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Volume 9 Issue 3

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

Regulations and Recruitment Experiences in the Middle East

Behind the Smoke and Mirrors of IDMP Solutions

The Role of Biomarkers in Parkinson’s Disease

The Epidemic “Fléau” of Diabetes Mellitus The Need for a New Era of Therapies and Prevention


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Contents

JOURNAL FOR

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Your Resource for Multisite Studies & Emerging Markets

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U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITOR Orsolya Balogh EDITORIAL ASSISTANT Maria Dominici maria@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH&CIRCULATION MANAGER Evelyn Rogers info@pharmapubs.com ADMINISTRATOR Barbara Lasco

FOREWORD

WATCH PAGES FDA Marks Milestone in Patient-focused Drug Development

In this Watch Pages item, Molly Fellin Spence, a medical and regulatory writer for the Cortellis database and AdComm Bulletin at Clarivate Analytics, discusses how the US Food and Drug Administration (FDA) has surpassed its commitment to obtain patients’ views in at least 20 disease areas over the course of five years, during its Patient-focused Drug Development (PFDD) initiative, scheduled to end in September 2017. In creating the PFDD initiative, the FDA believed that the human drug and biologic review process could benefit from a more systematic and expansive approach to obtaining input from patients who experience a particular disease or condition. 8

Recent Trends and Innovations in Outcomes and Design of Clinical Trials in Respiratory Drug Development: Part 1: Outcomes

In this paper, Robert Lins, MD, PhD, Respiratory Project Director at SGS, illustrates how respiratory drug development has, for years, been relying on the administration of new, mostly inhaled drugs, and on assessment by physiologic tests and questionnaires. The physiologic outcomes were mostly lung function tests; gradually more clinical and patient-reported outcomes have been applied. New insights in phenotypes, endotypes, basic mechanisms, and new targets for therapy have led to the need for more personalised, patient-centred approaches.

FRONT COVER istockphoto

10 Oncology – A Bouquet of Rare and Ultra-rare Diseases

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

Oncology clinical trials are widely recognised as being amongst the most complex trials to design, set up, and deliver. Whilst there is good progress in finding optimal and durable treatment solutions, the implementation of the enhanced understanding of molecular pathology adds an additional layer to clinical trial operational complexity, affirms Jozsef Palatka, MD, Vice President of Clinical Development of Oncology, INC Research. The demand to find treatment responses for various cancer indications is high, the research is intensive, and the number of sophisticated clinical trials is great.

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

REGULATORY 12 Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright. Volume 9 Issue 3 May 2017 PHARMA PUBLICATIONS

Facioscapulohumeral muscular dystrophy (MD), commonly known as FSHD or FSH, is a complex, inheritable muscle disease with an etiology that is rapidly becoming more elucidated; it appears to have varying molecular and genetic determinants with commensurate differences in disease progression. With this paper, Raymond A. Huml, MS, DVM, RAC, Vice President of QuintilesIMS Global Biosimilars Strategic Planning, and his team provide an overview of FSHD, discuss major clinical symptoms and ramifications of disease progression, provide a regulatory overview, and discuss two of the more commonly used surgical procedures to treat FSHD. 20 The Evolving Role of Medical Affairs: Opportunities for Discovery, Preclinical and Clinical Research Medical affairs and marketing worked hand in hand but at the

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Contents same time this relationship was sometimes also conflictual. It was common for the marketing department to see medical affairs as the “sales prevention department”. In this article, Manolo Beelke, Senior Medical Director, Medical & Scientific Affairs at Worldwide Clinical Trials, defines how this vision is changing now towards a solutions-focused partnership with marketing. These changes offer the opportunity for a new type of partnership between medical affairs and commercial activities. This collaboration can create scientifically-minded and medically-driven marketing. MARKET REPORT 26 A Touch of Pragmatism in Clinical Trials Since Schwartz and Lellouch coined the terms “pragmatic” in 1967 to describe trials designed to help choose between options for care, and “explanatory” to describe trials designed to test causal research hypotheses, the distinction between these two types of research has become even more prominent. However, there is an increasing recognition of the potential benefits of pragmatic trials in testing complex interventions. This brief review by Dr Evan Papanastasiou, MD MSc, a pharmaceutical physician and qualified psychiatrist with more than 15 years of clinical experience, aims to provide the reader with the highlights of the published literature in this rapidly evolving field of clinical research. 30 Regulations and Recruitment: Experiences in the Middle East The potential for the pharmaceuticals industry in the Middle East is vast, and growing. Clinical research is also growing, alongside pharma, in the region, despite variations in situation from country to country, and despite certain barriers that still need to be solved. The challenges of regulations and patient recruitment, in particular, are analysed. Bariş Erdoğan, PhD, Ömer Şeker, MD, and Le Vin Chin, of Clinerion Ltd, take a specific look at one of the most established countries in the region for clinical trials, Turkey, to see how it might act as a model for the rest of the region.

impact on the economies of developed nations such as the USA, UK and Australia. TECHNOLOGY 46 The Assumptions of Data Capture Within the field of clinical research, there has been, for many years, a move away from the use of paper as a form of data capture, in favour of electronic data capture, particularly within industry. The advent of the use of electronic case record forms (eCRFs) is nothing new from that perspective: what remains a challenge is the use of electronic data capture (EDC) at site. With this article, James Batchelor, Director of the Clinical Informatics Research Unit at the University of Southampton, UK, hopes, with some broad generalisation, to raise awareness of the issues from the sites’ perspective. 48 Behind the Smoke and Mirrors of IDMP Solutions Life sciences technology vendors and consultancies are busy promoting identification of medicinal products (IDMP) compliance solutions, which seems odd, given that many details of the final requirements have yet to be published. With a further two years to go until the latest deadline comes around, organisations have every reason to be sceptical of the value of investing now, says Marc Chaillou, International Markets Manager at Schlafender Hase. 50 Transforming Clinical Research through Cloud Computing Technology

THERAPEUTICS

The process of carrying out clinical research and conducting clinical trials is very expensive, complicated and time-consuming. Clinical research organisations (CROs) conducting trials in collaboration with pharmaceuticals must maintain confidentiality at all costs. Prasad Puranik and Shraddha Shetty of Comprinno Technlogies, together with Mischa Dohler of Worldsensing, give a detailed insight into cloud-based software solutions, which are the right way to move forward in the clinical research field. Adoption of good cloud-based information security management policies can further bolster information safety.

36 The Role of Biomarkers in Parkinson’s Disease

56 The AI Advantage

In Parkinson’s disease, PD, the examination of post-mortem brain tissue has led to the identification of relevant molecular pathways and genes that have allowed for targeted therapies, development of animal models, and new drug delivery systems. These targeted strategies have identified many biomarker candidates that are being actively evaluated for their potential as different types of PD biomarkers. The following article, written by Tomislav Babic, MD, PhD, Vice President of Medical and Scientific Affairs/Neuroscience Franchise at Worldwide Clinical Trials Inc., will discuss these biomarkers in depth.

Life sciences can’t afford not to take advantage of intelligent web and social listening technology. It is the only way they can hope to cut through the online noise and become truly vigilant about postmarketing patient safety in an always-on digital world. And they could pick up a lot of other valuable insights along the way if they teach systems what to look for, say Christopher Rudolf, CEO of Volv Partners and Adam Sherlock, CEO of ProductLife Group. CLINICAL SUPPLIES

42 The Epidemic “Fléau” of Diabetes Mellitus and the Need for a New Era of Therapies and Prevention.

60 The Pharmacy Adjudicated Clinical Study Supply Process Decreases Risk, Cuts Costs and Improves Efficiency when Providing Subjects Unblinded Clinical Study Supplies

Diabetes has reached epidemic proportions and currently affects 71 million people worldwide. Diabetes is a chronic disease that can seriously impact the quality of life of individuals and their families, through premature illness and death. In this article, Mona Dawood, Head of the Pharmaceutical Operations & Regulatory Affairs for CIDP Group, explains how the socioeconomic consequences of diabetes are likely to significantly impact the economies of many developing nations like Mauritius, in addition to their devastating

Supply chain efficiency in the conduct of clinical studies is a critical factor determining part of the overall cost. When appropriate, unblinded clinical study supply optimisation can save money, time and resources, and decrease risk, by preventing costly delays due to supply shortages. In this piece, Gerald L. Klein, MD and Maxwell O. Clarke of MedSurgPI, LLC analyse how the expansion of available resources towards the pharmacy network has helped provide more efficient clinical study supply management.

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Volume 9 Issue 3


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Foreword The spring edition of Journal for Clinical Studies welcomes its readers with an extensive regulatory paper, focusing on the Middle East; the potential for the pharmaceuticals industry in the Middle East is vast, and growing. Clinical research is also growing alongside pharma in the region, despite variations in situation from country to country, and despite certain barriers that still need to be solved. The challenges of regulations and patient recruitment, in particular, are analysed. Taking a specific look at one of the most established countries in the region for clinical trials, Turkey, to see how it might act as a model for the rest of the region, are Bariş Erdoğan, PhD, Ömer Şeker, MD, and Le Vin Chin of Clinerion Ltd.

solutions, which seems odd, given that many details of the final requirements have yet to be published. With a further two years to go until the latest deadline comes around, organisations have every reason to be sceptical of the value of investing now. The article by Marc Chaillou of Schlafender Hase will give JCS readers an extensive look into the world of Identification of Medicinal Products.

Parkinson's disease is a progressive neurological condition caused by damage to nerve cells in the brain that produce the chemical messenger dopamine. Symptoms of Parkinson's include tremors, rigidity and slower movement. Most people who get Parkinson's are in their 50s, but it can affect younger people. Around 1 in 500 people in the UK are affected by some degree of Parkinson's. The neurodegenerative condition is phenotypically characterised by akinesia, resting tremor and muscular rigidity. Tomislav Babic, MD, PhD, Vice President of Medical and Scientific Affairs/Neuroscience Franchise at Worldwide Clinical Trials Inc. will discuss this topic in depth.

Risk factors for type 2 diabetes mellitus are greater for some ethnicities, as mentioned before. Furthermore, those people who have a family history of the illness, who are overweight or inactive also face a greater risk of type 2 diabetes mellitus. Mona Dawood, Head of the Pharmaceutical Operations & Regulatory Affairs for CIDP group explains how the socioeconomic consequences of diabetes are likely to significantly impact the economies of many developing nations like Mauritius, in addition to their devastating impact on the economies of developed nations such as the USA, UK and Australia.

Life sciences technology vendors and consultancies are busy promoting Identification of Medicinal Products (IDMP) compliance

JCS - Editorial Advisory Board

Diabetes mellitus affects a variety of people of all races, ages and nations. It is unknown why some people develop type 1 diabetes. It may be linked to environmental factors or a virus, however, it has been established that if there is a family history of type 1 diabetes, then there is a higher risk of developing the disease.

The Journal for Clinical Studies team wishes you a pleasant summer and an enjoyable holiday season. Orsolya Balogh

• Hermann Schulz, MD, CEO, Synlab Pharma Institute

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

• Jerry Boxall, Managing Director, ACM Global Central Laboratory

• Bakhyt Sarymsakova – Head of Department of International

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

• Catherine Lund, Vice Chairman, OnQ Consulting

• Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

• Cellia K. Habita, President & CEO, Arianne Corporation

• Mark Goldberg, Chief Operating Officer, PAREXEL International

Cooperation, National Research Center of MCH, Astana, Kazakhstan

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

IDM Pharma.

Corporation

• Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

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

• Rabinder Buttar, President & Chief Executive Officer of ClinTec

• Elizabeth Moench, President and CEO of Bioclinica – Patient

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

Reuters

Recruitment & Retention

• Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

• Francis Crawley, Executive Director of the Good Clinical Practice

Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

• Georg Mathis, Founder and Managing Director, Appletree AG • Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

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International

Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

• Robert Reekie, Snr. Executive Vice President Operations, Europe, AsiaPacific at PharmaNet Development Group

• Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) • Stefan Astrom, Founder and CEO of Astrom Research International HB • Steve Heath, Head of EMEA - Medidata Solutions, Inc • T S Jaishankar, Managing Director, QUEST Life Sciences Volume 9 Issue 3


CIDP, the innovative clinical partner for your success story Our global presence provides you with a strategic link to a wide and competent network of investigators for conducting trials, and meet your project objectives. • Project Management • Medical Writing • Monitoring • Pharmacovigilance • Clinical Supplies Management • Regulatory Affairs • Biostatistics & Data Management

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Watch Pages

FDA Marks Milestone in Patient-Focused Drug Development The US Food and Drug Administration (FDA) has surpassed its commitment to obtain patients’ views in at least 20 disease areas over the course of five years, during its Patient-Focused Drug Development (PFDD) initiative, scheduled to end in September 2017. In April, the agency conducted its 21st PFDD meeting, which focused on patients suffering from sarcopenia. The 22nd meeting, focusing on autism, occurred in early May. The FDA plans to conduct two more meetings, on alopecia areata and hereditary angioedema, before the end of 2017. The PFDD initiative is one of the agency’s performance commitments, made as part of the fifth authorisation of the Prescription Drug User Fee Act (PDUFA V), covering fiscal years (FYs) 2013 through 2017, and signed into US law under the Food and Drug Administration Safety and Innovation Act (FDASIA) on July 19, 2012. According to the FDA, before the PFDD initiative, few venues had existed in which the patient perspective is discussed outside of a specific product’s marketing application review. In creating the PFDD initiative, the FDA believed that the human drug and biologic review process could benefit from a more systematic and expansive approach to obtaining input from patients who experience a particular disease or condition.

or for which the currently available therapies do not directly affect how patients feel or function. • That reflect a range of severity. • That have a severe impact on identifiable subpopulations. • That represent a broad range in terms of size of the affected population, including common conditions experienced by large numbers and rare diseases that affect much smaller populations. In May 2012, the FDA held a workshop to gather patient input on the regulatory process and asked a patient perspectives panel to issue statements on perceptions of patient representation and integration into the regulatory approval process at the FDA. The panel raised the issue of early integration of patient input, stressing that the FDA could not wait until the Phase III trials and FDA review timeframes. The panel also suggested that the agency should embrace partnerships with patient advocacy groups and facilitate collaboration between patients, clinical care experts, and drug reviewers. In October 2012, the FDA held a public meeting during which the public was invited to comment on a preliminary list of potential diseases areas the agency compiled as possibilities to focus on during the PFDD meetings.

As part of the FDA’s commitment to obtaining input from patients, the agency committed to conducting a series of public meetings to consider 20 different disease areas during the fiveyear authorisation of PDUFA. For each disease area, the FDA plans to conduct a public meeting that includes participation from FDA review divisions as well as relevant patient advocacy groups, patients and their caregivers, and other interested stakeholders. In addition, the FDA held a public workshop on March 31, 2016 in order to help patient advocacy groups and the public gain a better understanding of how to effectively engage the FDA’s Center for Drug Evaluation and Research (CDER). Presentations included introductions to the drug approval process, the PFDD initiative, drug safety and quality controls, and facts about generic and overthe-counter (OTC) drugs. During the presentation on PFDD, the agency described its process for selecting diseases for PFDD public meetings. The FDA selection criteria focused on disease areas: • That are chronic, symptomatic, or that affect functioning and activities of daily living. • For which aspects of the disease are not formally captured in clinical trials. • For which there are currently no therapies, very few therapies, 6 Journal for Clinical Studies

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Watch Pages

On April 11, 2013, the FDA published a Federal Register notice that announced the disease areas for meetings in FYs 2013-2015, the first three years of the five-year PDUFA V timeframe. The first meeting under the PFDD initiative was held on April 25-26, 2013, covering drug development for chronic fatigue syndrome and myalgic encephalomyelitis. Other meetings held in FY 2013 were: • Lung cancer • Human immunodeficiency virus (HIV) • Narcolepsy Meetings held in FY 2014 included: • Sickle cell disease • Fibromyalgia • Pulmonary arterial hypertension • Neurological manifestations of inborn errors of metabolism • Haemophilia A, haemophilia B, von Willebrand disease, and other heritable bleeding disorders • Idiopathic pulmonary fibrosis Meetings held in FY 2015 included: • Female sexual dysfunction • Breast cancer • Chagas disease • Functional gastrointestinal disorders • Huntington’s disease and Parkinson’s disease • Alpha-1 antitrypsin deficiency Meetings held or planned in FY 2016-2017 included: • Non-tuberculous mycobacterial lung infections • Psoriasis • Neuropathic pain associated with peripheral neuropathy • Organ transplantation • Sarcopenia • Autism • Alopecia areata • Hereditary angioedema www.jforcs.com

In August 2016, the FDA held yet another public meeting to discuss proposed recommendations for the reauthorisation of PDUFA for FYs 2018-2022. Among its proposals, the agency stated that it desires to build upon the PFDD initiative by bridging from that programme into “fit-for-purpose tools” that will enable the agency to collect meaningful patient input and incorporate it in regulatory review. The FDA proposed: 1. To conduct public workshops and develop a series of guidance documents on several topics (i.e., collecting comprehensive patient-community input about disease burden and current therapies, identifying disease/treatment impacts most important to patients, developing measures for specific sets of impacts, and performing clinical outcome assessments [COAs] and incorporating them as endpoints); 2. Revise manuals of policies and procedures (MAPPs) and standard operating procedures and policies (SOPPs) to incorporate the increased patient focus; 3. Publish a repository of publicly available tools on the FDA website; and 4. Enhance staff capacity to facilitate the development and use of patient-focused methods to inform drug development and regulatory decisions.

Molly Fellin Spence Writer and editor with more than two decades of experience in publishing. She has been employed by Clarivate Analytics for six years, specialising in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin. Email: molly.spence@clarivate.com

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Recent Trends and Innovations in Outcomes and Design of Clinical Trials in Respiratory Drug Development - Part 1: Outcomes Respiratory drug development, mainly for asthma and chronic obstructive pulmonary disease (COPD), has, for years, been relying on the administration of new, mostly inhaled drugs, and on assessment by physiologic tests and questionnaires. The physiologic outcomes were mostly lung function tests, measuring the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Gradually, more clinical and patient-reported outcomes have been applied. These function tests lack sensitivity for patient-relevant outcomes, and new insights in phenotypes, endotypes, basic mechanisms, and new targets for therapy have led to the need for more personalised, patient-centred approaches. Therefore, there is an unmet need for both better outcomes and study designs in the development of respiratory treatments. Asthma For asthma, the minimal recommended outcomes are pre- and post-bronchodilator respirometry; scores such as Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT), emergency department visits, steroid and rescue medication and biomarkers. Increasingly, alternative outcomes are being used, such as Fractional Exhaled Nitric Oxide (FeNO), an inflammatory biomarker; Health-Related Quality of Life (HRQOL); blood and sputum eosinophils and neutrophils; total and allergen specific immunoglobin E (IgE); and periostin. These help to define asthma

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phenotypes, predict asthma exacerbations, and act as targets for anti-inflammatory biotherapies. Induced sputum cells allow specific cytokines to be measured and targeted by new therapies. Exhaled breath condensate (EBC) analysis may also assess airway inflammation. Different challenge agents are increasingly used, including allergen bronchoprovocation and the human viral challenge model, based on developing insights of triggers for asthma exacerbations, increasing performance in drug development. COPD According to the FDA, primary efficacy endpoints should show improved airflow obstruction by the change in postdose (bronchodilator) and pre-dose (nonbronchodilator) FEV1 measurements. Other endpoints include symptom relief, alteration in exacerbations, disease progression and lung structure. Commonly used secondary endpoints include various lung function measures, exercise capacity, symptom scores, activity scales, HRQOL instruments and biomarkers. There is increasing interest in outcomes such as FeNO, EBC, eosinophils and new biomarkers. The challenge with biomarkers, scales and (electronic) patient-reported outcomes (ePRO) is obtaining proper validation. The performance of drug development can be improved by focusing on proof-of-concept studies. Inhaled drugs can be studied by lung deposition in humans, using local bronchial pharmacokinetics, functional respiratory imaging, and modelling and simulation techniques, to develop disease models that more accurately predict success and failure.

Volume 9 Issue 3


Watch Pages Rare Pulmonary Diseases For conditions including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF) and pulmonary arterial hypertension (PAH), improved insights into mechanisms and genetics can lead to the development of new targeted therapies. Outcomes in such conditions are lung function (FEV1, FVC), exacerbations, HRQOL, biomarkers, PROs and imaging techniques. In general for IPF, composite endpoints of all-cause mortality, progression-free survival (PFS), and FVC are used. In earlyphase studies, it is difficult to detect meaningful disease change, but exploratory omics-based research will hopefully improve this. Secondary outcomes are: six-minute walk test (6MWT), St George’s Respiratory Questionnaire for IPF (SGRQ), high-resolution computed tomography (HRCT) and positron emission tomography (PET). In CF, lung clearance index (LCI) based on multiple-breath inert gas washout (MBW) is a valuable tool. Combining CT and PET using fluorodeoxyglucose (FD) helps to detect inflammatory changes. Leverage of Lung Function Tests Using body plethysmography allows assessment of additional lung volumes and airway resistance (Raw). By adding dilutional gas methods, diffusion capacity can be measured. Forced oscillation technique (FOT) is a non-invasive test, providing unique information about lung mechanics not available from plethysmography and independent from performance of respiratory manoeuvres. Leveraging is also possible by modelling and simulation. If a classic analysis fails to detect a clear dose-response relationship, the development of a kinetic-pharmacodynamic (K-PD) model can appropriately predict the data, allowing the selection of doses for a subsequent dose-finding study. Role of Biomarkers Eosinophil granulocytes and IgE are used as indicators for T-helper cell (Th) type 2 activation. Nitric oxide is produced by inflammatory cells and measured by FeNO. Periostin is induced by IL-13 in the bronchial epithelium. Copeptin is a marker for increased cardiovascular risk in COPD. These, however, are not yet used as primary end-points for disease progression. The advances in omics technologies are expected to open the door to more personalised medicine. Imaging biomarkers such as quantitative CT, CT morphometry for airway remodelling, MRI for heterogeneity and PET/CT for pulmonary neutrophilic activity, have been validated. One of the most promising techniques is functional respiratory imaging (FRI), which combines HRCT with advanced computational fluid dynamics to produce highly clinically relevant, patient-specific biomarkers. For all biomarkers, validation and acceptance by regulatory authorities remains hard to achieve. Conclusion There exists a low performance of classical primary respiratory endpoints, showing a lack of sensitivity for patient-relevant clinical outcomes. Recently, a great number of techniques have been put forward, but further validation is needed before being accepted as primary outcomes. The most value has been demonstrated in early development, and extension to confirmatory trials and to real-world evidence is needed. A more patient-centric approach through all stages of clinical development is becoming mandatory. www.jforcs.com

Dr Robert Lins Project Director, Respiratory Diseases at SGS Clinical Research. He is an MD and certified specialist in internal medicine, nephrology and hypertension, and holds a PhD in medical sciences from the University of Antwerp, and is also a Fellow of the Belgian College of Pharmaceutical Physicians. He began his career over 35 years ago, working in animal clinical pharmacology at the Heymans Institute in Gent, Belgium, and has since been continuously active in the field of human clinical pharmacology. He first studied renal patients and later founded the SGS Clinical Pharmacology Unit in Antwerp, Belgium, where many innovative human pharmacology models were developed for the study of cardiovascular, metabolic, CNS, infectious and most recently respiratory drugs. These include bronchial challenge methods, a local bronchial PK model and sputum induction. Dr Lins has published many articles about clinical pharmacology in these different areas of research.

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Oncology – A Bouquet of Rare and Ultra-rare Diseases Oncology clinical trials are widely recognised as being amongst the most complex trials to design, set up, and deliver. Whilst there is good progress in finding optimal and durable treatment solutions for several cancer indications, the implementation of the enhanced understanding of molecular pathology adds an additional layer to clinical trial operational complexity, and makes finding increasingly discrete subsets of patients increasingly difficult. The demand to find treatment responses for various cancer indications is high, the research is intensive, and the number of sophisticated clinical trials is great. It is a major challenge for those working in clinical operations to succeed in timely delivery of the trials; to achieve this creativity is more needed than ever before. Modern molecular biology supports the hypothesis that cancer is actually hundreds or thousands of rare diseases. Several different clones of tumour cells grow simultaneously in each tumour and every patient’s cancer is, to some extent, unique.1 This partly explains why large-scale randomised clinical trials that test drugs individually in heterogeneous populations are often inefficient and bring disappointing results. Oncology trials nowadays are becoming highly specific by defining the targeted patient population using genetic markers of the studied malignancy that leads the main inclusion criterion to become a ‘rare-’ or ‘ultra-rare’ disease; hence, oncology studies can’t be run without the novel operational techniques utilised in rare-diseases trials. As an example, the age-standardised rate per 100,000 humans of lung cancer is about 42, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers.2 Recently, molecularly targeted therapies have shown remarkable benefit in NSCLC patients with specific genetic alterations. In particular, NSCLC with mutation in the epidermal growth factor receptor (EGFR) gene are sensitive to EGFR blockade with specific tyrosine kinase inhibitors (TKIs). Depending on the patient’s ethnicity, the EGFR mutation frequency is between 17 per cent (Caucasians) and 47 per cent (Asians) of all NSCLC cases.3 In spite of demonstrable efficacy, almost all patients with EGFR-mutant NSCLC develop resistance to EGFR-TKIs within 12 months and require further therapy. Various mechanisms of resistance to EGFR-TKIs have been identified, and understanding these is critical for development of effective treatment strategies for EGFR-TKI-resistant NSCLC. The major mechanism of acquired resistance reported is secondary T790M mutation on the EGFR gene, and additional mechanisms include amplification of the MET gene, PIK3CA mutation, BRAF mutation, epithelial-to-mesenchymal transition (EMT), and small cell lung cancer (SCLC) transformation. Each of these mechanisms requires different treatment strategies that can only be developed by working in these niche settings: the ASR for T790M mutated EGFR positive NSCLC patients is between 1-3 cases per 100,000, right at the mark for ‘ultra-rare disease’ definition of 2 in 100,000. To successfully run oncology trials, pharma companies or CROs must use the complete arsenal of operational methods of classical oncology trials together with those used in ‘rare diseases’ 10 Journal for Clinical Studies

indications, combined with novel operational and design strategies that are reshaping the drug development paradigms towards a truly patient-centric approach. Collaboration with large oncology institutions remains essential; these sites are often specialised to treat broad cancer indications, are skilled in complex screening procedures, and are educated in running clinical trials. Beyond the highly specialised therapeutic qualification of the participating centres, ‘rare disease trial’ features dominate the operational conduct of the oncology trials. Their planning and execution has more in common across distant indications that are similarly rare, than with other indications in the same therapeutic area. Even with the involvement of the most prestigious centres, finding suitable patients for a given trial as defined by the genetic markers is akin to finding a needle in a haystack, a hard task that requires a highly innovative approach and close collaboration of parties. It is common to see large sites only enrolling one or a few patients in a year, or even not succeeding to enroll patients at all. The high number of screen failures is a waste of time and resources for developers and sites, as well as a disappointment for heavily diseased patients. A number of operational, technical, and trial design responses to these challenges are outlined below. The need to find sufficient numbers of patients with a specific biomarker has generated large co-operative study groups. Consortia provide multiple molecular testing assays for patients and help them find the trial that is appropriate to their disease. An example of such large cross-sector initiatives is the government-based National Cancer Institute – Molecular Analysis for Treatment of Choice (NCI-MATCH). Cancer-specific advocacy groups can also lead co-operative study groups, such as the “Know Your Tumor” programme, established by the Pancreatic Cancer Action Network in the USA. The competition between oncology drug developers to partner with consortia is understandably ferocious. Another patient-centric approach is to “bring the site to the patient” as opposed to the traditional way of attracting the patients to initiated sites. In these cases, the sites are only activated when a suitable patient has been pre-identified for the trial. This is a scalable solution that can work well; however activating a centre for drug release might require some time, and cancer patients can’t be made to wait long to get their treatment. A specific response of the oncology community to the poor operational efficiency because of the fragmented cancer indications is given by the use of novel clinical trial designs. One way is the umbrella trial, which uses different drugs on different mutations in a single type of cancer (‘under the umbrella of one disease’). Patients are selected based on the genetic mutation most prominent in their tumour and treated with a number of medicines known to target this specific mutation. This approach helps researchers to confirm patient subgroups who would most benefit from those medicines tested. INC Research is involved in running the large umbrella trial called “Beat AML” for acute myeloid leukaemia patients. Basket trials test the effect of a drug on a specific mutation in a variety of cancer types (‘baskets’), allowing researchers to gain more Volume 9 Issue 3


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information about each individual cancer type, as well as assess the impact of the drug as a whole. The results of the first successfully run basket trial were published in 20154 and there are numerous such trials ongoing at the moment. Using this approach, it is possible to complete multiple Phase II trials through a single study, thus greatly speeding up the development process and expediting the delivery of an effective treatment to the patient. Conclusion Recent discoveries made in the molecular pathology of cancer diseases are creating opportunities for developing therapies with durable clinical benefits, while challenging the existing drug development process paradigms. Succeeding in the world of oncology clinical trials is becoming increasingly difficult for drug developers, who don’t only need to find the best drug candidate, but also need to find the responses to the operational difficulties caused by narrow indications, and the highly competitive and extremely agglomerated clinical trial landscape. In addition to the therapeutic expertise, clinical operations experience from ‘rare diseases’ trials and other areas are equally important for the developers to serve as a basis for creative solutions to these challenges. By generating a truly patient-centric mindset, the novel design and operational solutions in place in modern oncology represent important successful early steps towards precision medicine. REFERENCES 1.

Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin M-L, Ordóñez A. Comprehensive Catalogue

www.jforcs.com

of Somatic Mutations from a Human Cancer Genome. Nature 463 (14 January): 191–196. 2. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. 3. Midha A, Dearden S, McCormack R. EGFR mutation incidence in nonsmall-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5(9): 2892–2911. 4. Hyman et al: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 2015; 373:726-736 August 20, 2015.

Jozsef Palatka MD, Vice President of Clinical Development of Oncology, INC Research, has 17 years of clinical research and drug development experience gained from working as Drug Design & Development Lead, as well as in various roles in project management and global trial clinical operations of oncology studies. Dr Palatka holds a Doctor of Medicine degree from Semmelweis University of Medicine in Budapest, as well as a Masters’ of Science in Biomedical Engineering from University of Technical Sciences in Budapest. E-mail: jozsef.palatka@incresearch.com

Journal for Clinical Studies 11


Regulatory

Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates Facioscapulohumeral muscular dystrophy (MD) is a complex, inheritable muscle disease with an etiology that is rapidly becoming more elucidated. As a single clinical phenotype dominantly affecting the face (facio), scapula (scapulo), and humerus (humeral) muscles, it appears to have varying molecular and genetic determinants with commensurate differences in disease progression. Historically known as Landouzy-Dejerine disease – named after French neurologists Dr Louis Theophile Joseph Landouzy (1845-1917) and Dr Joseph Jules Dejerine (1849-1917) – it is more commonly known today as FSHD or FSH. Although frequently cited as the third most common type of MD in older reports, many newer sources, such as Orphanet, rank FSHD as the most prevalent type of MD, occurring at a rate of some 7 cases/1000 persons, as compared with Duchenne MD(DMD)/ Becker’s MD (BMD) (5 cases/1000) and myotonic dystrophy (4.5 cases/1000).1 The identification of FSHD as the most common type of MD has important ramifications; for example, when allocating future Federal (US) funding for research, and in terms of the potential market size for future FSHD treatments. FSHD has only recently attracted attention from the pharmaceutical industry, largely due to advances in our understanding of the genetic mechanisms of disease, including overexpression of a protein called double homeobox 4 or DUX4. There is currently no disease-modifying treatment or cure for FSHD. Most treatments proposed to “treat” FSHD have not yet been tested in randomised clinical trials. This paper will provide an overview of FSHD, discuss major clinical symptoms and ramifications of disease progression, provide a regulatory overview, and discuss two of the more commonly used surgical procedures to treat FSHD. Key barriers to rapidly finding a treatment for FSHD, as well as a brief discussion of potential pharmaceutical treatments and nonpharmaceutical interventions, will also be provided. Prevalence It is impossible to accurately assess the prevalence of FSHD because of disparate databases, differences in regions where clusters of FSHD patients are known to exist (e.g., the Netherlands), the lack of unified patient registries, and the reluctance of some US patients (with mild or moderate forms of FSHD or those whose onset of FHSD symptoms occurs later in life) to obtain either a clinical or molecular diagnosis of FSHD, for fear of insurance coverage discrimination. Although older sources list FSHD as third or fourth most prevalent of the nine types of MD recognised by the National Institute of Health’s (NIH’s) National Institute of Neurological Disorders and Stroke (NINDS), Dr Jean Mah and her team 12 Journal for Clinical Studies

recently performed a systemic review and meta-analysis on the epidemiology of the muscular dystrophies and concluded that the studies included in their analysis “differed widely in their approaches to case ascertainment and substantial gaps remain in the global estimates of (muscular dystrophies).”2 According to the November 2016 issue of the Orphanet Report Series, the gap may not be as great as some believed in the past, with a prevalence of 4.5/100k for FSHD (using European data) and 4.78/100k for Duchenne muscular dystrophy (DMD, using prevalence data).3 According to the University of Massachusetts Medical School’s Wellstone Center of FSHD, FSHD is the most prevalent hereditary muscular dystrophy affecting men, women and children and is more prevalent than any of the other types of muscular dystrophy. A conservative estimate of incidence for FSHD1, the most common type, is 1 in 14,286 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be as high as 1 in 7500.4 According to the FSH Society’s Website, FSHD is a genetic condition that affects around 1 in 8000 men, women and children and is among the most common forms of muscular dystrophy.5 Proposed Mechanism of Action FSHD is a heterogenous disorder and its genetic bases are complex, involving both genetic and epigenetic factors. Two forms of FSHD are recognised and reported in the literature: FSHD1 and FSHD2. About 95% of patients with FSHD have the FSHD1 form and about 5% have the FSHD2 form.6 In most cases, FSHD displays an autosomal dominant mode of inheritance with reduced penetrance. However, sporadic cases are frequent, accounting for 10-30% of FSHD1 incidence. Often, de novo cases are in the mosaic form and usually have milder phenotype; thus, these patients may go undetected.7 One study looked at de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a non-mosaic de novo patient.8 Both FSHD1 and FSHD2 share a common downstream mechanism – hypomethylation in the D4Z4 region, which leads to epigenetic derepression of the physiologically silenced gene, DUX4.9 The inappropriate expression of DUX4 is the most probable cause of FSHD.10 The DUX4 gene is located within the D4Z4 macrosatellite array on chromosome 4q35. More than 95% of patients have deletion of large repeat segments on 4q35, which are typical for FSHD1. Healthy Volume 9 Issue 3


Regulatory individuals display 11 to 100 D4Z4 repeats, while patients with FSHD1 have 1-10 D4Z4 repeats. The fewer the repeats, the earlier the disease onset and the more severe the phenotype.11

branch block (RBBB) with no progression on long-term follow-up has been reported and indicates selective involvement of the HisPurkinje system in FSHD.22

Less than 5% of FSHD patients do not show contracted D4Z4 array, have at least one permissive chromosome 4qA and demonstrate profound hypomethylation on chromosomes 4 and 10. In these cases, heterogenous mutations in the SMCHD 1 gene on chromosome 18 p11.32 are frequently found.12 Recently, in several patients, the SMCHD1 mutations were found to be causative in FSHD2, and to be modifiers of disease severity in FSHD1.10

As in other muscular dystrophies, a number of characteristic extramuscular manifestations are present in FSHD and usually these are found in patients with smaller numbers of D4Z4. Vision is typically normal; however, more than half of patients with FSHD1 show peripheral retinal abnormalities, with funduscopic examination frequently revealing retinal vessel telangiectasia.23 This finding – which corresponds to a developmental abnormality of the peripheral retinal blood vessels – is not progressive and remains clinically asymptomatic and often underdiagnosed. Nevertheless, a few patients with FSHD can develop an exudative retinopathy resembling Coats’ disease, with the risk of recurrent retinal detachment, a major complication that causes vision loss in the most severe cases.24 Bilateral Coats’ disease has been described in FSHD patients.25

Clinical Manifestations of FSHD FSHD presents with a characteristic pattern of muscle weakness and progression. Although facial muscles are usually affected early on, the presenting sign is frequently finding it difficult or impossible to lift the arm above the shoulder height due to shoulder muscle weakness. The degree of affectation of facial muscles varies from mild involvement manifesting only as a “sad expression” to typical horizontal smile, weak puckering of the lips and difficulty closing the eyes. The scapular stabilizers, such as serratus anterior, rhomboid and middle portion of the trapezius muscles, are weak early on. Weakness of these muscles leads to upward and lateral rotation of the shoulder blades, with subsequent scapular winging and the appearance of trapezius protuberance. Although the deltoid muscle is relatively spared, the sternocostal part of the pectoralis major muscle is frequently weakened.13 This is in line with MRI studies where the trapezius, teres major and serratus anterior were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major. This was in contrast to the musculus subscapularis and musculi spinati, which were consistently spared, even in late stages.14 The clavicles in FSHD patients are displaced horizontally, with a rounding shape seen in the shoulders. As the disease progresses, the upper arms, trunk and distal lower extremities become affected. Humeral musculature is weakened and forearm muscles become affected in later stages, with more prominent weakness of the wrist extensors than the flexors. Involvement of abdominal as well as paraspinal muscles leads to hyperlordosis. A bent spine phenotype due to prominent axial muscle weakness has been described in FSHD, both as an early and late symptom, and also as an isolated manifestation of FSHD.15, 16, 17 In the lower extremities, the tibialis anterior and gastrocnemius muscles are affected initially; proximal leg muscle weakness occurs later in the course of the disease. Due to pelvic muscles being affected in the later course of the disease, patients may have a waddling gait. It is quite common for patients with FSHD to exhibit an asymmetric muscle weakness pattern. Systemic features have been described in FSHD. Some patients develop respiratory complications. The estimated frequency varies among sources from 1.25% to 13%. In severe cases, respiratory muscle weakness can result in respiratory failure and the need for mechanical ventilation. Imminent respiratory failure may begin with sleep respiratory insufficiency, resulting in excessive daytime sleepiness.18 Cardiac involvement does not typically belong to the clinical picture of FSHD. Unlike other muscular dystrophies, dilated cardiomyopathy is not found in FSHD patients; however, subclinical cardiac involvement has been described and approximately 5-12% of patients suffer from asymptomatic supraventricular tachycardia.19, 20, 21 Increased prevalence of incomplete right bundle www.jforcs.com

Findings related to the frequency of hearing loss in FSHD are controversial, with one study reporting high-frequency hearing loss in nearly 50% of patients,26 while others conclude that the hearing loss in FSHD is typically no more prevalent than in the normal population.27 Specifics related to infantile onset of FSHD are discussed later. Pain is a common problem, occurring in up to 82% of FSHD patients;28 this is usually located in back, legs and shoulders. The pain in the shoulder region exacerbates the already-impaired shoulder and upper limb function.29 Considerable differences in both FSHD presentation and progression exist. Notably, a number of genetically confirmed variants have been identified, such as scapulohumeral dystrophy with facial sparing, limb girdle muscular dystrophy phenotype, distal myopathy, etc.30 Even within one family, a significant variability of clinical pictures may occur. The disease onset is usually before the second decade, and in milder cases the diagnosis is often delayed to early adulthood or even late adulthood. The loss of ambulation and need for wheelchair use occurs in about 20% of subjects older than 50 years old and life expectancy is not usually shortened.31 In general, the earlier the onset of symptoms in childhood, the more debilitating the course of the disease that ensues, including both the severity and rapidity of progression. The so-called “infantile” variant of FSHD accounts for approximately 4% of FSHD patients, and represents the most severe form. This involves initial presentation of facial weakness in the first few years of life, rapidly followed by shoulder girdle and hip girdle weakness, hyperlordosis and wheelchair confinement by the age of 12 or even earlier.32 Facial weakness is often severe, the children are unable to close eyes during sleeping and often cannot smile or show a facial expression. In an early childhood onset patient, delayed development of gross motor milestones was also noted.33 Respiratory insufficiency and swallowing difficulties have been described.34 Contrary to the more classical form, children with the infantile variant often demonstrate more systemic and extramuscular signs such as hearing impairment, retinal telangiectasia, cardiac arrhythmias and CNS involvement manifesting as mental retardation and seizures.35 Both FSHD1 and FSHD2 have similar clinical presentation, although it is possible that the striking similarity among FSHD1 and FSHD2 is due to ascertainment bias. Screening for FSHD2 among unidentified muscular dystrophies may reveal a wider FSHD2 clinical spectrum.36 Journal for Clinical Studies 13


Regulatory Barriers to a Cure In addition to differences in molecular structure associated with FSHD1, FSHD2 and possibly infantile onset FSHD, there appears to be marked variation in the severity and progression of disease in individuals diagnosed with FSHD. Although this list is not exhaustive, other key hurdles to the approval of products for treatment of FSHD include: • FSHD is an autosomal-dominant disorder localised to 4q35. Neither the gene nor gene product has been identified. The molecular basis for FSHD is not yet completely worked out. • Variability between males and females. • A lack of understanding around the clinical asymmetry associated with FSHD. • Animal models of MD do not accurately reflect human disease and thus, the majority of drugs tried in animal models have failed in human clinical trials.37, 38 There is a need for increased rigour and higher standards in the preclinical MD space. Current data suggest that there is a tendency to move to MD clinical trials too soon, based on insufficient data.39, 40 • It is difficult to define and measure the rate of change in slowly progressing conditions. • Variety and differences in the genetic mode of transmission (e.g., autosomal dominant inheritance, germline mosaic [resulting from a mutation during development which is propagated to only a subset of the adult cells, like sperm or eggs], de novo mutations, etc.). • Heterogeneity of the phenotypes within each form of FSHD with varying treatment goals at each stage. • Variability related to degree of ambulation. • Low numbers of patients available or eligible for study in clinical trials (thus FDA’s willingness to classify them as “orphan,” and garnering significant advantages for the sponsor, such as regulatory exclusivity and reduced fees during the application process). • Paediatric neuromuscular disease presents a challenge because patients lose muscle function as they grow into adolescence. The therapies, if not definitively curative, must provide a risk/benefit ratio acceptable to patients as well as caregivers; these two parties may not calculate the risk/ benefit ratio in the same way.41 • Currently, many registries are only offered in one geographic area (e.g., big cities). The lack of a fully operational central/ national registry database is problematic, but large patient advocacy groups are attempting to remedy this situation.42, 43,44, 45 • Lack of protein identification and complete mechanism of action in FSHD. • Lack of regulatory agreement on a pathway for the treatment of FSHD (see Regulatory Guidance below). Regulatory guidance is needed to de-risk the programmes of sponsors seeking to study and provide treatments for FSHD. • Lack of regulatory agreement on primary and secondary endpoints in the US for FSHD trials. Preclinical Models46, 47 Ongoing studies of preclinical animal models for FSHD are examining: • Zebra fish, with work underway to establish a DUX4 transgenic zebrafish to determine how the expression of DUX4 causes the FSHD phenotype. • Canine models, such as golden retrievers with the Duchenne mutation, which may also be relevant to FSHD. • Mouse models, with research being conducted at the University of Maryland in Baltimore, assessing the pathologic role of DUX4 in a humanised mouse model. 14 Journal for Clinical Studies

Regulatory Landscape Because FSHD can be life-threatening, new disease-modifying (serving to slow or halt progression) and curative treatments are desperately needed. No regulatory guidance exists in the highly regulated markets (e.g., US, EU), but the stage may be set for change. The European Medicines Agency issued a concept paper in 2011 and draft guidance for treatments related to Duchenne MD in early 2013.48, 49 Responding to an absence of FDA guidance and at the agency’s invitation, the Project Muscular Dystrophy (PPMD) organisation and more than 80 representatives of the Duchenne community submitted the first-ever patient advocacy-initiated draft guidance to the agency in June 2014.50 The FDA reviewed their submission and issued its own draft guidance on DMD/BMD in June 2015.51 Since FDA draft guidance for MD now exists, this DMD/ BMD template could potentially be used as a template by patient advocacy groups representing other types of MD, including FSHD. Overview of Pharmaceutical Treatments and Non-pharmaceutical Interventions There are no approved pharmaceutical treatments to cure or slow progression of FSHD. Symptomatic treatment can include physical therapy, speech therapy, and in some cases orthotic devices and surgical procedures. The encouraging news is that the number of interventional trials has increased in the past few years lending optimism that new treatments and interventions may soon be available. To assess treatments, we reviewed clinicaltrials.gov, PubMed and Orphanet for trial listings and publications related to research and treatment for patients with FSHD. From 2014–2017, there have been 19 studies registered with clinicaltrials.gov. Of these, 14 are interventional in nature. Several have been registered to assess investigational products, including ATYR1940 and ACE-083. In addition, studies are ongoing to assess albuterol, creatine monohydrate, and antioxidant supplementation. These will be explored in greater detail in a subsequent paper. There are several publications referencing treatment options for comorbidities and symptoms associated with FSHD. One case example highlights the potential risk for exudative maculopathy in patients with FSHD. In this case, a solution of intravitreal antivascular endothelial growth factor injections combined with focal laser photocoagulation was found to be beneficial.52 There are several studies that look at the potential for nonpharmaceutical interventions, such as diet and exercise to improve muscle strength and performance. These studies have had mixed results. Strength training and aerobic exercise have been shown in one study to benefit patients,53 while an older meta-analysis did not show any benefit to patients.54 Overall, these studies did not show an increased risk to patients. There are also theories regarding oxidative stress. To reduce or eliminate oxidative stress, several studies have evaluated vitamins and minerals to support muscle endurance and a reduction in oxidative stress. There is some evidence that vitamins can support patients with FSHD55, 56 and ongoing studies continue to look at the use of muscle oxygenation as a diagnostic tool (NCT02789059) to understand the impact of modification. Additionally, orthotic devices are often used to compensate for muscle loss; these include back and leg braces, girdles and other support clothing, or wheelchairs. Volume 9 Issue 3


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Regulatory Overview of Potential Surgical Treatments Weakness of the thoracoscapular muscles is a typical feature of FSHD, with patients having difficulties reaching upwards, washing, dressing, combing their hair and brushing their teeth. When shoulder elevation is attempted, the relatively spared deltoid muscle takes over, the scapula rotates and lifts off the chest wall, losing strength at the glenohumeral joint. This subsequently leads to an inability to sustain shoulder abduction and flexion.57 Surgical fixation of the scapula to the back of the thorax may enhance shoulder function, especially in regard to abduction, which should subsequently lead to improvement in activities of daily living. Besides a functional problem, winging scapula presents cosmetic deformity and contributes to pain in the shoulder region. There are two main types of surgical interventions in FSHD; thoracoscapular arthrodesis (scapulodesis) or thoracoscapular soft tissue fixation without arthrodesis (scapuloplexy). Scapulodesis fixes the scapula to the chest wall with screws, wires or plates, with or without a bone graft, to produce solid fusion. In scapuloplexy, fascial or synthetic slings are used to improve scapular fixation. The latter procedure might be better suited for individuals with impaired respiratory function and for whom prolonged immobility would be particularly high risk.58 Both procedures aim to achieve long-term stability of the scapula with maximal glenohumeral movement and reduced pain.59, 60, 61 The procedure may be performed both unilaterally and bilaterally. Historically, data have been published on bilateral procedures done at the same time; however, most frequently they are done separately.62, 63 The indication for surgery has been recently published in the 2015 American Academy of Neurology/American Association of Neuromuscular and Electrodiagnostic Medicine (AAN/AANEM) guideline. This states that “surgical scapular fixation might be offered cautiously to selected patients after careful consideration of the overall muscle impairment in the involved arm, assessment of potential gain in range of motion by manual fixation of the scapula, the patient’s rate of disease progression, and the potential adverse consequences of surgery and prolonged post-surgical bracing.” A comprehensive overview of the indication criteria has been also published.64 Although quite rare, both early and late post-operative complications have been reported and may include pneumothorax, hemothorax, non-union, pain, infection and decline in respiratory function.65, 66 Summary Facioscapulohumeral MD, likely the most prevalent form of MD, currently has no cure. The main regions affected by FSHD are in the face and arms; however, weakness in the legs and abdominal muscles are also common. Pain is a very common problem in patients with FSHD. In general, the earlier the onset of symptoms in childhood, the more debilitating the course of the disease. Cardiac complications are uncommon. Respiratory, peripheral, and hearing problems have all been reported and mental health in patients with FSHD is a significant factor that needs to be considered as well. The phenotypic differences in severity among patients with FSHD continue to pose problems in our understanding of FSHD. Varying rates of progression in different anatomical regions further add to the complexity of the clinical assessment. Although the over-expression of the DUX4 protein has been identified as a factor in FSHD, the gene and gene product have not been identified. There is currently no regulatory guidance available in ICH countries available for sponsors of FHSD treatments and there are currently no good animal models of the disease. 16 Journal for Clinical Studies

There are only two main surgical interventions for FSHD. Scapulodesis screws the scapula to the chest wall, while scapuloplexy uses fascial or synthetic slings to improve scapular fixation. Regarding nutritional supplements and treatments, there is currently no definitive evidence of any significant effect on FSHD. Certainly, maintaining a healthy diet, getting enough sleep, and keeping as active as possible without straining the muscles are all important for the patient. As FSHD becomes better understood, there is increasing investment by pharmaceutical companies in this rare disease area. It is hoped that ongoing and future clinical trials, with participants identified using “best in class” registries that gather natural history data, the disease mechanisms will become better elucidated and disease-modifying or curative treatments will reach the patients who need them. Acknowledgments The authors would like to thank Springer Publishing and the Regulatory Affairs Professionals Society (Regulatory Focus) for publishing some of the concepts discussed in this paper, and Jill Dawson, PhD, consultant to QuintilesIMS, for her editorial contributions and support. REFERENCES 1. Orphanet Report Series: Rare Disease Collection, 2014 2. Mah JK, Korngut L, Fiest KM, Dykeman J, Day LJ, Pringsheim T, Jette N. A Systemic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. Can J Neurol Sci. 2016; 43: 163-177 3. Orphanet Report Series: Rare Disease Collection. Number 1, November 2016, 66pp 4. http://www.umassmed.edu/wellstone/aboutfshd/fshdfacts/, accessed 31 January 2017 5. https://www.fshsociety.org/2015/11/dogs-destined-to-developmuscular-dystrophy-evade-their-genetic-fate/, accessed 31 January 2017 6. https://ghr.nlm.nih.gov/condition/facioscapulohumeral-musculardystrophy#statistics, accessed 27 March 2017. 7. https://www.ncbi.nlm.nih.gov/pubmed/15174019, accessed 01 March 2017 8. https://www.ncbi.nlm.nih.gov/pubmed/10631134, accessed 01 March 2017 9. https://www.ncbi.nlm.nih.gov/pubmed/19728363, accessed 29 March 2017 10. http://www.sciencedirect.com/science/article/pii/S0925443914001495, accessed 29 March 2017 11. https://www.ncbi.nlm.nih.gov/pubmed/8651646, accessed 29 March 2017 12. https://www.ncbi.nlm.nih.gov/pubmed/25370034, accessed 01 March 2017 13. Amato AA. Neuromuscular disorders, McGraw Hill Medical. 2008. 14. http://journals.plos.org/plosone/article?id=10.1371/journal. pone.0100292, accessed 01 March 2017 15. https://www.ncbi.nlm.nih.gov/pubmed/20658601, accessed 01 March 2017 16. https://www.ncbi.nlm.nih.gov/pubmed/21404293, accessed 01 March 2017 17. https://www.researchgate.net/publication/279300254, accessed 01 March 2017 18. https://www.ncbi.nlm.nih.gov/pubmed/26215877, accessed 01 March 2017 19. https://www.ncbi.nlm.nih.gov/pubmed/15907286, accessed 01 March 2017 20. https://www.ncbi.nlm.nih.gov/pubmed/9818880, accessed 01 March 2017 21. https://www.ncbi.nlm.nih.gov/pubmed/16804309, accessed 01 March 2017 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264782/, accessed 01 March 2017 23. https://www.ncbi.nlm.nih.gov/pubmed/23446679, accessed 01 March 2017 24. https://www.ncbi.nlm.nih.gov/pubmed/21071050, accessed 01 March 2017 25. https://www.ncbi.nlm.nih.gov/pubmed/21130700, accessed 01 March 2017 26. https://www.ncbi.nlm.nih.gov/pubmed/7739630, accessed 01 March 2017 27. https://www.ncbi.nlm.nih.gov/pubmed/17715463, accessed 01 March 2017 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828945/, accessed 01 March 2017 29. https://www.ncbi.nlm.nih.gov/pubmed/26942834, accessed 01 March 2017 30. https://www.uptodate.com/contents/facioscapulohumeral-musculardystrophy, accessed 28 March 2017 31. https://www.ncbi.nlm.nih.gov/pubmed/27922500, accessed 01 March 2017 32. https://www.ncbi.nlm.nih.gov/pubmed/16934468, accessed 01 March 2017 33. https://www.ncbi.nlm.nih.gov/pubmed/23434070, accessed 01 March 2017 Volume 9 Issue 3


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https://www.ncbi.nlm.nih.gov/pubmed/23434070, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/9633729, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/20975055, accessed 01 March 2017 Landis SC et al. A Call for Transparent Reporting to Optimize the Predictive Value of Preclinical Research, Nature, Vol. 490, 11 October 2012, pp187-191 Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM. Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments, PLOS Medicine, Vol. 10, Issue 7, July 2013 Mullard A. Reliability of “New Drug Target” Claims Called Into Question, Nature Reviews, Vol. 10, September 2011, pp.643-644 Prinz F, Schlange T, Asadullah K. Believe It or Not: How Much Can We Rely on Published Data on Potential Drug Targets? Nature Reviews, 2011, at www.nature.com/reviews/drugdisc, accessed 29 October 2013 McNeil DE, Davis C, Jillapalli D, Targum S, Durhowicz A, Cote TR (From FDA’s Office of Orphan Product Development and Office of New Drugs). Duchenne Muscular Dystrophy: Drug Development and Regulatory Considerations; 2010 Wiley Periodicals; Published on line in Wiley InterScience (www.interscience,wiley.com) The Myotubular and Centronuclear Myopathy Registry at http://www. mtmcnmregistry.org/, accessed 22 November 2013 Muscular Dystrophy Campaign Registry (UK) at http://www.treat-nmd. eu/, accessed 22 November 2013. National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry (for myotonic dystrophy and FSHD only) at http://www.niams. nih.gov/News_and_Events/Press_Releases/2000/12_11.asp, accessed 22 November 2013. Quintiles press release, Quintiles Selected by Muscular Dystrophy Association to Develop U.S. Disease Registry, at: http://www.quintiles. com/library/press-releases/quintiles-selected-by-muscular-dystrophyassociation-to-develop-u-s-disease-registry/, accessed 25 October 2013 Lek A, Rahimov F, Jones PL, Kinkel LM. Emerging preclinical animal models for FSHD. Trends Mol. Med. 2015 May; 21(5):295-306, https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4424175/, accessed 24 March 2017 Vieira NM, Elvers I, Alexander MS, Moreira YB, Eran A, Gomes JP, Marshall JL, Karlsson EK, Verjovski-Almeida S, Lindblad-Toh K, Kunkel LM, Zatz M. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. Cell, published online November 12, 2015. DOI: http://dx.doi. org/10.1016/j.cell.2015.10.049, accessed 24 March 2017 European Medicines Agency (EMA). Guideline on the clinical investigation of medicinal products for the treatment of Duchenne and Becker muscular dystrophy at http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2013/03/WC500139508.pdf, accessed 25 October 2013 EMA. Concept paper on the need for a guideline on the treatment of Duchenne and Becker muscular dystrophy at http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2011/07/ WC500108442.pdf, accessed on 25 October 2013 First-Ever Patient-Initiated “Guidance for Industry” for Duchenne Muscular Dystrophy Submitted to FDA, PR Newswire, June 25, 2014, at http://www.marketwatch.com/story/first-ever-patient-initiatedguidance-for-industry-for-duchenne-muscular-dystrophy-submittedto-fda-2014-06-25, accessed 05 July 2014 http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/UCM450229.pdf, accessed 01 February 2017 Ophthalmic Genet. 2017 Jan 25:1-4, accessed 22 March 2017 Medicine (Baltimore). 2016 Aug; 95(31):e4497, accessed 22 March 2017. Cochrane Database Syst Rev. 2010 Jan 20; (1):CD003907, accessed 22 March 2017 Free Radic Biol Med. 2014 Oct; 75 Suppl 1:S14, accessed 22 March 2017 Free Radic Biol Med. 2015 Apr; 81:158-69, accessed 22 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/20091543, accessed 28 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/10613155, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/16927655, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/20091543, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/23925745, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/18056023, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/23925745, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/23925745, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/20091543, accessed 01 March 2017 https://www.ncbi.nlm.nih.gov/pubmed/12917959, accessed 01 March 2017.

18 Journal for Clinical Studies

Raymond A. Huml MS, DVM, RAC, Vice President of QuintilesIMS Global Biosimilars Strategic Planning. Dr Huml has a personal interest in FSHD and works with the QuintilesIMS/ Muscular Dystrophy Association (MDA) team on their national patient registry. Dr Huml is a member of the FSH Society and has presented at FSH Society’s Biennial “FSHD Connect” meeting. Dr Huml is co-founder and member of the NC Chapter of the FSH Society. He is a member of MD STARnet’s North Carolina Advisory Committee, representing the interests of patients with FSHD. In 2015, Dr Huml edited and wrote or co-wrote eight chapters for the Springer book entitled “Muscular Dystrophy: A Concise Guide”, which covers all types of MD. Email: raymond.huml@quintiles.com

Lucie Undus MD, A board-certified neurologist with over a decade of experience in clinical medicine and clinical trials and seven years of industry experience both in the EU and the US. Dr Undus has a special interest in neuromuscular disorders, holds neuromuscular sub-specialisation and EMG licences, and has been working with mainly adult neuromuscular patients, including patients with muscular dystrophies. Dr Undus further subspecialises in neurological orphan indications and movement disorders. She has held academic positions, which included administering research grants and lecturing on neurology topics. She received her MD from the Charles University in Prague, Czech Republic, and trained further in neurology in Perugia, Italy and Toulouse, France.

Margaret Dean MBA, has 15 years of healthcare experience, with roles in clinical development and commercialisation. As Deputy Head of the Rare Disease Center of Excellence at QuintilesIMS, she leverages an analytical approach to understanding best practice trends in rare disease development. Margaret has a BS in Chemistry from the University of Richmond and an MBA from University of North Carolina - Chapel Hill’s Kenan-Flagler School of Business.

Meredith L. Huml A student at Wake Technical Community College, located in Wake County, North Carolina. She was diagnosed with FSHD in 2003 at Duke University Hospital. Meredith previously served as a photographer and writer during her tenure at Cardinal Gibbons College Preparatory High School. She authored Chapter 13, “Patient Advocacy,” for the book entitled “Muscular Dystrophy: A Concise Guide”, published by Springer in 2015, and coauthored the article entitled, “The Growing Case for the Rapid Identification of Patients with Muscular Dystrophy for Clinical Trials” in the Journal of Clinical Studies, published April 2016.

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Journal for Clinical Studies 19


Regulatory

The Evolving Role of Medical Affairs: Opportunities for Discovery, Preclinical and Clinical Research Historically, many, if not all, of the medical affairs functions were the responsibility of other teams, groups and departments. Historically, the emphasis of medical affairs with regard to data generation was simply to support the acquisition of the additional local datasets required for regulatory approval per country and region throughout the world. Though medical affairs would support additional trials, the key role at this time was the efficient communication of data from the initial regulatory approval. Throughout the evolution of medical affairs, the original intended function was supposed only to support marketing and sales activities from a medical perspective, for instance, development of observational studies as a marketing tool. Within this context, medical affairs and marketing worked hand in hand but at the same time this relationship was sometimes also conflictual. Indeed, it was common for the marketing department to see medical affairs as the “sales prevention department”. This vision is changing now towards a solutions-focused partnership with marketing. Importantly, the function of medical affairs in many companies is under ongoing change. This change, however, is not harmonised yet, and there is still space for improvement in the partnership between medical affairs, marketing, market access, and other departments. Based on the experiences of the past, the current ongoing changes within medical affairs have given impetus to a function seen as being completely independent from commercial activities. These changes offer the opportunity for a new type of partnership between medical affairs and commercial activities. This collaboration can create scientifically-minded and medically-driven marketing. How Different Terminology can Foster Relationships Between Medical Affairs and External Experts The terminology used in the past in medical affairs has been heavily influenced by expressions that underline the marketing perspective. The use of expressions like “key opinion leaders” (KOLs) or “key decision-makers and influencers”, emphasises the economic value for the company of medical experts within the medical field (or indication) of interest for the company. This use is based on the idea that external medical experts are organised according to a hierarchical structure, and that the opinion of a medical expert working within a higher international context might be perceived as being of higher value than the opinion of a local colleague. This perception of different values for different functions and levels at global, regional or local levels, is however often an assumption which does not reflect the reality. It is therefore recommended to replace marketing terminology with other titles which are unlinked to commercial interests. For example, replacing “KOL” with the title of “external medical expert” is preferable because it facilitates the establishment of partnerships between internal and external medical experts. This is particularly pertinent 20 Journal for Clinical Studies

in the development of relationships with healthcare professionals, because those relationships are primarily based on trust and common understanding. In the context of medical collaboration, the exchange of information cannot be biased by commercial considerations. Indeed, medical affairs has primarily a data-driven scientific nature based on the interpretation of facts, instead of the communication of opinions. Reshaping the Key Functions of Medical Affairs There is an increasing number of tasks and complexity of interactions foreseen for medical affairs. The changes within medical affairs develop at different paces within big pharma compared to a biotech environment. Biotech companies have often a more flexible structure, not only due to the inherent size, but culturally they are generally quicker to adapt to a changing environment than big pharma. A medical affairs department typically has diverse functions, encompassing the provision of information and education, management of publications, clinical trials input, developing fieldbased relationships, and providing both clinical and commercial support. However, while it is generally understood that medical affairs departments deal in facts and provide information on medicines, the key functions of medical affairs vary according to the size and location of the company. The spectrum of activity across the industry differs significantly between companies. All these activities rotate around the key function of the physician assigned to a therapeutic area, a specific indication or to a brand. Most companies include within medical affairs functions like publications, medical communication/medical information, health economics & outcomes research (HEOR). In some companies, these groups are then functionally led by the physician of the medical affairs department. Medical affairs is increasingly seen to be playing a central role in coordinating internal company stakeholders (including commercial, market access, regulatory, clinical development and drug safety teams) with the needs of external stakeholders. Medical teams need to communicate data in a clear and consistent way, and educate internal and external key stakeholders on the value of those data. Four components characterise medical affairs and are equally important: • • • •

Data generation and research Communication Intelligence Medical governance

The following section will describe how these four classical functions can further evolve to meet the new requirements medical affairs has to satisfy. Volume 9 Issue 3


Regulatory Data Generation and Research: Feeding the Pipeline through Post-marketing Studies In comparison to past practice, regulatory approval is only the first hurdle to reach the market and maintain market share over time. Nowadays, society has to consider the situation of spiraling healthcare costs. There is, therefore, the need for strong, valuebased decisions. Consequently, the need for data to clearly demonstrate the value of the drug has been extended from a situation in which only safety and efficacy were shown through pivotal trials to data sets, which includes also data from health economics analysis, comparative efficacy trials and real-world settings. This latter conglomerate of data sets is intended to show that those randomised clinical trials actually reflect efficiency of treatment and safety in the patients who are receiving – in a post-marketing situation – the prescribed drug, once approved. Thus, the medical affairs role has evolved to become an integral part of the drug development process. On one hand, medical affairs now ensures that the drugs are being developed to address access and reimbursement challenges, and on the other hand, medical affairs pursues opportunities to feed the companies’ discovery, pre-clinical and clinical research. Indeed, within an ideal context, medical affairs can be integrated into the entire drug development and commercialisation process from at least proof of concept up to the end of the life-cycle. Within this concept, a hypothesis developed during preclinical research about the potential mechanism of action of a drug will be developed further and tested also in medical affairs. Indeed, in early clinical development, through the use of proof-of-mechanism and proof-of-concept studies, this preclinical hypothesis will be confirmed in humans only partially. Clinical development is needed to reach the market, but frequently its mechanism of action and clinical value can be fully investigated only once the drug is prescribed when the use of the drug is available to the scientific community. Indeed, the full development and education process begins only once the drug is on the market. The full understanding of opportunities related to a drug, at present and in the future, can be developed best through a joint effort between pharmaceutical companies and academia together. In this way, there might be opportunities to identify biomarkers of prognostic value for the disease course or predictive in terms of treatment response. In addition, there might be opportunities to identify new treatment targets, new indications or any other benefits. Medical affairs drive the collection of these data, disseminate internally the findings from these post-marketing studies, even to the earliest stage of drug discovery. It is in this way that a life-cycle of a drug can be extended and used for the development of new life-cycles. If a pharmaceutical company conducts continuous research about the commercialised drug, this research, conducted within medical affairs, will nourish an actively developed pipeline of new drugs. The scientific value of the commercialised drug is then enhanced by other formulations or with the development of new drugs within the same indication. Though research may occur at various stages of drug development, pre- and post-marketing authorisation, the number of post-marketing clinical trials sponsored by the company is relatively limited. It is more common to financially support investigator initiated trials (IITs). www.jforcs.com

Pharmaceutical companies have the ethical responsibility to allow scientists to study the commercialised drugs. They might in this way find answers to questions which were not part of the company’s original clinical development plan. This type of interaction represents an opportunity for the pharmaceutical companies to enrich their strategic planning by selecting studies which might help to identify new targets, indications, subpopulations and other advances. It should be, therefore, part of the company’s strategy to identify new opportunities through post-marketing research programmes or IITs. The decision to fund these projects requires deep medical insight and knowledge combined with the ability to think out-ofthe box: a role which for consistency can be covered only under the guidance of medical affairs. Though it is not possible to solicit the investigator in doing a study that the company might wish to be done and the company is not allowed to influence the nature of the IIT, it is possible for the company to assume sponsorship of a trial, if the investigator agrees. It might be therefore possible to transform the original idea of an IIT into a larger trial sponsored by the pharmaceutical company. The medical affairs group will then help design this study, which the company will support and take responsibility to develop and deliver. This type of significant medical affairs activity should be done, ideally, in alignment with the R&D organisation. These Phase IV medical affairs studies can be designed and sponsored at the global, regional or country level; mixed sponsorship models are possible as well. They raise new questions which have not been investigated in the global R&D trials, such as aspects of the drug in specific populations, or to consider other scientific issues which might be of interest to a limited part of the scientific community. Despite the wide-ranging opportunities within Phase IV clinical trials and IITs, the decision for investment in any of these trials should be based on a structured strategic plan, such as an extension of the clinical development plan of the drug. This choice would allow companies to better streamline research and to invest in further development of the drug in an efficient way. Another area in which medical affairs is increasingly involved is real-world evidence. Within this context, the medical affairs team is aligning with the market access group in trying to generate data that will demonstrate to payers the value of their products. While this type of study is cheaper to perform than the randomised controlled trial, it is still not without costs or complexity. To achieve value from investment in these studies, it is important that they are properly planned from a methodological view and that they are conducted with the same quality expectation as a randomised controlled trial. Otherwise, there is a risk of collecting a huge amount of flawed and useless data (the big data phenomenon). Communication: Become the Voice and Face of the Company to the Outside World From a communication standpoint, many of the medical affairs activities, including independent medical education, speaker training, activities at medical congresses and publication planning, were historically managed by the marketing department. In some companies, these activities were first made part of R&D’s responsibility. Quite recently, however, these activities have become part of the tasks assigned to medical affairs. The same strategy should be applied to many other functions as well. A key example is health economics and outcomes research. Journal for Clinical Studies 21


Regulatory

Nowadays, medical affairs plays a key role in communication, assuring that there is transparency to all of the data that are generated and that the data are disseminated in an ethical fashion to ensure questions from patients, payers and providers are answered in an accurate, fair and balanced way. For this reason, medical affairs should become the voice and the face of a company to the outside world, including payers, patients, physicians, regulators and government agencies. At the same time, medical affairs is, in essence, the voice of the payer, the patient and the provider within the company because it is involved in all aspects of a drug’s life-cycle. Internally, the medical affairs department plays an important bridging role between R&D and commercial with respect to education and communication within the company. Among the key aspirations for medical affairs departments is to clearly demonstrate value to practitioners and payers throughout the life-cycle of each product. For this purpose, medical affairs should engage with a wide range of healthcare stakeholders in order to fully understand the different needs of patients and to be able to provide tangible value to patients. While the interaction depends on which stakeholders you are dealing with, this type of exchange has to be on a meaningful scientific basis that incorporates the medical affairs understanding of what the need is to treat patients better and the facts surrounding the drugs being developed. Intelligence: Enhance Value by Medical Understanding Intelligence was historically assigned to the sales representatives who were considered the eyes and ears on the ground, and who brought in “the voice of the customer”, i.e. the prescriber of the drug. Nowadays, what is considered the voice of the customer has become 22 Journal for Clinical Studies

much more complex and does not refer to healthcare providers exclusively. For this reason, it is now required that medical affairs steps into this role, too. The medical affairs function in this vision is, however, not in competition with the sales organisation. Indeed, in most pharmaceutical companies, medical affairs has become the voice of the customer: i.e., the patient, the payer and the provider. Medical affairs has to play a crucial role in listening to the outside world, bringing that intelligence into the company and making sure that this information is incorporated into all aspects of the company’s activities and strategies. Only with these insights from medical affairs, can a company address important questions which are relevant for future research and clinical development about the commercialised drug or for the development of new drug entities. The medical affairs role is, therefore, pivotal – not only in gathering intelligence, but in preparing a structured communication package and communicating it to the various stakeholders within the company and outside. Medical Governance: Deliver Training that Supports Objective Decision-making Among the key functions of medical affairs, the only one that has not significantly changed is medical governance. Medical governance is, indeed, the foundation of what medical affairs does. From a commercial standpoint, medical affairs ensures that promotional materials are accurate; they are fair, balanced and they are not overstating the facts, but are merely communicating what is in the label and what the data support. Medical governance, therefore, underlies how companies participate in ethical dissemination of data, and how they conduct their research. At the same time, the constantly changing regulatory framework makes this aspect of the role the most challenging to keep current. Volume 9 Issue 3


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Journal for Clinical Studies 23


Regulatory Part of medical governance are also the tasks related to “training and education”, which is a relevant activity due to time investment and strategic relevance. It allows both individuals and the company to develop their expertise within the therapeutic areas of interest. This type of training might also enable sales representatives to be perceived by healthcare providers as knowledgeable partners who understand strengths and weaknesses of a product and the data and scientific support required for an objective decision-making process. In the past, there was a widespread use of external experts for this purpose. However this should be replaced by high-quality educational training from the internal experts of the company. Similarly, external experts are asked to talk on the company’s behalf about its products or disease areas. They might also be asked to present the results of the data collected and analysed by the company to audiences who can prescribe or influence prescribing. Instead, pharmaceutical companies should increase their awareness of internal resources and the value they can provide. In this way, the internal medical and scientific capabilities can be strengthen to appropriately engage with healthcare providers. Through this engagement, they will be recognised outside of the company as experts in their field and gain the same degree of respect as external experts. This paradigm change of internal medical experts speaking as in-house representatives of the company also would provide more transparency to the scientific community and might abolish, over time, the view that science and business interests might be incompatible. The Relationship Between Medical Affairs, Market Access and Commercial While medical affairs operates in a strictly non-promotional environment, there has to be co-operation between market access, commercial and medical affairs, even though each department has its own defined tasks. Indeed, while there is a clear distinction between medical affairs and commercial operations, there is a need for the two to work together, particularly at a strategic level. Medical affairs within this context can support marketing messages by identifying and eventually collecting the data to prove commercial statements, such as having the best-in-class drug for a particular disease. Medical affairs can further promote the commercial need by using the facts and science. It is worth remembering that the marketing of drugs has to be guided medically and can only be driven by scientific data. Within the context of distribution of marketing material, medical affairs acts also as a control mechanism, avoiding both the external spreading of incorrect statements, and the use of publications of disputable quality for commercial claims. This kind of internal firewall helps to ensure that there will not be any legal complications by stating concepts which are not proven or not true. Similar changes are observed in the collaborative relationship between medical affairs and market access. In the past, medical affairs and market access were two clearly distinguished groups. Market access today cannot be seen alone without medical affairs’ support. Market access people are specialised in analysing the market, particularly providing meta-analysis and cost models; they are 24 Journal for Clinical Studies

very much health economics-focused. On the other hand, there are medical directors in medical affairs who understand the clinical nature of a problem, and the clinical benefit that a drug may provide. Thus, if it is about dealing with a stakeholder, a third payer or a health authority, it is important to defend the true clinical benefits, as well as justifying the economic model. The Partnership Between Medical Affairs and CROs CROs are classically involved in the operational conduct of clinical trials from Phase I to Phase III. There is also an increasing use of CROs for the conduct of Phase IV trials when they are sponsored by a pharmaceutical or biotech company. The conduct of a clinical trial at academic level such as in the cases of IITs, is a context in which CROs more rarely act, though their presence would increase the confidence about the quality and consistency of the data collected. The medical & scientific affairs department of a CRO is represented by medical directors and physicians with broad expertise in their field. These additional resources should be more intensively used to support the activities of a medical affairs department in a pharmaceutical or biotech company, because their experience is not limited to the clinical development of one or a few drugs within the same indication. Due to the nature of their business, they see many trials, and are able to understand the reasons for success and failure of a trial. They also frequently have an understanding about when a study design is methodologically flawed and how to put corrective measures in place. Considering the extended life-cycle of clinical development forecasted here in this article, there is an increased need to use this knowledge when clinical trials are planned to rejuvenate the life-cycle of a commercialised drug. Looking forward, further change can be expected in medical affairs, the concept of clinical development and the life-cycle of a drug, as well as parallel changes in the relationship between medical affairs working with internal departments and external partners, like CROs. Ongoing development and deployment of data integration/ visualisation, personalised medicine and mobile technology will continue to change the science and practice of clinical research, as well. Despite all the changes we might be able to anticipate, the value of medical knowledge and expertise will continue to be a fixed reference point for all of them. In the future, there might be an opportunity for a real partnership between pharmaceutical/biotech companies and academia, for the purpose of joint ventures in the clinical development of new drugs. The CROs within this context might take over a bridging function among all of these parties, and ensure the quality of the data collected and the exchange of their extensive experience.

Manolo E. Beelke MD, PhD; Senior Medical Director, Medical & Scientific Affairs, Worldwide Clinical Trials – Germany. He has worked overall in clinical research for more than 20 years with main focus in Neurology and Sleep Medicine, authoring more than 35 peerreviewed articles. He holds an MD (University of Genoa, Italy), a PhD in Sleep Medicine (University of Bologna, Italy). Email: manolo.beelke@worldwide.com

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Market Report

A Touch of Pragmatism in Clinical Trials Since Schwartz and Lellouch coined the terms “pragmatic” in 1967 to describe trials designed to help choose between options for care, and “explanatory” to describe trials designed to test causal research hypotheses,1 the distinction between these two types of research has become even more prominent, especially following the wide acceptance of the randomised controlled trial (RCT) as the ‘gold standard’ of experimental clinical trials. In our days, however, there is an increasing recognition of the potential benefits of pragmatic trials in testing complex interventions. This brief review aims to provide the reader with the highlights of the published literature in this rapidly evolving field of clinical research. What are Pragmatic Trials Trials of healthcare interventions are widely described as either explanatory or pragmatic.2 Explanatory trials generally measure efficacy, which reflects on the benefit a treatment produces under ideal conditions, usually employing carefully selected participants in a research centre. Pragmatic trials, in contrast, measure effectiveness – the benefit a treatment produces in a routine clinical practice. The focus in pragmatic trials lies on external validity, the ability to generate results in extended populations and clinical settings. As they are driven by the need to produce clinically applicable results, pragmatic trials allow maximal heterogeneity in all aspects of their design (such as participants’ eligibility, comparison treatments, variety of clinical settings and choice of participants to be included in outcome analysis) to reflect the conditions of daily clinical practice. An outline of the comparison between pragmatic and explanatory trials is found in Table 1.

A Pragmatic Trial Indicator Tool In order to help researchers determine how pragmatic or explanatory a trial is, Thorpe et al. have developed a comprehensive tool, called Pragmatic-Explanatory Continuum Indicatory Summary - PRECIS.3 PRECIS contains 10 key domains that determine the extent to which a trial is pragmatic or explanatory, across various areas of

Table 2: PRECIS domains illustrating the extremes of explanatory and pragmatic approaches to each domain. Adapted from Thorpe et al. (2009)3

differentiation, such as types of participants, interventions, clinical expertise, follow-ups and outcomes (Table 2 provides a detailed description of criteria applied in each of those domains). To illustrate, a strictly pragmatic trial across these 10 key domains would be:4

Table 1: Pragmatic versus explanatory trials 26 Journal for Clinical Studies

1. There are no inclusion or exclusion criteria. 2. Practitioners are not limited by guidelines on how to apply the experimental intervention. 3. The experimental intervention is applied by all practitioners, covering the full range of clinical settings. 4. The best alternative treatments are used for comparison with no restriction on their application. 5. The comparative treatment is applied by all practitioners, covering the full range of clinical settings. 6. No formal follow-up sessions exist. Volume 9 Issue 3


Market Report 7. The primary outcome is a clinical meaningful one that does not require extensive training to assess. 8. There are no plans to improve or alter compliance for the experimental or the comparative treatment. 9. No special strategy exists to motivate practitioners’ adherence to the trial’s protocol. 10. The analysis includes all participants in an intention-to-treat fashion.

3. Identifying a Comparison Group In pragmatic trials, use of a placebo-controlled group and blinding are not appropriate, and would damage the ecological validity of the intervention. The aim in a pragmatic trial is to maximise synergy, as it would happen in a routine setting. Consequently, it is sufficient to compare patients receiving the intervention with those receiving another intervention (established or not, of a same or a different class), which is deemed to have a similar chance of success.

The tool comprises the use of spider diagrams (the PRECIS “wheel”), which illustrate scores in each of the 10 domains in a graphic manner. A hypothetical comparison example between a highly explanatory and a highly pragmatic trial is shown in Figure 1.

4. Defining the Treatment Protocol As pragmatic trials are designed to capture everyday clinical practice, freedom is granted to practitioners to treat their patients as they would normally do, allowing the use of complex and individualised regimens. The options range from a widely ‘open’ protocol, which includes the majority of patients with the targeted condition, through to a ‘tighter’ protocol, addressing a more specific clinical sub-population, following consultation with KOLs. 5. Recruitment and Randomisation Referral procedures in pragmatic trials have to be practical and relevant to real-life choices. Advice for clinicians is valuable in determining whether the procedures used are workable and clinically meaningful. Retrospective recruitment is also an option, i.e. to identify patients with the condition of interest who have been diagnosed in the past. In other regards, recruitment and randomisation are similar for pragmatic and explanatory trials. 6. Clinical Outcomes The primary outcome of a pragmatic trial should be relevant to routine clinical practice such as patient’s function and quality of life. Longer follow-up allows for monitoring of outcomes across a wider spectrum, including changes to attitude and behaviour.

Figure 1: Hypothetical comparison between an explanatory and a pragmatic trial

Key Steps in Conducting Pragmatic Trials As discussed so far, the main strength of pragmatic trials is that they can lead to outcomes which are highly applicable in routine clinical practice. To achieve this aim, a number of considerations need to be made during the design and the conduct of a pragmatic trial:5 1. Research Question An adequate research question should relate to the overall effectiveness of the studied intervention; however, cannot address the contribution of its different components in the overall therapeutic outcome. Pragmatic trials can be used with the aim of providing the evidence to guide policy-makers, practitioners or patients to choose between two interventions; thus, they help to optimise the use of limited resources. 2. Defining the Patient Group, Ensuring Adequate Sample Size The sample of patients participating in pragmatic trials will have to be representative of the wider clinical population in which the studied intervention will be addressed. This variability between patients can dilute the treatment effect; as a result of this, larger samples are usually required, to allow for adequate power in order to detect small effects. Besides, a large sample could cover for discontinuation losses, which are common in pragmatic trials of lengthy follow-up. Given the inherited heterogeneity of patients’ group, it is, however, equally important to identify an appropriate therapeutic niche for the intervention, depending on the nature of the clinical condition and the intervention, current patterns of treatment and attitudes of patients. This would enable the demonstration of the maximum extent of action of the treatment in consideration. www.jforcs.com

7. Analysis An intention-to-treat (ITT) analysis is the gold standard in pragmatic trials, i.e. all patients who were enrolled and randomly allocated to treatment are included in the analysis and their data is analysed in the groups to which they were randomised (“once randomised, always analysed”). A considerable risk arises from the fact that patients in pragmatic trials are allowed to change their treatments (as they would do in real life) and thus a dilution of the treatment effect can occur. It is, however, important to record and report these variations, rather than try to distort what would happen normally by applying treatment restrictions. 8. Reporting and Dissemination Adherence to CONSORT guidelines can improve the reporting of all clinical trials, including the pragmatic ones.6 The CONSORT and PRACTICH (Pragmatic Trials in Healthcare) groups have proposed a number of extensions in the standard CONSORT statement to adapt for the reporting of pragmatic trials.7 The described modifications cover various items (background, participants, interventions, outcomes, sample size, blinding, participant flow, generalizability) with focus on the unique characteristics of pragmatic trials in those areas and the need to provide clear justification for any deviations from the standard procedures followed in explanatory trials. Mixed Methods in Pragmatic Trials Mixed methods design typologies can be extremely applicable to pragmatic trials, to address the need to effectively collect a mixture of qualitative and quantitative data.8 Examples of those designs are listed here: 1. Convergent Parallel Design: Simultaneous collection of quantitative and qualitative data. Data merged for analysis. 2. Explanatory Sequential Design: Quantitative data collection, Journal for Clinical Studies 27


Market Report followed by qualitative data collection. Qualitative data used to explain quantitative data. 3. Exploratory Sequential Design: Qualitative data collection, followed by quantitative data collection. Quantitative data used to explain qualitative data. 4. Embedded Design: One form of data is embedded within the other. Data collection may be sequential or concurrent. 5. Multiphase Design: A series of separate studies or phases using a combination of sequential and/or concurrent methods of qualitative and/or quantitative data collection. Because a given intervention may succeed in one situation and fail in another, quantitative data about effectiveness in a routine setting should not stand alone; similarly qualitative data alone are likely to provide limited insight into the effectiveness of an intervention, without the breadth provided by quantitative data. It is in the combination of the strengths found in different types of data that the most complete understanding can be achieved. The Cohort-Multiple Randomised Controlled Trial (cmRCT) Design Some of the problems associated with pragmatic trial designs, such as recruitment, can be tackled by considering an alternative design.9 The cmRCT design has several innovative features: a large observational cohort of patients is recruited and used as a multiple trials facility; each RCT uses random selection of some participants and patient-centred information and consent is applied. This design is best suited to a variety of trials, such as: open trials, where treatment as usual is compared with a new intervention; trials including easily measured and collected outcomes; conditions where many trials will be conducted; and trials of desirable or expensive interventions. Consent in Pragmatic Trials As pragmatic trials tend to assimilate regular clinical practice, there is always the temptation to normalise informed consent procedures. Following this direction, a group of researchers have proposed a No-Consent Model, according to which institutional review boards can waive or alter the requirement for obtaining informed consent when the following criteria are met:10

28 Journal for Clinical Studies

1. The research involves no more than minimal risk to the subjects; 2. The waiver or alteration will not adversely affect the rights and welfare of the subjects; 3. The research could not practicably be carried out without the waiver or alteration; and 4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation An alternative to the above consideration is a proposed model for informed consent when a pragmatic trial is testing commonly used treatments that in ordinary practice involve only brief verbal consent and that have been independently validated through wellcontrolled clinical trials.11 This Integrated Consent Model requires that once a decision is made by the patient to enroll in a pragmatic, randomised clinical trial, the physician does what they would ordinarily do in the course of their practice – that is, document the clinical interaction and record the fact the consent conversation took place; and this process is both necessary and sufficient from an ethical point of view. Economic Aspects of Pragmatic Trials Economic evaluations of the total healthcare cost are now commonly included in pragmatic trials designed to have an impact on medical policy. Despite the usually skewed distribution of cost data, analyses of arithmetic means appear to be the most informative measure.12 Wider recognition that pragmatic RCTs are the best vehicle for economic evaluations has led to the introduction of economic standard operating procedures (SOPs) in some units conducting similar research.13 Practical reasons support this notion, as the marginal cost of collecting economic data alongside clinical data is typically modest. Research Partnerships A successful pragmatic clinical trial starts with a strong partnership between researcher and healthcare system, goes through a rigorous objective evaluation of the ability of the partner healthcare system to participate, and ends with evidence about sustainable ways to improve care, as long-term scientific relationship.14 Pragmatic trials answer questions relevant to healthcare systems, so clinicians,

Volume 9 Issue 3


Market Report healthcare managers, health IT staff and clinical operations staff need to be involved in the study design. Participating in pragmatic clinical trials can provide healthcare systems with evidence and tools to improve healthcare, and researchers with opportunities to conduct high-impact clinical studies. In 2009, the USA congress passed the American Recovery and Reinvestment Act (ARRA), a multi-billion dollar stimulus package, including funds allocated towards the conducting of comparative effectiveness research (CER) “to evaluate the relative effectiveness of different health care services and treatment options” and “to encourage the development and use of clinical registries, clinical data networks, and other forms of electronic data to generate outcomes data.”15 Limitations Despite the presence of a number of strengths in pragmatic trials (delivering evidence of effectiveness in everyday clinical contexts; fitting well with the evaluation impact of the intervention; generating data that can help designing healthcare policies), there are also limitations inherent to their nature: • ‘Holistic’ assessment: cannot be used to determine what components of the treatment intervention might have caused any benefits, as it is a whole ‘package’ of care which is evaluated; • Increased costs for the larger sample sizes can be incurred; • Inadequate control of bias, linked mostly to the lack of blinding, can render pragmatic trials easily biased towards reporting a ‘positive’ outcome; favourable results could also be explained by regression to the mean, the natural history of the condition, the psychological effect of the ‘therapeutic relationship’ (performance bias) or the attention received from a health professional;16 • Reduced internal validity: any outcome, positive or negative, can be interpreted in more than one way, which led some researchers to view results generated by pragmatic trials as meaningless.17 Conclusions Successful policy-makers value pragmatism.18 As politics is the “art of the possible”, pragmatism is the “art of the practical and workable”. At a philosophical level, pragmatism advocates learning through action and building a knowledge base from experience and reflection. Down to the field of applied clinical research, pragmatism is constantly gaining popularity as a novel approach oriented towards translational research and evidence-based medicine,4 despite resistance by the majority of researches to throw off the shackles of RCT thinking. We hope that the present summary could increase our readers’ awareness of this interesting line of research. REFERENCES 1. 2. 3.

4. 5.

Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chronic Dis. 1967;20:637–48. Roland M, Torgerson DJ. Understanding controlled trials: What are pragmatic trials? BMJ [Internet]. 1998;316(7127):285. Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol [Internet]. 2009;62(5):464–75. Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci. 2011;13(2):217–24. MacPherson H. Pragmatic clinical trials. Complement Ther Med. 2004;12(2–3):136–40.

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6. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The Revised Consort Statement for Reporting Randomized Trials: Explanation and Elaboration. Ann Intern Med [Internet]. 2001;134(8):663–94. 7. Zwarentein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, et al. Improving the reporting of pragmatic trials: An extension of the CONSORT statement. BMJ. 2008;337:1223–6. 8. Albright K, Gechter K, Kempe A. Importance of mixed methods in pragmatic trials and dissemination and implementation research. Acad Pediatr [Internet]. 2013;13(5):400–7. 9. Relton C, Torgerson D, O’Cathain A, Nicholl J, Renton C, Torgerson D, et al. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ [Internet]. 2010;340(mar19_1):c1066. 10. Truog RD, Robinson W, Randolph A, Morris A. Is informed consent always necessary for randomized, controlled trials. N Engl J Med. 1999;340(10):804–7. 11. Scott YHK, Miller FG. Informed Consent for Pragmatic Trials — The Integrated Consent Model. NEJM [Internet]. 2014;370(8):769–72. 12. Thompson SG, Barber J a. How should cost data in pragmatic randomised trials be analysed? BMJ [Internet]. 2000;320(7243):1197–200. 13. Edwards RT, Hounsome B, Linck P, Russell IT. Economic evaluation alongside pragmatic randomised trials: developing a standard operating procedure for clinical trials units. Trials [Internet]. 2008;9:64. 14. Johnson KE, Tachibana C, Coronado GD, Dember LM, Glasgow RE, Huang SS, et al. A guide to research partnerships for pragmatic clinical trials. BMJ [Internet]. 2014;349(dec01_7):g6826. 15. Cassel C, Dickersin K, Garber A, Gatsonis C, Gottlieb G, Guest J, et al. Initial national priorities for comparative effectiveness research. Washington DC: National Academy Press; 2009. 16. Foster N, Little P. Methodological issues in pragmatic trials of complex interventions in primary care. Br J Gen Pract. 2012;62(594):10–1. 17. Ernst E, Canter PH. Limitations of “pragmatic” trials. Postgrad Med J [Internet]. 2005;81(954):203–203. 18. Maclure M. Explaining pragmatic trials to pragmatic policy-makers. CMAJ. 2009;180(10):1001–3.

Dr Evan Papanastasiou MD MSc, Senior Clinical Research Physician, Europital, qualified psychiatrist with more than 15 years of clinical experience, including appointments in academic settings (King’s College London) and major London teaching hospitals. He has hands-on clinical research experience in various therapeutic areas including schizophrenia, Alzheimer’s disease, osteoarthritis, fibromyalgia, atopic dermatitis and psoriasis, in addition to scientific experience in neuroscience. E-mail: info@europital.com

Mohamed El Malt MD, PhD, Chief Medical Officer, Europital. Oncology surgeon and expert scientific researcher with more than 32 years of experience as a medical doctor, including 18 years of clinical research and drug development experience in academic medical centres, pharma and CRO as investigator, project leader and medical director, in addition to 15 years of experience as general and oncology surgeon. E-mail: info@europital.com

Journal for Clinical Studies 29


Market Report

Regulations and Recruitment: Experiences in the Middle East The potential for the pharmaceuticals industry in the Middle East is vast, and growing. Clinical research is also growing, alongside pharma, in the region, despite variations in situation from country to country, and despite certain barriers that still need to be solved. The challenges of regulations and patient recruitment, in particular, are analysed. We take a specific look at one of the most established countries in the region for clinical trials, Turkey, to see how it might act as a model for the rest of the region. Home to 410 million people,1 or 5.6% of the world’s population, the countries of the Middle East form a small but significant patient cluster, not yet fully explored for the purposes of clinical research. The region actually runs 5.1% of the trials registered on clinicaltrials. gov, but Israel, which has a developed clinical infrastructure, takes a large proportion of this. Taking out Israel, the rest of the Middle East performs 2.5% of the trials, despite having a population which is 5.5% of the world’s.2 Of the remaining countries, the standout star, with a high number of trials and a high level of trials per capita, is Turkey. Table 1 shows the relevant numbers for each country, as well as for the region as a whole.

more than 2 million people in the Middle East suffering from a rare disease.4 Second, the high rate of economic growth has increased access to better healthcare, which has a number of consequences. Better healthcare in itself costs money, but the health benefits are improved mortality rates and longer life expectancy, meaning people have more years of treatment and drug consumption. Longer life expectancy also leads to higher incidence of lifestyle diseases, for example those associated with smoking and alcohol. Obesity, diabetes and cardiovascular disease are on the rise, and six countries of the Middle East are among the top 10 globally in terms of prevalence of Type-2 diabetes.5 Increased affluence also creates a more selective, healthconscious and treatment-aware population, with sophisticated healthcare needs. The Middle East shows a marked predilection for innovative treatments. In her essay “Diabetes in the Middle East and North Africa: a high growth pharmaceutical market receptive to innovation”, Carolyn Gauntlett reports: “… a strong share of spend on the modern insulins, and the newer innovative classes of preinsulin diabetes treatments, the DPP-IVs and the GLP-1s. In Kuwait, spend on innovative treatments accounts for 73% of all diabetes IMS audited diabetes spend; in the UAE this is 68%”.6 Governments across the region encourage strong healthcare programmes, backed up by reimbursement for rare disease treatments.4 Improvement of infrastructure increases the patient base by improving diagnosis rates, in turn. A combination of weaker IP protection and an encouragement of the development of local industry has gone hand in hand with a push for affordable, lowerpriced medication, meaning that generics will be a major market driver (and that market growth will come from volume growth).7

Table 1: Population, clinical trials and pharma size by country in the Middle East.

It should be noted that these statistics only reflect trials which are reported on clinicaltrials.gov. The authors’ own research has found that Iran, for example, is currently running up to 13,500 trials, reported in the country’s own registries, and run as investigatorinitiated trials. The Growth of the Pharma Market in the Middle East The global pharmaceuticals market is USD 1.2 trillion in size and is projected to grow to USD 1.5 trillion by 2021.3 Of that amount, USD 26 billion is projected to be spent in the Middle East in 2017. This is less than 2% of the total, but the Middle East share is growing at 12–14%, one of the highest growth rates in the world.4 In the Middle East, growth is driven by a number of factors. First, population growth has led to an increasing population requiring medical treatments. The area reportedly has a high prevalence for some rare and genetic diseases, with an estimated 30 Journal for Clinical Studies

Drivers for Clinical Research in the Middle East There are clear, high expectations for the growth in clinical trials in the Middle East. Quintiles has estimated a market of about USD 1 billion by 2022 in the whole MENA region.8 This growth will be driven by many factors. First, the region has a high and growing population. MENA had the highest rate of population growth of any region in the world in the 20th century, and the region is projected to increase by a further 87% again between 2001 and 2050.9 Both the growth of the population and the growth of the pharma market are drivers for the growth of clinical research in the region. With the growth of pharma comes the increased relevance of drugs developed for local genotypes, growth in local manufacture, and the efficiency savings of early regulatory approval. As we have seen, the Middle East has a high incidence of some rare diseases. According to the Center of Arab Genomic Studies (CAGS), there are 774 genetic disorders caused mainly by recessive genes, possibly as a result of a high rate of consanguineous marriages.4,8 These diseases include diabetes mellitus (for which people in MENA exhibit the second highest prevalence), and orphan Volume 9 Issue 3


Market Report diseases such as Gaucher’s disease, Fabry disease, Behçet’s disease, thalassemia and sickle cell anaemia. The region also has high levels of hepatitis, chronic respiratory diseases, such as asthma, cancer, cardiovascular disease, obesity and psychiatric diseases.8,10,11 Studies have shown that 3% of pregnancies result in a child with a significant genetic disease.11 As a result, governments in the Gulf region reimburse for rare diseases.4 Running clinical trials in countries with high prevalence of certain diseases also allows a headstart in regulatory registration: trial results can be designed for relevance to local regulations. Marketing authorisation approvals and subsequent reimbursement gain extra leverage when clinical research was done on a country’s own population. Looking at patients, there is a high willingness to join trials in the Middle East. Quintiles’ research shows that “data collected on patient recruitment-related site productivity—defined as the average number of patients recruited per site in a country— indicated that MENA, in terms of patients recruited per site, is more productive than the US. In fact, some parts of MENA proved incredibly productive: for example, the combination of Egypt, Jordan, Lebanon and Syria produced a patient recruitment–related site productivity of 475 per cent of US levels.”8 At the same time, the region has developed a very good infrastructure to run international clinical trials. There has been a rapid adoption of a high level of technology, e.g. Turkey’s new digitised submission process, which promises first feedback within 48 hours, making some medical facilities in the region world-leaders. Highly qualified investigators are available, many Western-trained and with excellent English language skills, which smoothens communications for international trials. Alongside that, there are highly centralised healthcare systems and strong levels of governmental support, with a clear focus on attracting research.8,10

In their paper “Clinical trials in the Middle East and North Africa (MENA) Region: Grandstanding or Grandeur?” the authors outline a few challenges, including that of familiarity with local regulatory rules and processes, which may vary wildly between different countries in the region. They also mention the need for monitoring and oversight, following Good Clinical Practice (GCP) requirements. Informed consent is also raised, citing issues of language and understanding, among a local population which needs translation into Arabic, and a migrant population who might speak one of many other languages where translation may not be easy, or might even have marginal literacy. Lastly, in standards of medical teaching, while the region is home to many excellent medical schools and teaching hospitals, the authors worry that research design is not taught and scientific research itself is undervalued.11 Quintiles quotes an EMA paper, which states: “There is growing concern both among regulators and in public debate about how well these trials are conducted from an ethical and scientific/ organisational standpoint (including GCP compliance) and about the available framework for the supervision of these trials.”8 We see a trend to shift regulatory responsibilities from Ministries of Health to independent authorities (for example, SFDA in Saudi Arabia, FDO in Iran, MCC in South Africa). Meanwhile, site administration and registry applications are separate processes in many countries. Countries such as Lebanon do not require a Ministry of Health registry, or approval, site approval is sufficient to initiate a trial. Although this is preferrable by companies who would appreciate a fast start, it is questionable from quality and safety perspective.

Arabic is spoken most commonly in the Middle East, and this supports a uniform systems language, across the whole region. A similar harmonised approach has been put in place for regulatory requirements10 These factors result in a region that can be approached in an efficiently consistent way.

Compatibility, or harmonisation, with international regulations is a mixed bag. Francophone countries are generally tied to French regulations. Turkey, meanwhile, has taken major steps towards harmonising with EU legislation. The GCC has had a central committee since 1999 to oversee the setting up of a uniform set of regulations for the seven member countries: the Kingdom of Saudi Arabia, the United Arab Emirates, Kuwait, Qatar, Bahrain, Oman, and Yemen. Likewise, African states are creating their own standards for harmonisation and cooperation, via the Africa Medicine Regulatory Harmonisation (AMRH) programme.

Recouping costs from ever greater efficiencies is, of course, a key driver for pharma companies. Studies show that trial costs in the countries of the GCC and MENA are 59% of equivalent trials in the US,11 making the siting of trials in the Middle East eminently sensible, economically, with companies ever looking for new ways to reduce cost per patient. The high level of patient acceptance in joining trials also allows the acceleration of trial timelines, boosting productivity, and reducing the overall cost per patient.

Barriers to Clinical Research: Patient Recruitment The barriers to patient recruitment in the Middle East are a lack of awareness about clinical trials in patients, the complexity of study protocols, and social and cultural issues related to trial participation.12 Patients entering the process will have fears of being guinea pigs and have anxieties about the side-effects of the medication. They will have trust issues with physicians who may not offer effective services to patients during the trial.

As we have seen, there is currently a very low density of trials in the Middle East, which means there is a wide-open field for growth.

Potential strategies to enhance subject recruitment, therefore, include:

Barriers to Clinical Research: Regulations Strong governmental support nothwithstanding, we do note hindrances arising from the regulatory landscape in the Middle East. Guidelines and procedures are not up to international standards, but rather just administrative. There is an inadequacy of resources and coordination between authorities; trials refused by one committee may be approved by another with no change in submission. Various sources define challenges still to be hurdled for clinical trials to take off in the region, standards and practices for trials among them.

• engaging a dedicated clinical research coordinator to manage the running of each trial • arranging for patient transport to trial site for study visits • designing a recruitment strategy prior to study initiation • interacting with the medical community in the local area regarding clinical trial recruitment • educating subjects on the clinical trial during routine outpatient department (OPD) visits • creating positive awareness about clinical trials among people through press and mass media • using technological tools to select sites with high numbers of

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Journal for Clinical Studies 31


Market Report qualifying patients and to identify potential patients • using technological tools to engage patients and to increase the retention rate • creating professional centers using a software-driven, full process management system, which allows the definition and measurement of key performance indicators.

Turkey: Challenges In Turkey, the most important problem in the clinical research process is the lack of administrative integrity. Institutions act independently, budgets are unpredictable, and there are significant differences in administrative evaluation processes. The Ministry is continuing work on this issue.

Country Insights As we have seen, countries in the Middle East each have their own disease profile. The UAE and Jordan, for example, have high prevalence of diabetes (the UAE has the second highest in the world).11 Egypt has a high incidence of hepatitis C.10 Saudi Arabia has the fifth highest incidence in the world for obesity.5 Just under a third of Saudis are classified as overweight, just under a quarter are habitual smokers, and just under a fifth suffer from diabetes.13 Authorities in Saudi Arabia are aware of this and have given free health plans for everyone in the Kingdom, creating a model healthcare system.5,13

Other restrictions that may impede site and patient enrolment include the fact that no payments can be made to assistant personnel (leading to low motivation on their part to enroll more patients than they have to), no advertising can be done to recruit patients for clinical trials and no payments can be made to patients in return for their study participation (except Phase I). One further limiting factor is that investigators cannot be paid directly for their trial involvement; payments must be made to the circulating capital department of the relevant institutions. Researchers receive around 60% of the trial-related payments.

Country Insights: Turkey Of all the countries of the Middle East, the authors have had the most experience with Turkey. Turkey has well-structured processes and systems in place for clinical trials and has had a long history in running them. In this way, it is seen as a model for countries such as Egypt and Saudi Arabia, who are trying to close the gap. The country’s clinical research profile is developing, supported by new regulations that are in accordance with international standards and European directives. As a country with a population of nearly 80 million, with high genetic diversity, Turkey is a country that offers great, new oppurtunities for clinical trials. The number of hospitals in Turkey shows an increasing trend. In 2012, the country had 62 university hospitals, 489 private hospitals and 843 government hospitals. By 2016, these numbers had risen to 70 university hospitals, 560 private hospitals and 874 goverment hospitals.14 The number of researchers in the hospitals is increasing day by day, with Good Clinical Practice (GCP) training throughout the country, instigated at ministry level. Beyond all of these advantages, trial costs are comparatively low relative to European Union countries and the United States of America.

32 Journal for Clinical Studies

In particular, with the increasing number of ethical committees over the last two years, both inexperienced committees and increased opportunities have emerged. Now it is easier to conduct a study without worrying about application timelines. But the major issues in clinical trial patient recruitment are the same issues felt elsewhere, around the world: • Finding the right sites, with high potential, for trials. • Reaching the targeted number of patients. To avoid this, trial principal investigators (PIs) give very low estimates. The numbers for recruitment in the country as a whole are very low. • It is not possible to identify non-diagnosed rare disease patients. • Hospitals do not have dedicated staff for trials. PIs have the initiative. This gives a lack of reputation among international studies. Only PIs with some degree of reputation are able to conduct trials. The rest of the researchers may have ambitions to run trials, but do not know how to get access to them. • Currently, hospitals have no idea about their own numbers for ongoing studies, completed studies, recruited patients, budgets used/missed, patients dropped/completed. • No transparency in trial revenues (cf. US Sunshine Act).

Volume 9 Issue 3


You are the person

Who called the expert

Who secured the release

Of the drug delayed in customs

So the landmark trial

Could be completed on time.

Clinigen CTS adopts a problem-solving approach to clinical trial supplies, anticipating hurdles and working swiftly to overcome them. Our aim is to deliver a clinical trial experience that is seamless, secure and hassle free. Email: ctsinquiries@clinigengroup.com Web: www.clinigengroup.com/clinical-trial-services

Trust our chain reaction

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Journal for Clinical Studies 33


Market Report Solutions? Ostensibly about research, conducting sponsored trials requires professionalism to thrive in a competitive world. This is valid for physicians, clinical trial centres, and even countries. Physicians should be GCP-certified. They should be encouraged to conduct trials. Universities should have programmes related to clinical trials. Processes should be in line with international standards, and transparent. Technology should be in place in every step of the process, starting from feasibility, until the end of the study, to take advantage of the technological improvements and speed up the clinical trials management process, in addition to reducing human error rate. Given Turkey’s high rate of patient record digitisation and excellent and consistent data quality, it would make sense to leverage hospital databases for checking trial feasibility and for patient identification during trial recruitment. Big-data-style analytics allow queries to be performed which can identify eligible patients fitting complex sets of inclusion and exclusion criteria. This means that even patients with conditions that have gone undiagnosed may still be found by triangulating on combinations of other diagnoses, lab values, demographic data, and so on. With a large enough database, patients with rare diseases may easily be found. We would also suggest that centres should be built for clinical trials. The whole process workflow of a clinical trial at hospitals could be coordinated by these centres electronically. This would give transparency and efficiency. Clinical research centres have the potential to be a lightning rod to attract new studies to their local regional hospital cluster, by showcasing the clinical potential of their local population. PIs associated with these centres would also have a platform to present their clinical expertise and capabilities. Conclusion The countries of the Middle East have a unique profile which makes them an ideal ground for running sponsored, international clinical trials. An expansion within the region would bring benefits both to patients and physicians in the form of better access to new and advanced healthcare options, as well as to the pharmaceuticals industry seeking better, more cost-effective, high quality clinical trials. REFERENCES 1. United Nations, Department of Economic and Social Affairs, Population Division. World Population Prospects: The 2015 Revision 2. clinicaltrials.gov 3. Outlook for Global Medicines Through 2021: Balancing Cost and Value Report, QuintilesIMS Institute, Oct 2016 4. Middle East Pharma Markets Continue to Soar: Here’s Why, Genpharm, 2017 5. Cecilia Chui, Middle East: The new “promised land” for pharma? IHS Markit, 27 February 2015 6. Carolyn Gauntlett, Diabetes in the Middle East and North Africa: a high growth pharmaceutical market receptive to innovation, pharmaphorum, September 23, 2013 7. Charlotte Pineau, Charles Rink, White Paper: Pharmerging markets. Picking a pathway to success, IMS Health, ©2013 8. Vladimir Misik, White Paper: Expected Growth of IndustrySponsored Clinical Trials in the Middle East Benchmarked on other Global Regions, Quintiles, 2012 9. Farzaneh Roudi, Population Trends and Challenges in the 34 Journal for Clinical Studies

Middle East and North Africa, Population Reference Bureau, October 2001 10. White Paper: 3 Steps to Middle East Success, PAREXEL, 2014 11. Satish Chandrasekhar Nair, Halah Ibrahim, David D. Celentano, Clinical trials in the Middle East and North Africa (MENA) Region: Grandstanding or Grandeur?, Contemporary Clinical Trials 36 (2013) 704–710 12. Kadam, R. A., Borde, S. U., Madas, S. A., Salvi, S. S. & Limaye, S. S. (2016). Challenges in recruitment and retention of clinical trial subjects. Perspectives in Clinical Research, 7(3), 137–143. http:// doi.org/10.4103/2229-3485.184820 13. Pharma sales make up more than half of the GCC market and are growing, The World Folio, 2015 14. TurkStat, Turkish Agency of Statistics—Hospital Number Report, June 2012 and 2016 15. Causes of death statistics, 2010, 2011 and 2012, Turkish Statistical Institute, No 15847, 16 April 2013 16. Transforming health in Turkey: 21st century opportunities, UCL School of Pharmacy, September 2012 17. IMS Health, Country report: Turkey, Pharmaceutical Market Europe, May 2011,Murray Aitken, Michael Kleinrock, Global Medicines Use in 2020 Outlook and Implications, IMS Health, 2015

Bariş Erdoğan PhD, studied computer engineering at the Middle East Technical University and holds M.Sc. and Ph.D. in educational technology. His expertise and experience include management of innovative Medical Informatics projects and implementation of end-toend Healthcare IT enterprise information systems, both in the public and private sectors. Email: baris.erdogan@clinerion.com

Ömer Şeker MD, MPH is a medical doctor with Public Health Masters and holds a bachelor’s degree in Business Administration. Although he has experience in full drug development life cycle, he is focused on phase II – IV site selection, patient recruitment and retention strategies. He is also interested in using real world data for health technology assessment and epidemiologic studies. Email: omer.seker@clinerion.com

Le Vin Chin 20 years of experience in the full spectrum of marketing activities, from strategic marketing, to value-chain marketing, to outbound marketing, with a background in a wide variety of industries, from speciality chemicals, to software solutions, to instrumentation. He holds a Bachelor of Arts in Engineering and Management Studies from the University of Cambridge, UK. Email: levin.chin@clinerion.com

Volume 9 Issue 3


OFFERING DEEP INSIGHTS INTO KEY AREAS OF CLINICAL DEVELOPMENT Bioclinica is specifically structured to create clarity in the clinical trial process — so you can make better decisions.

eHEALTH SOLUTIONS eClinical Solutions Safety & Regulatory Solutions Financial Lifecycle Solutions

GLOBAL CLINICAL RESEARCH Research Network Patient Recruitment & Retention Post-Approval Research

MEDICAL IMAGING & BIOMARKERS Medical Imaging Cardiac Safety Molecular Marker Laboratory


Therapeutics

The Role of Biomarkers in Parkinson’s Disease In many neurodegenerative diseases, the search for biomarkers has been driven by an extensive investigation and characterisation of the disease itself, as well as diseased tissue. In Parkinson’s disease, PD, the examination of post-mortem brain tissue has led to the identification of relevant molecular pathways and genes that have allowed for targeted therapies, development of animal models, and new drug delivery systems. These targeted strategies have identified many biomarker candidates that are being actively evaluated for their potential as different types of PD biomarkers. The following article will discuss these biomarkers in depth. Parkinson’s disease is a progressive, neurodegenerative condition, phenotypically characterised by akinesia, resting tremor and muscular rigidity. This “classical” clinical expression is a consequence of complex pathophysiological processes in the substantia nigra (SN), leading to intraneural accumulation of alpha-synuclein (a-syn), thus forming the so-called “Lewy bodies” and eventually degeneration and loss of dopaminergic neurons. However, it appears that this pathological process occurs long before clinical expression, as nearly 50-60% of dopaminergic neurons are destroyed within SN before the appearance of motor symptoms. In addition to typical motor symptoms, there are several nonmotor symptoms such as are constipation, depression, lack of smell sense and rapid eye movement sleep behaviour disorders (RBD) frequently present in Parkinson’s disease, before the onset of the classical motor symptoms. Whereas the first three symptoms are sensitive yet not specific to PD, RBD is now accepted as the most specific phenotype of the PD premotor phase with an associated risk of more than 80% of patients converting to PD, or dementia with Lewy bodies (DLB) or less frequently into multiple system atrophy (MSA).1 The average latency between onset of RBD and occurrence of parkinsonian motor symptoms is 12–14 years2, making the premotor period quite long. The pathogenic process that causes Parkinson’s disease is presumed to be underway during the premotor phase, involving regions of the peripheral and central nervous system in addition to the dopaminergic neurons of the SN3. Thus, this prodromal period provides a pivotal temporal window during which disease-modifying therapy could be administered to prevent or delay the development and progression of disease4. An emerging picture is one of a vicious cycle in which a-syn aggregation and mitochondrial dysfunction exacerbate each other, which could explain why these cellular changes are observed together in degenerating neurons in PD. As a result of oxidative stress, disruption of Ca homeostasis, abnormal kinase activity 36 Journal for Clinical Studies

and interaction with misfolded a-syn accumulation, neuroinflammation associated with T-cell infiltration and glial cell activation is becoming the salient feature of Parkinson’s disease6. Neuroinflammation is playing the vital role in degeneration of dopaminergic neurons7, which might be of great importance in development of new therapies for PD. Clinical diagnosis of PD in daily practice is often based on physician’s experience and impression rather than stringent use of standard clinical diagnostic criteria such as the UK Parkinson’s Disease Society Brain Bank (UKPDSBB) criteria or recently published MDS diagnostic criteria. In fact, diagnosis of PD in the early stage has been problematic, as nearly one-quarter of patients are wrongly diagnosed, even in specialised centres. The most common misclassifications in clinicopathological series are MSA, progressive supranuclear palsy (PSP) and, less frequently, corticobasal degeneration. In clinically-based studies, common errors relate to essential tremor, drug-induced parkinsonism and vascular parkinsonism8. Source data verification in various multicentre clinical trials has shown low concordance of existing PD diagnosis with requested criteria. The translation process from physician-based diagnosis of PD into scientific diagnostic criteria used in multicentre clinical studies in PD is difficult, often impossible. Moreover, the diagnostic accuracy at first visit is only slightly above 80%, as shown by a meta-analysis of eleven studies assessing a UKPDSBB-based clinical diagnosis against post-mortem pathological examination as the gold standard9. Such findings highlight the need for diagnostic tests and biomarkers to enhance diagnostic confidence in early disease, or to eventually diagnose PD in its prodromal stages10. The suitable biomarker would allow treatment with putative neuroprotective agents to begin long before the significant and irreversible loss of neurons, and would enable the assessment of disease modification in individuals receiving treatment11. It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models or drug discovery fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The Biomarkers Definitions Working Group12 has defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention”. PD biomarkers can be categorised as genetic, biochemical and imaging. The utility of either single or group biomarkers are limited, but when combined and considered collectively, biomarkers for PD may be more useful. Genetic biomarkers: Mutations on SNCA, LRRK2, or VPS35 are responsible for development of autosomal dominant forms of PD. Autosomal recessive PD with early onset and complex phenotypes that include parkinsonism have been assigned mutation on another Volume 9 Issue 3


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Therapeutics

PARK loci. There is increasing knowledge of other genes (including GBA, GCH1, ADH1C, and TBP) that contribute to an increased risk for the sporadic form of the PD. In fact, glucocerebrosidase (GBA) heterozygous mutation is the most prevalent genetic biomarker, affecting 5–10% PD population. As genetic PD is still rare, accounting for only 2–3% of all PD populations, genetic tests are not part of the standard diagnostic process. Biochemical biomarkers. There have been numerous attempts to identify specific and sensitive PD biomarkers in the body fluids and biopsy tissues. Blood, CSF and saliva have all been extensively investigated. Studies of a-syn in CSF showed conflicting results, although data has shown that PD patients have significantly lower a-syn levels. However, because a-syn and other proteins are present in the blood, erythrocytes and thrombocytes, even minor blood contamination may profoundly affect the results of CSF analysis. According to one research group, CSF samples should not contain more than 10 erythrocytes per microlitre CSF13, or 500 erythrocytes per microlitre CSF according to a European recommendation14. In saliva, a-syn was lower in PD patients compared to controls and this was inversely correlated with the change in UPDRS score15. Alphasynuclein has also been found in the colonic mucosa before the emergence of PD clinical symptoms16, and additionally, published data showing gut microbiota in subjects with PD might be another potential biomarker for diagnosis of premotor PD17. Development of new, powerful tools – so-called ‘omics’ techniques — such as proteomics, metabolomics and transcriptomics in PD biomarker research will certainly make significant progress shortly. Neuroimaging biomarkers have been widely used in visualisation of striatal dopaminergic depletion of neurons. Dopaminergic PET scan is sensitive in identifying dopamine deficiency, even during the preclinical disease, and it is potentially useful in quantifying disease progression. However, there are a number of challenges associated with neuroimaging biomarkers, such as: interpretation 38 Journal for Clinical Studies

of results may be affected by compensatory changes resulting from disease and pharmacological intervention, and dopaminergic PET is expensive, and needs specialised infrastructure and expert analysis. I-ioflupane single-photon emission CT (SPECT) (also known as DaTscan) is a more widely available and less expensive tool, which is already approved for routine clinical use. It can be used to differentiate between Parkinson’s disease and other diseases that manifest as PD, but are not associated with presynaptic nigrostriatal terminal dysfunction. Both dopaminergic PET and SPECT are useful adjuncts, but have shown limited correlation with clinical measures in therapeutic trials. FDG-PET in PD is helpful in differential diagnosis of parkinsonism and may be helpful in the assessment of disease progression. However, it is less specific than dopaminergic PET and it may be affected by compensatory changes or drug treatment. 123

Structural MRI is more widely available than PET or SPECT and it is useful in differential diagnosis to identify symptomatic parkinsonism. Newly developed MRI techniques can reveal specific changes in the basal ganglia (i.e. iron accumulation at SN during PD progression), whereas diffusion-weighted imaging, volumetric imaging, automated subcortical volume segmentation and multimodal imaging have been explored to enhance diagnostic accuracy for Parkinson’s disease versus other types of degenerative parkinsonism. Transcranial ultrasound (TCUS) has been used to demonstrate increased echogenicity in the midbrain of patients with PD, as a result of the increased nigral iron content in this region. Although TCUS can be useful in the detection of premotor PD and differentiations against other akinetic-rigid syndrome, the hyperechogenicity does not seem to increase with disease progression. TCUS is cost-effective and has shown promise as a possible imaging biomarker in PD, but it is very dependent on Volume 9 Issue 3


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Therapeutics sample sizes and lack of autopsy-verified diagnosis have limited the value of results. A viable application of this technique is in monitoring therapeutic responses in clinical trials. Conclusion Regardless of critical need, there is neither a fully validated diagnostic nor prognostic PD biomarker available for clinical studies and drug development. It seems that functional imaging, regardless of several limitations is still representing the best available tools to study PD progression in disease-modifying clinical studies. We believe that new methods like a-syn accumulation assessment or combination of markers will provide greater reliability in the forthcoming years. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

operator skill, it is not specific and requires an adequate temporal acoustic bone window for good imaging. Apart from dopaminergic biomarkers, there are a few nondopaminergic biomarkers useful in diagnosis of PD. Loss of cardiac sympathetic innervation can be documented in PD by decreased uptake of the sympathetic marker, 123I-metaiodobenzylguanidine (MIBG), in cardiac SPECT. Moreover, this marker contributes to the differential diagnosis between PD and other forms of parkinsonism such as MSA or DLB. MIBG is the only biomarker specifically addressed in the recently published Movement Disorders Society criteria for diagnosis of PD18. Uptake of 123I-MIBG in myocardial scintigraphy is often reported as a heart-to-mediastinum (H/M) ratio of count densities, whereas washout rate index may also be assessed using early and delayed images. MIBG should be considered in the light of the entire clinical presentation because various cardiovascular morbidities, latent cardiac disorder and medications may damage the postganglionic sympathetic neurons, leading to false positive findings. Additionally, 123I-MIBG H/M ratios may also decrease with age and show gender-specific variations, making it essential to use well-matched subgroups in clinical investigations. Neuroinflammation markers of activated microglia, such as C-PBR028-PET have been tested with varying success. Small

14. 15. 16. 17. 18.

Iranzo A, Fernández-Arcos A, Tolosa E, et al.: Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients. PLoS One. 2014;9(2): e89741. Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord 2012; 27: 617–26. Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015; 386: 896–912. Siderowf A, Lang AE. Premotor Parkinson’s disease: concepts and definitions. Mov Disord 2012; 27: 608–16. Bose A, Beal MF. Mitochondrial dysfunction in Parkinson’s disease. J. Neurochem. 139 (Suppl. 1), 216–231 (2016). Moehle MS, West AB. M1 and M2 immune activation in Parkinson’s disease: foe and ally? Neuroscience 2015: 302:59–73. Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:S210–S2. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol. 2006:5, 75–86 (2006). Rizzo G et al. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 2006:86, 566–576. Poewe W et al. Parkinson’s disease. Nature Reviews 2017:3:17013. Miller DB, O'Callaghan P. Biomarkers of Parkinson's disease: Present and future. Metabolism 2015:64:40-46. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69:89–95. Caudle WM et al. Using ‘omics’ to define pathogenesis and biomarkers of Parkinson’s disease. Expert Rev.Neurother. 2010:10, 925–942. Teunissen CE et al. A consensus protocol for the standardization of cerebro-spinal-fluid collection and biobanking. Neurology 73, 1914–1922. Devic I et al. Salivary alpha-synuclein and DJ-1: potential biomarkers for Parkinson’s disease. Brain 2011: 134, e178. Shannon KM. Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov. Disord. 27, 716–719. Scheperjans F. Can microbiota research change our understanding of neurodegenerative diseases? Neurodegener. Dis. Manag. 6, 81–85 (2016). Postuma RB et al. MDS Clinical Diagnostic Criteria for Parkinson’s Disease. Mov Dis 2015:30:1591-1599.

Tomislav Babic MD, PhD is Vice President of Medical and Scientific Affairs/ Neuroscience Franchise at Worldwide Clinical Trials Inc. Dr Babic is a board-certified neurologist and clinical pharmacologist, with particular interest in drug development for Alzheimer’s disease, Parkinson’s, and MS. He is the author of more than 60 peer-reviewed articles and books and has been integral to the development of many approved drugs for PD. His expertise has been widely noted in neurodegenerative disorders in both industry and academia for the past 25 years. E-mail: tomislav.babic@worldwide.com

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Therapeutics

The Epidemic “Fléau” of Diabetes Mellitus and the Need for a New Era of Therapies and Prevention Diabetes and Diagnosis Diabetes is one of the most common non-communicable diseases (NCD) globally and the fourth leading cause of death in developed countries. Today, it has reached epidemic proportions and currently affects 71 million people worldwide.1 The causes and symptoms of diabetes mellitus have been known for decades, and affect millions of people of all social classes and ethnic groups throughout the world. Diabetes mellitus is a metabolic disorder with several causes and is characterised by chronically high blood glucose levels (hyperglycaemia), with disturbances of carbohydrate, fat and protein metabolism.2 The classification of diabetes encompasses three clinical stages: Normoglycaemia (normal glucose regulation); Prediabetes (impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)); Diabetes (high blood glucose level – hyperglycaemia). The long-term effects of diabetes include damage, dysfunction and failure of organs and tissues, as well as high risk of cardiovascular disease.2 Fasting glucose levels are measured to classify diabetes. The World Health Organisation defines the following fasting glucose test results: • Normal: Below 6.1 mmol/l (110 mg/dl) • Impaired fasting glucose: Between 6.1 and 6.9 mmol/l (between 111 mg/dl and 125 mg/dl) • Diabetic: 7.0 mmol/l and above (126 mg/dl and above) Furthermore, measuring glycated haemoglobin (HbA1C) as a marker indicates the average blood sugar level over a period of weeks/months. This marker allows diagnosis of diabetes as indicated in the table below.

Table 1: Ranges of HbA1C and diagnosis of diabetes

Types of Diabetes There are different etiologic types of diabetes such as type 1, type 2 and gestational diabetes. Type I diabetes, once called “juvenile-onset diabetes,” is an autoimmune disorder involving the insulin-producing cells of the pancreas. It is also known as “immune mediated,” and type I has been considered to be the major form of diabetes found in children. Typical symptoms ultimately leading to testing and diagnosis are normal or below normal weight, increased thirst and urination, and tiredness.3 Type 2 diabetes (non-immune mediated) was formerly referred to as “adult-onset diabetes.” This condition occurs when either the cells in the body become resistant to insulin, when the body does not produce enough insulin, or both. In children, the condition 42 Journal for Clinical Studies

appears related to inappropriate insulin action which leads to a failure of cells to produce insulin. Individuals with type 2 diabetes are often overweight, have little or no excess thirst, no increased urination, and have a strong family history of diabetes. Historically, awareness of type 2 diabetes in children was limited. In 1979, Type 2 diabetes was first reported among adolescent Pima Indians living in Arizona. The Pima Indians have the world’s highest prevalence of type 2 diabetes.6 Type 2 diabetes constitutes at least 90% of all diabetes. For most countries, Type 2 diabetes has evolved in association with rapid social and cultural changes, ageing populations, increasing urbanisation, dietary changes and reduced physical activity, leading to obesity and other unhealthy lifestyle and behavioural patterns. The United Nations General Assembly recognised diabetes as a chronic and costly disease, accompanied by major complications, that has a major effect on both individual health and national productivity. Thus, the 14th November was declared as World Diabetes Day. The World Health Organization (WHO) estimated that the number of persons suffering from diabetes could rise to 438 million by 2030.3 In addition, impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate conditions in the transition between normal blood glucose levels and diabetes (especially type 2), though the transition is not inevitable. People with IGT or IFG are at increased risk of heart attacks and strokes. Gestational diabetes (GDM) is a temporary condition that occurs in pregnancy and carries long-term risk of type 2 diabetes. The condition is present when blood glucose values are above normal but still below those diagnostic of diabetes. Women with gestational diabetes are at increased risk of some complications during pregnancy and delivery, as are their infants. Gestational diabetes is diagnosed through prenatal screening, rather than reported symptoms. The intrauterine environment influences the risk of developing type 2 diabetes. Offspring from diabetic pregnancies are often heavy at birth, develop obesity in childhood, and are at high risk of developing type 2 diabetes at an early age.6 Diabetes Worldwide Conventionally, diabetes has been viewed as a disease of rich countries. However, IDF Diabetes Atlas has shown that four out of five people living in countries classified by the World Bank as low- and middle-income countries are diabetic.12 In 2011, out of 3.6 billion adults living in low- and middle-income countries, 291 million had diabetes compared to only 75 million living in highincome countries.13 Over the next 20 years, the numbers of people with diabetes will increase in low- and middle-income countries. This is led by an increase in the adult population, longer life expectancy, rapidly increasing urbanisation and development which consequently brings changes in behaviours, such as reduced physical activity, a shift to higher-calorie diets, and the associated increases in obesity. This transition becomes clearer when breaking down middle-income countries further into upper-middle-income and lower-middle-income. The prevalence of diabetes is higher in upper-middle-income countries (10.1%) than in lower-middleincome countries (8.6%).12 Volume 9 Issue 3


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Therapeutics Diabetes in Mauritius In Mauritius, a survey conducted in 2015 revealed the prevalence of diabetes among adults according to age and gender. The prevalence of diabetes (age- and gender-standardised to the national population of Mauritius) in adults aged 25–74 years was 22.8%: 23.5% for women and 22.0% for men. The prevalence of diabetes in adults aged 30–74 years was 25.8%: 25.3% in men and 26.6% in women.11 Figure 1 gives an apercu of the distribution of diabetes in the Mauritian population according to age and gender.11

Figure 1: distribution of diabetes in the Mauritian population according to age and gender

Mauritius has a multi-ethnic population of 1.3 million inhabitants, predominantly made up of Asian Indians (68%), Creoles (27%) and Chinese (3%). This diverse ethnic composition reflects the history of migration of slaves, indentured labourers and merchants from India, Madagascar, Africa and Asia. One of the reasons for Mauritius being among the countries with the highest prevalence of diabetes in the world is because most of the population is of Indian origin. Studies have shown that Indians are more prone to development of the complications of diabetes at an early age (20–40 years) compared with Caucasians (>50 years). The table below shows the age and gender prevalence of diabetes and ethnic groups in Mauritius:11

Table 2: Diabetes and ethnicities in Mauritius

Notes: *The ‘other’ population includes those who are ‘FrancoMauritian’. Prevalence data were standardised to the 2008 population of Mauritius aged 25–74 years.

Kingdom. In Japan, 80% of the reported cases of diabetes among children are type 2 diabetes. This is an emerging public health issue of significant proportions, as the fall in the age of onset of type 2 diabetes is an important factor influencing the future burden of the disease. Having diabetes during childhood is followed by many years of disease and a higher chance of having both micro- and macrovascular complications, often related to hypoglycaemic medications.5,3 The CDC findings also demonstrate that children and adolescents consume too much fat, saturated fat, and sodium, and insufficient vegetables, fruits, and calcium. Such dietary patterns are highly conducive to weight gain in children as well as adults. When obesity is associated with higher amounts of upper body, or central visceral fat, a 40% decrease occurs in insulin-mediated glucose disposal, making an individual more at risk for developing type 2 diabetes. The more obese the child, the greater the risk for type 2 diabetes, but not all children with this condition are overweight.8 The American Academy of Pediatrics reports that females face a slightly higher risk for being diagnosed with type 2 diabetes. While cases have occurred in early childhood, the peak age for diagnosis usually occurs during mid-puberty, when an increased resistance develops to the action of insulin. Perhaps the increased levels of growth hormone, which occur temporarily at this time, contribute to insulin resistance. Also, fat cells make a unique type of oestrogen, so overweight females may experience earlier pubertal development.7 Screening and Prevention For those with Type 2 diabetes, lifestyle changes are imperative. Dietary habits must be adjusted, but changes in eating patterns should be made with individual cultures and financial resources in mind. A balanced diet that limits fat and carbohydrates needs to be discussed with appropriate caloric intake, portion size, and frequency of meals and snacks. Dietary changes alone, however, will not sufficiently address the individual’s lifestyle. Exercise is associated with decreased insulin resistance as well as weight loss; children with type 2 diabetes should increase their daily levels of physical activity. Family members, schools, and community groups should make an effort to get all young people involved in a variety of physical activities that will appeal to them and be perceived as fun and socially acceptable. Exercise opportunities that keep children motivated are more likely to encourage them to incorporate the activities into their schedules. Government policies may help in creating guidelines on diabetes management, as well as funding community programmes for public awareness about the diabetes risk reduction, availability of medicines and diagnostic services

The epidemic of diabetes is not only seen among the young adults population, but also among children. The ethnicity predisposition remains a threat for Mauritius. With the rise towards “metissage” we cannot erase the fact that the statistics will only increase in Mauritius. Type 2 Diabetes in Children – A Rising Threat There is now a major emerging global phenomenon that reveals a new perspective of the global diabetes epidemic. Type 2 diabetes, which is considered to be a disease for adults, is now not only seen among young adult populations, but also in adolescents and children. Until now, type 1 diabetes has been the major form of diabetes in children, but it seems likely that type 2 diabetes is set to become the predominant form within the next 10 years in many ethnic groups and potentially in white children also.4 Type 2 diabetes has already been reported in children from Japan and other Asian nations, the USA, Hong Kong, Australia and the United 44 Journal for Clinical Studies

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Therapeutics to all sections of community. Efforts by various governments and agencies around the world to intervene in diabetes management have resulted in positive health outcomes for their communities. The Use of Metformin – Initial Drug Therapy Metformin is old, but is still the best treatment for type 2 diabetes. It can be used either alone or combined with other drugs, such as sulfonylores and thiazodiones. Its low cost, proven safety record, weight neutrality and possible benefits on cardiovascular outcomes have secured its place as the favoured initial drug choice. What researchers have learnt in the past several years is that metformin has many other positive benefits beyond controlling blood glucose levels with very low risk of causing hypoglycaemia (low blood sugar). One major effect of metformin is a decrease in the production and release of glucose from the liver. When used in combination with antidiabetic drug sulfonylurea or insulin, metformin also can help minimise the weight gain frequently associated with these medications. It can lower LDL (bad) cholesterol, lower blood fat levels and reduce the risk of cardiovascular disease. And when taken by individuals treated intensively with sulphonylureas, a class of oral medications that control blood sugar levels in patients with type 2 diabetes by stimulating production of insulin, or insulin alone, metformin also significantly decreased the risk of stroke. Although metformin is primarily used in the treatment of type 2 diabetes, it has also been safely used to treat diabetes that develops during pregnancy (gestational diabetes). In overweight individuals with prediabetes, it can help delay or prevent the development of full-blown diabetes. However, metformin has a few side-effects, the most common being nausea and diarrhoea. These effects can sometimes be avoided or minimised by taking a lower dose or extended release form of metformin.

Australia. With diabetes being one of the greatest threats to public health, especially in the low- and middle-income countries in the 21st century, strengthening efforts to prevent and control this menacing chronic disease remains a priority. REFERENCES 1. 2. 3.

4. 5. 6. 7. 8. 9.

10. 11.

DUAL THERAPIES AND NEW THERAPIES FOR DIABETES Dual Therapy If the HbA1c target is not achieved after three months, metformin is used in combination with other drugs. There are six different treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin. DPP-4 inhibitors (gliptins) is a relatively new class of drugs for type 2 diabetes which was approved in 2006. A study done to evaluate the effect of sitagliptin in people who have not achieved adequate blood glucose control with metformin alone, revealed that people on sitagliptin treatment in combination with metformin had a lower incidence of hypoglycaemia. Additionally, an average weight loss of three pounds was observed on this population.9 Studies have revealed that the use of DPP-4 inhibitors, such as saxagliptin alone, reduce HbA1c levels to 0.4 %–0.5%; however, when added to metformin, the HbA1c reductions are approximately 0.7%.10 Conclusion Diabetes is a chronic disease that, through its complications, can seriously impact the quality of life of individuals and their families through premature illness and death. Diabetes now affects much of the workforce; the socioeconomic consequences of diabetes are likely to significantly impact the economies of many developing nations like Mauritius, in addition to their devastating impact on the economies of developed nations such as the USA, UK and www.jforcs.com

12. 13.

International Diabetes Federation. National diabetes fact sheet 2017. Available at: http://www.idf.org/. Last accessed: 14 April 2017. Motala A, Rauff S, Hajira B. Cost effective Management of Diabetes Mellitus, 2006. World Health Organization Expert Committee. Definition, diagnosis and classification of diabetes mellitius and its complication. Report of a WHO consultation, part 1: diagnosis and classification of diabetes mellitus. Geneva: World Health Organisation; 1999. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 414:782–787, 2001. Gluckman PD, Hanson MA, D.Phil., Cooper C, MD, Thornburg KL. N Engl J Med 2008; Available at: http://www.nejm.org/doi/full/10.1056/ NEJMra0708473?query=recent&rss=1/ Last accessed: 14 April 2017. Dabelea D, Pettit DJ, Hanson RI, Imperatore G, Bennett PH, Knowler WC. Birth weight, type 2 diabetes and insulin resistance in Pima Indian children and young adults. Diabetes Care. 1999. Cam JF. Type 2 diabetes mellitus in children. Proceedings from the American Academy of Pediatrics annual meeting. Chicago, p.111, Oct 2000. Centers for Disease Control and Prevention. Guidelines for school health programs to promote lifelong healthy eating. MMWR. 1996. Inzucch SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peter AL, Tsapas A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes . Available at: http://care.diabetesjournals.org/content/38/1/140/ Last accessed: 14 April 2017. Marino M, MD. Diabetes Drugs: DPP-4 Inhibitors, Oct 2009. Available at: https://www.diabetesselfmanagement.com/blog/diabetes-drugsdpp-4-inhibitors/ Last accessed: 14 April 2017. Ministry of Health and Quality of Life. 2015, NCD Survey 2015. [ONLINE] Available at: http://health.govmu.org/English/Statistics/ Health/Mauritius/Documents/annual%20report%202014.pdf./ Last accessed: 14 April 2017. International Diabetes Federation, 2015. Available at: http://www. diabetesatlas.org/Last accessed on: 18 April 2017. The World Bank. Country and Lending Groups 2011. http://data. worldbank.org/about/country-classifications/countr-and-lendinggroups Last Accessed: 18 April 2017.

Mona Dawood Head of the Pharmaceutical Operations & Regulatory Affairs for CIDP group, Mona has a BSc (Hons) in Biomedical Chemistry from the University of Warwick (UK) and a Diploma in CRA from Sup-Santé, Paris, France. She has acquired expertise in specific monitoring in various therapeutic areas such as oncology, diabetes, paediatric. She has more than 7 years of experience in the field of research, monitoring and Trial Management, and an excellent knowledge in European & Asian Regulations, Regulatory Aspects, Claims validations, pharmacovigilance. CIDP Regulatory Affairs works in close collaboration with toxicologists and ensure timely reporting and good communication to Regulatory Authorities & Ethics Committees. E-mail: m.dawood@cidp-cro.com

Journal for Clinical Studies 45


Technology

The Assumptions of Data Capture Within the field of clinical research, there has been, for many years, a move away from the use of paper as a form of data capture, in favour of electronic data capture, particularly within industry. The advent of the use of electronic case record forms (eCRFs) is nothing new from that perspective: what remains a challenge is the use of electronic data capture (EDC) at site. This article will, I hope, with some broad generalisation, raise awareness of the issues from the sites’ perspective. A research nurse or person responsible for the recording of data relating to patients enrolled onto a study will inevitably be undertaking a number of clinical trials for different sponsors. They will, therefore, be using a number of different EDC products, each using a different platform and with different user credentials. In this article, by detailing their experiences and use of these platforms, I hope to highlight anecdotal issues and challenges that demonstrate the frustrations which we have discussed at various sites for a number of years. Historically, this started with the phenomenon of the industry study laptop and broadband line; it became the critical point of data entry for some clinical trials. Despite the availability of computers within the clinical setting, the sponsors perpetuated the delivery of individual laptops, and sometimes associated broadband lines, for each study. These laptops eventually became a burden to the site with the responsibility to catalogue and store large numbers of these devices, many of which remain uncollected ever since.

controls or require Java plug-ins, as this will ultimately – rightly or wrongly – produce frustration at the site. New Technology is Good, Right? We are in a world of technology that is helping us wander around the planet with a phone in our hand, enabling us to take pictures, book tickets and turn the heating on and off at home. Generally, most industry sectors are embracing new technology, both in terms of software and hardware. So therefore, it appears obvious that there are technology solutions to help sites in the conduct of clinical trials. This seems to be true in the minds of contract research organisations who are keeping pace with technology and development. There are several, seemingly obvious, technology solutions to aid the smooth running of clinical trials, ranging from infrastructure, small applications, add-ons and other opportunities which again, although well-meaning in a practical sense, are extremely difficult to implement into the actual site environment. Common misperceptions of the capabilities of a site are quite often the reason for the downfall of a project, where we have heard again and again the cry of “surely you are joking”, when this is explained.

The History of the Web Browser On the whole, the world is using the latest technology across a number of different devices and operating systems; however, monitoring undertaken by the University of Southampton Clinical Informatics Research Unit, across software used in 80% of the NHS, has identified that there is still a large amount of variation on the number of different types and versions of web browsers used, particularly Internet Explorer 7 and 8, which are still prominent at 60% of NHS sites. Recently, a number of technology demonstrations from EDC suppliers presented the functional benefits of their application to industry customers that will optimally operate in IE11 or the latest versions of other browsers; ironically, there is a lack of information to both industry and the EDC supplier to inform them that, although this application works well in rendering the forms as an application in their own offices, the view of the application from the site version of the browser presents a number of issues in rendering the forms, which can result in considerable difficulty for the end-user operating it. Optimised development of web-based solutions still needs to consider backwards compatibility with IE, or at least should be able to operate in Chrome with no requirements to install third-party 46 Journal for Clinical Studies

Volume 9 Issue 3


Technology Recently, I was asked about reviewing the option of remote data source verification by uploading a scanned copy of the clinical chart. For a start, the data protection and governance issues were going to be an issue with this approach but, from a technical perspective, there was the problematic fact that the sponsors presumed that we had multi-function devices that were capable of scanning and e-mailing a PDF or storing to a file location. In reality, this was going to make the whole process rather time-consuming: site staff would have to walk halfway across the site to find the one and only device with such a capability, before returning back to their desk to upload the PDF file into the sponsor’s or CRO’s system. This solution had not, it would appear, considered and examined the complex issues of taking a set of medical records apart in order to extract one page of data, copy and redact the sensitive information required, before scanning and then reconstructing the medical record. I mentioned this to a member of the nursing staff who proposed that whoever dreamt up this concept might like to visit the hospital site to be given a demonstration of the proposed solution in practice – a demonstration given by, I conclude, a rather angry and exasperated individual.

£

The concept of clinical research data capture can be demonstrated using the following supermarket analogy: each shopper (funder/sponsor) has their own till system that the checkout staff (nurse/responsible person) are expected to use. In most quick, random polls of check-out staff responsible for clinical data capture at site, the average number of tills (unique eCRF solutions) is between seven and ten. One session held to find out common complaints/problems about data capture, from the same staff, produced the following common complaints: • CRF pages do not load correctly and the content can be hard to navigate, in hospital IT browser estate • Systems’ and clinical process logic do not align • Too many login details for the same systems (single sign-in) • Quality of life questionnaires for patients using iPads requires a lot of work with patients to help them use or complete the questionnaire, and patients forget their login details or pin numbers • CROs are not collecting equipment after studies • There is an increasing requirement for the scanning of documents. Overall, there are exciting and obvious trends in adopting new technology and software. However, the question of whether the sites and patients are ready to implement and use this technology indicates that there are still some hurdles to jump before this technological approach can be fully adopted. Technology companies, sponsors and contract research organisations need to consider that, in some respects, the enduser IS the site, but there is currently very little dialogue with these users and implementers of technology for data capture. Their input should be key in taking this forward. I plead that the site staff supporting research data capture are openly engaged in conversations around data capture issues, and that they are willing to help industry understand these challenges: all you need to do is ask and involve them in the process of adopting new technology and solutions to make sure that the investment is worth it. www.jforcs.com

1

James Batchelor Director of the Clinical Informatics Research Unit at the University of Southampton, UK, and Professorial Fellow of Clinical Informatics and Healthcare Innovation. Approximately 15 years ago Professor James Batchelor developed EDGE, a Local Portfolio Management System (LPMS) that is now adopted across 80% of the NHS. Its ultimate aim is to unify clinical research teams nationally and internationally in order to influence and improve routine clinical care, and thereby enable a better quality of life for patients. He is also a Committee member and advisor to the Republic of Ireland e-Health Programme, as well as being involved in the development of clinical research standards with the University of Cologne, Germany, and within the CDISC. James has worked in this area of research for over 15 years and is well known within the research community, both in the UK and overseas, for his practical solutions to clinical informatics. Email: j.batchelor@soton.ac.uk

Journal for Clinical Studies 47


Technology

Behind the Smoke and Mirrors of IDMP Solutions Life sciences technology vendors and consultancies are busy promoting Identification of Medicinal Products (IDMP) compliance solutions, which seems odd, given that many details of the final requirements have yet to be published. With a further two years to go until the latest deadline comes around, organisations have every reason to be sceptical of the value of investing now, says Marc Chaillou of Schlafender Hase. It has been a source of consternation that the European Medicines Agency (EMA) keeps pushing back the deadline for ISO IDMP (Identification of Medicinal Products) compliance. The latest timescales give companies two more years to get their data in order before the authorities formally clamp down and expect full adherence. It does serve everyone’s interests that such a definitive international standard for product data exchange is effective, and supports the high quality and reliability that will ensure the data’s value. However, the proposed phasing of adoption and now further delays to publication of the fuller requirements, as well as the cutoff for compliance, are sapping any remaining momentum around the initiative and prompting life sciences companies to prioritise spending elsewhere. This has not stopped the life sciences technology and services industry from promoting IDMP software and solutions, however, which seems odd, given that the finer details of the medicinal dictionary definitions have yet to be set in stone. It would seem that vendors and consultancies are approaching the challenge/ opportunity the wrong way round – offering to get manufacturers’ databases and submissions systems up to spec even before that spec has been confirmed. Seeing that solutions are available on the market could lull companies into a false sense of security, and worse, encourage them to invest inappropriately – i.e. in the wrong order.

48 Journal for Clinical Studies

That is not to say that they shouldn’t be preparing. On the contrary, life sciences organisations have their work cut out with IDMP. It is such an ambitious project, on such an ambitious scale, that it will take a lot of time to align all the right pieces. And unless companies can deliver the quality and reliability EMA and ISO have in mind, they will compromise not only the payback on their own outlay, but also the intended benefit to patients. After all, it is their safety that IDMP is designed to ensure - by making the target database a robust, definitive, harmonised record of approved and marketed drugs, using agreed definitions and terminology. As such, IDMP will be central to mass-scale, cross-border pharmacovigilance. Its slowness to get off the ground is down to the ISO’s ambitions for the set of standards, which are much grander and more comprehensive than previous attempts at electronic publishing requirements (most recently XEVMPD), under the remit of regulatory affairs. The implications of this are that data preparation will now touch all corners of the organisation, as well as outlying parties including in-country affiliates and supply-chain partners. All have a part to play in ensuring that core systems and applications contain the latest, accurate information. Consistency and reliability are paramount. The upside of putting in all of the groundwork to get content in order is that life sciences companies stand to gain from this effort in many other ways. By investing in a central, definitive master resource of product data, they are creating new possibilities for the business and its operations, because that data potentially has value in a range of other scenarios, such as portfolio planning and improved operational management. But that’s only if the data is of high quality, and has been robustly tested to ensure this. This is the investment that companies need to be making now, irrespective of whether IDMP filing timelines may shift again, and of the final specifications that have yet to be agreed.

Volume 9 Issue 3


Technology A Stitch in Time Forward-thinking companies are treating this intervening time as an opportunity to quantify the data preparation task that lies ahead. First, they need to identify all of the source content, the different formats that it is held in, and where it resides within the global organisation. By creating a comprehensive inventory of files and file types, organisations can start to understand the size and scope of the task that lies ahead and begin to work out how they are going to tackle it. This preliminary process is likely to throw up a number of issues. For example, when there are multiple iterations of a document, which and where is the most up-to-date version? This might be in Regulatory Affairs, Legal or Marketing, for instance. If it is in a document management system, which one? Very few organisations have a single, comprehensive, centralised system for holding content – and in fact, many have a number of systems in use for different departments – so bringing content together or trying to compare one version with another is unlikely to be easy to achieve. So part of the task must be to itemise all the different software platforms and determine what is where. If the company has been subject to mergers and acquisition activity, and/or has amassed different legacy infrastructures over the years, all of this will add to the complexity of content management. Across the wider ecosystem, contract manufacturers, CROs, local representative offices, translation companies and other service providers will also need to be surveyed for contributing product information. Beyond structured databases and formal document management systems, there are likely to be assets stored on people’s desktops, attached to emails, or kept in folders on servers without a common naming convention. If documents are PDFs, and do not contain selectable text (i.e. if they are simply outlines or images), their content will be difficult to extract and re-use – machines will be unable to read it. Use of non-Unicode fonts – those that are displayed differently or incorrectly across software and operating systems – could also interfere with machine readability. Different languages, different spellings and corrupted content could all compromise consistency and accuracy as organisations work towards a definitive record of correct, current product information. Files may have been broken up by regulatory teams too – so that a master product information file running to 30–40 pages of detail on a drug may also exist as a series of separate Word files – e.g. containing the content for labelling, box content, patient literature – intended for the graphic design team. If these have been copied and pasted manually, and updated/corrected separately, the scope for variation will multiply. Given all of this complexity, it is surprising that so many life sciences companies continue to put off their preparations until they have the final IDMP specifications. Other than among some of the very large players, who have understood the broader benefit of getting their product data in order, there is still a wait-and-see mentality. Beware the Emperor’s New Clothes Companies will undoubtedly need help with all of this, but they need to be careful where they go for this assistance, especially in this intervening period where full IDMP solutions cannot possibly be what they claim. How content or data will ultimately be used is purely secondary. The first priority must be to ensure that that data is correct, complete and clean, that it is usable, and that it is of value to the organisation. Without that sure footing, companies will be progressing on shaky ground. Whether the later application is IDMP submission or something more operational and internal, the output www.jforcs.com

will only ever be as good as the source content. Put garbage in and you’ll get garbage out. If companies are making the investment, they may as well get the most they possibly can out of it – and one of the biggest benefits of IDMP (beyond improved patient safety) is expected to be huge efficiency gains and long-term cost savings for the industry. As long as the directory is of sufficient quality that it can be used confidently, that is. So how can companies get ahead, and make this work for them? What they cannot do is cut corners; otherwise they will render their efforts worthless. But they can harness automation, if they understand the task and pick the right tools. When it comes to selecting the definitive source documents, checking for updates, aligning languages, fonts and other intricacies, it is possible to very accurately compare files in different formats for the content they contain – as long as the technology can ‘read’ content at the right level – one that transcends ‘noise’ such as font or file type. This ability to quickly compare content of similar documents from multiple sources, in large batches, could help save organisations vast amounts of time in this laborious yet inevitable preparatory stage of getting the company’s product data assets in order. For now, the rest is just smoke and mirrors. It is too early to have a magic database that companies can use to submit to the IDMP. In any case, that final-stage task – definition refinement and submission – will be relatively easy compared to the work that needs to happen now. As long as all documents have been accounted for, crossreferenced and checked, and labelling and other patient content verified as correct and up to scratch, firms will stand themselves in good stead for what’s to come. The final step will be comparing precompliant content with the new specifications when the time comes – ideally with an ability to filter and flag key words (controlled vocabularies) to ensure that quality checks will be efficient and reliable. Developing a plan which takes companies on the journey mapped out here, offers their best hope of being ready, and of deriving the maximum benefit from investments in IDMP. In the meantime, firms would do well to keep checking the EMA website for new updates (http://www.ema.europa.eu/ema/ index.jsp?curl=pages/regulation/general/general_content_000645. jsp), and join the IRISS Forum (https://iriss-forum.org/). The latter, which costs a nominal fee of around $100 to subscribe to, is a notfor-profit body of pharma companies and technology vendors. It was set up as a single central forum to promote stakeholder discussion around evolving regulatory submissions standards, user requirements and practical global implementation issues for the mutual benefit of industry, government agencies and public health.

Marc Chaillou International Markets Manager at Schlafender Hase, whose Text Verification Tool (TVT) is the most used software for automatically comparing artwork files with original Word sources, to improve proofreading accuracy and efficiency in highly regulated markets such as the pharmaceutical industry. E-mail: marc.chaillou@sh-p.de

Journal for Clinical Studies 49


Technology

Transforming Clinical Research through Cloud Computing Technology The process of carrying out clinical research and conducting clinical trials is very expensive, complicated and timeconsuming. The necessary strict regulatory standards surrounding clinical research and the drug approval process further complicates things. Of paramount importance is the anonymity of human subjects, and clinical research organisations (CROs) conducting trials in collaboration with pharmaceuticals must maintain confidentiality at all costs. Cloud-based software solutions are the right way to move forward in the clinical research field, and choosing the right partner to build a CRO's cloud architecture is pivotal to its success. Going paperless can bring drastic security improvements to the entire process. Adoption of good cloud-based information security management policies can further bolster information safety. Taking medical research and drug development to the cloud also has the potential to reduce capital and operational expenditures and to fast-track innovation. Cloud-based techniques such as big data analytics and distributed computing can also improve collaboration through centralisation of computational and research tools.

US FOOD AND DRUG ADMINISTRATION (FDA): A CASE STUDY2,3 The challenge: The US Food and Drug Administration (FDA), which is responsible for protecting and promoting public health, receives around a million reports every year pertaining to drug safety in the form of emails, faxes, phone calls and around 100,000 handwritten reports. The agency badly required a way to consolidate this publicly-available information, make the data entry process more efficient and reduce costs. The solution: openFDA, an ongoing cloudbased initiative, indexes, formats and documents high-value, high priority and scalable publicaccess data in a way that’s easy for developers and consumers to access and make use of. The result: Amazon’s cloud service, along with their partner Captricity, enabled the FDA to quickly convert “manual reports into machine-readable information with 99.7% accuracy, reducing costs from $29 per page to $0.25 per page.” This data is then made available through a secure publicaccess portal. “The goal of the project is to create easy access to public data, to create a new level of openness and accountability, to ensure the privacy and security of public FDA data, and ultimately to educate the public and save lives.” the entire process becomes cumbersome, time-consuming and overly expensive as a result. Any method that can streamline clinical research activities is not only good for a particular organisation but for the entire industry as well.

Roles of a CRO CROs play a crucial role in the healthcare industry as their work is critical for the development of new drugs and treatment techniques. The functions of a CRO can be broadly classified as: • • • • •

Biological studies Biological analytics Biometrics Medical writing Regulatory services

Carrying out these functions while meeting ethical and regulatory standards set by entities like EMA and FDA is a challenge that every CRO and pharmaceutical company has to overcome. However, performing these functions manually, through physical, paper-based methods, adds an additional layer of difficulty that many small entities face today. Traditional methods, which include conventional internal IT solutions, make maintaining secrecy and following a zero-compromise security policy a nightmare. Besides, 50 Journal for Clinical Studies

The healthcare and pharmaceutical industry has traditionally been cautious and measured in the adoption of new technologies, mainly due to safety, security and scalability concerns. The stringent regulatory environment in which pharmaceutical companies operate also discourages many from switching to new technologies. One of the major reasons that holds these organisations from moving to the cloud is the apprehension about control and security of their data. After all, these organisations deal with large amounts of sensitive data, including intellectual property and patient information, which need to be safeguarded at all costs. In addition to the low technology adoption rate, several pharmaceutical companies and CROs face the challenge of a decentralised IT infrastructure and a heterogeneous distributed infrastructure. The over-provisioning and under-utilisation of IT resources are other areas of concern. Other common challenges faced by the pharmaceutical industry include the provisioning of IT workload, which is measured in weeks; capital intensive commissioning; and the high degree of friction in entry and exit of new/old workloads. Volume 9 Issue 3


Technology The Benefits of Cloud-based Storage and Software Solutions

KYTHERA BIOPHARMACEUTICALS INC.: A CASE STUDY4 The challenge: Kythera Biopharmaceuticals Inc. (now a part of Allergan Plc was struggling to manage an assortment of document repositories, each dedicated to specific functional areas, and document systems, including a file-sharing system for trial master file (TMF) documents. Considering the company had 26 clinical studies on file (of which four were undergoing trials), it amounted to thousands of documents that needed to be managed. This meant that Kythera was forced to contend with different versions of documents, all being used and exchanged by people with no true document accountability. The fact that Kythera was dependant on a legacy system meant it had no option to upgrade it for better efficiency. The solution: A cloud-based software suite that connected every department at Kythera and linked workstream activities across clinical, regulatory and medical affairs was the answer. This allowed real-time information exchange and greater transparency.

The healthcare and life sciences sector has gradually started making the shift to cloud computing in recent years. The wide-scale adoption of mobile devices, especially personal health monitoring devices and health-related mobile applications, capable of tracking treatments, are certainly contributing to this ongoing change. An interesting statistic that’s proof of this trend is that 84% of medical practitioners use smartphones to do quick online research during work. Carrying out clinical research and drug development work necessitates the use of a wide range of IT solutions for communication, data analysis and data storage requirements. These include clinical trial management systems (CTMS), electronic data capture (EDC) systems and electronic trial master file (eTMF) content management systems. Any IT solution needs to be wellstructured to enable CROs to carry out their responsibilities a lot faster and with greater efficiency, and thus enable new treatments to get to patients faster.

• The implementation of the cloud-based solution achieved positive results by some effective operational changes. • Protocols authored by the medical writers upon completion were automatically sent to the reviewers. • CRO collaborators were given access to clinical trial reports to improve trial update reporting. • All stakeholders were alerted to document expiration dates. • Documents were better managed through a site document report that displayed documents on file for individual sites. Also, a site initiation report maintained a status update about each document as it progressed. • Document centralisation and going digital made collaborating easier and helped with study start-up. Trial operations was also made more transparent. • The time required to align TMF documents was reduced by at least 40 per cent at the end of each trial period using an eTMF cloud system. The result: The company managed to save on opex by streamlining their operations and making processes more efficient, all thanks to their shift from internal IT services to a paperless, cloud-based software solution.

Cloud-based software solutions can make it easier for CROs and pharmaceutical companies to manage clinical trials, collaborate globally and conduct pharmacovigilance. The areas that will truly flourish with the adoption of cloud computing are mHealth, e-health and telemedicine services. Cloud computing is also helpful for e-commerce.

gathering, managing, storage, and analysis; making collaborations between organisations, physicians and patients easier through seamless and real-time exchange of information; and allowing everyone involved access to big data pools and enabling researchers to build their own extensive database for future references.

Easy global accessibility, which is an inherent part of cloud computing, makes sharing and managing lab data and patients’ personal and treatment information simpler. Cloud-based software also makes statistical analysis efficient. This enables seamless integration of data and its availability across devices for a lower cost. From a clinical research perspective alone, cloud computing offers a diverse range of opportunities to improve safety, security, efficiency, delivery time and accuracy. Cloud computing can make significant contributions by: streamlining information tracking,

A 2016 HIMSS survey paints a clear picture about the areas and factors that matter the most to healthcare companies during cloud adoption. Performance and reliability, ease of management and total cost of ownership (TCO) were the three reasons given by companies for adopting cloud-based solutions. On the other hand, adherence to regulatory requirements (HITECH), willingness to meet BAA requirements and technical security of the cloud service provider were the main factors considered before choosing a cloud services provider.1

www.jforcs.com

Journal for Clinical Studies 51


Technology Regarding Industry Adoption of Cloud Computing

According to an HIMSS survey1, 84% of IT executives working in the healthcare sector now rely on cloud services (with SaaS and IaaS models being the most popular) and 92% recognise the value add. In fact, cloud computing in healthcare as a market is estimated to hit the $5.4 billion figure by 2017. Many pharmaceutical organisations and CROs have started to recognise the benefits of cloud computing and have begun to embrace cloud-based technologies for drug development and healthcare research purposes. In fact, most of the big names from the healthcare industry have already made the shift to cloud and are reaping its benefits. Among the big names are 3M Health Information Systems (HIS), BristolMyers Squibb, Philips, Siemens Healthcare Diagnostics, Novartis, Orion Health and many more. Ensuring Data Security Through Hybrid Cloud Computing Hybrid cloud computing is best suited for the needs of the healthcare and medical research industry. That’s because a hybrid cloud computing environment brings the best of both worlds— public and private cloud computing. A hybrid cloud computing environment functions by integrating an on-premises, private cloud, which the organisation can completely control, and a public cloud service provided by a third party. Hybrid cloud computing thus allows sensitive data to be stored and operations to be carried out more securely on the private cloud, while the public cloud is used for all other computational requirements. And since both cloud environments are connected on a certain level, the hybrid cloud system manages to provide increased flexibility and more data deployment options. By deciding which type of data is most suitable for the private or public cloud, an organisation can ensure the integrity of its information. Beyond hybrid cloud computing, safety and security can be assured to a great degree by implementing certain safeguards. Organisations need to make sure their cloud environment is compliant with the highest level of global security standards. Additional security features never hurt and should be made a part of the system. For instance, file transfer traceability options provide great control and facilitate accountability. Implementing IT Infrastructure Structuring Moving information and applications to the cloud alone does not guarantee all the promised benefits as the shift to cloud computing is never straightforward. Proper structuring is critical for cloud IT implementation to succeed. Factors that can hamper effective implementation can be classified into two categories—generic technical factors and factors specific to the pharmaceutical and clinical research industry. Expert consultation and trial-and-error implementation of new methods can help CROs and pharmaceuticals overcome technical obstacles such as: • Service restrictions and limitations • Managing of replicating workloads 52 Journal for Clinical Studies

BAUSCH & LOMB: A CASE STUDY5 The challenge: The Indian division of Bausch & Lomb was responsible for handling most of its IT operations. But a tight budget stifled its growth (the company was growing exponentially, but its legacy applications lacked the capability to support the pace of change) and made it difficult for it to support business. The company realised that cloud computing would offer scalability, reliability and availability for its growth and deliver the best results, especially with low funds to work with. A management decision was made to shift its operations from its own IT solutions to the cloud. The solution: The company did not plunge into the cloud all at once and was very methodical and measured in its new approach. As a first step, it moved only a non-critical part of its IT infrastructure into the public cloud. Next, it consolidated all its data centres and eventually handed over its data centre-related activities to a private cloud outsourcing partner. Outsourcing its IT this way allowed it to move from a capex model to a totally pay-per-use opex model. However, this was still a private, caged cloud model and the company wanted to further deepen its cloud integration and this could only be achieved by moving to a public cloud. Every company that has ever moved to a public cloud has had concerns about safety and security and this is especially true in the pharmaceutical sector, which deals with private and sensitive patient information. But moving to the public cloud provides better ROI, allows improved scalability and provides more control. So, after much deliberation, the company finally took its IT entirely public. The result: This enabled them to reduce their capex cost by 20%. Their bold step allowed them to reach new heights at a pace and scale that was not possible without the cloud, and additionally, it provided them 24/7 availability to their data, along with a disaster recovery safeguard. The takeaway here is how they improved scalability, reliability, and availability on a low budget through cloud computing. • Managing information traffic flow • Reporting structure creation and management • Scalability Any cloud-based solution catering to the pharmaceutical or clinical research industry has to conform to the non-negotiable factors specific to this industry. These are as follows: • Information security • Industry regulations • Industry standards • Industry policies • Standard operating procedure (SOPs) • Traceability • Transparency • Validation before acceptance (and periodic validation) • Laws of land The desired results can be achieved when the cloud solution matches specific requirements of the pharmaceutical and clinical Volume 9 Issue 3


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Journal for Clinical Studies 53


Technology smaller and newer companies, as these can enable them to grow exponentially. But most importantly, carrying out clinical research procedures over the cloud is safer and more secure than traditional paper-based methods, and the cloud is a place that continually gets safer with the advancement of technology and introduction of newer techniques. REFERENCES 1. 2. 3. 4.

5.

https://www.cleardata.com/wp-content/uploads/2016/12/2016HIMSS-Analytics-Cloud-Study.pdf https://open.fda.gov/about/ https://aws.amazon.com/solutions/case-studies/us-food-and-drugadministration/ Cloud computing expanding into all areas of clinical trial conduct – The Center Watch Monthly (http://www.ppdi.com/~/media/Files/ PPDI%20Files/news/PPD%20In%20The%20News/CenterWatch%20 Monthly%202014%20August.ashx) http://www.cio.in/case-study/bausch-lomb-defies-conventions-andmoves-securely-public-cloud

Prasad Puranik

research industry, and through implementation of specific measures and by giving the right structure to the cloud solution. A cloud-based application suite and storage solution can be considered ideal when it has most, if not all, of the following features: • It should be an ISO27001 (international information security standard) compliant, validated cloud setup, confirming to industry regulations and standards. • It should be pre-crafted for industry best practices such as GAMP5. • It should comply with FDAs Title 21 CFR Part 11 regulation that sets guidelines for all types of electronic records (data and documents) and electronic signatures, so that they are considered trustworthy, reliable, and equivalent to paper records. • It must come with standard operating procedures (SOPs) for data backup and restoration, disaster recovery and business continuity. • It should implement strict access restriction through separation of duty. • It must not compromise on traceability, through audit trails and configuration change records. • It must allow all information/data to be validated through input qualification, output qualification and performance qualification (IQ/OQ/PQ). • It should comply with the law of land (for example, EU data protection directives). • It should support automated workflows. • It should provide mobility support for employees/contractors without compromising the security. • It should be backed-up by a fully managed service. Choosing the right cloud partner is crucial for any CRO. It’s important that this cloud partner is experienced and understands industry requirements to build a custom cloud solution or to structure an existing cloud architecture for maximum efficiency. Embracing cloud computing offers big advantages to the pharmaceutical and clinical research industry, and has the potential to revolutionise healthcare by enabling organisations to develop newer, more effective drugs and deliver them faster, at affordable prices. These make cloud-based solutions important, especially for 54 Journal for Clinical Studies

Founder & CEO at Comprinno Technologies. He’s a technologist and project management expert with 18 years’ experience in IT, telecom and pharma domains. He founded Comprinno Technologies, a cloud orchestration company specialized in setting up cloud infrastructure for industries like pharma, healthcare & finance while mitigating risk and ensuring industry and security compliance. Email: prasad.puranik@comprinno.net

Shraddha H. Shetty Director of Business Development at Comprinno Technologies. She is an IBM Certified Cloud Computing Infrastructure Architect & project management (PRINCE 2 ) expert with exposure to the manufacturing industry in UK and Europe. She has 10+ years’ experience in Cloud & SAP implementation and support, business analysis & process improvements. Her strengths include business analysis, risk assessment, demand management and application management. Email: shraddha.shetty@comprinno.net

Mischa Dohler Professor in Wireless Communications at King’s College London. Director of the Centre for Telecommunications Research Co-founder of the pioneering smart city company Worldsensing. Fellow of the IEEE and the Royal Society of Arts (RSA) Distinguished Member of Harvard Square Leaders Excellence He has pioneered several research fields, wireless broadband, IoT/M2M and cyber security standards, holds a dozen patents, was the Editor-in-Chief of two journals and authored several books. Email: mischa.dohler@worldsensing.com

Volume 9 Issue 3


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Journal for Clinical Studies 55


Technology

The AI Advantage

Life sciences can’t afford not to take advantage of intelligent web and social listening technology. It is the only way they can hope to cut through the online noise and become truly vigilant about post-marketing patient safety in an always-on digital world. And they could pick up a lot of other valuable insights along the way if they teach systems what to look for, say Christopher Rudolf of Volv Partners and Adam Sherlock of ProductLife Group. Making safety a differentiator, being seen to be more customercentric, reducing risk, and staying on the right side of regulators are among the many drivers causing life sciences to take a long, hard look at web and social media listening. It is no longer acceptable to be on the back foot in adverseevent and patient experience monitoring and reporting once drugs are on the market. Good pharmacovigilance practice demands that manufacturers go further – and become more proactive – in keeping patients safe. Meanwhile, brands seeking to differentiate themselves on how seriously they take their responsibility for that (i.e., their willingness to exceed regulators’ expectations) cannot practically achieve it as long as their vigilance is slowed by voluminous data feeds – feeds that are coming in faster than even the best-equipped teams can process. As long as market monitoring is mired in laborious manual processes, companies will never become able to get on top of what’s happening out in the real world. The situation is becoming only more challenging all the time, as digital channels evolve and multiply. When companies first started talking about social listening a number of years ago, they primarily meant the tracking of Twitter and public Facebook posts. In 2017, and in the context of life sciences, being vigilant about safety monitoring also means taking in web-based patient forums and special interest groups; blog articles and comments published through platforms like WordPress; complaints and feedback submitted via e-mail or web formats; scientific literature, including downloadable pdf attachments; and formats that depend less on the written word, such as YouTube and Pinterest. Some of this is mandatory, but all of it is recommended to build up the complete picture. A further complication is that relevant content could come in any language, from anywhere in the world. Monitoring all of the above adds up to a gargantuan task for even the best-resourced teams. Big data is every industry’s doubleedged sword. If it can be consolidated, filtered, analysed, and harnessed both efficiently and effectively, then detailed insights can be very powerful. If it cannot, it can weigh companies down. And that’s what’s been happening in life sciences. Every minute of every day, patients or professionals somewhere can be found discussing, reporting, or asking questions about drugs online – across any number of the channels mentioned above. But getting to the mentions that matter – those that could indicate a real problem or could save a life or could inspire a new product direction or dosage regime – feels impossible to achieve. Even if responsible teams 56 Journal for Clinical Studies

could process all of the available sources in the time available, they would be expensively inefficient and could easily miss something important. Improving Safety Rates Estimates suggest that 10 to 17% of adverse events go undetected today because companies are not “listening” to social media and other web channels other than those currently mandated by regulators. Those other channels could be in the forms of digital media beyond their own websites and communities, published scientific literature, and individual case safety reports. The life sciences industry is well aware of this, but hasn’t as yet found a practical way forward. Although the majority of pharmaceutical companies are thinking – and in many cases, seriously worrying – about web and social monitoring and how on earth they can do it in a way that’s compliant, efficient, and effective, only a handful have made real progress. That’s because the main options available to companies have been either to buy into very expensive proprietary turnkey analytics solutions like IBM Watson Analytics or to cobble something together from a series of tools designed for other purposes – like mainstream social listening. But what’s suitable for trawling Twitter is going to differ greatly from tools capable of scanning scientific literature or capturing the sentiment and context of online discussion forums, opinionated blog posts, or photo or video posts whose potential signals are visual rather than text-based. Monitoring every channel, format, or country and language separately creates more work and makes it harder to spot patterns. Unless monitoring efforts deliver something meaningful that can be relied on, companies will be wasting their time and budgets. With so many channels to keep track of, life sciences firms need a more consolidated, intelligent, and focused approach. AI: The Smart Way to Sift Through Big Data This is where artificial intelligence (AI) comes in by offering to take the strain from human teams so they can focus their time and budgets more productively. As optimised solutions for life sciences become available, AI is beginning to have a positively disruptive effect on companies’ ability to efficiently and reliably monitor any number of digital channels to distil the insights that count. That in turn is transforming what pharmacovigilance and safety teams can do—not to mention what other parts of the business can do too. First, using natural-language-processing algorithms and artificial intelligence, it’s now possible to sift and clean data, thereby reducing the noise (irrelevant or red-herring content) by looking for the right signals that match teams’ criteria. The ability to interpret natural human language and semantics means the technology isn’t just following blind search rules but can identify mentions in context and can read into subtext to determine how relevant the mentions are.The parameters for the task might vary between parameters needed to analyse a short mention on Twitter and those required to interrogate longer posts on WordPress, but the technology is sophisticated enough to recognise and adapt to those differences. Volume 9 Issue 3


Technology Teams can adjust the noise settings to let more or less data through, and once a subset of high-quality data has been created, the findings can be fine-tuned and improved with input from the teams using the data. As teams interact with and classify data, machine-learning algorithms enable the software to observe and adapt to teams’ preferences and to hone the next iterations of findings accordingly. An added opportunity at this point is that different teams, with their own individual tasks and interests, can train a system in their own priorities and preferences in order to support their own particular purposes. So, different task forces can derive their specific needs from the same master data without having to spend time looking through content that has no bearing on the work they’re doing. The clean, filtered data is served to users via the equivalent of an e-mail inbox, with an option to share findings with the team or feed important adverse-event findings into regulatory processes for urgent action. Incredibly, all of this can happen in near real time because the latest technology is capable of returning comprehensive but accurately filtered findings from entire global web and social media searches within just 90 seconds, and red-flag events can be moved through to supervisors just as quickly. Such speed of responsiveness to adverse events is unprecedented, and it is exactly what’s needed to keep pace with new findings given the continual refreshment of digital content and round-the-clock social posting. Making the Impossible Possible Many industries are concerned about AI’s undermining of people’s jobs, but in a skilled and resource-pressed environment as found in

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the areas of life sciences quality, safety, and regulatory affairs, time is what is crucial; and AI’s role is to enable teams to focus on what’s important. Given that the web never sleeps and that people are posting around the clock and across different time zones, another advantage of AI-based web and social monitoring is that it keeps working out of office hours, refreshing results minute by minute. No time is lost, and there is much less danger of falling behind. What was an insurmountable task for humans has now become viable. AI-based web and social listening can also significantly improve the accuracy and reliability of human-directed monitoring, thereby ensuring that nothing critical passes under the radar and no crossreferences get missed. When systems have been built specifically for life sciences and are supplied with preloaded algorithms, levels of accuracy start high—above 80%—even before the software has been trained in what’s of interest to a particular company and business function. That’s a substantial advantage in winning the big data war—and in sharpening a manufacturer’s safety credentials. Without AI, this kind of progress is unthinkable. Firms would have to hire more and more people to trawl Google, look through individual websites and forums, capture reports, highlight what’s of interest, enter findings into a database manually, and pass anything important on to decision makers. In that scenario, it could take days to find something of value, and in the meantime, much more could be missed. And because that cycle is so long, teams are perpetually playing catch-up yet falling further and further behind.

Journal for Clinical Studies 57


Technology

To maximise the impact of AI-based web and social monitoring, life sciences companies should be tracking everything holistically rather than in silos, where social channels get monitored separately from, for example, scientific studies. There also has to be efficient workflow that feeds straight into established systems and processes, such as existing pharmacovigilance systems and recognised regulatory procedures. Such a workflow requires an integrated, joined-up approach as part of broader pharmacovigilance and safety management, rather than making it a special separate activity.

Even if preventive safety action is a little way in the future, intelligent web and social monitoring can add plenty of other value today—for example, by helping companies keep track of regulatory changes and revisions to timelines, which can be hard to stay on top of globally. Commercially, the ability to gauge both (1) how a brand and product are perceived in the market and (2) how a product’s safety profile measures up to the competition, offers invaluable mass-scale insights that could be fed back to product development and marketing teams.

Staying Compliant, Spotting Opportunities Another very important capability that an AI-based approach brings to the table is the ability to adhere to strict rules designed to protect patient privacy—rules that can differ across international markets. The technology can, for instance, monitor for when relevant social media or web forum posts get subsequently deleted by the poster and can flag that event in the pharmacovigilance database, so that compliant processes around patients’ data privacy can be applied. Staying on the right side of regulators is essential in managing risk and maintaining public confidence.

Certainly there is a wealth of executable intelligence out there if companies can find efficient ways to extract and harness it. Discussions at the recent DIA EuroMeeting in Glasgow left no doubt that developing that kind of capability is high on life sciences organisations’ agendas—and not just as a means of regulatory adherence.

Once companies have seen the potential of AI-based web and social monitoring in safety management, the scope for additional applications comes into focus. With consent, firms have an opportunity to become more proactive in monitoring groups of patient users who have diseases firms are interested in—for example, discussions about hay fever—to get a clearer picture of where they stand in the market and where needs are not being met. Feedback could also help design more-well-rounded clinical trials, which supplement clinical data points, biomarkers, and reported outcomes and offer feedback from patients about how they’re feeling and measurements from connected devices that track key health statistics. Once companies can monitor and cross-analyse all of those signals, they can start to predict adverse events in an individual before events happen and then can intervene preemptively. This is the kind of development pharma companies are very interested in at the moment, and it’s already technically possible. AIbased data monitoring and analytics for life sciences are becoming increasingly accessible and affordable too, thanks to the emergence of open-source solutions that can be run in the cloud and even operated as a managed service on companies’ behalf. 58 Journal for Clinical Studies

We’ve only scratched the surface of AI’s potential to transform companies’ market knowledge and market responsiveness: the best is yet to come.

Christopher Rudolf CEO of Volv Partners, which harnesses state-of-the-art technologies such as AI to transform regulatory compliance, web and social listening, and predictive analytics for life sciences firms. Email: crudolf@volv.global

Adam Sherlock CEO of ProductLife Group, which provides a complete suite of pharmacovigilance solutions and services that help life sciences organisations manage information and stay compliant across the product life cycle. Email: asherlock@productlife-group.com

Volume 9 Issue 3


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Clinical Supplies The Pharmacy Adjudicated Clinical Study Supply Process Decreases Risk, Cuts the Cost and Improves the Efficiency when Providing Subjects Unblinded Clinical Study Supplies Purpose: A survey documenting clinical study supply chain management for unblinded supplies was undertaken to determine areas where a pharmacy adjudicated clinical study supply process could improve efficiency and reduce cost. The results could then be used as a potential means to reduce risk, costs and time in appropriate clinical study supply settings. Design/Methodology: A survey was sent to one hundred clinical study supply administrators to measure the potential efficiency of a pharmacy adjudicated clinical study supply process within the clinical study supply chain for unblinded supplies. The pharmacy adjudicated clinical study supply process is sponsor-funded and allows subjects to acquire their unblinded clinical study supplies through the pharmacy network. The survey response was analysed to determine a need and benefit for such a clinical study supply service. Findings: Clinical study administrators were supportive of this alternative as a means of overcoming issues related to clinical study supply shortages, time consumption and costs (both time and monetary) associated with clinical study supply management of unblinded medications, supplies and devices. Value: This paper provides details of a novel means for decreasing risks, manpower and costs in supply chain management of unblinded clinical study supplies. This paper lays the groundwork for a new step forward in supply chain management of clinical study supplies. Additionally, this paper highlights the degree of complexity in clinical study supply chain management and the need for a potential solution. Supply chain efficiency in the conduct of clinical studies is a critical factor determining part of the overall cost. When appropriate, unblinded clinical study supply optimisation can save money, time and resources, and decrease risk, by preventing costly delays due to supply shortages. The pharmacy adjudicated clinical study supply process is a sponsor-funded programme that allows subjects to acquire their unblinded clinical study supplies through the pharmacy network. As in all arenas, optimisation is the ideal and is rarely achieved in practice or with great efficiency. Various tools have been developed, attempting to improve forecasts of medication requirements for clinical studies, though many rely on deterministic calculations (or an applied set of sequenced calculations).1 However, significant improvement is achieved via Monte Carlo simulation techniques.2 Nevertheless, even with a more sophisticated supply strategy obtained via simulation, this approach remains limited and certainly not free of potential error when fully employed in the conduct of clinical studies. In order to minimise these issues related to unexpected gaps in the supply chain, another layer of protection is necessary for clinical study supply administrators. In the context of unblinded clinical study supplies, the expansion of available resources towards the pharmacy network (via a “pharmacy adjudicated clinical study process�) has helped provide more efficient clinical study supply management. The net benefit has been preventing and 60 Journal for Clinical Studies

minimising costs related to problems and delays with the traditional bulk purchase supply model, preventing clinical study delays. Typical hassles associated with the traditional bulk purchase supply model that can cause study delays and excess expense include vendor identification and validation, price negotiation, production and delivery timelines, packaging, labelling, storing, inventory management, shipping, reconciliation, reclamation and destruction. The pharmacy adjudicated clinical study supply process allows subjects to obtain their unblinded clinical study supplies through the pharmacy network without any subject out-of-pocket costs. This may aid compliance with unblinded components within a clinical study. Given the high cost of research and development, supply chain-related expenses are one potential area of savings. In 2010, R&D expenditures amounted to roughly $67.4 billion. These issues are compounded when also dealing with the realities of limited product shelf life and uncertain supply demand throughout the study, further resulting in the destruction of unused clinical study supplies.3 Deploying the use of a pharmacy adjudicated clinical study supply process reduces the overall burden on supply chain administrators to ensure that unblinded medication and supplies are readily available for study participants. This has the added benefit of reallocating human resources to where they are best suited and eliminated when they are deemed redundant.4 Although best practices for supply chain management in other industries do not always translate well in the setting of clinical trials (and healthcare in general), there are many avenues of greater efficiency that warrant consideration.5 It is that search for efficiency that gives birth to the possibility of employing a pharmacy adjudicated clinical study supply process for unblinded clinical study supplies. Methodology A survey to measure the efficiency of a pharmacy adjudicated clinical study supply process within the clinical study supply chain for unblinded supplies with clinical study supply administrators. There were one hundred surveys distributed and thirty-seven total respondents. These one hundred supply chain administrators were selected sequentially from a proprietary database. The survey was completed by administrators who have a working knowledge of the clinical study supply sourcing and procurement process for unblinded clinical study supplies (i.e.- comparator medication, rescue medication, co-medication and ancillary supplies). The majority of respondents were employed by either pharmaceutical manufacturers or contract research organisations (CROs). The response rate (thirty-seven per cent), was well within the typical rate of response for surveys collected from individuals (median of 52.7 with a standard deviation of 20.4) and just above the average response rate from institutions (median of 35.7 with a standard deviation of 18.8).6 Survey Response Surveying clinical study supply administrators revealed that almost fifty per cent of the companies had ten or more of their staff, in multiple departments, involved with sourcing, procuring, packaging, labelling, storing, managing inventory, shipping, reconciling, reclaiming and destroying unused clinical study Volume 9 Issue 3


Clinical Supplies subjects to a local pharmacy. However, over fifteen per cent of respondents indicated this usually triggered a delay in the study, clearly impacting the overall cost profile of the study. An added layer of frustration is often seen when dealing with comparator sourcing, particularly when the comparator is a key source of revenue for the manufacturer. The variability of comparator supplies also has the ability to trigger study delays, posing an additional layer of complexity when attempting to forecast their cost (as demand signals from sourcing managers have the potential to increase prices).

supplies. This effort combines to make more than seven different steps (often more than ten) in the entire clinical study supply process. Overall, clinical study supply administrators estimated that a significant number of hours could be saved over the life of a study if unblinded clinical study supplies did not have to be procured, distributed and managed by internal staff. Forecasting, sourcing, labelling, shipping and reclamation/destruction were typically identified as the most inefficient steps in the clinical study supply process, respectively. Supply sourcing was most commonly defined as the most frustrating step in the process, followed by forecasting, purchasing and shipping. It is in this mix of inefficiency and the distinct possibility that one of these vendors will fail at their task that the risk of costly study delays emerges. Decreasing this risk of a study delay is a major benefit of the pharmacy adjudicated clinical study supply process.

There are several identified factors that contributed most to the manpower and time spent on handling clinical study supplies. According to clinical study supply administrators, the most time-consuming activities were sourcing, labelling, packaging, forecasting and purchasing. Sourcing unblinded supplies via a pharmacy adjudicated clinical study supply process opens up internal resources to be deployed on other issues. In clinical study supply stock-out situations, staff were typically forced to seek replenishment from another supplier, while a minority directed www.jforcs.com

Time spent managing clinical study supplies becomes an even larger issue when considering the sequencing of activities. With nearly half of all survey respondents identifying ten or more steps, a delay of any length could have significant consequences for the clinical study. This contributes greatly to how long the entire clinical study supply process can take, particularly when accounting for the potential need to reorder supplies. Overall, the entire ordering process can typically take three to five weeks, though a larger majority of respondents identified time consumed by supply chain-related activities taking anywhere from two to five (or more) months. Another factor that could contribute greatly to time spent managing clinical study supplies are delays in supply production delivery dates (raw material shortages, increased trade demand and many other possible reasons). Taking this into consideration, a majority of survey respondents indicated expected delays of at least one month before a new production run could be utilised.

Discussion This survey highlights a new step forward in the strategic management of clinical study supplies. Improving the efficiency of unblinded clinical study supply management enables clinical study supply administrators to use those resources elsewhere, fostering better outcomes with respect to supply management in general. The cost savings achieved by sourcing unblinded clinical study supplies through the pharmacy network has the ability to reduce the overall cost profile of a given study. The potential timesaving benefit of utilising a pharmacy adjudicated clinical study supply process would be substantial. The pharmacy adjudicated clinical study supply process may obviate any discount from bulk purchasing, however this is offset by the cost of labelling, packing, transportation, manpower usage, etc. A pharmacy adjudicated clinical study supply process is an added layer of protection aimed at minimising the risk/consequences of running out of medication, shifting away from perfecting an imperfect practice and focusing on a fail-safe solution that would not occur with a more transactional Journal for Clinical Studies 61


Clinical Supplies

approach to this supply management.7 The pharmacy adjudicated clinical study supply process has the additional benefit of having a registered pharmacist reviewing the patient’s prescription record for potential drug-to-drug interactions. Conclusion This survey of clinical study supply chain managers has shown the potential benefit of a pharmacy adjudicated clinical study supply process that allows subjects to obtain unblinded clinical study supplies through the pharmacy network without costs to themselves. These potential benefits include decreased risk, cost prevention of some unexpected delays, less manpower expenditures and added safety. While this will not affect all clinical studies (since many studies do not have an unblinded component) the pharmacy adjudicated clinical study supply process may be a significant factor in those appropriate studies to optimise the supply chain management and therefore reduce costs and risks. REFERENCES 1. 2. 3. 4. 5. 6. 7.

Abdelkafi, Beck, David, Horoho and Druck. Balancing Risk and Costs to Optimize the Clinical Supply Chain—A Step Beyond Simulations. Journal of Pharmaceutical Innovations. 2009. Dowlman N, et al. Optimizing the Supply Chain Through Trial Simulation. Applied Clinical Trials. 2004. Lamberti MJ, Walsh T, Getz KA. Tracking trial cost drivers: the impact of comparator drugs and co-therapies. Pharmaceutical Executive. 2013. Kaplan, Norton and Rugeksjoen. Managing Alliance with the Balanced Scorecard. Harvard Business Review. 2010. Vries and Huijsman. Supply Chain Management in Health Services: An Overview. Supply Chain Management: An International Journal. 2011. Baruch and Holtom. Survey Response Rate Levels and Trends in Organizational Research. SAGE journals. 2008. Ware M. and Glass S. Transactional vs. strategic sourcing. A look at two approaches to comparative drug sourcing. Applied Clinical Trials. 2010

62 Journal for Clinical Studies

Gerald L. Klein MD, is an expert in Medical Affairs and Clinical Development and has published numerous scientific papers. He was a professor of Medicine and Pediatrics (Division of Basic and Applied Immunology) at University California, Irvine. Dr. Klein was a founder and the CEO of Entera Health Inc. He was the Chief Medical Officer of Talecris/Grifols. Klein has also been VP of Medical and Clinical Affairs at Dey/MerckKgAa, Clingenix, Specialty Labs, a founder and EVP Pathway Diagnostics, and Oxygen Biotherapeutic/Tanex. Dr. Klein began his career in industry by founding a CRO, San Diego Clinical Research (SDCRA), where he was CEO and Chief Medical Officer. SDCRA was sold to Quintiles and Dr. Klein, served as a SVP at Quintiles. He has also been on the board of directors of Nanocorp, Oxygen Biotherapeutics (Tanex Biotechnology) and the American College of Allergy Asthma and Clinical Immunology. Email: gklein@medsurgpi.com

Maxwell O. Clarke medical writer with MedSurgPI. As a trained economist, his interests and expertise are in the areas of health economics and supply chain management.across the product life cycle. Email: maxwellclarke@gmail.com

Volume 9 Issue 3


DIA 2017 ANNUAL MEETING JUNE 18-22 | CHICAGO

Global Life Sciences Event of the Year Coming to Chicago June 18-22! EVENT HIGHLIGHTS

Keynote Speaker Alexander Tsiaras

11 Tracks, 15+ Featured Topics • Data/Big Data/eHealth

• Specialty Populations

• Disruptive Technology

• Strategic Planning/Execution and Partnerships

• Medical Affairs and Scientific Communications

Interactive Storytelling and Personal Health Data Drives Unprecedented Patient Empowerment

• Patient Engagement

• Translational Science: Preclinical/Clinical and Product Development

• Regulatory

• Value and Access

• Safety and Pharmacovigilance

• Quality

Onsite Career Fair: Join us for the first-ever Choose from conversations on patient engagement, real world evidence, digital listening, global health care, the future of biopharmaceuticals, payer science, international regulatory convergence, FDA updates, EMA/FDA Q&A, and more!

Preconference Short Courses: Held on Sunday, June 18, DIA 2017 boasts multiple half day and full day short courses to enhance your meeting experience and maximize your time in Chicago.

Annual Meeting Career Fair, June 18 and June 19. Job-seekers and employers will meet face-to-face to discuss potential employment opportunities. Onsite interviews will also take place for interested employers and job-seekers.

Interested in showcasing your positions at the fair? Contact Heej.Ko@DIAglobal.org Interested in attending the career fair as a job-seeker? Contact Dinorah.Martinez@DIAglobal.org

The DIA 2017 Annual Meeting is the largest, longest-running event in the life sciences industry designed to foster the international exchange of actionable insights to improve health globally through the advancement of lifesaving medicines and technologies. Themed “Driving Insights to Action,” DIA 2017 will host more than 7,000 professionals in the pharmaceutical, biotechnology, and medical device communities from more than 50 countries around the globe. DIA 2017 boasts more than 450 exhibiting companies, 10+ tracks, and more than 160 sessions focused on Regulatory Science, Translational Medicine, Patient Engagement, and Value and Access. Follow DIA 2017 updates on Twitter using #DIA2017.

Explore DIA 2017 at DIAglobal.org/DIA2017 Join the conversation on social media using #DIA2017

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Journal for Clinical Studies 63


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Worldwide Clinical Trials

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