Volume 5 - Issue 5
Volume 5 - Issue 5
U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets PEER REVIEWED
Journal For Clinical Studies Your resource for Multisite Studies & Emerging Markets
Paediatric Patient Retention It’s Not Child’s Play
Macroeconomic Forces Driving Clinical Trial Costs
Clinical Investigation of Medical Devices Promoting Convergence www.jforcs.com
Investigators’ Legal Status in Entering Clinical Trial Services Agreements Should They be Registered as Entrepreneurs or Not
Contents JOURNAL FOR
U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets
MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker
MANAGING EDITOR Mark A. Barker EDITORIAL MANAGER Jaypreet Dhillon EDITORIAL ASSISTANTS Evelyn Rogers DESIGN DIRECTOR Aieden Menzies Designer vaishali Datta RESEARCH & CIRCULATION MANAGER Dorothy Brooks BUSINESS DEVELOPMENT Ovidiu Terinte 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: firstname.lastname@example.org www.jforcs.com The Journal for Clinical Studies – ISSN 1758-5678 is published by-monthly by PHARMAPUBS.
The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.
04 FOREWORD Watch Pages 08 H7N9 Influenza and the Rush to Vaccine Development On March 31, 2013, the Chinese health authorities announced the first human case of a new strain of avian influenza, a virus H7N9. By the end of April, 126 human cases of the new H7N9 virus had been reported. Walter Chalkley at Thomson Reuters explains due to a combination of the health measures put in place by Chinese officials, as well as the seasonal nature of avian influenza viruses, the outbreak was contained and cases of infection dropped off precipitously after April. 10 New Cardiovascular Safety Watch Column Central Arterial Pressure and Cardiovascular Safety The sphygmomanometer has been used for over 100 years to measure the systolic and diastolic blood pressures in the brachial artery. D. Winter at AtCor Medical Inc explains how blood pressure in the brachial artery can be very different from the pressure at the heart. 12 Cardiovascular Therapeutics Watch Column Both individual patient and public health considerations are extremely important when addressing a health issue of the magnitude of hypertension, which, as noted in the previous column, was recently and authoritatively designated as the greatest threat to the global burden of disease. R. J. Turner and Philip Galtry at Quintiles explain that therapeutically beneficial interactions between individual patients and their physicians are the cornerstone of the practice of both behavioural medicine and biopharmaceutical medicine. 14 Demystifying Clinical Trials Insurance Often the last thing considered when setting up a clinical trial is insurance, and yet it is a critical, albeit confusing, part of the project. To help shed some light on the issues faced, Chris Tait at Chubb Insurance discusses the basis upon which global trials should be insured, along with the types of insurance coverage available to the key players. He will also look at how “hold harmless” provisions between various parties should be designed and how the process can be managed efficiently. 16 Editing, Proofreading and Back-translation – Options in the Translator’s Toolbag Contracts, patient consent forms, protocols, clinical trial manuals, trial flowcharts or scientific reports need to be translated at some time or another. The individual sites and associated medical collaborators need to know precisely how to conduct the trial, and patient safety must never be compromised. Luigi Koechlin at Global Voices explains accurate and timely translation of all required study documentation is imperative, and so it becomes ever more important to identify a translation agency that has the experience and absolute focus on the quality and timeliness of the translation.
Volume 5 Issue 5 September 2013 PHARMA PUBLICATIONS www.jforcs.com
Journal for Clinical Studies 1
Regulatory 18 Investigators’ Legal Status in Entering Clinical Trial Services Agreements: Should They be Registered as Entrepreneurs or Not? Lana Sinichkina and Igor Svitlyk at Arzinger look into a question often asked lately by the community involved in clinical trials for medicines; whether individuals should enter into clinical trial services agreements with non-resident sponsors, and whether they may enter into such relations without becoming entrepreneurs. 20 Improving Transparency and Benefit/Risk Assessments with the New Risk Management Plan There is no doubt that the future of drug development lies in personalised healthcare – making sure the right medicine is given to the right patient at the correct time and dose. The rapidly expanding fields of pharmacogenomics and, more recently, metabolomics, are testament to this trend. However, for personalised healthcare to be effective, patients also have to be engaged and involved in the process. Both the regulatory authorities and the industry as a whole have recognised this and the process of drug development and treatment paradigms are changing as a result. Julia Forjanic Klapproth & Lisa Chamberlain James of Trilogy Writing & Consulting discuss the recent raft of changes in pharmacovigilance legislation.
Stephan Wnendt and Katja Neuer-Etscheidt at MLM Medical Labs discuss the different categories of laboratories involved in clinical labs, and this can be used as a brief guidance for a good match between study design and laboratory services. 36 Selecting a Right Patient Recruitment Company One of the major challenges that biopharmaceuticals and medical device companies are facing nowadays is the delay in getting their drug/device in the market through a successful development programme. Ashok Ghone at MakroCare looks at the most common reason for delays in clinical trial or development programmes. 40 Macroeconomic Forces Driving Clinical Trial Costs A lot has been written about the Affordable Care Act (ACA) recently. Key provisions are kicking in over the next few months and that has left everyone asking the same question — how will the ACA affect healthcare costs in the US? While “affordable” is right there in the title of the legislation, Ryan McGuire of Cutting Edge Information discusses another important question we should be asking, which is “Will the ACA provide any relief to the increase in clinical trial costs by giving payers even more control over reimbursement decisions?”
24 Clinical Investigation of Medical Devices: Promoting Convergence The safety, performance and effectiveness of medical devices are evaluated by clinical investigation before they enter the market. The integrity of the data is ensured using international standards like ISO 14155:201, Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice or ICH E6 Guideline for Good Clinical Practice (GCP), or other GCPs. A clinical investigation design should be made which is appropriate and acceptable by many regulatory bodies. This article by Shilpi Khattri, V. Balamuralidhara and T. M. Pramod Kumar of JSS College of Pharmacy, JSS University, Mysore, brings out the differences between ISO GCP and ICH GCP. Market Report 28 Clinical Trials in Russia – Report on Q2 of 2013 Igor Stefanov at Synergy Research Group provides an overview of recent movements of the Ministry of Health of the Russian Federation, and how they have approved 199 new clinical trials of all types, including local and bioequivalence studies during the second quarter of 2013. 32 Choosing the Right Lab: Big is Not Always Beautiful Many challenges have to be properly addressed in order to conduct a clinical study successfully: defining the right study design for a given drug candidate, selecting appropriate study centres with excellent access to the study population, identifying a central lab which can manage all study-related tasks and which provides valid and reliable laboratory data with short turn-around times. 2 Journal for Clinical Studies
Volume 5 Issue 5
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Therapeutics 44 Pediatric Patient Retention: It’s Not Child’s Play In June 2013, the European Commission published a report on the first five years of the Paediatric Regulation that came into force in the European Union (EU) on 26 January 2007. The regulation aimed to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years, and ensure that medicines for use in children are of high quality, ethically researched and authorised appropriately. But the inclusion of children in clinical research brings unique complexities. Elizabeth Moench of MediciGlobal Ltd. discusses why paediatric clinical trials involve a distinctive set of challenges that can result in increased costs for patient retention, as well as additional time required to develop customised and meaningful retention programmes.
56 Sustainable Design of Temperature-Controlled Packaging: Single Use Versus Reusable Packaging Many companies are beginning to make a conscious effort to think about the environmental impact of their temperature-controlled packaging use. But this isn’t just limited to whether the packaging is single-use, returnable or made using recyclable materials; there are many more considerations to be accounted for to ensure that a temperature-controlled packaging’s design is really valued as sustainable. Karen Adams from DS Smith Plastics Cool Logistics explains.
46 Adjunctive Treatment with Atypical Antipsychotics Among Adolescents with Major Depressive Disorder Among adolescents, lifetime prevalence estimates for major depressive disorder (MDD) range as high as 8-11%. Depressed adolescents are also at risk for psychiatric hospitalisation, suicidal ideation and completed suicide. Miranda Porter at INC Research provides an overview of why researchers and clinicians emphasise the immediate and critical need for clinical trials investigating safety and efficacy of AAs in adolescent MDD. 48 The Role of Central Laboratories in AD Trials Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that mainly affects the elderly population. The prevalence of AD is predicted to increase to 115.4 million by 2050. Tatiana Souslova at ACM Global Central Lab looks into why, despite having the first drug Tacrine approved by the FDA in 1993, there has been little progress made in the development of pharmacotherapy for AD treatment. IT & Logistics 52 Safety Data Management for Clinical Trials Capture and management of safety data is a critical component of the clinical trial (CT) process. Suhasini Sharma, Chitra Lele and Darshan Bhatt at Sciformix discuss why ensuring safety of clinical trial participants, systematic capture and analysis of safety data from CTs is important for developing the safety profile of the drug and contributing to its benefit-risk assessment, which is a key consideration in the approval decision.
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Volume 5 Issue 5
Foreword Currently, an estimated 50,000 clinical trials are being run worldwide. Over 40 per cent of these new studies are taking place in so-called nontraditional research areas — countries that are experiencing epidemiological change associated with declining health resources but that have little share in the world’s pharmaceutical market. The bulk of these trials are commercially sponsored, and they range from gene therapy studies for rare diseases to studies for treatments for more common disorders; from studies of compounds mimicking existing drugs to studies in search of secondary uses for them.. With the continued expansion of Journal for Clinical Studies, we have covered many of these growing markets, and highlighted the benefits and advantages these countries can bring. In this issue of JCS, we have another set of interesting features, which will guide you progressively. We have a new contributor for our Cardiovascular Safety Watch Page. D. Winter at AtCor Medical Inc discusses Central Arterial Pressure and Cardiovascular Safety, while Dr. R. J. Turner and Philip Galtry of Quintiles explain that therapeutically beneficial interactions between individual patients and their physicians are the cornerstone of the practice of both behavioural medicine and biopharmaceutical medicine, in the Cardiovascular Therapeutics Watch Column. The Regulatory section starts with Lana Sinichkina and Igor Svitlyk at Arzinger asking the question regarding Investigators’ Legal Status in Entering Clinical Trial Services Agreements: Should They be Registered as Entrepreneurs or Not?
Julia Forjanic Klapproth and Lisa Chamberlain James of Trilogy Writing & Consulting discuss the recent raft of changes in pharmacovigilance legislation. In the Market Report Section, we feature a report by Igor Stefanov of Synergy Research Group who provides an overview of recent movements of the Ministry of Health of the Russian Federation, and Stephan Wnendt and Katja Neuer-Etscheidt at MLM Medical Labs discuss the different categories of laboratories involved in clinical labs, and how this can be used as a brief guidance for a good match between study design and laboratory services. In the Therapeutics Section, Elizabeth Moench of MediciGlobal Ltd. discusses why paediatric clinical trials involve a distinctive set of challenges that can result in increased costs for patient retention, as well as additional time required to develop customised and meaningful retention programmes. Miranda Porter at INC Research provides an overview of why researchers and clinicians emphasise the immediate and critical need for clinical trials investigating safety and efficacy of Atypical Antipsychotics in Adolescents with Major Depressive Disorder. I am sure you are all preparing for CPHI/ICSE in Frankfurt, and Partnership in Clinical Trials Europe – Vienna. JCS will be exhibiting at both these events. I hope you can come by and visit our stands. I wish you all a brilliant 4th Quarter, and look forward to seeing you all in November. Mark. A. Barker Publisher
Until now, the front cover of JCS has featured the national flower of one of the emerging countries analysed in that issue. This has been a very popular and thought-provoking concept. From this current issue, we will be changing the front cover to highlight one of the therapeutic areas we will focus on in that particular issue. For instance, we have a feature on Paediatric Patient Retention, where regulation is aiming to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years. This theme is represented as the front cover picture.
Editorial Advisory Board Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc. Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories
Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group
Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP
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
Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH
Catherine Lund, Vice Chairman, OnQ Consulting Janet Jones, Senior Director, ICON Clinical Research Cellia K. Habita, President & CEO, Arianne Corporation Jerry Boxall, Managing Director, ACM Global Central Laboratory Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters
Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma. Jim James DeSantihas, Chief Executive Officer, PharmaVigilant
Elizabeth Moench, President and CEO of Medici Global Eileen Harvey, Senior VP/General Partner, PRA International 6 Journal for Clinical Studies
Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation
Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories Rabinder Buttar – President & Chief Executive Officer of ClinTec International Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA - Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences
Volume 5 Issue 5
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H7N9 Influenza and the Rush to Vaccine Development On March 31, 2013, the Chinese health authorities announced the first human case of a new strain of avian influenza A virus H7N9. The announcement was repeated by the World Health Organization (WHO) the next day. By the end of April, 126 human cases of the new H7N9 virus had been reported. Due to a combination of the health measures put in place by Chinese officials and the seasonal nature of avian influenza viruses, the outbreak was contained and cases of infection dropped off precipitously after April. As of mid-August 2013, Chinese health officials report that a total of 130 people have been infected, an increase of only four since the end of April. This steep decline in case numbers, while positive, should not be seen as an end to the concern surrounding H7N9. In fact, world health officials are taking them as simply the potential “calm before the storm.” For instance, of the 130 infected individuals, 45 have died. The virulence of the new H7N9 strain is strong and marks it as quite different from previous H7N9 circulating strains. Human disease progression starts with a high fever and/or a cough, advances quickly to severe pneumonia, septic shock, and acute respiratory distress syndrome, and culminates eventually in multi-organ failure, which leads to death. What appeared to be beneficial in containment of the strain may instead be the current inability of this new H7N9 to spread from human to human. Until the first week of August 2013. During that week, the Jiangsu Provincial Centre for Disease Control and Prevention reported the case of two family members who were infected with the new H7N9 strain, and stated that one (the father) likely transmitted it to the other (his daughter). The genetic strains infecting both were nearly identical, and the daughter’s only exposure to potential avian viruses was through her sick father. The infection was limited and not sustained. No other family members or neighbours who had come in contact with the man had been infected, and the infection was contained. This does suggest the possibility, however, that it is merely the seasonal nature of avian viruses (like human influenza viruses) that is slowing the development of more human-to-human cases. Experience with previous avian influenza viruses that develop the ability to infect humans (particularly H5N1) shows that, eventually, it is possible for the strains to evolve in such a way as to allow infection between humans. If the strain does so in a particularly aggressive way, the
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threat of a pandemic moves from the realm of the theoretical to the possible, and preventative measures are undertaken. On April 11, 2013, the Centers for Disease Control and Prevention (CDC) received the first H7N9 virus isolate from China, and development began on a candidate vaccine for use in the event that the virus establishes human-to-human transmissibility. Development has continued apace, particularly in light of the coming influenza season and the unknown direction that the H7N9 virus evolution could take. A number of vaccine developers have stepped up development of a vaccine using the available candidate vaccine viruses on file with the WHO. In early July, Inovio Pharmaceuticals announced that its preclinical trial using a vaccine based on the A/Anhui/1/13 strain of H7N9 virus showed that the vaccine protected 100% of the vaccinated animals when challenged with a lethal dose of the strain. At the same time, Novavax announced that a similar trial using the same virus strain was showing positive results. Vaxart announced in late June that the company had developed a vaccine pill in just 20 days that suggested effectiveness against the new strain. The benefits of a vaccine pill would be greater and quicker distribution of the vaccine, including via postal delivery, to ill or housebound individuals. In addition, Medicago is working on a plantbased vaccine that is able to produce what the company claims is a viable vaccine using only the strain’s sequence, thus greatly reducing vaccine production time over traditional methods. Health officials worldwide have stressed that the potential pandemic ability of the H7N9 avian influenza strain should not be underestimated or dismissed. They have also noted that the coming influenza season should tell the tale. Until then, developers continue to prepare candidate vaccines and new methods of production to allow a quick response should the virus become more aggressive.
Walter Chalkley is a senior editorial project manager for Cortellis Regulatory Intelligence, a regulatory affairs information database and part 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: email@example.com
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Central Arterial Pressure and Cardiovascular Safety The sphygmomanometer has been used for over 100 years to measure the systolic and diastolic blood pressures in the brachial artery. However, blood pressure in the brachial artery can be very different from the pressure at the heart. Three aspects of central blood pressure are especially important: • Blood pressure at the heart predicts clinical outcomes and target organ damage with a sensitivity and specificity that is significantly better than brachial pressure1. • The difference between central and brachial blood pressure varies from one person to the next; this variability means that central pressures cannot be reliably inferred from brachial pressures2. • Medications can have significantly different effects on central as compared to brachial pressure3. Brachial blood pressure has become an essential measurement tool in identifying cardiovascular risk. However, the central organs such as the heart, brain, and kidney, are subjected to central rather than brachial pressure. This fact, when combined with the variability in the difference between individuals in their central and brachial pressure, leads to the improved predictive capability of central over brachial blood pressure. This improved predictability leads to an improved individual risk assessment and greater statistical power (fewer required subjects) in clinical trials4. Today, new technology allows the non-invasive measurement of the central systolic and diastolic pressure with the same ease as a brachial cuff measurement. In addition, this new technology can provide a high-fidelity ascending aortic waveform that contains significantly more information on the state of the vascular system and ventricular-vascular coupling. Numerous studies in both healthy and diseased subjects have consistently demonstrated that elevated central blood pressure is associated with increased cardiovascular events independently of brachial pressure, and is superior to brachial pressure as a predictor of those events. The evidence that CBP is independently related to end-organ damage was recently reviewed by Patel et al.1 Central pressure, independent of brachial pressures, has been shown to be related to left ventricular, vascular, first onset of atrial fibrillation, and heart failure (both left ventricular dysfunction and heart failure with preserved ejection fraction). Abnormal values or changes in central blood pressure have also been associated with other diseases and conditions such as kidney disease, diabetes, cognitive function, chronic obstructive pulmonary disease, preeclampsia, depression, obstructive sleep apnea, inflammatory diseases, smoking, and erectile dysfunction. Several studies have shown that central pressure and central pressure indices can distinguish those individuals who, although not hypertensive, can be found to have end-organ damage. Just as importantly, brachial pressures could not make such a distinction. In a study of 1169 participants, Booysen et al. reported that the classes of normal vs. high normal brachial blood pressure did not distinguish those with or without end-organ damage5. However, when the same group was divided according to normal vs. high normal central systolic pressure, the groups with and without such damage could be identified. Also, Kaess et al., in a report from the Framingham Heart Study, showed that central pressure waveform features predicted the development of hypertension in those who were originally 10 Journal for Clinical Studies
normotensive6. Brachial pressure measurements were not predictive of the development of arterial stiffness, a major indicator of end-organ damage. Conversely, a European study of 354 young and middle-aged people with untreated Stage 1 hypertension showed that those with low central systolic pressure (<125mmHg) were at significantly less risk of requiring antihypertensive medication than those with high central systolic pressure7. Different classes of antihypertensive medications can have different effects on the central pressure values compared with their effect on brachial pressure4. In general, vasoactive medications have a more beneficial impact on central blood pressure than non-vasoactive drugs. Arterial vasodilators promote relaxation of vascular smooth muscle cells, delaying the return of the reflected wave and reducing central systolic pressure. However, the effect of vasoactive drugs on central pressure varies by class, and even within the same class of drugs, central pressure response can vary from one person to another. In summary, central arterial pressure, along with information in the arterial waveform, provides information on cardiovascular disease risk that is independent of, and more sensitive and specific than, standard brachial blood pressure. In addition, central pressure can provide important information to improve drug profiling and differentiation. And the technology available now makes this measurement as simple and straightforward as a standard brachial cuff measurement. References 1. Patel et al., Indices of central aortic blood pressure and their impact on cardiovascular outcomes J Cardiovasc Med, 2012; 13:38–45 2. McEniery et al., Central pressure: variability and impact of cardiovascular risk factors, 2008; 51:1476-82 3. Manisty et al., Meta-analysis of the comparative effects of different classes of antihypertensive agents on brachial and central systolic blood pressure, and augmentation index, Br J Clin Pharmacol, 2012; 75(1): 79–92 4. Hashimoto et al., Indices of Pulse Wave Analysis Are Better Predictors of Left Ventricular Mass Reduction Than Cuff Pressure, Am J Hypertension, 2007; 20:378–384 5. Booysen et al., Aortic, but not brachial blood pressure category enhances the ability to identify target organ changes in normotensives, J Hypertension, 2013; 31:1124–30 6. Kaess et al., Aortic stiffness, blood pressure progression, and incident hypertension, JAMA, 2012; 308(9):875-81 7. Saladini et al., Isolated systolic hypertension of young-to-middle-age individuals implies a relatively low risk of developing hypertension needing treatment when central blood pressure is low, J Hypertension, 2011, 29:1311–9 Dr. Winter is currently Vice-President of Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial tonometry. He is an internationally recognized expert in physiological fluid mechanics, biomechanics and medical device development. Email: firstname.lastname@example.org Volume 5 Issue 5
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Cardiovascular Therapeutics Watch Column Both individual patient and public health considerations are extremely important when addressing a health issue of the magnitude of hypertension, which, as noted in the previous column, was recently and authoritatively designated as the greatest threat to the global burden of disease. 1 While therapeutically beneficial interactions between individual patients and their physicians are the cornerstone of the practice of both behavioural medicine and biopharmaceutical medicine, professional organisations such as the European Society of Hypertension 2 and the American Society of Hypertension 3 are actively involved in preparing and publishing treatment guidelines and Position Papers to guide the treatment of hypertension. 4-6 Guidelines are also issued by governmental agencies. 7
systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2013;380: 2224-2260. 2. European Society of Hypertension website. Available at:
org/ (Accessed 18th August, 2013). 3. American Society of Hypertension website. Available at: http://www.ash-us.org/ (Accessed 18th August, 2013). 4. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281-1357. 5. O’Brien E, Parati G, Stergiou G, et al: on behalf of the European Society of of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension Position Paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31:1731-1767. 6. American Society of Hypertension Position Papers. Available at: http://www.ash-us.org/ Publications/ASH-Position-Papers.aspx (Accessed 18th August, 2013).
Through these guidelines and Position Papers, clinical research and individual clinical trials inform clinical practice and evidence-based medicine. Much research has been conducted on the blood pressure (BP) consequences of three related behavioural interventions: increasing physical activity, losing weight, and modifying dietary habits. 8,9 Accordingly, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) observes that “Adoption of healthy lifestyles by all persons is critical for the prevention of high BP and is an indispensable part of the management of those with hypertension.” 7 With regard to biopharmaceutical medicine, preapproval clinical trials bring new drugs to market and provide the information contained within each drug’s prescribing information (label). This information concerning the drug’s safety and therapeutic benefit (the best available information at the time of approval: additional information is gathered once a drug is being prescribed to patients) guides treatment decisions at the individual patient level. Also, as previously noted, clinical trials generate the evidence contained within treatment practice guidelines, which have a broader reach across populations of patients. 10 Ongoing and future clinical research in this therapeutic area therefore continues to influence the choice of target BPs for various patient populations and treatment algorithms. Since non-adherence to behavioural interventions is equally as problematic as non-adherence to biopharmaceutical interventions, 11-13 considerable research has been directed at ways of improving adherence, including educational programmes and the use of the internet. 14-16 While such strategies have been demonstrated to be successful in relatively small studies, the challenge is to make them successful on a much larger public health scale. A recent and very informative publication by Jennings is entitled “Recent clinical trials of hypertension management.” 17 It covers pharmacological and non-pharmacological interventions, and also the treatment of drug-resistant hypertension, a very ‘hot topic’ in the hypertension literature, and the topic of our next column.
7. US Department of Health and Human Services. The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf (Accessed 3rd July, 2013). 8. Shantha GP, Kumar AA, Kahan S, Cheah SY, Cheskin LJ. Intentional weight loss and dose reductions of antihypertensive medications: a retrospective cohort study. Cardiorenal Med. 2013;3(1):17-25. 9. Hassapidou M, Papadopoulou S, Vlahavas G, et al. Association of physical activity and sedentary lifestyle patterns with obesity and cardiometabolic comorbidities in Greek adults: Data from the National Epidemiological Survey. Hormones (Athens). 2012;12(2): 265-274. 10. Turner
1. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a
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11. Turner JR, Strumph P. The moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity, Part I: A focus on type 2 diabetes mellitus. Journal for Patient Compliance. 2012;2(1):32-36. 12. Richards AL, Turner JR. The moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity, Part II: A focus on cardiovascular disease. Journal for Patient Compliance. 2012;2(2):36-41. 13. Turner
J Clin Hypertens (Greenwich). 2013;15:447-452. 14. Ferrara AL, Pacioni D, Di Fronzo V, et al. Lifestyle educational program strongly increases compliance to nonpharmacologic intervention in hypertensive
2-year follow-up study. J Clin Hypertens (Greenwich). 2012;14(11): 767-772. 15. Lauzière TA, Chevarie N, Poirier M, Utzschneider A, Bélanger M. Effects of an interdisciplinary
Can J Cardiovasc Nurs. 2013;23(2): 12-19. 16. Liu S, Dunford SD, Leung YW, et al. Reducing blood
pressure with Internet-
based interventions: a meta-analysis. Can J Cardiol. 2013;29(5):613-621. 17. Jennings GLR.
Recent clinical trials of hypertension management. Hypertension.
J. Rick Turner, PhD, is Senior Scientific Director, Clinical Communications, Quintiles. He is also a Senior Fellow at the Center for Medicine in the Public Interest, and a Fellow of the Society of Behavioral Medicine. Email: email@example.com. Philip Galtry is Vice President and Cardiovascular Therapeutic Metabolic
J Clin Hypertens (Greenwich). 2013;15:306-309.
Philip holds an Honours degree in Biochemistry from the University of Bristol, UK, and has worked in the management of cardiovascular studies for almost 25 years. Volume 5 Issue 5
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Demystifying Clinical Trials Insurance Often the last thing considered when setting up a clinical trial is insurance, and yet it is a critical, albeit confusing, part of the project. To help shed some light on the issues faced, I am taking the opportunity to discuss the basis upon which global trials should be insured, along with the types of insurance coverage available to the key players. We will also look at how “hold harmless” provisions between various parties should be designed and how the process can be managed efficiently.
insurance documentation in time. Frustration builds as delays can lead to millions of dollars of lost revenue as the clock ticks on the compound’s period of patent exclusivity. To minimise this risk, some insurance companies offer an online system to automate the issuance or modification of certificates. With such a system, a sponsor, its insurance broker, or its CRO can be empowered to make the necessary modifications and secure new documentation instantaneously.
The Sponsor’s Trials Coverage The actual Clinical Trials policy will be purchased by the sponsor although it will be of interest to all stakeholders. This policy secures the sponsor’s own financial backing in the event of a claim, and may also offer indemnity to other parties. Despite the best efforts of all involved, an investigational product in a clinical trial presents bodily injury risk to participants and consequently possible financial and reputational risk to all involved in the trial. A well-designed insurance programme mitigates against this. As an example, a sponsor who is planning a 35-month trial in numerous countries would generally be insured under a combination of policies, including: • a number of locally-issued insurance policies (known as an “admitted” policy) by an insurer authorised to do business in that country. These will often be mandatory covers to deal with local requirements and methods of settlement along with prescribed limits. For example, in France this could be €1m per patient with a €6m aggregate per trial, but French regulations stipulate that the policy must have a provision that it will remain available to pay claims made up to ten years after the trial is completed. • the sponsor’s over-arching (or “master”) product liability and clinical trial liability policy should pick up claims arising in countries where admitted policies are not needed. It may also insure gaps in cover where the admitted policies provide restricted coverage. For example, the standard German clinical trial insurance policy excludes non-economic damages, so allegations of pain and suffering in a clinical trial liability lawsuit in Germany would be excluded under the German admitted policy, but may instead be insured under the master policy. A key distinction between the two types of policies is that the admitted policies are usually issued specifically for the trial in question and the period of insurance will match its length, whereas the master policy will be renewed annually. If the clinical trial takes longer than expected, the locally-admitted policies would need to be extended, but the applicable ethics committees would also usually wish to verify that the master policy has been renewed appropriately and remains in place.
Provisions and Liabilities for Liability Assumed by Others Under Contract Although all players in the clinical trial process must secure insurance for their own negligence, it is the norm that contractual agreements provide that certain parties will indemnify and defend other parties in specific circumstances. As examples: • a clinical investigator who follows the protocol as designed by the sponsor but is nevertheless sued for injuries sustained by a trial participant should expect the sponsor to defend and indemnify him/her from such claims. • a CRO who agrees to act as the local legal representative for a non-European sponsor of a European clinical trial should expect the sponsor to indemnify it for liabilities it incurs by assuming that responsibility. It is therefore important for the sponsor’s master policy to ensure that such agreements are covered. This can be done by appropriate extensions in cover, but care should be taken not to assume any liabilities beyond the sponsor’s stipulated responsibility.
Certificates of Insurance Required by Ethics Committees Certificates of insurance in the local language detailing the clinical trial’s key features are very often prerequisites before an EC approval is given. It is a truism, however, to say that with the best will in the world changes to the trial details often occur right up to the last moment. As a result, approval may be delayed simply due to the inability to produce the required 14 Journal for Clinical Studies
Underwriting Considerations Insurance underwriters are responsible for assessing the risk of a trial and for determining whether to offer insurance cover. If cover is offered, the underwriter will determine the policy terms, conditions and pricing. Underwriters may consider the following factors, among others, when assessing a trial: • the presence in the informed consent form of all the required and other appropriate elements relating to the trial, with a special emphasis on comprehension/ readability. • analysis of the investigational product. • apacity (limits of insurance) required. With the interplay of regulations, business practices, and litigation environments in multiple countries, liability insurance for global clinical trials is especially complex. Insurers who are active in the field are most likely to be familiar with these complexities, will keep up to date with recent global developments and will provide appropriate cover.
Chris Tait of Chubb Insurance continues to build on more than 20 years of predominantly casualty experience in insurance broking, reinsurance and direct insurance, in recent years Chris has been responsible for Chubb Insurance’s Life Science development in Europe which now has Life Science underwriters in 10 countries. Email: firstname.lastname@example.org Volume 5 Issue 5
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Editing, Proofreading and Back-translation: options in the translatorâ€™s toolbag The translation of clinical data is not a job for the faint-hearted (excuse the pun!). Linguists must have a minimum of five years experience within the life science industry and a degree in translation studies and must translate only into their mother tongue. Unfortunately translation can be very subjective and no two linguists will translate a document in exactly the same way (unless it is highly technical). In order to ensure high quality and that the meaning is retained, documents need to be back-translated or proofread. Contracts, patient consent forms, protocols, clinical trial manuals, trial flowcharts or scientific reports need to be translated at some time or another. The individual sites and associated medical collaborators need to know precisely how to conduct the trial and patient safety must never be compromised. To these ends, accurate and timely translations of all required study documentation is imperative, and so it becomes ever more important to identify a translation agency that has the experience and absolute focus on the quality and timeliness of the translation. In addition, our long association within the life science and clinical sectors has shown us that projects and clinical trials may be brought forward with little or no notice. As the average cost of taking a drug to market now exceeds a billion dollars, getting a pharmaceutical product authorised and on the pharmacy shelf even only a month earlier means that companies can start to claw back some of their development outlay and, as such, this will mean a substantial initial payback. As a leading language supply provider (LSP), what are the steps involved that guarantee timeliness, accuracy and quality? Firstly, we need to demonstrate flexibility and capacity to immediately respond to our clients needs. Taking the example of clinical trials, as soon as authorisation has been given for the trial to proceed, the client must move as quickly as possible. Sites will be instructed to immediately recruit and within days there will be patients brought in for treatment. Clinical staff on site will require translated patient consent forms, manuals and flowcharts in order to follow the study protocol precisely (other documentation may be required). Demonstrating the above flexibility and ability to immediately expand our capacity, we would now prepare the translated documentation in a timely manner, but how do we ensure that it is accurate and of the required quality? As a leading LSP, we initially concentrate on editing. This is the big-picture process. The translation is compared 16 Journal for Clinical Studies
to the original (source) text, and the translated text is reviewed as a whole. The editor should check for things like word choice, clarity, conciseness, consistency, jargon, and register. Does the translation accurately convey the meaning of the source text? Does the translation use the appropriate terminology and style for its intended audience? Is the translated text consistent? (This is especially important when more than one translator was involved.) The next option is proofreading. This involves a forensic inspection. At this stage, the goal is to clean up the text; the source text is still used but the translated text must stand on its own upon reading. Issues to consider are mechanics: spelling, capitalisation, punctuation, abbreviations, numbers. Sentence structure should also be examined: run-on sentences, comma splices, sentence fragments. And of course we must consider regional differences: UK v. US English spelling and punctuation (synchronization with a â€˜zâ€™ !) Finally, the gold standard is where our texts benefit from back-translation - as performed by trained professional translators. In brief, back-translation can be defined as the procedure according to which a professional translator interprets a document previously translated into another language back to the original language. Usually this process is made by a translator or translators who had not been previously involved in the project and who have no prior knowledge of the objectives or its specific context. The process of back-translation is especially useful for clients who wish to ensure the most absolute quality and accuracy to their projects. Despite taking extra time and cost, back-translation is an excellent way of avoiding errors later on. Regarding clinical trials, the priority is that patient safety is paramount and experience has shown that the above approach ensures that we act as a partner with our clients in contributing fully to make this so.
Luigi Koechlin was born and lived in Peru until the age of 12. After a year in LiberiaMonrovia he moved to Villars-Switzerland where he finished his education in a British School. Since then, Luigi has traveled extensively throughout Latin America, Europe, Asia, and Africa and has worked in Singapore, Hong-Kong, and Switzerland. With a deep understanding of different cultures gained from his travel and work experience. Luigi founded Global Voices in 2005 and since this time has provided language solutions to life science organisations. uk.linkedin.com/in/luigikoechlin Email: email@example.com Volume 5 Issue 5
Investigators’ Legal Status in Entering Clinical Trial Services Agreements: Should They be Registered as Entrepreneurs or Not? A question often asked lately by the community involved in clinical trials for medicines is whether individuals entering into clinical trial services agreements with non-resident sponsors may enter into such relations without becoming entrepreneurs? Doubts as to whether individuals (non-entrepreneurs) may enter into agreements with non-residents arise from the ambiguous interpretation of the Law of Ukraine “On Foreign Economic Activity” (hereinafter the Law on Foreign Economic Activity). In accordance with the provisions of Paragraph 2, Article 5 of the above Law, individuals having permanent residency in Ukraine may engage in foreign economic activity if they are registered as entrepreneurs according to the Law of Ukraine “On Entrepreneurship”. In other words, an individual may engage in foreign economic activity (hereinafter FEA) only on being given the status of a entrepreneur. Armed with this legal provision, some lawyers argue that individuals may not enter into agreements with non-residents until they are registered as entrepreneurs. However, this conclusion causes reasonable doubts due to the following reasons. Based on the analysis of legislation, we can conclude that entering into agreements with non-residents will not always be deemed FEA, thus the above restriction will not be applicable. In accordance with Paragraph 12, Article 5 of the Law on Foreign Economic Activity, no provision of Article 5 may be interpreted as prohibiting individuals, legal entities or other FEA subjects from entering into any relationships that do not fall within the definition of foreign economic activity. Thus, the Law on Foreign Economic Activity confirms the existence of activities that do not fall under the definition of FEA. It should also be noted that, based on the definition, FEA shall mean activity of business entities. In other words, the activity carried out by a person that is not a business entity may not be deemed FEA in the meaning of the above Law. Below, we will try to find out in which cases an individual shall be considered a business entity. In accordance with Paragraph 2, Article 55 of the Commercial Code of Ukraine, business entities are, inter alia, citizens of Ukraine doing economic activity and registered as entrepreneurs under the law. In accordance with Article 128 of the Commercial Code, a citizen shall be deemed a business entity, if he/ she has been doing economic activity and has been registered as an entrepreneur without being given a legal entity’s status. Due to that, a person that is not registered as an
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entrepreneur shall not be considered a business entity in formal terms, and thus cannot be a FEA subject. Therefore, based on the provisions of the above Article 5 of the Law on Foreign Economic Activity, such a person performs activities that do not fall under the definition of FEA. Namely, it is involved in property and personal non-property relations governed by the Civil Code of Ukraine (Article 4 of the Civil Code). However, it should be remembered that if a person’s activity acquires signs of entrepreneurship, that person will be required to register in accordance with the law in order to avoid the negative consequences described below. Additionally, the Tax Code of Ukraine confirms the possibility of earning income from non-entrepreneurial activity. Thus, in accordance with Article 1.14.54 of the Tax Code, income from sources in Ukraine is any income earned by residents from any type of activities in Ukraine, including, but not limited to, income in the form of: i) salary, other benefits and remunerations paid under the terms of a labour or civil contract ii) income from entrepreneurial or independent professional activity. Given this, we can conclude that Ukrainian legislation provides for a type of economic activity exercised by an individual to generate income (in particular, through the conclusion of civil contracts or due to professional activity such as research), which is not FEA.
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Regulatory QRTD (Quantitative Real Time Diagnostics) is brought to you by Considering the above arguments, if a civil contract is concluded between an investigator that is not registered as an entrepreneur and a sponsor/contract research organisation, their contractual relationship will not fall under the definition of foreign economic activity and, therefore, the restrictions imposed by the Law on Foreign Economic Activity will not apply thereto. In addition to the above, the principle of general permissibility applying in civil relations allows doing anything that is not prohibited by law. As no law prohibits entering into civil contracts between Ukrainian individuals and non-residents, such actions are permitted. The consequences of recognising an individual’s activity as entrepreneurial should also be taken into account. It is well known that one of the key criteria for entrepreneurial activity is its regularity. The concept of regularity has been construed by the Supreme Court of Ukraine as execution of works or services at least three times in a calendar year. The question is what action shall be considered as one time in a calendar year? In our opinion, such action is an investigator’s signing a contract and performing the full scope of work under that contract within one clinical trial. That is, if an investigator signs more than two ontracts a year and performs certain work followed by respective payment there under, such activity can be considered as entrepreneurial. Such activity without proper registration constitutes an administrative offence, and can entail the imposition of fines on the investigator (up to 500 taxfree minimum incomes of individuals – 8500 UAH) and confiscation of money obtained through that offence. Another negative consequence may be tax liabilities, if tax on income derived from such activities has not been paid in full. Therefore, if service activities related to the conduct of clinical trials are regular, investigators shall acquire the entrepreneur status in order to avoid the undesirable consequences described above.
Lana Sinichkina, Partner, Head of Life Sciences and Healthcare Arzinger’s practices, a well-recognized specialist in aforementioned industries leading a big team of lawyers and providing legal support to major international companies on a daily basis. Lana has a deep expertise in antitrust and competition law. She is also engaged in supporting of IT clients. Email: firstname.lastname@example.org Igor Svitlyk, Associate, specialises in Life Sciences & Healthcare. He handles legal support of foreign and Ukrainian pharmaceutical companies and contract research organizations in the field of import, manufacturing and advertising of medicines and clinical trials of medicines and medical devices. Email: email@example.com
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‘Results when you need them’ For further information on QRTD or our dosing bundles for Phase II and III studies: UK Tel: 0800 324 7836 | USA Tel: 1877 8360762 Email: firstname.lastname@example.org
mesmglobal.com Journal for Clinical Studies 17
Improving Transparency and Benefit/Risk Assessments with the New Risk Management Plan There is no doubt that the future of drug development lies in personalised healthcare – making sure the right medicine is given to the right patient at the correct time and dose. The rapidly expanding fields of pharmacogenomics and, more recently, metabolomics are testament to this trend. However, for personalised healthcare to be effective, patients also have to be engaged and involved in the process. So called ‘shared decision making’ is an ideal strived for in medicine but is a utopia that we have failed to realise effectively, because if patients are to be involved in the decisionmaking process, they must be empowered to do so. This means that they must be able to understand not only the benefits and potential harms of a treatment, but also be able to weigh this against the consequences of not having the treatment at all. To do this, patients need information about the medicines and their risks and benefits in a format that they can understand and evaluate. Both the regulatory authorities and the industry as a whole have recognised this, and the process of drug development and treatment paradigms are changing as a result. Recent changes in European pharmacovigilance (PV) legislation are affecting the way the assessment of medicinal products is carried out in both pre- and post-authorisation phases, including new obligations to marketing authorisation holders for continuous benefit/ risk assessment throughout the drug life cycle, and the need to make this information available to the general public. Coupled with this is a general industry movement towards greater transparency and patient engagement and involvement in healthcare decision making. The ongoing assessment of a medicinal product’s safety and efficacy is not a new requirement, but these assessments were traditionally made in documents written specifically for regulatory assessors. The language used was that of specialists, which is no longer sufficient to fulfil the need for transparency and broader stakeholder (e.g. patient) involvement. Similarly, although benefit/ risk assessments of medicinal products were made in the context of applying for drug approval, risk management focussed almost exclusively on safety in the post-marketing arena. Again, this does not address the need for the benefits of the medicine to be considered alongside the risks, nor how those translate into what may be a changing benefit/risk ratio over the long term. Hence the recent raft of changes in PV legislation. These are the greatest changes in this legislation for almost 20 years, and although the changes affect many areas, 20 Journal for Clinical Studies
broadly speaking they all aim to increase transparency and emphasise the benefit of a medicine relative to its risk (both of which may change over time). The changes introduced to the risk management plan (RMP) exemplify this shift in thinking, both for increased transparency and a more holistic benefit/risk assessment. The purpose of an RMP is to provide a description of the risk management system that a company plans to implement to identify, characterise, and prevent or minimise risks associated with the use of its product. It must be written and submitted with most applications for marketing authorisation and must consider how the safety profile of the product may change once the product is being used in settings different from those in clinical trials. European legislation requiring submission of an RMP was first made in 20041, followed by the issuing of guidelines2 and a template3. Those guidelines were updated this year in light of the general overhaul of the PV legislation and a new RMP template was issued 4. The original RMP template consisted of two main parts: Part I addressed risk assessment and Part II addressed risk minimisation. The RMP was a means to make companies identify any important risks that may not otherwise have been recognised, as well as to consider in advance how they would watch for safety signals and react swiftly should a signal arise. The focus was solely on the adverse effects of the product. The new template now divides the document into six main parts. Part I of the old template has been split into a section that describes what we already know and do not know about the safety of a product (the safety specification), and a section that lays out what we can do to increase our knowledge about the safety of a product (the pharmacovigilance plan). This highlights the desire to delve more comprehensively into the understanding of the safety profile for a product, teasing apart available knowledge from information that remains to be gained.
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Regulatory Outside of greater structural granularity, however, there are two main changes that bring the template up to date with the current PV mindset. The first is the need to address how increased knowledge on the efficacy of the product will impact on the risk assessment as a whole. Whereas in the past, companies were only expected to consider and perform studies that would further the understanding of the drug’s safety profile, now the same is expected for efficacy. Post-authorisation efficacy studies need to be considered that can close the gaps in knowledge about the efficacy of a product in the target population. The purpose is not to explore other areas of use for a product but to continue to expand on the knowledge base for the approved indication by gaining data on parameters such as the efficacy in notable subgroups and long-term efficacy. The inclusion of this new section (Section IV) makes clear just how serious the regulators are about making sure companies are assessing the ongoing benefits as well as the risks. The second, even more astounding addition to the new RMP, is a section whose sole purpose is to summarise all the salient points of the RMP in lay language (Section VI). This includes an overview of the disease epidemiology and a summary of the treatment benefits, including any possible unknowns about those benefits, a summary of any safety concerns and what risk minimisation measures are being implemented, a description of what post-authorisation studies are planned and a summary of any changes that have been made to the RMP over time. It is not really clear how exactly this new public summary will be used by the public, but it is a huge step forward in transparency and ensuring communication with stakeholders. By translating this kind of information from regulatory jargon into lay language and making it publically accessible, this will open whole new avenues for patient advocacy organisations, self-help groups, and patients themselves to better understand the products available to them. This will certainly aid in bringing these stakeholders closer to true empowerment in the decision-making process. However, explaining risk ratios is challenging even when the audience is familiar with this type of information. Explaining the risks and benefits in a way that enables patients to make an informed decision about their treatment can be exceptionally difficult. This is partly because patients do not have a clear understanding of risk, which is often further muddled by their fear of the situation5. It is also because the way that risk and benefit information is presented is often confusing and difficult to understand, leading to misinterpretation at best. The goal then of Section VI of the RMP is to simplify and explain the very complex information contained in the body of the RMP, so that patients can make an informed choice about their medicine. Starting with an explanation of the disease in question, it should explain why that disease should be treated and the medicines currently available for doing so. Such epidemiological data can be as difficult to understand as benefit/risk assessments, and so this also needs to be simplified as much as possible and any limitations of the data (e.g. if the information is only available for a certain area and estimates have been extrapolated) should be made clear. www.jforcs.com
The difficulty lies in really understanding what the general public truly knows. For example, when alternative treatments are being discussed, some context should be given – patients may not understand what terms such as ‘gold standard’ or ‘first line’ really mean, and so it is helpful to explain how and why particular medicines are used more often than other medicines. When considering particular sub-populations (e.g. the elderly), the language used needs to be clear enough to be sure people reading it understand if they belong to that group. There are many 70 year-olds who do not consider themselves to be ‘elderly’! Another possible hurdle to effective communication to a lay audience is the use of several tables outlining the ‘important identified risks’, ‘important potential risks’ and ‘important missing information’, followed by tables summarising the risk minimisation measures etc. These tables are arguably the most important part of the section, but also the most difficult to write. The lay public is not used to scanning tables for messages the way people in the industry are. The tables presented in this section need careful designing to make sure the information is complete, unbiased, and intelligible by the patient. As with all documentation, a well-structured, logical flow enhances the readability enormously. Plain language is also essential, and scientific, medical and statistical jargon should not be used, or at least explained in plain language in addition to the technical term. Relative risk information needs to be communicated in a way that anyone can grasp. For example, instead of stating that drug X can reduce hypertension by 50%, it is better to explain using a frequency as an absolute risk, saying the risk of developing hypertension is reduced from 4 people in 100 to 2 people in 100 by taking drug X. Although studies have been inconclusive about whether patients understand risk better if it is presented as frequencies rather than percentages 6, it has been shown Journal for Clinical Studies 21
Regulatory that the perception of risk is lower when the information is presented as a percentage7, while changes in risk seem larger when presented as relative risk 8, 9, 10, 11, 12. Beyond the discussion of risk, it’s equally important that patients are fully informed about the benefits of treatment options. In addition to describing ‘preventability’ and ‘risk minimisation measures’, the existence of baseline risks, i.e. the risks that patients would face without any kind of treatment, need to be discussed as well. This is to avoid scaring people away from available treatments because they mistakenly believe that the only risks are those caused by the treatment and that they would not have any adverse outcomes if they refused the medicine. Getting this balance right is vital to truly empower patients to evaluate all of the treatment options available to them. Personalised healthcare will soon be of age, and greater transparency in the communication of knowledge around the available treatments is a necessary step in the evolution of drug development and healthcare provision. The success of this hangs on our ability to provide information that enables everyone to understand and interpret complex data and concepts. Although challenging, this is not impossible, and is crucial not only for patients but for every audience - from regulators through to healthcare professionals, as their role grows from assessment of medicines to helping patients interpret their benefit/risk ratios. References 1. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Available from http: //eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L: 2004:136:0034:0057:EN:PDF. 2. EMEA/CHMP/96268/2005 Guideline on Risk Management Systems for Medicinal Products for Human Use. 3. EMEA/192632/2006. Annex C: TEMPLATE FOR EU RISK MANAGEMENT PLAN (EU – RMP) 4. EMA/838713/2011 Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems 5. Riva S, Monti M, Iannello P, Antonietti A. The representation of risk in routine medical experience: what actions for contemporary health policy? PLoS One. 2012;7(11):e48297. 6. Fagerlin A, Zikmund-Fisher BJ, Ubel PA. Helping patients decide: ten steps to better risk communication. JNCI 2011;103(19):1436-43 7. Peters E, Hart PS, Fraenkel L. Informing patients: the influence of numeracy, framing, and format of sideeffect information on risk percep¬tions. Med Decis Making. 2011;31(3):432–436. 8. Malenka DJ, Baron JA, Johansen S, Wahrenberger JW, Ross JM. The framing effect of relative and absolute risk. J Gen Intern Med. 1993;8(10):543–548.
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9. Forrow L, Taylor WC, Arnold RM. Absolutely relative: how research results are summarized can affect treatment decisions. Am J Med. 1992;92(2):121–124. 10.Baron J. Confusion of relative and absolute risk in valuation. J Risk Uncertain. 1997;14(3):301–309. 11. Akl E, Oxman AD, Jerrin J, et al. Using alternative statistical formats for presenting risks and risk reduction. Cochrane Database Syst Rev. 2011;(3):1–85. 12. Covey JA. Meta-analysis of the effects of presenting treatment benefits in different formats. Med Decis Making. 2007;27(5):638–654.
Julia Forjanic Klapproth: After receiving her PhD in Developmental Neurobiology, Julia Forjanic Klapproth started her career as a medical writer in the pharmaceutical industry at Hoechst Marion Roussel (later Aventis) in 1997. Since then she has been President of the European Medical Writers Association (EMWA) twice (2001-2002, 2007-2009). Julia is also an experienced trainer of medical writers, regularly running workshops for EMWA and pharmaceutical companies around the world. In 2002, Julia co-founded Trilogy Writing & Consulting, a company specialised in providing medical writing. In addition to company management activities as Senior Partner and CEO, she continues to contribute her enthusiasm to client projects, writing a wide array of clinical documents. Numerous clients have depended on and appreciated her expertise in writing and coordinating study protocols, study reports, and CTD submission dossiers. Email: email@example.com
Lisa Chamberlain James: Lisa Chamberlain James is a Senior Partner and CEO of Trilogy Writing and Consulting Ltd., a specialised medical writing company founded in 2002. Aside from management activities, she also contributes to client projects, with extensive experience in a variety of documents. After receiving her PhD in Pathology, Lisa began her medical writing career in Cambridge in 2000. Since then she has also been involved in the European Medical Writers Association (EMWA); she is a member of the EMWA Educational Committee, a leader and assessor of EMWA workshops, has helped to produce the EMWA conference programme from 2010 onwards, and holds an EMWA personal development certificate. Lisa is also a member of TOPRA and is a Fellow of the Royal Society of Medicine. Email: firstname.lastname@example.org
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Page 23 â€“ Advert 11 Eurofins
Clinical Investigation of Medical Devices: Promoting Convergence
Abstract The safety, performance and effectiveness of medical devices are evaluated by clinical investigation before they enter the market. The integrity of the data is ensured using international standards like ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice, or ICH E6 Guideline for Good Clinical Practice (GCP) or other GCPs. A clinical investigation design should be made which is appropriate and acceptable by many regulatory authorities that acts as a “gateway” for data transportability and removes all trade barriers. This article brings out the differences between ISO GCP and ICH GCP. Also, it discusses the need for harmonising various GCP standards. Since consistency is essential among GCPs to avoid duplication of work and to allow data from a clinical investigation to be used in another country for marketing approval (data transportability); so it is important that the standards are harmonised. Keywords: Clinical Investigation Plan, Harmonisation-byDoing, ISO14155, Convergence, Good Clinical Practices Introduction Regulations for conducting medical device (MD) clinical trials around the world have varied widely. Complications that arise between trials conducted under different protocols make bringing a device to market difficult in a stricter country. Data may be considered questionable given different requirements1. Reciprocal acceptance of Good Clinical Practices (GCPs) would facilitate multinational studies and promote the use of clinical data to support regulatory submissions in multiple countries 2. Objectives • To bring out the differences between international standards like ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practices (GCP) or ICH E6 GCP. • To discuss the advantages of harmonisation of these guidelines for the benefit of the medical device industry and public health. ISO 14155:2011 ISO 14155:2011 addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety or performance of medical devices for regulatory purposes. The principles set forth in ISO 14155:2011 also apply to all other clinical investigations and should be followed
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as far as possible, depending on the nature of the clinical investigation and the requirements of national regulations. ISO 14155:2011 specifies general requirements intended to protect the rights, safety and wellbeing of human subjects, ensure the scientific conduct of the clinical investigation and the credibility of the results, define the responsibilities of the sponsor and principal investigator, and assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.3 ICH GCP The ICH-GCP is a harmonised standard that protects the rights, safety and welfare of human subjects, minimises human exposure to investigational products, improves quality of data, speeds up marketing of new drugs and decreases the cost to sponsors and to the public. Compliance with this standard provides public assurance that the rights, safety and wellbeing of trial subjects are protected and consistent with the principles of the Declaration of Helsinki, and that the clinical trial data is credible. 4,5 Differences 6 ISO 14155:2011
ISO technical committee – regulators and (predominantly) medical device industry
Joint initiative – regulators and pharmaceutical industry
Goal – international standardisation of clinical investigations of medical devices
Goal – harmonise requirements in order to aid global drug development
ISO14155 assesses clinical performance
ICH GCP assesses efficacy
Investigator is qualified by education, training and experience
Investigator is a qualified physician or dentist
ISO 14155:2011: investigator brochure to contain a summary of relevant manufacturing processes and related validation processes
ICH GCP – in accordance with applicable Good Manufacturing Practice
ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects– GCP – not globally adopted
ICH GCP guidance introduced in 1996 – widely adopted in USA, Europe, Japan and many others
Adverse events Adverse device effect – insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or any malfunction of the investigational medical device Device deficiencies – inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance Adverse events not restricted to subjects – can also be users or other persons
Adverse event is related to the drug. Due to the systemic nature of drugs, all adverse events will need to be captured and analysed as potentially related to the drug.7
Reporting – ISO 14155:2011 doesn’t differentiate the reporting of foreseeable adverse events and anticipated adverse device effects from unanticipated events / effects
Reporting serious reactions, product quality problems, therapeutic inequivalence / failure with drugs
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Regulatory (FDA) regulations and guidance, Japanese GCP ordinances Problems6 • ISO 14155 perceived as “weaker” than ICH GCP. • ICH GCP too pharmaceutically-oriented for medical devices. • Terminology: (i) Manufacture in accordance with GMP. (ii) Pharmacokinetics, metabolism, pharmacodynamics, dose response, efficacy, and other pharmacological activities… • Safety reporting: not always applicable to devices – adverse drug reaction – devices fail in different ways to drugs. • Lacking in some areas – training / data management / subject identification log. Solution8 • Release of ISO 14155:2011 is a positive step towards harmonisation. • Disparities still exist for significant trial concepts. • Standards bodies may adapt the new guidance as they deem necessary. • Objective to create one uniform measure to demonstrate a specific regulatory requirement has not yet been realised. Data Transportability of Clinical Trials The transportability of medical device clinical data obtained from a GCP-compliant study has a great impact on the marketing approval of an MD9. Reports and regulatory discussions have suggested differences between GCP in the different countries that make it difficult to analyse and utilise clinical trial data from one GCP system in support of marketing approval in the other. Language and cultural barriers may add to the complexity. By understanding the nature of these differences, it may be possible to more accurately determine whether data from an alternate GCP provide similar assurances of valid scientific information and patient protection. GCP, as described in standards and regulations, governs the quality of clinical trials for medical products, including medical devices, but the differences between GCP requirements have not been well studied. Further study of these differences is needed to enhance the meaning of compliance with one set of GCP requirements versus another2. Benefit of GCP Convergence for Patients10 • Improve safety and timeliness of new devices. • Encourage innovation of medical device therapies. Convergence May10 • Promote multi-national studies. • Provide similar assurances of valid scientific information and patient protection. • Support reciprocal acceptance of clinical data to support regulatory submissions in multiple countries. International Effort Towards Harmonization Four GCPs are most applicable to US and Japanese marketing approvals: US Food and Drug Administration www.jforcs.com
and notifications, ISO14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice and ICH E6 (R1) Guideline for Good Clinical Practice. Clinical and regulatory experts in the US and Japan formed a group – Harmonization-by-Doing (HBD), a cooperative effort to move Japan and the US toward international regulatory harmonisation. HBD Working Group 4 performed a line-by-line evaluation and comparison of the four GCPs mentioned above. The convergence of US and Japanese medical device regulations and practices provides an opportunity to accelerate delivery of innovative medical devices to patients in need of medical treatment. 2 Although that study identified numerous differences in wording, organisation, specificity and depth of topic coverage, in general, the GCPs were found to be quite similar. The differences were assessed with respect to four fundamental criteria: 9 1) 2) 3) 4)
Rights, safety and welfare of trial subjects, Scientific integrity of trial methods, Accuracy of the data, and Reliability as a basis for regulatory decision-making.
Differences were categorised as substantive, non-substantive or administrative. Harmonization-by-Doing Programme’s Working Group4 (WG4)11 ‘Harmonization-by-Doing’, commonly known as HBD, is an international effort to develop global clinical trials and address regulatory barriers that may be impediments to timely device approvals. This process is a cooperative effort to move both Japan and the US toward international regulatory harmonisation. Participants in this process include: • U.S. Food and Drug Administration (FDA) Centre for Devices and Radiological Health (CDRH), • Japan’s Pharmaceutical and Food Safety Bureau (PFSB) of the Ministry of Health, Labour, and Welfare (MHLW) Journal for Clinical Studies 25
• • •
and its review agency, the Pharmaceutical and Medical Devices Agency (PMDA), Duke Clinical Research Institute (DCRI), Japanese academic community, and Japanese and US medical device industry.
What is the HBD Initiative?11 The HBD initiative is a pilot project launched in December 2003 that seeks regulatory convergence between FDA and MHLW-PMDA premarket review of device cardiovascular technology. Instead of taking a theoretical approach to harmonisation, HBD will utilise parallel development, application submissions and review of actual medical device projects by FDA and MHLW-PMDA. The objective is to eliminate redundancies, added costs, and time delays inherent in sequential trials. The intent of HBD is not simply to create guidance and discuss policy but to develop common protocols for investigational clinical studies that would allow safe and effective medical devices to benefit patients worldwide. What are the Benefits of HBD?11 FDA and MHLW-PMDA share similar scientific concerns and reviewers pose similar safety and effectiveness questions. While there may be divergence in regulatory practices, the two agencies are willing to consider ways of approaching the differences in order to allow the availability of novel treatments and innovative, safe and effective medical devices to patients more quickly. Only through international collaboration can global market reviews be conducted in a timely manner. HBD provides: • More robust clinical trials • Improved clinical research infrastructure • Better clinical trial data • Better understanding of how the U.S. and Japanese experiences can complement one another • A new approach to early market availability of new treatment and devices to benefit patients in both countries • A mechanism to decrease lag time between U.S. and Japanese product approval • An atmosphere of international collaboration between regulators, regulated industry, clinical researchers, patients and academia • A continuous progression in global harmonisation The HBD concept is also a process that can be broadened in scope beyond premarket activities. It can also be applied to post-market clinical studies, collection of post-market data and patient registries. Regulatory Approach12 It is a step-by-step process within the current regulatory framework as shown in Figure 1. “Aligning” the regulatory roadmaps – tools already exist in both countries as shown in Figure 2.
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Figure 1: The Regulatory Approach
Figure 2: “Aligning” the Regulatory Roadmaps – Tools already exists in both countries
Global Clinical Trial Challenges12 • Pooling data (demographics, differences in practice of medicine, protocol-related factors). • Review of foreign data (applicability to country’s population and medical practice). • Statistical methodology (comparing foreign data to native country data, adjustment for covariate differences). • Identifying safety and effectiveness endpoints necessary for market approval. • Cultural and language issues. • Variations in medical practice and healthcare systems. • Ethical issues concerning clinical research. • How to communicate effectively with sites. • Establishing realistic timelines and other logistics. Challenges can be overcome with creative and well planned clinical trial designs.
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Regulatory Importance of Globally Standardised Clinical Trials 12 • High scientific and ethical standards. • More robust clinical trials and better data. • Globally acceptable clinical data. • Widely applicable conclusions – more interpretable and more informative safety and effectiveness data. • Quicker and more cost-effective generation of clinical data. Conclusion Compliance with GCPs alone does not ensure transportability. The clinical investigation design, including the choice of patient population, sample size, endpoints, follow-up periods and statistical analysis plans must address the requirements of various regulatory authorities. Early consultation with the relevant regulatory authorities may facilitate development of a clinical investigation design that is mutually acceptable to those authorities. So, the intent of convergence is not simply to create guidance and discuss policy but to develop common protocols for investigational clinical studies that would allow safe and effective use of MD to benefit patients worldwide. References 1. Clinical Device Group: ISO 14155, Good Clinical Practice for Medical Device Trials. Available at: http://www.standardslearn.org/standardization_case_ studies.aspx 2. Fearnot Neal E., Comparing GCP Requirements for Medical Device Clinical Trials in the US and Japan. Regulatory Focus. April 2010; pp. 40-44 Available at: http://www.jfmda.gr.jp/hbd/pdf/GCP_en.pdf 3. ISO 14155:2011 Clinical investigation of medical devices for human subjects -- Good clinical practice. Available at: http://www.iso.org/iso/catalogue_ detail?csnumber=45557 4. European Medicines Agency. ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (PMP/ICH/135/95) London: European Medicines Agency; 2002 5. Vijayananthan A., Nawawi O. The importance of good clinical practice guidelines and its role in clinical trials. Biomed Imaging Interv J 2008;4:e5. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC 3097692/#R8 6. Welch S, ISO14155 & ICH GCP the differences & similarities highlighted. 33rd Annual Conference & Exhibition 2012 May. London. 7. Maddock S. The Difference is in the Details - Drugs vs. Devices. Available at: http://www.imarcresearch.com/ Portals/149400/docs/drugs-vs-devices.pdf 8. Frestedt J. Using ISO 14155 to Guide Compliance for Medical Devices. Socra 21st Annual Conference. Sep. 2012. 9. Fearnot Neal E., GCP Convergence Improves Transportability of Medical Device Clinical Data.
Regulatory Focus. January 2013. Available at: http://www.raps.org/focus-online/news/ news-article-view/article/2705/gcp-convergenceimproves-transportability-of-medical-device-clinicaldata.aspx 10. Fearnot Neal E., Focus on Good Clinical Practices for Medical Device Clinical Investigations. 2010 AHC Workshop on Medical Devices November 15-16, 2010 Seoul, Korea. Available at: http://www.apec-ahc.org/files /tp201003/FocusonGCP_NealFearnot.pdf 11. Fda.gov. Japan - U.S. “Harmonization By Doing” HBD Pilot Program Initiative. Available at: http://www.fda. gov/MedicalDevices/DeviceRegulationandGuidance /InternationalInformation/ucm053067.htm 12. Carey Carole C., Overview of HBD/Collaborative Consultation and Premarket Review Pilot Programs. 2010. Available at: http://www.apec-ahc.org/files/tp201003/ MultiregionalClinicalTrial_CaroleCarey.pdf
Shilpi Khattri is currently pursuing full time Ph.D in Regulatory Affairs from JSS University, Mysore. She secured the highest marks in M. Pharma (Regulatory Affairs). She is graduated (B. Pharma) from Manipal University, Manipal. She published an article titled Pharmacovigilance Regulations in India: A Step Forward in a reputed journal. Email: email@example.com Balamuralidhara V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 10 years. He has authored 16 International and 11 National publications in reputed journals and a Book. He has attended various conferences and currently he is working on Biosimilars. Email: firstname.lastname@example.org
T. M. Pramod Kumar is Professor and Head in the Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 20 years. He has guided 5 Ph. D candidates. He has authored 70 International and 50 National publications and has chaired scientific sessions nationally & internationally. Email: email@example.com
Journal for Clinical Studies 27
Clinical Trials in Russia Report on Q2 of 2013 The Ministry of Health of the Russian Federation approved 199 new clinical trials of all types, including local and bioequivalence studies, during the 2 nd quarter of 2013 (23% less than in the same period of the last year).
The main contribution to the total number of studies is made by multinational multi-centre clinical trials (MMCT), the number of these studies decreased from 102 to 81 new studies in Q2 2013. The number of bioequivalence studies decreased from 107 studies in Q2 2012 to 76 in Q2 2013. The number of local clinical trials decreased from 48 to 42. The share of multinational multi-centre clinical trials was 41% of the total number of clinical trials in Q2 2013, while the local and bioequivalence studies amounted to 37% and 22%, respectively. Clinical trials in Russia in Q2 2013 were sponsored by companies from 24 countries. The greatest number of trials (92) was initiated by Russian sponsors. American sponsors with 30 new studies took the runner-up place; they are followed by German and Swiss sponsors with 12 trials, and the group of leaders is concluded by Indian (nine) and French (seven) sponsors. Nine new clinical trials of Phase I were launched in Q2 2013, which is one trial less than in Q2 2012. The number of the Phase II trials decreased from 27 in Q2 2012 to 21 new studies in Q2 2013. The number of Phase III trials decreased from 102 to 88 studies, 14% less than in Q2 2012. Phase IV trials demonstrated a two-times decrease from 11 studies in Q2 2012 to five studies in Q2 2013. The number of subjects which are planned to be enrolled in Phase I-IV trials launched in Q2 2013 is 14,654 - 15% less than the Q2 2012 figure, when 17,293 patients had been planned to be enrolled. Novartis, sponsoring seven new studies, is on the top of the heap in Q2 2013. It is followed by GlaxoSmithKline having five new trials. The top five is concluded by Servier, Merck&Co and Bayer, each having four new trials and differentiating in the number of subjects. The Russian company OOO Atoll, sponsoring ten new clinical trials, ranked number one among domestic pharmaceutical manufacturers by the number of new studies in Q2 2013. Vertex, with nine new trials and Biocad with seven new studies took the runner-up place. They are followed by Medisorb with five studies. The top five of Q2 2013 is concluded by Sotex, with four new trials. More than three-quarters of new studies in Q2 2013
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were initiated in seven leading therapeutic areas: the largest number of studies was initiated in oncology (26); 18 new studies were instigated in diseases of the circulatory system; 16 studies in musculoskeletal diseases; 12 new studies in endocrinology; nine studies in pulmonology, and seven studies each in infectious and parasitic diseases and in neurology. The Center for Drug Evaluation and Research (CDER) of the FDA approved 20 new drugs during Q2 2013, and four of them were studied in clinical trials conducted in Russia. During Q2 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMEA) gave positive recommendations on 31 new drug applications . Negative opinion was adopted for one drug. Of the drugs which received positive opinions,18 were (or are being) tested in clinical trials in Russia. â€ƒ Clinical Trials by Type and Manufacturing Country The MoH of the Russian Federation approved 199 new clinical trials of all types, including local and bioequivalence studies, during the 2 nd quarter of 2013, demonstrating a 23% decrease in comparison with the same point of the last year. As shown in Figure 1, the main contribution to the total number of studies was made by multinational multi-centre clinical trials (MMCT); the number of these studies decreased, and amounted to 81 new studies in Q2 2013, demonstrating a 20% fall in comparison with the same period of the last year. The number of bioequivalence studies decreased from 107 studies in Q2 2012 to 76 in Q2 2013. The number of local clinical trials has slightly decreased from 48 to 42 clinical trials, demonstrating a 12.5% fall in comparison with the same period of the last year. Figure 1. Clinical trials in Russia in Q2 2013
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The proportions between different study types (multinational multi-centre clinical trials, local studies and bioequivalence trials) slightly changed since last year (see Figure 2). The share of multinational multi-centre clinical trials studies stayed almost at the same rate: 41% of the total number of clinical trials approved in Q2 2013. The share of the local trials increased at 21%, and the share of bioequivalence studies decreased from 42% to 38% of the total number of trials approved during Q2 2013.
the total number of clinical trials. The largest number of trials (92) was initiated by Russian sponsors. American sponsors, with 30 new studies, took the runner-up place; they are followed by German and Swiss sponsors with 12 trials, and the group of leaders is concluded by Indian (nine) and French (seven) sponsors.
Figure 4. Countries presented on the Russian clinical trials market in Q2 2013
Figure 2. Clinical trials by type in Q1 2013
The proportions between sponsors did not significantly change in comparison with the same period last year. 54% of the total number of new studies in Q2 2013 were sponsored by foreign companies, which is 107 study approvals. The share of studies of local manufacturers insignificantly increased and amounted to 92 studies (Figure 3). Figure 3. Russian and International sponsors in Q2 2013
Among others are: UK (six); Belarus, Belgium, Hungary, Denmark, Poland, Czech Republic (three studies each); Italy and Latvia (two trials each); and Austria, Israel, Korea, Luxembourg, Netherlands, Macedonia, Romania, Croatia, and Japan each started one new study in Q2 2013.
Clinical Trials by Phase The number of Phase I clinical trials changed insignificantly and stood at nine new studies in Q2 2013. The number of Phase II trials decreased from 27 in Q2 2012 to 21 new studies in Q2 2013 (Figure 5). The number of Phase III trials decreased from 102 to 88 studies, 14% less than in Q2 2012. Phase IV trials demonstrated a decrease of more than two times, from 11 studies in Q2 2012 to 5 studies in Q2 2013. Figure 5. Clinical trials in Russia in Q2 2013 by phase 1
Clinical trials in Russia in Q2 2013 were sponsored by companies from 24 countries. Figure 4 demonstrates the input of the leading countries of sponsorsâ€™ origin into www.jforcs.com
Journal for Clinical Studies 29
Market Report As shown in Figure 6, the share of Phase III trials in Q2 2013 is 72% of the total number of studies; the share of Phase II trials accounted for 17%; Phase I trials is 7%; and the share of Phase IV studies amounted to 4%. Figure 6. The proportions between study phases in Russia in Q2 2013
Rating of International Sponsors Novartis, sponsoring seven new studies, is on the top of the heap in Q2 2013. It is followed by GlaxoSmithKline, having five new trials. The top five is concluded by Servier, Merck&Co and Bayer, each having four new trials and differentiating in the number of subjects. The top five international sponsors by the number of new studies in Q2 2013 are presented in Table 1.
Table 1. Top 5 international study sponsors in Q2 2013
The number of subjects which are planned to be enrolled in Phase I-IV and BE trials launched in Q2 2013 is 14,654, 15% less than the Q2 2012 figure, when 17,293 patients were planned to be enrolled. 236 subjects will be recruited in Phase I trials; 1873 patients in Phase II trials; 9871 subjects in Phase III studies and 697 patients will be enrolled in Phase IV studies. Other subjects (1977) are healthy volunteers and patients who will enter into bioequivalence studies The minimal number of subjects in a single study is ten, the maximum number is 800. The proportion of the number of patients between different phases is shown in Figure 7. Only studies in which phase is specified were included.
Rating of Russian Sponsors The Russian company OOO Atoll, sponsoring ten new clinical trials, is ranked number one among domestic pharmaceutical manufacturers by the number of new studies in Q2 2013. Vertex, with nine new trials, took the runner-up place. It is followed by Biocad and Medisorb, with seven and five studies, respectively. The top five of Q2 2013 is concluded by Sotex, with four new trials.
Table 2. Top-5 Russian study sponsors in Q2 2013
Figure 7. The number of patients in Q2 2013 by study phase
Therapeutic Areas of Clinical Trials in Russia in Q2 2013 More than three-quarters of new studies in Q2 2013 were initiated in seven leading therapeutic areas: the largest number of studies was initiated in oncology (26); 18 new studies were instigated in diseases of the circulatory system; 16 studies in musculoskeletal diseases; 12 new studies in endocrinology; nine studies in pulmonology, and seven studies each in infectious and parasitic diseases and in neurology. The proportions between different therapeutic areas are shown in Figure 8.
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Market Report Figure 8. Clinical trials in Russia in Q2 2013 by therapeutic area
Clinical Trials Results The Center for Drug Evaluation and Research (CDER) of the FDA approved 20 new drugs during Q2 2013; four of them are new molecular entities (NME); others are new dosages, manufacturers or indications of the already marketed drugs. Four drugs were studied in clinical trials involving Russian sites. Table 3 shows the drugs which were approved by FDA in Q2 2013 that were being tested in clinical trials in Russia. Table 3. New drugs approved by FDA in Q2 2013 and tested in Russian sites
During the second quarter of 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMEA) gave positive recommendations on 31 new drug applications . Negative opinion was adopted for one drug. Of the drugs which received positive opinions, 18 were (or are being) tested in clinical trials in Russia (see Table 4).
Table 4. New Drugs approved by EMEA in Q2 2013 and tested in Russian sites
Igor Stefanov, MBA. General Manager After an engineer degree at the Moscow Aviation Institute in 1989 Mr. Stefanov joined the leading Russian defense R&D Institute as the First-class Engineer for Battle Aircraft Design and Efficiency Evaluation. After the collapse of the Soviet Union in 1991 he became a Research, and then a Senior Research Fellow at the Institute for New Technologies of the Russian Academy of Science. After an MBA in Economics at the Moscow International University in 1993 he went into the business consulting area developing and implementing localization strategies for the Fortune 500 companies in Russia comprising General Motors, 3M, Unilever, Kodak and Shell, to name but a few. Prior to joining SynRG in January 2007, Igor was General Manager of Smartlock, the Russian hi-tech biometric company and was recognized as an entrepreneur of the month by the Russian edition of Forbes magazine in 2005. With in-depth macro- and microeconomics knowledge, strong management skills and solid local expertise Mr. Stefanov has been providing various consulting services to large multi-national companies in Russia since 1993, and there are a number of Big Pharma representatives on the list including Pfizer, J&J, GlaxoSmithKline, Roche and others. His other areas of interest comprise Chinese calligraphy, weiqi (Go) and shakuhachi (Japanese flute). Email: firstname.lastname@example.org
Journal for Clinical Studies 31
Choosing the Right Lab: Big is Not Always Beautiful Many challenges have to be properly addressed in order to conduct a clinical study successfully: defining the right study design for a given drug candidate, selecting appropriate study centres with excellent access to the study population, and identifying a central lab which can manage all study-related tasks and which provides valid and reliable laboratory data with short turn-around times. This paper will discuss the different categories of laboratories involved in clinical labs and may be used as a brief guide to a good match between study design and laboratory services. The importance of laboratory data within clinical studies is often only fully recognised when clinical studies are being delayed or otherwise affected by the lack of reliable data. A few examples shall be used to illustrate the consequences of an improper choice of clinical laboratory: 1. Inclusion of patients can be significantly impaired when screening data are not available on the same or next day of the screening visit. 2. Data of pharmacodynamic endpoints can be misleading if non-validated methods have been used. 3. Several analytes are not stable in normal serum or plasma and need specific stabilisers or storage conditions. In cases where these requirements are not properly defined by the lab this may lead to analytical artifacts. However, due to the fact that design, geographic spread and read-out of clinical trials is very diverse, it is also recommended to consider different categories of lab partners for different trials.
The different lab categories can be discriminated according to the following scheme: Page 1 of 1
Type of laboratory
Laboratory facilities Wholly‐owned sites on different continents
Head‐ count 1000‐ 2500
CAP, ISO15189, GCP, compliance with EMA and FDA standards including GCLP
Validated according to EMA/FDA guidelines
International central laboratories with qualified partner labs
Wholly‐owned central lab and multiple regional independent partner labs
CAP, ISO15189, GCP, compliance with EMA and FDA standards including GCLP
Independent central laboratories with international experience
Wholly‐owned central lab
CAP, ISO15189, GCP, compliance with EMA and FDA standards including GCLP
Wholly‐owned speciality lab or subsidiary of CRO
Pharmaco‐ kinetic studies
GLP, compliance with EMA and FDA standards
Local reference laboratories or hospital laboratories
Independent lab or lab belonging to a laboratory chain
Standard medical care
CLIA or ISO15189
GCP/GCLP‐ compliant, archive with raw data, validated computer systems GCP/GCLP‐ compliant, archive with raw data, validated computer systems GCP/GCLP‐ compliant, archive with raw data, validated computer systems GLP/GCLP‐ compliant, archive with raw data, validated computer systems Standard result reports
International multisite central laboratories, often associated with global CROs
Validated according to EMA/FDA guidelines
Validated according to EMA/FDA guidelines
LC/MS‐MS methods validated according to EMA/FDA guidelines Verified according to standards sufficient for patient care
The evaluation of advantages and disadvantages of the different lab types has to be discussed in the context of the needs that have to be addressed for a given clinical study. Large international Phase III studies with more than 2000 patients conducted on different continents clearly benefit from the global infrastructure of an international multisite 32 Journal for Clinical Studies
Source: MLM Medical Labs’
laboratory. The same is also true for studies conducted in China, where national regulations restrict the export of clinical trial samples and where generallyonly international multisite laboratories arerepresented with established lab facilities. Large multisite central laboratories that are associated with a global CRO are also often chosen when the overall study management is in the responsibility of the CRO they belong to. Finally, international multisite central laboratories are often involved in clinical studies of different phases due to preferred provider agreements with global pharmaceutical companies. The global infrastructure of international multisite laboratories offers the benefit of potentially uniform procedures and harmonised SOPs. However, one should also take into account that these international multisite central laboratories have been generally built by the acquisition of national or regional laboratories with their own infrastructure. Therefore, the different subsidiaries do not necessarily have uniform methods and SOPs. This aspect should be challenged when choosing the right partner. International central labs with independent qualified partner labs can offer a valuable alternative, especially when it comes to multi-centre Phase II studies or Phase III studies with up to 2000 patients. These laboratories often work with strong qualified partners and therefore provide a great deal of experience that will facilitate the conduct of the clinical trial. The involvement of partner laboratories that are in direct reach of the clinical study sites can reduce logistic costs and avoid delays due to customs clearance. Furthermore the arrangement with partner labs offers the advantage that management attention is focused on the optimal conduct of clinical studies – provided that reliable and efficient partners have been chosen – and is not diluted by running a global organisation with all financial and regulatory implications. International Phase II and Phase III studies can also be supported by independent central laboratories with international experience. These laboratories often provide a broad portfolio of standard and speciality parameters as well as all flanking services like kit-building, logistics and data management. Therefore such independent laboratories are especially of interest for clinical studies from Phase I-III Volume 5 Issue 5
CENTRAL LAB SERVICES FOR CLINICAL TRIALS · 11 labs on all continents · dedicated project management · reliable shipping logistics · broad analytical portfolio
INTERLAB central lab services – worldwide
EUROPE · THE AMERICAS · ASIA/INDIA/CHINA · AUSTRALIA · SOUTH AFRICA · NEAR/MIDDLE EAST
Market Place that rely on non-standard biomarkers as clinical endpoints, and which are challenging with respect to method development, logistics or project management. In order to illustrate the potential of independent central laboratories, two case studies are presented here: Case study # 1. An independent laboratory was chosen by a global pharmaceutical company as central lab for an international study in the area of metabolic disease. The study was conducted in the US, and Central and Eastern Europe. Total ketone bodies, beta-hydroxybutyrate and acetoacetate were selected as biomarkers, among others. Unfortunately the stability of acetoacetate is very limited: serum samples are stable for only three days at -30째C. The laboratory started a new stability testing and demonstrated that stability could be increased to six days by storing these samples at -80째C. This allowed the sending of samples in bundled shipments on dry ice, dramatically reduced shipment costs, and led to reliable analytical results due to extended stability and immediate testing after arrival. One reason among others for the involvement of the independent central laboratory was that this laboratory was interested to establish and validate the assay of beta-hydroxybutyrate and acetoacetate in contrast to other labs, including international multisite central laboratories. Case study # 2. According to EMA guidelines, almost all new drugs licensed through the centralised procedure have to come with a pediatric implementation plan for clinical studies with infants. There are multiple challenges for pediatric studies. One is the limited volume of blood drawn and the need to restrict the number of blood draws per visit to the absolute minimum. An independent central laboratory has been selected by a large global sponsor as a central lab for a global pediatric study. One of the most important reasons for this choice was the fact that this lab was able to present a concept for analysing all desired parameters with very low blood consumption and a reduced number of blood draws per visit, which facilitates the recruitment of subjects in this ethically very sensible study collective. An international multisite central laboratory has offered a different approach involving different lab sites in different countries which would have done only a few of the numerous biomarkers of interest. This would have automatically resulted in multiple blood draws and a larger sampling volume which was not acceptable for the sponsor. The independent central laboratory offered the advantage that all analyses were conducted at only one laboratory site with a small sample volume. Independent central laboratories are often privately-held companies and provide the advantage of flat hierarchies and a generally low turnover of personnel, which translates into fast and direct communication with the clients with a stable team of project managers as key contacts. The low turnover guarantees a constant and seamless communication between client and laboratory staff when multiple projects are being conducted for the same client. In addition, these laboratories often do not rely on larger preferred provider arrangements and have to generate 34 Journal for Clinical Studies
their revenues from multiple clients with smaller projects. Therefore they are very flexible and willing to adjust to the requirements of the sponsor. It has been observed that this business attitude is often very attractive for smaller and mid-size biotech and pharmaceutical companies that are less interesting targets for international multisite central laboratories, since these clients do not offer the revenue potential of global pharmaceutical companies. Finally, local reference or hospital laboratories are still being used for clinical studies. However, in 2012 the EMA issued new regulations on the use of clinical laboratories in clinical trials 1. The EMA reflection paper defines several criteria for laboratories involved in clinical trials, which can be regarded as a merger of the standards of good laboratory practice (GLP) and of ISO15189 or CAP requirements. The criteria requested by the EMA can also be summarised under the quality standard good clinical laboratory practice (GCLP). The EMA reflection paper requires a high degree of organisation of the clinical laboratory, regular GCP training, defined procedures for study-related processes, a stringent and audit-safe documentation of all laboratory activities, and a fully-developed quality management system. These requirements are difficult to meet by hospital and reference laboratories that primarily focus on patient care. Therefore it can be expected that this type of laboratory will play an increasingly marginal role in upcoming years, whereas central labs will be the predominant providers of laboratory data for clinical studies. When choosing the right lab for a given study, the different types of central labs discussed here should be carefully evaluated. Especially in the case of large multinational Phase III trials, international multisite central laboratories offer clear advantages. However, in the case of Phase I studies and mid-size Phase II or III studies clients can take advantage of the high flexibility, service attitude and experience of independent central laboratories or international central laboratories with qualified partner labs. Reference 1. Reflection paper for laboratories that perform the analysis or evaluation of clinical samples (EMA/INS/ GCP/532137/2010
Prof. Dr. Stephan Wnendt, biochemist and CEO of MLM Medical Labs, has held senior positions in pharmaceutical industry, medtech and biotech in Germany and the US before joining MLM in January 2008. Besides his work in industry Dr. Wnendt is honorary professor at the University of Technology in Aachen, Germany. Email: email@example.com Dr. Katja Neuer-Etscheidt, was trained in chemistry at the University of Technology in Aachen, Germany, and did her PhD at the University of Technology in Munich, Germany. From April 2008 onwards she has held a position in Business Development at another central laboratory before joining MLM in October 2011 as Director of Business Development. Email: firstname.lastname@example.org Volume 5 Issue 5
Page 35 – Advert 14 – medici
Selecting A Right Patient Recruitment Company
One of the major challenges that biopharmaceuticals and medical device companies are facing nowadays is delay in getting their drug/device to market through a successful development programme. The most common reason for delays in clinical trials or development programmes is failure to recruit potential patients on a study as per the planned timeline. Patient recruitment timelines represent 22.3% of entire clinical development timelines1. Almost 80% of clinical trials fail to meet enrolment timelines2 resulting in a loss of more than a million dollars per day for a given candidate, considering its post-marketing revenue. Patient recruitment is one of the most important aspects of clinical trials and a key determinant of the success of a drug development programme. Patient recruitment has always been a challenge for some complex studies and indications. It is becoming more challenging with the increased complexity of study protocol design, difficult new study procedures, stringent eligibility criteria and the requirement for targeted patient populations. Such complex, “difficult to recruit” kinds of studies require specialised support from a patient recruitment company to ensure timely and successful completion of a clinical trial or programme. In the last two decades, investigational sites used to provide their total patient enrolment by reaching into their own database of patients. However, due to complexity of the current protocols, rigorous eligibility criteria and the rarity of some disease conditions, sites need to go beyond their practice to achieve their recruitment targets on time. The longer it takes to complete the recruitment, the more money and resources sponsors have to spend to complete the trial. If a study is outsourced to CRO, sponsors have to shell out additional budget on change orders for extended enrolment timelines, as well as additional spending for adding more sites and countries to the study when the existing sites’ in-practice patient pool fails to reach the recruitment goal. Moreover, due to delays in patient recruitment, sponsors fail to achieve their critical, planned milestones of “time to reach market”. The old model, with CROs having dual responsibilities for monitoring a trial and looking into patient recruitment strategies, is not producing the necessary results any more, especially for “difficult to recruit” kinds of protocols and rare/ orphan disease indication studies. CROs have limited expertise and limitations in patient enrolment activities due to their responsibilities of monitoring a clinical trial. They often simply present patient recruitment rates to sponsors based on what investigational sites predict, and fully depend on sites’ capabilities to deliver on patient recruitment. Therefore, it is very crucial for the success of clinical trials and drug 36 Journal for Clinical Studies
development programmes, that sponsors have to foresee risks and reach an agreement internally to use the right patient recruitment company for managing patient recruitment and retention on “difficult to recruit” and complex studies. Usually the protocols in therapeutic areas like oncology, CNS and CVS have stringent eligibility criteria, and it is difficult to find protocol-specific patients. Apart from the complex indications, some of the simple indication studies like diabetes and infection conditions also pose challenges in patient recruitment due to requirements for targeted patients, such as certain age groups of pediatric or elderly patients. It is difficult to get patients for some of the medical device studies, even with common indications, as these studies require advanced emerging techniques with some surgeries about which patients are apprehensive due to lack of information. For such clinical trials to recruit patients, special expertise is needed in terms of educating patients and referral physicians by a Clinical Trial Educator (CTE), a specialised resource offered by some patient recruitment companies. For complex studies with anticipated challenges with regard to patient recruitment and retention, it is advisable to have a strategic approach to get a right patient recruitment company on board right from the start of the clinical trial. Waiting a long time to see progress on patient enrolment and then struggling with rescue operations leads to a loss of critical time and money. Moreover, the selection of a patient recruitment company in the beginning will help the sponsor to get better insight into the selection of the right countries and sites for their study protocols, based on its earlier experience in managing similar kinds of studies. Thus, selecting the right partner as a patient recruitment company helps sponsors to fulfill their operational objectives, reduces timeline and cost, cuts down the amount of associated stress, and improves overall efficiency in clinical trial management.
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Patient recruitment services are offered by different firms like specialised patient recruitment companies, advertising firms, call centres and some of the clinical research organisations (CROs) as a separate division. Partnership with the right firm will not only prevent unnecessary spending due to delays in patient recruitment, but will also shorten the time to reach market and thereby ensure a good return on investment. With the expertise and experience in therapeutic area and geographic area of a planned study, an experienced patient recruitment partner helps in effectively overcoming the hurdles in patient enrolment, which might otherwise be seen as major challenges by sponsors/CROs and sites. However, the key here is selecting the right partner to ensure success. Selecting a speciality patient recruitment company that has significant experience working with different indications, countries and sites, and a company which can price based on measurable enrolment milestones, will help the sponsor to achieve its objectives. While selecting a patient recruitment partner, a few aspects need to be taken into consideration to ensure right selection. •
Selecting a company which offers comprehensive solutions for patient recruitment and retention: There are different methodologies for patient recruitment and retention, like the use of local clinical enrolment specialists (CESs) and clinical trial educators (CTEs) to work with sites and carry out strong field-based activities, various advertisement options (e.g. TV, radio, print, online, social media) and call centre support. Different studies require different approaches to accomplish patient recruitment in the planned timeline. Most of the time, to deliver on patient enrolment commitments, it is necessary to carry out field-based activities within and around investigational sites to identify study-specific potential patients and funnel them to sites. Therefore, it is important to select the patient recruitment company which offers a powerful field-based activities approach, with other options like media advertisement with call centre support. For some studies, companies which only offer an advertisement option may not be the right option to have a “complete solution” to take up all recruitment challenges. The patient recruitment company with comprehensive solutions can offer flexible approaches and a variety of innovative solutions by effectively addressing protocol-specific challenges and hurdles in patient enrolment. Patient recruitment company offering other allied services like site management and feasibility: A patient recruitment company which also offers site management services generally has a good network of sites as partner, and/or their own exclusive sites. Their good relationship with this network of sites can help to form a referral network locally in the country of study to funnel the patients from these referral sites to investigational sites. As these are the partner sites or exclusive sites or have established relationships with the patient recruitment company, they might not show much resistance to send their potential patients to study sites, if they feel the study treatment can benefit the patients and they do not anticipate
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any concerns about patient safety. This approach of establishing a local network of referral sites to funnel patients to the investigational sites can be used as a “strategic approach” while selecting the study sites right in the planning stage. Also, if a patient recruitment company offers feasibility services, it will help the sponsor to select the right countries and sites for their given study, to understand protocol-specific challenges especially with regard to patient recruitment and retention, and also to predict the optimum clinical trial cycle time based on their earlier experience. Operational presence with local expertise in the countries of study conduct: The patient recruitment company should be able to offer the right local experienced resources who will be able to formulate country- and site-specific result-oriented strategies, and offer targeted, customised methodologies in patient enrolment based on their experience in those countries within the framework of the local regulatory and ethical environment. As many clinical trials are moving to emerging regions like Asia-Pacific, Central & Eastern Europe (CEE) and LA nowadays, the patient recruitment company having experience in these emerging regions should be preferred. Proven track record of enrolling the required pool of patients: Every study is different. However, the proven track record of a patient recruitment company with successful experience in enrolling the required patient pool in earlier studies in the same countries increases the chances of success for a given study. It is important to look into performance metrics of these companies on their earlier studies in similar patient populations. Having experience and past success in getting patients beyond investigational sites’ reach: Most times, investigational sites are able to enroll patients who are there in their database. In order to accelerate and enhance patient enrolment, the key is tapping the patients who are otherwise “out of reach” patients for the sites, and this is the real support that any patient recruitment company can offer to sites and sponsors to maximise the potential patient pool. The patient recruitment company should have strategies and capabilities to reach such sites’ “out of reach” patients. Past Performance (Key Performance Indicators): The best way to assess patient recruitment company’s capabilities is looking into their past performance on similar studies. The key performance metrics that can be checked before selecting the patient recruitment services include: (i) Time to randomise first patient after site activation (ii) Shortening/reducing the overall enrolment timeline with regard to the planned one (ii) Percentage of patients randomised from sites’ “out of reach patients” (iv) Increase in enrolment rate (if support is offered to part of sites on the same study and comparing with the performance of sites which are not supported by the patient recruitment company) (v) Patient retention rate or patient discontinuation rate (if retention service is offered)
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Experience in working with CROs assigned by sponsors: As many times the studies are managed by CROs on behalf of sponsors, the patient recruitment company should have experience and “success stories” of working with sponsors’ CROs. To ensure success in patient enrolment, it is necessary to establish effective co-ordination and communication with the sponsor’s CRO, and they need to complement/supplement each other without creating any conflict of interest. Performance-based pricing: Sponsors always look at outsourcing patient recruitment as a “risky business”. If sponsors pay the patient recruitment company a regular monthly payment based on activities done, but these activities do not yield any result in terms of patient randomisation; then what? Therefore, it is advisable to select a patient recruitment company which offers a fee structure based on per patient randomized, i.e. performance-based per randomised patient pricing. This means a significant amount of total professional fees goes into success fees in terms of patient randomisation. This true “risk-sharing approach” will benefit sponsors and take away their concerns regarding the non-performance of a patient recruitment partner.
The following table gives a broad idea about selecting the right patient recruitment company considering its capabilities/ features and looking into a study’s requirements
Capabilities / features of a patient recruitment company
Factors to be considered in determining weightage
Offers comprehensive solutions for patient recruitment and retention
Low / medium / high
This is a high weightage factor if a study requires all kinds of recruitment modalities, like fieldbased activities, various channels of advertisements and call centre support. Weightage would be medium/low if the study requires only a specific patient recruitment solution e.g. only advertisement
Local expertise / experience in countries of study conduct
Medium / high
This is a high weightage factor if there are country-specific recruitment challenges.
Proven track record on enrolling required pool of patients
Medium / high
This is a high weightage factor if there are indication-specific challenges, especially if it is a rare / orphan disease indication study.
Excellent performance High record in earlier studies (key performance indicators / metrics):
This factor should have a high weightage while selecting a patient recruitment company
Performance-based pricing model
This factor will have medium / high weightage based on sponsor risktaking capacity, and also it is based on overall pricing structure offered by a patient recruitment company
Medium / high
A patient recruitment partner should have experience not only in developing right, innovative, practical study-, countryand site-specific strategies, but also should be able to effectively implement those strategies in a cost-effective manner. A patient recruitment partner should be confident and thorough in its assessment of the enrolment challenges to ensure achievement of the required patient recruitment number for a given study. The close collaboration between a patient recruitment company and a sponsor makes both parties aware of each others’ needs and limitations. A patient recruitment company should also help a sponsor to maintain long-term relationships with sites and Investigators. Sponsors should ask their outsourcing representatives to source multiple proposals and look for the company that offers a detailed enrolment plan and roadmap to success in the proposal. With the right partner on board, patient recruitment is a predictable, reproducible process that optimises site performance and prevents budget overruns caused by adding time, and paying for vendors’ change orders. Conclusion: Some complex, “difficult to recruit” and rare disease indication studies require specialised support from a patient recruitment company to ensure timely and successful completion of a clinical trial / programme. Selecting the right patient recruitment company is the key to success. The various aspects, qualities and capabilities of a patient recruitment company, like breadth and depth of the patient recruitment and retention solutions offered, other allied services presented, past experiences, expertise of local resources, past performance metrics on earlier studies and pricing model need to be assessed thoroughly against a study/ clinical programme needs while selecting the right partner for the patient recruitment services. A partnership with a patient recruitment company will not only improve efficiencies, quality, and effectiveness of a clinical programme by eliminating problems such as low patient enrolment, missed deadlines, language barriers, and other trial-related issues, but also it will create a new paradigm benefiting sponsor, patients and investigational sites. References 1. Beth D. Harper, Projecting Realistic Enrollment Rates Principles and Methodology; Monitor 2004 2. http://www.drugdevelopment-technology.com/features/ featureclinical-trial-patient-recruitment
Ashok Ghone, Ph.D. is Vice-President, Global Services at MakroCare USA. He has extensive experience and understanding of global clinical research which includes hands-on experience in clinical operations, project management, process improvment and patient recruitment activities. At MakroCare, he also leads MCSMO division which offers patient recruitment & site management services. Email: email@example.com
Journal for Clinical Studies 39
Macroeconomic Forces Driving Clinical Trial Costs
A lot has been written about the Affordable Care Act (ACA) recently. Key provisions are kicking in over the next few months and that has left everyone asking the same question — how will the ACA affect healthcare costs in the US? While “affordable” is right there in the title of the legislation, here is another important question we should be asking ourselves — will the ACA provide any relief to the increase in clinical trial costs by giving payers even more control over reimbursement decisions? According to benchmarking research conducted by Cutting Edge Information, per-patient costs for clinical trials have risen in each stage of drug development over the past five years. Certainly, the Affordable Care Act is not responsible for this increase in global clinical trial costs over the past five years, as the legislation is far too new. But other market forces in healthcare have made serious contributions to the rise in clinical trial costs. In 2008, average per-patient costs for a pivotal Phase III trial hovered near $25,000 [Figure 1]. Recent data show costs have nearly doubled in five years, with the average Phase IIIb trial costing $48,500 per patient. Higher trial costs are not simply a latestage phenomenon. Early-stage trials have actually experienced higher cost increases on both a dollar and percentage basis.
Phase I trial costs experienced the largest increase, rising $23,600 per-patient, or 157% in the past five years. Phase II trials were not too far behind, rising 108% during the same time period. While pivotal studies saw a dramatic cost increase between 2008 and 2011, new data indicate that per-patient costs in Phase III trials have actually experienced moderate cost decreases. This article will look to three macroeconomic factors that are impacting clinical trial costs. • Renewed focus on drug safety to receive regulatory approval • Demand for health economics and outcomes data by payers • Shift of R&D resources toward personalised medicine and orphan drug development To be clear, none of these factors are bad for society or individual patients. Quite the contrary — these trends are great. But each of them has had a profound impact on clinical development and clinical trial costs. 40 Journal for Clinical Studies
Safety is the New Efficacy In the wake of several high-profile drug recalls, government regulators have showed a renewed focus on safety data. Patient safety has always been important, but regulators like the FDA are not hesitating to ask for more safety data before approving a new drug. One clinical director interviewed for our study admitted that safety data has taken top priority for her team. “Safety is the new efficacy,” she said to describe the changing times. Clinical development teams have tried enrolling more patients into clinical trials in an effort to comply with requests for stronger safety data. Getting safety data correct the first time is essential to keeping drug development on schedule, since delays at this final stage are particularly costly. There have been several recent cases in which regulators request additional safety data upon review of the product’s new drug application (NDA). This request can delay final approval for two years or longer. The FDA has placed a special emphasis on new classes of diabetes drugs. In March 2010, the FDA delayed approval for Amylin’s Bydureon, a longer-lasting version of the companies’ existing drug, Byetta, which incorporates extended released technology from Alkermes. In October of the same year, the FDA formally rejected the drug’s NDA and requested a new cardiac study be performed to assess safety concerns. In January 2012, 22 months after the initial delay, Bydureon received FDA approval. A similar scenario is ongoing for Bristol-Myers Squibb’s and AstraZeneca’s new diabetes drug dapagliflozin. The FDA sent a complete response letter to the companies’ NDA in January 2012. After fulfilling the regulator’s request for additional safety data, the NDA was resubmitted 19 months later in July 2013 and is still awaiting US approval (dapagliflozin received EMA approval in November 2012). It is not uncommon for Phase IIIb trials to attempt to recruit more patients than Phase IIIa. Clinical teams use Phase IIIb to continue the search for answers to questions of clinical significance. Adding more patients to the protocol is an easy way to gain more definitive answers. Data in Figure 2, from our new benchmarking study, show the average Phase IIIb trial enrolled 868 patients versus the average Phase 3a trial at 795 patients. Phase 4 trials require the largest patient enrollment with an average of 1086 patients.
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Market Place Unfortunately, the quest for more patients is accompanied by trial delays. An analysis of clinical managers’ planned trial duration versus actual trial duration revealed that the average mid- to late-stage trial runs over estimates by 25%. Clinical managers repeatedly report the longest delays occur during the patient recruitment stage — specifically the period from 50% enrolment to last patient in (LPI). Even when patient recruitment gets off to a strong start, high enrolment targets make finding the final 50% of patients even more challenging. Usually there are several contributing factors. Sites may overestimate their access to qualified patients. They often enroll a majority of patients during the first half of the trial and then struggle to meet their estimates in the second half of recruitment. Sometimes site staff may lose energy and enthusiasm for a trial if they feel as if they aren’t getting the support they need from a sponsor. For this reason, it is critical that sponsors listen to investigator sites and stay well connected to site staff throughout the entire process. Clinical Teams Help Create the Value Proposition Health economics, health outcomes and comparative effectiveness research (CER) are all major buzzwords in healthcare right now. Government payers and third-party insurers have been demanding more data from pharmaceutical and biotech companies to secure reimbursement for years. As a consequence, clinical teams have been expanding Phase II protocols to include more health economic endpoints. This effort to produce data that payers want to see comes at a price, and has been a driving force behind the 108% cost increase in Phase II cost per patient. A Phase II oncology trial in our new benchmarking study included a branded comparator arm. The comparator drug — a high-priced biologic treatment — increased the total cost of the trial by $1.5 million. A closer look at the cost breakdown for the trial reveals the comparator drug accounted for more than 10% of the total cost of the trial. Clinical managers for this trial wrestled with the idea for a lower-cost alternative protocol. The prospective protocol would have instead compared their experimental cancer treatment to a commonly available, and reimbursed, chemotherapy. The trial would have enjoyed cost savings of $1.2 million. Ultimately, the company knew that the head-to-head comparison data would improve the drug’s chances for market access and allow the business development team to make an informed decision on whether to proceed with Phase III testing. This example shows the direct cost that comparative effectiveness research can impart on clinical trials. The addition of even simple health outcomes elements into a protocol can extend overall trial duration, affecting opportunity cost. Many trials look to long-term follow-up visits as a means of collecting health outcomes data, but this method acts as a double-edged sword. Health economic data are essential for drugs that are second or later to market in a given disease area. The collection of this data can add six months to a year onto trial duration. Extending trial duration not only occupies valuable clinical resources, but also further entrenches the market share of those medicines already on the market. This trade-off — more data versus more time — will continue to give pharmaceutical executive fits as payers, not regulators, take a larger role in reimbursement decisions. Personalised Medicine Changes the Clinical Landscape The poor reimbursement climate for me-too drugs has accelerated pharmaceutical expansion into personalised medicine. More 42 Journal for Clinical Studies
resources than ever before are dedicated to addressing the unmet clinical needs of those suffering from rare or terminal diseases. As is often the case, those companies looking to achieve scientific breakthroughs must invest great amounts of time and resources, particularly during clinical development. While it’s beneficial to those patients suffering from rare diseases and the medical community that treats them, developing an orphan drug presents a number of challenges for drug manufacturers. Testing personalised medicines and orphan drugs typically requires pharmaceutical companies to develop costly assays and companion diagnostics during early-stage clinical trials. Clinical trials for rare diseases are able to add efficacy assessments as early as Phase I, which has contributed to a dramatic rise in Phase I costs. These factors combine to raise the average per-patient trial cost for Phase I and Phase II trials to $38,637 and $43,653, respectively. Those costs are in line with the traditionally more costly Phase IIIa and Phase IIIb trials, which average per-patient costs of $41,325 and $48,451, respectively. Beyond the additional technology required, companies that develop personalised medicines also face greater complications in patient recruitment. First, they must target a smaller patient population, which forces clinical trial managers to cast a wide net and initiate more investigator sites than they typically would in a more conventional therapeutic area. Data show the effects of a more taxing patient recruitment effort. Figure 3 shows the minimum and maximum range of patients recruited per trial site by each phase of development. Rare disease trials recruit at the minimums of these ranges because of the paucity of patients available to them. For example, the average Phase II clinical trial site recruits 17.3 patients. But for a rare disease trial, each site may be able to recruit between one and two patients to the study. These low levels of recruitment cause delays in trial duration and, of course, create higher costs.
Ryan McGuire, Research Team Leader, Cutting Edge Information Ryan McGuire is a proud graduate of Rutgers University with a degree in finance. Born and raised in New Jersey, Ryan moved to North Carolina in 2008 to start a new career with Cutting Edge Information. Since joining CEI Ryan has led research projects in topic areas such as: clinical operations, market access, medical affairs, patient recruitment, lifecycle management, investigator-initiated trials (IITs), medical publications and medical information. Much of the data in this article draws from our latest benchmarking study on clinical trial costs due to launch at the end of the year. Email: firstname.lastname@example.org Volume 5 Issue 5
Your Right Arm in Clinical Research Nagy research is a Contract Research Organization providing superior clinical trial partnership in the Middle East and North Africa. It is a leading, multi-country enterprise with more than 20 years of expertise in research and data management with high cultural competence in the MENA region. It is highly experienced in clinical monitoring and trial management and offers a range of services including: • • • •
Clinical Trial Feasibility Regulatory Submissions Clinical Trial Monitoring Data Management
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Kuwait Lebanon Morocco Jordan Qatar Contacts: Magda Shafik MBBCh, MSc Head of Clinical Department Mobile: +20122 3189427 E-mail: email@example.com Website: www.nagyresearch.com
Paediatric Patient Retention: It’s not Child’s Play
Challenges and Opportunities In June 2013, the European Commission published a report on the first five years of the Paediatric Regulation that came into force in the European Union (EU) on 26 January 2007. The regulation aimed to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years, and ensure that medicines for use in children are of high quality, ethically researched and authorised appropriately. The recent report concludes that paediatric development has become a more integral part of the overall development of medicinal products in the EU, with the Regulation working as a major catalyst to improve the situation for young patients. But the inclusion of children in clinical research brings unique complexities. Paediatric clinical trials involve a distinctive set of challenges that can result in increased costs for patient retention, as well as additional time required to develop customised and meaningful retention programmes. The Ever-changing Population The universal challenge of conducting long-term paediatric studies is the constant growth and development of the young patient; an issue less profound with retention programmes designed for adult populations. Materials developed to support the participation of children in clinical research must be designed with a keen awareness for the rate of continuous developmental change. Depending on the length of the study, multi-year paediatric protocols may require the recruitment and retention of children ranging in age from 2-17 years. The cognitive and physical stages of development represented by this group span from the point a child begins to talk through adolescence and into adulthood. Retention materials must follow the child through study participation and be targeted based on development. Retention programmes for paediatric studies must address the dynamic nature of this ever-changing population, following the evolution of the child from early childhood to tween, teen and young adult, over the course of a multi-year study. In contrast to paediatric studies, retention challenges for adult studies are commonly situational rather than developmental. For instance, situational factors for adults in their 30s and 40s are related to the impact of study participation on family and work. For the elderly, the situational issues may relate to transportation logistics and familiarity with the study site’s location. The result is higher development costs compared to retention programmes designed for adults, and the design of such programmes can warrant the inclusion of a multi-speciality team including child psychologists, educators, parents, children, and healthcare professionals.
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The ‘Mother Factor’ As research participants, children are more vulnerable than adults. Parents, guardians, and other carers are extremely protective of their child’s wellbeing and rights when participating in clinical research. For this reason, the retention of children in clinical studies that span weeks, months, even years, or involve multiple overnight stays with burdensome tests, requires the retention of parents, particularly the mother; adding yet another layer of complexity to the paediatric recruitment and retention process. When the chronic illness of a child intimately affects the everyday life of the entire family, together with the added complexity of study participation, it is important to identify factors that encourage mothers to keep their child involved in a clinical research study. Keeping children in a research study, and compliant with the study’s treatment regimen until study completion, requires the active engagement of the child, the mother and potentially other siblings as well. Mothers are often the most affected by the diagnosis of a child with chronic illness; taking on the major responsibilities and demands of the study’s treatment regimen such as organising meals, monitoring symptoms, arranging healthcare and study visits, and potentially balancing the needs and wellbeing of other children as well. In addition to the logistical demands of caring for an ill child, there is also support that must be provided to a child or adolescent striving to develop a sense of autonomy in the face of their medical condition. The integral involvement of the mother in the daily management of their child’s physical and emotional health illustrates the significance of gaining an understanding of this caregiver’s perspective and decision-making processes. Key motivators should be identified and considered prior to the development of a recruitment or retention programme targeting this population. Assessing the Research Opportunity Clinical research can be intimidating for adults. Imagine the depth of the decision parents make when choosing to enroll their child in a clinical study. First is the careful consideration of the potential consequences for their child. A parent will always consider risks before benefits. Next is an understanding of whether the study will disrupt their child’s wellbeing. For example, a parent needs to understand the careful monitoring involved in a “washout” period, and/or the possible disruption of the family - disrupted meal times, changes to siblings’ schedules. While the risk factors are often weighed first, parents also want to know and understand the potential benefits gained from study participation. Study physicians and study coordinators must be prepared to answer the fundamental question of “what’s in it for my child to participate in this study?” A consideration of study benefits involves a balancing of the opportunities afforded by research participation measured
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Therapeutics Technology Can Make the Study Fun Today’s technology, such as mobile devices (smartphones and tablets), is an important enabler in any paediatric retention programme. Clinical research centres catering to a paediatric population can be provided with retention tools that include pre-loaded, ethics-approved age-appropriate games, with the necessary parental controls. No longer are clinics required to have a cupboard filled with toys, books and other age-appropriate distractions. Additionally, between visits, web-based retention programmes provide the ability to connect with study subjects and their parents, in an online environment that today’s paediatric population is all too familiar with. Furthermore, a digital retention programme means that updates, changes and programme additions can be implemented faster and in a less costly manner. The in-clinic study experience must be supported by a between-visit study experience that rewards for compliance, is interactive, and fosters the relationship between the child, the study and the site’s medical team. against the risks and burden of study tests and/or the current treatment options or medical prognosis by not participating. In general, mothers want an assurance that the decision to participate is in the best interest of their child, and that depending upon the age of the child, the child also has a sufficient understanding of the clinical study to provide assent before a final decision about enrolment is made. Some mothers will calculate risk for their child based on the knowledge that the new treatment or technology has been successfully tested in adults or is a standard of care for children in other countries. While this type of data is reassuring, the decision to participate is often based on less concrete evidence, their trust of the study physician or information they have obtained from other mothers. A mother’s decision to enroll her child in clinical research comes with the expectation that there may be a direct and immediate advantage for her child, such as an oral medication versus an “injectable”, or reduction in daily dosing. While these factors take precedence and monetary remuneration is not necessary for retention, most mothers recognise that an incentive is important for maintaining child and adolescent interest in clinical research. Supporting the Mother-child Relationship Mothers expect study nurses and physicians to be knowledgeable, approachable, personable, and trustworthy. Well-designed recruitment and retention tools that describe the study in a way that children can understand help to establish the foundation of a trusting relationship. Some children are intrigued with research participation after the doctor or study nurse clearly explains the process while treating them with respect. Any positive interactions with study staff leave a lasting impression and help to instill trust in both the child and parent to encourage compliance. A mother’s observation of a study coordinator interacting with her child in a responsive, caring, and patient manner is invaluable for retention. Additionally, other factors that can influence patient retention include flexible scheduling of study visits to adjust to a mother’s “hectic” schedule as well staff turnover, specifically change of coordinator assignments, which can disrupt the continuity of care and trust for both the mother and child. www.jforcs.com
Personal Touch…Personal Benefits Without exception, mothers expect that their child will personally benefit from participation in a clinical research study. Just as a mother desires involvement with the family paediatrician, she expects to see the study doctor at every visit. The reality of clinical research dictates that a single physician at a busy research centre will not be able to spend time with the parent at every visit. A deficit in this personal attention communicates a lack of concern and credibility. Paediatric retention programmes, tailored by age, and designed to engage the child in activities during study visits, can help to bridge this gap of an uninvolved doctor making study visits easier for children and mothers alike. These types of programmes provide an added personal touch to study participation and tell mothers that their child is of special importance. Furthermore, changes in a child’s self-perception or attitude toward their medical condition can also be a personal benefit of study participation. Study participation can build up a child’s self-esteem, especially when a personal touch such as a “certificate of achievement”, signed by the study doctor, is presented to the child at the study’s conclusion to say “thank you for contributing”. Plus, it has the added benefit of communicating to the child, specifically those with chronic conditions, that they have been an active partner in improving the quality of their own life. As research participants, children are more vulnerable than adults with regard to cognitive and emotional development, level of autonomy, and dependence on family influence. Regardless of whether the study participant is an adult or a child, successful clinical studies still require a personal touch supported by a well-thought-out patient retention programme. Elizabeth Moench, President and CEO Medici Global Ltd. For 22 years MediciGlobal has been supporting paediatric recruitment and retention, developing recruitment and retention programmes for fragile paediatric populations including schizophrenia, eczema, eosinophilic oesophagitis, spina bifida with voiding dysfunction, ADHD, and others. Contact MediciGlobal at +1 (484) 674-6825 (US), +44 (0) 208 834 1447 (UK) or firstname.lastname@example.org. Journal for Clinical Studies 45
Therapeutics Adjunctive Treatment with Atypical Antipsychotics Among Adolescents with Major Depressive Disorder
Among adolescents, lifetime prevalence estimates for major depressive disorder (MDD) range as high as 8-11%1,2. MDD is a serious mental illness that impairs school, peer and family functioning in affected adolescents. Adolescents with MDD often experience recurrent episodes of depression and psychiatric comorbidity, including anxiety, disruptive behaviour and substance use disorders1. Depressed adolescents are also at risk for psychiatric hospitalisation, suicidal ideation and completed suicide3. MDD is a disorder that is experienced as disabling and distressing, not only by the adolescent, but also by the parents and broader family. Thorough, accurate evaluations as well as safe, effective treatment are critical to patient care. The American Academy of Child and Adolescent Psychiatry practice parameters for depressive disorders state that all treatment approaches should include non-pharmacological components1. In more complicated cases, pharmacological treatment is warranted. The first-line pharmacological approach in adolescents with MDD is to use a Food and Drug Administration- (FDA-) approved antidepressant treatment (ADT), such as fluoxetine or escitalopram. Formal practice guidelines state that atypical antipsychotics (AA) in combination with ADTs may be warranted in cases of psychotic depression, complex comorbid conditions or treatment resistance1,4. Although there are AAs approved for adjunct therapy in treating adult MDD, this is not the case for adjunct treatment in pediatric or adolescent MDD. Aripiprazole, risperidone, seroquel, olanzapine, and paliperidone are FDA-approved for use in some childhood and adolescent disorders. However, these approvals are limited to schizophrenia, bipolar I disorder and irritability associated with autism. Treatment with AAs targets aggression and irritability, as well as psychosis in applicable cases. Of note, irritability and anger are often more salient than sadness and loss of energy among adolescents with MDD5.
the lower propensity for motor side-effects compared to older antipsychotic medications1. Not surprisingly, off-label use of AAs to treat MDD in adolescents is on the rise, even more so than the overall increase in AA treatment in adolescents6 Based on the National Ambulatory Medical Care Survey, in the period between 19931998 and 2005-2009 there was a 4.7-fold increase in the percentage of physician visits for mood disorders that resulted in an AA prescription among youths6. Depending on the exact patient pool and timeframe studied, data indicate that depression was diagnosed in 30% to 45% of adolescents who receive treatment with an AA at a physician visit (2001-2009 across studies)6, 7. Given recent diagnostic changes in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition8, the offlabel use of AAs to treat mood disorders in adolescents may continue to rise. The DSM-V introduced a new depressive disorder, Disruptive Mood Dysregulation Disorder (DMDD), which requires childhood onset. The core features of DMDD include a chronic and severe irritability, punctuated by frequent temper outbursts (for at least one year). Dangerous behaviour and severe aggression are common. The DMDD diagnosis will increasingly capture the same behavioural issues that are most linked to antipsychotic prescriptions currently given for children and adolescents (P. Harrington, personal communication, August 2013). By necessity, clinicians are likely to use AAs to treat DMDD prior to any controlled clinical trials.
Historically there have been no well-controlled trials investigating the efficacy and safety of AAs in adolescents with MDD4. A current search (August, 2013) utilising CiteLine’s proprietary TrialTrove® database yielded no planned or open industry-sponsored trials of this nature. As such, clinicians are left “empty-handed” when it comes to referencing evidencebased medicine in these instances3. Clinicians and families alike must carefully weigh the need for treatment with their concern for safety, given that AAs are associated with such side-effects as weight gain and metabolic changes, despite
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Researchers and clinicians emphasise the immediate and critical need for clinical trials investigating safety and efficacy of AAs in adolescent MDD9,10. Such clinical trials would promote evidence-based treatment and minimise off-label treatment in this population. Patients and their families lack definitive medical data to guide important treatment decisions. Medical ethics experts urge stakeholders to explore ways to implement such trials while upholding all applicable ethical principles for human research in vulnerable populations10. The FDA has enacted specific regulations and legislation in a step-wise approach over time to encourage, and ultimately require, a closing of the pediatric knowledge gap within drug development. As such, this is a topic that will warrant increased attention and discussion in the regulatory and public health sectors, with foreseeable impact on the pharmaceutical development of this important class of drugs.
References 1. American Academy of Child and Adolescent Psychiatry (2007). Practice Parameter for the Assessment and Treatment of Children and Adolescents with Depressive Disorders.
Journal of the American Academy of Child and Adolescent Psychiatry, 46(11), 1504-1526. 2. Merikangas, K. R., He, J., Burstein, M., Swanson, S. A., Avenevoli, S., Cui, L., Benjet, C., Georgiades, K. & Swendsen, J. (2010). Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey ReplicationAdolescent Supplement (NCS-A). Journal of the American Academy of Child and Adolescent Psychiatry, 4(10), 980989. 3. Ginicola, M. M. & Saccoccio, C. (2011). When research fails to inform: Current treatments for depressed children in an inpatient setting. Retrieved from http://www.priory.com /psychiatry/depression_childhood_treatment.htm 4. American Academy of Child and Adolescent Psychiatry (2011). Practice parameter for the use of a typical antipsychotic medications in children and adolescents. Retrieved from http://www.aacap.org 5. National Alliance on Mental Illness (2010). What Families Need to Know About Adolescent Depression (2010). Retrieved from http://www.nami.org/Content/Content Groups/CAAC/FamilyGuidePRINT.pdf 6. Olfson, M., Blanco, C., Liu, S., Wang, S. & Correll, C. U. (2012). National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Archives of General Psychiatry, 69(12), 1247-1256. 7. Pathak, P., West, D., Martin, B. C., Helm, M. E. & Henderson, C. (2010). Evidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001-2005. Psychiatric Services, 61(2), 123-129. 8. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 9. Pasquali, S. K., Burstein, D. S., Benjamin, D. K., Smith, P. B. & Li, J. S. (2010). Globalization of pediatric research: analysis of clinical trials completed for pediatric exclusivity. Pediatrics, 126(3), e687-e692. 10. Tishler, C. L. & Reiss, N. S. (2012). Psychotropic drugs and paediatrics: a critical need for more clinical trials. Journal of Medical Ethics, 38, 250-252.
Miranda Porter, Phd is Senior Vice President of CNS Clinical Development at INC Research. She has 13 years of experience in the drugdevelopment industry, including clinical experience in neurocognitive assessment and treatment of the full spectrum of neuropsychiatric disorders. Email: email@example.com. Website: www.incresearch.com.
Journal for Clinical Studies 47
The Role of Central Laboratories in AD Trials
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that mainly affects the elderly population. The prevalence of AD is predicted to increase to 115.4 million by 2050 1. Despite having the first drug, Tacrine, approved by the FDA in 1993, there has been little progress made in the development of pharmacotherapy for AD treatment. Currently there is no cure for AD, and treatments are symptomatic only. Even with the investment of more than a billion dollars by pharmaceutical companies, there have been no reliable disease-modifying therapies discovered that have received FDA approval2. It is imperative to find better treatments for AD to alleviate patients’ and their families’ suffering, and to prevent a potential AD-associated global economic crisis. Recently, major changes were made in the diagnostic criteria for AD and encompass the latest findings in the field, which is helping to facilitate more clinical research. Already, the usual clinical interview can be coupled with brain imaging testing approved by the FDA for the diagnosis of AD in live patients. Several disease-modifying or disease-preventing therapies are also appearing in clinical trials. Central laboratories can play a key role in clinical trials for AD drug development by assisting with patient population identification and by detecting, at an early stage, drugs that are likely to fail, leading to important time and costs savings. This article will discuss the latest advances in the AD field and explain how central laboratories can contribute to the progress in the battle against this disease by supporting clinical trials through quality testing.
disease that begins decades before the appearance of clinical symptoms, and the addition of biomarker tests. The new guidelines classify AD into three stages: 1) preclinical, asymptomatic stage (intended for research use only); 2) mild cognitive impairment; and 3) dementia, the end stage of the disease. In addition, the preclinical AD can be staged with biomarkers from stage 1 to stage 3, although it is for research use only at this moment (Table I) 6, 7, 8, 9. These changes in AD diagnostic criteria have an important impact on clinical trials because they open the door for early-stage drug development and AD prevention trials.
Alzheimer’s Disease (AD) Diagnostic Criteria A century ago, Alois Alzheimer performed an autopsy on one of his patients who had suffered from early onset of dementia. This autopsy revealed the presence of sclerotic plaques spread throughout the cortex with neurofibrillary tangles, known today as hallmarks of the disease named after him. AD is a progressive neurodegenerative disorder characterised by a gradual, irreversible impairment of cognition, memory and personality leading to dementia 3. In general, AD affects the older population, with familial cases accounting for less than 1%. So far, AD mutations have been identified mainly in genes encoding for the proteins involved with the formation of amyloid plaques 4. The clinical diagnosis of AD was first described in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRA)5. New developments in the AD field have initiated the revision of NINCDS-ADRDA diagnostic criteria. In 2012, new criteria and guidelines were proposed by expert workgroups spearheaded by the Alzheimer’s Association (AA) and the National Institutes of Health’s (NIH’s) National Institute on Aging (NIA). These guidelines reflect new advances in the field aimed at facilitating clinical research. The major change from 1984 in AD diagnostic criteria is the acknowledgement of AD as a progressive
1-Radioimaging It is well documented that amyloid plaques are composed of amyloid beta 42 (Aß42)10. There are several methods that have been developed for the measurement of amyloid beta peptides. The most noticeable technique is commercially available and FDA-approved. In 2012, FDA approved flobetapir F18 (Amyvid) to become available as a diagnostic aid in the diagnosis of AD in live patients. It is a radiodiagnostic agent tagged with a radioisotope fluorine-18 that binds to amyloid plaques and can be imaged using positron emission tomography (PET). Its sensitivity and specificity is influenced by the level of the reader’s training, and ranges from approximately 69%-95% for sensitivity and from 90%100% for the specificity of the scan11. It is recognised as a real breakthrough in the AD field because, for the first time, amyloid plaques can be reliably detected with FDA-approved radioimaging agent in live patients. A multitude of other agents are now in development, with Pittsburg compound B (PIB) being the most used in clinical trials in the past12, 13.
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Diagnostic Tests in AD In the past, the 1984 NINCDS-ADRDA criteria were used with a sensitivity of 81% and specificity of only 70%, with postmortem brain examination as the gold standard for AD diagnosis 5. These criteria were not very helpful for clinical trials of drug development where the effect of drug treatments could be confirmed postmortem only. In addition, the diagnosis of AD was given when the irreversible neuronal cell death had already begun to occur, therefore limiting effective drug therapy. The new diagnostic criteria are giving a vital role to central laboratories for AD diagnosis and clinical trial structure. Although the working groups currently don’t recommend the use of these diagnostic tests in the clinical settings due to the lack of standardisation and firm evidence, it is clear that they are becoming an important part of clinical trial protocols. Currently, the proposed AD biomarkers are mainly targeting the amyloid plaques and neurodegeneration in cerebrospinal fluid (CSF) and by neuroimaging techniques.
2-Cerebrospinal Fluid (CSF) Testing In the amyloid theory, the biomarker Aß42 is the main constituent of amyloid plaques. The AD neurodegeneration is characterised by the appearance of neurofibrillary tangles in the Volume 5 Issue 5
Therapeutics Table I: AD Stages, Biomarkers, Clinical Trials and Patient Population Selection.
wbrain, which are thought to be caused by total Tau protein (T-tau) and phosphorylated Tau protein (P-tau)14. Many studies have shown a marked increase in CSF T-tau and P-tau, with a marked decrease in AĂ&#x;42 in AD cases with dementia15. Consequently, this hallmark of AD pathophysiology can be successfully quantified with commercially available enzyme-linked immunosorbent assay (ELISA) kits, such as INNOTEST ELISA (Innogenetics, Belgium), the multiplex INNO-BIA AlzBio3 kit (Innogenetics, Belgium), and bead-based multiplex xMAP Luminex platform (Luminex Corp., Tx, USA) (Table II). However, the lack of standardisation is a major limitation in the use of these biomarkers. There are no established cut-offs or reference ranges available for their measurement, but fortunately several national and international standardisation initiatives are ongoing at this time, such as the Alzheimerâ€™s Association external quality control programme, which is run in conjunction with the Clinical Neurochemistry Laboratory in Gothenburg, Sweden. They have determined that the between-laboratory coefficients of variation (CVs) can be as wide as 13-36% in 40 participating laboratories, with within-laboratory CVs as large as 2.3-26% found at six experienced laboratories16,17. Central laboratories can play a central role in AD clinical trials by providing the most accurate results for AD fluid biomarker measurements.
4-Fluorodeoxyglucose-PET (FDG-PET) It has become increasingly clear that AD is not just an accumulation of amyloid plaques and neurodegeneration in random brain regions leading to dementia. The specific brain regions involved in AD pathophysiology have aberrant neuronal networks, synaptic dysfunction and degeneration of specific neuronal populations that are critical factors leading to known AD with dementia. Therefore, synaptic dysfunction with neuronal injury and loss will lead to a decreased metabolism in the parietal and temporal areas of the brain. This metabolic decline can be measured with FDG-PET, which is currently approved for clinical use to distinguish AD from frontotemporal dementia because the latter is characterised by hypometabolism in the frontal and not the posterior brain regions 20. Future Perspectives and Conclusions For years, central laboratories have helped clinical trials with drug safety monitoring. Today, as technologies become more and more complex, central laboratories can also help clinical trial sponsors select the most useful biomarkers to support the type of drug therapy being tested. Choosing the correct patient population for potential clinical trials is critical. Central laboratories can guide sponsors in selecting the most informative biomarkers to use in determining the proper patient population (Table I). In addition, it is not the measurement of isolated biomarkers that is most informative for AD diagnosis and prognosis, but their combination. It is well illustrated in studies that mild cognitive impairment (MCI) subjects with high CSF tau/AĂ&#x;42 ratios were the most likely to progress to AD dementia, while normal subjects were most likely to progress to MCI. However, the same biomarkers were completely uninformative as predictors of change in subjects that had already developed dementia due to AD 21. The correct selection of biomarkers can demonstrate target engagement in the brain and identify drugs that will most likely fail early in the study, preventing time loss and additional costs. The currently available biomarkers are far from perfect, and the search for ones that offer earlier detection windows and are more accessible than CSF samples is ongoing22. Central laboratories can keep clinical trial sponsors informed about the trends in future biomarker developments. Out of all the mental illnesses, the most progress has been made in the understanding of AD pathophysiology. Today, the AA-NIA recommendations for AD diagnosis are being tested, and the preliminary results indicate that the use of biomarkers can help in patient population staging and prognosis23. Although many Table II: AD Diagnostic Tests.
3-Volumetric MRI The pathophysiology of AD also includes widespread brain atrophy, which can be visualised and quantified using FDAapproved automated medical device image analysis software, such as NeuroQuant (CorTechs Labs, Inc., CA, USA). The most prominent brain structure that is important for memory is a medial temporal structure called the hippocampus. The atrophy of medial temporal structures has been linked with a high risk of decline to dementia18, 19. www.jforcs.com
Journal for Clinical Studies 49
clinical trials have failed in the development of AD diseasemodifying drug therapies, the recent progress in the AD field is very encouraging. The past failures can become important learning experiences in the development of future AD clinical trials. It is clear that AD cannot be treated exclusively as a pathophysiology with amyloid plaque accumulations and neurofibrillary tangles formation, because many amyloid and Tau targeting therapeutic strategies used in isolation have failed. Moreover, not all patients with these abnormalities will develop cognitive impairments. Therefore, a combination of drugs targeting several different neuropathological pathways will likely be the most successful. Currently, it remains difficult to delineate the useful outcome measures for clinical trials and predict drug failures in the early phases. In these situations, strong collaboration between clinical trials and central laboratories can become the key for a successful AD drug development strategy.
References 1. Alzheimer’s Disease International. World Alzheimer’s Report 2009: 25-46. 2. Tayeb HO, Yang HD, Price BH, Tarazi FI. Pharmacotherapies for Alzheimer’s disease: beyond cholinesterase inhibitors. Pharmacol. Ther. 2012;134(1): 8–25. 3. Higgins ES, George MS. Neuroscience of clinical psychiatry: the patho-physiology of behavior and mental illness. Philadelphia: Lippincott; 2007. 4. Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 2012; 33:1340–4. 5. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol Aug 2007; 6(8):734–46. 6. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7(3):263–9. 7. Jack Jr CR, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. Introduction to the recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7(3):257–62. 8. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7(3):280–92. 9. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s
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disease. Alzheimers Dement 2012;8(1):1-13. 10. Strozyk D, Blennow K, White LR, Laurner LJ. CSF Ab 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology. 2003; 60(4): 652-56. 11. Romano M, Buratti E. Florbetapir F 18 for brain imaging of ß-amyloid plaques. Drugs Today (Barc) Mar 2013;49 (3):181–93. 12. Herholz K, Ebmeier K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol. 2011; 10(7):667-70. 13. Klunk WE, Engler H, Norberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburg compound-B. Ann Neurol. 2004; 55(3):306-19. 14. Buerger K, Ewers M, Pirttila T, et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain. 2006; 129(Pt 11):3035-41. 15. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009; 302(4):385-93. 16. Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, et al. The Alzheimer’s Association external quality control program for cerebro-spinal fluid biomarkers. Alzheimers Dement 2011;7(4):386–395.e6. 17. Mattsson N, Andreasson U, Carrillo MC, Persson S, Shaw LM, Zegers I, et al. Proficiency testing programs for Alzheimer’s disease cerebrospinal fluid biomarkers. Biomark Med 2012;6(4):401–7. 18. Heister D, Brewer JB, Magda S, Blennow K, McEvoy LK. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011; 77(17):1619-28 19. McEvoy LK, Brewer JB. Quantitative structural MRI for early detection of Alzheimer’s disease. Expert Rev Neurother. 2010; 10(11):1675-88. 20. Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005; 32(4):486-510. 21. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5:228-34. 22. Fagan AM and Perrin RJ. Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer’s disease. Biomark Med 2012; 6(4):455-76. 23. Knopman DS, Jack, Jr CR, Wiste HJ, Weigand SD, Vemuri P, Lowe V, et al. Short-term clinical outcomes for stages of NIAAA preclinical Alzheimer disease. Neurology 2012; 78(20): 1576-82.
Tatiana Souslova, M.Sc., Ph.D. is principal scientist at ACM Global Central Lab, which specialises in delivering high-quality testing services designed to optimise clinical trial outcomes. For more information, visit http://www.acmgloballab.com/. Email: firstname.lastname@example.org.
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IT & Logistics reporting of all aggregate safety data in the form of Developmental Safety Update Reports (DSUR – ICH E2F) in the EU, or IND Annual Safety Reports in the US. The regulatory landscape for safety monitoring of healthcare products has changed considerably in recent years. The new safety regulations require all stakeholders to be more proactive in processing safety information, detecting new risks early and putting in place adequate risk management /mitigation measures throughout the product life cycle. The US FDA published a final rule amending the safety reporting requirements under 21 CFR Part 312 (IND studies) and 21 CFR Part 320 (BA-BE studies) in September 2010. The US regulations (effective March 2011) and the European Commission’s detailed guidance (‘CT-3’, June 2011) on the collection, verification and presentation of adverse event/reaction reports arising from CTs lays strong emphasis on early reporting of serious events with a reasonable possibility of being associated with the drug, so that safety analysis is not confounded by unnecessary noise and product safety can be assessed more meaningfully. Under the previous US regulations, the IND sponsors were often reporting to the agency and clinical investigators, in an expedited manner, a substantial number of serious adverse events, irrespective of relationship to the study drug. Under the current regulations, the IND sponsors must report to the agency and the investigators, on an expedited basis, only those events that are serious, unexpected (not listed in the investigator‘s brochure) and suspected to be caused by the drug (i.e. there is a reasonable possibility or evidence to suggest that the drug caused it). The events need to be reported preferably in an unblinded manner.
Precautions to ensure patient safety require that clinical investigators must report to the sponsors all serious adverse events on an expedited basis, regardless of whether they are considered drug-related or not. Events which cannot be analysed as single cases need to be assessed on an aggregate basis and reported if there is a difference in the reporting rates between the drug and the control groups. As an additional measure to protect patient safety, the FDA also recommends that proceedings of the DSMBs be sent to the institutional review board (IRB) for review. Under the current European regulations (‘CT-3’, 2011/C 172/01 June 2011) the investigator must report all serious adverse events immediately to the sponsor, except for those that the protocol or investigator’s brochure identifies as not
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Safety Data Management for Clinical Trials Capture and management of safety data are critical components of the clinical trial (CT) process. In addition to ensuring safety of CT participants, systematic capture and analysis of safety data from CTs is important for developing the safety profile of the drug and contributing to its benefit-risk assessment, which is a key consideration in the approval decision. During the pre-approval CTs (Phase I – III) the safety profile of the drug is largely unknown. The objectives of collecting safety data from CTs are early detection of important safety signals, protecting patients from unnecessary risks, and developing a safety profile of the drug, contributing to its benefit-risk assessment. Safety data from ongoing CTs influences the clinical care of patients enrolled in these and other trials. The ultimate goal is to evolve medically useful safety label information, and to ensure that safety data generated during clinical development can be seamlessly merged with post-marketing data to develop a comprehensive safety profile for the product over a reasonable timeframe.
What Constitutes Safety Data in CTs? Safety data from CTs covers all safety-related information, including serious and non-serious adverse events, vital signs,
laboratory parameters including the ECG, medical history, concomitant medications and demographic details. Some issues specific to collecting safety data from CTs are when to start collecting adverse events (AEs), and what data other than AEs is important for safety assessment. As per the ICH GCP, all AEs reported after the written informed consent is obtained from the patient, must be collected. Concomitant illnesses which existed prior to entry into the clinical study, and abnormal laboratory values (with some exceptions) are not recorded as AEs. If an abnormal laboratory value/vital sign/ECG is associated with a clinical sign or a symptom, the sign/symptom should be reported as an AE and the associated laboratory result/vital sign/ECG is considered additional information. Morbidity and mortality endpoints (disease progression or death due to disease) are treated as protocol-specific issues and not safety events. CT Safety Reporting Requirements Safety data from CTs is reported from investigators to sponsors or their representatives, and from sponsors to regulators and data safety monitoring boards (DSMBs). This involves expedited reporting of serious, unexpected suspected adverse reactions (SUSARs) within seven (fatal and life-threatening) to 15 (other serious) days, and periodic
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IT & Logistics requiring immediate reporting. The sponsor needs to report on an expedited basis only the SUSARs, preferably unblinded, within seven days for fatal or life-threatening events and 15 days for the other SUSARs. The sponsor reports the SUSAR directly as an individual case safety report (ICSR) to the national competent authority (CA) of the relevant member state, and also indirectly through the electronic gateway to the Eudravigilance Clinical Trial Module (EVCTM). Annual safety reports must be generated throughout the CT and sent to the national CA and the ethics committees/ IRBs. These reports must contain a listing of all suspected serious adverse reactions which have occurred over this period, and a report of the subjects’ safety. Investigators should receive a line listing with a summary of evolving safety issues. There are separate guidelines on periodic safety update reports during the developmental phase in the form of Developmental Safety Update Reports (DSUR – ICH E2F) in the EU and IND Annual Safety Reports in the US. Though the regulations focus on serious adverse events, the sponsor is expected to monitor all adverse events during drug development, including the non-serious ones. Data Quality & Medical Insight Collecting good quality data is of paramount importance to draw right conclusions about the safety profile of a product, and the quality process for this needs to begin early. The quality of safety data depends on an appropriately designed study, standardised terms and definitions of anticipated safety issues and an adequately designed CRF that captures relevant safety data at all time points during the study. The key to good quality data is accuracy, reliability and timeliness with standardised definition of medical concepts, good coding practices, clear patient narratives and filling the data gaps by adequate case follow-up. Over-collection of data is counterproductive in CTs and needs to be avoided. Good medical insight is required in the analysis of safety issues and their impact on the health of individual patients and risk populations. This requires knowledge of mechanism of action specific to the product / class of product and an understanding of the natural history of the target disease. Safety Data Management in CTs – A Team Effort Managing CT safety data is a collaborative effort among personnel from study management, the investigator sites, data management and patient safety groups. It requires standardised coding practices, regular data reconciliation between the CT and safety databases, and a timely analysis of individual cases and aggregate data to evaluate potential safety issues. The sponsors/CROs, and DSMBs share the responsibility for scrutinising and evaluating safety data proactively and on an ongoing basis. CT safety data management requires a high regard for patient safety, knowledgeable and trained multidisciplinary teams, knowledge of regulatory compliance requirements, robust systems and processes, and sound clinical judgment for assessment of safety data. Good quality data from pre-approval studies can form a solid base for the comprehensive safety profile of the product which gets consolidated during the post-marketing phase. In keeping with the outsourcing trend in
54 Journal for Clinical Studies
pharmacovigilance, safety data from CTs is also often managed by partners. If the study is outsourced to a CRO, the same organisation may enter and analyse safety data from the studies. Alternatively, if the sponsor has a partner for safety data management, the same company may be responsible for managing safety data from CTs in addition to managing post-marketing spontaneous reports. Due to the growing emphasis on collating all available safety data and mining it for trends and signals, sponsors often find it advantageous to use a single partner and a single database to capture all safety data, whether it’s from CTs or from the post-marketing phase. Mandatory electronic reporting in Europe requires registration with the Eudravigilance, and sponsors who may not have the resources and experience may delegate indirect reporting to a partner. When the study is outsourced to a CRO and safety data is managed by another partner, the hand-offs and communication between the investigator, sponsor, CRO and the safety data management partner has to be seamless and timely. Reconciliation of safety data between the CT database and the safety database also involves multiple organisations. Roles and responsibilities of all groups have to be clearly defined and agreed.
Chitra Lele, has a distinguished academic background with a PhD in Statistics from Stanford University, and over 20 years of experience in the healthcare industry. Prior to Sciformix Chitra Lele was with Pfizer for 10 years, where she was Executive Director responsible for India operations of Pfizer Global R&D. Chitra established India’s first Biometrics Center providing services in clinical data management, statistics, programming and medical writing, and successfully grew it to a size of over 400 staff. Chitra’s experience includes work as a biostatistician in cancer epidemiology at Stanford University and University of California, San Francisco and as a faculty member at the School of Statistics at the University of Minnesota and IIT, Mumbai. Email: email@example.com. Suhasini Sharma, is a physician with over 25 years experience in pharmaceutical medical affairs, clinicalresearch and drug safety. At Sciformix she provides subject matter expertise in the areas of clinical research & post-approval support, regulatory writing and signal detection & risk management. Email: firstname.lastname@example.org.
Darshan Bhatt is a postgraduate in medicine and holds an M.Phil. degree in Hospitals and Health Systems Management. He has clinical experience of more than 20 years and 15 years experience in applied biomedical research. He worked for 10 years with AstraZeneca to provide strategic inputs to drug discovery and development in India and UK. Currently he is the Subject Matter Expert in Patient Safety and Pharmacovigilance at Sciformix Technologies and chairs the Data & Safety Monitoring Board for several clinical studies for other clients. Email: email@example.com.
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Sustainable Design of Temperature-Controlled Packaging: Single Use Versus Reusable Packaging Many companies are beginning to make a conscious effort to think about the environmental impact of their temperaturecontrolled packaging use. But this isn’t just limited to whether the packaging is single-use, returnable or made using recyclable materials; there are many more considerations to be accounted for to ensure that a temperature-controlled packaging’s design is really valued as sustainable. Karen Adams, Technical Manager from DS Smith Plastics Cool Logistics explains. Environmental Awareness The global cold chain, similar to many worldwide industries, is experiencing major challenges as it’s becoming more commonplace to look at reducing environmental impact, due to pressures from government and regulatory organisations, and corporate social responsibility policies. However, temperature-controlled packaging (TCP) manufacturers need to reduce carbon emissions, while having the added demand of maintaining the crucial temperature required. Whether it is chilled, frozen or ambient, the temperature environment is necessary to support the effectiveness of temperaturesensitive products, including life-saving biologics and vaccines. This stable temperature must be maintained at all times during transit from the despatching site to its end destination, or pharmaceutical companies run the risk of losing their high-value cargo. The implications of this would result in millions of pounds worth of product loss, as well as creating potential health risks. Therefore, the challenge of maintaining strict safety standards, while improving a packaging’s environmental credentials, within budgetary guidelines, means that developing a suitable and sustainable TCP system is now more demanding than ever. In order to achieve this, TCP manufacturers must develop a balance between creating the right design and using the correct materials. Sustainability and the Cold Chain Sustainable packaging includes the design and use of a TCP system, which results in improved sustainability over other packaging options. Many TCP designs are single-use, but new efforts to choose more sustainable options are increasing the interest in reusable designs. However, choosing a more sustainable option is not simply a case of switching from a single-use to a reusable solution; in fact, the science behind a sustainable packaging’s design is far more complex. Before offering a customer the best system for their requirements, TCP manufacturers need to undertake an in-depth analysis of the route and destination, review the choice of materials, have an understanding of the packaging’s life cycle and adhere to a long list of regulatory compliance requirements. Sometimes, sustainable design considerations need to
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go beyond the basic understanding of what sustainability is perceived to be. This includes looking at what methods would be most effective in eliminating factors or issues that may damage the environment (reaching further than assessing the type of materials), as well as evaluating how the packaging is used, in what environment it’s applied, and if it’s being used effectively. The answer may not be as straightforward as you may think. If a pharmaceutical company switches from single-use packaging to a reusable system, is it automatically considered more environmentally friendly? Not necessarily so. Ultimately, it’s not just about reducing the amount of packaging used or considering a reusable option, because sometimes, if not used correctly, a reusable system can in fact work out more costly for the environment and the customer. Evaluating the Options Each of our customers has different needs. For some customers it might be important to have a biodegradable system, whereas other customers might place an emphasis on the number of trips a system can make before requiring a replacement. The development process for each of these systems would require a completely different design path to be taken, and the result might end up being a completely bespoke system for the customer involved. As a first step, the TCP manufacturer must consider the journey that the product has to endure on a specific route to ensure that the packaging fulfils the function of protecting its contents. This is particularly challenging during long distances and durations, which potentially subject the packaging to different excursion hazards. For example, it may be stored for long periods in a warehouse or refrigeration unit, or left on the tarmac where it could be exposed to extreme cold or heat, moisture and light penetration. In addition to evaluating these risks, the packaging solution must also be robust, secure, compact and lightweight, in order to keep shipping costs down. Once these elements are secure, it is only then that we can begin to look at the more intricate areas of the design, for example, insulating material and its mechanical and thermal properties, or a unique end-of-life story for components used. For example, would you like to water your flowers with the coolant used to ship your product after its use? Or fertilise your plants with the insulative material used to keep your products safe? Single-use Versus Reusable The key to finding the most sustainable and best-performing solution is to dig deeper than looking at whether the materials used are recyclable; it’s really about evaluating the operational benefits, which can determine whether using a particular solution (whether it is single-use or reusable) is more efficient
Volume 5 Issue 5
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and effective in a real-world situation. This could basically come down to the physical size of the system itself. Is the system design efficient enough to save volumetric weight? For example, if you can deliver the same level of thermal performance in a smaller, functional system, can you save the customer freight costs or fit more on a vehicle, thereby reducing the carbon footprint of the system? The final destination of a product also needs to be taken into account, as a large number of clinical trials have to be conducted in extremely remote areas of the world in order to gain access to naïve patient groups. The most commonly available insulating materials seen in the cold chain industry mean that there is a trade off between sustainable design and practical use. For example, a vacuum insulation panel (VIP) and an alternative phase change material (PCM) would generally give stable and high performing results. However, the design trade-off would be with end of life of these components and can be of high cost to the customer. The decision should be taken by the customer as to what their priority is. The combination of getting reusable systems to these patients or a key location in these emerging markets tends to cause unexpected excursion risks during the cold chain, largely due to the country’s poor transport infrastructure. However if a pharmaceutical company uses a reusable system to ship products to remote global regions, they may not get the packaging’s materials back and therefore, by default, the packaging would become single-use. Normally the characteristics of a reusable system require the use of durable premium technology, as well as hardwearing materials such as plastic cases, metal-skinned insulation panels, or rigid plastic refrigerant components.
Because of this, they generally have higher cost implications, so while a system that has these added security factors ensures that a product will reach a remote destination safe and sound, they also generally make the initial cost of investment higher. So, with no way of getting the reusable components back, the investment ends there. However, with the right returnable logistics in place, this additional cost can be recouped quickly. In certain cases, a reusable system can be used numerous times. So to fully benefit, both environmentally and financially, from this type of TCP solution, it really comes down to the type of operation that uses it most effectively. This is another opportunity for TCP manufacturers to work with the customer by understanding whether they operate a closed-loop return on systems by utilising a 3PL or courier, or whether they make intra-company shipments between sites effectively, utilising the systems at each step so they are never shipping fresh air. It is important to remember that a reusable package would be classed as an asset to the customer, not something which serves a single purpose. For a system to be termed as sustainable, it is of vital importance to be able to track it when it is out in the field, and to know when it will be returned and how often it’s used, whether this is through a pen-and-paper inventory, a more innovative web-enabled database, or using the scanning and tracking software of the courier. Ultimately these ingredients need to come together in order to make a reusable system the most sustainable it can be. Creating a Sustainable Design An important factor that temperature-controlled packaging manufacturers take into consideration in the sustainable design of a system is energy efficiency, and how the solution
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IT & Logistics
is created in order to serve its purpose. For example, if a solution is manufactured locally, as opposed to having to import components before it’s assembled, consideration needs to be given to the transport needed to get it from its global destination to the local site, before it’s even put together for its purpose. Consideration will always be given by the customer as to the manufacturing locations of their TCP supplier versus the distribution hubs that they have in place. The closer TCP manufacturers are to the distribution sites, then the lower the potential carbon footprint for transportation. Therefore, the design itself needs to account for so much more than just the materials themselves; it requires an understanding of how the materials are being applied, used and transported. Before it goes out in the field, the system will have its temperature profile qualified in the laboratory to ensure that it will work in a real-world situation. To do this, many temperaturecontrolled packaging manufacturers test their products in an environmental chamber. While exposure to unexpected temperatures, such as an unscheduled stop to remove cargo (which changes the ambient temperature) would not be accounted for in a controlled environment chamber, this is why pharma companies primarily test to “worst case” – to prove a system is capable of maintaining temperature when there are “unusual” incidents. The idea is that the more TCP manufacturers understand the different variables that an ambient profile has, the better they can say that the appropriate system can be used. That itself leads to a more sustainable design. The use of innovative simulation technology, such as multiphysics (MP) can cut down the time for design in the chamber because the initial development phase is firstly performed virtually on a computer, before any prototypes are developed or initial testing is carried out. Technologies such as MP can enable TCP manufactures to achieve a near-accurate result in a shorter 58 Journal for Clinical Studies
space of time, thereby drastically cutting the design’s carbon footprint by using less electricity. Conclusion Evaluating the sustainable credentials of a packaging system, with its ability to protect valuable contents consistently whilst acknowledging a customer’s potentially unique take on the term “sustainable”, and also being cost-effective, can be a challenge. But by taking into account the life cycle of a packaging system and undertaking an in-depth assessment of an organisation’s requirements, it is possible to find a suitable sustainable solution, which ticks all the boxes. Factors to take into consideration when designing a sustainable solution: • Payload to external size ratio • Material properties – Are they biodegradable? How strong are they? • End-of-life properties of components • Inbound and outbound transportation costs • Local manufacturing • Number of times a system can be re-used Karen Adams is Technical Manager at DS Smith Plastics Cool Logistics. Karen is responsible for all aspects of product development, innovation in new product development, and qualification. Karen has been with DS Smith Plastics Cool Logistics for five years, and has over 10 years’ experience in both the pharmaceutical and FMCG sectors. Karen is a time-served indentured apprentice and has a bachelor of engineering (BEng) in mechanical engineering design. Email: firstname.lastname@example.org Volume 5 Issue 5
20-21 November 2013, Reed Messe Wien, Congress Center, Vienna, Austria
Drive performance: Be inspired to make a practical change in your role The Partnership Cliff: What happens now? Adrian Otte, VP Global Development Operations, Amgen, USA
Paula Gildert, Global Head Development Strategic Sourcing, Novartis, Switzerland John Oidtman, Vice President, Clinical Trial Support & Compliance, WW Development Operations, Pfizer, USA Barbara Valenta-Singer, Senior Director Global Clinical Operations and Acting Head Clinical Development, Baxter, Austria
TransCelerate: A pioneering consortium Dalvir Gill, Chief Executive Officer, TransCelerate Biopharma
A patient’s story: “What happened when I enrolled in a clinical trial” Trudie Lobban, Chief Executive, Atrial Fibrillation Association (AFA), UK
Exploring how technology will shape and innovate clinical trials Barbara E. Tardiff, M.D., Vice President, Development Operations, Global Head Clinical Innovation and Informatics, Worldwide Research & Development, Pfizer, USA Steven Labkoff, Head, Strategic Programs, Research & Development Information, AstraZeneca, USA
To register: +44 (0) 20 7017 7481 email@example.com www.ct-partnerships.com Please quote VIP Code: CQ3008SMDAD
CPhI Worldwide event preview (22-24 October 2013):
Last year CPhI Worldwide once again delivered an exceptional platform for both innovation and growth in the pharmaceutical industry. With more than 30,000 visitors and over 2,200 exhibitors, this year’s edition provides the opportunity for attendees from more than 133 countries to meet under one roof. There will be 20 d edicated zones covering ingredients, APIs, excipients, finished dosage, contract services, packaging, machinery and more. Running alongside the pharmaceutical ingredients halls are three sister brands, which help visitors to quickly identify the right halls for their needs. ICSE is an outsourcing focussed area designed to connect the pharmaceutical community with contract service providers in the field of clinical trials, CRO, logistics, data management and CMO. InnoPack brings together buyers and specifiers from the packaging and pharmaceutical industries. Finally, P-MEC Europe features exhibitors from traditional large-scale capital equipment to companies focussed on instrumental analysis, measuring and testing technologies, materials testing, quality control and laboratory. As you prepare your itinerary to attend this year’s CPhI Worldwide, make sure you factor in attending the CPhI Pre-Connect Conference on 21 October. Comprised of 6 modules featuring Drug Delivery Systems and Biosimilars and Biobetters, the Pre-Connect Conference offers the exclusive opportunity to join senior executives and influential speakers from across the pharma industry. Representatives from Wockhardt, Novartis, Merck and PwC to name just a few, will help you get a head start on your networking in an informative and interactive environment. Additionally, the show features a constant stream of informative content on the latest key developments via the CPhI Pharma Awards and free exhibitor sessions in the Speakers Corners. You will have the opportunity to hear first-hand from exhibitors across the globe about the latest trends within the Pharma industry whilst also finding out about their latest products, innovations, services and more! Since visitors are increasingly operating in the biopharmaceutical sector, there will be a specific Biopharma zone and a Bioservices zone at Messe Frankfurt this October. CPhI Worldwide holds a unique position in hosting the largest number of traditional pharmaceutical suppliers and buyers, alongside an array of top biopharmaceutical companies, including Therapeutic Proteins International, Biosidus, Amega Biotech, Mabion and Toxicon Corporation.
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Within the biopharma zone and throughout the wider show, exhibitors and visitors should set some time aside to take advantage of key biopharmaceutical presentations taking place. Topics on this year’s schedule include: • The future of manufacturing technologies: promoting innovation in complex biopharmaceutical manufacturing • Challenges of biopharmaceutical development, manufacturing and commercialisation • Development of protein engineering platforms to improve stability, safety and productivity of biopharmaceuticals • Outsourcing as viable R&D and manufacturing strategies: adapting business models to maintain the market position Attendees will also be able to take advantage of CPhI’s unique matchmaking programme to help make the most of their time at the event. It allows for direct access to individual exhibitors that meet your needs. The customised program facilitates high quality meetings, boosting ROI for all participants, across the 3 show days. CPhI Worldwide 2013 will, undoubtedly, provide a highquality platform to help in further augmenting growth and driving innovation within the pharmaceutical and biopharmaceutical markets. To register for CPhI Worldwide 2013 please visit: http://www.cphi.com/register-your-interest-2013
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Page 61 â€“ ICSE Preview advert
are promising, they need to be replicated on a bigger scale and evaluated over time to determine how long the protection lasts. The results of the Phase 1 study of PfSPZ are exciting, but they also highlight a broader challenge of translating clinical results into effective interventions. In the trial, 15 participants received a high dose of the vaccine, 17 received the low dose, and 12 patients did not receive the vaccine. Only three patients receiving the higher dose of the vaccine contracted malaria. Fifteen lowdose participants and 11 of the participants who did not receive the vaccine came down with malaria. These encouraging results will spur the vaccine on to further study, where investigators can determine optimal dosage and delivery route. Anti-cancer drug T-DM1 benefits women with advanced breast cancer who have failed several previous treatments: results from TH3RESA trial First results from a phase III clinical trial of the combination drug, T-DM1, show that it significantly improves the length of time before the disease worsens in women with advanced HER2 positive cancer whose cancer has recurred or progressed despite previous treatments, including trastuzumab and lapatinib. In a late-breaking presentation to the 2013 European Cancer Congress (ECC2013) , Professor Hans Wildiers will say: “This study shows that even in heavily pre-treated women, 75% of whom had cancer that has spread to the internal organs, T-DM1 nearly doubles progression-free survival - the length of time before disease progression or death, whichever occurs first - compared to standard therapy, and with a more favourable safety profile. Few drugs have been able to achieve both improved progression-free survival and a better toxicity profile. These results indicate this drug has important clinical benefit for patients.” T-DM1 is a conjugated monoclonal antibody in which trastuzumab is combined with a cellkilling drug emtansine (DM1) to target and kill breast cancer cells that have large amounts of the protein HER2 on their cell surfaces - known as HER2 positive breast cancer. T-DM1 has already been shown to benefit patients with HER2 positive breast cancer that has spread to other parts of the body (metastasised), and who have already been treated with trastuzumab and a taxane-based chemotherapy. New £4m clinical research centre opens in Belfast A new £4m medical research centre in Belfast will allow more people than ever before to take part in clinical trials in Northern Ireland. It will also benefit patients with rare conditions who previously had to travel to England to participate in trials. The centre opens later on Wednesday and will be based at Belfast City Hospital. It will concentrate on four main areas; cancer, nutrition and metabolism, vision science and respiratory research. The facility is a joint venture between Queen’s University Belfast, the Belfast Health and Social Care Trust, the University of Ulster, and Health and Social Care Research and Development (HSC R&D), a division of the Public Health Agency (PHA). It will be called The Welcome Trust-Wolfson Foundation Northern Ireland Clinical Research Facility (NICRF). www.jforcs.com
Health Minister Edwin Poots said: “This new state-of-the-art facility is an important element of Northern Ireland’s health research infrastructure and will enhance our ability to produce valuable, usable results. “Research, development and innovation are essential for modern healthcare systems so we can advance the quality of our services, whether in disease prevention, diagnosis or treatment. Research also provides vital knowledge that can improve the cost-effectiveness and value for money of our health services.” Glenmark gets research fee payment from Forest Laboratories Glenmark Pharmaceuticals has received a small research fee payment from Forest Laboratories Inc on collaboration for the development of molecules to treat chronic inflammatory conditions. The company, however, did not disclose the exact quantum of payment. “The company has received a small research fee payment from Forest Laboratories Inc on collaboration for the development of novel mPGES-1 inhibitors to treat chronic inflammatory conditions to support the next phase of work,” Glenmark Pharmaceuticals said in a statement. The company is expecting an additional payment to support the advancement of the programme, it added. As per the terms of agreement between the two companies, Forest has an exclusive option to obtain licence rights to the programme upon the completion of pre-clinical trials. “Under the terms of the agreement signed in FY 2012-13, Forest had made $ 6 million upfront payment to Glenmark and also made an additional $3 million to support the next phase of work for the development of novel mPGES-1 inhibitors to treat chronic inflammatory conditions, including pain,” Glenmark said. Shares of Glenmark Pharmaceuticals closed almost flat at Rs 522.85 per scrip on BSE. Clinical trials in India to get stringent In an attempt to bring about reforms in drug regulation and clinical trials, a six-member expert panel constituted by the ministry of health and family welfare has said that in future, these trials can only be carried out in accredited centres. Also, the principal investigator and ethics committee of the institute where the trial is being done should also be accredited. Only then will trials be approved. These recommendations, already up on the website of the Central Drugs Standard Control Organization (CDSCO), are part of the Professor Ranjit Roy Chaudhury Expert Committee on New Drugs and Clinical Trials Approvals and attempt to weed out fly-by-night operators who collude with drug companies and doctors to approve drugs whose trials have never taken place. “While some of the recommendations can be implemented within two months after consultations, others will require an amendment of rules,” says a senior health ministry official. “The government will ensure that clinical trials are done legally and the safety of participants is adhered to.” Dr Roy Chaudhury, adviser, department of health and family welfare, says the lack of regulation in clinical trials has seen India lose out to China, Malaysia and Singapore. “But this is set to change; we want India to once again be the centre for clinical trials.” Journal for Clinical Studies 63
CureDuchenne Ventures launched to accelerate drug discovery and development National nonprofit CureDuchenne has launched CureDuchenne Ventures, a new initiative to identify and develop a robust pipeline of therapies to treat Duchenne, the most common and lethal form of muscular dystrophy. This drug discovery and development initiative is based on CureDuchenne’s venture philanthropy model, in which the organization provides early stage funding to biotechnology, pharmaceutical companies and academic investigators to help develop breakthrough therapies to treat Duchenne. Currently, there is no treatment for Duchenne. Duchenne is a progressive muscle-wasting disease that impacts approximately 1 in 3,500 boys. Boys with Duchenne are usually diagnosed before the age of five and are in a wheelchair by age 12; most don’t survive their mid-20s. CureDuchenne Ventures will focus on venture philanthropists, foundations and donors with an interest in scientific research for rare diseases, such as Duchenne. The first research project to be funded through CureDuchenne Ventures is a collaboration with biopharmaceutical company Lexicon Pharmaceuticals. Lexicon’s experimental drug, LX2931, which is in clinical development as a potential treatment of rheumatoid arthritis and autoimmune disease, currently is being evaluated for its potential to initiate muscle regeneration in studies with the mdx mouse model of Duchenne. CureDuchenne plans to raise $5 million to support clinical development of LX2931 as a potential treatment for Duchenne, with clinical studies slated to begin as early as 2014. Cancer Research Technology Pioneer fund, BACIT, Sareum ink agreement The Cancer Research Technology Pioneer Fund (CPF), Battle Against Cancer Investment Fund (BACIT) and drug discovery company Sareum, have entered into an agreement to co-fund the further development of a class of cancer drugs called CHK1 inhibitors. The candidate inhibitor originates from research in the Cancer Research U.K. cancer therapeutics unit at The Institute of Cancer Research (ICR), London, by scientists funded by Cancer Research U.K. working alongside Sareum’s researchers, and in collaboration with Cancer Research Technology (CRT). Further work will be carried out at the ICR, and it is expected that the drug candidate will be taken into clinical development at The Royal Marsden NHS Foundation Trust. The rights to the preclinical program have been licensed into CPF from CRT and the ICR. CPF obtains worldwide rights to the preclinical CHK1 inhibitor program and is responsible for future development and commercialization funded by CPF, BACIT and Sareum. CRT and the originating research partners, Sareum and the ICR, are entitled to an up-front fee plus success milestone and royalty payments. Financial terms of the license were not disclosed. CHK1 inhibitors control a cancer cell’s response to DNA damage. Blocking CHK1 could boost the efficacy of chemotherapy drugs by blocking repair of the DNA damage caused by these drugs, but without harming healthy cells. The developers of the program believe the candidate CHK1 inhibitor to be developed could potentially treat a range of cancers including pancreatic, bowel and non-small cell lung cancer (NSCLC) in combination with DNA-damaging chemotherapy drugs 62 Journal for Clinical Studies
and radiotherapy. The inhibitor could also potentially treat certain neuroblastoma and acute myeloid leukaemia (AML) types when dosed alone. Global Health Investment Fund launched for late-stage vaccines A new investment fund structured by JPMorgan Chase and the Bill & Melinda Gates Foundation will, for the first time, allow individual and institutional investors the opportunity to finance late-stage global health technologies that have the potential to save millions of lives in low-income countries. With $94 million committed by a pioneering group of investors— including anchor support from Grand Challenges Canada (funded by the Canadian government), the German Ministry for Economic Cooperation and Development and the Children’s Investment Fund Foundation—the Global Health Investment Fund (GHIF) will help advance the most promising interventions to fight challenges in low-income countries such as malaria, tuberculosis, HIV/AIDS and maternal and infant mortality. To help mitigate the risk of investing in the clinical development of new technologies, the Gates Foundation and the Swedish International Development Cooperation Agency have committed to partially offset potential losses in the Fund, which will seek a financial return for investors by targeting high-impact technologies with public health applications in both developed and emerging markets. “GHIF demonstrates the potential for innovative collaborations and thoughtful financial structures to mobilize new sources of capital for social challenges,” said Jamie Dimon, chairman and CEO of JPMorgan Chase. “This product brings a diverse group of investors together around the shared objective of developing life-saving technologies in a financially sustainable way.” LHGP Asset Management, a Londonbased asset manager specializing in sustainable development, will be responsible for originating, managing and exiting GHIF portfolio investments. The Fund’s investor group currently includes International Finance, GlaxoSmithKline, Merck, Pfizer, Storebrand and JPMorgan Chase. “We invest in global health because we know that when health improves, life improves by every measure,” said Bill Gates, co-chair of the Bill & Melinda Gates Foundation. “This innovative fund is mobilizing financing for medical advances that could potentially save millions of lives,” said Jim Yong Kim, World Bank president. “It shows that we can align the needs of investors with the need for cures for diseases which cause so much suffering in developing countries.” The GHIF will invest in new drugs and vaccines, emerging diagnostic tools, child-friendly formulations of existing products and expanding manufacturing capacity. Early Clinical Trial Results Take a Bite out of Malaria Vaccine Search Pesky mosquitoes have forced an early end to many swampy summer nights. But these parasites pose a much greater risk for the nearly 200 million people infected with malaria each year. In a small Phase 1 clinical trial, a potential vaccine demonstrated encouraging results. PfSPZ was highly effective in patients receiving the highest dose. Developed by biotechnology firm Sanaria, the vaccine is in early testing stages. Although the results Volume 5 Issue 5
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12th Annual Partnerships in Clinical Trials Congress Aenova Holding GmbH AndersonBrecon (UK) Limited (Packaging Coordinators, Inc) Cmed Group Ltd Cool Logistics Dora Wirth Languages Durbin PLC Eurofins Farmasoft INTERLAB central lab services - worldwide GmbH International Contract Services Expo MediciGlobal MediLingua Medical Translations B.V. MENE CLINICAL RESEARCH MESM Ltd MLM Medical Labs GmbH Nagy Research MEACRO PDP Courier Services Ltd Poseidon Pharma CRO Synevo Central Lab Trilogy Writing & Consulting GmbH Vitaphone Nederland BV Woodley Equipment Company Ltd
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Paediatric Patient Retention It’s Not Child’s Play
Macroeconomic Forces Driving Clinical Trial Costs
Clinical Investigation of Medical Devices Promoting Convergence
Investigators’ Legal Status in Entering Clinical Trial Services Agreements Should They be Registered as Entrepreneurs or Not www.jforcs.com
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