With respect to the national opioid overdose epidemic regularly referred to in the news media, drug overdose is the leading cause of accidental death in the US, with 47,055 lethal drug overdoses in 2014. Opioid addiction is considered by some to be driving this epidemic, with 18,893 overdose deaths related to prescription pain relievers, and 10,574 overdose deaths related to heroin in 2014 (http://www.asam.org/docs/default-source/ advocacy/opioid-addiction-disease-facts-figures.pdf). This is precisely why AADPAC’s recent work has been focused on abuse-deterrent formulations of opioid products, with the intent to reduce drug dependency and abuse. In my home state of Massachusetts, it is recognised that there is an opioid epidemic. Opioid-related deaths in Massachusetts increased more than 350% from 2000 to 2015. Statistics reveal that there were 1256 unintentional overdose deaths in the state in 2014. Of these deaths, 10%, or 119, were from Western Massachusetts, which is where I reside. According to the Massachusetts Department of Public Health (MDPH) Bureau of Substance Abuse Services (BSAS) in 2014, there were 104,233 admissions to substance abuse treatment programmes statewide (http://www.mass.gov/eohhs/ docs/dph/substance-abuse/care-principles/state-andcity-town-admissions-fy14.pdf). More recent data released by the Massachusetts Department of Public Health indicate that there is support for the hypothesis that increased risk of fatal overdose is associated with concurrent use of opioids and benzodiazepines. Based on observed 2015 data, the concurrent use of benzodiazepines and opioids is associated with a fourfold increase in risk of fatal opioid overdose. Also important is the finding that of those who died of an opioid overdose with toxicology reports, approximately 83% had illegally-obtained or likely illegally-obtained substances in their system at time of death (Massachusetts Department of Public Health, Assessment of Massachusetts Opioid-Related Deaths, July 1, 2016). Also important to consider are the economic impacts from a workforce perspective, such as lost wages, lost revenue, or time away from work. SAMHSA estimated in 1999 that the total productivity costs of substance abuse nationally were $338 billion (http://www.samhsa. gov/sites/default/files/cost-benefits-prevention.pdf). It is likely this figure is much greater now, but no recent data could be found that support this conclusion and there is www.jforcs.com

no such statistic for Massachusetts alone. A number of questions posed to the AADPAC committee relate to the understanding of the risks and benefits of the drug products under review. We discuss the efficacy, effectiveness, and safety profile of each drug product under review. We are also asked to opine on the language that may be used for labelling the given products. Committee members spend a number of hours reviewing background materials provided by both the product sponsor and the FDA, to be informed about the topic at hand and make educated recommendations for approval or disapproval. I estimate that I personally spend about 20 hours preparing for each meeting. The vast majority of materials provided for review are confidential and committee members are prohibited from revealing the confidential information that they review, sometimes even after the meeting is over and the public has been made aware of the meeting’s activities.

Dr Jennifer Higgins. A graduate of the Gerontology Ph.D. Program at the University of Massachusetts, Dr Higgins will serve as principal investigator for this project. For her dissertation, she conducted a nationwide study of senior centre gambling policies designed to regulate problem gambling. Results of the preliminary analyses conducted for this dissertation have recently been published in the Journal of Aging and Social Policy and the Journal of Aging Studies. Dr Higgins has presented her work at gambling conferences in the United States and Canada. Over the course of her academic career, Dr Higgins has conducted policy analyses and participated in numerous research projects at the University of Massachusetts/ Boston Gerontology Institute, the Boston University School of Social Work, Simmons College School of Social Work, the Massachusetts Department of Public Health, and the Massachusetts Council on Compulsive Gambling. In 2002, she was invited to join an expert panel of problem gambling clinicians and academics at the University of Windsor Ontario for the purpose of designing the first senior problem gambling diagnostic tool. Presently, Dr Higgins is a Quality Management Specialist at the Center for Human Development in Springfield, Massachusetts. The agency serves 23,000 clients with mental health care, covering a territory from Northwestern Connecticut to the Berkshires in Massachusetts. Email: higginsjennifer0228@gmail.com Journal for Clinical Studies 17


Regulatory Risk-based Quality Management: Improving Trials Data through Minimalism There is no doubt about the importance of maintaining quality standards throughout clinical research processes, but in recent years the regulatory bodies have begun to question the industry’s approach to quality management. This has led to an addendum to the good clinical practice (GCP) guidelines that advocates rethinking of current quality management practice during clinical trials. While any perceived change in regulations is likely to throw the industry into turmoil, the latest guidance intends to help drug companies to streamline their research through riskbased approaches to quality management. This article considers the new way of thinking, which promises to allow more focused and cost-effective trials that could reduce considerably the enormous time and cost burdens of current quality management practices. Over the past twenty years, regulatory requirements have become more stringent throughout all stages of the pharmaceutical research and development pipeline. For clinical trials in particular, pharmacovigilance expectations have increased dramatically, requiring thousands of additional patients for every Phase III study and, typically, resulting in several billion dollars of additional work for every potential blockbuster drug. For many drugs produced today, the clinical phases account for the majority of the drug’s total development costs (around 75 per cent), far outweighing the investment required for all other steps, including discovery, preclinical development and manufacturing. Furthermore, approximately half of these inflated clinical costs are spent on oversight – especially source data verification (SDV), the labour-intensive checking and verification of all clinical data in order to demonstrate that quality standards are being upheld. Many pharmaceutical companies have adopted 100% SDV within their quality management processes, and routinely spend millions or even billions of dollars per trial checking that every single data point in the trial CRF matches the original data source information. However, it has recently become apparent that this costly approach does not necessarily meet the data quality requirements for the industry. According to the European Medicines Agency (EMA), every clinical trial must be conducted to acceptable quality. Crucially, acceptable quality means the data collected must be of sufficient quality to support good decisionmaking – i.e., fitness for purpose. All trials are likely to contain some data errors and it would be unrealistic to set a specific tolerance level for errors within the good clinical practice guidelines 1. The important point here is that the data must be good enough for the authorities to make the right decision when reviewing a trial report. In other words, the decision made following the study would be the same decision if the data were perfect. 18 Journal for Clinical Studies

The Need for Change The guidance clearly does not require 100% SDV, but many sponsors insist on including full SDV within their trials and are perhaps reassured by generating large volumes of checked data. In reality, quantity does not guarantee quality and such reliance on SDV can leave sponsors oblivious to two worrying truths. Firstly, verifying that all original source data match the trial’s CRF data does not prove that the original source data were inputted correctly in the first place. As a result, the trial data could contain major systematic errors that severely impact the quality and trial outcomes, but these errors would not be detected through SDV. Secondly, conducting 100% SDV typically requires huge use of resources that can preclude any other type of error-checking from taking place during the trial, again meaning that systematic errors are not detected early on, resulting in poor quality data collection. In 2014, TransCelerate Biopharma assessed the value of SDV through a literature review and retrospective multistudy analysis of clinical trial data 2. The analysis found that SDV has a negligible impact on data quality, and across 1168 studies, only 3.7% eCRF data was corrected by any method after initial data entry by site personnel; only 1.1% was corrected by SDV methods 2. Incredibly, 96.3% of the data collected in the studies was never corrected. The regulatory authorities have recognised the growing problem with current approaches to quality management. In 2011, the EMA produced a draft reflection paper that was adopted by the GCP Inspectors Working Group in 2013. The paper identified the shortcomings of current practice, in particular the disproportionate costs and time-consuming nature of oversight, and the lack of prioritisation, risk identification and risk mitigation within trial designs 3. It recommended that sponsors move towards a more proportionate, systematic and risk-based approach in quality management, facilitating new thinking in trial design that would focus on the most important issues and priorities. Risk-based approaches have similarly been recommended by the FDA 4 and MHRA 5; elsewhere, TransCelerate Biopharma has been working to find ways for pharmaceutical companies to accommodate this industry shift in a simplified fashion 6. Becoming Minimalistic Risk-based quality management (RBQM) represents a significant change in mentality compared to traditional quality processes. The aim is to focus on the reliability of the trial results, and the wellbeing and safety of trial subjects, by identifying the trial priorities and ways to mitigate significant and serious risks 3. RBQM is a systematic way of thinking that must be applied right from the start of a study, because it dictates the trial Volume 8 Issue 6


Regulatory design and influences numerous fundamental decisions, such as which parameters to include, how and when to collect data, and how frequently to check the data. Risk mitigation can then be built into the protocol design and monitoring plan. For example, rather than reactively checking all the data points collected during a trial, RBQM should ensure that inputs can only be entered correctly in the first place. By rethinking quality management in this manner, sponsors will not only improve the quality of their clinical trials, but also be able to streamline trial designs, thereby saving vast amounts of time and expense.

GCP guidelines have been updated with requirements for a risk-based approach that includes a risk assessment to be made prior to the trial, with SOPs and appropriate plans in place to support risk control and risk reporting, as well as centralised and on-site monitoring 7. The shift towards RBQM will require sponsors to demonstrate that they have applied the principles correctly in order to establish and prioritise the risks, while meeting GCP objectives. When assessing trial reports, the regulatory authorities will then need to be able to understand those thought processes underlying the trial design.

RBQM involves conducting a risk assessment for every trial to consider what might go wrong, how and where, so that ways can be identified to prevent problems arising in the first place. The risk assessment considers risks to trial patients, risks to the data (impacting decisions made based on the trial outcomes and, therefore, affecting future patients), risks to the trial provider and even risks to the sponsor. It forces sponsors to ask themselves what level of risk is acceptable and set their own quality control processes to ensure these limits are in place. Ultimately, by considering these risks, companies are encouraged to focus on the most relevant and important points for their quality management. By doing so, they can minimise the introduction of systematic errors into the study, resulting overall in better quality data, without having to check every data point in the CRF. Traditional SDV-focused approaches to data quality management focus primarily on on-site monitoring. In contrast, implementation of RBQM should involve a combination of both on-site and centralised data monitoring methods. On-site monitoring does not have to involve frequent site visits and SDV, but should focus on compliance of the protocol and documentation of collected data and processes, ensuring any systematic errors are spotted and dealt with early in the trial. Centralised monitoring includes checking for data anomalies, higher frequency of errors and protocol violations 4. Standard checks might include data range, consistency and completeness, and checking for unusual distribution of data between sites. With today’s EDC and eCRF technologies, centralised monitoring can easily be carried out remotely at the sponsor or CRO’s facilities. It focuses on review and assessment of reported data, including checking the quality of real-time data entry, statistical analyses of data across different sites to identify outliers, analysis of site characteristics and performance metrics, and detection of data trends that would not be spotted through on-site monitoring. The combination of on-site and centralised monitoring is expected to ensure that patient integrity and safety are upheld, and that the data collected are trustworthy. Empowering Sponsors RBQM clearly offers important advantages for the pharma industry as well as for patients. Accordingly, the 19 Journal for Clinical Studies

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Regulatory On the face of it, drug developers may feel that the introduction of yet more guidelines and documentation can only increase their burden of quality management, and set back timelines for new trials. Arguably, however, the principles of RBQM were included in the 1996 GCP guidelines 1: “The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial” (§5.18.3). The recent addendum to GCP simply places more emphasis on empowering the sponsors to decide on a suitable quality management system for their specific trial. Some pharma companies may not like being forced into a new way of thinking. The pharma industry is renowned for being highly regulated, but it is becoming apparent that some of the perceived constraints and administrative burdens are practices that sponsors have themselves instigated through over-interpretation of the guidelines. For example, there is no GCP requirement to perform on-site monitoring at a specific frequency, but simply “before, during and after the trial”. This contrasts with current popular belief that on-site monitoring should be conducted at regular and very frequent time intervals. The principles of RBQM clearly require fresh thinking for each trial, so sponsors cannot expect to receive template risk assessment forms to complete and directions on which quality control methods to include in their trial design. GCP guidelines also specify that the responsibility of the risk assessment, plans and documentation lies with the sponsor. When partnering with a CRO, therefore, it will be essential that the sponsor and CRO have full and joint understanding of the risk assessment, trial design and RBQM underpinning the trial. Sponsors will benefit from working with a proactive and up-to-date CRO that has fully embraced the concept of RBQM. At our company, for example, we are accustomed to working in a transparent, well documented and collaborative manner with the sponsor. Furthermore, our senior advisory team includes experienced GCP inspectors and offers a wealth of expertise to guide RBQM, trial design and conduct. By focusing only on essential trial activities, with assessment and QC methods that are proportionate to the risk, we can help our partners to design efficient and simple, yet high quality studies, in line with the latest regulatory requirements. Conclusions and Future Directions RBQM is a simple principle that directs pharma companies to focus on the most relevant points for a specific trial and spend less time on data and processes that are not so important for the study outcome. This is an important step forwards for the industry, that will help companies to work in smarter, more efficient ways that use fewer resources. However, the success of such an approach relies on being able to empower people with greater responsibility and strip out the layers of duplicated 20 Journal for Clinical Studies

responsibilities that are created by repeated checking of controls. This requires a complete change of mindset in the current industry that may take several years to show results, but the expectation is that everyone will gain in the long term. References 1. ICH Guideline for Good Clinical Practice E6 (R1) 1996. Available at: http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/ E6/E6_R1_Guideline.pdf 2. Sheetz N, Wilson B, Benedict J, Huffman E, Lawton A, Travers M, Nadolny P, Young S, Given K, Florin L (2014). Evaluating Source Data Verification as a quality control measure in clinical trials. Therapeutic Innovation & Regulatory Science 48(6): 671-680. 3. European Medicines Agency, 18 November 2013. Reflection paper on risk based quality management in clinical trials. EMA/269011/2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2013/11/WC500155491. pdf 4. Guidance for Industry Oversight of Clinical Investigations – a risk-based approach to monitoring. FDA Procedural August 2013. Available at: http:// w w w . fd a . g o v / d o w n l o a d s / D r u g s / . . . / G u i d a n c e s / UCM269919.pdf 5. MHRA (2011). Risk-adapted approaches to the management of clinical trials of investigational medicinal products. 6. Position paper: Risk-based monitoring methodology (2013). TransCelerate Biopharma Inc. Available at: http://www.transceleratebiopharmainc.com/ wp-content/uploads/2013/10/TransCelerate-RBMPosition-Paper-FINAL-30MAY2013.pdf 7. ICH Guideline for Good Clinical Practice E6 (R2) 2015 (draft). Available at: http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_ guideline/2015/08/WC500191488.pdf

Gunnar Danielsson has a wealth of experience from the pharmaceutical industry, having spent 40 years in clinical research, focusing on quality management, electronic systems, data management, and clinical design and conduct. Gunnar served as a renowned GCP Inspector for the Swedish MPA for over 10 years, and is currently a key advisory resource at PCG Clinical Services, where he helps to design partners’ studies in the most effective way, meeting the latest regulatory requirements. Email: info@pcg-clinical.com Volume 8 Issue 6


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Regulatory Medical Management in Clinical Trials: A Roadmap to Operational Excellence (Part 4 – Close-out Phase) Being the final feature of this four-part series of medical management of clinical trials, this article will focus on the medical activities during the close-out phase of a clinical study. The close-out phase here refers to the period from last patient out (LPO) till the issuing of the final clinical study report (CSR). As the study conduct operations come towards a conclusion, the routine medical monitoring activities give way to the intense data cleaning, data review and reports development phase. This same set of activities will also be carried out in the event that interim analyses need to be performed at predefined time points of the study. This last phase holds major significance as patient data from the study will be extracted, organised, evaluated and formulated in the CSR, in order to provide a comprehensive presentation of the study results. Insight from the medical monitor (MM) is needed at this critical juncture to generate evaluable data, and to structure the data presentation in such a way as to support the assessment of study objectives. The role of the MM in the close-out phase therefore is pivotal, as medical management and guidance in this final stage is imperative in realising the desired goals of the study.

entry in case report form (CRF), last query answered, database lock (DBL), production of data output and, when applicable, closure of sites. The data review activities are intensified to meet the timelines and the methodology of data cleaning and review is followed per the data management plan (DMP) and medical management plan (MMP) established during the study set-up phase. The clinical operations members play an important role in supporting the sites to provide all required data within the CRF, conducting site visits to perform source data verification (SDV) and ensuring that data entry obligations are kept up by the sites. The agreed data listings and patient profiles are generated by data management at the planned data cut-off for clinical database output, generally after the last data entry. The medical review cycle is then started, marked by MM review and query generation by the use of a designated medical query tracker (MQT) that can be circulated within the study team. The number of review cycles depends on the volume and quality of data available at cut-off date. Besides the patient profiles used for in-depth review of individual subject data, aggregate data listings are also utilised. When applicable, the review can also be done

Data Review and Cleaning After data entry cut-off for all subjects in the study, the MM holds the responsibility to review the presented study data for accuracy, consistency and medical logic. The MM plays a vital role in ensuring that all raised medical queries have been adequately addressed and answered satisfactorily by study sites, and that clarifications, where needed, have been provided.

using smart listings that are designed and programmed to capture critical parameters. The smart listing is a customised tool to review specific data sets representing information usually entered in various locations within the CRF such as relevant efficacy, safety or eligibility parameters. This could also be a useful tool to assess consistency and identify any discrepancy between data entered in different electronic platforms. A good example of that would be the randomisation/enrolment data or study drug assignment information entered both in various CRF pages and in the interactive web response system (IRS). Additionally, reconciliation between safety and clinical database is performed, usually by the data manager and the concerned pharmacovigilance (PV)

The timelines for data cleaning and review are agreed between data management, medical and project management teams. This plan should include agreed dates, from the last patient last visit (LPLV) onwards, thereby bringing into line scheduled dates for last data 22 Journal for Clinical Studies

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Regulatory

officer, with any needed medical support provided by the MM. The medical coding of the events and medications are also reviewed by the MM, with reference to the applicable coding conventions. The medical dictionary for regulatory activities (MedDRA) is commonly used for the coding of adverse events and medical history conditions; while the World Health Organization–Anatomical Therapeutic Chemical (WHO-ATC) classification is used for coding the medications. Ambiguous reporting of events or medications is queried and resolved at this stage so that right coding terms are assigned before the safety analyses. Wherever local laboratories are used for the study assessments, the MM provides inputs to harmonise the results across sites during the generation of conversion tables to aid the review. The finalised list of protocol deviations (PDs) is also reviewed by the MM to determine the effect of major deviations on data analysis based on pre-defined study population. When applicable, said deviations are also classified accordingly, to foresee the impact on planned intention-to-treat (ITT) or perprotocol analysis. Narratives Review The date of last data entry is approximately a couple of weeks post-LPLV and the process of narrative writing commences parallel to the data cleaning activities, while the finalisation of case narratives is planned so that they can be included in the CSR. The narrative categories required for the study are first established and then all the cases that fall into the selected criteria are extracted in the narrative listings. The narrative listings, along www.jforcs.com

with clinical and safety databases, serve as the reference source for the writers to draft the initial narratives. The MM reviews the narratives and provides comments or queries based on the review outcome. The queries are handled by the DM and operations in a similar pathway as the medical queries issued following data review. When all the narrative queries have been answered by sites and considered closed, the new or changed information is imbibed into the narratives, thereby generating revised narratives, which can then be finalised after a second medical review. Our recommended approach for narratives review is to establish a three-step process of verification, medical review and quality control (QC). The verification step is to ensure the completeness and correctness by cross-checking narratives contents with the source of information in the clinical and/or safety DB. Medical review is performed to confirm the plausibility and medical logic within the narrative content. Finally, a QC by a second medical reviewer stamps the narrative content for finalisation. In a Phase III study where the volume of case narratives can be high, the workflow needs to be planned in advance so that different sets of narratives are phased out to coincide with the data cleaning timelines and the finalised narratives are delivered before CSR drafting. During these reviews, the scientific integrity of the study data should be the underlying objective to govern the actions to be taken for any observation or discrepancy identified by the MM. Tables, Listings and Figures (TLFs) Once the data cleaning measures have been completed, Journal for Clinical Studies 23


Regulatory the DBL takes place and data is transferred to the statistics team in order to generate TLFs as detailed in the statistical analysis plan (SAP). More often than not, the SAP provides drafts for the TLF shells, which are essential for presenting the study findings in a clear and concise manner, and to best interpret study results. Where available therefore, pre-planned TLF shells will be employed for dry runs by the statistical team. Together with the statisticians, a review of the mock output by MM is thereafter conducted to guarantee its conformity to study objectives and endpoints, and, where required, adapt or create additional TLFs, leading to subsequent approval of the TLF shells. Following the production of the actual data output and its validation by the responsible statistician, the produced TLFs will once again be closely reviewed by the MM. A statistical output comments document may be used by the involved team members to list the review findings by the MM, and the relevant actions taken by the responsible statistician or data manager. A data review meeting (DRM) can be scheduled after review of TLFs to discuss the findings. Where applicable, discrepancies identified will be addressed and the most appropriate course of action will be agreed upon. For minor errors or inconsistencies in the generated output, footnotes might be used in the presentation of the TLFs. It is important to bear in mind, however, that said notes should provide adequate clarifications concerning the issue at hand. Additionally, wherever required, a note to file (NTF) can be documented and referenced to clarify any unclear situations, discrepancies and missing data, among others. Major inconsistencies, on the other hand, present a considerably bigger problem and relevant standard operating procedures (SOPs) or guidelines, when available, should be followed while handling these cases. Major issues will, inevitably, require unlocking of the database for necessary corrections to be made. This is a very crucial step, and needs to be adequately implemented, following laid-down specifications and guidelines in order to maintain data integrity. For the specific issue in question, and when required, the site is responsible for providing needed clarifications or making any necessary corrections. These changes are all tracked and reviewed again by MM to guarantee consistency. Subsequently, the database is locked up again and the TLFs are re-run and analysed if the desired consistency and structure of data sets have been achieved. The MM works closely with the statistician, besides the core team, to finalise the TLFs to allow drafting of the CSR. When applicable, a top line results meeting is scheduled to share available results with the core study and programme management teams to gather inputs on how best the data can be presented within the CSR and/or utilised in subsequent steps of the development programme. Clinical Study Report (CSR) The CSR represents a major milestone in the clinical development programme and is a crucial document for any investigational drug or device. The structure and 24 Journal for Clinical Studies

content of the CSR are dictated by the ICH E3 guideline 1, where it is defined as “an integrated report of a study of any therapeutic, prophylactic or diagnostic agent in which the clinical and statistical description, presentations and analyses are provided in a single report, incorporating tables and figures into the main text of the report and in appendices�. Once the TLFs and narratives have been finalised, the multidisciplinary team comprising, among others, the medical writer, project manager, MM and responsible statistician, follow the established plan with the associated timelines for the development of the CSR. An established CSR template, where available, would be Volume 8 Issue 6


Regulatory contribution of the responsible MM might be required with regard to the publication plan; this may include review for study abstracts, poster presentations for scientific conventions, or a full manuscript for publication in a scientific journal. Closing Remarks Critical inputs are required from the MM during this close-out phase and is demonstrated by the significance of the activities detailed here. Clinical data is the single most pertinent product of a study that serves as the base for the analysis and results interpretation; due diligence therefore is expected during final data review process. Understanding of the design concept, strategic positioning and study objectives and endpoints are essential for performing the MM tasks during this phase. The complexity of clinical trials during drug development is steadily increasing and the MM plays a challenging part in steering the team and the study towards the finish line. Reference 1. ICH E3: Structure and content of Clinical Study Reports http://www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Efficacy/E3/E3_ Guideline.pdf

used by the medical writer to prepare an initial draft of the CSR that is subsequently distributed for review by the various team members. The MM review should take into consideration the objectives of the study while focusing on the efficacy and safety analyses and the conclusions drawn from the respective data. During review, the MM should pay considerable attention to the various sections of the CSR, including the synopsis, that should ideally provide a concise and comprehensive summary of the study and its results. Additionally, all observations and analyses need to be explained in the discussion section, along with the arguments that justify the conclusions derived from the study data. Background information and relevant literature on competitive products should be incorporated to provide a comparative analysis in the discussion, followed by a brief summary of the efficacy and safety findings outlined in the concluding section. In applicable cases, the MM should keep in mind during the review the position of the current study with respect to the study drug development plan so that the study observations are evaluated as per the overall strategy of the programme. When required, a comments review meeting (CRM) is scheduled where the core study team, including the MM, discuss the review findings, agree on resolutions for conflicting review comments and provide guidance to the writer on the final contents of the CSR. Following the availability of the study results, additional www.jforcs.com

Mohamed El Malt, MD, PhD. Chief Medical Consultant, Europital. Oncology surgeon and expert scientific researcher with more than 32 years of experience as a medical doctor, including 18 years of clinical research and drug development experience in academic medical centres, pharma and CRO as investigator, project leader and medical director, in addition to 15 years of experience as general and oncology surgeon. Email: info@europital.com Vijayanand Rajendran, MD. Senior Clinical Research Physician, Europital. Qualified physician with over nine years of clinical and research experience. Handson experience in safety monitoring of Phase I-IV trials in a variety of therapeutic areas including oncology, haematology, gastroenterology and the musculo-skeletal system. Email: info@europital.com Kelechi K. Olu MD, MSc. Physician with strong research interests, Dr. Olu has garnered considerable experience in various aspects of clinical drug development and post-marketing surveillance, and in clinical research at large. As a clinical epidemiologist, Dr. Olu has also worked extensively on several research projects investigating underlying factors that lead to premature discontinuation of approved clinical trials. Email: info@europital.com Journal for Clinical Studies 25


Market Report Clinical Research Association: A Leading Civil Society Organisation in Turkey Introduction As seen in all areas, civil society organisations and initiatives are of key importance in clinical research. In order to translate the ideas and requirements raised by any stakeholder into structured and constructive policy initiatives, societies, non-profitable organisations and associations are actively involved in activities in clinical research around the world. The Society for Clinical Trials (http://www.sctweb.org/public/home.cfm), the Association of Clinical Research Professionals (http:// www.acrpnet.org/), and Develop Innovate Advance (http://www.diaglobal.org/) in the United States, and the Institute of Clinical Research (ICR) in the United Kingdom are some major examples of such civil organisations. In Turkey, a similar organisation, the Clinical Research Association (Klinik Arastirmalar Dernegi – KAD) is the important initiative which deals with the improvement of clinical trials in Turkey. Founded in 2006, the Clinical Research Association is the first and only civil society organisation in Turkey in the human clinical research field, which is open to all clinical trials professionals from all stakeholders. It is a not-forprofit organisation, guided by a Board of Directors who are elected by the membership and are based at its head office in Ankara, the capital city of Turkey. The association assembles the pharma industry, academy, regulatory authorities, clinical research organisations, other academic and civil associations and all professionals involved in this area 1. The board is made up of three academicians, two CRO executives, one SME (subject matter expert), and one pharmaceutical company clinical research director. The idea of building up the KAD came from the multidisciplinary contribution to improving clinical trials in specific areas, some of which are listed below: • • • •

• • • • •

Alignment of all stakeholders in the country in regard to the regulatory and operational aspects Coming together, sharing experience, discussing the areas of improvement, generation of action plans Enhancing clinical research quality standards with appropriate training and conferences Providing a web portal and website as a common place for reference information for local and international members Enabling communication between all involved parties National and international networking and learning from others Increasing public awareness of clinical trials Optimising the predictability of the clinical research regulatory timelines Increasing the attractiveness of the country and

26 Journal for Clinical Studies

region for clinical trials, comparable with EU countries Contributing to local innovative medicinal products research and development in Turkey

Members are involved in the regulating, controlling, designing, management and conduct of industry sponsored or academic clinical trials on humans, and they are engaged directly and/or indirectly in all aspects of work in clinical research. The mission of the association is to contribute to the conduct of clinical trials in Turkey to the highest international standards, and to organise comprehensive educational supportive activities to reach this goal, and the vision is to bring the academy, industry and regulatory authorities together. The aim of this paper is to provide detailed information about the Clinical Research Association’s structure and activities, and the value it has been adding to the clinical research area and the future perspective in the light of clinical research milestones in Turkey. 1 Membership and Board The KAD has regular Board of Directors meetings to determine and prioritise the activities. Since it was founded in 2006, there have been regular board meetings taking place to enhance the quality and the number of clinical trials conducted in Turkey. The number of KAD members which are individuals rather than organisations, as per the association charter, has increased throughout the years. The details of membership profiles are demonstrated in Figure 1 and Figure 2, including the distribution and the origin of the members. As seen in the membership profile, KAD has a multidisciplinary and heterogeneous population of members which in turn supports the information exchange, networking, sharing experiences and discussion of ways to make it smoother for clinical research in the country from different insights. Among the members

Figure 1 Volume 8 Issue 6


Corporate Profile

CO Research

Perfect Partner For You In Turkey Local And Global Solutions For Clinical Research Turkey has a great potential in medical research with GCP experienced physicians and large patient populations. CO Research is a full-service contract research organisation and perfect partner for you in Turkey. CO Research was established by Çiğdem Çizenel and Özlem Sabancılar in 2015 with 15 years of experience in clinical research, CO Research providing high quality services in line with ICH GCP and ethical rules. CO Research provides services pharmaceutical, medical device and cosmetic industries with high quality clinical services as well as providing guidance, support or full turnkey solutions in research, training and outsourcing. We provide tailor-made solutions to your projects. CO Research offers a complete range of services with personalized attention and flexibility. Through close cooperation and continuous dialogue with customers, our services can be customized according to your requirements. CO Research has a wide staff network in many different cities in Turkey and it provides cost effectiveness and quick solutions for client's requiretments. CO Research offer following services; • Clinical Research • Site Management Organization • Biostatistics and Data Management • Medical Writing • Regulatory Management • Training Clinical Research We have extensive experience in many therapeutic areas such as oncology, cardiology, haematology, Infectious disease, diabetes, Ophthalmology and different industries such as pharmaceutical, medical device and cosmetic industries. We offer the following services for your clinical trials; • Feasibility Assessments • Site and investigator selection • Clinical Monitoring (Phase I-III, Late Phase) • Project Management • Interactive Response Technologies (IXRS) • Patient Recruitment • Newsletter • BE/BA Studies • Audit/Compliance www.jforcs.com

Site Management Organization CO Research provides partnering with medical professionals in promoting and conducting clinical trials ethically, efficiently and systematically. The success to your project depends excellent team support, organisational skills, scientific knowledge and communication skills. CO Research with wide ranging professional site staff in many different cities in Turkey has access to a network of investigators/specialists to manage your multi-centric clinical trials in different therapeutic areas. Biostatistics and Data Management CO Research is specialized in providing high quality service related to the management and analysis of data generated during clinical trials. Following activities are conducted by our experienced specialists. • • • • • • • • • • • •

Electronic case report form (eCRF) design, database design and study setup CRF Completion Guidelines Clinical coding with industry standards and clientspecific dictionaries Reconciliation of safety and external data Data validation and query management Project management of data and technical services Data Management Plan (DMP), Statistical analysis plan (SAP) development Database Build & Design Data processing through double data entry Sample size calculation Randomization Statistical analysis and reporting

Medical Writing • CO Research provides following services with our experienced medical authors. • Clinical study report • Study protocols, amendments, and administrative changes • Abstracts, Article • Training material • Poster CONTACT INFORMATION Web site: www.co-research.com Contact: info@co-research.com Tel: +90 216 969 40 06 Fax: +90 216 850 317 73 55 Istanbul, Turkey Journal for Clinical Studies 27


Market Report • • • • •

there are professionals from an academic environment from medical, dentistry, and law, professionals from the pharma industry (pharma companies, contract research organisations and direct vendors), members of ethics committees and professionals from the Turkish Health Authority (Turkish Medicines and Medical Devices Agency - TMMDA - under the Turkish Ministry of Health). The Board of Directors, some of whom are co-authors of this paper, are also from academia and industry, and regularly interact with the regulatory authorities, ethics committee members, key opinion leaders, and other civil society organisations. 2 Activities Over ‘Three Cs’: Cooperation, Collaboration, Communication Prioritising the enhancement of cooperation and collaboration amongst the clinical research stakeholders, facilitating smooth and clear communication, and targeting local clinical trial activities to contribute to harmonising country and global principles, KAD has been involved in several activities and initiatives. KAD sees that the ‘Three Cs’ are the key elements of the adoption of the innovation in global clinical research and development into local expertise and know-how. 2.1 Web Portal as a Milieu for Information Exchange: Internet use is a fundamental part of modern society. Web portals for different target user profiles and different aims have been used increasingly over the last decade. A web portal is a website or service that offers a broad array of resources and services, such as e-mail, forums, search engines, and on-line shopping malls. In recent years, many health portals have emerged which offer services to lay people or health professionals. The use of the portals was also reported in medical literature 2. The portals may be designed for assisting patients 3 or providing organised resources for professionals 4, 5, 6. Recognising this interesting and powerful modern life tool, KAD began to provide its web-user members with the association’s official web portal (klinikaraştırmalar. org.tr), regardless of whether they are official members of the association or not. KAD also has a web portal for English-speaking members (www.klinikarastirmalar.org/ en). The web portals have been: 28 Journal for Clinical Studies

offering real-time regulatory updates from the country and from all over the world hosting a repository for the regulatory reference documents announcing and/or organising conferences, congresses, seminars offering a forum environment for discussions linking with the clinicaltrials.gov website’s Turkeyspecific data.

News is offered from the country and all over the world in regard to regulatory changes, recent updates, and any publication or written opinion that contributes to increasing quality on an ongoing basis. The news sharing started in the KAD website very early, right after the establishment of the association, and supported the spread of information across the country. In Figure 3, the numbers of news items shared per year between 2006 and 2015, and the origin of these items, are illustrated. The released news and alert information lines reached a peak in 2008-2009, and during 2013 and 2015. These dates are the ones when regulatory changes occurred.

Figure 3

Between 2008 and 2009, among enormous interest from and effort by the Turkish Regulatory Authority, the EU Clinical Trials Directive principles were adapted within the Turkish Clinical Research Regulation with Regulation number 27089 dated 23 December 2008, published in the Official Gazette 7. As in this regulation, the regionally established MOH-accredited central ethics committee (EC) concept is accepted, all local ECs were closed and the regional central ECs started to work. Timelines and transition periods were well defined by the MOH to facilitate the change and minimise any risk arising from the change; however, this was followed by some other regulatory challenges which are elaborated in another article published recently 8. Currently, clinical trials with human subjects using investigational medicinal products are initiated, conducted, ruled and controlled under the valid regulation dated 13 April 2013, which was revised on 25 June 2014 and 13 September 2015, in compliance with agreed international acts, EU standards and the Good Clinical Practice rules as confirmed in Article 1 of the regulation. Both documents are available for reference in the MOH web page [www.titck.gov.tr]. The health authority continuously requests official opinion and comments on the clinical trials’ specific regulatory process documents, including the regulation amendments and guidelines set up from the stakeholders, which the Ministry of Health recognises as respectful collocutors. Volume 8 Issue 6


Market Report KAD is one of these collocutors as it is recognised as a main stakeholder of the clinical trial industry. The Clinical Trials Regulation dated 2013 and its amendments from 2014 and 2015 are the major documents that can be given as examples for the regulatory document which KAD contributed with association opinions. Releasing the news and alerts, KAD took the web portal communication as an opportunity to share recent updates across the country, and being read by all stakeholders contributed to minimising the regulatory risk that might have arisen from the regulatory changes. Data about the news and alerts is recorded and kept perpetually in a database which is maintained by an IT company (Pleksus IT, Ankara, Turkey), and the personal data of the users is not shared with the sponsor companies or any third parties. By the end of May 2016, there are 4397 members registered to the KAD web page, and 431 of them are registered to the English webpage. 2.2 Congresses and Conferences Organised and Hosted Clinical trials have been conducted in Turkey since 1993 with the first clinical trials regulation having been issued. Growing the number of clinical trials and the interest of the regulators and stakeholders enabled the European Union-compliant Clinical Research Regulation to come into force as of December 2008 8. One of the most inspiring events KAD organised is the First National Clinical Research Congress, with international participation by speakers and attendees. This event was held on 2-4 May 2013 in Istanbul. The Congress, being the first scientific congress on clinical trials, gathered all stakeholders from all over the country, enabled verbal and poster presentations, and served as an open venue for specific and fruitful panel discussions. There were 37 verbal, and 61 poster presentations shared during this event. The presentations’ topics varied, including almost all aspects of the clinical trials, including but not limited to biosimilar products, medical herbal products, medical cosmetic, medical devices, investigational medicinal products research, and development opinions and review papers 9. It is worth noting that KAD prepared the ‘Very Firsts in Clinical Trials Area – Achievement Flow’ and this was also appreciated by all congress participants (Table 1). This Achievement Flow was a sort of time-machine, demonstrating the evolution of the clinical trials industry in the country and the leaders inspiring and driving the evolution. With high interest from the clinical research professionals, the Second National Clinical Trial Congress followed the first Congress two years later, taking place on 27-28 March 2015 in Istanbul, with 24 verbal and 39 poster presentations. During the meeting, the presentations were evaluated and accepted by the organisation committee per the main discussion points 29 Journal for Clinical Studies

such as logistics, quality, data handling, operational challenges, regulatory highlights, medical device and biosimilar drug studies, and cosmetic and herbal clinical trials, as well as the social, legal and ethical considerations 10. The board members of the KAD participated in the Clinical Research Workshop organised in February 2015 by the Turkish Ministry of Health and the Medicines and Medical Devices Agency as invited panel speakers. The KAD members participated in the discussions and brainstorming sessions, and recommendations were compiled in different panel desks. All outcomes of this workshop were published in a workshop report, and professional opinions and suggestions by the regulatory decision-makers in Turkey were taken 11. For the first time in Turkey in the clinical research area, KAD organised and hosted the open-access webbased live panel meeting called ‘Ethics Committees Are Inquiring’ on 4 April 2016. The meeting was moderated by the KAD Chairperson, Prof. Dr Hamdi Akan, with accompanying conference speakers from the Turkish Ministry of Health, and the Ethics Committee Chairperson and members. A total of 207 participants attended the meeting interactively, asking specific questions and getting relevant advice from the speakers. Open live sessions let all the parties involved in clinical research freely and directly communicate with the regulatory authority and ethics committee delegate to determine the way to proceed in the studies. 2.3 Book and Publication Contributions Being dedicated to adding value to the clinical research environment in Turkey, KAD board members contributed to a number of books in Turkish published in different years. Some of these are: a. Clinical Trials Book, Bilimsel Tip Yayinevi, by Hamdi Akan, Hilal Ilbars, Nursah Cetinkaya b. Good Clinical Practice Handbook, 2015, Bilimsel Tip Yayinevi, Clinical Research Association c. Clinical Trials Dictionary, Bilimsel Tip Yayinevi, by Hilal Ilbars d. Good Presentation Skills Book, 2014, Bilimsel Tip Yayinevi, edited by Hamdi Akan e. Clinical Trials Methodology and Design Book, 2016, Bilimsel Tip Yayinevi, edited by Hamdi Akan Since being published, these books were represented as reference sources for all stakeholders with different roles and origins. KAD board members also prepared the articles on specific research and development considerations and regulatory highlights which were published in several journals. Interest in the publications has been remarkably high, as proven by the citation of these in other papers, and their use as references for several conferences with the data included in 7, 12, 13.

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Clinical Research Association:

Market Report A Leading Civil Society Organisation in Turkey Table 1: Firsts in Clinical Trials in Turkey– Achievement Flow Achievement 1st Bylaw (Regulation) on Clinical Trials 1st Central Ethics Committee (EC) 1st Good Clinical Practice Guideline 1st RA Approval of a Clinical Trial 1st Contract Research Organisation 1st Good Clinical Practice Training 1st Bioanalytical Center 1st Bioequivalence and Bioavailability Clinical Trials Center 1st Journal 1st FDA Clinical Site Inspection 1st FDA Inspected/Accredited EC 1st Regulatory Authority Drug Safety and Pharmacovigilance Office 1st Civil Society 1st EMA bioavailability and bioequivalence center inspection 1st International Good Clinical Practice Training 1st EMA Clinical Site Inspection 1st Book 1st CRO Association 1st Regulatory Authority Clinical Trials Infrastructure 1st RA Accredited Phase I Center 1st Government Regulatory Authority Agency 1st Dictionary 1st Congress on Clinical Trials 1st Advanced GCP Course

Information Released by Turkish Regulatory Authority (RA) (number 21480)

Year 1993

Established by the approval of Turkish RA Released by Turkish Regulatory Authority Omega CRO Course on Clinical Trials in Psychiatry Novagenix Erciyes University Hakan Cetinsaya GCP Center

1993 1995 1995 1997 1998 2000 2000

IKU (Journal of GCP) Ege University Medical Faculty, Department of Gastroenterology Ankara University Medical Faculty Ethics Committee Turkey Pharmacovigilance Center

2001 2004 2004 2005

Clinical Trials Association Erciyes University Hakan Cetinsaya GCP Center

2006

Organized by Sanofi, Akademika

2008

Ege University Medical Faculty, Department of Surgery Clinical Trials Book, Prof Hamdi Akan, SAKDER (Contract Research Organization Association) Department of Clinical Trials and Drug Safety under Turkish Ministry of Health, General Directorate of Drug and Pharmaceuticals Ege University Drug Development and Pharmacokinetics Research and Application Center Turkish Medicines and Medical Devices Agency

2009 2009 2009 2009

Clinical Trials Dictionary, Dr Pharm. Hilal Ilbars, PHD 1st National Clinical Research Congress In the context of the 1st National Clinical Trials Congress

2013 2013 2013

2012 2012

Table 1: Firsts in Clinical Trials in Turkey– Achievement Flow

2.4 Surveys materials and the standards given are mainly based on Table 2: Meetings organised by KAD Surveys were performedfacilitated prior to and planned activities in the Helsinki Declaration and ICH-GCP, but also as per KAD. The first survey in 2014 was organised for ethics the specific guideline on organising and managing the Date members to Meeting Locationby the Turkish committee understand whether online training courses on clinical trials released 11 May 2007 Interpretation of Budget and Insurance Processes in Clinical Trials Ankara training is favourable. After the results were gathered, Regulatory Agency. 17 Nov 2007 Meeting for Evaluation of Development Processes in Clinical Trials Istanbul the KADUZEM online training module was of prepared 2009 Clinical Trials: The Story Last Year, Updated Regulation and Future Insights Ankara and released for2009 use. TheKAD-ECRIN second survey was about an KAD represented Turkey in the Bioconvention meeting 13-14 March Joint Meeting Istanbul online3-4 live Q&A ethics committee members, May 2013session for 1st National Clinical Research Congress in the United States in 2014, and during Istanbulthe convention, with representatives from Good the authority. The interest wasTraining distributed the brochure that was approved by the Turkish 13 Jan 2015 Clinical Practice Fundamental Izmir 25 Febwith 2015 survey results Training for the Ethicsonline Committees Kayserithe networking confirmed and live Q&A MOH. It was a great opportunity to enable 27-28 2015 2nd National Clinical Research Congress in a large event with all participating Istanbul countries and session wasMarch organised. 4 April 2016 Online live broadcast ‘Ethics Committees Q&A to Authority and EC Ankara companies. Representative’ 2.5 Facilitating Ongoing Training Sessions KADUZEM is an online asynchronous webcast-based GCP 2.6 Transparency Issues education programme approved by the Ministry of Health. KAD cooperated with www.clinicaltrials.gov to post all The programme consists of basic, advanced and clinical the clinical trial activities in Turkey on the association research nurse GCP education modules. By the end of webpage using the interface in Turkish Page(http://www. 9 of 9 May Clinical 2016, 400 participants had joined thisCivil programme. clinicaltrials-tr.org). Research Association: A Leading Society Organization in Turkey There have been other training and educational meetings facilitated and organised by KAD. For the list of these KAD is the first active supporter of the AllTrials clinical meetings, please refer to Table 2. The ongoing educational trials transparency initiative in Turkey (www.alltrials.net) support is one of the most important initiatives taken by and the voice of AllTrials activities in Turkey is via the KAD to make sure the regulatory risk is minimised and association’s webpage. the current legal framework is correctly interpreted by the stakeholders country-wide. Detailed analysis and outcome 3 Future Perspective and Last Words of the educational and training activities of KAD will be According to the analysis ‘Challenges and Opportunities the subject of another review article. The educational for Clinical Research in the Middle East’ 14, amongst the 30 Journal for Clinical Studies

Volume 8 Issue 6


1st Civil Society 1st EMA bioavailability and bioequivalence center inspection 1st International Good Clinical Practice Training 1st EMA Clinical Site Inspection 1st Book 1st CRO Association 1st Regulatory Authority Clinical Trials Infrastructure 1st RA Accredited Phase I Center 1st Government Regulatory Authority Agency 1st Dictionary 1st Congress on Clinical Trials 1st Advanced GCP Course

Clinical Trials Association Erciyes University Hakan Cetinsaya GCP Center

2006

Organized by Sanofi, Akademika

2008

Ege University Medical Faculty, Department of Surgery Clinical Trials Book, Prof Hamdi Akan, SAKDER (Contract Research Organization Association) Department of Clinical Trials and Drug Safety under Turkish Ministry of Health, General Directorate of Drug and Pharmaceuticals Ege University Drug Development and Pharmacokinetics Research and Application Center Turkish Medicines and Medical Devices Agency

2009 2009 2009 2009 2012 2012

factors having an Clinical impact on the country’s attractiveness, Trials Dictionary, Dr Pharm. Hilal Ilbars, PHD 2013 1 National Clinical Research Congress 2013 two very important ones In the context ofdominate: the 1 National Clinical Trials Congress 2013 st

st

Table 2: Meetings facilitated and organised by KAD Date 11 May 2007 17 Nov 2007 2009 13-14 March 2009 3-4 May 2013 13 Jan 2015 25 Feb 2015 27-28 March 2015 4 April 2016

Meeting Interpretation of Budget and Insurance Processes in Clinical Trials Meeting for Evaluation of Development Processes in Clinical Trials Clinical Trials: The Story of Last Year, Updated Regulation and Future Insights KAD-ECRIN Joint Meeting 1st National Clinical Research Congress Good Clinical Practice Fundamental Training Training for Ethics Committees 2nd National Clinical Research Congress Online live broadcast ‘Ethics Committees Q&A to Authority and EC Representative’

Market Report

Location Ankara Istanbul Ankara Istanbul Istanbul Izmir Kayseri Istanbul Ankara

opportunities provided, and remarkable efforts of the members, KAD represents a unique, pioneering, and leading civil society organisation in Turkey.   References 1. KAD Association Charter, available on klinikarastirmalar.org.tr 2. Pankaskie M, Sullivan J. Health care web portals. J Am Pharm Assoc (Wash). 2000; 40: 117-8. 3.

Page 9 of 9 Relevant expertise (number of clinical research organisations, number of clinical trials, size and 4. availability of labour force and relevant skills) (15%) and 5. Infrastructure and environment (protection of intellectual property, level of healthcare and country 6. infrastructure, country risk factors) (15%) 14.

Clinical Research Association: A Leading Civil Society Organization in Turkey

7.

The rapid and robust prosperity of clinical research will be possible by addressing the above-mentioned specific areas for improvement by all stakeholders, including the regulatory authority, academy, research institutes, associations and the pharmaceutical industry. In order to achieve this common goal, KAD keeps providing institutional opinions and ideas, upon request of the Turkish Health Authority, for setting up and improving the local regulatory processes of clinical trial conduct. Also, KAD is continuously engaging in efforts to increase communication, collaboration and cooperation amongst all parties with the publicly open scientific, social, and ethical platforms.

8.

Clinical Trials Journey of Turkey-Long and Thin Road, Ilbars, et al. J Clin Trials 2015, 5:2

9.

1. Ulusal Klinik Arastirmalar Kongresi Bildiri Kitabı, Klinik Arastirmalar Dernegi, (Abstract Book, 1st National Clinical Research Congress) 2013 2. Ulusal Klinik Arastirmalar Kongresi Bildiri Kitabı, Klinik Arastirmalar Dernegi, (Abstract Book, 1st National Clinical Research Congress) 2015 Klinik Araştırmalar Calistayi (Clinical Research Workshop) Calistay Raporu (Workshop Report), 2015, Turkish Medicines and Medical Devices Agency, Hilal Ilbars, Gokhan Ozkan. Ilbars H, Irmak DK, Akan H. Orphan Drugs: R&D Challenges with Updates from Turkey and Middle East Countries, Journal for Clinical Studies, Vol 6 Issue 2 Transparency in Clinical Trials, Nursah Omeroglu, Applied Clinical Research, Clinical Trials & Regulatory Affairs, 2015, Vol. 2, No. 2 Yoruk S, Tetik E. Challenges and opportunities for clinical research in the Middle East, Applied Clinical Research, Clinical Trials & Regulatory Affairs, 2014, 1, 83-87 

10. 11. 12. 13. 14.

It is worth mentioning that with the valuable contribution of KAD, there has come the alignment of all stakeholders in the country, creatively planning and organising relevant meetings for all to come together and have a free and unbiased interaction environment. These, in turn, are seen as impacting on the following: •

Information and experience sharing to minimise the regulatory non-compliance risk in clinical trial conduct, via contributing to the set-up of the regulatory guidance documents Continuous training on the current and new rules and meeting organisations to maximise the relevant country expertise and to improve the infrastructure Optimising the predictability of the regulatory timelines.

All together, these represent the important activities for evolution and enhancement of relevant expertise, and enabling the driving of the best clinical research infrastructure set-up, as well as providing an important contribution to the journey of Turkey’s clinical trials’ successful harmonisation with the global principles of clinical trials. With its establishment, ideas created, venues and www.jforcs.com

Do N, Marinkovich A, Koisch J, Wheeler G. Electronic access to care system: improving patient’s access to clinical information through an Interactive Voice Response (IVR) system and Web portal. AMIA Annu Symp Proc. 2003; 830.; Wald JS, Bates DW, Middleton B. A Patient-controlled Journal for an Electronic Medical Record: Issues and Challenges. Medinfo. 2004; 2004: 1166-72. Aymard S, Falco L, Dufour JC, Joubert M, Fieschi M. Modeling and implementing a health information provider on the Internet. Stud Health Technol Inform. 2003; 95: 89-94. Crass T, Antes I, et al. The Helmholtz Network for Bioinformatics: an integrative web portal for bioinformatics resources. Bioinformatics. 2004; 20: 268-70. Cognetti G, Cecere L. E-oncology and health portals: instructions and standards for the evaluation, production organisation and use. J Exp Clin Cancer Res. 2003; 22: 677-86.]. Turkish Clinical trials Regulation dated 23 December 2008 with number 27089

Duygu Koyuncu Irmak,PhD, Associate Director in INC Research Turkey Email: duygu.irmak@incresearch.com

Nursah Cetinkaya, Founding Partner at NER Medical Research Consulting Kubra Ebru Taskent, Director in ICON Clinical Research Turkey Aydin Erenmemisoglu, Prof, Erciyes University Medical Faculty Betul Erdogan, Director, Merck Turkey Ismail Hakki Ayhan, Prof, Ankara University Medical Faculty Hamdi Akan, Prof, Ankara University Medical Faculty Journal for Clinical Studies 31


Market Report

How Emerging Companies Can Make Being Small a Strategic Advantage Small to mid-sized (aka “emerging”) firms bring fewer resources to bear on the same drug development problems as large pharmaceutical companies. All developers face rising regulatory requirements, Phase III clinical trial failure rates that are north of 50 per cent, proliferating reimbursement and market access hurdles, a low probability of success and a declining return on investment (ROI) for R&D. But, on top of these common challenges and risks, emerging companies face unique pressures. They have relatively smaller financial reservoirs (so they need their ROI to come faster). They rely on funding from increasingly skeptical and sophisticated investors who are conducting more rigorous due diligence than in the past, and are turning to outcomes-based financing models (i.e., if you don’t hit development milestones, you don’t get the promised funding). Often, gaps in capacity and/or expertise (relative to big companies) hamper their ability to translate good science into proof of concept (POC). Nowadays, whether an emerging developer is actively seeking a corporate buyer, a licensee, or a partner for a given product, or is hoping to pursue regulatory approval on its own, it must achieve POC at the earliest possible development stage. And POC today requires more clinical and market data than ever before due to cost-constrained healthcare budgets worldwide, and powerful market gatekeepers, such as health technology assessment (HTA) agencies. Furthermore, viable early-stage products now need common technical documents (CTDs), and a target product profile (TPP), with validated endpoints, to justify investment. It’s already hard being an emerging pharmaceuticals firm, and it’s not getting easier. A Narrower Margin for Error, Plus More Pressure to Produce No company, large or small, new or old, can afford to advance borderline drugs, but emerging companies have a narrower margin for error than their mammoth counterparts. Because smaller companies begin with fewer financial, technological and scientific resources, they must husband what they have if they are to survive. Unfortunately, the pressure to produce can force errors. Common emerging company mistakes include advancing a drug despite borderline data because: • • •

The company needs to impress investors (this backfires when the drug fails) There is nothing else in the pipeline (that is, it is a single-product or single-technology enterprise) The company is spellbound by the science (whether or not a drug has a realistic chance of succeeding

32 Journal for Clinical Studies

in the market) The technological resources are just not there to make better decisions.

For example, with pharmacogenomics tools, a validated biomarker, and a defined subpopulation, researchers can determine whether the efficacy (and/or the biologic activity) signals coming from a clinical trial are powerful or weak. Pharmacogenomics data enables a more robust assessment by a developer’s decisionmakers. Unfortunately, smaller companies may not have access to the tool. If their access to technology, expertise, and experience is limited, emerging companies will have difficulty making the right advancement decisions. Turn Your Size into a Strategic Advantage Despite these challenges, emerging companies can succeed by concentrating on science, filling in expertise or resource gaps when needed and pivoting agilely – all tactics that may be harder for their big pharma counterparts to execute. For example: •

• • •

An intense scientific focus may actually make it easier to acknowledge expertise gaps in other realms and seek out external expertise on regulatory and market access considerations; Smaller size promotes agility, making it easier to act on advice from regulators more quickly; Limited resources can encourage streamlined development work; A shorter track record means outdated or ingrained workflows and processes have had less time to take root.

At PAREXEL, we advise our small to mid-sized clients that the path to success involves taking three big steps toward smarter go/no-go decisions: 1. Assess before you invest 2. Right-size your data package 3. Prune your protocols Assess Before You Invest Emerging companies with constrained resources may be tempted to skimp on investing in a comprehensive market landscape assessment. That’s a mistake. Money spent to thoroughly analyse the market potential of a product candidate is a fraction of the total drug development cost. For example, out of an overall budget of $700 million, analyses to define the markets, risk factors and probability of success for a compound are about $1-2 million, or between one and two per cent. A competitive landscape evaluation will provide a roadmap to regulatory approval for a drug candidate, Volume 8 Issue 6


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Market Report and should answer the following questions: • • •

• • •

What does the market access and reimbursement future look like for this drug? What level of real-world evidence (RWE) will be needed, and when? What is the overall probability of success in this therapeutic area (for example, cancer vs. autoimmune disease) or technology (monoclonal antibody vs. synthetic)? Can we use adaptive trial designs to streamline development and get to “no” faster? Will there be clinical trial drug supply issues (stability, purity, distribution)? What technologies and logistic capabilities will be needed, and do we buy or build them?

Companies, especially smaller ones, need to pick the right initial indications based on the competitive landscape, and go after those with the greatest potential. Failure to accurately assess the landscape means piling on unnecessary risk to an already risky business. For example, a respiratory drug was recently approved in France but did not win reimbursement from the country’s National Agency for the Safety of Medicine and Health Products (ANSM) because there was a more cost-effective drug already on the market. If the drug’s sponsor had examined the available evidence on the existing product, they could have anticipated this outcome. Their failure to map out a market access strategy, and build a product value story that had a realistic chance of penetrating such an important market in the chosen indication, cost it dearly. Right-size Your Data Package Drugs today need a large and comprehensive data package to tell a value story to multiple stakeholders. But companies can also err by generating too much data. An evidence generation plan needs to be prudent and fit for the purpose (a thorough assessment helps achieve that). Emerging companies need a package that is not overwhelming, but will contain data that demonstrates sufficient clinical activity, meets regulatory requirements, supports the potential for reimbursement and makes investors confident. At PAREXEL, we have worked with several small to mid-sized clients to alter their data collection plans – sometimes by increasing, sometimes by decreasing the number of data points collected. In some cases, suggesting changes to clinical trial protocols may end up boosting upcoming rounds of financing. Too many companies find they have a lot of data, but too little of it is critical. A constrained budget can actually be an advantage if emerging companies use the need to control costs as a driver for more efficient, less wasteful development decisions. 34 Journal for Clinical Studies

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Market Report surveillance and analysis of data (versus waiting until the end of a trial to find out what happened), which in turn supports data-driven (and less risky) advancement decisions. However, ATDs also impose great demands. Investigative sites must have the personnel, equipment, and technology to handle the increased burden of blinding requirements, and principal investigators and physicians must be knowledgeable in, and comfortable with the ATD approach. Designing and conducting adaptive trials also requires increased dialogue with regulators throughout development.

Prune Your Protocols Smaller companies often take a copy-and-paste approach to clinical trial protocols, resulting in bulky, expensive trials stuffed with just-in-case endpoints. It’s better to spend time and money pruning a trial design to make it fit for purpose rather than attempting to save time by recycling a protocol with extraneous data collection. A streamlined clinical trial has the minimal rational number of endpoints that will support your strategy – no more, no less. Protocol optimisation is key. Off-the-shelf protocols with more than 30 secondary endpoints in one clinical trial are not unheard of. Each additional endpoint in a trial requires procedures, monitoring, and data collection, adding enormous time and cost, all because the company thought it could save money by recycling a protocol. Instead, companies should select: • • •

A limited number of primary endpoints A tightly relevant subset of secondary endpoints – not dozens, but 5-10 at a maximum Precise patient-reported outcomes (PROs), with clarity on what is collected and why

Adaptive trial designs (ATDs) to allow more flexibility and to facilitate more informed go/no-go decisions were initially resisted by regulatory agencies (due to concerns about the validity of results), but are now gaining traction as the agencies warm to them. With proper safeguards to ensure statistical integrity and adequate blinding, ATDs can streamline development. If appropriate, ATDs are an excellent tool for emerging companies in particular as they allow for real-time www.jforcs.com

It’s Not So Bad Being Small Because smaller companies are not slaves to tradition, and have not therefore developed rigid organisational cultures, it may be easier for them to listen and learn, abilities that confer an advantage in today’s increasingly interactive healthcare market. “Knowing what they don’t now” can foster a willingness to partner that can help them fill in gaps and boost their chances for success. It’s often much harder for large companies to partner, especially with a genuine spirit of give-and-take. That said, small companies must not be reluctant to invest in a comprehensive landscape assessment before they invest in a new product (it will be the best money they will ever spend, and it’s a relative bargain). It’s not bad being small if you’re knowledgeable and careful. If you’re not, you may be in for a rough ride.

Ubavka DeNoble, MD, Corporate Vice President, PAREXEL In her role as Corporate Vice President, Phase II/III, Key Accounts, Dr. DeNoble is responsible for the global management of the PAREXEL phase II/III business as well as overseeing the quality, delivery and client satisfaction on key accounts. Dr. DeNoble works with her team to identify client needs and develop solutions for projects, leveraging expertise, operational capabilities and technologies. She also identifies new business opportunities and help tailor appropriate strategy. Prior to joining PAREXEL, Dr. DeNoble was the Senior Vice President, Global Project Management at I3, a therapeutically specialized CRO. Previously, she held several senior executive positions at Kendle, Charles River Laboratories and Inveresk Research Group. Dr. DeNoble earned her M.D. at University of Sarajevo Medical School and completed a residency in internal medicine at Naval Hospital Split, Military Academy, Belgrade, Yugoslavia. She is board-certified in internal medicine. Email: ubavka.denoble@parexel.com Journal for Clinical Studies 35


Market Report

Boldly Going Where Few Have Gone Before: Key Considerations for ‘Siteless’ Clinical Trials Advancements in technology are impacting many aspects of clinical research, opening doors to innovative study designs and clinical operations that may not have been possible even five years ago. This is especially true when evaluating the potential of emerging technology for home-based assessments as a component of observational or interventional research. In this article, we’ll explore the implications of ‘siteless’ clinical trials for patients and researchers, the range of potential clinical assessments within these studies, and key considerations for exploiting this emerging opportunity. Siteless Clinical Trials A siteless clinical trial (also referred to as a remote trial or a virtual trial) is the concept of designing a clinical trial that uses site visits in combination with mHealth or digital technological capabilities to enable patients to complete assessments that would traditionally occur within a clinic 1. This convenience is particularly relevant for patients with conditions characterised by significant morbidity in which access to centres of excellence is impaired and it brings benefits for sponsors, including enhanced patient interest, reduced dropout rates, environmentally relevant outcomes and reduced study visit costs. Clinical Assessments in Siteless Studies There is a rich mosaic of potential clinical assessments contingent upon indication, phase of research, and the intended study objective. Devices such as smartphones and wearable technologies particularly have piqued the industry’s interest in a siteless approach to research due to their capability to offer continuous monitoring for physiological parameters such as activity, electrocardiography, electroencephalography, blood pressure, glucose, sleep quality, diurnal variation in fatigue, and other modalities. Additionally, the accelerated use of electronic medical records has created the potential for linkages between diverse sources of information that could help populate a clinical trials database. For example, the High-STEACS trial has no trial-specific data collection visits and illustrates the potential of this approach 2. The MI-FREE study in contrast employs a healthcare database to follow participants longitudinally with outcomes that are determined through an algorithm 3. However, the shift towards home-based trials is about more than just putting a device into the hands of patients and linking data across platforms. Today, typical studies have 5 to 15 safety and efficacy assessments within a given protocol. While home-based studies may refine and reduce some of these assessments, ultimately, there will still be a number of safety and efficacy assessments required from multiple perspectives in the vast majority 36 Journal for Clinical Studies

of trials. A hybrid approach incorporating site- and homebased assessments seems more likely. The impetus for home-based measures is particularly acute with patient-reported outcomes (PRO) which have been the most compatible for developing protocols for home-based assessments. As noted by Gnanasakthy et al. in 2012 4, the FDA is now accepting PRO data for secondary claims associated with safety, but also as primary efficacy points associated with a PRO. Currently pain assessments are the most common, closely followed by assessments of mood, behaviour, and function particularly within neurological/psychiatric indications, although virtually every therapeutic area is amenable to this consideration. While growth in PRO assessments will be the easiest to incorporate in home-based protocols, biomarker or surrogate endpoints derived from some of these devices may also be considered. Limitations would need to acknowledge the sentiments of both regulatory authorities as well as clinicians who require companion endpoints related to functional, behavioural or symptomatic effects. Put simply, not all endpoints are amenable to capture through a wearable, digital device or electronic diary. Correspondingly, trials will still need to heavily rely on an element of clinic-based, clinical reported outcomes (ClinRO) as well. PRO Considerations for Siteless Trials There are multiple versions of PROs available, each with differing endpoints and specifications for use. The selected PRO has to be fit for use for the specific underlying disease or indication. In addition to including appropriate clinical constructs, linguistically and culturally validated translations for every geography in which it will be used are required. Statistical considerations become prominent due to the multiplicity of assessments, as continuous monitoring may change some of the statistical aspects of the sampling process. Study teams also have to be mindful of the quality of PROs, ensuring that there is an appropriate recall period, with provisions available to address missing assessments. Self-reported data by definition are subject to delays in availability and incompleteness as well as possible distortions due to the influence of social media exchanges. The use of paper-based assessments versus ePRO provides another dimension for consideration. While it is easy to assume that electronic methods would be the obvious choice, moderating variables include the nature of the indication, demographics, geographies in which ePROs are introduced, and the extent of training required to assure adherence to guidelines for specific assessments. While there is some conflict in opinion, it can be said that the frequency of assessments as well as Volume 8 Issue 6


Market Report length and complexity are a significant factor dictating ePRO selection, along with the hierarchy of these measures as primary or secondary endpoints within a proposed study.

in study design as well as trial conduct. This brings us to the question of how we embrace new technology in this area and what will it mean for patients, healthcare providers, sponsors, and other stakeholders.

ClinRO Considerations for Siteless Trials ClinRO, where an investigator or specialised clinician undertakes an assessment of patients involved in a clinical trial, is often thought of as being too difficult for homebased assessments. However, remote administrations of very complex assessments are already included in many studies and, increasingly, are considered as standard for many subjective endpoints, especially in neurological and psychiatric indications, as well as indications in which assessments such as global measures of improvement and symptom severity are included. In these settings, the method of acquisition becomes a moderating influence, i.e., phone- or web-based assessment, or a trained nurse or expert physician that can conduct assessments either through web-enabled technology or through a homebased visit.

Where Do We Go From Here? Bringing new patient-centric technologies into clinical trials requires understanding of the patient experience and journey, particularly for those illnesses characterised by chronicity and multiple comorbidities. For example, Generation X (birthday: 1965-1980) and Millennials (birthday: 1981-1996) have a relationship with technology that is largely incorporated into their everyday lives and it reasonable to conclude that integration of advanced technology into the process of healthcare for these individuals can be used to benefit long-term health promotion and treatment outcomes. Pragmatic trials informing healthcare policy decisions, for example, likely can exploit this penchant and familiarity with an electronic media interface for both data acquisition and patient management to support adoption for novel interventions into clinical practice 5.

Best Practices for Operationalising Late Phase Research Worldwide is currently using a direct-to-patient Research Contact Center to collect data from 5000 patients taking part in a large cardiovascular outcomes study across multiple geographies. The design of the protocol has facilitated ethics committee approval of direct patient contact by telephone to collect PROs as well as other healthcare utilisation data without the mediation of study sites. Data is collected at six-monthly intervals from both patients and caregivers with a response rate of approximately 90%, which, after three years of research, is high. Part of this success is attributable to flexibility in the timing of patient contact, as well as automated local language SMS and email to maintain study visibility and ensure assessments are conducted within a defined visit window structure. Using methods and tools that suit the target population with professional staff familiar with culture, language, and standards of clinical care is essential to the success of this approach. Early engagement of regulatory authorities is required. As an industry steeped in precedent within a matrix of regulation, hesitancy in incorporation of electronic data platforms for patient assessments during prototypical registration programmes is anticipated, and perhaps prudent. The move towards home-based studies, or hybrid investigations that include a mix of clinic versus home assessments, means that we are now detecting sitebased operational issues within the home setting, such as incomplete or out-of-window assessments, patient noncompliance, issues with gathering and verifying source documents, as well as challenges in scheduling travelling nurses to undertake assessments or problems with visits cancellation. In addition, the necessary shift in training patients and caregivers rather than staff at sites creates an impetus for creativity both in terms of appropriate content, and study logistics. Nevertheless, an ability to utilise technology early in research facilitates innovation www.jforcs.com

The use of data mining and analytics also is allowing us to use these technologies to extract scientifically sound data characterising longer-term patient outcomes for regulatory agencies and healthcare providers who particularly wish to define the value of an intervention, given the therapeutic novelty. Risk stratification algorithms based upon these data, for example, could help prioritise the range of treatments likely to have the most significant clinical impact for given patient characteristics 6, specifically, the therapy most likely to produce a substantive impact and be adopted by a patient. That being said, there are many areas where the industry now needs to work together to ensure the best standards and practices are adopted. Collaboration is essential across consenting processes, data cleaning activity, analytics, and data accessibility to enable this area to mature and evolve into new ways of operationalising home-based assessments. Implications for “Best” Practices Technology has a considerable impact on most areas of our lives. How many of us would choose to live without our smartphones or our tablets for just a day? The same phenomenon increasingly is relevant for the design and operation of clinical trials. The IT team now plays a major role in the cross-functional study team, sitting alongside site management, project management and regulatory operations, and is increasingly involved in every aspect of study operational planning – providing the “enabling infrastructure” which is necessary for successful study operations. As an industry, therapeutically focused, smaller, more informed teams with a creative problemsolving mindset appear ideal and critical for successful CRO-sponsor collaboration. This will be foundational in conducting siteless clinical trials, given the interplay of clinical, technological, and regulatory constraints. As new practices and standards are developed, the Journal for Clinical Studies 37


Market Report evolution of roles within the industry will also need to be considered. In the future, for example, the CRO may play a larger role in training and site management and surveillance for medical convergence of diverse assessments, in addition to ensuring the accuracy of data through traditional site-based monitoring. Some of data monitoring responsibility is already subsumed under the umbrella of various technologies employing error-detecting algorithms, allowing site management to assume an increasingly strategic role. This will especially be the case in late phase research, where the continuum of clinical research shifts toward a pragmatic rather than explanatory trial focus. In this environment, data warehousing and analytics will take centre-stage. A Harbinger for Changes in Clinical Research Having the ability to place assessments at home, whether they are physiological assessments, measures of functional status, or assessments of quality of life, can exist in service to a number of objectives. Use of homebased assessments facilitates study participation by patients with significant morbidity located remotely from centres of excellence, and it enables acquisition of a range of measures sampling different dimensions of patient health in a continuous rather than episodic fashion. In earlier phase explanatory research, the use of homebased measures permits access to additional dimensions of data that hitherto had not been considered based upon exclusive reliance on within-clinic assessments. In the post-approval environment, reliance upon home-based assessments permits continued evaluation of “under-investigated” treatment modalities in more heterogeneous patient populations, which potentially is more representative of patients likely to receive therapy than those that may have been evaluated during the pre-registration process. This last activity generates ecologically relevant data that better maps into the practice of medicine, providing a more nuanced and expanded operational definition for translational research, i.e., research that transitions from clinical development into commercialisation. *This article is informed by discussions shared during a Worldwide Clinical Trials webinar – ‘Are we moving towards ‘siteless’ clinical trials?’ To listen to the webinar, please visit www.Worldwide.com. References 1. Dustin J. Experiences & Lessons from Conducting Global mHealth Enabled Clinical Trials. mHealth for Clinical Trials. Boston. June 13-16, 2016 (http:// mh e al t h - c l in icalt ri a ls . c om /s em i n a r/ex p e rienceslessons-learned-from-conducting-global-mhealthenabled-clinical-trials/) 2. Carlton E, Greenslade J, Cullen L, Body R, Than M, Pickering JW, Aldous S, Carley S, Hammett C, Kendall J, Keevil B, Lord S, Parsonage W, Greaves K. Evaluation of High-Sensitivity Cardiac Troponin I Levels in Patients With Suspected Acute Coronary Syndrome. 38 Journal for Clinical Studies

JAMA Cardiology. 2016 Jul 1;1(4):405-12. 3. Choudhry NK, Avorn J, Glynn RJ, Antman EM, Schneeweiss S, Toscano M, Reisman L, Fernandes J, Spettell C, Lee JL, Levin R, Brennan T, Shrank WH. PostMyocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial. Full coverage for preventive medications after myocardial infarction. N Engl J Med. 2011 Dec 1;365(22):2088-97. 4. Gnanasakthy et al. (2012) Potential of patientreported outcomes as nonprimary endpoints in clinical trials. Health Qual Life Outcomes. 2013; 11: 83. 5. Ford, I, Norrie, J. Pragmatic Trials. N Engl J Med 2016; Aug 4 (375) :454-463. 6. Huang Z, Dong W, Duan H. A probabilistic topic model for clinical risk stratification from electronic health records. J Biomed Inform. 2015 Dec;58:28-36.

Dr Murphy’s professional career has spanned 25 years and his positions within the pharmaceutical industry emphasise the integration of medical and scientific acumen with operational excellence. He is board-certified in psychiatry and has a doctorate in pharmacology, with training at Tulane University, Stanford University and the Mt. Sinai School of Medicine. His supervisory responsibilities as Chief Medical & Scientific Officer at Worldwide Clinical Trials are international in scope and include strategic programme and protocol design contributions for translational research activities, particularly for orphan disease indications. He is Research & Development Editor for American Health & Drug Benefits™ a publication which focuses upon cost, quality and access in the transition of novel diagnostics and therapeutics from discovery to commercialisation. As a lecturer within the Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology (HST) for 17 years, he contributed to the curriculum for a twoyear Clinical Investigator Training Program for physicians seeking advanced credentialling in experimental medicine and protocol design. He is a contributor to the Harvard Catalyst lecture series supporting the Clinical and Translational Science Center. Volume 8 Issue 6


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Outcomes of International Trials can be Affected by Poor-quality Translations The 8-language trial is completed, the data analysis is done. The medical writers have started writing the report. Then something happens. One of the writers notices that the answers to some of the most crucial questions in the French questionnaire do not match those from the other language versions. You take a closer look and find out that, indeed, the French questionnaire has not been translated correctly. In fact, it is so bad that much of the French research data should be discarded. The answers cannot be pooled with those from other language areas because the meaning of the questions had gone lost in translation. A trial organiser’s nightmare? No, I am afraid not… This one has happened for real! Quality in translation is important. Everybody knows that. While an error in an instruction guide for a microwave is simply annoying, an error in a medical document can injure or kill a patient, and in the worst case it can put you in front of a US jury sympathetic to a grieving widow. In the translation world some terrible stories go around about injury and death due to translation errors in medical instruction text (see sidebar). Below I will show you how to stay away from US court rooms, and also how to prevent a nightmare scenario such as described above. It is really rather simple: make sure your source text is of high quality and free of errors, jargon and ambiguities, then involve qualified translators who know what they are doing, and check or test the quality. High-quality medical translation results from the combination of human expertise and language skills, of computerassisted translation (CAT) tools, and of very serious quality assessment. In the optimal mix of these three, the translation quality will be high and the risk of court cases close to zero. Translation Errors Can Kill Fortunately it does not happen very often, but people can get injured as a result of poor medical translations. In France, four patients died and dozens of others were injured due to an incorrect translation. Hospital staff had translated the software messages of a medical device that was used for the treatment of prostate cancer patients. For 12 months, and due to a translation error, the system administered radiation overdoses, with fatal outcomes for four patients. In Germany, 47 patients who had undergone total knee replacement suffered a lot of pain and had to go for a second surgery after it turned out that the knee components had to be cemented into the femur. The translated instructions stated that the new knee could be implanted without using cement. 40 Journal for Clinical Studies

Human Factor The human language skills and expertise can be found in experienced medical translators. Remember that it is very hard to polish up a poorly translated (or written) text. ‘First time right’ is key; when the initial translation is done by a quality translator, reviewing this work takes far less time and the risk that any errors are overlooked is minimised. It goes without saying that medical translators must be native speakers of the target language and be very experienced in medical. The golden rule is that one translator makes the initial translation, the next one will review the work, and a proofreader will make sure no errors survived these steps. This process is also what customers can expect to receive from a translation provider certified under ISO 17100:2015, the recent translation services standard. Computer-assisted Translation Translation memory (TM) tools are widely used CAT tools. These specialised tools are available ‘off the shelf’ from a dozen different developers. When such tools are used, the source and target language segments are stored, during translation, in a database. A segment is most often a complete sentence, but segment can also be defined as a string of text between punctuation, or as a bullet item in a list. Whenever a previously translated segment occurs again (further down in the same text, or in a new text), the translation memory software will present the existing translation and the translator can accept it, or simply revise it, and go on to the next segment. These tools help translators to be more consistent in the use of specific terms, and to be more cost-effective. The human translator has the lead in this process; the CAT tool is an efficiency tool. CAT tools are different from what is referred to as ‘machine translation’ (MT), where a computer provides the translation. The best MT example is Google Translate. Many people also find this a good example of how poorly computers can translate. And up to a certain level they are right; often such automated translations make not much sense, can be laughable, and should be used with the utmost care. However, MT output can certainly be used for ‘gisting’ purposes, giving the reader the gist of what the source language version roughly says; in certain cases this may be enough. And MT may have a bad name, but especially for language combination that are in high demand, for example from English into French, the output is not all that bad. As long as the English source text is clear and simple, without errors and ambiguities, the French will come out rather well. Even so, the output of MT should always be very carefully reviewed and compared with the source text. MT will be beneficial when this review time takes considerably less than the amount of time it takes for the traditional translation plus review.

Volume 8 Issue 6


Market Report Quality Assessment Part of creating a high-quality medical translation is quality assessment. Translation services providers do QA as part of their work, and if they are ISO certified, they can be expected to do it, although not every provider takes this seriously enough. There are automated QA tools that can detect errors in translations. These tools will identify words or sentences that have not been translated, numbers and values that are different in source and target languages. They will also mark decimal points vs. commas, and thousands separators that are often different in English than in most other languages. It would be good if QA tools would also be able to check if word like ‘not’ or ‘increased’ have been correctly translated; these are the types of errors that can injure or kill a patient. Apart from automated QA tools, the human involvement is crucial. There are various additional ways to assess translation quality. One is to let two independent translators make a translation and then carefully compare the two. Another one is the backtranslation, which is a QA method almost exclusively used for clinical trial documents. The most precisely documented method is referred to as ‘the ISPOR method’. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) proposed a very detailed framework for the translation of instruments such as questionnaires.1 It includes translation into the target language by two independent translators, then these forward-translations are reconciled into one ideal version. The reconciled version should then be translated back into the source language by an independent translator, a native speaker of the original source language. The back-translation must be carefully compared with the reconciled forward translation, which will be finalised at the end of this process. This final version must then be tested, also referred to as ‘cognitive debriefing’. During this test, the translated instrument is used on representatives from the target population in which the questionnaire will eventually be used. Only after it is clear that the translation is correct can it be used during a trial. Why Would a Translation Still Contain Errors? Often, translation errors are caused by the low-quality level of the source text. It is hard to correctly translate a poorly written text, and if translation providers notice a source text is not clear, they should be asking you questions about the specific meaning of certain phrases. If they do, your alarm bells should go off. Often the translators are the first ‘close readers’ of your text and when they have questions, you should take these very seriously, and even be prepared to revise your original text. Translators are usually highly-educated professionals and if they don’t understand something, this tells you more about your text than about them. And if they don’t fully understand your text, how likely is it that the average reader will? In summary, produce a high-quality source text, select reliable translators, and check their work. The risk of having to discard all French answers to your most crucial questions is then close to zero. www.jforcs.com

Cheap Can Be Risky A few years ago, the UK government invited translation companies to submit a bid for all government interpretation work. One of the lowest bidders won the contract. However, it soon became clear that they could not deliver: instead of 1200 interpreters, they only had 400 or so. In the midst of this, the company was taken over and it took the new parent company quite some time, and a lot of effort, to put things right. The Swedish government did something similar concerning all government translation work. Again, one of the lowest bidders won the contract and, again, the winner could not deliver. In the end, even the Prime Minister’s department refused to work with the selected company. Also in this case, the result was that hospitals, courts and asylum centres were not getting the services they needed, jeopardising the health of patients and causing asylum procedures to take many months instead of weeks. What these cases have in common is that the selected company, which on paper had an attractive priceperformance ratio, could not meet the requirements. The price was low, for sure, but so was the quality. The net savings resulting from both of these tenders are probably negative, and all stakeholders have been very unhappy. The Clinical Trial Regulation and its Impact on Language The new Clinical Trial Regulation (EU 536/2014) defines lots of new requirements for trial organisers, but most of these do not concern language and are therefore outside the scope of this article. Let’s take a language look at the regulation. Language of Dossier A concerned EU member state can decide on the language requirements for the application dossier. It should be in a ‘commonly understood language in the medical field’, which may be different from the national language, as long as it only concerns ‘documentation not addressed to the subject’ (art. 26). This means that the government of, for example, Germany may agree to accept an Englishlanguage dossier, but that documents to be used by, or for, participants, such as informed consent form or questionnaires, should be translated. Language of Informed Consent Before obtaining informed consent, the potential subject should receive information to enable him or her to understand all aspects, including all risks, of the trial. This information has to be ‘comprehensive, concise, clear, relevant, and understandable to a layperson’, and the trial organiser must verify that the subject has understood all information (art. 30). This means that it is up to the national authorities to decide how to assess whether the information is ‘clear’ and ‘understandable’ Journal for Clinical Studies 41


Market Report to the subject. It can be expected that this means that the ICF must be translated in the national language(s), which is rather common practice anyway. Language of Official Reports A concerned member state can request the translation in the EU language of their choice of ‘inspection reports of third country authorities concerning the clinical trial’. The trial sponsor shall submit such reports ‘in an official language of the Union’ as indicated in the request (art. 53). This means that the trial sponsor may need to provide several translations of these reports, depending on what the member states demand. Language on Labels The concerned member state can decide in what language the label information of the trial medicine must be provided. The trial medicine may be labelled in several languages (art. 69). Reference 1. Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation. (Value in Health, 2005, vol. 8, no. 2, 94-104) https:// www.ispor.org/workpaper/research_practices/ PROtranslation_adaptation.pdf

Simon Andriesen is founder and CEO of MediLingua, specialising in the translation of medical information. Since 1996 the company has exclusively been working for pharma, CROs, medical device manufacturers, and developers of medical apps. Simon is also a board member of Translators without Borders, a volunteer organisation of 3000 professional translators providing language support to around 300 humanitarian organisations. He has set up medical translators’ training centres in Kenya and in Guinea to help create a translation infrastructure in these areas, characterised by many patients, few doctors and hardly any medical translators around. Email: simon.andriesen@medilingua.com 42 Journal for Clinical Studies

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Prioritising Health Economics Responsibilities To Impact Payer Pricing and Formulary Decisions

Creating A Culture of Trust and Breakthrough Innovation in Pharma

Volume 6 Issue 4

Peer Reviewed International Pharmaceutical Industry

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ED

Volume 7 - Issue 2

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SUSAR Consolidation New Procurement Approach in Pharmacovigilance

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IPI – International Pharmaceutical Industry

IPI – International Pharmaceutical Industry

Transparent Regulations for Prescription Medicines The Australian way

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Peer Reviewed by recognised industry experts, IAHJ looks into the entire outsourcing management of the Veterinary Drug, Veterinary Devices & Animal Food Development Industry. IAHJ focusses on Regulations & Validation, Drug Discovery, Development & Delivery, Clinical Research, Custom & Contract Manufacturing, Primary & Secondary Packaging, Logistics & Supply Chain Management. www.animalhealthmedia.com

Volume 7 - Issue 2

Volume 7 Issue 2

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Volume 6 Issue 4 - Winter - 2014

Volume 7 Issue 2 - Summer - 2015

Volume 7 Issue 1

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Peer reviewed by its distinguished editorial advisory board, JCS provides you with the best practice guidelines for conducting global clinical trials. JCS is the specialist journal providing you with relevant articles which will help you to navigate emerging markets. www.jforcs.com

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Therapeutics

Mitigating Risks of Block-enrolled Ophthalmology Studies The use of block enrolment in ophthalmology trials helps enrolment keep up with the speed of these studies. However, the challenges inherent in their successful execution are numerous. Some studies complete enrolment in a single day, while others enroll in “blocks” over consecutive days or weeks to take advantage of this accelerated recruitment. These aggressive timelines create risks in the logistics of successful study completion. Therefore we, at Ora, Inc., have developed effective practices to mitigate these risks. A standard, multi-person team contains a single technician per principal investigator (PI). Typical blockscreening organisation sets up processes which allow for efficient movement of patients through the visit in a time and space-dependent manner. A waiting area is set up and logical, protocol-driven rooms are arranged to move the subjects through proficiently, allowing individual oversight at each test point by the PI and the study staff. This process ensures timeliness and most importantly, protocol adherence. As mentioned above, block enrolment allows a site to efficiently fulfill its recruitment goals while theoretically minimising site disruption during trial progression. Some of the advantages of block enrolment: • Standardisation – with groups of patients being enrolled simultaneously, inclusion and exclusion criteria variance can be minimised, and protocol adherence policed • Reduces bias – increasing the probability that each trial arm will be properly weighted – enrolment over a number of weeks can allow bias creep since real-time baseline comparison of enrollee demographics is not possible • Consistency of data – since the data is entered in block format and thus reduces errors on transcription • Site-to-site reproducibility – because the block model forms a single virtual construct, site-to-site variability is minimised • Accelerates timelines – all of the above leads to a shortening of project timelines with concomitant gains for the sponsor and sites. While the advantages of block enrolment are manifold, particularly for ophthalmic trials which may last only a few days, the risks and hurdles of block-enrolment are also plentiful and varied. It is critical to be aware of these risks and mitigate them at every stage of the project. Some of the disadvantages and areas for oversight of block enrolment: •

Meeting recruitment targets – it is important to be

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aware of the date of enrolment and the travelling that patients must undergo. For instance, a Day 1 visit on a Saturday will have a detrimental effect on the enrolment efficiency if patients have weekend commitments. For other patients, weekend travel may be the only option if work-week commitments preclude them from visits during this time. Thus recruiters must be primed for flexibility in patient scheduling. Sites must also support this flexibility to mitigate any effect on enrolment. •

• • •

Maximum patient numbers – it is critical to be aware of the number of patients a clinic can realistically handle and customise the block size accordingly Effective advertising is tailored to site location, patient demographics and trial time commitment Paediatric population (i.e. recruitment and compliance) Lengthy clinic visits (sometimes >7 hours) – the availability of on-site comforts should not be underrated. Movies, hot and cold drinks, Wi-Fi and charging stations can all enhance the patient experience and therefore the patient enrolment and compliance Cumbersome paper diaries and EDC entry – perhaps the largest single risk for block enrolment is the diary and data entry. Without data, monitoring cannot be performed, and timeline creep with increased errors ensues. It is critical that the site staff can keep up with the data entry requirements of block enrolment, especially if paper diaries are used. Thus the block size must be tailored to site logistics. Ora has staff at the site initially to train and aid in this.

As shown above, Ora’s strategy to overcome these hurdles has evolved and strengthened with our experience. Further to this, our responses to some of the critical factors in trial risk are discussed in detail below. Recruiters Ora has a team of recruiters who access an in-house database as the first step in recruitment. Site-specific patient databases are incorporated to enhance enrolment further. In our experience, a direct conversation with the patient which outlines realistic time commitments for study participation yields a greater likelihood of enrolment. Allowing time for the recruiter to describe the protocol in detail and answer any questions allows the patient or caregiver to make an informed decision about moving forward with a screening visit. Sometimes, in ophthalmic studies, problem enrolment can be eased using referrals from opticians’ offices, optometrists’/paediatricians’ offices and University clinics. Patient-to-patient referrals can also be helpful, but it is the Volume 8 Issue 6


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Who contacted the expert

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Therapeutics advertising on an “oldies” radio station might yield more interest than advertising on a “pop music” station. If the target is a 21-year-old+ population, then advertising on social media may generate the best response. In a recent study which included a paediatric population, we found patient-to-patient referrals attributed to about 5% of enrolment. The success of an advertising campaign should be an ongoing process. Our experience with block enrolment supports continuous reassessment during the trial to allow for the ability to redirect efforts when results are subpar, which is crucial to continued recruitment success. Monitoring Monitoring for these studies is also performed in blocks, creating travel and schedule headaches. Often monitors are away from home for 2-3 weeks at a time, which does not support a healthy work-life balance. To manage this, we set realistic expectations up front, before the study begins, mapping out a tentative calendar schedule. Allowing the monitors to return to their home base on weekends is paramount. To cope with the rigorous schedule and potential “burn-out” rate, we have comonitors trained on the study who can back up the primary monitor, as needed. A weekly check-in from Monitoring Management continually assesses the pulse of the on-site monitor and lends support, when needed.

responsibility of the recruiter to confirm patient suitability. Meeting the aggressive timelines of block-enrolled studies may be jeopardised by difficulty in scheduling follow-up clinic visits within window, especially those visits which are lengthy (>3 hours). To accommodate work schedules and help overcome this type of protocol deviation, we routinely offer visits in the evening and on the weekends, in addition to the standard visiting hours during the week, which we have found leads to greater compliance. Another important factor that is often overlooked is the clinical environment. By making the environment as comfortable and stress-free as possible, the longer study visits, and, by extension, patient compliance, are enhanced. In this regard, the clinics are supplied with snacks, movies, current magazines, device chargers, and toys/games for our paediatric patients. Lunch and dinner are also provided, and the all-important Wi-Fi should be made available at all times. Advertising Advertising often supports recruitment by producing a previously untapped patient population. The key to effective advertising is correctly targeting that population. In ophthalmic drug development, the patients often have reduced visual acuity. Thus radio and local TV adverts may be more effective than printed media. Another question to ask is whether the required demographic is an older patient group. If so, then 46 Journal for Clinical Studies

Ora’s COO, Donna Welch, was integral in the initial design and implementation of the block-enrolled model. “With proper controls and execution, block-enrolled studies have enhanced efficiency and consistently deliver quality data while reducing timelines.” In summary, block enrolment is crucial for accelerated trial designs. The advantages include data integrity and reduction in demographic variability. However, care must be taken in monitoring and managing the risks inherent in this model.

Simon Chandler, Ph.D.: Dr. Chandler is the Senior Director of EU Clinical and Regulatory Operations for ORA, Inc. He has more than 20 years of ophthalmic industry experience across Europe and the US focusing on retina and anterior segment indications. He has led successful drug development teams in anti-infective, anti-allergic, glaucoma and refractive surgery. Jocelyn Wise, MA, CCRC: Ms. Wise is Director of Monitoring at ORA, Inc. She has over 25 years of clinical research experience in drug and device trials, including overseeing clinical operations in paediatric and adult cardiology, OB/GYN, nephrology, endocrinology, anesthesiology, pain management, and ophthalmology. Volume 8 Issue 6


Technology New Approaches to Measuring Health Outcomes Leveraging a Gaming Platform Clinical trials employ a variety of approaches to measure the health status of patients and changes in their health due to treatment. In many therapy areas, subjective ratings made by the patient (patient-reported outcome measures – PROs) or by a clinician (clinician-reported outcome measures – ClinROs) are used to measure status or change over time. Patient-reported outcomes measures, such as a daily symptom diary or a quality of life questionnaire, importantly measure the perspective of the patient regarding the effects of treatment, and in some cases (e.g. pain assessment) may be the only way to assess outcomes. ClinROs include measures of symptoms through direct observation of the patient. For example, depression symptoms and severity may be rated by a trained clinician following a structured interview using the Hamilton Depression Rating Scale. A further clinical outcome assessment, and the one on which we focus in this article, is the performance outcome (PerfO). This is a measurement by a healthcare professional based upon observation of a task performed by the patient. In some cases, these PerfOs are measured using subjective assessments. Quite a number of subjective measurement scales are used in clinical trials to assess balance, movement or mobility based on observation of the patient conducting a specified movement or activity. Some examples of these are detailed in Table 1, although many others exist. Scale Fugl-Meyer Assessment Tinetti Balance Assessment Berg Functional Balance Scale Dynamic Gait Index Hauser Ambulation Index

Measurement Arm, hand and shoulder movement Balance and walking movement Balance and movement Gait features Walking ability

Table 1. Examples of common subjective performance outcomes used in today’s clinical trials Subjective ratings (e.g. assessing the patient using a verbal response scale) are not very sensitive to detecting small improvements, and different investigators may rate patients differently based upon their interpretation of the scale requirements. For this reason, it is sometimes difficult to make measurements that are sensitive enough to detect treatment-related changes and are able to conclusively show treatment effects when they exist. In addition, using investigator observation, it is less likely that detailed or subtle aspects of movement and mobility can be recorded. In this article we describe a simple proof of concept developed by ICON’s Product Innovation team to leverage the Microsoft Xbox gaming platform to generate objective measures as a possible alternative to subjective PerfO instruments.

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Current Use of Gaming Platforms in Health and Wellness A number of gaming systems enable motion-based gaming experiences and utilise a depth camera to track movements to enable players to engage with video game content. These same platforms can be leveraged to track movement in a range of healthcare and wellness applications. In particular, the Microsoft Kinect sensor, a component of the Xbox gaming system, has been particularly successful in enabling the development of health applications due to the ability of the Kinect to operate on a PC platform and the utility of its associated Software Development Kit (SDK) to facilitate the development of applications that track body movements. In particular, there is a growing body of applications leveraging Microsoft Kinect in developing interactive solutions for rehabilitation, including novel ways of engaging patients in regular exercise regimens and solutions to ensure that exercises are performed correctly for optimal outcomes. Examples include rehabilitation solutions in the areas of stroke (1), Parkinson’s disease (2), multiple sclerosis (3) and cerebral palsy (4). These applications use the skeletal tracking module within the Kinect SDK, which enables the 3D position of 26 body joints to be tracked over time without the need for the patient to wear sensors, special clothing or special markers (Figure 1). This same capability can be used to record and measure aspects of movement during performance tasks completed by the patient. As a proof of concept, we have developed a simple application that runs on a Windows 8.0 or 10.0 PC or laptop with a USB 3.0 connection, along with an Xbox Kinect 2.0 sensor and a Kinect for Windows adapter. This equipment is inexpensive (approximately $150 for a sensor and adapter) facilitating its use for in-clinic assessments within large-scale clinical trials.   Figure 1. Body joint skeletal tracking using Microsoft Kinect. Volume 8 Issue 6


Technology Proof of Concept – Measurement of Shoulder Range of Motion Using the 3D coordinates of a number of body joints, it is possible to measure the range of motion associated with the upper extremity movement, in particular shoulder range of motion. This could be of value in assessment of adhesive capsulitis treatment or measuring changes in upper arm movement in stroke patients, for example. In this application, we used the position of shoulder, elbow, wrist and spine to calculate range of motion angles during a sequence of movement tasks performed by the patient (Figure 2).

Figure 3. Software application for shoulder range of motion assessment

Figure 2. Performance tasks in the Microsoft Kinect application for shoulder range of motion Using formulae for the angles between vectors, we were able to convert joint coordinates to calculate the angles achieved during these performance tasks, and also to record the path of motion traced during the conduct of the tasks (Figure 3). The angle of abduction (A) we calculated from the maximal angle achieved between upper arm and spine while raising the straight arm above the head along the coronal plane. We calculated adduction by reversing this motion as far as possible in the opposite direction, across the body (B). Similarly, we calculated forward flexion by requesting the subject to raise their arm above the head away from the body along the sagittal plane (C). We calculated rotation by asking subjects to move their wrist away from the body along the transverse plane while holding the elbow close to the body (D), assessing the maximal angle achieved between forearm and upper arm. Finally, we estimated angles of internal and external rotation in abduction (E) while the subject kept their elbow at shoulder height and rotated by moving the forearm up (external rotation) and down (internal rotation).

These tests are performed with the patient standing around 2 m from the Kinect sensor (Figure 4).

Figure 4. Measuring abduction angle using the Microsoft Kinect application (subject is author DW) Initial tests comparing angles measured by the Kinect system to those using a goniometer have suggested good concordance in measurements, although the tracking of joints was seen to be less reliable during the adduction task. Moving the arm across the body appeared to make it difficult for the depth camera algorithms to assess the position of the elbow and wrist accurately. However, the approach has shown promise in the other range of motion assessments studied and has indicated good utility for the conduct and instrumentation of these simple in-clinic performance tests.

www.jforcs.com

Journal for Clinical Studies 49


Technology The Potential of Gaming Platforms to Measure Health Outcomes While more testing is needed to assess the accuracy and utility of the application we have developed to measure shoulder range of motion, it is clear that the Microsoft Kinect platform offers a versatile and low-cost approach to measure novel health outcomes. This may add significant value and utility to clinical drug development, in particular in replacing conventional subjective measures. The potential of this approach will be dependent on being able to develop simple performance tasks that can be completed and measured within the depth range (0.5 to 4.5 m) and field of vision of the depth camera. Potential tests may include a number of approaches, such as: • Assessing gait parameters in a short walking test where patients walk in a straight line towards the sensor, or navigate simple obstacles • Measuring upper and lower body functional mobility • Detecting and measuring involuntary movements during still standing or sitting tasks • Measuring body sway during standing or balancing tasks. One nice property of the Kinect approach is that it provides a full picture of the entire body while the patient performs the requested movement(s). This provides a richer picture than some alternative instrumented approaches, such as using a body-worn accelerometer. Further testing will determine which tasks are best suited to the capabilities of Microsoft Kinect to provide accurate measures of interest. The sampling rate and resolution of the camera, for example, may limit its ability to measure finer or more rapid movements. Conclusions Our study has indicated good proof of concept. While more work is needed to understand and assess the accuracy and precision of the Kinect sensor, initial findings have been promising. The use of games platforms such as Microsoft Kinect to measure clinical outcomes offers a versatile, easy to use and low-cost approach that may have value in generating health outcome measures during in-clinic performance tasks. Of course, additional work on the validity and reliability of data collected in this way would be required for use in clinical trials. In addition, an assessment of the interpretability of outcomes derived – such as understanding the minimal clinically important difference in measurements observed – will be important when utilising this approach, as with any new approach to the measurement of health outcomes. As seen in the area of rehabilitation, however, gaming platforms offer a novel and potentially engaging approach that may enable researchers to understand more, and characterise more precisely, the effects of treatment in a wide range of disease indications. We anticipate further research and development activity seeking novel application 50 Journal for Clinical Studies

of these platforms in the field of clinical research and clinical trials. References 1. Sin, H., Lee, G. Additional virtual reality training using Xbox Kinect in stroke survivors with hemiplegia. Am. J. Phys. Med. Rehab. 92, 871–880 (2013). 2. Galna, B., Jackson, D., Schofield, G. et al. Retraining function in people with Parkinson’s disease using the Microsoft Kinect: game design and pilot testing. J. Neuroeng. Rehabil. 11, article 60 (2014). 3. Ortiz-Gutiérrez, R., Cano-de-la-Cuerda, R., Galán-delRío, F. et al. A telerehabilitation program improves postural control in multiple sclerosis patients: a Spanish preliminary study. Int. J. Environ. Res. Public Health 10, 5697–5710 (2013). 4. Luna-Oliva, L., Ortiz-Gutiérrez, R., Cano-de-la-Cuerda et al. Kinect Xbox 360 as a therapeutic modality for children with cerebral palsy in a school environment: a preliminary study. NeuroRehabilitation 33, 513– 521 (2013).

Bill Byrom, Senior Director, Product Innovation, ICON Clinical Research Bill Byrom has worked in the pharmaceutical industry for 25 years and is an experienced eClinical product strategist, working within ICON’s Product Innovation team. Bill has expertise in electronic clinical outcome assessments (eCOA) and wearable technology, and is interested in developing new approaches to objective outcomes measurement in clinical trials. Email: bill.byrom@iconplc.com

Darragh Walsh, Intern, Product Innovation, ICON Clinical Research Darragh is a final-year student studying multimedia, mobile and web development at Maynooth University, Ireland. He is currently working on an IT development internship within the Product Innovation team at ICON Clinical Research where he has been programming a number of applications for measuring performance outcomes in clinical trials. Email: darragh.walsh@iconplc.com

Willie Muehlhausen, Head of Product Innovation, ICON Clinical Research Willie Muehlhausen is the head of innovation at ICON and has 20 years of experience with eClinical systems. Willie is recognised as a leader and subject matter expert in the area of electronic clinical outcome assessments (eCOA) within the clinical trials industry. Email: willie.muehlhausen@iconplc.com Volume 8 Issue 6


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Journal for Clinical Studies 51 europe.thermoking.com


Technology eSource: Optimising the Sponsor, Site, and CRO Experience The clinical research industry has long hungered for a next-level innovation to make paper all but obsolete in clinical research. In eSource, that innovation has finally arrived. After all, while EDC has brought significant gains to clinical research in terms of speed and data integrity, it has not eliminated paper entirely. eSource enables researchers to finish the job, and may constitute the most significant cutting out of the middle man in the history of the industry. This revolutionary technology is not only recognised, but encouraged by the FDA, who in 2013 released its official guidance for how best to implement it. And at a time when international outbreaks like Zika and Ebola are leading to calls for fast-tracked FDA approval 1, this breakthrough in efficiency is taking place not a moment too soon. At its foundation, eSource technology simply allows researchers to electronically capture data that can later sync with an EDC system, instead of initially recording it on paper and transcribing it into an EDC later. But the technology has developed rapidly since its inception – for example, while it typically entails the import of data from EHRs into CRFs, the industry has begun to see products offering eSource through tablet-based data capture – and has branched out into various niches within clinical research. Now, thanks to this evolution, the benefits and beneficiaries of eSource are many. In the space that follows, we’ll take stock of the different ways various players in clinical research benefit from this groundbreaking technology. Time and Precision: Sponsors’ Key Concerns Any tool designed to simultaneously enhance efficiency and data integrity is ultimately most valuable to the

52 Journal for Clinical Studies

party that holds the lion’s share of responsibility, both financial and regulatory, in a clinical trial. While all involved in clinical research do important work, this party is, all things considered, the sponsor. It is the sponsor who must answer to the FDA; it is the sponsor whose investments are at stake, and whose reputation is most publicly in the line of fire if a trial fails due to inadequate data integrity or any other reason. Any pressure felt at the CRO or site level often emanates from the pharma company governing the trial. A sponsor’s concerns during a clinical trial generally fall into two categories: time and precision. And as far as time is concerned, eSource is a game-changer. As there is no need to wait for data to travel through a paper case report form (CRF) before being stored and saved electronically, the time taken to transcribe data from paper to EDC is reduced or eliminated. And with remote data sharing, sponsors are able to more quickly, easily, and frequently check in on a study’s progress and ensure that it’s moving along in alignment with the necessary timeline. These data-sharing capabilities also allow sponsors to be more quickly alerted to any red flags that may pose a threat to a study. If, for example, a study is behind on enrolment, eSource reduces the turnaround time between the problem arising and the sponsor acting upon it. Beyond the benefits to a study’s timeline, eSource serves sponsors by fostering better data integrity and facilitating the process of gauging the success of the study. Remote data-sharing helps sponsors determine which sites are having data collection issues, and realtime edit checks offer reassurance that errors will be

Volume 8 Issue 6


Technology found and corrected in a timely manner, before those errors can compound with data down the line and lead to more inaccuracies. But perhaps no greater benefit comes from remote data-sharing than savings on source data verification (SDV), the process of comparing data stored in an EDC to its paper origin in search of any inconsistencies. A major expense that can comprise up to 40% of a clinical trial’s budget 2, SDV is essentially rendered moot for sponsors who use eSource to eliminate paper transcription. Overall, the enhancements to data integrity that eSource can provide allows sponsors to make a stronger case to regulators, and to save time and money through reductions to SDV and monitoring. But as the collection and management of data is often outsourced, sponsors don’t always directly utilise the tools that create these enhancements. In these cases, contract research organisations (CROs) and site staff feel the more immediate benefits of eSource technology. Let’s move on to the ways eSource makes a difference for those who spend time on-site, entering data and interfacing with subjects. Sites: Opening their Doors While sponsors largely concern themselves with drug design and regulatory issues, the staff at the trial sites are the essential foot-soldiers of clinical research. These are the professionals who actually capture data onto CRFs, and as such, are able to work much more quickly and efficiently when armed with a well-designed eSource application allowing them to perform this task electronically. This, along with the elimination of quality control, storage and retrieval of paper, and other tasks that the use of paper makes necessary, gives sites a huge leg-up on the competition when pursuing business from sponsors and CROs. In fact, eSource can make a difference even before all the necessary materials are in place to begin data collection. In the event that a site hasn’t yet been supplied with CRF templates by the scheduled start of data collection, that site would typically have to create a temporary CRF on a word processor; eSource eliminates this necessity by allowing sites in this position to borrow a blank CRF electronically from other sites. But site workers don’t just capture data; they’re also, from the perspective of the subjects, the face of a clinical trial. And as a subject’s experience is partly defined by his or her interactions with these workers, that relationship is crucial. As a result, eSource innovators have developed applications that allow site staff to maximise the subject experience. Some of these products aim to improve the collection of patient-reported outcomes with tablets or mobile devices. Companies have also developed eSourceequipped products for informed consent, allowing researchers to bolster the consent process with videos, pictures, and other layperson-friendly media that allow subjects to cut through medical jargon and better understand their studies. Others have also created products that use features like handwriting- and voice54 Journal for Clinical Studies

recognition, as well as special keyboards for numbers and special characters, to add even more convenience for researchers and subjects alike. Clinical trials can be long-term, sprawling projects, with protocols often calling for large numbers of sites to be employed. 3 With their space and resources occupied by meticulous research endeavours, sites have a major stake in the efficiency of eSource, especially when it comes time for data and site monitoring. Here, the ability to share data digitally, and the possibility for remote monitoring that arises from that ability, has a major impact. Monitoring requires significant time and action on the part of clinical trial sites. Numerous types of monitoring visits are carried out periodically over the course of a trial, as well as the occasional site audit by the FDA. These visits are not exactly passive occasions: sites need to ensure that they are in an appropriate condition for the monitor to tour the facilities, and often must provide a quiet workspace for the monitor, equipped with numerous amenities. 4 Remote monitoring allows sponsors and CROs to satisfy the requirements of site monitoring without a physical visit, which can be a major relief for a site’s resources. As has by now been demonstrated, numerous parties involved in clinical trials find relief and efficiency in remote data-sharing. But one feature of eSource particularly relevant to sites is the capacity for offline data entry. Even today, some sites, such as those in remote or rural areas, lack dependable access to the internet. 5 This creates uncertainties related to study timelines and calls into question whether data is stored safely in a trial’s EDC. eSource applications allow data to be stored electronically, even without an internet connection; the data then automatically syncs with the EDC when connectivity is restored. For sponsors and CROs, this, of course, offers much-appreciated reassurance; for sites, it provides the ability to viably contend for business, regardless of internet connectivity.

CROs: Between Subjects and Sponsor While some sponsors continue to handle their clinical research in-house, more and more sponsors today are outsourcing the day-to-day operations of clinical trials to contract research organisations. 6 The value of eSource for these organisations is, in many ways, very much aligned with the ways the technology benefits sponsors and sites. For example, while electronic data entry and real-time edit checks help sponsors largely by offering financial and regulatory peace of mind, it’s the CROs who must ensure that data management duties are executed efficiently and accurately at the site level, and who are better enabled to do so thanks to these features. The improved data quality that eSource allows sites to achieve, in turn allow CROs to more quickly and easily analyse the collected data. Like sites, CROs can take advantage of the potential Volume 8 Issue 6


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Technology for remote monitoring that electronic data-sharing makes possible. As CROs often assume the responsibility of hiring the monitors who perform SDV and other tasks, remote monitoring can alleviate a CRO’s workload: fewer monitors to dispatch to sites means fewer things to do. This, in turn, cuts costs and reduces timelines, ultimately making eSource-savvy CROs stronger candidates as they compete for business from sponsors. Also like sites, CROs, as the entity responsible for patient recruitment, have a lot to gain from the enhancements to PRO collection and informed consent that eSource proffers. The approachable, digestible, and subject-friendly way that eSource products for informed consent present information can go a long way toward setting a tone that ensures subjects feel comfortable and informed throughout the trial, potentially yielding higher rates of patient retention. Things to Keep in Mind The recurring mentions, in this review, of remote datasharing suggests that this is the most impactful feature of eSource technology across all major aspects of a clinical trial. Indeed, the benefits of this feature are universal: eSource has built upon the remote datasharing capabilities of EDC by making it easier to share data in real time, yielding time savings for essentially all professionals involved. But the true measure of any innovation in clinical data management is whether it can better ensure data integrity; this is the core value of eSource. Every transfer point through which data passes on its journey to an EDC is an opportunity for transcription error; by simplifying and automating much of that journey, eSource eliminates those risks, and is thereby ushering in an era of vastly improved data integrity. But it would be somewhat disingenuous to suggest that eSource has been universally embraced. Many CROs and pharma companies employ research staff who, being accustomed to paper-based data management, are wary of a new paradigm requiring them to learn new skills just to continue the work they’ve spent their entire careers performing. To address any resistance, eSource products must be designed to enable researchers to collect and manage data as fast as, or faster than, they would on paper. This means that in addition to offering flexibility through various perks and features, it must be fundamentally intuitive and easy to learn. In other words, simply existing is not enough; the technology must earn its widespread adoption. Fortunately, that seems to be happening. eSource was only developed a handful of years ago; that it has already, in that short time, moved through the complex and slow-moving federal regulatory apparatus to earn the official backing of the FDA suggests a clinical research industry enthusiastic enough to push it to that point. The technology has yielded native tablet applications for capturing data directly onto eCRFs, boosting efficiency and enhancing data integrity. And the development of eSource-equipped products for patient-reported outcomes 56 Journal for Clinical Studies

and informed consent suggests that researchers and EDC vendors are using eSource to contribute to the ongoing trend toward patient engagement, thereby binding the technology to the future toward which clinical research is headed. For years, the clinical research industry has heralded electronic data capture as a high-tech alternative to paper. But while EDC has indeed led to serious reductions in the amount of time and money spent on paper use, it isn’t a panacea. Through most of the history of EDC, the technology has served as a final destination for data still originally recorded on paper. Only now that we are seeing the advent of eSource does clinical research have the opportunity to establish the kind of fully electronic-based paradigm that early EDC pioneers likely envisioned. References 1. 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 / p re d i c t i o n s - 2 0 1 5 - t re n d s - c l i n i ca l - t r i a l - p ro c e s s e s , visited on 20 Sept 2016 2. h t t p s : / / w w w . n c b i . n l m . n i h . g o v / p m c / a r t i c l e s / PMC3857788/, visited on 14 Sept 2016 3. h t t p : / / w w w . n a t i o n a l a c a d e m i e s . o r g / h m d / ~ / media/34D1A23404A8492998AD2DF0CB6CD4D1. ashx, visited on 14 Sept 2016 4. h t t p s : / / c c t s . o s u . e d u / e d u c a t i o n - a n d - t r a i n i n g programs/research-education-and-trainingprograms/clinical-research-coordinator-resources/ site-monitor-visits, visited on 14 Sept 2016 5. h t t p s : / / w w w . c n e t . c o m / n e w s / p r e s i d e n t - o b a m a presses-for-high-speed-internet-for-rural-americans/, visited on 15 Sept 2016 6. h t t p : / / w w w . p h a r m o u t s o u r c i n g . c o m / Fe a t u r e d Articles/174597-The-Increasing-Shift-of-ClinicalTrials-to-CROs/, visited on 15 Sept 2016

Mike Novotny is the founder and CEO of Medrio. He previously served as president of the EDC software company Ninaza, before founding Medrio in 2005. Mr Novotny has 20 years of experience in research and software, and holds a BA from Stanford University and an MBA from Columbia University. He can be reached at mnovotny@medrio.com Nick O’Brien is the Marketing Copywriter at Medrio, where he writes the company blog as well as press releases and other copy. Mr O’Brien has extensive experience writing for blogs and other media, and holds a BA in English with an emphasis on creative writing from Kenyon College. He can be reached at nobrien@medrio.com

Volume 8 Issue 6


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Technology Going All In on eCOA Significant growth opportunities in the eCAO field mean the industry is calling out for solutions, advice and guidance that can help deliver on its promises. Here, nine experts from organisations across the sector share their insights on some of the industry’s most pressing questions surrounding this expanding market. Why, in this day and age, are some clinical trials still clinging on to the use of paper to capture patientreported outcomes? Adam Butler, Senior Vice President, Strategic Development & Corporate Marketing, Bracket Global In today’s age of rapid digitisation across industries spanning banking, retail, healthcare and countless others, clinical trials has been relatively slow to adopt electronic methods and instead, reverts to traditional paper approaches for capturing patient-reported outcomes. Attributed to the industry’s stringent regulations that make it difficult to wholly rely on electronic methods, the slow adoption can also be ascribed to clinicians’ requirements for maintaining reporting flexibility during data capture. Often, it is difficult to fully predict the breadth of information and level of specificity that will need to be captured during a study session and the connotation that technology cannot rapidly adapt to such evolving needs is still perceived. On the contrary, electronic clinical outcomes assessments (eCOA) offer myriad benefits that not only meet clinicians’ requirements of adaptability, but have also been proven to increase patient compliance, reduce site monitoring costs and limit data variances – a challenge that paper records have long produced. The streamlined functionality of electronic methods is actually increasing data quality by capturing categorical and statistical information, not unstructured text. In fact, digitisation in clinical trials is driving the “Blockbuster Drug of the Century” movement, which refers to patient engagement’s ability to drive better outcomes and lower healthcare costs. As such, as digitisation continues to reveal quantifiable benefits, the movement will soon outweigh any traditional, unstructured data capture needs, and ultimately move clinical research into the twenty-first century.

58 Journal for Clinical Studies

In your opinion, what major hurdles still exist in the industry when it comes to ePRO adoption? Ron Sullivan, Executive Vice President and eCOA Product Line Executive, ERT As global adoption of eCOA continues to grow, so does our understanding of the benefits delivered as well as stakeholders’ needs when implementing technology in clinical trials. Research has repeatedly shown that patients prefer electronic collection methods over paper, trial sponsors continue to see improved data quality, and global regulators have issued guidelines for eCOA data collection in clinical trials. Any hurdles remaining for even greater eCOA adoption likely stem from sponsors’ and CROs’ study teams’ perceptions of operational obstacles that could disrupt their internal processes. For example, the perception may be that eCOA data capture would require earlier decisions and process changes than paper COA collection. While programming an eCOA study requires more time than printing paper copies at study start, there is considerable time saved with eCOA throughout study execution via electronic scale measurement, transcriptions, data entry, data queries and source data verifications. Another perception may lie within the implementation of eCOA – specifically that electronic solutions may interfere with the normal patient rapport that is required during the clinical assessment process. Does eCOA present a physical barrier to the clinical interview process? Quite the contrary. Well-established literature provides evidence that eCOA improves patient/clinician communication and candour, while mitigating site rater variability and enabling better care. Despite these lingering (mis)perceptions, eCOA adoption is projected to grow three times faster than COA within clinical research, even before the accelerator of BYOD that is working its way into the equation. Clinical trial sponsors looking to adopt and implement an eCOA strategy can do so successfully by collaborating with clinical trial teams, eCOA providers and COA experts familiar with transitions from paper-based COA data collection.

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Technology How is ePRO driving more responsive study designs? John Sage, Senior Vice President, Respiratory & eCOA at iCardiac Technologies, Inc. ePRO enables more responsive clinical study designs, primarily from two perspectives: speed of data exchange and expansion into new modes of patient monitoring.

in the study. Asking them to turn off their personal device, in favour of a dedicated device, is becoming increasingly problematic in our smartphone-centric world. Higher completion rate: This advantage is greater in outpatient studies (such as a large Phase I or Phase II study), since the patient is not at risk of forgetting to bring that dedicated device. Furthermore, critical reminders that enhance participation are more likely to be received when using the patient’s native phone. Access to onboard sensors: While still in the early stage of market acceptance, utilising the patient’s onboard sensors creates the opportunity to reduce the burden of active patient reporting/data collection, to passively collected information from their native phone, thereby reducing burden.

ePRO designs are integrating predictive algorithms that measure if a patient is experiencing a worsening of conditions. These algorithms combine inputs from the patient responses to the patient-reported outcome (PRO) instrument, and from the deployed patient measurement device to assess changes in the patient’s condition. Specifically in the respiratory space, the combination of PRO input and daily pulmonary function data are utilised to alert both the research site and the patient, if the patient is trending towards a potential exacerbation. Simple reminders are sent to patients to perform routine cleaning of devices like metered dose inhalers (MDIs) and peak flow meters, thus supporting continuity of data accuracy during the treatment period.

In addition, real-time compliance monitoring allows the site and the clinical research associate (CRA) to be very responsive in working with the patient to stay current on their diary submissions. Rapid response helps with patient retention. Study designs are now able to take advantage of new modes of quality of life (QOL) monitoring with the integration of physical activity monitors and new exploratory endpoints being written into protocols to capture the patient’s activity levels. These data can then be correlated with standardised PRO instruments to gain more insight into how the patient is performing daily routines during the course of the trial.

Cameron Robertson, Director – Business Operations at Exco InTouch There is little doubt of the value of eClinical integration. Data is king in clinical research and historically, systems such as EDC and eCOA have been deployed to collect clean, reliable data for evaluating drug development. In recent years, eClinical has evolved to encompass additional technologies such as wearables, EHRs and eConsent. Integration of these systems ranges from simple data transfers between databases, to real-time consolidation of data from various sources into one database accessed via a single customised web portal.

The benefits of BYOD are well understood for latephase studies. How are we likely to see BYOD impacting earlier phases? Jeff Lee, CEO at mProve Health It is common to equate BYOD with reduced hardware costs on large studies. I’m not convinced that cost-saving is the only, or even the primary, advantage of BYOD. BYOD offers greater convenience for patients, a strong case for a higher completion rate, as well as access to the onboard sensors of modern smartphones. Arguably, these elements constitute a more patient-friendly approach to data collection, which is very applicable to early-phase research. Let’s examine the relevance of each of these BYOD advantages: • Convenience for patients: Even in an inpatient, Phase I study, with a small number of participants, allowing the patients to utilise their personal phones creates a more inviting environment for their stay 60 Journal for Clinical Studies

For these reasons, our clients enjoy meaningful value from BYOD in early-phase settings. With the continuous emergence of front-end and backend systems, are we likely to see more collaboration and consolidation with a greater focus on eClinical integration?

Standardised data formats are essential for eClinical integration. Likewise, integration is crucial in order to maximise the process and cost-efficiency gains afforded by standardisation. The biggest challenge to integration is the standardisation of the metadata that flows between systems, which is evidenced by the increased prominence of organisations such as CDISC (Clinical Data Interchange Standards Consortium). A business case by CDISC in 2014 suggests using data standards saves 70-90% of time and resources during study start-up and ~75% of time during study conduct. For regulatory eSubmissions, standardising data saves ~$180m per submission and a 12-year clinical programme can be reduced by two years. In addition, regulators will soon require CDISC standards for eSubmissions in the US (FDA) and in Japan (PMDA) as they enable higher quality reviews. eClinical integration has other significant challenges, including the need to replace entrenched non-compatible legacy systems and nervousness around displacing Volume 8 Issue 6


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Technology tried and tested methodologies; however as with other eClinical technologies, we can only expect to see greater adoption in coming years as the industry drives further efficiency to decrease the time and cost of conducting clinical research. What impact are eConsent technologies having on the industry? Mika Lindroos, Director of Product Management at CRF Health Emerging eConsent solutions hold the promise of improving participant comprehension in the onboarding stages of clinical trials while eliminating many of the regulatory deficiencies common to the informed consent process. The availability of innovative new technology is driving sponsors to explore how best to implement an electronic consent approach into their studies, but also leaving many understandably cautious of the potential complexity that adoption might bring. Similarly, investigative sites are also likely to be wary of the integration of yet another technology platform into their study management, and all the training and process adaptions that come along with it. A seamless approach is on the horizon. Integrating ePRO and eConsent solutions so that they can be delivered on a single device and as part of a single data collection platform, enabling sponsors and study teams to gain all the benefits associated with both, without adding layers of additional technology, could represent the most investigator- and participant-friendly option. While better supporting the process for development, approval and management of informed consent content, a single-platform solution holds the potential to enhance patient understanding, increase regulatory compliance and reduce quality risks, as well as remove the additional burden for sites and participants that would go hand-inhand with the use of a separate platform. At a point when we are seeing an influx of new technology across clinical trials, getting systems to work together as much as possible, so that the end user has the experience of a single platform, is key. For today’s investigators and sponsors, integrating ePRO with eConsent represents a welcome step. How are ePRO technologies supporting the surge towards risk-based monitoring? Steve Young, Senior Vice President of US Operations at CluePoints ePRO is a form of direct electronic source data entry, and as such there is no separate source residing at each site requiring onsite monitoring review or transcription into an eCRF and subsequent on-site SDV. This therefore reduces the overall on-site monitoring effort which very much supports the RBM paradigm. 62 Journal for Clinical Studies

Beyond this, and perhaps more importantly, use of ePRO technologies enables pro-active, ongoing, centralised access to patient diary data for study team review and assessment. ePRO data includes audit trail information (such as the date-time stamps associated with each entry), which supports deeper assessment of diary data reliability that is impossible using paper diaries. Central statistical monitoring (CSM) techniques – which are a key component of RBM – can be applied to this ePRO data to detect anomalous patterns in both diary answers and audit information. These anomalies can then be investigated and action taken. Indeed, remarkable findings of misuse of ePRO devices have been made in ongoing clinical trials analysed using CSM. In one trial, the unusual timing of entries from different patients raised red flags and revealed a case of fraud at a site that would have been nearly impossible to detect using traditional monitoring and data management checks – and completely impossible if the diaries were paper-based with no accompanying audit trail. In this case, it was ultimately found that ePRO devices had not even been distributed to patients, and instead the diary entries had been fabricated by site staff! CSM techniques were applied to the ePRO data and revealed that a preponderance of entries at one site were being made between 6pm and 7pm local time, which was a unique pattern when compared with data from other sites. Only the use of ePRO could enable this type of robust statistical monitoring which is core to an RBM approach. Advances in wearable device technology are creating new opportunities across the life sciences sector. How can pharma integrate these tools in a more impactful way in the clinical trial space? Tom Evans, R&D Director at CamNtech Wearable devices must be looked at in the context of an intended use and what measurable results can be captured from them. Some systems carry exciting promises and visualisations, but may only reach a fraction of the intended population, not measure what is needed today and be unreproducible in three years’ time. Consideration must be given to exactly what underlying feature will be measured and whether the system as a whole is designed with that in mind. Using resources to collect large-scale data without precise planning in the hope that “data mining” will produce the desired results is optimistic at best. Similarly, some ePRO options will limit themselves to sections of the population, or produce distortions as participants more or less familiar with a device family are forced to operate it. Used correctly, wearable devices can reliably collect data which would be inaccessible by other means, and make it cheaper and easier to process than ever before. They can be integrated into the design at an early stage Volume 8 Issue 6


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Technology

to capture precisely the important measures, or they can also be “added in” to a trial without impacting the core. But in either case a clear idea must be maintained of the intended value and use of the data. From an ePRO perspective, what do you think clinical trials will look like in 10 years’ time? Jeffrey Zucker, MS, Vice President, Feasibility, Recruitment Optimization, and Clinical Assessment Technologies at Worldwide Clinical Trials. ePRO technologies will continue to transform how clinical trials are delivered, especially in studies where they can demonstrate real value in increased accuracy of data and improvements in patient convenience. In 10 years’ time there will still be paper-based patient-reported outcomes (PRO) being collected, largely due to patient preference and the nature of the PRO itself. However, I am confident we will see these technologies used to collect the routine daily diary entries, such as those relating to pain scores, glucose readings and values for concomitant medication information, in nearly 100% of the trials taking place.

I through to post-marketing. While this wider adoption will no doubt be spurred by costs being driven down as a result of broader take-up, the growth of BYOD – and its further validation – will also serve to bring costs down. The last decade has seen the birth and growth of the ePRO field and I fully expect the next 10 years to bring significant further growth – especially with more BYOD options. With the continued focus on patientcentricity in clinical trials, the evolution and maturity of the technology will really lead to widespread adoption; this will further drive increased reliability of the data, spurring a self-sustaining cycle and driving more sponsors and research sites to adopt ePRO-based solutions.

For some patients who struggle to use devices, particularly those with neurological conditions, there will still be the need for paper-based tools. However, in the coming years we will see ePRO span more and more indications and grow in all phases of research, from Phase 64 Journal for Clinical Studies

Volume 8 Issue 6


Cardiovascular Safety

Cardio-oncology: Safeguarding the Cardiovascular Safety of Anti-cancer Therapies Introduction The ratification of the E14 guideline in May 2005 by the ICH steering committee presented the first major safety guidance adopted by a global regulatory body (recognising the pivotal role of the corresponding European CPMP guidance, released in 1998). However, this landmark regulation, appropriately for its time, focused on only one aspect of drug induced cardiotoxicity – QT prolongation and pro-arrhythmia. Moreover, at its outset, regulatory interpretation of the E14 guidance excluded drugs with potentially lifesaving benefits, primarily anticancer agents, as inappropriate for the hallmark feature of the ICH-E14 guidance - the thorough QT (TQT) study. By prioritising the benefit:risk principle over safety considerations, regulators expressively agreed that anticancer drugs should not be subjected to the same safety standards as all other drugs in development. This notion has since been repealed, acknowledging the growing body of scientific and clinical evidence, showing the extent of cardiovascular toxicity of oncology agents. The importance of this understanding is further emphasised by the growing global community of cancer survivors, the primary population at risk for developing long term ‘malignant’ cardiovascular morbidities as a direct consequence of their life saving anti-cancer therapy. The emerging field of oncology drug-induced cardiovascular toxicity, also known as ‘cardio-oncology’ (CO), expanded the boundaries of the current cardiac safety model beyond QT prolongation and proarrhythmia, to include all forms of drug-induced cardiovascular toxicities, from myocardial damage and heart failure, through vascular injury and thrombosis, to haemodynamic changes and hypertension. The following monograph will provide a brief summary of oncology drug-induced cardiotoxicity, limited in scope and size to discuss only some of the major oncology drug classes. It will also provide some insights into the regulatory and drug development considerations. Background It is estimated that nearly two-thirds of adults with newlydiagnosed cancer will survive the first five years and longer. Although cardiotoxicity of cancer chemotherapy has been recognised since the 1970s, the growing life expectancy of cancer patients lowered the tolerance for major, life-threatening, oncology drug-induced toxicities. This brought on the recognition that cardiovascular toxicity is not limited to one class of anti-cancer drugs (i.e., anthracyclines), but is a widespread issue involving most classes of cancer therapies, including the recently introduced targeted therapies. 66 Journal for Clinical Studies

Anthracyclines, including doxorubicin and epirubicin, have been the mainstay of breast and other cancer chemotherapy since the 1960s. Anthracyclines’ therapeutic action is thought to be mediated through their intercalation within the DNA of replicating cells. However, long-term cardiotoxicity following anthracycline therapy, initially reported in survivors of childhood cancers 1.2, soon became a critical limiting factor for their utility. With the growing global experience, it became evident that the risk of anthracycline cardiotoxicity is not limited to the paediatric population, but exists in all cancer populations 3 and is associated with a particularly poor outcome for cancer survivors who developed systolic dysfunction and heart failure 4. At the other end of the cancer treatment spectrum, targeted therapies represented by highly-specific monoclonal antibodies designed to bind specific receptors or ligands, were also associated with significant cardiovascular side-effects. The first approved and most recognised agent is trastuzumab (Herceptin) 5, targeting the erbB2 receptor on breast cancer tumour cells. Trastuzumab was initially considered a ‘breakthrough’ therapy, due to its high efficacy in the treatment of HER-2 positive breast cancer that, until that time, was considered resistant to conventional therapy and carried an exceptionally poor prognosis. Unfortunately, early reports found an unexpected incidence of cardiac events that included clinical and asymptomatic decline in left ventricular ejection fraction (LVEF) and heart failure. In recent study involving 59,739 cases of cancer chemotherapy-induced cardiotoxicity reported in the FDA Adverse Event Reporting System (FAERS), trastuzumab had the highest number of death and disability outcomes reports, due to adverse event, as a single agent (OR = 5.74; 95% CI = 5.29-6.23) or in combination with cyclophosphamide (OR = 16.83; 95% CI = 13.32-21.26) or doxorubicin (OR = 17.84; 95% CI = 13.77-23.11). While some degree of cardiotoxicity might have been acceptable for an effective treatment for a particularly malignant cancer, the use of trastuzumab as an adjuvant therapy raised serious safety concerns and led to the development of clinical protocols for cardio-protection. Mechanisms of Cardiotoxicity Molecular mechanisms of drug-induced cardiotoxicity vary between different drugs and by clinical effects within the same drug. Two of the key anti-cancer drugs, anthracyclines and trastuzumab, target different yet complementary molecular pathways for their cardiac effects, as described below. Other drug classes, particularly Volume 8 Issue 6


Cardiovascular Safety

the growing family of tyrosine kinase inhibitors, and other drug effects which are not discussed here, present additional mechanism of cardiotoxicity. Anthracyclines-induced cardiac injury is thought to be mediated through generation of reactive oxygen species (ROS) and free-radical injury, resulting in myocardial oxidative stress and permanent changes to cellular ultrastructural . Recent studies also suggested that mitochondrial iron overload may play a key role in anthracyclines-induced cardiotoxicity 8. Trastuzumab, on the other hand, targets and blocks the erbB2 receptor tyrosine kinase expressed on certain tumours. However, the erbB2 receptor is also expressed in the human cardiomyocytes and is essential for normal cardiac development and repair. By inhibiting the erbB2 pathway, trastuzumab is preventing the normal development and repair of the myocardium, resulting in myocardial injury. Evidence also supports the critical role of neuregulin 1 (NRG1), a ligand for the erbB2 receptor, in maintaining cardiac function. Drug-induced left ventricular dysfunction and heart failure typically trigger compensatory mechanisms, including activation of the neurohumoral pathways such as the renin-angiotensin and adrenergic system, myocardial hypertrophy, and possibly survival factors such as the neuregulin/ErbB system. Concurrent treatment with anthracyclines and trastuzumab block both erbB2 and NRG-1, which may induce myofibrillar injury and account for the clinical toxicity of trastuzumab in the setting of concurrent anthracycline therapy 9. Moreover, the inhibition of ErbB2 signalling by trastuzumab in patients receiving anthracyclines may interfere with the protective effects of neuregulin on the anthracycline-damaged myocardium. This may account for the increased cardiotoxicity observed with concurrent and sequential anthracycline– trastuzumab administration.

number of cardiotoxicity categories, more specific definitions may be required for the individual categories described below. For example, left ventricular (LV) dysfunction is commonly defined as a drop of >10 percentage points in LVEF to below 50% 10. Oncology drug-induced cardiomyopathy has also been classified as reversible (Type I) or irreversible (Type II). This approach has recently been challenged 11, especially since early detection and intervention has changed the course of the cardiomyopathy 12. Another common approach is to describe the temporary relations between treatment exposure and onset of signs or symptoms as acute, early-onset chronic progressive and late-onset chronic progressive 13. Oncology drug-induced cardiotoxicity largely falls into the following five major categories (Table 1): 1. Electrophysiology and repolarisation-related cardiotoxicity, involves drug-induced QT prolongation and Torsade de Pointes (TdP) ventricular arrhythmia, which may result in sudden cardiac death. Other frequently reported arrhythmia are atrial fibrillation and atrial flutter and possibly other (non-TdP) ventricular arrhythmia. Atrioventricular blocks and bradycardia have also been reported. 2. Myocardial tissue-related cardiotoxicity, involves impaired contractility leading to (systolic) left ventricular dysfunction and eventually to heart failure and possibly death. Diastolic dysfunction has also been described. 3. Vascular-related toxicity, may lead to venous and arterial thromboembolic disease, coronary artery disease with myocardial ischemia and infarction, cerebrovascular disease which may result in stroke, and peripheral vascular disease. 4. Haemodynamic changes, which may start with

Definition and Classification of Cardiotoxicity No common definition for oncology drug-induced cardiotoxicity has been adopted. However, in broad terms, cardio-oncology can be defined as acute, subacute or chronic clinical or laboratory impairment of the cardiovascular system following exposure to chemical, biological or radiology anti-cancer therapy. Given the growing Table 1. Cardio-oncology Classification by Toxicity Category www.jforcs.com

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endothelial dysfunction and vessel wall changes, may lead to blood pressure changes, arterial hypertension and also pulmonary hypertension, with their associated clinical complications. 5. Other toxicities, including valvular heart disease, pericardial and pleural disease, pericarditis and myocarditis-like syndromes, autonomic nerve dysfunction and primary sudden cardiac death, to mention a few. Additional taxonomy is the grading of cardiotoxic sideeffects. The most widely-used system is the Common Terminology Criteria for Adverse Events (CTCAE) 14, which is a set of criteria intended to standardise the classification of adverse effects of drugs used in cancer therapy. The Clinical Response The clinical community was the first to recognise and respond to the cardio-oncology challenge. The launch of the International Cardio-oncology Society (ICOS) in 2009 was promptly followed by the creation of national cardiooncology organisations in North America, Europe and the Middle East. In August 2016, the European Society of Cardiology (ESC) issued the first position paper on cancer treatments and cardiovascular toxicity 10. The ESC position paper covers the full spectrum of cardiotoxicities recognised today, with a focus on what appears to be the primary clinical issue – LV dysfunction and heart failure. The paper calls for a multidisciplinary approach, involving specialists in cardiology, oncology and other related fields, with the aim of providing optimal care for both cancer patients and cancer survivors. These goals also involve the development and the safety evaluation of new cancer treatments, as well as the longterm surveillance of cancer survivors with a potential for late-onset cardiovascular complications. The newly-created cardio-oncology discipline is also setting academic training programmes 15 within teaching hospitals and dedicated centres, and is working towards the academic and regulatory recognition of this subspecialisation. Due to the short format of this article, the reader is referred to the bibliography list for further information. Regulatory Considerations With the growing body of evidence showing that oncology drug-induced cardiotoxicity is not limited to time-honoured treatments such as anthracyclines and radiotherapy, but is also pertinent to new drugs in development, regulatory agencies and the pharmaceutical industry also turned their attention to the problem. The first C-O category to be addressed was QT prolongation and pro-arrhythmia, primarily because this topic has already been addressed in the ICH-E14 guidance 16. Oncology drugs, which were initially exempted from 68 Journal for Clinical Studies

the E14 thorough QT/QTc study (TQT), are now required to undergo either a standard TQT study, where feasible, or an alternative version thereof 17 when a full TQT study may be impractical or unethical. The alternative approach, also known as the intensive QT/QTc (IQT) study, involves intensive sampling of ECGs (in replicates) with concomitant drug plasma concentrations (PK) at multiple time points, and relies primarily on comparisons to baseline (dQTc) and concentration:response analysis. This approach has recently been documented in an ICH-E14 questions and answers document 18 and is discussed in detail in other articles in this cardiac safety miniseries. Other cardiotoxicity categories are not covered by regulatory guidance, but are increasingly gaining regulatory attention and scrutiny, primarily the druginduced LV dysfunction and blood pressure effects. As a result, manufacturers are increasingly adopting early detection strategies, including incorporating CV biomarkers (e.g., troponins), imaging modalities (Echo, MUGA and MRI) and electrocardiograms (ECGs) in the early-phase oncology drug development programmes. Drug Development Considerations Non-clinical Research The non-clinical evaluation of cardiac safety (in general) and of new anti-cancer drugs were defined by two ICH guidance documents, the ICH-S7B 19 and the ICH-S9 20 respectively. The emphasis on safety pharmacology (S7B) and toxicology (S9) studies overall streamlined the non-clinical assessment of cardiovascular safety of new cancer therapeutics, both small-molecule and biologics, regardless of their route of administration. With the clinical recognition of drug-induced cardiotoxicity and the introduction of advanced nonclinical drug-testing platforms, safety research of new drugs in development is increasingly shifting towards basic and non-clinical assays. Conventional in-vitro tests such as cell viability and apoptosis assays, isolated heart preparations and ion channel assays, supported by invivo animal studies, remain the mainstay of non-clinical safety evaluation. Nonetheless, progressive approaches such as human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are increasingly used for electrophysiology, contractility and other safety and efficacy tests. Likewise, in-silico computer models for drug effects have sufficiently advanced for scientists and regulators to accept them as part of new drug assessment and approval paradigms. The Comprehensive in-vitro Proarrhythmia Assay (CiPA) 21 (discussed elsewhere in this series), which is intended to replace the current ICH-E14 model, is a primary example of this trend. This is a fully integrated biological systems model, from hiPSC-CM, through ion channel and in-silico models to the human ECG, which is designed to address multiple aspects of drug-induced proarrhythmia. Volume 8 Issue 6


Cardiovascular Safety

Other non-clinical systems to assess contractility, haemodynamic and rheological properties of drugs are available to support an early CV safety profile characterisation of new drugs in development. Clinical Research As discussed above, the clinical research approach for drug-induced QT prolongation and pro-arrhythmia has been defined by the ICH-E14 guidance and focuses primarily on Phase I studies. However, while some oncology drugs underwent formal TQT studies, most took the alternative approach, integrating intensive ECG and PK assessments in early-phase oncology studies as well as in late-phase sub-studies. While the early development approach appears to be preferred by large pharmaceutical sponsors, as part of their early drug iteration strategy, other sponsors tend to delay QT assessments to Phase II or even later studies. The US FDA typically requires cardiac safety (QT) data by the end of Phase II meeting, but sometimes agreed to delay these assessments in return to continued QT monitoring in the late-phase studies, until the cardiac safety data is available. In planning your oncology cardiac safety study, it is important to pay attention to some critical aspects. To mention only a few – cancer patients have been shown to have a higher baseline QTc than healthy volunteers 22; most oncology studies do not employ placebo, consequently, the primary endpoint cardiac safety variable is the change from baseline (d)QTc, which requires a careful collection of baseline ECGs; robust baseline ECG sampling is also important to avoid the ‘regression to the mean’ phenomenon; many cancer patients have pre-existing ECG abnormalities and require a careful and rigorous assessment of the ECGs by an experienced core laboratory; oncology treatments are typically administered in cycles, and it is important to monitor ECGs and other CV safety parameters at all relevant time points and cycles based on the non-clinical safety (pharmacodynamics) and clinical pharmacology (PK) considerations; relationships to comorbidities, prior cancer therapy (especially with QTc prolonging drugs), concomitant medications, and arrhythmias should be assessed; concentration effect modelling is the primary cardiac safety analysis and requires a considerable number of PK and QT data samples across multiple time points and heart rates; QT and heart rate variability are high in sick cancer patients, possibly leading to error in QT correction and assessment; QT:RR hysteresis and possibly PK hysteresis (delayed effects) are more likely in the oncology settings and should be accounted for. When it comes to assessing cardiac contractility, LV function, haemodynamic and other drug-induced cardiovascular effects, most sponsors still do not have a systematic approach, from benchside to bedside. In the absence of relevant non-clinical studies, sponsors may move into an early clinical programme based on heart wish rather than evidence, potentially missing www.jforcs.com

unique opportunities to identify and mitigate early signs of cardiotoxicity. A systematic approach to CV safety assessment should start with appropriate non-clinical planning, as described above, and should be followed with careful assessment and translation of the nonclinical data onto early human studies. The planning and design of clinical CV safety assessments in early-phase oncology studies should begin with the end in mind, appropriately incorporating ECGs, molecular biomarkers and CV, imagining assessment endpoints as relevant, based on relevant statistical considerations and analysis plans. Unfortunately, the scope of this paper doesn’t allow a detailed discussion of the oncology CV safety study design and the reader is referred to the accompanying bibliography. Summary Advances in medical knowledge and technology introduced new treatment options for cancer patients, resulting in significant improvement in cancer survival rates. However, increased life expectancy of cancer survivors highlighted a key issue in cancer therapy – treatment-related cardiovascular toxicity leading to increased (non-cancer) morbidity and mortality. Current scientific and regulatory standards require that new drugs in development undergo rigorous assessments for potential cardiotoxicity. However, while regulatory guidelines established a clear framework for the assessment of drug-induced QT prolongation and proarrhythmia, other key areas of oncology drug-induced cardiotoxicity are still lagging behind. International efforts by clinical, academic, industry and regulatory organisations are underway to increase awareness, establish protocols and improve the overall assessment, prevention and treatment of oncology drug-induced cardiotoxicity. References 1. Steinherz LJ, Steinherz PG, Tan CT et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266: 1672–1677. 2. Armstrong GT, Kawashima T, Leisenring W et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol. 2014 Apr 20;32(12):1218-27. 3. Gianni L, Herman EH, Lipshultz SE et al. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 2008; 2: 3777–3784. 4. Felker GM, Thompson RE, Hare JM et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342: 1077–1084. 5. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11): 783-92. 6. Wittayanukorn S, Qian J, Johnson BS, Hansen RA. Cardiotoxicity in targeted therapy for breast cancer: Journal for Clinical Studies 69


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7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

A study of the FDA adverse event reporting system (FAERS). J Oncol Pharm Pract. 2015 Dec 8. pii: 1078155215621150. Gianni L, Herman EH, Lipshultz SE et al. Anthracycline Cardiotoxicity: From Bench to Bedside. J Clin Oncol. 2008 Aug 1; 26(22): 3777–3784. Ichikawa Y, Ghanefar M, Bayeva M et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest. 2014;124:617–630. Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002 Apr 2;105(13):1551-4. Zamorano JL, Lancellotti P, Rodriguez Muñoz D et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur J Heart Fail. 2016 Aug 27. doi: 10.1002/ejhf.654. [Epub ahead of print] Riccio G, Coppola C, Piscopo G et al. Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies? Hum Vaccin Immunother. 2016 May 3;12(5):1124-31. Cardinale D, Colombo A, Bacchiani G et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015 Jun 2;131(22):1981-8. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 Published: June 14, 2010. https:// evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_5x7.pdf Lenihan DJ, Hartlage G, DeCara J et al. CardioOncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty. J Card Fail. 2016 Jun;22(6):465-71. ICH Harmonised Tripartite Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. ICH-E14, Current Step 4 version. 12 May 2005. http:// www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Efficacy/E14/E14_Guideline.pdf Rock E, Finkle J, Fingert H et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 2009;157:827-836. E14 Implementation Working Group: ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Questions & Answers (R3). Current version dated 10 December 2015. http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/ E14/E14_Q_As_R3__Step4.pdf

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19. ICH S7B. The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. Step 4 version. 12 May 2005. http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/ Step4/S7B_Guideline.pdf 20. ICH S9. Nonclinical Evaluation for Anticancer Pharmaceuticals. Step 4 version. 29 October 2009. http:// www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Safety/S9/Step4/S9_Step4_Guideline.pdf 21. Colatsky T, Fermini B, Gintant G et al. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress. J Pharmacol Toxicol Methods. 2016 SepOct;81:15-20. 22. Sarapa N, Britto MR. Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents. Expert Opin Drug Saf. 2008 May;7(3):305-18.

Boaz Mendzelevski, MD is a consultant cardiologist at Cardiac Safety Consultants Ltd. Dr Mendzelevski received his degree in Medicine and Board Certification in Internal Medicine from the Ben-Gurion University Medical School and Soroka Medical Center in Beer-Sheva, Israel. He then obtained his Board Certification in Cardiology from the ShaareZedek Medical Centre in Jerusalem, Israel. He completed a subspecialty training in Interventional Cardiology and Electrophysiology at the Royal Brompton Hospital in London, UK. Dr Mendzelevski co-founded the first European Pharmaceutical-focused ECG core laboratory, Cardiac Alert Ltd, in 1995 in London, UK. The lab was acquired by Quintiles transnational in 1998 to become the QECG laboratory. Dr Mendzelevski served as the Quintiles Vice President of Cardiology and the QECG CMO. He moved to Covance in 2003 to launch its European Cardiac Safety Services and in 2008 he joined Medifacts International, which later merged into CoreLab Partners and then BioClinica, as Vice President of Cardiology. Dr Mendzelevski serves as a consultant to the pharmaceutical and biotechnology industry and provides expert input regarding cardiovascular safety in drug development. He has published in several journals and authored more than 280 cardiology expert reports. He served on several data safety monitoring boards (DSMBs/ DMCs) and provides input on safety issue to the industry and regulatory agencies. Dr. Mendzelevski supported the development of the ICH-E14 cardiac safety guidance and the implementation of ICH-E14 in US, Europe and Asia. He chaired the European DIA Cardiac Safety Conferences since 2006 and the US DIA/FDA CV Safety conferences on Type 2 Diabetes. He is the chair and co-chair of the Annual Japan and China DIA Cardiac Safety Workshops since 2010 and is a regular speaker at other scientific and industry meetings. Volume 8 Issue 6


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Cardiovascular Safety

The Comprehensive in Vitro Proarrhythmia Assay The focus of the Comprehensive in Vitro Proarrhythmia Assay (CiPA) is on delayed repolarisation and Torsades de Pointes (TdP) proarrhythmia, a rare but potentially lethal drug-induced arrhythmia that can lead to ventricular fibrillation and death. To address limitations with the present approaches (refer to other papers in series), the goal of CiPA is to provide a new in vitro-based paradigm that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic liability of evolving drugs. 1,2 Fortunately, the electrophysiologic mechanisms responsible for TdP are now well understood. 3 This allows CiPA to move beyond the traditional, presently accepted paradigm for evaluating preclinical proarrhythmic liabilities (drug block of the influential repolarising current in human ventricles (hERG/iKr)), as discussed in the ICH S7B Guidance, 4 as well as the evaluation of clinical proarrhythmic liability based on QT prolongation assessed in thorough QT (TQT) studies as discussed in the ICH E14 Guidance. 5 Indeed, CiPA is intended to replace the cumbersome (and expensive) TQT study typically conducted late in drug development with earlier, mechanistic-based studies that will include robust preclinical and clinical assessments. This paradigm will also guide a more rational drug candidate selection process, coupling early clinical studies (using exposure response modelling derived from first in human studies: refer to other papers in series) to confirm non-clinical findings of minimal electrophysiologic effects. The CiPA paradigm relies on four components to define an overall integrated proarrhythmic risk assessment, as illustrated in Figure 1. First, drug effects on multiple cardiac ionic currents are defined using human ionic channels in simplified heterologous expression systems. The net

electrophysiologic effect of a drug on ventricular electrical activity is then characterised based on the integrated electrophysiologic response provided by welldefined in silico reconstructions of human ventricular myocytes. Results from the in silico reconstructions are then compared to known clinic risks characterised for 28 drugs divided into three categories of proarrhythmic risk (high, intermediate, and low/no proarrhythmic risk), providing a clinically-based “gold standards� metric by which to calibrate the CiPA paradigm. The in silico findings are also verified empirically using human stem cell-derived ventricular myocytes, ensuring that any novel mechanisms are considered. Finally, drug effects on ECGs from early, well-controlled, first in human clinical studies are evaluated for unanticipated electrophysiologic effects. More recent clinical studies have demonstrated that specific morphological characteristics of human ECGs could serve as additional reliable biomarkers of proarrhythmic risk. 6 This overall strategy for CiPA is founded on deep mechanistic insights of the underlying cellular ionic factors responsible for interfering with cardiac repolarisation that are directly amenable to study. Drugs that hinder repolarisation may affect the strength or synchrony of repolarisation or generate premature electrical activation. This cellular effect may be manifest as irregular activity in one area that propagates away and subsequently returns, thus creating an electrical circuit supporting TdP. It should be noted that all facets of CiPA are based on human-derived data, thus avoiding potential species differences that may be present when translating non-clinical data from animals to human studies. CiPA evolved based on remarkable progress made

Figure 1. Elements of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) (Reproduced with permission from Gintant et al., Nature Reviews Drug Discovery, 2016). 72 Journal for Clinical Studies

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in recent years in understanding TdP proarrhythmia. Based on multiple years of research (which started with the description of polymorphic ventricular tachycardia by the French clinician Francois Dessertenne some 50 years ago), we now have a firm understanding of the mechanisms responsible for genetic- and drug-induced TdP. Technological advances now provide commercially available human ionic currents expressed in various “background” cell types for all prominent cardiac ionic currents. Advances in engineering now provide automated patch clamp platforms able to easily interrogate the functional concentration-dependent effects of drugs on ionic currents. Such studies have demonstrated the importance of considering block of multiple cardiac currents (beyond simply iKr/hERG current alone) in defining proarrhythmic risk, emphasising that the potency of block of only one of multiple cardiac currents defining ventricular repolarisation is insufficient. 7 In vivo and in vitro studies with human ventricular myocardium have provided sufficient data to support the development of robust in silico models of human ventricular activity to define drug effects on cardiac repolarisation. Such reconstructions 8 (based on the O’Hara-Rudy model 9) are already freely available online. 10 Also, advances in stem cell technologies have provided human-derived ventricular myocytes for in vitro studies (thus overcoming the lack of human tissues for studies). While not fully recapitulating all aspects of adult ventricular myocytes, stem cell derived cardiomyocytes have repeatedly demonstrated their ability to detect well-recognised proarrhythmic drugs. Higher-throughput techniques are available to evaluate effects on repolarisation using stem cell derived ventricular myocytes (including multielectrode arrays 11,12 and voltage-sensing dyes 13 [which provide for direct measures of drug-induced changes in extracellular and intracellular electrical activity] as well as measures of extracellular impedance 14 and calcium transients 15 [providing indirect measure of electrophysiologic effects]). Clinical experience, along with multiple TQT study results generated over the last decade, have provided the basis for classifying drugs for

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proarrhythmic risk. Finally, the standardisation of the clinical evaluation of ECGs (involving clinical protocols as well as waveform analysis and interpretation) based on TQT study experience has proved invaluable in defining the clinical standards for the evaluation of QT effects in early first in human studies. Indeed, such studies support the exposure-response modelling and evaluation of T-wave morphology changes as part of the mechanistic assessment of proarrhythmic risk. Organised as a public-private collaboration, CiPA represents a consortia effort including the United States Food and Drug Administration (FDA), Health and Environmental Sciences Institute (HESI), Cardiac Safety Research Consortium (CSRC), Japan National Institutes of Health Sciences, Health Canada, European Medicines Agency (EMA), and the Japanese Pharmaceutical and Medical Devices Agency. At present, multiple working groups are further defining the roles of multiple CiPA components. 16 The Ion Channel Working Group is conducting studies defining potency of drug block of seven cardiac ionic currents (four repolarising potassium currents [iKr/hERG, IKs, Ito, iK1], as well as early (INa,Fast) and later (INa,Late, ICa) depolarising currents). In anticipation of a validation study, the In Silico Working Group is identifying candidate proarrhythmic metrics that classify TdP risk using a training subset of 12 drugs categorised for proarrhythmic risk by the Clinical Working Group. Recognising the importance of the dynamics of block of iKr/hERG current, the In Silico group is also evaluating the utility of incorporating a dynamic model of hERG block into the O’Hara-Rudy in silico reconstructions. Following up on an initial pilot study, the Myocyte Working Group is conducting a validation study defining the concentration-dependent electrophysiologic effects of the 28 CiPA compounds on two commercially available stem cell derived cardiomyocyte lines across two technology platforms (microelectrode array (MEA) and voltage-sensing optical (VSO)) at multiple sites. Finally, the Clinical Translation Working Group (under joint direction from the CSRC and HESI) completed the

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categorisation of proarrhythmic risk for a set of 28 clinical drugs representing a diverse class of chemical structures and therapeutic indications. Since the initial public discussion of CiPA in July 2013, significant scientific progress has been made within CiPA. The CiPA Steering Committee is providing the ICH S7B/E14 Discussion Group with ongoing updates on working group progress and seeking input from ICH on the regulatory implementation of CiPA as the effort evolves over the next ~ 1.5 years, and the CiPA effort is on track to complete the necessary work by the end of 2017. A meeting to discuss progress of the CiPA initiative is scheduled for December 2016. References 1. Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart J. 2014;167:292-300. 2. Gintant G, Sager PT, Stockbridge N. Evolution of strategies to improve preclinical cardiac safety testing. Nat Rev Drug Discov. 2016;15:457-471. 3. Roden DM. Predicting drug-induced QT prolongation and torsades de pointes. J Physiol. 2016;594:24592468. 4. ICH Guideline S7B. May 2005 (a). Available at: h t t p : / / w w w . i c h . o r g / f i l e a d m i n / Pu b l i c _ We b _ S i t e / ICH_Products/Guidelines/Safety/S7B/Step4/S7B_ Guideline.pdf (Accessed 12th August 2016) 5. ICH Guideline E14. May 2005 (b). Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Efficacy/E14/E14_Guideline.pdf (Accessed 12th August 2016) 6. Vicente J, Johannesen L, Mason JW et al. Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil. J Am Heart Assoc. 2015;4(4). 7. Kramer J, Obejero-Paz CA, Myatt G et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep. 2013;3:2100. 8. Beattie KA, Luscombe C, Williams G et al. Evaluation of an in silico cardiac safety assay: using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. J Pharmacol Toxicol Methods. 2013;68:88-96. 9. O’Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol. 2011;7:e1002061. 10. Williams G, Mirams GR. A web portal for in-silico action potential predictions. J Pharmacol Toxicol Methods. 2015;75:10-16. 11. Harris K, Aylott M, Cui Y et al. Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol Sci. 2013;134:412-426. 12. Nakamura Y, Matsuo J, Miyamoto N et al. Assessment www.jforcs.com

of testing methods for drug-induced repolarization delay and arrhythmias in an iPS cell-derived cardiomyocyte sheet: multi-site validation study. J Pharmacol Sci. 2014;124:494-501. 13. Taylor AE, Zamora V, Hortigon-Vinagre MP et al. Electrophysiological characterization of iCell2 hiPSC derived cardiomyocytes: the new generation of CDI hiPSC-CMs. Safety Pharmacology Society Meeting 2015. Available at: http://www.clydebio.com/wpcontent/uploads/hIPSC-CMs-CDI-2nd-GenerationClydeBiosciences-SPS2015.pdf (Accessed 12th August 2016) 14. Zhang X, Guo L, Zeng H et al. Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment. J Pharmacol Toxicol Methods. 2016 Jun 7 [Epub ahead of print] 15. Lu HR, Whittaker R, Price JH et al. High throughput measurement of Ca++ dynamics in human stem cellderived cardiomyocytes by kinetic image cytometery: a cardiac risk assessment characterization using a large panel of cardioactive and inactive compounds. Toxicol Sci. 2015;148:503-16. 16. Fermini B, Hancox JC, Abi-Gerges N et al. A new perspective in the field of cardiac safety testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm. J Biomol Screen. 2016;21:1-11. Given these considerations, other paradigms for investigating proarrhythmic risk are of considerable interest. These are discussed in the next two papers.

Gary Gintant, Research Fellow, Abbvie Dr. Gary Gintant is a Senior Research Fellow in the Dept. of Integrative Pharmacology, Integrated Science and Technology, at AbbVie. He is involved in multiple internal drug discovery and safety initiatives internally; external activities include various cardiac safety initiatives (such as ILSI/HESI Proarrhythmia Models Project, the Cardiac Safety Research Consortium, and the Comprehensive in Vitro Proarrhythmia Assay Initiative) while serving on various journal editorial boards, NIH study sections, and Safety Pharmacology Society committees. Research interests include cardiovascular pharmacology, cellular electrophysiology/ion channels, arrhythmias, application of stem-cell derived cells and tissues to drug discovery efforts, and translational medicine. He gained his MA, M.Phil. and PhD degrees from the College of Physicians and Surgeons of Columbia University. Journal for Clinical Studies 74


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Cardiovascular Safety

Which Protocol Should I Use: The Standard ICH E14 Thorough QT/QTc Study or Concentration-effect Modelling? The article by Dr Robert Kleiman in the previous issue of this journal 1 described a method for evaluating repolarisation effects of new drugs that has recently been accepted 2, and to a considerable extent, advocated 3 by the US Food and Drug Administration (FDA). The concentration-effect modelling approach is appealing because it is intended to be performed at the very beginning of the clinical development phase, and to be a simple add-on to the usual first-in-human dose escalation pharmacokinetic study. This means that the ethical issue of exposing volunteers and patients through Phases I and II, before definitively determining if the drug is electrophysiologically safe, is solved, and the time, effort and cost of the drug’s development that would have taken place through Phase II can be avoided for drugs with prohibitive ECG effects. In addition, moving the ECG assessment to the beginning of Phase I clinical development may make some sponsors more willing to bring drugs with a non-clinical ECG signal to the clinic, knowing that the ECG issue will be resolved much sooner than usual. This reduces concern that potentially safe and effective treatments are being discarded because of non-clinical observations that might not be real safety issues in clinical use. The purpose of this article is to help pharmaceutical sponsors decide between the two accepted methods for assessing ECG liability of new drugs. First we consider those situations in which only one of the two options for thorough ECG screening is appropriate, and then we consider the host of factors that would favour one or the other approach when there is a choice. Finally, we provide some qualitative estimates of the risk of using one rather than the other method. The concentrationeffect modelling approach will be referred to as CEM, and Tables the standard ICH E14 approach described in the original Guidance 4 and its first two Q&As 2 will be referred to as Table 1: Categories of drugs for which a thorough TQTS.

done

No-choice Situations Neither Method Appropriate First, let’s examine the situations for which neither method is appropriate or necessary. These are listed in Table 1 and are, for the most part, self-explanatory. Toxic drugs that cannot be administered without a potential benefit cannot be placebo controlled, except when tested as an add-on to standard treatment, but in the latter situation a rigorous TQTS or CEM design is usually not possible. Drugs that do not reach the systemic circulation or cannot access the intracellular compartment are not required to undergo QT testing, with rare exceptions. Finally, drugs known or intended to prolong QT are waived from the requirement. Note, however, the drugs waived because of placebo control and other protocol design limitations still require an alternative assessment of their QT effects. CEM Method Not Appropriate, but TQTS Appropriate Known pharmacokinetic – pharmacodynamic (PK-PD) hysteresis: If a drug’s effect on the ECG is known to be delayed, with its peak effect occurring an hour or more after Cmax is achieved, the drug is a poor candidate for the CEM approach. While there are several options for dealing with hysteresis, none seem to be perfect solutions, especially in the presence of potential participant-related random effects. 5,6 Very long half-life: Drugs that persist in the circulation for many days or weeks with little change in plasma concentration are not good candidates for CEM because the variability of ECG measurements over such a protracted period of sampling may obscure or simulate a drug effect. This problem may, in some cases, be manageable by collection of frequent samples while the drug is being administered, in the case of infusions, or immediately after oral administration, making it unnecessary to track ECG assessment cannot or should not be the subsequent slow decline in plasma concentration.

Cytotoxic oncology drug Other drugs that cannot be placebo-controlled Drugs without systemic availability Biologicals too large to access the cytosol Drugs with already proven QT effects Antiarrhythmic and other drugs that intentionally prolong QT Table 1: Categories of drugs for which a thorough ECG assessment cannot or should not be done

Table 2: Factors Bearing on Choice of Method Factor

Favoured Method

Price and time very critical to sponsor Clinical dose cannot be reliably

CEM CEM

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Weight of Factor H M

Herbal and multiple-moiety drugs: When the active chemical entity is not known, or multiple parent entities are potentially active, the CEM method cannot be used because a clinically or regulatorily useful relationship between plasma concentration and ECG effect cannot be established. Dose-effect modelling might be an alternative in some of these cases, but a time-point-oriented E-14 approach is more appropriate.

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Drugs with already proven QT effects Antiarrhythmic and other drugs that intentionally prolong QT

Cardiovascular Safety

Table 2: Factors Bearing on Choice of Method Factor

Favoured Method

Weight of Factor H M

Phase III, the sponsor would spend less using the standard method at the end of Phase II.

Speed In general, using the CEM approach is much faster, because the PK and the ECG objectives are achieved in a single study, eliminating the time CEM M required to perform the standard TQTS H TQT study at the end of Phase II. TQTS H In addition, in most situations the CEM study can be completed more TQTS H quickly than the standard TQTS. TQTS L This is primarily due to the fact TQTS M that most standard TQT studies have a crossover design, requiring a washout period between arms, TQTS L and virtually all treatment arms in the standard TQTS are completed using two or more cohorts. In the Table 2: Factors Bearing on Choice of Method CEM approach, assuming that a TQTS Not Appropriate, but CEM Appropriate parallel design is used, each arm is completed without There may be no real situations in which a standard TQTS the need for an inter-arm washout, and each arm is approach could not be used, but a CEM approach could completed with a single cohort. Exceptions to this time be used. A theoretical possibility would be a drug with difference would include PK studies with a large number unpredictable or random Tmax. In this situation, the of tested doses and those in which it is necessary to await time-point-oriented analysis might miss a substantial PK results before proceeding to the next escalation. ECG effect because it would be diluted across time, whereas the CEM method would capture the relationship SAD/MAD Studies Already Done of drug concentration to effect. In this early period of availability of the CEM method for QT assessment, many sponsors have already completed When There is a Choice their SAD/MAD experiments. Naturally, they are reluctant In this section we explore the relative importance of to consider repeating the PK studies (modified to include multiple features of the two methods, as well as potential thorough ECG assessment), because it seems redundant features of the study drugs in choice of the method to be and wasteful. But, in fact, it is not fiscally wasteful, in used. Most of these factors are summarised in Table 2. most instances, and the previous completion of PK studies provides an additional advantage. As pointed out Price above, the CEM study costs less and can be completed The standard TQTS approach costs more than the CEM more rapidly than the standard TQTS. Thus, there is approach in most cases. For the “pure” case of a single no waste in repeating a PK-style protocol, but rather a dose experiment with relatively few (i.e., four) dose saving in both money and time. And, with the safety and levels, the CEM methods cost about half as much as the tolerance information derived from the original PK study, standard TQT study. The lower cost is related primarily to the CEM study can use a non-serial, parallel design with the smaller number of participants and lack of need for multiple dose cohorts run simultaneously without the the confinement during washout that is associated with need to determine safety and tolerance between cohorts. the typical crossover TQTS. If higher doses need to be explored, only those doses would need to follow the usual serial assessment. Thus, if There is a very interesting sidebar to the price PK studies were already done, the CEM study can be done consideration. While the sponsor may save money by very quickly and efficiently. doing a CEM study instead of a TQTS, using the CEM strategy for all of the sponsor’s drugs that reach clinical Single vs Multiple Dose development may, in the long run, cost more. While If multiple doses of the test drug over multiple days virtually all drugs that graduate to clinical assessment are required to achieve the necessary supratherapeutic undergo a first-in-human PK study (where the CEM ECG exposure, depending on the details, this situation assessment would be grafted on), many drugs fail to reach might favour the standard TQTS protocol. In the latter, the end of Phase II, at which point the standard TQTS multiple days of dosing would only be required for the has usually been done. If the average cost of the latter is supratherapeutic dose of the test drug and the placebo double, but fewer than half of the drugs that enter Phase arms, while the remaining moxifloxacin treatment could I are successful enough to undergo a TQTS preceding be achieved with a single dose. But, in a CEM study, a

Price and time very critical to sponsor Clinical dose cannot be reliably predicted Tmax highly variable Known PK-PD hysteresis Very long half-life Herbal, multiple moieties Multiple days of dosing required Only relatively low exposure achievable Crossover cannot be done H – high; M – medium; L – low weight

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CEM CEM

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lengthy dosing period would be required for all arms. If many dose levels were required, the duration of the CEM approach would exceed that of the TQTS, despite its washout confinement, and the cost of housing the volunteers might raise the cost of the CEM beyond that of the standard TQTS.

some drugs (especially those with long half-lives), the parallel design might be forced on the sponsor. In these instances, the speed advantage enjoyed by the CEM approach might be lost, as a parallel designed QT study can be executed faster than a crossover design in Phase I units large enough to accommodate large cohorts.

Achievability of the Exposure Requirement This may be the deciding factor in many instances. FDA has repeatedly made it clear that the maximum exposure achieved in the CEM approach must exceed that of the standard TQT method. Exactly what multiple of the usual clinical exposure is required for either study method, however, is not specified in the ICH E14 Guidance or its subsequent Q&As. The original ICH E14 document refers to “substantial multiples” (Section 2.2.2 4). In practice, a three-fold exposure has commonly been achieved in TQT studies and this has been considered sufficient during the review process. Of course, there are surely exceptions to this rough guideline – both higher and lower multiples being appropriate for specific drugs. Thus, in the typical CEM protocol, it would seem necessary to achieve at least four-fold exposure in a substantial number of subjects, and I have recently been recommending five-fold as the minimal target. For many new drugs, a five-fold exposure cannot be achieved. In these cases, the standard TQTS approach is more likely to satisfy regulators. The recent Q&A, ICH E14 Q&A (R3) 2, and public statements by FDA officials, indicate that the positive control of the standard TQTS provides the needed reassurance when only threefold or even lower supratherapeutic exposures can be achieved.

Relative Risk of the Two Approaches Each of the two methods has a risk of failure. The relative risks should be considered in making a final choice.

The same sources have indicated that inclusion of a positive control in a CEM protocol could reduce the need for a very high supratherapeutic dose. While this is an appealing strategy, I have seen results from a few studies recently in which the positive control arm failed to meet standard ICH E14 assay sensitivity criteria (the expected pattern of response over time, and a lower bound of the two-sided 90% confidence interval above 5 msec) – almost surely the result of the active control cohort containing the same small number of subjects enrolled in the other cohorts. Proving assay sensitivity in the CEM approach will probably require enrolling large active control cohorts, similar to or approaching the usual cohort size in the standard TQTS. This might tip the balance in favour of doing a standard TQTS rather than inserting a small active control cohort into the CEM approach. Crossover Not Possible When a crossover design cannot be used in a standard TQTS, should this influence the choice of study method? Perhaps. Typically, a sponsor would not select the parallel design for a standard TQTS if an efficient crossover is feasible, due to the extra cost of participant recruitment, the larger number of participants needed in each treatment arm, and the loss of power that might not be fully compensated for by the larger enrolment. But, for 78 Journal for Clinical Studies

Dose limitation: In the first-in-human setting, the sponsor only has an educated guess as to what maximum dose and exposure can be achieved in humans, and a less well-educated notion of how that relates to the usual clinical exposure. If, for example, only two or three doses can be tested due to intolerance, the experiment might not provide sufficient PK-PD sample pairs covering a sufficiently wide range of plasma concentrations. This would result in a failed CEM study. This risk could be averted by delaying the thorough ECG assessment to the end of Phase II. As a result, the maximum achieved exposure in the first-in-human experiments might, when more clinical experience has been collected, turn out to be insufficiently greater than the usual clinical exposure. In these cases, a standard TQTS might be the only way to resolve the issue, subjecting the sponsor to the loss of time and expense of doing both studies. This situation can be obviated by defaulting to the standard TQTS approach at the end of Phase II. Unexpectedly high clinical exposure required for efficacy: This problem is related to the one above. The maximum achieved exposure in the first-in-human experiments might, when more clinical experience has been collected, turn out to be insufficiently greater than the usual clinical exposure. This would most commonly occur when the sponsor limited the SAD/MAD dosing levels on the basis of the expected clinical dose, rather than pushing the SAD/MAD doses to intolerance. In these cases, a standard TQTS might be required to resolve the issue, subjecting the sponsor to the lost time and expense of doing both studies. However, this very same problem may affect a standard TQTS done at the end of Phase II, because, in general, it is only in Phase III that the final clinical dose is determined. Standard TQT studies have had to be repeated because of the Phase III finding that efficacy requires a large dose. 7,8 Interestingly, the CEM approach is probably the best way to protect against this unwanted outcome. That is because ICH E14 Q&A (R3) specifically allows for metaanalysis of PK-PD data collected in multiple independent protocols. Thus, the sponsor could simply perform a limited CEM study covering the higher exposure levels, add the new data to the previous CEM data and produce a satisfactory analysis. This would be much easier, faster and less expensive than repeating an entire TQTS. Volume 8 Issue 6


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Failure to prove assay sensitivity: This is a risk only in the standard TQTS approach (assuming no active control is incorporated in the CEM study). If it occurs, the TQTS might have to be repeated. The risk can only be avoided by choosing the CEM approach. However, in cases in which assay sensitivity criteria are not met, there is often an explanation or mitigating circumstance, with the result that the TQTS findings are accepted and a repeat study is not required. Summary We now have two methods to fulfill the regulatory requirement to thoroughly evaluate ECG effects of new drugs. Superficially, the CEM approach may seem preferable because it gives early answers at a lower cost and with considerable time savings. But, there are many factors that must be considered in making the choice between the CEM and the standard TQTS approach. The standard approach will be found to be a better strategy in many circumstances, despite the attractiveness of the CEM method. A decision list like the one shown in Table 2 could be used to help direct the decision process. References 1. Kleiman RB. Use of concentration effect modeling for cardiac safety ECG assessments. Journal for Clinical Studies. 2016;8(5):68-70. 2. E14 Implementation Working Group. ICH E14 Guideline: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs. Questions & Answers (R3). December 2015. Available at: http://www.ich. o r g / f i l e a d m i n / P u b l i c _ We b _ S i t e / I C H _ P r o d u c t s / Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf (Accessed 4 September 2016) 3. Darpo B, Garnett C, Keirns J, Stockbridge N. Implications of the IQ-CSRC Prospective Study: Time www.jforcs.com

to Revise ICH E14. Drug Saf 2015;38:773-80. 4. ICH Guideline E14. May 2005. Available at: http:// w w w . i c h . o r g / f i l e a d m i n / P u b l i c _ We b _ S i t e / I C H _ Products/Guidelines/Efficacy/E14/E14_Guideline.pdf (Accessed 2 September 2016) 5. Louizos C, Yanez JA, Forrest ML, Davies NM. Understanding the hysteresis loop conundrum in pharmacokinetic/pharmacodynamic relationships. J Pharm Pharm Sci 2014;17:34-91. 6. Wang J, Li W. Test hysteresis in pharmacokinetic/ pharmacodynamic relationship with mixed-effect models: an instrumental model approach. J Biopharm Stat 2014;24:326-43 7. Darpo B, Lee SK, Moon TE, Sills N, Mason JW. Oritavancin, a new lipoglycopeptide antibiotic: results from a thorough QT study. J Clin Pharmacol 2010;50:895-903. 8. Mason JW, Bellibas SE, Huang NY, Sanabria CR, Darpo B. Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin. Clin Pharmacol Drug Dev 2016.

Jay W. Mason, MD. Dr. Mason is Professor of Medicine (Cardiology) at the University of Utah, Chief Medical Officer at Spaulding Clinical Research, and an independent consultant in cardiac safety. He was Chief of Cardiology at the University of Utah from 1983 to 1999, and Chairman of the Department of Medicine at the University of Kentucky through 2003, after which he served as Medical Director at Covance Cardiac Safety Services. Journal for Clinical Studies 79


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