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Volume 7 - Issue 1 Volume 7 - Issue 1


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


Journal For Clinical Studies Your resource for Multisite Studies & Emerging Markets

Cardiac Safety Investigations 10 Years after ICH Guidance E14 Overcoming Regulatory Challenges In Cognitive Drug Development Family Medicine Clinical Trials Enhancement at the Patient’s Level

Understanding the Importance of Mobile Health for Pharma

I Journal for Clinical Studies

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08 New Pregnancy Labelling for Risk Communication A much-anticipated push toward improved medical communication is happening in June, when a final rule takes effect to revise an outdated prescription labelling system in the US for pregnancy. The proposed rule was issued in May 2008. For approved drug and biological product applications that are subject to the Physician Labelling Rule (PLR), the final rule requirements will be gradually phased in. Deborah A. Komlos, MS, Senior Medical & Regulatory Writer from Thomson Reuters explains the new Pregnancy Labelling for Risk Communication. 10 Heart Failure – What can we Learn from the Pulse The central aortic pressure waveform is actually a composite of two separate pressure waves: 1) an incident wave generated by left ventricular ejection and 2) a series of reflected waves returning from the periphery. In its simplest form, the interaction of the incident and the composite reflected pressure wave is predominantly determined by the arrival time of the reflected wave, which is largely influenced by arterial stiffness. Dr David Winter, Vice-President of Scientific and Clinical Affairs for AtCor Medical, and Bobby Stutz, Senior Research Engineer for AtCor Medical provide an article on heart failures, and with their help we can learn more from the pulse.

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

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 7 Issue 1 January 2015 PHARMA PUBLICATIONS

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12 ASH 2014: A Mirror on Progress, Challenges and Opportunity for New Therapies in Haematologic Malignancies “For the eighth consecutive year, my colleagues and I have had the good fortune to attend the Annual Meeting of the American Society for Hematology (ASH).” Nicholas Kenny PhD, Executive Vice President and General Manager from INC Research, shares his researches and experiences within this white paper regarding the progress, challenges, and opportunity for new therapies in haematologic malignancies.

REGULATORY 18 Overcoming Regulatory Challenges in Cognitive Drug Development In recent years, numerous pharmaceutical and biotechnology companies have undertaken development programmes intended to assess the efficacy of various pro-cognitive drugs on a wide variety of cognitive domains across several psychiatric and neurologic conditions. Henry J. Riordan, PhD, Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials, presents an editorial on cognitive drug development by paying attention to overcoming regulatory challenges.

14 Family Medicine – Clinical Trials Enhancement at the Patient’s Level General practice and primary care are fundamental to the success of healthcare systems. There is strong evidence that primary care services achieve better healthcare outcomes at lower cost, providing comprehensive, continuous and personalised contact with the patient. Paweł Kabata MD, PhD, Medical Director at MedSource Polska, and Janusz Kabata, MD, PhD, MBA, co-founder and Chief Medical Officer at GlobalCare Clinical Trials Ltd submit an editorial on family medicines, explaining clinical trials enhancement at the patient’s level. 16 Australia – An Attractive Location for Clinical Studies Sue Lee of World Courier looks at Australia, which is a member of the United Nations, G20, Commonwealth of Nations, ANZUS, Organisation for Economic Co-operation and Development (OECD), World Trade Organization, Asia-Pacific Economic Cooperation, and the Pacific Islands Forum, and is a very attractive location for clinical studies.

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Cardiac Safety Investigations 10 Years after ICH Guidance E14: - Evolving Industry and Regulatory Viewpoints on Evaluation of Proarrhythmic Risk during New Drug Development The year 2015 marks the 10th anniversary of the release of two ICH Harmonised Tripartite Guidelines that have governed the cardiac safety regulatory landscape, more specifically the proarrhythmic cardiac safety landscape, since their release in May 2005. In this article, Snehal Kothari, MD, DM, FACC, FESC, Cardiologist and Senior Medical Director & Head of the Cardiac Safety Center of Excellence at Quintiles, Dilip R. Karnad, MD, FACP, FRCP (Glasg), Head of the Quintiles Cardiac Safety Services Research Team, Gopi Krishna Panicker, BHMS, PGDCR, Medical Writing Manager at Quintiles Cardiac Safety Services Research Team, J. Rick Turner, PhD, member of Quintiles’ Cardiac Safety and Cardiovascular Centers of Excellence, and Cardiac Safety Research Consortium’s Executive Committee give us an insight into cardiac safety investigations 10 years after ICH Guidance E14. Volume 7 Issue 1

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Contents 32 Centralised Monitoring: A Smart and Cost-efficient Approach The clinical monitoring cost is one of the major costs and accounts for one-third of the overall cost of clinical trial management. As the complexities in clinical trials have increased significantly in the last few years, the clinical monitoring cost, and in turn the trial management cost, has increased immensely in order to achieve higher data quality and better monitoring of patient safety. Within the following editorial, Ashok Ghone, PhD, Vice-President, Global Services at Makro Care USA, talks about centralised monitoring. MARKET REPORT 36 Comparison of Marketing Authorisation and its Requirements for Brunei Darussalam and Indonesia Brunei Darussalam and Indonesia are the only countries in ASEAN who have well-established pharmaceutical regulations and are more strict with regard to quality and safety of drugs. This excellent article on the Comparison of Marketing Authorisation and its Requirements for Brunei Darussalam and Indonesia is the focus of G. Ravi, Raja Mohan Reddy, D. Krishnaveni Reddy and N. Vishal Kumar Gupta.

TECHNOLOGY 46 Understanding the Importance of Mobile Health for Pharma Mobile health (mHealth) may be the buzzword of today, but unlike many other buzzwords, this one will not be just another flash in the pan. Mobile health offers the life sciences industry far-reaching capabilities to connect with various stakeholders — from patients and caregivers to physicians and pharmacists. Sarah Ray, Senior Research Analyst from Cutting Edge Information, provides this article on understanding the importance of mobile health for pharma, with the mention of some mHealth figures. 50 Can mHealth be thought of as the Default Solution for Accelerating Completion and Increasing Success Outcomes in Clinical Trials? Clinical trials are the experimental foundation on which modern medicine is built. Human medicines cannot be sold without permission from a licensing authority, and permission will not be granted unless a clinical trial has demonstrated the medicine’s success in treating the condition for which it will be marketed. Within this paper, Sarah Iqbal, established business scientist from FirstApp, tries to answer the question: Can mHealth be thought of as the default solution for accelerating completion and increasing success outcomes in clinical trials? 56 Mobile ePRO as a Cost-effective Method of Patient Data Capture As digital technology plays an increasingly important part in our everyday lives, it comes as no surprise that it has a huge potential to address some of the key challenges faced by the pharmaceutical industry as well. Tim Davis, CEO and Founder, Exco InTouch, provides this white paper on the collection of electronic clinical outcomes assessments, observer-reported outcomes, clinician-reported outcomes data via PDA and smartphone, and incorporating patient data capture using mobile ePRO. LOGISTICS


60 Get Back - Managing your Return Logistics for Clinical Trials Over the last ten years, the way that the pharmaceutical industry is expected to deliver new drug products to market has seen symbolic change. This shift in process has been driven by a number of significant factors. In the next five years the industry is expected to lose around $290bn in revenue from branded prescription medications going off-patent (the patent cliff) and overall drug development timelines are coming under continued scrutiny. Internal and external pressures mean traditional approaches to drug development are difficult to sustain, and speed to market is paramount to success. In this editorial, Gavin Morgan - Manager, Global Storage and Distribution from PCI’s European logistics operation, explains how to manage your return logistics for clinical trials.

42 Pyoderma Gangrenosum: A Systemic Review of the Incidence and Prevalence Pyoderma gangrenosum (PG) is a rare and serious skin disease in which a painful nodule breaks down to form progressive enlarging ulcers, and leads to a severe and significant increase in morbidity and mortality. The exact prevalence of Pyoderma gangrenosum has not been systematically reviewed and made available, except for the US and Europe. Within this paper, Ashvini D Soni and Drasty S Vora, Master’s degree students of clinical pharmacy from Nirma University, and Ali S. Bohra, country head and Director Clinical Operations from the Asia Pacific region with QED Clinical Services India Pvt. Ltd, write about methods, results and the limitation of the Pyoderma gangrenosum disease within a systemic review of the incidence and prevalence.

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Foreword First of all the Journal for Clinical Studies and the Pharma Publications team would like to thank all the authors for their many interesting and informative articles. The health industry is facing increasing challenges and coming up with new results year after year. When we look back over the last year, we see we had the chance to read about the new FDA guidance on clarifying the transfer of clinical research projects. Within JCS, we looked into the rapid development of mobile technologies and mobile applications for clinical trials, and we learned more about the role of mobile technology in the pharmaceutical industry. In 2014, children were not ignored either. Many articles were published on the regulation of paediatric drug development in different countries. In the last edition of 2014, we presented articles on bio-bank ethics, and we gained an insight into the last 15 years of clinical trials on Huntington’s disease as well. After this short retrospective, the Journal for Clinical Studies is starting the year 2015 with more interesting articles on various subjects for the clinical trials industry. The heart is always a central issue in healthcare. In our accelerated world, our pulse is always trying to keep up with the pace. Dr David Winter, Vice President of Scientific and Clinical Affairs for AtCor Medical, and Bobby Stutz, Senior Research Engineer for AtCor Medical, provide an article on heart failures, and with their help we can learn more about the pulse. The year 2015 marks the 10th anniversary of the release of two ICH Harmonised Tripartite Guidelines that have governed the cardiac safety regulatory landscape, and more specifically the proarrhythmic cardiac safety landscape, since their release in May 2005. Snehal Kothari and his associates give us an insight into the cardiac safety investigations 10 years after ICH Guidance E14. The clinical research industry is in critical need of supporting patient-centricity. Patient-centricity is about engaging the patients in clinical research and bringing the trials to their homes. This is recognised as a key element in patient recruitment and retention. Paweł Kabata, MD, PhD, Medical Director at MedSource Polska, and Janusz Kabata, MD, PhD, MBA, co-founder and Chief Medical Officer at GlobalCare Clinical Trials Ltd, discuss family medicines and their role in clinical trial enhancement at the patient’s level. Tumours of the haematopoietic and lymphoid tissues, or haematopoietic and lymphoid malignancies, are tumours that affect blood, bone marrow and lymph nodes. Nicholas Kenny, PhD, Executive Vice President and General Manager at INC Research, shares his researches and experiences within his article regarding the progress, challenges and opportunities for new therapies in haematological malignancies. We are delighted to publish an article by Henry Riordan of WWC Trials, which goes through the regulatory challenges in cognitive drug development, mentioning the numerous pharmaceutical and biotechnology companies’ development programmes of recent years, on bipolar disorders, major depression, Parkinson’s disease, PTSD and schizophrenia. Understanding the importance of mobile health for pharma is another milestone in the pharma industry. mHealth offers the life sciences industry far-reaching capabilities to connect with various stakeholders — from patients and caregivers to physicians and pharmacists. After a successful 2014 launch event, MCT is returning this spring! Learn more about mHealth and network opportunities, and visit our journal in Edinburgh on 24th25th March! Orsolya Balogh Editor Editorial Advisory Board Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc.

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

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

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

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

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

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

Georg Mathis, Founder and Managing Director, Appletree AG

Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories

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

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

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

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

Catherine Lund, Vice Chairman, OnQ Consulting Cellia K. Habita, President & CEO, Arianne Corporation

Janet Jones, Senior Director, ICON Clinical Research Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global

Jerry Boxall, Managing Director, ACM Global Central Laboratory

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

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

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

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

Elizabeth Moench, President and CEO of MediciGlobal

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Eileen Harvey, Senior VP/General Partner, PRA International

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA - Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

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Watch Pages New Pregnancy Labelling for Risk Communication A much-anticipated push toward improved medical communication is happening in June, when a final rule takes effect to revise an outdated prescription labelling system in the US for pregnancy. The proposed rule was issued in May 2008. For approved drug and biological product applications that are subject to the Physician Labeling Rule (PLR), the final rule requirements will be gradually phased in. For more than 30 years, pregnant women and their providers have turned to product labelling to find particular risk/benefit information described under one of five pregnancy categories (A, B, C, D, or X). The US Food and Drug Administration (FDA) adopted this category system in 1979 to convey risk and benefit information related to potential or documented human teratogenic risk and potential maternal/foetal benefits associated with drug treatment during pregnancy. In December 2014, the FDA issued a final rule1 that includes elimination of the pregnancy category system, which the agency notes “has long been criticised as being confusing and overly simplistic.” The FDA learned through experience and stakeholder feedback that the pregnancy categories: •

were heavily relied upon by clinicians but misinterpreted, misunderstood, and incorrectly used as a grading system where foetal risk increased from A to X; gave the incorrect impression that drugs in the same category carried the same risk or potential for human adverse developmental outcomes; did not discriminate among risk information obtained from non-clinical animal studies and post-marketing human studies and did not discriminate among drugs associated with adverse outcomes of differing severity or incidence; and focused on structural abnormalities and thus did not adequately address the full range of potential developmental toxicities.

Thus, the FDA concluded that using a category system to characterise the risks of using drugs during pregnancy would not be appropriate because of the complexity of medical decision-making needed when determining safe medication use in pregnant women. Under the December 2014 final rule, narrative summaries of the risks of drug use during pregnancy and discussions of the data supporting those summaries are required in labelling. This approach, the FDA states, is best able to capture and convey the potential risks of drug exposure based on animal or human data, or both. Moreover, it is consistent with other aspects of product labelling; for instance, numeric or letter or other categorical gradations of risk have never been used for safety labelling because safety and risk are complex constructs in clinical medicine. Apart from elimination of the pregnancy categories, the final rule also requires that for the labelling of certain drug products, the subsections “Pregnancy,” “Labor and delivery,” and “Nursing mothers” be replaced by three subsections entitled “Pregnancy” (which includes information on labour and delivery), “Lactation,” and a new subsection, “Females and Males of Reproductive Potential,” which provides information on pregnancy testing, contraception, and infertility. Through implementing the various changes to the labelling subsections, the FDA concluded that following a standardised structure is essential for effective communication. Also, the final rule would ensure that these subsections contain the most up-to-date information available and provide prescribers with clinically relevant data that they can use in their decision-making processes.

Through a specially established internal working group, the FDA carefully investigated a “multitude of models” 1,2 to determine whether a different pregnancy category system could communicate differences in degrees of maternal and foetal risk both accurately and consistently. One idea was to develop a new model that would use alpha-numeric symbols or character/graphics to represent a continuum of risk. This approach included generating tables and matrices of evidence-based criteria that might underlie each category along the risk continuum. When the working group applied these criteria to actual animal and human data findings for drugs with identified risk profiles, none of the models produced differentiations of risk that were clinically informative and reliable. 8 Journal for Clinical Studies

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In terms of implementation timeframe, prescription drug labelling for all applications (including new drug applications [NDAs], biologics license applications [BLAs], or efficacy supplements) that must follow the requirements of the PLR (i.e., those approved on or after June 30, 2001) must have revisions to the content and format of their pregnancy and lactation sections in labelling according to the implementation schedule published in the final rule. Holders of applications approved before June 30, 2001 (i.e., applications not subject to the PLR), would not be required to implement the new content and format changes. Instead, if the labelling for such applications contains a pregnancy category, the application holders would be required to remove the pregnancy category designation by three years after the effective date of the final rule. Concurrent with the final rule, the FDA issued a draft guidance for industry on “Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products—Content and Format.” 3 This document is intended to assist applicants in drafting the Pregnancy, Lactation, and Females and Males of Reproductive Potential subsections of labelling for prescription drug and biological products. It provides recommendations for applicants revising labelling of already approved products and for applicants drafting labelling for new products that will be submitted as part of an NDA, BLA, or efficacy supplements to approved NDAs or BLAs.

To ensure that the FDA considers public feedback on the draft guidance before it begins work on the final version, the agency is requesting the submission of comments by February 2, 2015 (Docket No. FDA2014-D-1551). 4 References 1. Federal Register: December 4, 2014 (Volume 79, Number 233) (Pages 72064 – 72103) 2. Federal Register: May 29, 2008 (Volume 73, Number 104) (Pages 30381 – 30868) 3. Draft Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products— Content and Format, December 2014; available a t : h t t p : / / w w w . fd a . g ov / d o w n l o a d s / D r u g s / G u i d a n c e C o m p l i a n c e R e g u l a t o r y I n fo r m a t i o n / Guidances/UCM425398.pdf 4. Federal Register: December 4, 2014 (Volume 79, Number 233) (Pages 72104 – 72105)

Deborah A. Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis Regulatory Intelligence US Module at Thomson Reuters. Her previous roles have included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work. Email: Journal for Clinical Studies 9

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Heart Failure – What Can We Learn from the Pulse? When considering the information obtained through evaluation of the arterial pressure pulse, more often than not it is limited to the maximum and minimum pressure in the vessel (i.e. the systolic and diastolic brachial blood pressure) and the heart rate. While the informative value of these three numbers cannot be disputed, this is very much a rudimentary approach. As was appreciated well before Riva-Rocci’s cuff and Korotkov’s sounds, and which has recently regained interest, analysis of the entire arterial pressure wave contour provides a more comprehensive understanding of the state of the arterial system and its interaction with the left ventricle. This is especially true when evaluated in the major, central arteries and so will be the focus of this column. The central aortic pressure waveform is actually a composite of two separate pressure waves: 1) an incident wave generated by left ventricular ejection and 2) a series of reflected waves returning from the periphery. In its simplest form, the interaction of the incident and the composite reflected pressure wave is predominantly

determined by the arrival time of the reflected wave, which is largely influenced by arterial stiffness. With stiffer arteries the reflected wave arrives earlier in the cardiac cycle and has negative consequences on afterload and coronary perfusion. Thus, by evaluating the central aortic pressure waveform contour it is possible to obtain information regarding arterial stiffness and wave reflection, the load it imposes on the left ventricle, and its effects on coronary perfusion pressure, as well as the central blood pressure, which can differ substantially from that in the brachial artery 1. The renewed interest in pressure waveform analysis has driven the development of technologies which now allow for the routine, non-invasive assessment of the arterial pressure pulse. In turn, the widespread incorporation of these technologies into numerous cross-sectional and longitudinal research studies has elucidated the role played by the pulse, and its determinants, in renal, cerebral, and cardiovascular complications 2,3. The increased knowledge of the role of the pressure pulse has resulted in understanding the heart and arteries as a coupled system in which changes in arterial stiffness, for example, can influence and sometimes drive pathologies of the heart. Thus, diseases such as heart failure are now understood as vascular, as well as cardiac, diseases 4. It should come as no surprise that central aortic blood pressure, specifically central systolic pressure, is more strongly related to left ventricular geometry and hypertrophy as measured by left ventricular mass index and relative wall thickness than is brachial blood pressure 5. Central aortic blood pressure is typically determined in the ascending aorta, which suggests that it provides for a better approximation of the load imposed on the ventricle than does brachial pressure. The strength of this relationship goes even further in that changes in wall thickness are strongly related to the changes in central aortic blood pressure 6. Additionally, measures of pressure wave reflection have been found to be the strongest determinant of left ventricular mass index change 7. A recent report from the Multi-Ethnic Study in Atherosclerosis investigated pressure waveform parameters in approximately 6000 subjects initially free of cardiovascular disease, and followed them for an average of seven-and-a-half years. The results showed that the magnitude of the reflected pressure wave relative to the pressure wave produced by ventricular ejection was a significant and independent predictor of incident congestive heart failure (Figure 1) 8. These findings, along with the already known associations between pressure wave characteristics and cardiac structure, illustrate the value of pressure waveform analysis in identifying those at risk for and prevention of heart failure.

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Watch Pages 3. Briet et al. (2012, Aug). Arterial stiffness and pulse pressure in CKD and ESRD. Kidney Int, 82 (4), 388400. 4. Borlaug, BA et al. (2007, Oct 16). Impact of arterial load and loading sequence on left ventricular tissue velocities in humans. J Am Coll Cardiol, 50(16), 1570-7. 5. Roman, MJ et al. (2010, Feb). Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study. J Hypertens, 28(2), 384-8 6. Kampus, P et al. (2011, Jun). Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension, 57(6), 122-8. Figure 1: Cumulative hazard for heart failure among subjects stratified according to tertiles of 7. Hashimoto, J et al. (2007, Apr). reflection magnitude Indices of pulse wave analysis are better predictors of left ventricular mass reduction than cuff pressure. Am J Hypertens, Possibly the most impressive work, though, is that 20(4), 378-84 which has been conducted in the treatment of heart 8. Chirinos, JA et al. (2012, Nov 20). Arterial wave failure patients. When compared to those receiving goalreflections and incident cardiovascular events directed heart failure therapy, heart failure patients who and heart failure: MESA (Multiethnic Study of were treated based upon their central aortic pressure Atherosclerosis). J Am Coll Cardiol, 60(21), 2170-7. profile demonstrated clinically meaningful improvements 9. Borlaug, BA et al. (2014, Mar 20). A randomized pilot in exercise capacity. Improvements were on par with other study of aortic waveform guided therapy in chronic heart failure therapies such as cardiac synchronisation 9. heart failure. J Am Heart Assoc, 3(2), e000745. 10. Go AS et al. (2014, Jan 21). Heart disease and stroke Heart failure contributes to one in every nine deaths in statistics – 2014 update: a report from the American the US. According to recent projections from the American Heart Association. Circulation, 129(3), e28-e292. Heart Association, by 2030 the incident rate is expected 11. Packer M et al. (2014, Nov 17). Angiotensin receptor to increase by almost 50% and total cost of heart failure neprilysin inhibitor compared with enalapril on the is going to jump ~127% to $69.7 billion 10. Recent novel risk of clinical progression in surviving patients with pharmaceuticals have shown promise for improving the heart failure. Circulation, Epub ahead of print. prognosis of heart failure 11; however, the mechanisms by which these improvements are mediated have yet to Dr Winter is currently Vice-President of Scientific be identified. Given the ability to predict heart failure and Clinical Affairs for AtCor Medical, Inc. Prior to from analysis of the central aortic pressure pulse and the joining AtCor, he was Director of Bioengineering improvement in heart failure patients when treatment at Southwest Research Institute, where he is guided by waveform analysis, an understanding of developed the first commercial blood pressure the mechanisms by which new therapies alter outcomes monitor based on arterial tonometry. He is an in heart failure patients must necessarily include an internationally recognised expert in physiological understanding of the effect of the arteries and arterial fluid mechanics, biomechanics and medical pulse. device development.   Email: References 1. Adji et al. (2011, Jan). Arterial stiffness, its assessment, prognostic value, and implications for treatment. Am J Hypertens, 24(1), 5-17. 2. Vlachopoulos, C et al. (2010, Aug). Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J, 31(15), 1865-71.

Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. He has spent the last seven years in the medical device industry after earning his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C. Email:

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Watch Pages ASH 2014: A Mirror on Progress, Challenges, and Opportunity for New Therapies in Hematologic Malignancies For the eighth consecutive year, my colleagues and I have had the good fortune to attend the Annual Meeting of the American Society for Hematology (ASH). Held this year in San Francisco, and attended by more than 18,000 people, ASH continues to excite and amaze me with the pace of progress of new therapies in many hematologic malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), and the seemingly intractable nature of other illnesses such as acute myeloid leukemia (AML). The depth and breadth of our understanding of the biological complexities of hematologic malignancies, and what this new-found knowledge reveals about opportunities for development of new interventional therapies, is astonishing to witness. ASH truly brings together a powerhouse of clinical investigators to review, discuss and learn about these developments. What then stood out for our team in 2014? While the advances we’ve seen with agents such as Imbruvica, Zydelig (and the emergent ABT-199) are remarkable (and continue to offer expanded benefit across a range of tumours), the following items should be remarked. Immunotherapies on the rise: Therapies designed to restart the body’s own disease-fighting mechanisms are re-emerging as an increasingly promising avenue in oncology. Two notable “entrants” at ASH were

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the Chimeric Antigen Receptors (CARs) and Immune Checkpoint Inhibitors such as the PD-1 class. It will be interesting to see in 2015 if CARs in B-cell cancers, which show early encouraging clinical data, and the significant investments made into companies like Juno Therapeutics will deliver on their promise. For the PD-1 drugs such as Keytruda ® (Merck) and Opdivo ® (Bristol-Myers Squibb/ Ono Pharmaceuticals), it will be fascinating to see if their promise/approvals in solid tumours like melanoma will translate to benefits in hematologic cancer where ASH 2014 became a beachhead for this drug class. There was some promising early data among patients who have not responded to other therapies, most notably from the Phase Ib Keynote-013 study in Hodgkin’s lymphoma patients who had relapsed/refractory disease, where Keytruda showed a 66 per cent response rate … in patients who had all failed on Adcetris, and 69 per cent response rate of those who had failed prior transplant. Similarly, early-phase studies with Opdivo showed an 87 per cent response rate, which manifested very quickly after initiation of therapy, in classic Hodgkin’s lymphoma patients who had up to six prior therapies, a remarkable early showing in such a clinical setting. If the clinical benefits of PD-1 therapy are confirmed in several planned larger trials, then the designation of Breakthrough Therapy (e.g. for Opdivo) will be well-warranted. Translation of these benefits into other hematologic cancers is eagerly watched for in 2015.

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Watch Pages most common genetic blood disorders, requires lifelong transfusions for patients, and patients left untreated die in their forties. Data presented at ASH this year showed that four patients who had been given a single therapy of Bluebird’s LentiGlobin BB035 were essentially cured, after showing sufficient hemoglobin production to reduce or eliminate the need for transfusion support during followup between three and 12 months.

New light in AML treatment? While AML has been the subject of intense clinical trial investigation for many years, 7+3 remains the clinical backbone of therapy, and many new agents have failed in Phase III in several AML settings. Is this landscape changing with a new approach? Certainly the IDH-2 inhibitor approach, championed by Agios (Cambridge MA) and supported by Celgene, offers new hope. AG-221 targets a genetic mutation in IDH2 that prevents specific white blood cells from normal maturation, leading to development of acute myeloid leukemia and other blood cancers. Reports at ASH from Agios’ early trials indicate that blocking IDH-2 led to complete or partial remissions in 56 per cent of advanced/ relapsed AML patients, remarkable data in this advanced disease setting that historically has seen little progress. It will be fascinating to track the long-term impact of AG221 in treated patients and see data from expanded trials with this agent. Gene therapy approach yields impressive data: Gene therapy has for many years offered potential clinical promise, but has been plagued by a series of practical and safety challenges. Is this now changing? Certainly the early data from Bluebird Bio’s clinical trials in betathalassemia patients offer tangible promise. This disease, characterised by a reduction in hemoglobin and one of the

Excellence in education: A hallmark of ASH continues to be the high standard and utility of the educational programme. Nowhere was this more evident than in the coverage of MM, both at the Ham Wasserman lecture from Dr San Miguel and in the point/counter-point led by Drs Moreau and Richardson in the “Myeloma; Controversies in Therapy” presentations. It is remarkable to reflect on advances in the treatment of MM patients over the past decade; they are unprecedented by any measure – overall survival, time to progression, quality of life, treatment options – and have resulted in the incorporation of novel agents into treatment plans at various stages of the disease, as well as changing treatment paradigms. Novel mechanism of action drugs highly effective in MM, such as proteasome inhibitors (PIs) and IMiDs, have resulted in 1st, 2nd and now 3rd generation agents, improving on effectiveness and toxicity profiles of earlier agents. In addition, options for front-line or salvage therapy use of ASCT are now being considered, with evaluations of longterm maintenance therapy under active investigation. From the perspective of patients who have a very active and engaged advocacy community, the outlook is bright. Is it getting brighter yet? Certainly the addition of CD38 monoclonals showing promise in clinical trials (e.g. BMS’/ Abbvie’s Elotuzumab) and newer HDAC inhibitors, such as Acetylon’s Ricolonistat, continue to add promising clinical data to the armamentarium physicians may be able to offer their myeloma patients. Tracking all of these advances into 2015 will be fascinating, and seeing these novel developments pull through from clinical research into clinical practice will be one of the best gifts that 2015 can bring to the many patients afflicted with these biologically complex hematologic diseases.

Nicholas Kenny, Ph.D., Executive Vice President and General Manager, Oncology and Hematology, provides global oversight for all of INC Research’s Oncology and Hematology-Oncology business. His background includes clinical development and regulatory strategy consulting services, international project management, and process development and integration expertise to a variety of pharmaceutical and biotech companies. Oncology clinical research is a personal and professional passion of his. Email: Website: www. Journal for Clinical Studies 13

Watch Pages Family Medicine – Clinical Trials Enhancement at the Patient’s Level General practice and primary care are fundamental to the success of healthcare systems. There is strong evidence that primary care services achieve better healthcare outcomes at lower cost, providing comprehensive, continuous and personalised contact with the patient. So far, primary care professionals have rarely been involved in clinical research. Bringing family physicians and general practices who are close to patients both in terms of personal contact and geographical location, to clinical research, supported by innovative mobile technologies, can significantly enhance patient recruitment and retention. The clinical research industry is in critical need of supporting patient-centricity. Patient-centricity is about engaging the patients into clinical research and bringing the trials to their homes. This is recognised as a key element in patient recruitment and retention. There are several innovative solutions supporting patient-centricity in clinical trials, like direct-to-patient studies, information and communication technologies (ePRO, social media networking), patient advocacy groups, pharmacy-directed outreach, etc. The patient–centric approach can be facilitated by conducting study visits at patient’s homes. Many

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patients prefer home care to any other options, as for some people leaving home can be disruptive and depressing, and in several medical conditions, even impossible. In many countries, home visits are claimed to be a central element of primary care provided by both nurses and physicians since the early 1900s. Over the last 20 years, home care has experienced significant changes. The home visit industry varies between countries and depends on specific local regulations and cultural aspects of societies. In the United States, home care services are delivered by thousands of nursing agencies spread all over the country. In Europe, nursing agencies are not as common, but home care visits are available through very well-developed primary care infrastructure, based mostly on family medicine and general practitioners. Home care services provided by healthcare systems include technical nursing care (blood draws and biological sampling, vital signs measurement, wound care, etc.), drug administration as well as rehabilitation, supportive care, health promotion or disease prevention, both for chronic and acute conditions. However the use of home visits in clinical trials is limited. This is mostly due to challenges in standardisation of services across the studies, and the availability of properly trained home care service providers close to

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Watch Pages Even these tools often don’t comply with clinical research expectations and regulations, and electronic infrastructure and preparedness for implementing hightech solutions varies between places. Family physicians and their teams have very high levels of literacy in novel information and communication technologies, and can be easily trained on new sponsor and study-specific applications. Implementing an integrated patient-centred model, connecting the clinical research industry with professionals who are closest to the patient might be a faster, cheaper and easier solution for these trials, which can be conducted outside of specialist centres. Centralised management of standardised, high quality services performed by a network of GCP-trained family physicians and their teams, supported by modern mobile technology, enables the conduct of clinical trials regardless of patients’ location. The scope of services includes home visits for blood draws and biological sampling, drug administration, clinical assessments, patient and caregiver training, etc. Engaging family physicians in clinical research opens a brand new pool of clinical trial-naïve patients, as well as increasing a pool of patient-centric investigators. At the patient’s level, this model offers not only access to novel treatment and medications, but is also brought to them by fully trained and well-known nurses and physicians. Being first-line medical support in everyday practice, family physicians have the best and most complex knowledge about patients’ medical status. They know how to communicate trial results in lay language to study volunteers. patient location. Even though the clinical research industry recognises the value of home care, there are still challenges to face implementing these services to international, multi-centre trials. One of the biggest is the access to service providers who are close to patients’ locations, experienced in clinical research and willing to participate in clinical trials. This applies especially to nurses and family physicians located outside of academic facilities, in smaller cities and rural areas. Most often they don’t have access to sponsors and other clinical research institutions, facing the first entry barrier. As a result, these clinicians do not play a significant role in the research industry, while they can be a valuable source of both service providers and potential research-naïve subjects. The value of this group of healthcare professionals was highlighted in the Report on General Public and Patient Perceptions of Clinical Research published by CISCRP in 2013, which shows that for 52% of patients, the primary care physician is the preferred source of clinical research information. In contrast to the results of the survey, upto-date engagement of family physicians and general practitioners in clinical research is very limited. Electronic medical records, telemedicine and mobile technology have become more and more important aspects of the provision of home care services, and in many countries are commonly used by primary care physicians.

This approach can strengthen the relationship between sponsors, research community and patients as well as rebuilding public trust in clinical research. Janusz Kabata, MD, PhD, MBA is co-founder and Chief Medical Officer at GlobalCare Clinical Trials Ltd, the leading global provider of home care services. He developed and manages the network of home care service providers in Europe and Asia. Prior to joining GlobalCare, he was associate professor at Gdańsk Medical University. He founded Nova Medical (now Synevo Central Lab), the first central laboratory for clinical trials in Central Eastern Europe. He is a specialist in public health and laboratory medicine. Email:

Paweł Kabata MD, PhD Medical Director at MedSource Polska. Has 13 years’ experience in clinical research, both as country coordinator of Ambulant Care Services for GlobalCare Clinical Trials, and investigator of academic and industry-sponsored trials. He also works as a surgeon in the Department of Surgical Oncology at Medical University of Gdańsk, Poland and in family-owned general practice. Email: Journal for Clinical Studies 15

Watch Pages Australia – An Attractive Location for Clinical Studies This issue we’re going to look at Australia, which is a member of the United Nations, G20, Commonwealth of Nations, ANZUS, Organisation for Economic Co-operation and Development (OECD), World Trade Organization, Asia-Pacific Economic Cooperation, and the Pacific Islands Forum, and is a very attractive location for clinical studies. It is the world’s sixth-largest country by total area, with a population of 23.6 million people, and the fifthhighest per capita income globally according to the IMF 2013 figures. We should not underestimate how vast this country is. Perth is closer to Singapore and Jakarta than to Canberra. Australia has the fourth-highest life expectancy in the world after Iceland, Japan and Hong Kong, although as might be expected, due to the hole in the ozone layer it has the highest rates of skin cancer in the world, and that’s before you encounter all the hazardous creatures like box jellyfish, platypus, spiders and snakes (which I am reliably informed are mostly avoidable).

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The population is very diverse, which can provide companies with extensive data from different ethnicities and genotypes. Typical Western diseases including cardiovascular disease and diabetes are prevalent, together with dementia and Alzheimer’s. It has for years been a great area for both pharmaceutical R & D and for clinical trials, with 4487 trials run to date. Almost half of trials are concentrated in Victoria, which is the most densely populated state. Australia operates a universal healthcare system, with one doctor per 322 people, and 8.5% of GDP spent on healthcare. Australia has a mutual recognition agreement in place with the European Medicines Agency for pharmaceutical manufacture and inspection. The Australia Therapeutic Goods Administration (TGA) is part of PICS – the Pharmaceutical Inspection Cooperation Scheme, so dealing with Australia should be as simple as with the EU or North America, reducing numbers of audits and site visit requirements and relieving some of the paperwork pressures on exported materials.

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Watch Pages be listed on the CTN import paperwork during the CTN application. There is a special exception to the above from the TGA. A shipment may be imported into Australia while the CTN is “pending approval”. The conditions are that the drug must not be distributed or supplied prior to the CTN approval, or must be destroyed if approval is not obtained within 12 months. A declaration from the importer of record is required to confirm understanding that the drug will be stored and not distributed/supplied. Biological-based drug requires an AQIS import permit from the Australia Quarantine Inspection Service, and if the drug contains any controlled substance(s), a single-use import permit from TGA Dept Health & Ageing may be required. Original permits must be available at the time of import. If the commodity is subject to quarantine clearance, then clearance must be obtained during the normal business hours of the Quarantine Department. If it is scheduled to arrive over a weekend, then pre-clearance must be arranged by 1630 Friday, and weekend clearance can be arranged.

There are excellent airline services, with plenty of flights particularly into Melbourne and Sydney, although international clearance can be made at Adelaide, Perth, Sydney, Brisbane and Melbourne, with pre-clearance setup options available, allowing documents to be sent in advance by fax or email. Clearance normally takes just a couple of hours, but in the event of a delay then refrigerant can be added/changed a. when under Customs control b. when under airline control c. when being domestically transhipped. Importing Clinical Trial Drug All drugs require a customs invoice which must be dated and include the following information: • •

• • • • • •

Name of product If the product contains no ingredients of animal, plant or microbial origin, the following statement is required. “100% synthetic contains no ingredients of animal, plant or microbial origin” No. of vials Value (noting that NCV – No Commercial Value – is NOT accepted) House airwaybill number Shipper’s signature Incoterms are required if the FOB value is AUD1000 and above Customs Harmonised Tariff code

Clinical trial drugs also require an import licence called a CTN (Clinical Trial Notification). Usually this is obtained by the sponsor of the trial. Only a copy is required for clearance, not the original. The investigator site must

For North American and European companies in particular, Australia is a very safe option. No language barriers, mature investigational sites mostly based within Victoria State, lots of local infrastructure in place, with well-established CROs, SMOs and depots which can also supply other parts of Australasia – in fact the only disadvantage might be the time difference, although Australians recognise that issue and are very flexible, in my experience, at taking late-night and early-morning calls. It’s an excellent place to do business, and a great source of well-researched and compliant data.

Sue Lee has worked for World Courier for 25 years. During this time she has experienced a variety of customer service and operational functions, including the setting up of numerous, multi national, clinical sites for the transportation of biological samples in her capacity as Head of the Major Clinical Trial Unit. Sue has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. More recently in her role as Regional Quality Manager, Sue has been auditing and developing procedures and systems for regulatory compliance, package and vehicle testing, as well as temperature control and mapping. Currently, Sue’s role includes delivering pertinent, technical information and updates on latest industry developments via technical presentations, articles and white papers, workshops, association and discussion group involvement and direct links with other industry professionals. This also includes direct involvement delivering and maintaining World Courier’s online presence. Email: Journal for Clinical Studies 17

Regulatory Overcoming Regulatory Challenges in Cognitive Drug Development In recent years, numerous pharmaceutical and biotechnology companies have undertaken development programmes intended to assess the efficacy of various pro-cognitive drugs on a wide variety of cognitive domains across several psychiatric and neurologic conditions. Findings from these studies have suggested that several putative cognitive enhancers have some limited efficacy across a wide variety of indications, including ADHD – (attention deficit and hyperactivity disorder), bipolar disorder, major depression, Parkinson’s disease, PTSD – (posttraumatic stress disorder) and of course schizophrenia. Despite progress to date regarding the development of compounds intended to treat Cognitive Impairment Associated with Schizophrenia (CIAS) there is relatively little information available on how to determine the legitimacy of a given cognitive therapeutic target outside of schizophrenia. The following is an attempt to describe some of the more salient regulatory challenges involved in determining the appropriateness and legitimacy of a possible target involving cognitive impairment associated with various CNS – (central nervous system) disorders and how to overcome these challenges. To date most CNS drugs have registered claims for a recognised specific disease or syndrome, and for the most part these claims tend to be focused on the disease entity rather than specific features of the disease. More recently, however, regulatory agencies have approved development programmes and several compounds for indications reflecting specific features of a disease such as negative symptoms, suicide ideation and cognitive impairment in schizophrenia; agitation in bipolar disorder and autism; impulsive aggression in ADHD; and even walking in multiple sclerosis. Given that these indications have been considered legitimate targets for drug developers, many drug developers have maintained that cognitive impairment associated with other CNS disorders would also represent a legitimate target. By way of example, this watch article will posit that a specific type of cognitive impairment known as Executive Dysfunction (ED) is a cardinal feature of both untreated and treated child and adult ADHD, and therefore would represent a legitimate target for drug developers. The assumption is based upon a general consensus from a variety of cognitive, behavioural and imaging data, suggesting that a wide array of cognitive difficulties can be subsumed under the construct of ED, which has also been referred to as Executive Function Disorder, Dysexecutive Syndrome, Cognitive Dysexecutive Disorder, Prefrontal Executive Dysfunction, Fronto-Cortical Dysfunction, and Fronto-striatal Dysfunction, depending upon the indication with which it is associated. Given the myriad designations there initially needs to be agreedupon terminology to characterise and denote ED in 18 Journal for Clinical Studies

ADHD. This moniker should distinguish the uniqueness of ED as reflected in diagnostic nomenclature that signifies that this cognitive construct is different from any other constructs that regulatory bodies may be currently entertaining in ADHD or other disorders. It is important to note that ED is also a key symptom readily apparent in Parkinson’s disease, Bipolar/Unipolar Depression, Traumatic Brain Injury, and Obsessive Compulsive Disorder, as well as in non-psychiatric disorders such as primary breast cancer. Thus, it is important to determine if the ED associated with ADHD manifests itself differently from other indications and importantly that this ED is a symptom of the ADHD and not simply a result of treatment. The presence of symptoms across the natural history of the indication is also important to establish, as ideally symptoms should be apparent in early untreated patients and be fairly constant and refractory to medications designed to treat symptoms of ADHD later in the disease. Regardless of the exact terminology used, or even the indication under investigation, it is generally agreed that the underlying neurocognitive construct constituting ED is composed of difficulties across many of the following cognitive domains: • • • • • • •

Organisation and planning Working memory and self-monitoring Sustained attention / divided attention or vigilance / distractibility Impulsivity / behavioural inhibition Set shifting / cognitive inflexibility / perseverations Processing speed Initiation and fluency

These cognitive domains can be accurately measured by a number of validated and reliable neuropsychological and behavioural measures, suggesting that any changes associated with novel drug intervention can be measured effectively in a controlled clinical trial setting. As cognitive measures sample multiple areas simultaneously (for example, most tests will simultaneously examine divided attention, processing speed and visual reasoning) it is important to determine exactly how individual cognitive tests are assigned to their respective domains. It is unclear if a MATRICS-type (Measurement and Treatment Research to Improve Cognition in Schizophrenia) initiative will be required to define these cognitive domains, their constituent parts and their relative contribution (weight) to the overall ED construct or how these should be best accomplished (e.g., via a Rand-type panel methodology, the consensus of a formal neurocognition committee, exploratory/confirmatory factor analysis or some combination of these). Once the agreed-upon cognitive construct of ED is firmly established, it is necessary to provide evidence that existing ADHD drug treatments do Volume 7 Issue 1

Clinical documents are the visible part of your clinical programme Are the regulators seeing what your documents have to say?

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Regulatory not have a meaningful effect on ED; or that there is no meaningful treatment for a specific subtype of the ADHD characterised by a prominence of ED symptoms. It is possible to have a legitimate drug target and subsequent label, even if ED exists only in a small portion of patients. It can be argued that the cognitive impairment associated with ED in ADHD diminishes the response to ADHD medication such as psychostimulants and the overall treatment response. In either case the approved drugs for ADHD should not meaningfully treat the construct of ED. Importantly, data establishing this non-response can help to provide evidence to regulatory agencies that the intended target is not pseudo-specific. The notion that a claim is pseudo-specific remains one of the single biggest hurdles to overcome in cognitive drug development. Pseudo-specificity is a term coined by Paul Leber and was first applied in connection with claims advanced for the use of benzodiazepines in anxious patients suffering from specific medical conditions (anxiety of heart disease, cancer, etc.) 1. Leber opined that such claims were misleading because they sought to promote a distinction without meaning; consequently, these claims were rejected because they were held to be in violation of the requirement that a product’s labelling not be false or misleading. As an example, Leber suggested that a claim that a marketed antibiotic is effective for the pneumonia of dementia even if based on empirical evidence is a pseudo-specific, because the linkage between pneumonia and the diagnosis of the patients treated is of no pharmacologic or biological importance, existing solely because of the sponsor’s decision to select demented patients with pneumonia as subjects for study. By contrast, a legitimate disease-related claim requires a demonstration that the effect of the drug is in some way conditioned on the presence of the diagnosis (the diagnosis of the disease controls to what extent, if any, the effect of the drug is expressed) 1. Another way to think of pseudo-specific claims is to consider them as artificially narrow claims. Some examples of such narrow claims centre around artificially narrow subgroups, symptoms or symptom clusters, or comorbid conditions, and examples of these which have been ruled on as pseudo-specific by regulatory agencies include depression in women, depression in the elderly, hallucinations in schizophrenia, depression in Parkinson’s disease and dental pain 2. A claim would be considered pseudo-specific or artificially narrow by focusing on a subgroup within the population of interest or on a particular aspect of the illness, such as a particular symptom in the absence of any empirical evidence to support such a restricted focus. As such, these claims serve only to permit a promotional advantage for the drug, since they imply an advantage of that drug over other drugs in the class for the symptom of interest 2. Thus, regulatory agencies must be supplied with data suggesting that the treatment of ED in ADHD is not too narrow a disease-related claim, and therefore, not pseudo-specific. 20 Journal for Clinical Studies

There are several empirical approaches to overcome regulatory concerns that a claim is too narrow or pseudospecific, and given these approaches, CNS drug developers should always approach any regulatory rejection of an initial claim as a straw man position that can be overcome with empirical data indicating the value of targeting the particular domain or subgroup 2. Fortunately, CIAS serves as an example of a successful disease-related target within the schizophrenia syndrome, and as such is a target that can be utilised as a model to overcome regulatory concerns of pseudo-specificity in other CNS indications. Briefly, the claim for CIAS was established and legitimised based on several factors, including the fact that CIAS is a valid and well-known aspect of schizophrenia, that available treatments do not impact CIAS, and that the time course of CIAS is different from other important symptoms such as positive symptoms, and is present before the onset of positive symptoms and present in residual stage of illness 3. Using similar arguments and methodologies, cognitive impairment associated with depression is now under consideration as a legitimate target for drug development. Specifically, the methodological approaches to overcoming regulatory concerns regarding pseudospecificity revolve around providing evidence that in residual phases of illness there is a persistence of symptoms; in this case ED persists despite broad ADHD treatment; or that that ADHD treatment is not beneficial for a distinct subtype or subgroup of patients who have ED. There are several experimental design options that are available to researchers that could potentially demonstrate the above assertions. Two of these designs involve patients in the residual phase of illness, and one design involves more acute patients 2. The first of these designs is intended to demonstrate efficacy in an adjunctive study targeting ED in ADHD patients who are on stable doses of medication such as psychostimulants, but who are still experiencing ED. In this case, the novel drug under investigation would adjunctively treat only the ED and not overall ADHD symptoms such as hyperactivity. If the addition of the novel drug improves overall ADHD symptomatology, the drug would not meet the hurdle for a specific claim for ED and would be rejected based on the pseudo-specificity argument 2. A recent example of this can be seen in Shire’s lisdexamfetamine dimesylate augmentation study of persistent executive function in adults with partial or full remission of recurrent major depressive disorder, which reportedly improved executive function based on the Behavior Rating Inventory of Executive Function-Adult Version Global Executive Composite T-score (BRIEF-A GEC T); but also unfortunately improved symptoms on a measure of depression (MADRS), albeit mostly on items related to cognition4. As such, lisdexamfetamine dimesylate would at most be considered as an adjunctive antidepressant by regulatory authorities based on this trial, but would not meet the regulatory hurdle for a legitimate target claim of ED in depression. Volume 7 Issue 1

Regulatory The second of these designs involves a switching maneouvre in residual-phase ADHD patients showing continued benefit on ADHD symptoms but increased benefit (or decreased ED) when switching to a novel drug. Data from this study would need to demonstrate that the overall ADHD response remains adequate during the switch and that ADHD symptoms are maintained at similar levels 2. However, cognition as measured by ED scales should improve when the subjects are switched to the novel drug. An essential problem with this type of switching design lies in regard to the interpretation of superiority as there is no placebo control. Without a placebo control it is unclear if the novel drug has true pro-cognitive effects and is increasing executive abilities; or if the novel drug simply impairs EF to a lesser degree than the comparator drug; or if the novel drug is neutral in terms of EF while the comparator drug is detrimental 2. A third type of study design involves acute-phase patients comparing two drugs on the construct of ED, the novel drug and a comparator. This type of study would need to provide data that both drugs have effects on overall ADHD symptoms but only the novel drug would be superior to the comparator on ED. In this case, both drugs would need to be shown to positively impact overall ADHD symptoms by being superior to placebo on an ADHD scale measuring broad symptomatology 2. However, it is important to note that claims of superiority in ED measures could potentially mean that the novel drug beats placebo only on ED measures while the active control does not beat placebo, or that the novel drug is also superior to the active comparator on ED measures. It is unclear at this point if regulatory bodies will insist on the latter requirement but this seems unlikely. Should superiority over the comparator be mandated this represents a very high hurdle for CNS drug developers 2. Finally, regulatory agencies have differed on their view of the necessity of a functional co-primary for labelling pro-cognitive drugs. Researchers have long posited that improving cognitive dysfunction should lead to enhancing functional outcomes as cognitive deficits have been implicated as an impediment to gaining enhanced functional status, and a direct relationship has been demonstrated between cognitive impairment and poor functional outcomes for various patient groups such as schizophrenics 3. However, this type of evidence may not be enough to satisfy issues regarding clinical meaningfulness, and US regulatory agencies have traditionally insisted on a functional co-primary or proxy in prior cognitive dysfunction programmes 2. Many drug developers may simply view the mandate for a coprimary as a relic from the well-established Alzheimer’s disease labelling requirements, but US regulatory bodies have suggested this as a way to overcome any concerns regarding clinical relevance of any small benefits that might be seen on cognition and thus, the use of a coprimary functional measure or proxy has been mandated for all CIAS studies. The exact type of functional co-primary or proxy measure is open to discussion with regulators.

In contrast, European regulatory bodies have taken a somewhat more lenient stance and have instead opined that a functional measure serving as a key secondary outcome would be enough to establish a treatment label 5. However, European regulatory authorities typically require experimental deigns to be of longer duration than their US counterparts. Thus, designs establishing three or four months of efficacy data would not be considered to be of long enough duration and a minimum of six months of efficacy data would be needed for labelling purposes. In addition, a claim for a maintenance effect would need to be established for European regulators using a randomised withdrawal-type study design 5. Once again, the exact programme characteristics may be open for discussion with regulators. In summary, regulatory agencies are open to considering cognitive targets such as EF in ADHD, especially when there is preexisting data reflecting some consensus regarding the prominence, stability and time course of cognitive symptoms in a given indication. Recently, there has been a large increase in the number of studies assessing the effects of various pro-cognitive drugs on cognitive impairment associated with depression, ADHD, Parkinson’s disease and bipolar disorder. Given issues regarding pseudo-specificity, it is important for drug developers to partner early with regulatory officials in order to design studies which will provide adequate data to overcome any issues regarding pseudo-specificity. There are several designs that have been sanctioned by regulatory authorities, that if implemented successfully would provide the type and amount of data needed to secure successful treatment labelling. References 1.

Leber, P. Regulatory Issues in Neuropsychopharmacology. The Fifth Generation of Progress. Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, and Charles Nemeroff. American College of Neuropsychopharmacology (2002).


Laughren, T. Targeting Cognitive Impairment Across CNS Disorders. Session presented at the International Society for CNS Clinical Trials and Methodology Autumn Conference. Oct. 7, Boston MA (2014).


Breier, A. Developing Drugs for Cognitive Impairment in Schizophrenia. Schizophrenia Bulletin vol. 31 no. 4 pp. 816–822 (2005).


Madhoo, M, Keefe, RS, Roth, RM, Sambunaris, A, Wu, J, Trivedi, MH, Anderson, CS, Lasser, R. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. May;39(6):1388-98 (2014).


Broich, K. Targeting Cognitive Impairment Across CNS Disorders. Session presented at the International Society for CNS Clinical Trials and Methodology Autumn Conference. Oct. 5, Boston MA (2014)

Henry J. Riordan, Ph.D. is Executive Vice President of Medical and

Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. He has been the primary author of >75 CNS protocols as well as several clinical development programmes. Dr Riordan specialises in clinical trials methodology and has advanced training in biostatistics, experimental design, neurophysiology, neuroimaging and clinical neuropsychology. He has over 90 publications, including coauthoring two books focusing on innovative CNS clinical trials methodology. Email: Journal for Clinical Studies 21

Regulatory Cardiac Safety Investigations 10 Years after ICH Guidance E14: Evolving Industry and Regulatory Viewpoints on Evaluation of Proarrhythmic Risk during New Drug Development The year 2015 marks the 10 th anniversary of the release of two ICH Harmonised Tripartite Guidelines that have governed the cardiac safety regulatory landscape, more specifically the proarrhythmic cardiac safety landscape, 1 since their release in May 2005. ICH S7B addresses the non-clinical evaluation of the potential for delayed ventricular repolarisation (QT interval prolongation) by human pharmaceuticals, 2 and ICH E14 addresses the clinical evaluation of QT interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs, with a focus on the Thorough QT (TQT) Study. 3,4 Our discussions in this paper focus on clinical evaluations. Although it has been extremely effective in preventing approval of drugs with QT liability without clear characterisation of their proarrhythmic potential, there has been considerable debate about the need for modifying the current regulatory landscape to focus on earlier QT assessment in Phase I clinical pharmacology studies. 5,6 This paper therefore has several goals. First, the current landscape is reviewed: this is done succinctly since there are already multiple publications in the literature discussing the requirements and consequences of ICH E14 and the associated “Questions and Answers” documents since their release. 7-20 Second, it reviews various professional society activities and publications in the literature that document the background and motivation for an influential Think Tank meeting held on December 12 th, 2014, at the US Food and Drug Administration (FDA) Headquarters, Silver Spring, MD, USA, which was attended by representatives from industry, academia, and regulatory agencies from multiple countries. Third, it documents the main results of a prospective study entitled “Can early ECG assessment using exposure response analysis replace the Thorough QT Study?” that were presented at that meeting. 21 Finally, it provides a consideration of the potential ramifications of these results in both the short- and long-term evolution of the proarrhythmic cardiac safety landscape. Current Clinical Cardiac Safety Requirements Across the last two decades or so, cardiac safety has been a major concern in the development, approval, and marketing of new non-cardiovascular drugs (drugs not intended for a cardiac or vascular indication), 22 with a substantial number of drugs being restricted in their clinical application or withdrawn from the market due to adverse cardiovascular effects. There were 47 instances of post-marketing withdrawal of drugs between 1957 and 2007; 45% of these were due to concerns regarding cardiovascular toxicity. 23 Similarly, 27% of the potential new drug molecules that failed in the pre-clinical phase in the last two decades did so because of cardiovascular toxicity. 24 Consequently, significant attention has been 22 Journal for Clinical Studies

focused on the prospective exclusion of unacceptable cardiovascular risk during drug development. The level of risk that is deemed ‘acceptable’ differs based on the disease for which a drug is being developed, the relative severity of the adverse cardiovascular effects, and the availability of safer alternatives. Among the possible cardiovascular risk liabilities, the risk of drug-induced torsades de pointes (TdP), a rare but potentially fatal ventricular arrhythmia, has been a major reason for the withdrawal of licensed drugs, accounting for around 26% of drugs withdrawn from the market between 1990 and 2005. 25 This risk was not identified prospectively during the development of these drugs given the relative rarity of these events and the limited number of clinical trial participants studied in the pre-approval period. However, a common thread which subsequently emerged in these cases was their association with prolongation of the QT interval on the surface ECG. Figure 1 provides a highly-stylised representation of the ECG, the QT interval, and QT interval prolongation. It was also apparent that these occurrences were concentration-related and almost exclusively linked to delayed cardiac repolarisation due to drug-induced inhibition of the rapid delayed-rectifier potassium current (I Kr), which is the main repolarising current in ventricular cardiomyocytes. 26,27 This I Kr current occurs due to an efflux of potassium ions through the I Kr channel encoded by the human ether-a-go-go-related (hERG) gene, and is therefore also referred to as the hERG channel. 28 It followed, therefore, that the proarrhythmic liability of drugs could be prospectively investigated during drug development by using the QT interval on the surface ECG as a surrogate for their ability to delay cardiac repolarisation. Thus, the current cardiac safety testing paradigm came to be primarily based on the predictive link between drug-induced hERG channel blockade in vitro in preclinical studies, QT interval prolongation on the ECG in clinical trials, and the occurrence of TdP when a subsequently approved drug is used in patients. Since its implementation in 2005, the TQT Study, which has been the cornerstone of clinical assessment of the potential of non-cardiac drugs to cause TdP, has been very successful. 29,30 Not a single drug with unanticipated potential for TdP has entered the market since 2005. 30 However, over-emphasis of this surrogate marker has important limitations and is believed to have adversely impacted the development of potentially valuable therapeutics and increased the cost of developing safe drugs considerably. 31

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Regulatory The ICH E14 Guidance In 1997, the Committee for Proprietary Medicinal Products (CPMP) of the European Medicines Evaluation Agency (EMEA, now the European Medicines Agency [EMA]) was the first to issue a regulatory document that highlighted the association between QT prolongation and the increased risk of TdP, and proposed making druginduced QT prolongation a definitive aspect of cardiac safety testing. 32 This document gave the impetus for deliberation between regulatory agencies, cardiologists, pharmacologists, and statisticians that ultimately resulted in the formulation and release of ICH E14 in 2005. 3 The TQT study for an investigational drug is usually a blinded, randomised study with four treatment arms – two treatment arms of the investigational drug (the proposed therapeutic dose and a supra-therapeutic dose), a negative control treatment arm (placebo), and an active positive control treatment arm (usually moxifloxacin). 27 The TQT study is designed with the objective of identifying the drug’s effect on the QT interval, with a mean placebo-adjusted QTc (QT adjusted for heart rate) prolongation of ≥5 milliseconds (msec) or a one-sided 95% upper confidence interval of ≥10 msec indicating a QT prolongation risk. 3 ICH E14 recognises that there can be considerable variability in QT measurement. This is particularly relevant when the threshold of regulatory concern is small i.e., a mean QT prolonging effect of 5 msec. High reader variability also contributes to large withinsubject and between-subject variability in QT interval, which in turn increases the calculated sample size of a TQT study. Central ECG laboratories, necessarily, have stringent quality control processes and can maintain high standards of ECG data quality. The ICH E14 guidance, therefore, recommends that ECGs should be read in a central laboratory by a small group of trained readers blinded to treatment, time, and participant identifiers to maintain consistency in QT measurement and to prevent reader bias. Methodological rigour is therefore a critical component of drug-induced QT prolongation evaluation, 33-44 a key point that will be emphasised in a different setting in due course. Since the implementation of the ICH S7B and E14 guidelines in 2005, the FDA’s QT-Interdisciplinary Review Team (QT-IRT) has reviewed and provided advice on over 400 TQT study protocols and over 250 new drug application (NDA) submissions, as well as proposals for ECG monitoring and TQT study waivers. 30 An assessment of the FDA regulatory decisions database for TQT studies between 2006 and 2013 revealed that 46 drugs out of the 205 NDA submissions were identified as QT prolonging drugs. 45 Of these 46 drugs, 41 drugs were approved with appropriate labelling restrictions such as QT-related Boxed Warnings, Contraindications and Precautions, as well as descriptions in adverse reactions, drug interactions, over-dosage, and clinical pharmacology 24 Journal for Clinical Studies

sections of the package insert. 45 Thus, the TQT regulatory approach has made drug safety labelling pertaining to potential cardiac proarrhythmic risk more objective and informative. The most important measure of the success of this approach undoubtedly has been the fact that no new drug approved for marketing after 2005 has been withdrawn due to an increased risk of TdP or sudden cardiac death due to arrhythmias. 30 One of the limitations of the present ICH S7B-E14 paradigm, however, is that while all drugs which produce TdP prolong the QT interval, not all drugs which block hERG or prolong the QT cause TdP. The current emphasis on hERG/QT prolongation does not take into consideration a compound’s effects on other cardiac ion channels which may mitigate proarrhythmic risk. The ICH S7B/E14 approach could have unnecessarily eliminated older drugs like verapamil, which is a potent hERG blocker and prolongs the QT, but is not proarrhythmic due to its effects on calcium currents. Thus, while the current conservative regulatory approach will no doubt protect against the introduction of drugs which may cause TdP, it relies on imperfect surrogates and does not truly assess proarrhythmic risk. An adverse consequence of this hERG-TQT regulatory approach has therefore been that the development of a large number of valuable drugs may have been terminated by risk-averse sponsors at an early stage due to perceived proarrhythmic risk. 20,29 De Ponti estimated that as many as 60% of new molecular entities developed as potential therapeutic agents have been abandoned early in development for I Kr blocking liability. 46 This is also supported by the trend of positive TQT studies, which has shown a decline from 60% in 2005 to 10% in 2012, 45 implying that many companies are probably abandoning a drug candidate with a pre-clinical signal of QT liability due to concerns that the drug would encounter significant challenges and regulatory hurdles at later stages of drug development. This raises legitimate questions on the impact of these guidelines on the promotion of public health, which, along with the protection of public health, is an equally important goal of regulatory authorities. 30 Cost is an important factor that has influenced sponsors’ approach to TQT studies. The need for conducting a TQT study for all drugs at the current cost of US$2-3 million, regardless of their pre-clinical effects on the I Kr channel, is seen as a major financial burden, especially for pharmaceutical start-ups. 5,47 The likely therapeutic dose of the study drug is usually decided at the end of Phase II. The supra-therapeutic dose to be studied in a TQT study depends on plasma concentration levels seen in patients with hepatic or renal failure or with metabolic inhibitors. 32 As this information is usually available only by the end of Phase II, TQT studies for most drugs conducted to date have been conducted just prior to Phase III clinical development. The need to conduct the TQT study in late Phase II or early Phase III means that substantial costs are incurred even before the TQT Volume 7 Issue 1

Regulatory study is planned, and having to abandon a drug at this late stage could be financially challenging, justifying the adoption of a ‘fail early, fail cheaply’ strategy by many pharmaceutical companies. The Early QT Assessment Strategy To facilitate early internal decision making on the viability of continued development of drug candidates, many large pharmaceutical companies started collecting robust QTc data in early-phase single ascending dose (SAD) and multiple ascending dose (MAD) studies by incorporating the elements of rigorous ECG collection and analysis utilised in TQT studies. 5,48 These SAD and MAD studies often explore the highest concentrations ever tested in humans. While these studies are not statistically powered to detect a small QT change, robust ECG assessment in these studies can sufficiently improve the power to provide useful predictive information on clinically important QT liability, and hence inform critical go/no-go decisions or the timing of the TQT study. 49 Additionally, characterisation of the concentrationQT relationship has become an important component of regulatory review of TQT studies since 2008. 50 This evaluation can be used in these early studies which, as just noted, often explore the highest concentrations ever tested for a drug candidate in humans, and also collect pharmacokinetic (PK) information that can be correlated with ECG data. 5 The collective experience over the last

several years has shown that PK/QTc modelling making full use of paired PK and QTc data across a wide range of plasma concentrations improves the precision in estimating the QTc effect, and several published examples have shown concordance of Phase I PK/QTc modelling with TQT study results. 5 FDA/CSRC Co-sponsored Think Tank, 2012 As a result of all these deliberations, in February 2012 the Cardiac Safety Research Consortium (CSRC) 51 held a Think Tank meeting at FDA Headquarters to discuss the various options for improving the confidence in QT assessment in early clinical development, and to assess circumstances under which such ‘early QT assessment’ could replace the TQT study. 5 This meeting discussed the FDA’s perspective and industries’ experience in using concentration-effect modelling for assessing a drug’s effect on the QTc interval. The meeting also considered alternative approaches to demonstrate assay sensitivity in early clinical trials, such as autonomic maneouvres and food effects, 52,53 as well as quality criteria based on intrasubject variability and inter-baseline stability. These deliberations were aimed at potentially moving the definitive assessment of QTc prolongation from the end of Phase II into early in Phase 1 clinical development, thus allowing for informed decision-making at an early phase of the clinical drug development timeline. This would decrease resources expended on a separate TQT study by ‘piggybacking’ the QT assessment onto studies

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Regulatory routinely performed as part of clinical development. To explore the validity of the early QT assessment strategy, a collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development (IQ) 54 and the CSRC was formed in 2013. The IQ-CSRC group designed a clinical study in healthy participants to determine whether the TQT study could be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Human (FIH) SAD studies. 6 The ‘IQ-CSRC Prospective Clinical Phase 1 Study’ is a three-period, third-party blinded, randomised, placebo-controlled study in 20 healthy participants conducted in a design similar to a SAD Phase I study, with the primary objective being to estimate the effect of the drugs on the QTc interval using ER analysis. Six marketed drugs with well-characterised QT effects were selected for the evaluation, including five “QT-positive” drugs and one “QT-negative” drug. The QT-positive drugs were ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide: the QT-negative drug was levocetrizine. The QT-positive drugs were chosen after discussions with FDA. Selection criteria included a drug’s toxicity profile (did it allow ethical administration of the drug to healthy participants?), lack of substantial heart rate effect, and the degree of QTc prolongation. The lower dose utilised on Day 1 was recommended by the FDA, and is meant to achieve a mean placebo-corrected, changefrom-baseline QTc (ΔΔQTc) of 9 -12 msec. A higher dose, expected to result in ΔΔQTc of around 15-20 msec, was given on Day 2. The higher dose was chosen to mimic a typical SAD study. In addition to similarity with a SAD design, the higher dose was intended to increase the precision of the slope of the estimated ER model when data from the two dose levels were pooled. ECG recording, processing, and analysis were performed using rigorous methods as currently used in TQT studies. It was agreed ahead of time that if the results of the study were to show a positive QT-prolonging effect (upper bound of QTc change from baseline ≥10ms at mean C max ) by concentration-effect modelling (CEM) for all five “QTpositive drugs,” and additionally excluded a QTc effect for levocetirizine (the negative control drug), it would be deemed to have met its objective successfully. 5,6 Results of the IQ-CSRC Study Twenty healthy participants were randomised to a threeperiod crossover study design, where they received three of the six study drugs or placebo in an incomplete block design that resulted in each study drug being administered to nine subjects and placebo being administered to six subjects in separate periods. Results showed that the upper bound of the 90% confidence interval (CI) of the mean predicted placeboadjusted QTc change from baseline at geometric Cmax with all five QT-positive drugs exceeded 10 msec, and that the slope of the ER model was positive for all of these 26 Journal for Clinical Studies

five drugs. In contrast, the upper bound for levocetrizine (the negative control drug) was less than 10 msec even when a single dose comprising six times the therapeutic dose was administered. Using data from nine participants in each group treated with the study drug and six participants receiving placebo, the means (90% CI) of the predicted ∆∆ QTcF at geometric C max were as follows: 9.5 msec (7.2, 13.5) for ondansetron; 9.8 msec (6.7, 17.3) for quinine; 6.8 msec (3.4, 11.6) for dolasetron; 11.7 msec (10.6, 17.9) for moxifloxacin; 11.3 msec (6.1, 14.6) for dofetilide; and 2.0 msec (-2.6, 6.0) for levocetrizine. While two participants received placebo in a crossover design in this study, FIH studies usually do not involve a crossover placebo period. After excluding these two participants, results for seven participants who had received the study drug or placebo in a parallel design were similar. While the study does serve as proof-of-concept, it has limitations and raises some concerns: 55 1. Clinically relevant plasma concentrations of the drug and its metabolites are usually not known in early-phase clinical development. Doses tested may sometimes be lower than the eventual therapeutic doses. 2. Choice of ECG time points is limited by lack of knowledge of the pharmacokinetics of the parent drug and metabolites. 3. SAD studies may be too short to detect delayed effects. There is a need to demonstrate retrospectively that relevant concentrations and time points were studied. 4. The absence of a positive control to verify assay sensitivity in the proposed early-phase QT studies raises concerns about the risk of false negatives, i.e., the study excludes a QT effect for a drug that has one. 5. ER modelling is not standardised and the results can be operator- and model-dependent. 6. The utility of this approach using challenging compounds remains to be evaluated. This includes drugs with prominent effects on heart rate, drugs that affect QT by mechanisms other than hERG channel blockade, drugs with slow elimination, and drugs with poor tolerability. 7. Drugs with long half-lives of the parent drug or active metabolites may need to be studied in MAD studies. The IQ-CSRC study did not address the design or analysis required in MAD studies. Implications of these Results for the Near- and Longterm Future of Cardiac Safety Assessment There has been some discussion in recent publications on replacing the TQT by incorporating robust ECG monitoring during early Phase I studies. 56,57 The successful outcome of the IQ-CSRC study has already triggered discussions Volume 7 Issue 1

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Regulatory on whether a similar approach could serve regulatory agencies, who may now accept this as an alternate path to replace the TQT study. It is believed that the ICH E14 Discussion Group activities for 2015 will include a review of the data from the IQ-CSRC study, as well as drug development programmes with ECG data from both SAD and MAD studies and thorough ECG studies. 55 The group is also expected to reflect upon the role of a positive control in ECG assessment. If these discussions lead to a change in regulatory position, this could be addressed by an updated “Question & Answers” document or revision to the ICH E14 Guideline itself. Should this occur, however, it would not involve a considerable reduction in the amount of rigorous clinical QT assessment needed; it would simply transfer the intense ECG collection and analysis activity from TQT studies to early-phase studies. Methodological rigour would be equally as critical a component of QT evaluation in early-phase investigation as it has been for TQT studies. Based on the authors’ recent experience, the average number of ECGs in a typical TQT study is approximately 10,000. A typical FIH SAD study has six to eight dose groups with eight participants in each group. The number of time points would be comparable to a TQT study (approximately 12 time points). In most TQT studies, triplicate ECGs are acquired at each of these time points. Based on these assumptions, the number of ECGs projected in a typical SAD study would be estimated to average around 2000-2500. Although these calculations are based on the assumption that triplicate ECGs are recorded at each time point, it should be recalled that 10 replicate ECGs were recorded at each time point in the IQ-CSRC early clinical phase QT study discussed in this paper. Several replicate ECGs are recorded at each time point to decrease the between- and within-subject variability in placebo-adjusted change from baseline in the QTc interval. A previous study has shown that increasing the replicate number of ECGs beyond four results in a progressive decline in benefit. 58 The ideal number of replicate ECGs that would be required in ECGintensive SAD studies requires further research. Typically, SAD/MAD studies outnumber TQT studies by far due to attrition at various stages of drug development related to safety or efficacy concerns. The clinical trials registry of the United States National Library of Medicine has 373 SAD/MAD studies registered in the three year period 2010-2012. In the corresponding period, 46 TQT studies were registered on the website. A review of the clinical pharmacology studies conducted by a large pharmaceutical company during a recent three-year period likewise showed a yearly average of three TQT studies and 24 SAD/MAD studies. Therefore, assuming that there will be eight times as many SAD/MAD studies as TQT studies, that conservatively 50% of these will be ECG-intensive, and the number of ECGs in each such early-phase study will be 25% of those in a TQT study (2500 ECGs vs. 10,000 ECGs), the number of ECGs for which sponsors will need to obtain central reading 28 Journal for Clinical Studies

will essentially remain similar to the number required at current TQT study volumes. One option that some sponsors may choose in some cases is to collect highquality ECG data in SAD/MAD studies, store the digital ECGs, but defer centralised analysis until later phases of development, by when it will be clear whether or not there are other safety issues and whether or not the preliminary efficacy data seem favourable. For the initial years until consensus, experience, and confidence develop, and guidelines are amended and accepted in all major regulatory regions, it is possible that sponsors may be encouraged or choose to do both ECGintensive early-phase studies and TQT studies. Thorough ECG studies may still be needed when the sponsor does not accept evidence of an ECG effect in SAD/MAD studies, regulators do not accept lack of evidence of an ECG effect in SAD/MAD studies, or when either/both parties believe that effects in SAD/MAD studies need further characterisation. A limitation that the early-phase QT evaluation approach shares with the thorough ECG study is that it continues to rely on an imperfect surrogate for predicting proarrhythmic risk. It is hoped that in the longer term this would be addressed by the ongoing efforts to develop the Comprehensive in vitro Proarrhythmia Assay (CIPA), a new preclinical cardiac safety paradigm to directly assess proarrhythmic risk using a combination of non-clinical in vitro and in silico models. 59,60 This will be complementary to clinical ECG assessment, which will continue to be important. This is an exciting time for the cardiac safety world. Though the past response to the issue of QT liability and drug-induced TdP has been over-engineered and resourceintensive, it has worked well, albeit with the unintended consequence of higher attrition of potentially valuable drugs. The proposed modifications of the cardiac proarrhythmia safety paradigm seek to build on this success while addressing some of the limitations of the current strategy of proarrhythmic risk assessment. This is likely to trigger a change from an environment in which a dedicated TQT study is conducted in later phases of clinical development to an intensive ECG evaluation in the early phase of drug development using existing FIH studies. ECG evaluation will thus continue to remain an important tool to assess proarrhythmic cardiac safety.

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2010;Summer issue:64-67. 17. Darpo B. The Thorough QT/QTc Study 4 years after the implementation of the ICH E14 guidance. Br J Pharmacol. 2010;159:49-57. 18. Satin LZ, Durham TA, Turner JR. Assessing a drug’s proarrhythmic liability: an overview of computer simulation modeling, nonclinical assays, and the Thorough QT/QTc Study. Drug Inf J. 2011:45;357-375. 19. Shah RR, Morganroth J. ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies. Br J Clin Pharmacol. 2013;75:959-65.

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Snehal Kothari, MD, DM, FACC, FESC, is a Cardiologist and Senior Medical Director & Head of the Cardiac Safety Center of Excellence at Quintiles. He is widely published in the areas of electrocardiography and cardiac safety, and has supervised centralised ECG services for several hundred studies spanning all phases of drug development including thorough ECG studies. Email:

49. Sethuraman V, Sun Q. Impact of baseline ECG collection on the planning, analysis and interpretation of ‘thorough’ QT trials. Pharm Stat. 2009;8:113-24. 50. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol. 2008; 48: 13-8. 51. CSRC web site. Available at: (Accessed 23 November 2014).

Dilip R. Karnad, MD, FACP, FRCP (Glasg), is Head of the Quintiles Cardiac Safety Services Research Team. Until recently, he was Professor of Medicine at the Seth G S Medical College, Mumbai, India, and Adjunct Professor of Medicine, Baylor College of Medicine, Houston, TX, USA. Email:

52. Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ. Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol. 2012;52:1558-65. 53. Hnatkova K, Kowalski D, Keirns JJ, van Gelderen EM, Malik M. QTc changes after meal intake: sex differences and correlates. J Electrocardiol. 2014 Aug 2. [Epub ahead of print] 54. International Consortium for Innovation & Quality in Pharmaceutical Development. Available at: (Accessed 23 November 2014). 55. Strnadova C. Is there sufficient scientific support for replacing the E14 Guidance with a new paradigm? Talk given at the 1st DIA China Druginduced Cardiovascular Toxicity Workshop, Beijing, China, November

Gopi Krishna Panicker, BHMS, PGDCR, is Medical Writing Manager at Quintiles Cardiac Safety Services Research Team. He has authored/ co-authored 24 peer-reviewed papers on ECG measurement methodology and variability, automated ECG algorithms and benchmarking of central lab processes. Email:

23-24, 2014. 56. Sager PT, Kowey P. The thorough QT study: Is its demise on the horizon? Ann Noninvasive Electrocardiol. 2014;19:1-3. 57. Salvi V, Karnad D, Kothari S, et al. The contribution of early-phase clinical data to a drug’s integrated cardiac safety portfolio. Journal for Clinical Studies. 2011;3:26-31 58. Natekar M, Hingorani P, Gupta P, et al. Effect of number of replicate electrocardiograms recorded at each time point in a thorough QT study on sample size and study cost. J Clin Pharmacol. 2011;51:908-14. 59. Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N. Rechanneling 30 Journal for Clinical Studies

J. Rick Turner, PhD, is a member of Quintiles’ Cardiac Safety and Cardiovascular Centers of Excellence, and a member of the Cardiac Safety Research Consortium’s Executive Committee. He has published more than 100 peer-reviewed papers and a total of 14 authored and edited books. Email: Volume 7 Issue 1

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Journal for Clinical Studies 31

Regulatory Centralised Monitoring: A Smart and Cost-efficient Approach The clinical monitoring cost is one of the major costs, accounting for one-third of the overall cost, of clinical trial management. As complexities in clinical trials have increased significantly in the last few years, the clinical monitoring cost and in turn the trial management cost has increased immensely in order to achieve higher data quality and better monitoring of patient safety. However, traditional ways of conducting frequent monitoring visits every 4-8 weeks to investigational sites and 100% source data verification do not necessarily result in higher data quality, better patient safety, or in an understanding of the critical issues early in the process. Therefore, it is essential to look into alternative, intelligent and smarter ways to achieve improved data quality and patient safety in a cost-effective way. Considering innovative monitoring approaches, centralised monitoring appears to be the most suitable approach available today to proactively identify risks to data quality, and patient safety, in a cost‐efficient manner. The FDA guidance for industry “Oversight of Clinical Investigations – A Risk Based Approach to Monitoring”, finalised in August 2013, states that the focus for clinical trials is now on critical data and advocates the use of a number of monitoring activities, but encourages greater reliance on centralised monitoring practices where appropriate. This view is echoed by the EMA and the Competent Authorities in Europe. Therefore, there is no doubt that there will be a considerable impact on the monitoring of clinical trials in the near future. The FDA guidance document states that centralised monitoring is “a remote evaluation carried out by sponsor personnel or representatives (e.g. clinical monitors, data management personnel, or statisticians) at a location other than the sites at which the clinical investigation is being conducted”. Centralised monitoring processes can provide many of the capabilities of on-site monitoring as well as additional capabilities. With the advent of eCRFs (electronic case record forms) and other eDCT (electronic data capture tools) it is easy to check things centrally or remotely. The right implementation of a centralised monitoring approach is essential in maximising benefits with regard to higher quality of study conduct, reporting and better monitoring of patient safety with a reduced number of on-site monitoring visits. The successful implementation of centralised monitoring requires effective planning, process restructuring, cross-functional expertise alignment, and the right technology in place. Designing realistic efficient monitoring plans with pre-defined risk indicators, thresholds with suggested action plans, training of resource, selection and validation of analytical tools are important aspects of adopting a centralised monitoring approach. 32 Journal for Clinical Studies

For efficient and effective centralised monitoring, there is a need to have a well-thought-out centralised monitoring plan to decide what can be achieved through centralised monitoring and how the findings of centralised monitoring will decide not only planning of site contacts or on-site monitoring visits based on the critical issues identified, but also increase the effectiveness of on-site monitoring. In the centralized monitoring plan, the key risk indicators (KRI), thresholds and performance metrics which need to be tracked during centralised monitoring will be identified upfront and monitored throughout the process. The centralized monitoring plan will also define effective communication and co-ordination between the centralised monitoring team and different stake-holders, especially with on-site monitors to relay key findings of centralised monitoring. This will arrest any critical issues as early as possible which affect data quality, integrity and patient safety. The centralised monitoring plan also states the frequency and extent of centralised monitoring and also provide a well-designed template to report centralised monitoring findings. Table 1: Defining Risks, Metrics and Thresholds Key Risks Areas


Expected Value*


Subjects are properly consented before participating in any study screening activities

Number of incidences of improper or inadequate informed consent process/documentation



Number of subjects randomised that do not meet eligibility criteria



Number of patients randomised with wrong treatment group



Number of deviations that affects efficacy evaluation of the study drug



Number of patient visits which occurred beyond window period



Number of SAEs not reported within 24 hours of investigator awareness of SAE



Protocol deviation related to eligibility criteria Protocol deviation in randomisation procedures

Protocol deviation in a critical procedure related to efficacy end point Protocol deviation due to deviation in patients’ visits

SAE reporting timelines from site to sponsor

*Values are examples and will change as per the study requirements

One of the benefits of centralised monitoring is to have real-time or on-time access to data

once the sites enter the data in the system. In order to maximise the use of the data there Table 1 shows some of the examples of key risk areas, metrics and should be proper infrastructure, systems in place to pool the data from the different threshold values. However, the key risk indicators and their target sources to provide the relevant reports, analytics to identify and arrest issues, risks related threshold values will vary from study toduring study. to dataand quality, patient safety or sites’ performance as documented the risk identification, risk assessment and planning prior to the study. Table 2 provides some

examples of activities that can be through centralised monitoring, One of the benefits ofaccomplished centralised monitoring isand toalso have lists the sources of the data. real-time or on-time access to data once the sites enter the data in the system. In order to maximise the use of the data there should be proper infrastructure and systems in place to pool the data from the different sources to provide the relevant reports, analytics to identify and arrest issues, risks related to data quality, patient safety or sites’ performance as documented during the risk identification, assessment and planning prior to the study. Table 2 provides some examples of activities that can be accomplished through centralised monitoring, and also lists the sources of the data.

Volume 7 Issue 1


The issues related to site performance and patient safety can be identified based on the reports generated from CTMS and EDC data. Table 3 gives an idea of how one can identify site-specific risks during centralised Table 2: Examples of Centralised Reviewrisks Areas,and Specific Risks and monitoring. Depending onMonitoring the issues, threshold Sources of data Table 2: Examples of Centralised Monitoring Review Areas, Specific Risks and values, the sites may be contacted or visited. Type of data Sources of data Type of data Subject data Subject data

Specific Risks

Sources of data

Specific -MeetingRisks eligibility criteria

-Protocol deviation / violations

Sources data lab report, EDC, of safety e-subject diary

-Meeting criteria EDC, safety lab report, (relatedeligibility to protocol procedure, -Protocol deviation / violations assessment, patient visits schedule etc.) e-subject diary (related protocol procedure, -AE or to SAE qualification, concomitant assessment, medicationpatient visits schedule etc.) -AE or SAE concomitant -Safety / qualification, SAE reporting medication -Safety / SAE reporting

Multiple subject data across a -Data quality related to efficacy and safety EDC, safety lab reports and site or all subject across adata study end quality points related to efficacy and safety EDC,reports through Multiple across a -Data safety lab reportsCSM and -Consistencies of data, data outlier, data reports (central statistical site or all across a study end points through CSM trending monitoring) -Consistencies of data, data outlier, data (central statistical -AE / SAE trending trending monitoring) -Data fraud / fabrication -AE / SAE trending Sites performance Sites performance

-Data fraud / fabrication

-Patient recruitment rate


-Patient recruitment CTMS, EDC, IVRS/IWRS, -Patient screeningrate failure rates CSM (central statistical -Patient screening failure rates CSM monitoring) (central statistical -Patient discontinuation/dropped out rate -Patient discontinuation/dropped rate monitoring) -Number of DCFs generated perout site -Number of DCFs generated per site

The issues related to site performance andMonitoring patient safety can be identified based on the Table 2: Examples ofperformance Centralised Areas, Specific The issues related to site and patient safety can Review be identified based on the reports fromCTMS CTMS and EDC data. Table 3 gives an idea of how one can identify reports generated generated from and EDC data. Table 3 gives an idea of how one can identify Risks and Sources of data site-specific risks during during centralised centralisedmonitoring. monitoring. Depending issues, site-specific risks Depending on on the the issues, risksrisks and and threshold values,the thesites sitesmay maybebecontacted contacted visited. threshold values, or or visited.

reduce the number of DCFs. How centralised monitoring is conducted varies across organisations. Each organisation will define and adopt its own approach and define processes to document its systems. The basic premise is that central monitoring reviews reports from databases, or statistical sampling methods, that can be used for validation checks of data and help identify triggers or signals that may highlight areas of non-compliance. Centralised monitoring allows a direct comparison across sites and shows trends in data or outliers that may not be identified by a monitor using a traditional approach. The result of centralised monitoring activities is to identify when to conduct a site visit or another form of intervention. Though implementation of a centralised monitoring process can vary from organisation to organisation, the following figure illustrates one of the process flows that can be considered for a multicentre and multinational study where a dedicated centralised monitoring team

Table interimreport reportshowing showing sites’ performances Table 3: An interim sites’ performances Parameters Parameters

Site ## 1 1 Site # 2# 2 SiteSite # 3# 3SiteSite # 4 # 4Site Site #5 #5 Site Site

Numberof of patients patients Number randomised randomised


Number of of patients Number patientsscreened screened 1 1 failed failed Number of patients Number of patients discontinued


Average number of SAEs

Average of SAEs reportednumber per patient reported per patient Number of DCFs generated Number of DCFs generated







1212 2 2 4






9 9 6 6 0


0.33 19

0.33 19

11 11 1 1

1 1

0.45 58

0.45 58

13 13 2 1 0.61 20


Protocol & Other study documents

Study data

1 0.61 20

Table 3: An interim report showing sites’ performances Parameters

The report generated above shows that screening failure rate at site # 3 is higher than the other sites. This raises the question whether there are any issues in identifying the right patients at this site. Has the site understood the protocol or inclusion / exclusion criteria? A discussion with the site is required to understand if there is a problem with regard to patient screening and if so, the site may require further guidance or training. Regarding site #2, there is a high percentage of patient discontinuation rate compared to other sites, and also the number of reported SAEs is high. One needs to check with site # 2 to ascertain the reasons for early discontinuation. Are the drop-outs related to the higher number of SAEs per patient? Or is there any causal relationship between SAEs and study drug intake? Are the site staff adhering to the protocol procedures correctly and only entering eligible patients to the study? Considering the total number of data clarification forms (DCFs) generated for site # 4, one needs to analyse the nature of the DCFs and consider the impact on the quality of the data produced. It may indicate areas where the site needs further training to address issues and to

On-site visits (critical SDV feedback or any other finding

Risk identification & Assessment

Analytical & visualization tool

Defining Key Risks Indicators & Thresholds

Assessment of KRI & reports Centralized monitoring team (central monitors, medical reviewers, data manager, Biostatistician

On-site monitors Site-level risks

Study level risks

Site level corrective actions (by contact or visit)/study level corrective actions/ communication & documentation

Study Manager/Pro ject /program manager Monitoring visit planning or monitoring plan amendment, if required

Figure1: Centralised Monitoring Process Flow (for a multicentre & multinational study) is located at one place and the local monitors in each country will be performing on-site monitoring visits. Technology is an area of focus for central monitoring roles. In general, integration of clinical and operational data from disparate sources — for example, electronic data capture, CTMS, IVRS / IWRS, etc. are necessary to enable the activities of central monitoring. The key is to select the right combination of technologies that can handle the required data volumes. As far as technology is concerned, there is a need to combine the right technology (collaborative, analytical and visualisation tool) with the process to make the centralised monitoring process more innovative, efficient and reliable. The right analytical tool is important to identify operational risks like patient recruitment rate, patient screening failure rate or drop-out rate, or to identify non-performing sites. The technology should Journal for Clinical Studies 33

Regulatory Table 4: Metrics for Centralised Monitoring

be robust enough to establish data quality issues like number of protocol deviations, violations, AE/SAE rates, data trending or data outliers etc.

Quality Metrics

They identified two main areas: overall use and reporting, visualisation requirements. There were a number of requirements generated for overall use. In general, the user-friendly system should be able to identify trends, patterns, and outliers to gauge performance at the programme, protocol, country, and/or site level, integrating RBM methodologies and data sources for analysis. There should be a tracking mechanism for issue management, including identification, escalation, and resolution at the various levels. From the reporting and visualisation perspective, the system should have the capability to review and analyse the data and provide core graphical and visual representations that may be used across various studies, but be flexible enough to allow trial-specific information to be displayed. Users should have the ability to drill down to review and analyse source data. The dynamic system should lend itself to modifications if new KRIs, triggers or thresholds occur, and be able to send and receive relevant information such as alerts and recommend monitoring interventions or actions in line with key risk indicators. Algorithms should be created to allow customisation for each trial. The system should generate reports in various formats which are user-friendly for ease of use. If trials are outsourced, the technology should work seamlessly with third-party systems and also, where appropriate, allow for access/licenses to third parties. Whichever system is employed, there has to be rigorous system validation to ensure compliance with regulatory requirements, to ensure that the system consistently meets its specification, and is therefore suitable for its intended purpose. Looking at the various aspects of centralised monitoring, one feature is to have the correct personnel in place. The team should comprise central monitors, data management, medical reviewers, biostatisticians and a technology support group in order to accomplish the required results. The central monitors will spend a considerable amount of time monitoring the data remotely and reviewing the reports identifying the risks, issues and planning actions. Central monitors require qualities such as a good knowledge of clinical trial management and data management activities. They should have good communication, coordination, and analytical skills, and critical thinking to identify trends and outliers, and to highlight risks to data quality or patient safety. 34 Journal for Clinical Studies




Metrics • •

TransCelerate have conducted research based on technology requirements for effective implementation of RBM systems. The paper presents the results of a gap analysis to generate a list of capabilities most desirable in a future system. These include capabilities around data aggregation / integration, analytics and visualisations, and issues / action management.

Timelines Metrics

• •

Number of protocol deviations / violations Number of DCFs generated per site Number of major audit findings Number of unreported SAEs / delay in reporting SAEs (safety)

• • •

Average number of days from DCFs generation to resolution Average number of days from data entry to centralised monitoring Average number of days from patient visits to data entry

• • •

Number of monitoring visits per site Frequency of monitoring visits per site On-site monitoring visit cost

Table 4: Metrics for Centralised Monitoring

The monitoring of the metrics related to quality, safety, The qualitative aspects monitoring should also be and addressed.monitoring It is difficult timelines and ofbudget using acaptured centralised to measure this data but one method is to add quantitative data points as yes/no questions approach will help understand the benefits and potential to a monitoring report that derives from qualitative measures. For example: Do the site of centralised monitoring and will give further insight personnel understand the protocol? Are the site staff maintaining the site file? to the industry in developing processes, resources and Centralised monitoring relies heavily on computer systems to reduce human error and technology to ensure better outcomes. Some of the enable remote activities, therefore, the FDA have put a corresponding emphasis on examples of these metrics are listed in Table 4. validation auditing.

As discussed, a vital part of centralised monitoring is the monitoring plan. The FDA

The qualitative aspects of monitoring should also be guidance suggests the monitoring plan might include “planned audits of monitoring to captured and addressed. It is difficult to measure this ensure that sponsor and CRO staff conduct monitoring activities in accordance with the data but one method is to add quantitative data points as monitoring plan”. It goes on to say, “Auditing is a quality assurance tool that can be used to yes/no questions a monitoring report that derives from evaluate the effectiveness to of monitoring to ensure human subject protection and data integrity.” qualitative measures. For example: Do the site personnel understand the protocol? Are the staff maintaining So to demonstrate compliance, do companies simply have site to follow the plan? Or is the FDA the site asking if thefile? monitoring is effective? If so, how do companies demonstrate effectiveness? Centralised monitoring relies heavily on computer systems to reduce human error and enable remote activities, therefore, the FDA has put a corresponding emphasis on validation auditing. As discussed, a vital part of centralised monitoring is the monitoring plan. The FDA guidance suggests the monitoring plan might include “planned audits of monitoring to ensure that sponsor and CRO staff conduct monitoring activities in accordance with the monitoring plan”. It goes on to say, “Auditing is a quality assurance tool that can be used to evaluate the effectiveness of monitoring to ensure human subject protection and data integrity.” So to demonstrate compliance, do companies simply have to follow the plan? Or is the FDA asking if the monitoring is effective? If so, how do companies demonstrate effectiveness? The regulators require a systematic approach to decision-making. The approach has to be scientifically sound, documented, adequate and plausible, and based on accepted methods, e.g., as provided by ICH Q9. Have all of the relevant key risk indicators (KRI) been captured? Although KRIs are effective, their implementation is far from straightforward and they have to be justified. They need to be pre-defined, programmed, tested, and validated, and they can only use part of the massive volumes of data collected in clinical trials. In addition, the choice of triggers for targeted monitoring needs to be considered and justified. Are any interventions timed appropriately, or are the triggers indicating on-site visits too little or too often? Evidence of central monitoring activities should Volume 7 Issue 1

Regulatory be retained, for example reports generated from interrogating the database, documents received from investigator sites, and evidence of review, as well as records of decisions or escalation in activities. Interventions to address deficiencies must be based on the root cause(s), in order to be effective and prevent issues from occurring or recurring. It is imperative to include evaluation design in the interventions so that performance can be measured and assessed. This approach also encourages addressing the environment or systems-level factors. Instead of being primarily reactive and trying again and again to fix similar problems, it is critical to put the RCA (Root Cause Analysis) at the frontend with risk assessment and action planning. Organisations should consider maximising the capabilities of technology, integrating their quality management systems to not only track risks but also tie in audit findings and corrective and preventive action (CAPA). This would lead to the increased ability to demonstrate that risks are appropriately managed and used to design better trials. Many organisations are still developing and standardising their centralised monitoring process together with its evaluation and the integration of current key processes such as data collection, cleaning and monitoring. With the appropriate system, process and trained resources, centralised monitoring is an effective tool to meet the growing challenge of ensuring that the study protocol is being correctly interpreted and executed, resulting in effective patient care and valid study results whilst simultaneously reducing clinical trial costs.

References 1. Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring U.S. Department of Health and Human Services Food and Drug Administration A u g u s t 2 0 1 3 w w w . fd a . g o v / d o w n l o a d s / D r u g s / Guidances/UCM269919.pdf

2. Technology Considerations to Enable the Risk-Based Monitoring Methodology, Therapeutic Innovation & Regulatory Science 2014, Vol. 48(5) 536-545 3. International conference on harmonization of Technical Requirements for registration of Pharmaceuticals for human use: Quality Risk Management Q9 guidelines/quality/article/quality-guidelines.html International

Ashok Ghone, Ph.D. is Vice-President, Global Services at MakroCare USA. He has around 20 years of experience in the pharmaceutical and clinical research industry. He has good knowledge and understanding of global clinical research with hands-on experience in clinical operations, project management, clinical trial management, process development, site management and patient recruitment activities. He has led various cross-functional teams successfully by providing strategic direction and guidance for accomplishment of local, regional and global projects involving early and late phase clinical studies in various therapeutic areas. Ashok has been involved in development of process, system and training related to risk-based monitoring and centralised monitoring at MakroCare, which offers these specialised services to biopharmaceutical and medical device companies to support their endeavours in implementation of the RBM approach. Email:

Sue Fitzpatrick has more than 30 years’ pharmaceutical industry experience. She has been responsible for the management and audit of CRAs and clinical trials in a wide range of therapeutic areas. As former Head of Education and Training at the Institute of Clinical Research, she was responsible for the provision of training courses for the industry and for postgraduate courses in collaboration with several UK universities. Sue continues her collaborations but as a consultant trainer and is an accredited teacher with Cranfield University. Sue is currently a Director of Redtree People and continues her work on enhancing competencies and standards, writing industry gold standards for CRAs in collaboration with COGENT, the sector skills council. She was a member of the GCP committee of the Faculty of Pharmaceutical Medicine and helped develop a certification examination for physicians and other research personnel. She has authored many articles and books on clinical research and career development topics. Sue is currently working on a book in clinical and healthcare research for publication with the Oxford University Press. Email: Journal for Clinical Studies 35

Market Report

Comparison of Marketing Authorisation and its Requirements for Brunei Darussalam and Indonesia Abstract: The availability of generic medication is an important issue in the ASEAN region. The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for companies to develop a single drug which can be simultaneously submitted in all countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirements of that country. This process involves the assessment of critical parameters during product development. Regulatory requirements and generic drug registration for ASEAN regions is made at the end of the section. In the ASEAN region, documentation can be filed in the ACTD format. Keywords: ASEAN, ACTD, Documentation, Regulatory Authority. Introduction The ASEAN (Association of Southeast Asian Nations) group of nations, namely Indonesia, Malaysia, Philippines, Singapore, Thailand, Brunei Darussalam, Vietnam, Laos, Myanmar and Cambodia, has recently been the eyecatcher for most pharmaceutical companies due to the growing population and attractive pharmaceutical market growth. A recent development includes the harmonisation of regulations favouring the market entry to these nations 2. ASEAN was established on 8 August 1967 in Bangkok by the five original member countries, Indonesia, Malaysia, Philippines, Singapore and Thailand. On 8 January 1984, Brunei Darussalam joined ASEAN, followed by Vietnam on 28 July 1995, Laos and Myanmar on 23 July 1997, and Cambodia on 30 April 1999. In 1999 a harmonisation initiative was started among the 10 ASEAN countries. One aim of this harmonisation should be to harmonise quality guidelines that are valid for all countries involved. Another focus lies in the technical co-operation. Therefore the ASEAN Consultative Committee on Standards and Quality Pharmaceutical Product Working Group (ACCSQ PPWG) was established. The objective of the ACCSQ PPWG is the development of “harmonisation schemes of pharmaceuticals’ regulations of the ASEAN member countries to complement and facilitate the objective of ASEAN Free Trade Area (AFTA), particularly, the elimination of technical barriers to trade posed by 36 Journal for Clinical Studies

these regulations, without compromising on drug quality, safety and efficacy.” ASEAN established the so-called ASEAN Common Technical Document (ACTD) and the ASEAN Common Technical Requirements (ACTR) to create harmonised requirements and a common format for all submissions of dossiers in the ASEAN countries. The ACTD is a common format and content acceptable for an application in the ASEAN member countries. The ACTR are a set of written requirements or guidelines intended to provide guidance to applicants in order to be able to prepare application dossiers in a way that is consistent with the expectations of all ASEAN DRAs. The strategy of the ACCSQ PPWG is the “exchange of information on the existing pharmaceutical requirements and regulation implemented by each ASEAN member countries, to study the harmonized procedures and regulatory systems implemented in the ICH region, development of common technical dossiers with a view of arriving at (Mutual Recognition Arrangements) MRAs.” From August 2003 – December 2004 ASEAN countries implemented ASEAN requirements (like ATCD and ACTR). The full implementation of the ASEAN requirements was originally planned for January 1 st, 2005. The transition period for the ASEAN requirements was extended to December 31 st, 2008 as it was not possible for the ASEAN countries to implement the ACTD until January 1 st, 2005. The full implementation of ACTD for new products was planned to be done in the ASEAN countries at different points in time between 2005 and 2008, which are summarised here: • • • •

Singapore and Malaysia by December 2005 Thailand by December 2006 Indonesia and Vietnam by December 2007 Philippines, Cambodia, Laos and Brunei by December 2008

All regulatory agencies in these 10 countries have a relatively weak infrastructure and limited resources. The agencies are structured differently and standards of scientific guidelines are not well-established. A big problem of the agencies is the lack of consistency and transparency, especially regarding the evaluation of dossier. To solve these problems, they are constantly improving with more dialogues with the industry. In all ASEAN countries a Certificate of a Pharmaceutical Product (CPP) from the reference country is required and builds the basis of the drug approval as the Drug Regulatory Authorities (DRAs) do not have the possibilities, capacities and scientific know-how to make a full evaluation of the submitted dossier (especially with regard to preclinical and clinical data). Volume 7 Issue 1

Market Report Dossier Format –ASEAN CTD As mentioned before, the ASEAN countries established the ACTD as their format for submissions. It is a standard derived from the ICH CTD. The ASEAN CTD is a guideline of the agreed-upon common format for the preparation of a well-structured ACTD application that will be submitted to ASEAN regulatory authorities for the registration of pharmaceuticals for human use. The ACTD is similar to the ICH CTD. The ICH CTD is divided into five modules whereas the ACTD contains of four parts. The reason for doing this is the fact that the ASEAN countries normally receive a reference application, which is a dossier which was already approved in other countries in the world (mostly EU and USA) and make the evaluation of the parts mainly based on the overviews and summaries. Based on this, the need for detailed documentation is in most of the ASEAN countries less compared to the ICH countries, e.g. most study reports are not required to be submitted. Module 1 of the CTD, containing the regional registration and administrative information, is still presented as Part 1 of the ACTD. Module 2 of the CTD does not exist itself for the ACTD. The Quality Overall Summary (QOS) and the overview and summaries of the non-clinical and clinical documentation (similar to the documents in ICH Module 2) are included at the beginning of these Parts. Part II of the ACTD contains the pharmaceutical-chemical-biological documentation (the quality information), which corresponds to ICH Module 3. The non-clinical information is presented as Part III of the ACTD (equivalent to ICH Module 4) and the clinical documentation is contained in Part IV of the ACTD (to be consistent with ICH Module 5). The differences between ICH-CTD and ACTD are presented in the comparison pyramid (Figure 1). As demonstrated in figure 1the ACTD is organised in four parts • Part I: TOC, Administrative Data and Product Information • Part II: Quality Document • Part III: Non-Clinical Document • Part IV: Clinical Document Dossier Requirements The requirements for the dossier for the ASEAN countries are in principle very similar to the requirements for the ICH countries. The non-clinical overview and summary, as well as the clinical overview and summary, is put at the beginning of part 3 and 4, followed then by the study reports and literature. For some ASEAN countries these non-clinical and clinical overviews and summaries are sufficient and no additional study reports need to be submitted. In most of the cases, it is sufficient to submit some publications from the mentioned studies in addition to the non-clinical and clinical overviews and summaries.

Figure 1: ACTD & ICH Pyramid

Brunei Darussalam Legal Framework and Regulations 2 • The Food Safety & Quality Control Division under the Department of Health Services (MOH) is responsible for enforcement, monitoring and surveillance of food supply in ensuring its safety and quality. • There is collaboration with other ministries in sharing the responsibility in order to improve food safety monitoring and surveillance and strengthen cooperation among agencies concerned.  Format followed: ACTD format is followed. Application Procedures For Medicinal Product Registration 3 1. The responsibility of applying for product registration rests with the firm responsible for the introduction of the product into the Brunei Darussalam market, i.e.: • In the case of an imported product, the manufacturer’s local representative or its appointed sole agent. • In the case of a locally manufactured product, the manufacturer of the product or the local product owner. 2. Applications for provisional product registration are to be made by submission of the 3. letter of intent and by using the prescribed forms issued by the DPS. Application forms are charged at B$2.00. 4. The submitted application will be screened and validated for completeness within 14 days. 5. Submission of the applications must be made by appointment with the concerned officer at the above address. Journal for Clinical Studies 37

Market Report 6. The processing fee of B$100.00 per product is payable at the point of submission of the application. Payment shall be made in the form of cash and it is non-refundable. 7. Upon acceptance of an application, an acknowledgement for the receipt of the application will be issued and a reference number will be generated. The reference number shown in this acknowledgement should be used in all subsequent correspondence relating to the application.  Documents Required for Application for Registration of Generic Medicinal Products 3 All applications for provisional product registration are to be made by submission of the required documents which are in line with the ASEAN Common Technical Dossier (ACTD) for the registration of pharmaceuticals for human use. The application dossier required will consist of four parts, as follows: Part I: Administrative Date and Product Information Section 1: Application Form (Form No:DPS/DRS/01) Section 2: Letter of Authorization Section 3: Certifications Section 4: Labelling Section 5: Product Information Part II: Quality Section 1: Application Form for Requirements of the Drug Substance (Form DRS/02/A) Section 2: Application Form for Requirements of the Drug Product (Form DRS/02/B)

Appeal against Drug Registration Committee Decisions For products that have been rejected for provisional registration by the Drug Registration Committee, an applicant may make a written appeal to the Chairperson of the Committee by using the prescribed form (Form No: DPS/DRU/Appeal/01) issued by the DPS within thirty (30) calendar days from the date of the committee’s notification. Application form obtained at B$200 per set from DRU Application form filled according to guidelines Appointment made with DRU for submission of application Application form with relevant documents submitted to DRU

Quality No:DPS/ Quality No:DPS/

Part III: Non-clinical (For a submission of New Chemical Entity, Biotechnological Products and some Major Variation Products only) Non-clinical documents (Part III) are not required for generic products, minor variation products and some major variation products. Part IV: Clinical Documents (For a submission of New Chemical Entity, Biotechnological Products and some Major Variation Products only) Clinical summary is not required for generic products, minor variation products and some major variation products. Processing of Application 3 Review follows the appropriate evaluation queue. Priority review may be granted where the product is intended for treatment of a serious or life-threatening disease. During product evaluation, the Drug Registration Unit may request further information and additional supporting documents from the applicant, which should be made available within 60 days from the date of the request. The application will be rejected / closed if no 38 Journal for Clinical Studies

response is received from the applicant after the 60 days given, and a new application will have to be submitted if the applicant wishes to pursue registration of the product.  The applicant will be informed of the decision of the Drug Registration Committee (Provisional) in writing as to whether the application has been approved or rejected.  A registration number will be given when a product is registered.

Documents screened and validated by DRU for completeness according to checklist

Incomplete Applicant informed that application is not complete

Complete Receipt of applications acknowledged by DRU

Payment of processing fees of B$100/product Receipt of payment issued to applicant

Submitted documents checked for additional information and supporting documents


Applicant in formed to submit additional supporting documents

Application rejected if no response is given in 60 days

Complete Documents submitted in 60 days


Committee meeting


Applicant informed

Approved Applicant informed Certificate of product registration issued

*Products rejected for registration, applicants can make a written appeal within 30 calendar dates

Figure 2: Flowchart on the Procedure of Application for Provisional Registration of Medicinal Products 4

Indonesia Legal Framework and Regulations 5, 6 The decree of the head of the National Agency of Drug and Food Control, Republic of Indonesia, number: Volume 7 Issue 1

Market Report HK. on criteria and procedure of drug registration enlists the country-specific requirements for Indonesia. A new regulation issued by the Minister of Health, namely the Regulation of the Ministry of Health in Indonesia No. 1010/MENKES/PER/XI/2008 regarding the Registration of Medicines (“Regulation 1010/2008”) - states that a medicine to be distributed in Indonesia must be first registered before a Distribution License (Izin Edar) can be applied for. Format followed ACTD format with some country-specific requirements. Regulatory system: Regulatory Structure of Indonesia 1. Drug registration shall be submitted by the applicant to the Head of the National Agency. 2. Drug registrations are categorised into: • New registration • Registration of drug variations Category 1 : is a new drug registration with new active pharmaceutical ingredient, new derivative or new combination or biological product with new active ingredient or new combination or in a new dosage form Category 2 : is new drug registration with old composition in a new dosage form or new strength or similar biological product Category 3 : is registration of drug or biological product with old composition with: 3.1. new indications 3.2. new posology Category 4 : is registration of copy drug: 4.1. copy drug with a trade name 4.2. copy drug with a generic name Category 5 : is registration of another preparation containing the drug c. The registration of a copy drug (generic) comes under Category 4. 5 Regulatory Requirements: a. Completion of registration forms should be in Indonesian or in English; b. Registration documents can be in Indonesian or in English; c. Labelling of over-the-counter drug/limited overthe-counter drug must be in Indonesian; d. Labelling of drugs for export only should at least be in English. 5 C. Country-specific Requirements which may also be Included with the ACTD Submission: • Traditional medicine name

• • • • • • • • • • • • • • •

Package size Registration number, name and industry address (at least name of city and country) Composition (species name of raw ingredient) Effects/usefulness Usage Warning and contra-indication (if they exist) Production code number Expired date Level of production/standard operational procedure; utility or machine Source of available raw ingredients Methods and test result of stability/durability Efficacy and adequate safety proven through preclinical and clinical trial Proof in accordance with the development of relevant scientific knowledge Production process in accordance with the GMP Specifications and documents of the method of analysis of all materials used in the finished product Letter of Attorney submitted by the applicant of imported drug 9

B. Drug Registration: The drug registration process consists of two stages: 1. Pre-registration 2. Submission of the registration dossier 1) Pre-registration Steps: The pre-registration process is conducted to determine the application review and evaluation pathway. The NADFC reviews drug applications via one of three pathways (Path I, II or III). a. Path I includes drug applications for products used to treat serious or life- threatening diseases, or for essential generic drugs for public health programmes. b. New drugs already approved in certain designated countries may qualify for the Path II registration process. c. Any drug applications for products that do not qualify for Path I or Path II evaluation processes will be reviewed via the Path III process. Generally, applications are reviewed within the following timeframes: Path I: 100 working days Path II: 150 working days Path III: 300 working days for new drugs; for all other drugs, 80 working days. 5, 7, 8 2) Registration steps (Submission of registration documents and evaluation process): The registration forms and accompanying documents can be in Bahasa Indonesian or English. Drugs produced for export-only are not required to have labels in Bahasa Indonesian; only English labels are required. 8

Journal for Clinical Studies 39

Market Report For registering a product in Indonesia, complete registration form, floppy disk, receipt of payment of evaluation and registration fee and the result of preregistration is attached and sent. ii. For the purpose of evaluation on quality, applicant should submit drug sample for analysis 3 (three) times, and standard raw material should conform to the specification and method of analysis of the active ingredient of the objective drug. iii. Registration dossier of copy drug with an active ingredient that has already been available in the Electronic Information Standard (STINEL =Standar Informasi Elektronik), should consist of a floppy disk that has been completed in line with the data in Form A and Form B21-13, and Forms A, B1, B214, B4, C1, and D. iv. Registration dossier of copy drug with an active ingredient that has no STINEL should consist of a floppy disk that has been completed with the data in line with Form A and Forms A, B1, B2, B3, C1, and D.

Table 1: Administrative Documents Comparison


a. Form A - name and address of the applicant and manufacturing industry and information of the drug b. Form B1 - administrative documents c. Form B2 - product information that covers the aspects of efficacy, safety and quality d. Form B3 - the procedure of batch numbering system e. Form B4 - price information f. Form C - contains documents that must be attached to support the information mentioned in Form B2 g. Form C1 - documents on quality and technology h. Form C2 - preclinical documents i. Form C3 - clinical trial documents j. Form D - list of submitted drug sample and its reference standard 31.






Application Form


Copy of Valid Certificate of Brand

Name Clearance 3







License For Pharmaceutical Manuf.




Permission For Manufacturing &

Marketing In Country of Origin 9



Labeling Documents


Patent Information








Mock Up And Specimen


Environmental Risk Assessment


Product Information Already Approved

In Any State /country *1=provided in 1st dossier then reference is sited.

Table 1: Administrative Documents Comparison Table 2: Technical Documents Comparison INDONESIA


Quality Overall Summary

General Information

Manufacture Of Drug Substance


QC of Drug Substance

Reference Standards

Container Closure System





Table 2: Technical Documents Comparison

Figure 3: The drug registration process in Indonesia Manufacturing site should be inspected by local inspector according to GMP requirements

Drugs divided into 10 Categories


Submission of registration dossier (Submit with registration fees & the result of pre-registration)

Evaluation of Supporting Documents

Submission of Form(s) (Form A/ Form B/ Form C/ Form D


Evaluation of Application

Track I

Track II

Table Documents Comparison Table3:4:Technical Non Clinical Documents Comparison

Track III



Non Clinical Overview

Non Clinical Written & Tabulated

Non Clinical Study Reports

Literature References

Summary Marketing Authorization Post Marketing Surveillance

Figure 3: The drug registration process in Indonesia

40 Journal for Clinical Studies

Table 4: Non Clinical Documents Comparison

Volume 7 Issue 1

Market Report Table 5: Clinical Documents Comparison [Accessed on September 30th 2013.]



Clinical Overview

Clinical Summary

Tabular Listing of All Clinical

Only BE

Only BE

Studies Clinical Study Reports List of Key Literature References

Table 5: Clinical Documents Comparison

Conclusion: It is noticeable that harmonisation of standards and regulations, as well as MRAs, are a major contribution to the integration of the ASEAN market. Even if tariffs are done away with and even with the most efficient transportation, true market integration will be out of ASEAN’s reach if the flow of products is hampered and slowed down by inconsistent regulations and varying standards. ASEAN Standards Bodies and Regulatory Authorities have been working closely with the private sector to address these technical barriers. None of the above achievements can happen without regional cooperation and strong collaboration of stakeholders. Moreover, regional cooperation on standards and conformance compels standards officers, regulators and industry to meet frequently and network effectively. Brunei Darussalam and Indonesia are the only countries in ASEAN who have well-established pharmaceutical regulations and are more strict with regard to quality and safety of drugs. These countries believe in innovation and give full protection to them. Hence there may not be many opportunities for small- and medium-scale generic companies in these countries unless their manufacturing procedures are to do with regulatory requirements. References 1.

The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. [Internet] [Accessed on June 15th 2013.]


An overview of Food Safety. National Food Control System & Risk Analysis in Brunei Darussalam. [Internet] events/apec-scientific-seminar-workshop-on-food-safety-risk-benefitanalysis/Appendix%206.pdf [Accessed on July 5th 2013.]


Guide to application for registration of Medicinal Products. Department of Pharmaceutical Services. 2nd Edition. October 2008. [Internet] Application%20for%20registration%20of%20Medicinal%20Products. pdf [Accessed on July 25th 2013.]


Indonesia. [Internet] [Accessed on February 15th 2013.]


Indonesia. The Head of National Agency of Drug and Food Control. Criteria and procedure on drug registration. The Head of National Agency of Drug and Food Control Republic of Indonesia; 2003. [Accessed on August 18th 2013.]


Makarim, Taira. S. Indonesia – Registration of medicines. [Internet]


New business opportunities for EU companies in the ASEAN area. European Commission Asia-Invest programme. [Internet] www.europa. [Accessed on November 10th 2013.]


Gross Ames, Weintraub Rachel. Indonesia pharmaceutical regulatory update. [Internet] pharmaceutical_regulatoy_update [Accessed on December 27th 2013.]


Joseph G.V.R. Drug registration in ASEAN countries. Department of Ayush, Ministry of Health and family welfare. Government of India. [Internet] on%20drug%20registration%20in%20vietnam&source=web&cd=1&v ed=0CDAQFjAA& oads%2FDrug%2520Registration%2520in%2520ASEAN%2520Count ries.ppt&ei=N5QWT7ueN4TXrQfw8pVW&usg=AFQjCNHyz6GYRMG9saQ QdJya7HUKHhNP5Q [Accessed on January 7th 2014.]

10. ASEAN Project on Intellectual Property Rights (ECAP III). [Internet] r e g i o n a l / d a ta _ p r o t e c t i o n _ 2 0 0 4 / i n d o n e s i a _ d a ta _ p r o t e c t i o n . p d f [Accessed on February 15th 2014.]

G. Ravi is pursuing Masters in Pharmaceutical Quality Assurance from JSS University. He is undergone training in Quality Assurance Department in NATCO Pharma Limited, Hyderabad. He is graduated (B. Pharma) from Rajiv Gandhi University. Email:

Raja Mohan Reddy. G is pursuing Masters in Pharmaceutical Regulatory Affairs from JSS University. He is undergone training in Regulatory Affairs Department in Dr. Reddy’s Laboratories Limited, Hyderabad. He is graduated (B. Pharma) from Acharya Nagarjuna University. Email:

D. Krishnaveni Reddy is pursuing Masters in Pharmaceutical Quality Assurance from JSS University. He is undergone training in Quality Assurance Department in Kopalle Pharmaceutical chemicals Limited, Hyderabad. He is graduated (B. Pharma) from JNTU University,Hyderabad. Email:

N. Vishal Kumar Gupta is Asst. Professor, Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 10 years. He has guided 20 M. Pharm candidates. He has authored 10 International and 20 National publications and has chaired scientific sessions nationally & internationally Email: Journal for Clinical Studies 41


Pyoderma Gangrenosum: A Systemic Review of the Incidence and Prevalence Introduction: Pyoderma gangrenosum (PG) is a rare and serious skin disease in which a painful nodule breaks down to form a progressive enlarging ulcer and leads to a severe and significant increase in morbidity and mortality. The exact prevalence of Pyoderma gangrenosum has not been systematically reviewed and available except for the US and Europe. Reports published in various cited national and international journals claim the prevalence of Pyoderma gangrenosum to be 2-3 cases per 100,000 of population

related to the systemic disease in approximately 50% of patients. The aetiology and pathogenesis for PG are still poorly understood. The treatment of the disease is multifunctional and multidirectional depending on disease location and severity. Pyoderma gangrenosum is classified broadly in two parts (Figure 1) such as Typical (classical PG, characterised Introduction by ulcers usually located on the lower proximities such Pyoderma gangrenosum is a rare and serious skin disease in which a painful nodule breaks down to as and commonly form legs, a progressive enlarging ulcer and leads to aassociated severe and significantwith increase inunderlying morbidity and mortalityorof patients. It is also known as serious rare non-infectious neutrophil dermatitis. IBD rheumatoid arthritis) and Atypical Pyoderma Pyoderma gangrenosum is related to the systemic disease in approximately 50% of patients. The gangrenosum PG isThe characterised aetiology and pathogenesis(non-classical for PG are still poorly understood. treatment of the disease isby multifunctional andon multidirectional on disease location and severity. ulceration upperdepending extremities such as mouth, face, abdomen, vulva, andbroadly is associated systemic Pyoderma gangrenosum is classified in two parts (Figurewith 1) such other as Typical (classical PG, characterised by2 ulcers usually located on the lower proximities such as legs, and commonly diseases). associated with underlying IBD or rheumatoid arthritis) and Atypical Pyoderma gangrenosum (non[1]

Methods: The aim of the present study was to find out the incidence and prevalence of Pyoderma gangrenosum in countries outside the US and Europe. Eliminating the US and Europe, a planned prospective study with a standardised protocol for several different geographical locations was carried out. The search term used was “pyoderma gangrenosum”. Cases from 1979 to 2014 were screened in databases such as PubMed, MEDLINE, and Science Direct, and scrutinisation of all the cases was carried out. Results: Country-wise, data was obtained and analysed. A qualitative review of case reports and case series was carried out, and 2423 cases of PG were reported. Of those, 232 cases were identified as having classical PG, and 172 cases were of non-classical PG. Also, aggravating comorbid factors resulting in PG were found; for example, in the case of Japan, PG was mostly associated with Takayasu’s arteritis, and in Canada, PG is mostly seen in association with Crohn’s disease and arthritis. Similarly, cases from the Middle East region, South Africa and Asia Pacific were also analysed, with Chile and Tunisia reported to have the highest number of classical PG cases. Limitation: - The limitation of the study was that number of hospitalised PG patients in the present year was not found; also 177 cases were not analysed as complete data for those was not available. Conclusion: - A qualitative review of case reports and case series was carried out and 2423 cases of PG were reported. Of those, 232 cases were identified as having classical PG and 172 cases were of non-classical PG. From the study, the prevalence of PG was estimated and also co-morbid diseases associated with PG were known. Introduction Pyoderma gangrenosum is a rare and serious skin disease in which a painful nodule breaks down to form a progressive enlarging ulcer and leads to a severe and significant increase in morbidity and mortality of patients. 1 It is also known as serious rare non-infectious neutrophil dermatitis. Pyoderma gangrenosum is

42 Journal for Clinical Studies

classical PG is characterised by ulceration on upper extremities such as mouth, face, abdomen, vulva, and is associated with other systemic diseases).[2] Figure 1: CLASSIFICATION OF PG

Pyoderma gangrenosum

Atypical PG

Bullous PG

Vulvar PG

Typical PG

Pustular PG

Involving lower extremities

Pyoderma gangrenosum treatment can involve a variety of health professionals as it is commonly associated with systemic conditions. The few associated systemic diseases are depicted in Figure 2.[3]


Miscellaneous – Thyroid diseases, sarcoid, diabetes mellitus, HIV, COPD

Inflammatory bowel disease 15%

Drugs like Alpha 2-b Interferon

Rheumatoid arthritis and systemic lupus erythematosus (37%)


Solid tumours like colon, bladder, prostate, breast, bronchus, ovary, adrenocortical carcinoma

Hematological and liver disorders

Acute and chronic myeloid leukaemia, multiple myeloma, monoclonal gammopathy, Waldenstrom’s macroglobulinemia

Immune abnormalities

Humoral, Immunodeficient/ Immunosuppressed

Chronic active hepatitis, cryoglobulin and hepatitis C, primary biliary cirrhosis

 LymphomaHodgkin's

Figure 2: SYSTEMIC DISORDERS ASSOCIATED WITH PG Figure lymphoma, 2: SYSTEMIC DISORDERS ASSOCIATED WITH PG nonHodgkin’s lymphoma  Polycythaemia Vera Collecting Data: Materials  andLarge Methods granular Lymphocytic A systemic literature search was carried out with the aim of finding the incidence and prevalence of Volume leukaemia Pyoderma gangrenosum worldwide. The regions included in the study were Asia Pacific, Middle East, Myelofibrosis Africa, and Latin America. The cases were classified as classical PG, non-classical PG and other types of PG (including PG with HIV, cancer, pregnancy, and PG in children).

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Therapeutics Collecting Data: Materials and Methods A systemic literature search was carried out with the aim of finding the incidence and prevalence of Pyoderma gangrenosum worldwide. The regions included in the study were Asia Pacific, Middle East, Africa, and Latin America. The cases were classified as classical PG, nonclassical PG and other types of PG (including PG with HIV, cancer, pregnancy, and PG in children). Computerised databases such as PubMed, MEDLINE, and Science Direct were selected for literature review. The search term used was “Pyoderma gangrenosum”, with PubMed showing 2346 articles and other databases showing 77 cases of PG. Thus the total number of cases available was 2423. The language of the search used was English. Data Analysis The data obtained was divided into two classes as: - (a) basic data and (b) advanced data. Basic data includes year of publication, author, country, retrospectively or prospectively gathered data, number of patients in the particular study, age group, other comorbid conditions like HIV, cancer, etc., and advanced Data Analysis data includes information of patients having classical PG obtained was divided into two classes as: - (a) basic data and (b) advanced data. (ulcerationThe data specifically involving leg) and patients having Basic data includes year of publication, author, country, retrospectively or prospectively gathered other typedata,ofnumber PGof patients (including bullous, PG,like etc.). in the particular study, age group, othervulvar co-morbid conditions HIV, cancer, etc., and advanced data includes information of patients having classical PG (ulceration specifically involving leg) and patients having other type of PG (including bullous, vulvar PG, etc.). Records identified from PubMed database

Records identified from other sources


(n=77) Total records available of Pyoderma gangrenosum (n=2423)

Other cases are excluded from the study because they are from other countries which are not specified here (Europe etc.)

Cases screened (n=581)

Unknown (no exact information about case of classic PG)

Cases of classic PG

Other type of PG




Including Bullous PG (n=2) Vulvar PG (n=8) Oral PG (n=5) PG with other disease (n=98) PG in pregnancy (n=1) PG in HIV (n=4) PG in children (32)

Figure 3: Flow diagram: Description of literature search

Analysis of Data Region-wise Latin America Countries like Brazil, Argentina, Chile, and Columbia were used in the study. Among these countries, a high prevalence of PG was found in Brazil and Chile. For Brazil, PG along with UC, IBD, rheumatoid arthritis, myelodysplastic syndrome, adenocarcinoma, etc. were reported. Out of 48 cases, only eight cases were of classic 44 Journal for Clinical Studies

PG and the other cases were PG with a combination of other diseases such as HIV, cancer, PG in pregnancy and childhood. Mexico was reported to have 23 cases, out of which 14 were of classic PG and the others were of non-classic PG. Here, the association of PG was mainly observed with UC, IBD, and RA. Only limited cases were reported which showed the association of PG with diseases such as Takayasu’s arteritis and caval thrombosis. 4 Several case series were reported in Chile. 5 Out of 17 cases, 16 cases were of classic PG and most were associated with UC. Africa In Africa, a high number of cases were reported in Tunisia and West Africa. 6,7 Out of a total of 84 cases reported in Africa, 61 cases were of classic PG and the others were atypical/non-classic PG. Specifically, in Tunisia, 38 cases were reported and all were associated with UC or IBD. Additionally, for West Africa the case reports were available, involving 16 cases of PG associated with HIV (one case) 8, Takayasu’s arteritis (one case) 9 and ulcerative colitis (14 cases). 10 Thus it can be concluded that PG in Africa is mostly associated with UC. Middle East In the Middle East region, the total number of cases reported was 49. Among them, 31 cases were of classic PG and the others were non-classic PG. In the Middle East region, Israel was reported to have the highest cases of classic PG. Also, PG in Israel is mainly associated with UC, CML, LAD, neutropenia, TB, scleroderma, occult colorectal malignancy, Behcet’s disease, osteoporosis, systemic sclerosis, Takayasu’s disease, etc. 11,12 Asia Pacific [102-245] The country-wise data of different countries of Asia Pacific was used to assess the epidemiology of Pyoderma gangrenosum. In Australia, a total of 88 cases of Pyoderma gangrenosum were reported. Out of them, 28 cases were of classic PG. 13 Cases such as PG at multiple sites 14, Pyoderma with secondary pyarthrosis were present 15. Australia was among the major countries in which Pyoderma gangrenosum cases were highly reported. 16,17 In Japan, 78 cases of PG were reported. Of those, 16 cases were of classic PG. Cases of Pyoderma gangrenosum such as PG with ulcerative colitis, tuberculosis 18, limb ischemia 19, Takayasu’s arteritis 20, Behcet’s disease 21, etc., were reported. Figure 4 depicts the epidemiological data of available cases of Pyoderma gangrenosum in the several countries. Limitation: A limitation of this study is that the number of hospitalised patients of Pyoderma gangrenosum in the present year was not found out. Also, 177 cases of PG were not analysed as full data was not available. So, Volume 7 Issue 1

Therapeutics there may be a probability of the presence of a few more cases of classical PG cases from these unknown cases. Results: Country-wise data was scrutinised and different case reports and case series were analysed. Out of 2423 reported cases (from PubMed and other resources like Science a reported. few Ofonline journals search In Japan, 78Direct, cases of PG were those, 16 cases were of classicand PG. Casesthe of Pyoderma , limb ischemia 232 , Takayasu’s gangrenosum such as PG of with ulcerative colitis, tuberculosis engine, Google) Pyoderma gangrenosum, cases [18]


arteritis[20], Behcet’s disease[21], etc., were reported. Row Labels Argentina Australia Bangladesh Bhutan Brazil Cambodia Canada Chile China Colombia Egypt Fiji Islands Hong Kong India Iran Israel Japan Jordan Korea Lebanon Malaysia Mexico Nepal New Zealand Nigeria Pakistan Philippines Saudi Arabia Singapore South Africa Sri Lanka Taiwan Tonga Tunisia Turkey West Africa Grand Total

Classic PG 7 28 1 9 9 16 4 9 1

19 2 21 16

4 14 1 3

3 1 12 1

Other Types of PG 1 1

27 9 2 1 2 1 2 37 3 4 31 3 7 1 5 2 1 5 2 1 1 1 11 1 6

PG type not known 1 59 1 12 2 4 1 24

7 2 1 31 2 1 3 4 8 1 3 1 1 1 6 1

37 14 232

1 1 2 172


Grand Total 9 88 1 1 48 2 22 17 30 10 3 1 2 63 7 26 78 3 9 6 3 23 10 2 9 5 2 5 3 23 7 7 1 38 1 16 581

were identified as having classical PG and 172 cases were identified having non-classical PG. Also the association of aggravating factors was found. Corresponding to Japan, PG is mostly associated with Takayasu’s arteritis; in Canada, PG is associated with Crohn’s disease and arthritis. Cases from the Middle East region, South Africa and Asia Pacific were analysed and among them Chile and Tunisia were reported with the highest cases of classical PG. Thus it can be predicted that development of PG is high in diseases such as ulcerative colitis, Crohn’s disease, rheumatoid arthritis, Takayasu’s arteritis (mainly in Japan), and Behcet’s disease (for some cases). Conclusion: A qualitative review of case reports and case series was carried out and 2423 cases of PG were reported. Of those, 232 cases were identified as having classical PG and 172 cases were of non-classical PG. From the prevalence data information related to types of PG, the total cases of PG and its associated co-morbid disease is known and from this data a systemic approach should be followed for the treatment of this rare disease. Thus further research and analysis in this study may throw a light on the prevalence and incidence of PG in these regions.

Abbreviations: • PG: Pyoderma gangrenosum • IBD: Inflammatory bowel disease • UC: Ulcerative colitis • CML: Chronic myeloid leukaemia • RA: Rheumatoid arthritis References 1. 2. 3. 4.

5. 6. 7. 8.

9. 10. 11.

12. 13.

Wollina U. Pyoderma gangrenosum – a review. Orphanet Journal of Rare Diseases April 2007; 2(19): Wollina U. Pyoderma gangrenosum – a review. Orphanet J Rare Dis. 2007; 2: 19. Published online Apr 15, 2007. doi: 10.1186/1750-1172-2-19 Renu Saigal R, Singh Y, Mittal M, Kansal A and Maharia H. Pyoderma Gangrenosum. Journal of the Association of Physicians of India June, 2010; 58: 378-383. Barrera-Vargas A, Granados J, García-Hidalgo L and Hinojosa-Azaola A. An unusual presentation of Takayasu’s arteritis in two Mexican siblings. Modern Rheumatology Nov 4, 2013. López de Maturana D, Amaro P, Aranibar L and Segovia L. Pyoderma gangrenosum: report of 11 cases. Revista Médica de Chile Sept 2001; 129(9): 1044-1050. Riahi I, et al. Pyoderma gangrenosum. 15 cases. Annals of Internal Medicine Feb 2001; 152(1): 3-9. Mlika RB, et al. Pyoderma gangrenosum: a report of 21 cases. International Journal of Dermatology Feb 2002; 41(2): 65-68. Ecra E, et al. An uncommon localization of pyoderma gangrenosum on the penis of an HIV infected patient in the Ivory Coast. Bulletin de la Société de pathologie exotique May 2009; 102(2): 85-87 Aoussar A, et al. Pyoderma gangrenosum revealing Takayasu’s arteritis. Annales de dermatologie ET de venereologie March 2007; 134(3): 264-267. Diallo M, Kane A, Sy N and Ndiaye B. Pyoderma gangrenosum in Dakar: about 14 cases. Dakar Médical 2005; 50(2): 52-55. 11. Menachem Y and Gotsman I. Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease. The Israel Medical Association journal: IMAJ Feb 2004; 6(2): 88-90. Tamir A, Landau M and Brenner S. Topical treatment with 1% sodium cromoglycate in pyoderma gangrenosum. Dermatology 1996; 192(3): 252-254. Cabalag MS, Wasiak J, Lim SW and Raiola FB (29 July 2013) ‘Inpatient Management of Pyoderma Gangrenosum: Treatments, Outcomes, and Clinical Implications.’, Annals of Plastic Surgery, pp. [Online].


Ye MJ, Ye JM, Wu L, Keating CP and Choi WT. (Mar-2014) ‘A challenging diagnosis: case report of extensive pyoderma gangrenosum at multiple sites.’ Clinical, Cosmetic and Investigational Dermatology, 7(10), pp. 105-109


Darben T, Savige J, Prentice R, Paspaliaris B and Chick J. (Aug-1999) ‘Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil.’ The Australasian journal of Dermatology, 40(3), pp. 144-146


Li J and Kelly R. (Oct 2013) ‘Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent.’ Journal of the American Academy of Dermatology, 69(4), pp. 565-569


Saracen A, Kelly R, Liew D and Chong A. (Aug-2011) ‘Pyoderma gangrenosum requiring inpatient management: a report of 26 cases with follow up.’, The Australasian Journal of Dermatology, 52(3), pp. 218-221


Matsui M, Ohtoshi E, Yamaoka J, Matsuyoshi N, Ohta K, Toda K, Horiguchi Y and Imamura S. (Jan-2000) ‘Cutaneous tuberculosis and pyoderma gangrenosum.’ International Journal of Dermatology. 39(1), pp. 38-40


Takahashi Y, Yamaguchi Y, Itoh K, Sano S, Morita A and Katayama I. (Apr-2009) ‘Intractable wounds caused by pyoderma gangrenosum in a patient with critical limb ischemia treated with cyclosporine and adjuvant sympathectomy.’ American Society for Dermatologic Surgery, 35(4), pp. 699-703 Ujiie H, Sawamura D, Yokota K, Nishie W, Shichinohe R and Shimizu H. (Jul-2004) ‘Pyoderma gangrenosum associated with Takayasu’s arteritis.’ Clinical and Experimental Dermatology, 29(4), pp. 357-359



Nakaura T, Yagi H, Kurachi K, Suzuki S and Konno H. (Feb-2006) ‘Intestinal Behcet’s disease with pyoderma gangrenosum: a case report.’ China National Journal of New Gastroenterology, 12(6), pp. 979-981

Ashvini D Soni is currently pursuing Masters in Clinical Pharmacy, from Institute of Pharmacy, Nirma University, Ahmedabad, India. She has been working as intern with QED Clinical Services India Pvt Ltd.

Drasty S Vora is currently pursuing Masters in Clinical Pharmacy, from Institute of Pharmacy, Nirma University, Ahmedabad, India. She has been working as intern with QED Clinical Services India Pvt Ltd.

Ali S. Bohra is Country Head and Director Clinical Operations – Asia pacific region with QED Clinical Servcies India Pvt. Ltd. He has been actively working in the orphan drug development area. Ali has over 10 years of clinical development experience working within CRO industry. Email: Dr. Jigna S Shah, Professor and HOD of Pharmacology and Clinical Pharmacy at Institute of Pharmacy, Nirma University, Ahmedabad, India. She is distinguished guide for masters as well as Ph.D. and has guided more than 30 post graduate students. She has published 30 research papers in national and international journals. She is life member of IPA and IPS. She has 17 years of teaching, research and administrative experience.

Journal for Clinical Studies 45

Technology Understanding the Importance of Mobile Health for Pharma Mobile health (mHealth) may be the buzzword of today, but unlike many other buzzwords, this one will not be just another flash in the pan. Mobile health offers the life sciences industry far-reaching capabilities to connect with various stakeholders — from patients and caregivers to physicians and pharmacists. This connectivity makes mobile health a valuable tool not likely to be disposed of anytime soon. Projections show the mobile health industry increasing dramatically: for example, Mobile Health Market News projects that clinical mHealth spending will grow to $5.4 billion in 2016 from $2.9 billion in 2011 (USD). 1 in 2011 (USD).1 In first quarter of 2014, the total number of mobile health applications available on iOS and Android platforms topped 100,000 and has continued to grow.2 Five percent, or 5,000, of these apps earned revenues exceeding $1 million over the past two and a half years. This growth is predicted to continue: mHealth Watch projects that the mHealth market will be worth $26 billion by 2017. 2 So what is it about mHealth that is going to fundamentally change healthcare? The Technology is Here — Let’s Use It The internet grants greater access to medical services than ever before. Almost 3 billion people (40% of the world’s population) were online in 2014, compared to 18% in 2006, cites the International Telecommunication Union (ITU). 3 Much of this growth is seen in developed markets, where internet users grew from 974 million in 2009 to 1.9 billion in 2014. This growth stems from increasingly developed infrastructure for broadband systems as well as decreasing broadband prices. A large portion of these internet users seek medical information online. Indeed, a study by the Pew Internet Project and California HealthCare Foundation found that 72% of internet users in the US (87% of adults) use the internet to research medical information. 4 Beyond internet use, mobile-cellular use is also growing: there are almost 7 billion mobile-cellular subscriptions globally (ITU). More than half (3.6 billion) of these subscriptions are in the Asia-Pacific region. In fact, the majority (90%) of American adults have a mobile phone, and of those, more than half (58%) are smartphone owners (Pew Internet). 5 Mobile phone access is also prominent in developing countries. NPR cites that, according to India’s census, 60% of households in India have a mobile phone, whereas only 36.4% have toilets. 6 Smartphones are not required for mHealth initiatives, because text message campaigns, which do not require smartphones, can be highly effective. Yet many cell phone users do have plans including internet access. In mid-2014, there were almost 2.3 billion active 46 Journal for Clinical Studies

mobile broadband subscriptions (ITU). Globally, mobile broadband penetration is 32%, which is almost double the rate from 2011. Europe has the highest penetration rate at 64%, followed by North and South America combined, at a rate of 59%.. Some of these mobile users actively seek out medical information with their devices: 31% of all US-based cellphone users and 52% of smartphone owners research health-related information on their device (Pew Internet). Working within the parameters of different markets and having a firm understanding of the technologies available are paramount to the success of a company’s endeavour into mobile health. The varying degree of worldwide access to mobile technologies has large implications for companies creating mobile initiatives. For example, companies may want to consider the average broadband speed for a territory’s internet users. Developed countries typically have speeds of at least over 2 Mbit/s (ITU). The Republic of Korea leads the way with speeds of 10 Mbit/s or higher, followed by France, Iceland, Denmark and Hong Kong. At the low end of the spectrum, the majority of people in countries such as Ghana, Uganda, Lesotho, Benin and Malawi have access speeds of less than 256 kbit/s. These different factors directly impact a company’s launch strategy for mobile health initiatives. If companies create advanced mobile initiatives designed to target populations in these regions, they should be mindful of these varying speeds and their impact on the programme’s ease of use. An app requiring high speeds will not, for example, be successful in markets that lack the necessary internet access speeds. In such markets, more simplified initiatives may be a more effective route to explore. It is important that companies do not ignore countries without high-speed internet access, however. Even basic initiatives can have far-reaching implications. For example, one text message reminder programme designed to encourage parents to vaccinate their children from the flu virus has been found to be effective (albeit slowly at first), as shown in study results reported in The Journal of the American Medical Association. 7 ...But Don’t Forget it is Merely a Tool and Not the End Goal While prevalence of technology by itself isn’t enough to warrant wide-scale change for healthcare, mobile health is a vital tool companies can use to improve the quality of healthcare worldwide. Examples of initiatives span a wide spectrum, from SMS programmes (short Volume 7 Issue 1

Technology message service, or text messages) to highly interactive diabetes management systems 8 that coordinate glucose meters with mobile apps. Even SMS programmes vary widely from programme to programme, from helping to encourage people to stop smoking 9 or lose weight 10 to encouraging patients to stay adherent to treatment regimens. For example, one programme in Pakistan is designed to curb non-adherence rates for tuberculosis treatments. Tuberculosis is treatable but requires compliance. The initiative, X Out TB, requires users to urinate on small filter papers with hidden codes. These codes are only revealed by patients who have taken their medication (mHealth Alliance, The Lancet). 11, 12 Patients then email their codes to their hospital for economic incentives, which can come in the form of extra mobile minutes. SMS programmes — or any other kind of mHealth initiative — do not need to be complicated to be effective. In some cases, simplicity may lead to higher efficacy rates. A pilot programme in Tanzania called SMS for Life was led by Novartis, the Roll Back Malaria Partnership, IBM, Vodafone and the Ministry for Health of Tanzania. SMS for Life is designed to track stock levels of malaria treatments at hospitals. 13 Without supplies of medication, people cannot be treated for malaria, leading to deaths that could be avoided with improved access. During the pilot programme, 95% of facilities provided stock data. In some districts, stock-outs were avoided within two months (Roll Back Malaria). 14 This programme highlights the dramatic improvements mobile health initiatives can make to patients’ lives. There is no limit to how mHealth can change medicine. Consumers have the technology, and they are looking for ways to improve their health. They are downloading mHealth apps at astonishing rates: Juniper Research projects downloads of mHealth apps to reach 142 million by 2016, up from 44 million by the end of 2012. 15 Now it is just up to companies to jump on board and get creative. So How Should Pharma Get Involved? The proliferation of mobile applications within the life sciences industry has prompted the FDA to examine the extent to which it may need to regulate the growing mHealth sector. Beginning with the passage of the Food and Drug Administration Safety and Innovation Act in 2012, the FDA has begun developing regulatory guidance outlining which types of mobile applications will be subject to regulatory oversight and which will fall outside its purview. Final guidance released in September 2013 emphasized that the FDA would focus its attention primarily on medical mobile devices. This guidance defined what constitutes a “mobile, medical app” and affirms that the FDA plans to set its sights on regulating these applications above other, nonmedical applications.17 In general, the FDA intends to exercise its regulatory oversight on mobile apps that

either work in conjunction with a separate medical device or transform an existing mobile platform — such as an iPhone, Android, tablet, or the like — into a regulated medical device. Basically, if a mobile application has the potential to affect patient safety for better or for worse, the FDA intends to review it. By comparison, the FDA will examine other mobile initiatives — including those that may be considered “medical devices” but do not pose an immediate risk to patient safety — on a case-by-case basis. For example, under its final guidance, the FDA plans to review lifestyle apps, including those that support eating well and exercising regularly — and that otherwise encourage healthy living — at its discretion. Many companies see the activity and excitement surrounding mobile health and want to develop initiatives themselves. Indeed, mHealth is another opportunity for pharma to establish itself as a patient-centric industry and enact positive changes in people’s lives. Yet until recently, unresolved questions still permeated the mobile medical space. Namely, even with guidance in place, companies previously had no real-world applications as to how the FDA might enforce its final ruling. In 2015, however, the FDA removed some regulatory uncertainty by providing the industry with its first case study. On January 23, 2015 the FDA approved the marketing of a series of mobile medical applications developed by glucose monitoring system manufacturer Dexcom.18 This approval marks the first clearance of a mobile medical device since the FDA issued its final guidance back in 2013. Using an iOS platform, Dexcom aims to help diabetic patients track their glucose levels in real time. This application also allows users to share their data with others. Of note, when delivering its marketing decision, the FDA rated the risk posed by the newly approved mobile medical system as “low-to-moderate.” Likewise, this favorable assessment may help alleviate companies’ previous regulatory concerns and encourage dedicated teams to contribute to the ever-growing number of mobile medical applications available. Yet applicable FDA regulations are not the only factor companies should consider during the mHealth development stage. Before jumping head first into unfamiliar territory, companies should first ask themselves why they want to go mobile. After all, designing a mobile initiative merely to be “mobile” is a mistake. Plenty of apps are developed, downloaded and then only used for a brief period — namely because they generate little perceived value for the end user. Creating initiatives that impart a long-lasting return on end users means companies need to have a clear understanding of what they want to get out of a mobile initiative. Incidentally, having clear expectations from project onset also makes quantifying initiative outcomes that much easier. Journal for Clinical Studies 47

Technology The primary steps for designing a mobile initiative are outlined below. They reflect the overall process for designing an initiative.

mobile team structures, usage of mHealth initiatives, best practices and 10 mobile application case studies.

1. Understand why. What are the primary goals of creating a mobile initiative? Is it to raise adherence? Is it to promote access to medical care? Is it to increase disease awareness? Is it to help provide diagnostic tools easily? Have a firm grasp of your objectives before designing an initiative. 2. Understand who. Who will the initiative target? Are patients the end users? Will physicians be using it in their practice? Will the initiative primarily be targeting users in developing countries? The target audience will have large implications in what kind of initiative should be designed. 3. Collect and incorporate user feedback. This saves time — and money — by ensuring the initiative is something people want and would actually use, thereby elevating its effectiveness for the end users. 4. Create a dedicated team. Whether this team is small or cross-functional, certain individuals must be responsible for marshalling the initiative through development. Some companies choose to use vendors specialised in mHealth at this stage in the process. Others use internal departments to direct strategy. 5. Develop the programme. In many cases, companies are now able to address coding needs internally. Touch base with the end users throughout this stage to monitor the programme and adapt it as necessary. 6. Deploy the initiative. This requires a cohesive marketing plan. To create a solid marketing strategy, all internal stakeholders need to be on board and fully understand the initiative’s goals. A well-planned launch can make all the difference in the reception of an initiative. 7. Revisit and improve the initiative over time. Once an initiative is deployed, users may request changes to improve its functionality. This step is crucial; an effective initiative is never fully complete. It needs to adapt to stay relevant.

PH196 - Pharmaceutical Digital Marketing: Transforming Your Multichannel Marketing Mix to Unlock Brand Value As regulatory and logistical barriers to digital undertakings lessen, eMarketing is growing more prevalent in pharma. The digital space unlocks great potential for companies to expand market reach. New online channels, including social media and mobile technology, are finding their way within each company’s marketing media mix.

Of course, no two initiatives are exactly alike: a programme designed to use QR (quick response) codes to direct users to mobile-optimised websites, for example, will have different needs than a programme for healthcare workers to diagnose disease states. Nevertheless, having a clear plan forward is the first step for all mobile health initiatives. Related Reports By Cutting Edge Information PH174 - Pharmaceutical Mobile Health: Transforming Brand Marketing, Healthcare Communication and Patient Adherence Explore in-depth mobile health (mHealth) data including 48 Journal for Clinical Studies

References 1.

“Total U.S. Clinical Mobility Spending Forecast to Reach $5.4 Billion by 2016,” Mobile Health Market News, July 24, 2013.


Frank, John N. “Mobile health app revenue to grow tenfold by 2017, study predicts.” Modern Healthcare, May 22, 2014.


Essany, Michael. “mHealth Market Projected to Reach $26 Billion by 2017,” mHealth Watch, July 26, 2013.


“The World in 2014: ICT Facts and Figures,” International Telecommunication Union, 2014.


“Health Fact Sheet,” Pew Research Internet Project. health-fact-sheet/


“Mobile Technology Fact Sheet,” Pew Research Internet Project. fact-sheets/mobile-technology-fact-sheet/


Hannon, Elliot. “India’s Census: Lots of Cellphones, Too Few Toilets,” NPR, April 8, 2012. http://


Stockwell, M. S., Kharbanda, E. O., Martinez, R. A., Vargas, C. Y., Vawdrey, D. K. and Camargo, S. “Effect of a Text Messaging Intervention on Influenza Vaccination in an Urban, LowIncome Pediatric and Adolescent Population: A Randomized Controlled Trial,” The Journal of the American Medical Association 307, no. 16, April 25, 2012. article.aspx?articleid=1148197.


iBGStar. Sanofi Diabetes, January 2012. (accessed August 2, 2012).


Smokefree TXT. (accessed August 2, 2012).


Patrick, K., Raab, F., Adams, M. A., Dillon, L., Zabinski, M., Rock, C. L., Griswold, W. G. and Norman, G. J.. “A Text Message-Based Intervention for Weight Loss: Randomized Controlled Trial,” Journal of Medical Internet Research 11(1):e1, January 13, 2009.


“The Role of mHealth in the Fight Against Tuberculosis,” mHealth Alliance and Stop TB Partnership. TB%20by%20mHA%20&%20STBP%202012.pdf.


Barclay, Eliza. “Text messages could hasten tuberculosis drug compliance,” The Lancet, 373, issue 9657, January 3, 2009. PIIS0140673608619388/fulltext?_eventId=login&rss=yes.


“SMS for Life: Improving medicine access through innovation,” Roll Back Malaria. http://www. (accessed August 2, 2012).


“SMS for Life: An RBM Initiative,” Roll Back Malaria. smsWhatIsIt.html (accessed August 2, 2012).


“Press Release: Mobile Healthcare and Medical App Downloads to Reach 44 Million Next Year, Rising to 142 Million in 2016,” Juniper Research, November 29, 2011. http://www.


17. U.S. Food and Drug Administration. “Mobile Medical Applications: Guidance for Industry and Food and Drug Administration Staff.” September 25, 2013. MedicalDevices/.../UCM263366.pdf. (accessed January 23, 2015)


“FDA Approves First Mobile App to Monitor Real-Time Glucose Levels.” iHealthBeat, January 26, 2015.

Sarah Ray is a Senior Research Analyst at Cutting Edge Information. While in this role, she has covered a wide array of report topics including digital marketing, medical publications and riskbased monitoring. Outside of researching key trends within the life sciences industry, she is focused on learning Spanish and training for her first 10 mile race. Email: Michelle Vitko, Senior Research Analyst Volume 7 Issue 1

Journal for Clinical Studies 49

Technology Can mHealth be Thought Of as the Default Solution for Accelerating Completion and Increasing Success Outcomes in Clinical Trials? Clinical trials are the experimental foundation on which modern medicine is built. Human medicines cannot be sold without permission from a licensing authority, and permission will not be granted unless a clinical trial has demonstrated the medicine’s success in treating the condition for which it will be marketed 1. Clinical trials, in addition to generating valuable scientific evidence, also provide some patients with an important way of accessing products that have not yet reached the market, offering hope to those for whom existing treatments have failed. The necessity for a clinical trial to be performed before a medicine can gain regulatory approval means that trials are also big business.

Costs are Rising Clinical trials have been regularly criticised for their high cost. In the overall process of developing new drugs, the clinical trial contributes to the highest cost. Approximately 90% of the R&D development cost focuses on effectiveness and preservation, which is Phase III of the process 6. This phase is usually the most extensive and expensive part of drug development. The rising costs of expensive part of drug development. The rising costs of clinical trials show no sign of declining, for many reasons.

expensive part of drug development. The rising costs of clinical trials show no sign of declining, for many reasons.

As important as clinical trials are, they are, unfortunately, a painstaking but necessary process in bringing drugs to market. Clinical trials are costly, take a great deal of time, demand intensive effort, and can have a very high failure rate 2. However, the return on investment can be huge if the medicine works, and Table 1: Breakdown of the clinical phases according to percentage of becomes a blockbuster drug. 3 clearance and years taken to conduct the trial Clinical phases Pre-clinical Phase I Phase II Phase III Phase IV (post-market surveillance)

Percentage of clearance 30% 14% 9% 8%

# Years taken to conduct 1-6 years 6-11 years 11-14 years

Figure 1: The different phases of drug development corresponding to its Figure cumulative cost1: The different phases of drug development

corresponding to its cumulative cost

According to the Pharmaceutical Research and Manufacturers of America (PhRMA), the total cost of Phase I-III research has increased by 250% since 2001 –no to slightly $40 billion7. The table below reasons. clinical trials show sign over of declining, for many shows a breakdown of the estimated cost for each clinical phase Figure 1: The different phases of drug development corresponding its According to thea drug: Pharmaceutical Research toand incurred while developing

cumulative cost

Manufacturers of America (PhRMA), the total cost of Table 2: Breakdown of the estimated cost for each clinical trial phase Phase I-IIItoresearch has increased by Manufacturers 250% since According the Pharmaceutical Research and of 2001 Function Dollars Share of Total has increased 7 America (PhRMA), total cost($M) of Phase research – to slightly overthe$40 billion . TheI-III table below shows a 728.6% Pre human/preclinical $11,717.40 by 250% since 2001 – to slightly over $40 billion . The table below According to 1: Table 1, in a study conducted, aboutaccording 30% clearto Phase I breakdown of the estimated cost for each clinical phase Table Breakdown of the clinical phases shows a breakdown of the estimated cost for each clinical phase Phase I $3752.90 9.2% trials, 14% clear Phase II trials and only 9% pass through Phase3 III incurred while developing a drug: percentage of clearance and years taken to conduct the trial incurred while developing a drug: Phase II $7123.70 17.4% trials. (Phase IV occurs after the drug is approved.) This entire process Table 2: Breakdown of the estimated clinical trial phase $16,300.10cost for each 39.8%

Phase III may take anywhere from six to 10 years, which excludes time spent on Approval preclinical drug research. (Disclaimer: There are other factors that According to Table 1, in a study conducted, about Function Total R&D up to FDA contribute the highI cost of drug development whichIIare not discussed Pre human/preclinical approval 30% cleartoPhase trials, 14% clear Phase trials and Phase IV here. This article highlights the most prominent ones.)

only 9% pass through Phase III trials. (Phase IV occurs after thethedrug is approved.) This entire process (CSDD) may In 1975, Tufts Center for the Study of Drug Development reported that the from pharmaceuticals $100 take anywhere six to 10 industry years, spent whichapproximately excludes time million in today’s dollars for research and development of the average spent on preclinical drug research. (Disclaimer: There are drug approved by the US Food and Drug Administration (FDA). By other contribute the By high cost drug 1987, factors that figurethat had tripled, to $300to million. 2005, this of figure had development which to are not discussed article more than quadrupled, $1.3 billion. The true here. amountThis that companies 4 spend per drug is almost certainly highlights the approval most prominent ones.) even larger today . Now, it

is estimated the global cost of drug development is between $1.2 billion and $1.8 billion per year5.


Dollars ($M) $40,941.00 $11,717.40 $5302.70


Share of Total 100.0% 28.6% 13.0%

Phase I $3752.90 9.2% Phase II Annual Member Survey, 2011;$7123.70 17.4% 7 PhRMA DiMasi et al., J Health Econ 22(2003):151–85 <> Phase III $16,300.10 39.8% Approval $2046.90 5.0% Total R&D up to FDA $40,941.00 100.0% approval Phase IV $5302.70 13.0% Uncategorised $197.80 0.5%

7Table Breakdown of the each clinical trial PhRMA 2: Annual Member Survey, 2011;estimated DiMasi et al., Jcost Healthfor Econ 22(2003):151–85 <>

In 1975, the Tufts Center for the Study of Drug phase Costs are Rising Development (CSDD) reported that the pharmaceuticals industry spent approximately $100 million in today’s Clinical trials have been regularly criticised for their high cost. dollars for research and development of the average Over the years, clinical trail research for pharmaceutical In the overall process of developing new drugs, the clinical trialdrug approved US Food and Drug Administration (FDA). and biological products has increased globally 8. All contributesby to the the highest cost. Approximately 90% of the R&D focuses effectiveness and million. preservation, which is this research and development yielded an extensive Bydevelopment 1987, thatcost figure hadontripled, to $300 By 2005, Phase III of the process6. This phase is usually the most extensive and this figure had more than quadrupled, to $1.3 billion. The amount of new drugs, making it increasingly difficult for true amount that companies spend per drug approval is pharmaceutical companies to prove their products are 3 FDA almost certainly even larger today 4. Now, it is estimated superior to those already on the market. This is because 4 Avik Roy. (2012). How the FDA Stifles New Cures, Part I: The Rising Cost of Clinical Trials. Available: global cost of drug development is between $1.2 clinical trials development is becoming ever more complex, the-rising-cost-of-clinical-trials/. Last accessed 14th Jan 2015 5 5 Economist. billion and(2014). $1.8Thebillion per year . specifically from the regulatory perspective, with greater Price of Failure. Available: Last accessed 1st Jan 2015

S. A. (2012). Cost of Lengthy Clinical Drug Trials. Manhattan Institute for Policy 506 Avik Journal forRoy. Clinical Studies Research. Available

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Technology emphasis on data and site/patient monitoring. The need to accumulate more data to show modest benefits has resulted in drug companies investing more in recruitment for clinical trials, which further increases the cost. In addition, the challenge of finding new products has led some companies to develop treatments for chronic conditions and degenerative diseases. The clinical trials for these types of drugs tend to be long, complex and expensive. More importantly, clinical trials commonly over-run their intended completion dates. In some studies, about 80% of clinical trials fail to meet their milestone. 9 These delays causes companies to lose between $600K and $8M each day a drug is delayed from the market 10. Subjects/patients are the most important assets of a clinical trial. And the number one cause of delayed completion is patient recruitment and retention, as well as the clinical trial process itself, which is the main discussion of this article. Since clinical trials contribute the biggest cost percentage in drug development, it is clear there is a need to reduce the cost of clinical trials in order to reduce the cost of medications for patients. Drug manufacturers are under pressure to cut the cost of drug. As the recent controversial review of the UK Cancer Treatment fund, drugs perceived to be expensive can be dropped without consultation or warning 11. Reducing the costs of trials is absolutely crucial for the public good. Reducing the cost of clinical trials and time to market is the ideal scenario, however, reducing time to market will be discussed in more detail in future articles. Reducing the duration and cost of clinical trials increases the potential to make profit on a drug, whilst also driving down the cost of treatment, and ultimately improving the outcomes for patients. Strategies for reducing cost already include offshore trials and outsourcing. Now, mobile health also has a role to play in clinical trial efficiency, and ultimately reducing the cost.

should always be considered as an option to streamline the processes in order to reduce cost 13. Studies have shown mHealth can reduce cost . So, can mHealth be thought of as the default solution for accelerating completion and increasing success outcomes in clinical trials? As mentioned previously, the number one cause of delayed completion is due to patient recruitment and retention. Since this is one of the significant reasons why clinical trials are delayed, it is important to see the reasoning behind it. There are various initiatives and organisations that have been set up to offer patient and volunteer recruitment to clinical trial sponsors and some CROs claim to have a high rate of patient recruitment. Despite this, it still remains the number one reason for delays. Why is this still happening? A possible reason is that they fail to track recruitment efforts. According to Lopienski (2014) one of the biggest mistakes that can be made in patient recruitment is not tracking the results 14. It is important to ask each subject/volunteer how they heard about the study and document the information and how it is obtained. Sites can use metrics and analytics with mHealth giving hard data to justify why they need an increased advertising budget. Examining what was effective and what did not work helps plan future recruitment, knowing what to continue doing and to avoid making the same mistakes. Using mHealth in Recruitment Integrating mHealth with patient recruitment websites and having tracking software can help track such information to innovate the recruitment process. Patient accrual in clinical trials relies heavily on effective patient recruitment, but enrolment goals are not met for a variety of reasons. No matter the cause, delays in clinical trials affect sponsors, CROs, and sites. Making improvements to recruitment efforts and working more as a team can increase the efficiency of clinical trials to keep studies on track.

Offshoring and Outsourcing The increasing cost of clinical trials is affecting the drug industry in several ways as more organisations are using different and innovative ways to make the process more efficient and cost-effective. One way used to cut costs includes companies conducting clinical trials in other countries, such as China and India, where costs can be as much as 60% lower. Because the apparent clinical trial processes can be complicated, a new industry has arisen to drive the studies through the tangled regulatory underbrush; commercial contract research organisations (CROs). Revenues for CROs will reach $32.73 billion in 2015, with the industry pursuing this route thanks to its ability to drive cost advantages and offer regional expertise by way of its research service providers 12.

Using mHealth in Retention In the issue of retaining the patients, this comes to the subject of patient engagement. A growing body of evidence 15 demonstrates that patients who are more actively involved in their healthcare experience better health outcomes and incur lower costs. It is clear how important patient engagement is. This concept can be, and is already being, extended to the clinical trial space. As a quick brief, “patient engagement” is a concept that combines patient activities with interventions designed to increase activation and promote positive patient behaviour, such as obtaining preventive care or exercising regularly16. Patient engagement is a strategy to achieve the “triple aim” of improved health outcomes, better patient care, and lower costs.

Mobile Health (mHealth) As feasible as all of these ways are, it is important to note that mHealth is also one way that clinical trials can reduce costs. Technology, particularly mobile technology,

But Who Provides the Device? More and more people now own mobile phones, tablets and gadgets and are using apps to regulate their daily lives and routines. With smartphones, roughly 5% of the

52 Journal for Clinical Studies

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Technology Case Study As an example, in a patient engagement study published in Health Brief, patients who received enhanced decision-making support* ultimately had overall medical costs that were 5.3% lower than for those receiving only the usual support*. They also had 12.5% fewer hospital admissions and 20.9% fewer preference-sensitive heart surgeries. Using this similar concept, incorporating mobile technology to engage patients in the clinical trial setting, the same cost savings concept can be applied. *Enhanced support includes a patient who is engaged by health coachers over telephone, mail and Internet (which is higher coaching versus the usual support)

global population owned a smartphone in 2009. That number is expected to hit 35%, or 2.5 billion people, by the end of 2015, which is approximately the population of China and India combined. 17 Considering the everquickening pace of technological innovation and the shrinking cost of processors and microchips, it can be projected that by 2017, half the world will be hooked up to the internet with portable devices. Practically everyone will “always be online” on data connection or 3g/4g Wifi, even in developing countries. It is the connectivity and not just the device itself that provides the opportunity for real-time clinical monitoring and data collection. But Who Provides the Device? other wireless devices and Smartphones, tablets, “going online” have radically changed many aspects More and more people now own mobile phones, tablets and gadgets ofareour everyday lives, their from to shopping to and using apps to regulate dailybanking lives and routines. With entertainment. devices already feature biometric smartphones, roughlyMany 5% of the global population owned a smartphone in sensors 2009. Thatsuch numberasis expected to hit 35%, or 2.5 billion by heart rate monitors, andpeople, medicine the end of 2015, which is approximately the population of China and and healthcare is next. Hence, it makes sense that we India combined17. Considering the ever-quickening pace of integrate innovation these devices with mHealth applications. technological and the shrinking cost of processors andDoing so puts itthe patient in 2017, sync half with daily microchips, can savvy be projected that by thetheir world will be lives hooked the internet with portable their devices. Practically will whenupittocomes to managing health, andeveryone now the opportunities are spreading to embrace this technology 17 Wired Magazine 02.2015 proactively, in particularly with clinical trial subjects. Since most people have a smartphone, it can be proposed that trial subjects can possibly use their own devices, in this case a smartphone in a clinical trial setting. As a result, the “bring your own device” (BYOD) approach may be able to reduce clinical trial cost. BYOD allows participants in a clinical trial to use their devices (with which they are already familiar) to access and respond to study-related questionnaires. Moreover, the connectivity of such devices affords an opportunity for real-time data collection and reporting. So theoretically, clinical trial sponsors would not need to supply a specific device when using mHealth in clinical trials, and this is seen as a way that may lead to cost reduction. Of course, if the patient does not have a device to use, the sponsor could provide it, but the cost of this is expected to be considerably smaller (with the assumption that most clinical trial subjects own a mobile device). As in the workplace, the use of the patient’s own device in clinical trials or any medical setting is controversial. Cost is perhaps the least significant factor, as reasonable reimbursement could be made for the provision and connectivity of a suitable device. More significant

objections stem from the security and protection of the personal data. Hence it is important to take appropriate measures in a similar way to mobile banking, or the payment card industry (PCI). Best practices include endto-end encryption of the data, and working with mobile apps that are developed to a standard of assurance for use in the medical sector. In engaging the patient, we look at streamlining the clinical trial processes. When looking at streamlining the clinical trial processes, a further problem area that mHealth can help with is the initial and ongoing capture of data. In most trials, data capture continues to be done via paper. The clinical trial subjects are the key element in the studies as the data coming from them is most valuable, however self-recording using paper is prone to error and inevitably introduces delays. Data required from the subjects include: dosage of drug taken, timing of dosage taken, questionnaires, side-effects and many others. However, errors in capturing these very important data results in the further increased cost of clinical trials. Patients may forget to take the drug or even perhaps take it at the wrong time, and may forget or delay to fill in the questionnaires after taking the drug; all of these lead to delays, which have a cost value to them. In addition, when taking data on paper, the turn-around time for the data to come back to the clinicians (from the patients) may take a few days, as it is not on real time (patient may need to travel back to the site and so forth). Data collection has been improved with electronic data capture (EDC) packages such as ePro 18, where patients are able to do this on a website via a computer with internet connection. However, it seems that it is still not enough to fully streamline the clinical process because of delays between data capture and data entry, i.e. sometimes because the subject just tends to forget or delay them; ultimately the data is not on real time. Having a mobile application will make the patient more engaged (vs. using paper or website) because real-time automated data capture allows the patient to submit data on the spot – for many of us, devices like our smartphones are among our most valuable possessions that we cart with us everywhere we go. It is a more accessible device compared to the computer. Hence, it is important to integrate a mobile element to these web elements in order to make data capture real time, which can streamline the clinical trial process. Wearable Tech The emergence of wearable technology and popularity of patient-centric applications for them also provides a great opportunity for pharmaceutical manufacturers to engage patients and create a customised, direct relationship with them. The clinical trial space provides an excellent channel to leverage these technologies. The integration of wearable and mobile technology in new clinical trial design and business strategy development holds promise for aligning site and patient needs with faster study execution and reduced costs. In relation to Journal for Clinical Studies 53

Technology this, the application of statistical analysis to biological data, i.e. biometrics, could be a great advantage for some trials. Using a wearable tech, specifically in clinical trials (and not just for fitness) like a handheld electrocardiograph or a blood regulator microchip patch, and consolidating the data collected via an app, would be useful in streamlining the process. These biometrics can be especially useful for clinical trials that are conducted on subjects that have two or more chronic conditions like diabetes and heart attack, or patients with degenerative diseases like Alzheimer’s, as tracking and measuring data from them (people who need a long-term commitment to measuring and tracking their health) would be useful for pre- and post-clinical trial studies. Hype or Hope? The hype of leveraging mHealth in clinical trials has stirred some drastic movements within the industry. The pharmaceutical and drug development industry will either choose to go digital or be forced to. Earlier adopters of digital may already be realising the future potential, impact and benefit that mHealth has to offer in cost reduction and streamlining the clinical research process. The laggards may be more established, enabling them to compete for longer with their old models, but sooner or later all players will be adopting digital. This can be seen in an example from a CRO perspective. CROs specialise in optimisation of the trial process, therefore a proper strategy to use mHealth is vital. This creates a good business strategy for the CROs to develop their own business because more and more clinical research is looking to go digital. Time for a Lean Approach? In the entrepreneurial world, the sooner a failure can be identified, the more productive time can be devoted to successful ventures. Because of the high failure rate in clinical trials, adopting the lean method may be equally beneficial for the process. Using digital and mHealth can facilitate this “lean method” in clinical trials. If you were to fail, fail at the early stages. Reducing product failures at the later stages of the clinical trial process has also been stressed as a way to reduce costs. mHealth can enable the leaner approach to clinical trials as real-time data enables earlier visibility of side-effects and risks. So if the drug is not working, this will become evident sooner, allowing earlier failure, which can reduce cost and help them to pivot (make a structural course correction to test a new fundamental hypothesis about the product, strategy and engine of growth) to a different solution. Because mHealth has been shown to be able to streamline the clinical trial process, pharmaceutical companies realise the benefits of mHealth, hence they are even putting aside special budgets for their pilot projects in mHealth. Pharma giants such as Novartis, Pfizer, Astra Zeneca and GlaxoSmithKline are betting big on leveraging mHealth technologies in the drug development process, so we should expect the increased use of mobile health tools in clinical trials in the near future. 54 Journal for Clinical Studies

This goes to show that pharmaceutical companies already believe in the importance of using mobile technology in the drug development process, specifically for patient engagement, and hence the mHealth industry is projected to grow even more in the very near future. Data is in the Cloud As more data are collected, study timelines grow longer, patient recruitment and retention grows more difficult and drug development costs increase (CSDD) 20. This is because of the collection of data from various centers and is also due to the way data is collected, i.e. in paper form, there are still data being collected by paper. This has a negative impact on the bottom line. The cloud has proven to be a useful tool in consolidating data and collecting data via technology. Further falling costs are also predicted as the cost of cloud computing and storage 21 drops. Also, data loss is much reduced when compared to paper systems. This effort has already been initiated with the NHS patient data is already in the cloud, under a project with Microsoft UK patient records, which are stored in the Azure data centers in Ireland 22. In addition, collection of data from various resources e.g. multi-trial centres causes data fragmentation, and would cause data retrieval to be difficult. Answering key questions regarding a study is time-consuming and has a negative impact on the bottom line. Consolidating data in the cloud could streamline the multiple clinical trial centre using the same study, so all healthcare professionals involved in the study will be able to have access. Technologies for analysis of cloud-stored “big data” are also making great strides, which can only help accelerate the efficiency of data capture, analysis and reporting, whilst cloud providers such as Google and Microsoft are making great strides to overcome concerns about data security and privacy. Conclusion It has been demonstrated that integrating mHealth in clinical trials can reduce cost. However, are these cost savings enough to make any significant impact revenuewise in the long term? Clinical trials are still the basis for deciding how good and safe new drugs are, and that’s true even more so now than in the past. The challenges that mHealth has to overcome in the industry are primarily due to regulations, so working together with the regulatory landscape will be best to push mHealth to fully leverage mHealth. mHealth, mobile and cloud technology and BYOD opens many opportunities for improving clinical trials provided the concerns are overcome. Trends in healthcare and technology are driving the adoption of mobile health, but many obstacles remain. Risk is big issue in clinical trials - risk of things going wrong, risk of adverse reaction, and risk of the drug failing. However, risks associated with clinical trials can be managed more closely with the immediate and real time feedback from embedding mHealth.

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Figure 2: Integrating mHealth into a clinical trail study

To capture mHealth’s full potential, industry stakeholders will need to act in a coordinated fashion to redesign their approach in streamlining the clinical trial process. Working with a trusted developer that has the experience and capability in medical deployment is also key to a successful outcome in mHealth in clinical trials. References 1. MHRA, medicines and medical devices regulation: what you need to know, 2008, p 5; Council Directive 2001/83/EC 2. report that only 5 in 5000 drugs that enter preclinical testing progress to human testing. One of these five drugs that are tested in people is approved. The chance for a new drug to actually make it to market is thus only 1 in 5000. 3. FDA 4. Avik Roy. (2012). How the FDA Stifles New Cures, Part I: The Rising Cost of Clinical Trials. Available: Last accessed 14th Jan 2015 5. Economist. (2014). The Price of Failure. Available: business/21635005-startling-new-cost-estimatenew-medicines-met-scepticism-price-failure. Last accessed 1st Jan 2015 6. Avik S. A. Roy. (2012). Cost of Lengthy Clinical Drug Trials. Manhattan Institute for Policy Research. Available fda_05.htm 7. PhRMA Annual Member Survey, 2011; DiMasi et al., J Health Econ 22(2003):151–85 <http://www.> 8. Clinical Available at: https://clinicaltrials. gov/ct2/resources/trends. 9. State of the Clinical Trials Industry, CenterWatch, 2009 10. Accelerating Clinical Trials: Budgets, Patient Recruitment and Productivity, Cutting Edge Information 11. Gallagher, J 2014, ‘Cancer drug funds to be

says NHS’ BBC News Health, 12 November < http://> 12. Jennifer Zaino. (2011). The State of the Global Clinical Trials. UBM Tech Web Available at: http://www.wipro. com/documents/TW_1108035_StofClinTrials_REV_ v1.pdf 13. See case study in text box 14. Lopienski, K (2014) ‘Why Do Recruitment Efforts Fail to Enroll Enough Patients? Available at: http:// dpuf ‘ 9 May Forter Research Systems Available at: ttp:// 15. See case study in text box 16. Kristin L. Carman, Pam Dardess, Maureen Maurer, Shoshanna Sofaer, Karen Adams, Christine Bechtel, and Jennifer Sweeney, “Patient and Family Engagement: A Framework for Understanding the Elements and Developing Interventions and Policies,” Health Affairs 32, no. 2 (2013): 223–31 17. Wired Magazine 02.2015 18. Epro is a web-based clinical information management system that enables healthcare professionals read and write access to full patient records, treatments and lab reports at the point of care © Copyright Bluewire Technologies 2001 – 2015 [] 19. Ries, E (2011). The Lean Startup. U.S.A: Penguin Books 20. Getz, Kenneth, et al. “Quantifying the Magnitude and Cost of Collecting Extraneous Protocol Data.” American Journal of Therapeutics, 2013. 21. Services such as Microsoft Azure offer cheap and reliable storage for less than $1USD per month per GB of data. This is also compliant with international standards required for data security compliance, e.g. IL2/3 22. Microsoft Azure Trust Center. Available at: http://azure.

Sarah Iqbal is an established business scientist with a background in biopharmaceuticals and business entrepreneurship. She is active in the intersection of IT and healthcare, focused on building mobile and digital applications for Healthcare and Clinical Trials. She strives in the efforts to digitalize healthcare through a trusted and credible team at company FirstApp. Email: Journal for Clinical Studies 55

Technology Mobile ePRO as a Cost-effective Method of Patient Data Capture As digital technology plays an increasingly important part in our everyday lives, it comes as no surprise that it has a huge potential to address some of the key challenges faced by the pharmaceutical industry as well. The collection of electronic clinical outcomes assessments (eCOA, which includes patientreported outcomes (PRO), observer-reported outcomes (ObsRO) and clinician-reported outcomes (ClinRO)) data via PDA and smartphone devices is an area of clinical research that benefits from digital technology in particular. The revolution in personal mobile adoption and advances in wireless data exchange technology now make it possible to design flexible technology solutions that align with the needs of the target patient population, rather than mandating a â&#x20AC;&#x2DC;one size fits allâ&#x20AC;&#x2122; approach across all demographics. Mobile technology allows researchers to communicate with patients remotely between site visits through a medium that patients carry with them wherever they are. It provides an effective system for sending reminders to ensure timely actions such as attending clinic visits, correct drug intake, fasting, etc., while also serving as the means to communicate much more broadly with the patient, facilitating a two-way open communication channel that allows patients to respond to prompts as appropriate. Alongside this ability to engage patients, eCOA facilitates real-time data collection and, through using a mobile ePRO approach, the benefits of electronic data capture can be incorporated in a cost-effective manner.

budgets. Additionally, the approach can reduce support and training costs during studies themselves, as selecting a familiar device can simplify training requirements and limit the number of support queries, while the use of up-to-date devices can lead to fewer failures in the field. Applying ePRO solutions through apps can further enhance efficiencies and cost savings, for example deploying interim study updates remotely without the need to recall patients and their devices back to site. A common misconception regarding the use of ePRO is the perceived difficulty in the deployment of validated instruments. This is because when certain instruments are used to collect primary end point data for label claims, it may be necessary to validate on the selected ePRO modality. To achieve this when using a mobile approach, the author/owner of the instrument must first approve the use of the scale using the chosen modality. Typically a usability study will then be performed to ensure patients can interact with the electronic version and then a validation study will be conducted to assess psychometric equivalence compared to existing modes of delivery. An example of such a study is the m-WOMAC Osteoarthritis Index, which was found to be valid and reliable using a simple mobile phone application and showed no statistically significant difference between mobile and paper scores2.

Benefits of ePRO in Clinical Trials The increasing popularity of mobile ePRO tools has transformed the way patients engage in clinical trials. Providing familiar technology to patient populations facilitates the collection of time-stamped data, and, as mobile technology has propagated across the globe, it serves as an ideal mechanism for communicating and collecting data from hard-to-reach patients in developing markets such as Eastern Europe, Asia Pacific, and Latin America. Ensuring the simplicity of the data collection interface is especially crucial considering that paper diary compliance is proven to be as low as 11%1. ePRO solutions can provide a simple, effective modality to communicate and collect data and information from patients. As users are already familiar with the technology, they can navigate easily through the different steps of the data-collection process. Consequently, these tools facilitate simple, real-time, and reliable collection of data from study participants, irrespective of age or demographic. Mobile ePRO solutions can be customised to suit the specific requirements of each trial. The assessment could consist of a series of text messages sent intermittently to a patientâ&#x20AC;&#x2122;s mobile phone to deliver online questionnaires, which can then be answered instantly via the mobile device. Alternatively, assessments could be delivered via an app, which is particularly useful when connecting with patients in regions with limited connectivity, as data can be stored within the app and transmitted when connection is available. Adopting a mobile ePRO approach can be extremely costeffective for sponsors. The flexibility to select a device that fits the required functionality allows providers to work within study 56 Journal for Clinical Studies

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Technology Medical device readings are also an important part of eCOA data. The move towards ePRO data collection and the addition of Bluetooth® technology on many devices now enables integration of medical device readings into regular ePRO collection by the patient, such as blood glucose meters and spirometers, whether it is as part of a clinical trial or in a realworld setting. Furthermore, alongside the collection of primary outcomes data, ePRO can incorporate secondary outcomes data through the passive integration with lifestyle devices (such as activity trackers, thermometers or weighing scales) which are becoming increasingly popular tools for use in clinical research. BYOD in Clinical Research Whilst many studies require a provisioned model, the BYOD (bring your own device) approach is now recognised as a viable method of engaging and collecting data from trial participants through the ability to recognise device parameters and optimise the configuration of data according to the device in use (e.g., laptop, tablet, mobile phone). BYOD offers the eCOA market true scalability with potential to service studies which would not fit into the fully-provisioned model. The growth of digital and mobile technology has resulted in many patients already owning a device that can be used during the study. Device analysis can easily be integrated into patient enrolment, and provisioning can typically be reduced to as little as 10% or 20% of study participants. In some cases, this approach has the potential to remove the need for provisioning altogether such that the patients’ own devices are employed throughout the entire study, although it is also important to appreciate some level of device provisioning is likely to be required for the foreseeable future. Case Study – Incorporating Patient Data Capture Using Mobile ePRO Trigemina’s TI-001 is a patented application of a formulation including oxytocin with a novel mode of action (MOA) as a therapy for high-frequency migraine. Following several singledose trials in which TI-001 demonstrated promising analgesic effects, a new Phase II trial was initiated in mid-2013 to seek analgesic effects and reduction in frequency of migraine headache days in a chronic and high-frequency episodic migraine population. The decision to use electronic patient-reported outcomes data (ePRO) was an important part of Trigemina’s clinical strategy. Migraines are not timed events. In a multi-month trial such as Trigemina’s, in which patients record their headaches round the clock, ePROs were vital components of the study protocol. Although missing data is known to be a major problem with PROs recorded on paper, Trigemina were far more concerned with data integrity. Knowing that patients are under no direct obligation to enter data on a real-time basis, and that they can wait days or even weeks and then try to recall their experience, ePRO provided the necessary assurance that data was entered by the patient at the time the migraine episode occurred. There were a number of considerations when selecting the best approach to incorporate ePRO into the TI-001 study, a key one of which was cost. The study required provisioning of mobile devices to all patients to preserve psychometric validity and a consistent user experience across the patient population for the collection of primary endpoint data. Despite the 100% provisioning requirement, the mobile ePRO approach offered a more cost-effective solution than other alternatives, whilst 58 Journal for Clinical Studies

providing all the necessary reassurance of experience, data security and quality. The selection of mobile ePRO had a positive impact on the conduct of the TI-001 study, most notably through the immediate access to data it has provided for review and progression. It was not only important to monitor the progression of the study itself, but the ePRO data collected to date has shown positive results and has been a pivotal factor in securing further funding from investors. Additionally, these exciting early results have enabled Trigemina to significantly expand the study. The trial population has been increased almost threefold and sites in Australia and New Zealand have now been introduced, to meet their desire to garner data from multiple ethnic populations. The use of mobile ePRO to collect primary endpoint data has been a pivotal factor in the progress and expansion of the TI001 Phase II clinical trial. The deployment of this cost-effective ePRO service enabled Trigemina to review data in real time. This ability has been especially valuable as they were able to observe the exciting early results of the study and use these positive indications to secure additional funding, which in turn has facilitated the expansion of the study into two new countries. Conclusion Looking at the current landscape of the pharmaceutical industry, mobile ePRO will evidently play a large role in the drug development process through its cost-effectiveness, improved quality of patient data and the simplicity of data capture. Electronic data capture holds huge opportunities for clinical research, with the key potential to reduce the major financial burdens of running clinical trials in the long run. ePRO is increasingly being used as a means of collecting patient data across broad demographics and multiple locations in both clinical studies and healthcare programmes. The universal nature of mobile devices and the ability to select the right tool according to the type and specifications of a study makes the technology well-placed for integration into global markets. References 1. Stone, A.A. et al., “Patient non-compliance with paper diaries”, (2002), BMJ, Vol. 324 p.1193 2. Bellamy, N. et al., “Osteoarthritis Index Delivered By Mobile Phone (m-WOMAC) is valid, reliable, and responsive,” (2011), Journal of Clinical Epidemiology, 64(2) pp.182-190.

Tim Davis is CEO and co-founder of Exco InTouch, the leading provider of mobile and digital patient engagement solutions to support the Clinical, Late Phase and mHealth industry. Having worked in the clinical research technology industry for over 17 years, Tim is passionate about leveraging everyday technology to simplify the process of clinical data capture, both for the pharmaceutical industry and for the patients themselves. As a subject matter expert in the clinical technology arena Tim was recently recognized as one of the PharmaVOICE 100 for his vision in utilizing mobile technology to engage patients throughout the clinical trial and healthcare process. Volume 7 Issue 1

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Screening Kidney Function in People with Carotid Artery Disease May Help in Development of Early Intervention Strategies Pharmapack Europe 2014: A New Impulse Towards Internationalisation Drug Delivery & Packaging

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Enabling Technologies Mobile Helps to Successfully Integrate Patient Engagement into Global Clinical Trials Effecting Change. Affecting Lives The Case of Schizophrenia Patients Harnessing Technology To Improve Patient Outcomes Through Engagement Compliance Against the Odds Keeping Pace with the Complexities of an Ageing Population JPC Volume3 Issue1 OFC & spine 213x297mm.indd 1

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Logistics Get back - Managing your Return Logistics for Clinical Trials Over the last ten years, the way that the pharmaceutical industry is expected to deliver new drug products to market has seen symbolic change. This shift in process has been driven by a number of significant factors. In the next five years the industry is expected to lose around $290bn in revenue from branded prescription medications going off patent (the patent cliff) and overall drug development timelines are coming under continued scrutiny. Internal and external pressures mean traditional approaches to drug development are difficult to sustain and speed to market is paramount to success. R&D costs are continuing to grow aggressively; it is estimated that an investment of at least $1.3billion is now required to successfully initiate a new drug to market1, in some instances ranging up to in excess of $5 billion for some of the industryâ&#x20AC;&#x2122;s leading firms2, whilst bringing a new molecule from laboratory to approval can take up to 12 years. These factors, coupled with approximately only 1 in 5000 drug candidates which enter preclinical testing making it to market3, the industryâ&#x20AC;&#x2122;s focus is on developing quality drug candidates and getting them through clinical development as quickly, efficiently and cost-effectively as possible. Upfront study planning is crucial to ensuring that planned clinical studies are executed in a timely fashion, however, the end of the trial and the final milestones are often not given as much consideration. Investigational clinical studies have continued to evolve and have become more complex. Today a clinical trial will involve a substantial amount of logistical challenges to guarantee successful project execution. Sourcing developmental drug product, the development and interpretation of study protocol, coordinating language translations, labelling and executing packaging, sourcing comparator drug product, and executing monitored logistics in getting IMP drug to investigational sites around the globe are activities best left to the experts, and even then there can be unforeseen and unanticipated challenges. With the noteable use of emerging markets being used

for the execution of clinical studies, countries such as Russia and Eastern Bloc countries, Asia Pacific countries, China, or South America present a large number of unique cultural and regulatory challenges that have to be considered. As such, due to the complex nature of planning and executing such studies, it is often true that the preparation for the end of the study and the return logistics of unused drug product are not always given consideration until it is upon the sponsor company. IMP regulations mandate that all unused study medication must be returned and accounted for at the completion of each study. Reverse logistics back to the sponsor or designated returns vendor may involve hundreds or thousands of packages to be returned and individually accounted for. For some studies, this may involve accountability down to the individual dose level. For example, controlled substances require meticulous reconciliation to the tablet. Detailed records must be maintained and returned drug must be efficiently processed. To significantly ease the returns process, sponsor companies can clearly outline and agree the process for receipt, reconciliation, notification (to sponsor) and destruction of study materials at the outset of their study. By providing clear and concise instructions to investigator sites at the onset of the study and mandating the process by which samples should be returned, sponsors can ensure a smooth returns process, which is vital for a studyâ&#x20AC;&#x2122;s success. Clear expectations should also be provided for the parties providing the returns management service to ensure prompt processing of returned product. Returns may of course begin to be received ahead of the conclusion of a study, as investigator sites often have very limited space for storing study materials; sponsor companies need to be aware of this and ensure it is planned into their study process. Prompt and efficient handling of returned study material is best accomplished by a dedicated returns management team who have the necessary skill and training required for this type of precise and essential service. Ensuring a clear and concise communication plan between

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all parties is critical from the onset of a study, namely how frequently communications should be expected and by what mechanism. Increasingly, this requires data entry and returns accountability confirmation via common cloud-based electronic third-party IVR/IRT systems. Choosing the most appropriate IT system when setting up a study will have a tremendous impact on the returns management process agreed throughout the lifecycle of a study. Having an effective and user-friendly returns module in the IVR/IRT system can expedite information reporting timelines and data processing. Non-user-friendly systems encumber the returns process and can prevent timely resolution of discrepancies. Timely processing and communication is vital to ensure decisive resolution of any potential discrepancies between what was thought to have been sent from the investigator site and what the returns processor has actually received. Investigator sites and returns processors need to understand the implications and ramifications of discrepancies that may arise. Valuable time and resource can be wasted whilst looking to reconcile any discrepancy and potentially inhibit the sponsor’s ability to formally close the study. It is important to ensure any discrepancies found upon return are communicated to the sponsor, documented and closed out so that there aren’t any gaps in the chain of custody. If this piece is clearly defined up front in the process set-up, there are fewer issues down the road. Product un-blinding is also a potential issue in the returns process; as such both the investigator sites and the returns processors need to understand the potential impact that this can have on the integrity of the study. It is also important to understand that the study’s integrity must be maintained for the duration of the project, which can often be as long as three years. This timescale underscores why a returns management strategy that maintains study blinding is essential. Giving forethought as to what the process for when returned drug product is received and processed will also ensure significant benefits for the sponsor company. By determining whether product should be immediately destroyed, or stored and catalogued until the completion of that study/phase allows

a sponsor to establish cost estimates and budget for the returns at the onset of the project. A lack of these conversations upfront can lead to project creep and unexpected costs at the end of a study. Returns management service providers help mitigate these additional costs by working with clients to create dialogue on potential options and industry best practices. A returns management provider must work with customers early in their study development to ensure they avoid the frustrations common to sponsors in the latter returns management process. This helps clients focus their energies on the next phase of their development and ultimately successful commercialisation of their lifesaving therapy. References 1. Herper, Matthew (2012). Forbes, 2nd Oct 2012: “The Truly Staggering Cost of Inventing New Drugs.” 2. Herper, Matthew (2013). Forbes, 11th Aug 2013: “The Cost of Creating a New Drug Now $5 Billion, Pushing Big Pharma to Change.” 3. “Drug Approvals - From Invention to Market ... A 12- Year Trip.”

Gavin Morgan - Manager, Global Storage and Distribution. With over 12 years’ experience working in Clinical Trial distribution, Gavin is responsible for the direction of PCI’s European logistics operation. Based in Treforest, South Wales, Gavin works to develop and implement effective strategies for storing, processing and shipping supplies to third party depots and international investigational sites globally, ensuring policies and processes are met to guarantee that all shipments are in compliance with international regulations and standards and managing the importation and QP release of Clinical Supplies into the EU. Gavin joined PCI in Dec 2009 after working with both DHP Ltd and Bilcare as logistics manager. Email: Journal for Clinical Studies 61


Sheffield to Analyse Potential New Drug in a Fight Against Tinnitus Patients suffering with tinnitus, a common condition that causes continuously buzzing, ringing or humming sounds, will be able to access a pioneering treatment thanks to a new clinical trial in which Sheffield is playing a leading role. Professor Jaydip Ray, Consultant Ear, Nose and Throat (ENT) surgeon at Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children’s Hospital NHS Foundation Trust, is the national Coordinating Investigator of the QUIET-1 study (QUest In Eliminating Tinnitus) study, which aims to analyse the potential of a new drug in reducing the symptoms of tinnitus in people who have had the condition for at least six months. The trial is being run by Autifony Therapeutics Ltd at 12 key hospital sites across the UK, including the NIHR Sheffield CRF at the Royal Hallamshire and Northern General Hospitals. MRC Technology Appoints General Counsel and Company Secretary MRC Technology (MRCT) has appointed Dr Edward Bliss in the new role of General Counsel and Company Secretary. Edward will join MRCT on 16 March from Shire Pharmaceuticals plc, where he is currently Legal Director. Prior to that he was the General Counsel and Company Secretary at Ark Therapeutics Group plc, and he joined Ark from private practice with the international life sciences law firm Covington and Burling LLP. A solicitor, Edward also holds a degree in physiology and a PhD in neuroscience, and brings a wealth of experience to the role. His responsibilities will include licensing, governance, compliance, and in-house legal affairs. Welcoming Edward, Dave Tapolczay, Chief Executive Officer, MRC Technology said: “Ed will be a great asset and we look forward to him joining. Licensing is a key part of our mission to drive scientific research to benefit patients. We have already negotiated over 400 commercial licences and Ed will continue to build on this success.” Dr Edward Bliss said: “It is a tremendous privilege to be joining MRC Technology and I look forward to working with Dave Tapolczay and his team in their important goal of progressing the further development of innovative medical research.” Senate GOP Eyes Major Reforms for Health Agencies Senate Republicans are pledging to reform two of the government’s largest health agencies as part of their effort to fix a medical industry that they say “takes too long and costs too much” to find new cures. In a wide-ranging report released Thursday, the GOP leaders of the Senate Health Committee announced plans to modernise both the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), two agencies they said “every American is personally affected by”.

NIH is responsible for helping to create them. But Sens. Lamar Alexander (R-Tenn.) and Richard Burr (R-N.C.) warn that “regulatory realities” of these agencies, particularly the FDA, often hinder private companies that are trying to create or sell their products. Trial Finds GSK Ebola Shot is Safe and Provokes Immune Response First results from a human trial of an Ebola vaccine from GlaxoSmithKline show it is safe and generates an immune response, scientists said on Wednesday, but larger trials are needed to see if it protects and if a booster is needed. The vaccine is being developed by the US National Institutes of Health (NIH) and GSK against the Zaire strain of Ebola – the one circulating in West Africa – and the first doses for a larger trial arrived in Liberia last week. That trial is the first of several mid-stage studies planned for West Africa and aims to test GSK’s vaccine and one from Merck and NewLink. Johnson & Johnson and Bavarian Nordic have a vaccine in early-stage clinical tests. The early-stage Phase I trial of GSK’s vaccine was primarily designed to test safety, but Adrian Hill, who led the work at Oxford’s Jenner Institute, said it was “encouraging” that the shot also prompted responses from the immune system “The safety profile is pretty much as we’d hoped and the immune responses are okay, but not great,” he told Reuters. The data, published in the New England Journal of Medicine, were from 60 healthy volunteers given the vaccine in Britain between Sept. 17 and Nov. 18 last year. The volunteers got one of three doses – low, medium, or high – and data from 28 days after vaccination showed the shot was safe at these doses, with only mild side-effects. “People typically experienced mild symptoms that lasted for one or maybe two days, such as pain or reddening at the injection site, and occasionally people felt feverish,” Hill said. However, the antibody response was weaker than was found in a trial of the same Ebola vaccine in macaque moneys, in which the animals were also found to be protected. Hill said the lower antibody levels, together with a lower response detected in the immune system’s T-cells, suggested to him that a booster may well be needed. Jeremy Farrar, director of the Wellcome Trust charity, which helped fund the trial, said it provided “good initial evidence that the GSK vaccine will be safe to use in people”. “However, we still don’t know whether it will provide protection against Ebola infection in a real-world situation,” he said. “That’s why trials in West Africa of this, and the other vaccines in development, must begin as soon possible.”

The two agencies have major roles in healthcare: The FDA is responsible for regulating all drugs and treatments, while the 62 Journal for Clinical Studies

Volume 6 Issue 1

News JCS News

Sanofi and MannKind Announce Afrezza®, the Only Inhaled Insulin, Now Available in the US Sanofi and MannKind Corporation announced today that Afrezza® (insulin human) Inhalation Powder, the only inhaled insulin, is now available by prescription in US retail pharmacies nationwide. Afrezza is approved by the US Food and Drug Administration to control high blood sugar in adults with type 1 and type 2 diabetes. “Many people living with diabetes are not able to control their blood sugar on their current medications and may benefit from using insulin. Now they have another option to administer insulin that is not an injection,” said Dr Janet McGill, MD, Professor of Medicine at Washington University School of Medicine in St Louis, and Afrezza clinical trial investigator. “This delivery option may help change the dialogue between healthcare professionals and people living with diabetes about initiating or intensifying insulin therapy.” Afrezza is a drug-device combination product that consists of a dry formulation of human insulin delivered from a small and portable inhaler to help patients achieve blood sugar control. Afrezza is rapidly absorbed and has a short duration of action. It is administered at the beginning of a meal. Afrezza can help control high blood sugar as part of a diabetes management plan that may include diet, exercise and other diabetes medications. Afrezza should not be used in patients with chronic lung disease such as asthma or COPD. Afrezza cannot be used to treat diabetic ketoacidosis. Afrezza is not recommended in patients who smoke or who have recently stopped smoking. “Afrezza is an important addition to Sanofi’s growing diabetes portfolio of integrated, personalised offerings, and it is one that highlights our dedication to bringing innovative therapies to people with this disease,” said Pierre Chancel, Senior Vice President Diabetes Division, Sanofi. “There is a recognised need for an insulin that doesn’t require an injection, and our organisation is committed to making this new treatment option available to patients.” “We are extremely proud to see the many years of work that went into developing Afrezza culminate in the day when it is now available to help people manage their diabetes,” stated Alfred Mann, Executive Chairman, MannKind Corporation. CRF Health Announces Receipt of Regulatory Approvals and Completion of Investment by Vitruvian Partners CRF Health, the leading global provider of eCOA solutions for the life sciences industry, today announced the completion of the investment by funds managed and advised by Vitruvian Partners (“Vitruvian”), positioning Vitruvian as the majority shareholder of CRF Health. The transaction has now received all regulatory approvals.

management team look forward to working with Vitruvian to continue the development of CRF Health. Together we have ambitious plans for the growth of the company both from a resource and technology perspective to ensure high levels of customer satisfaction.” Philip Russmeyer, a Partner at Vitruvian, added: “CRF Health has experienced phenomenal growth and we believe that through this investment we can bring new resources, strategic insight and scale that will take an already outstanding business to a new level. We look forward to working with CRF Health’s executive team to further build on their vision and dedication to deliver patient-focused technology solutions with the highest quality outcomes for the pharmaceutical industry.” Aesica Secures Continuing FDA Approval of its Bulk Manufacture and Packaging Sites in Germany FDA inspection results mean Aesica will continue to grow its manufacturing and packaging services for pharmaceutical products for the US market. Monheim, Germany, 2nd February 2015 – Aesica, the global pharmaceutical contract development and manufacturing organisation (CDMO), a division of Consort Medical plc, today announces it has received continuing FDA approvals for both its bulk manufacturing and packaging operations in Germany. As a consequence, Aesica can continue to grow its manufacturing and packaging services for pharmaceutical products destined for distribution and export to the strategically important US market. The approvals follow the successful FDA pre-approval inspections of the Zwickau site, which bulk manufactures pharmaceutical tablets, capsules and controlled release products; and the Monheim site, which houses logistics and distribution centres. In addition, both sites have also secured successful inspections from ANVISA for the Brazil market as well as from the German Health Agency. Dr Werner Schick, Aesica’s General Manager, Germany, commented: “We are extremely pleased that the FDA continue to approve our German sites for bulk manufacture and packaging. This is a testament to the quality of the technology, services and people at both of our German facilities. “These approvals will allow Aesica to substantially grow its contract manufacturing and packaging services for supply of pharmaceutical products to the US market.” Zwickau manufactures in excess of 90 products produced from over 40 different APIs and has on-site process development and QC laboratories. At Monheim, Aesica currently completes packaging for 1100 SKUs, produced with multiple indications for all geographic markets.

Rachael Wyllie, who will continue to lead CRF Health as Chief Executive Officer, said: “We are very pleased to announce the completion of this investment by Vitruvian Partners. The

Journal for Clinical Studies 63

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