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Volume 9 Issue 6


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


Regulations and Recruitment

Challenges and Experiences in Bulgaria

Updated Research Criteria for Clinical Trials Across the Alzheimer’s Disease Continuum

eClinical: How One Major BioPharma Company is Embracing the New World of Digital Clinical Research

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Part 1: An Overview of the Diseases

Dr. Barry Drees, Senior Partner Warrior Skills — Passion, precision, a steadfast commitment to excellence

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U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITORIAL MANAGER Virginia Toteva DESIGNER Jana Sukenikova RESEARCH&CIRCULATION MANAGER Evelyn Rogers ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: Journal by Clinical Studies - ISSN 1758-5678 is published bi-monthly by PHARMAPUBS


WATCH PAGES Modern Tools to Advance Generic Drug Development and Review

Generic prescription drugs that are approved by the FDA have the same high quality and strength as brand-name drugs. Likewise, the manufacturing and packaging sites for generic prescription drugs must pass the same quality standards as those of brand-name drugs. Deborah A. Komlos at Clarivate Analytics discusses why FDA prioritises the review of these drug applications. 8

Gene Therapy in Rare Diseases: From a Clinical Research Perspective

Many rare diseases are “monogenic” – that is, they are the consequence of a defect in a single gene. Daniel Mazzolenis and Jozsef Palatka at INC Research/inVentiv Health discuss how initial attempts at gene therapy for monogenetic diseases were unsuccessful both for safety and efficacy reasons, but with current scientific advances in the field, gene therapy can offer life-changing efficacy. 10 Patient Safety Monitoring and Beyond: How AI is Transforming Innovation in the Life Sciences Lifecycle Whether enabling new approaches to patient safety monitoring and clinical trials, or improving success rates for regulatory submissions, artificial intelligence (AI) offers enormous potential to transform many routine pharmaceutical processes. Marco Anelli at ProductLife Group discusses the timely and beneficial outcomes of AI. REGULATORY 12 FDA Guidance Recommends Diversity in Clinical Trials, but Can’t Require It The US Food and Drug Administration (FDA) frequently stress the importance of enrolling diverse patient populations in clinical trials conducted to support product applications. Meg Egan Auderset at Clarivate Analytics discusses the multiple recommendations from FDA and how sponsors can meet agency expectations to get products approved. 16 Intellectual Property Strategies ‘Crucial’ to Protecting Future of Medical Innovation

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 6 Nov 2017 PHARMA PUBLICATIONS

Robust intellectual property protection is essential to safeguarding the future of revolutionary biomedical innovations, which transform healthcare for millions of people worldwide. Jim Robertson and Jayne Nation at Wynne Jones IP discuss how an IP strategy is vital to helping a company identify its strengths and weaknesses. 20 The Lay Summary – Remember the Reader As part of its Clinical Trial Transparency initiative, the EMA mandated a requirement for clinical trial sponsors to prepare a summary of the results of every clinical trial written in language understandable to lay persons (patients and others not in the pharmaceutical industry). Lisa Chamberlain and James Barry Drees at Trilogy Writing & Consulting discuss how important is the requirement to prepare a summary of the results of every clinical study. Journal for Clinical Studies 1

Contents MARKET REPORT 24 Regulations and Recruitment: Challenges and Experiences in Bulgaria Rossen Mihaylov at Ramus Medical discusses the challenges faced during the preparation and conduct of clinical investigations. For both medical drugs and devices, CROs face a variety of regulatory and scientific challenges, provoking different initiatives for managing and balancing them. 28 eClinical: How One Major BioPharma Company is Embracing the New World of Digital Clinical Research The major objective of pharmaceutical research & development is to bring new health solutions to people who need them. Lionel Bascles and Victoria (Vicky) DiBiaso at Sanofi discuss how Sanofi has made progress each year in delivering increasingly accelerated drug development, as a result of improving its end-to-end clinical trial process. 30 Challenges with Cash Management and Reforecasting Clinical Trials Clinical trials are becoming increasingly complex, particularly with broader scopes, globalisation, changing and expanding regulatory requirements and a greater number of players, such as contract research organisations (CROs), sites, laboratories and vendors. Lorie McClain at Bioclinica discusses the consequences of poor forecasting and the great benefits of special technology tools designed for clinical research. THERAPEUTICS 34 Pre-clinical Data Analysis Ensuring Relevant First-in-human Clinical Trials The first-in-human trial (FIH) is an important milestone in the development of a potential new drug. Nariné Baririan at SGS discusses how going ahead with something that will, in all likelihood, fail is a waste of time and money that could better be invested in something that is more likely to succeed. 38 E. coli in Urinary Tract Infections between 2000 and 2016 Urinary tract infection (UTI) is one of the most common infectious diseases and the most common nosocomial infection in the developed world. Complicated urinary tract infection occurs in individuals with functional or structural abnormalities of the genitourinary tract. In this article, Milica Cerovic, John Riefler, Maxim Belotserkovskiy and Maxim Kosov at PSI CRO AG discuss the prevalence of E. coli in different countries.

46 Thinking Big: SCAPIS – The Ideal Cohort for Studies on CVD, COPD and Related Metabolic Disorders Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention are believed to be outdated because of recent changes in risk factor patterns. In this article, Cecilia Stroe, Staff Writer at JCS, looks into Europe’s largest screening study, The Swedish CardioPulmonaryBioImage Study (SCAPIS). 48 Acne Vulgaris and Associated Impact on Quality of Life Acne vulgaris or ‘Pimples' is a very common inflammatory skin disease affecting young adults all over the world, irrespective of race, ethnicity and geographical location. Dr Gitanjali Petkar at CIDP discusses how the psychological consequences of living with skin diseases can be significant. TECHNOLOGY 54 Improving the Performance of Clinical Trials Several metrics systems exist to measure performance. The most significant parameters, however, are the course of patient recruitment, how many patients complete the study, and the quality of the data generated. In this article, Robert Dannfeld at Pharmatio GmbH suggests the course of patient recruitment and the quality of the data generated as essential indicators for the performance of clinical trials. 58 Gathering Substantial Data for Faster Clinical Trial Approval Pharmaceutical manufacturers have long struggled to create an efficient clinical trial process for faster next-phase approval. The root cause of most failures is a lack of necessary efficacy data to support clinical trial claims. Moses Zonana and Danahlyn Tamola at CMT discuss the ways that will contribute to more efficient follow-up of clinical trials and therefore for faster clinical trial approval. CLINICAL SUPPLIES 62 Customised Supply Solutions for Investigator-initiated Trials Investigator-initiated Trials (IITs) are an integral and increasingly important part of the clinical research landscape. In this article, John Denier at Clinigen discusses the potential benefits of utilising an outsourced or customised service designed to meet the unique drug supply needs associated with IIT programmes.

42 Updated Research Criteria for Clinical Trials across the Alzheimer’s Disease Continuum The National Institute of Aging and Alzheimer’s Association (NIAAA) have recently proposed a common research framework to help investigators establish a research agenda and evaluate the impact of various therapeutics in the Alzheimer’s disease (AD) continuum. Henry J. Riordan and Natalia E. Drosopoulou at Worldwide Clinical Trials discuss the importance of biomarkers that help to define the condition of the disease and to track the progression and treatment effects of AD drugs. 2 Journal for Clinical Studies

Volume 9 Issue 6


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Foreword Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application in humans should result in at least partial correction of a number of genetic disorders. However, the safety of the procedures must still be established by further animal studies before human clinical trials would be ethical. Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance the potential to enable effective disease prevention or treatment. In this issue, we have brought you in the Watch Pages a blog by Daniel Mazzolenis and Jozsef Palatka at INC Research/inVentiv Health. They discuss how initial attempts at gene therapy for monogenetic diseases were unsuccessful, both for safety and efficacy reasons, but with current scientific advances in the field, gene therapy can offer life-changing efficacy. The Regulatory section contains an article by Meg Egan Auderset at Clarivate Analytics, in which she discusses the multiple recommendations from FDA and how sponsors can meet agency expectations to get products approved. Amongst other interesting Market reports, the one I would like to highlight here is the editorial by Rossen Mihaylov at Ramus Medical, in which he discusses the challenges during the preparation and conduct of clinical investigations – both on medical drugs and devices – in Bulgaria. The CROs are facing a JCS – Editorial Advisory Board • Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA • Bakhyt Sarymsakova – Head of Department of International

Cooperation, National Research Center of MCH, Astana, Kazakhstan

• Catherine Lund, Vice Chairman, OnQ Consulting

variety of regulatory and scientific challenges, provoking different initiatives for managing and balancing them. Everyone has experiences with embarrassing pimples at least once in their lifetime. The hardest part is facing the world when acne breaks out. Typically, breakouts are the main contributor to self-esteem issues and insecurities in those who suffer from chronic acne; notably during adolescent years when acne disrupts skin the most, and many cannot stop touching their blemishes. In the Therapeutics section, this everlasting topic is presented by Dr Gitanjali Petkar of CIDP. In this article, she reveals to readers how the psychological consequences of living with skin diseases can be significant. The Technology section contains an article by Moses Zonana and Danahlyn Tamola of CMT. The subject matter is how to create an efficient clinical trial process for faster next-phase approval. In the Clinical Supplies section, John Denier at Clinigen presents an article on the potential benefits of utilising an outsourced or customised service designed to meet the unique drug supply needs associated with IIT programmes. I hope you enjoy the articles which my team and I have brought together in this issue. We wish you all a Wonderful Festive Season. Look forward to seeing you again in 2018. Virginia Toteva, Editorial Manager You may be wondering why we feature flowers on the front cover of JCS? Each of the flowers we feature on the front cover represents the national flower of one of the countries we feature an analysis on, in that issue. In this issue we have featured a report on Bulgaria. The rose is the national flower of Bulgaria, which features on the front cover. I hope this journal guides you through the maze of activities and changes taking place in the clinical research industry worldwide.

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

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

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

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

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

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

of Europe

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

• Elizabeth Moench, President and CEO of Bioclinica – Patient Recruitment & Retention

• 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 • Hermann Schulz, MD, Founder, PresseKontext 4 Journal for Clinical Studies

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 6

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Modern Tools to Advance Generic Drug Development and Review In news releases issued by the US Food and Drug Administration (FDA), “firsts” always catch the eye. Because the majority of prescriptions in the US are dispensed with generic medications, announcements of new “first generics” are especially noteworthy. These products are the first approval by the FDA that permits a manufacturer to market a generic drug product in the US. The FDA considers first generics to be important to public health, and prioritises the review of these drug applications. Generic prescription drugs that are approved by the FDA have the same high quality and strength as brand-name drugs. Likewise, the manufacturing and packaging sites for generic prescription drugs must pass the same quality standards as those of brand-name drugs. At a public meeting held in early October – Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review – FDA Commissioner Scott Gottlieb, MD, shared that generic drugs accounted for 89% of all prescriptions in the US in 2016. This translated into an estimated $227 billion saved on healthcare for consumers. Given these realities, Gottlieb stated that he has chosen to make access to quality, affordable generic drugs a priority issue. Spurring innovation in the generic drug realm will require, as Gottlieb described, the use of “more rigorous science, quality data, and the use of sophisticated quantitative methods and computational modeling in drug development, evaluation, and review.” He noted that the FDA has already begun to adopt many of these advanced tools, including more widespread use of modelling and simulation, on the new drug side; for example, model-informed drug development (MIDD) has been incorporated into more than 90% of new drugs and biologics currently approved. MIDD includes pharmacokinetic/pharmacodynamic (PK/PD) models, physiologically-based pharma-cokinetic (PBPK) or absorption models, systems pharmacology, quantitative risk modelling, and emergent machine learning tools. As with its use in the new drug realm, MIDD can also enable more efficient approvals of generic drugs, Gottlieb said. During her presentation at the October public meeting, Director of the FDA’s Office of Generic Drugs (OGD), Kathleen Uhl, MD, summarised the current key uses of quantitative methods and modelling for new drugs. She noted that the FDA has the most experience with PK/PD and PBPK as related to drug-drug interactions; however, additional applications are: • Dosing recommendations in labelling; • Dose extrapolation (paediatrics or other populations); 6 Journal for Clinical Studies

• Dose determination for patients with organ dysfunction (e.g., renal or hepatic impairment); • Justification for prioritising studies (“when” to conduct certain studies); and • Supporting a particular study design (“how” to conduct certain studies). There are numerous opportunities for the use of quantitative methods and modelling for generic drugs, Uhl said. Regarding generic drug development, review, and regulatory decision-making, Uhl explained that it will be critical to leverage knowledge and experience in the new drug setting and to identify best practices to improve the use and acceptance of quantitative methods and modelling. Under the FDA’s generic drug programme, Uhl noted, approximately 1000 abbreviated new drug applications (ANDAs) are submitted annually; this is ten-fold higher than the new drug side, she added. Within fiscal year (FY) 2017 (11 months), there were 855 ANDA approvals; these comprised 693 full approvals and 162 tentative approvals. Currently, there are approximately 10,000 approved ANDAs; roughly 25% of these were approved within the past five years, since passage of the Generic Drug User Fee Amendments of 2012 (GDUFA I). This “huge volume” of applications presents abundant opportunities in the generic drug space to use quantitative methods and modelling, Uhl said. Complex Matters A specific category of drugs that has at times been difficult to “genericise,” Gottlieb said during the October meeting, is complex generic drugs. These, he explained, represent some very expensive and widely-used medicines. To support the development of high-quality ANDAs for complex generic drugs, the FDA in October issued a new draft guidance for industry, Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA. This document describes an enhanced process for discussions between the FDA and a prospective applicant preparing to submit (or an applicant that has submitted) an ANDA for a complex generic drug product to the agency. As defined in the GDUFA Reauthorization Performance Goals and Program Enhancements for FYs 2018-2022, also known as the GDUFA II “goals letter” or “commitment letter,” complex products are: • Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of active pharmaceutical ingredients [APIs], naturally-sourced ingredients); complex formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally-acting drugs such Volume 9 Issue 6

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as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., transdermals, metered dose inhalers, extended-release injectables); • Complex drug-device combination products (e.g., auto-injectors, metered dose inhalers); and • Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement. Mechanism-informed modelling can help develop complex drug products and facilitate their review and approval, said Uhl at the October public meeting. This work, based on knowledge of drug substance property, formulation characteristics, in vitro release profiles, and physiologic variables, is used to create and develop PBPK models and to do hypothesis testing and risk assessment, Uhl said. In the world of modelling and simulation where one requires “priors” to help define assumptions and create models, there are plenty of priors in the generic space, Uhl explained. Much is known, she said, about formulations and about the reference listed drug (i.e., the brand-name drug) that the generic drug is trying to copy. All this translates into opportunities

for more efficient development of drug products with limited generic competition, Uhl noted, including dermal, inhalant, ophthalmic, nasal, and transdermal complex generic drug products. Gottlieb summarised at the October public meeting that the described FDA actions within the generic drug setting, including the issuance of relevant guidance documents, are part of a broader effort by the administration to address the high and rising cost of drugs.

Deborah A. Komlos, MS The Senior Medical & Regulatory Writer for the Cortellis Regulatory Intelligence US module at Clarivate Analytics, formerly the IP & Science business of Thomson Reuters. Her previous roles have included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work. Email:

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Gene Therapy in Rare Diseases: From a Clinical Research Perspective

Rare Diseases and Genes Many rare diseases are “monogenic” – that is, they are the consequence of a defect in a single gene. Because of this, monogenic defects are simpler targets for gene therapy than ones resulting from multiple genetic factors. Gene therapy is beginning to show clinical promise as a strategy for treating rare diseases, and the historical challenges around safe, consistent, and durable gene delivery to targeted tissues are gradually being addressed. Even for the monogenic rare diseases where therapy is available (e.g. chronic replacement of a missing functional protein), the cost and complications associated with conventional therapy make gene therapy an attractive alternative. While initial attempts at gene therapy for monogenetic diseases were unsuccessful both for safety and efficacy reasons, with current scientific advances in the field, gene therapy can offer life-changing efficacy. Clinical Research Issues The number of approved gene therapy clinical trials worldwide has been steadily increasing over the last few decades (Chart 1) and the indications vary widely across therapeutic areas (Chart 2).

Gene therapies are required to advance through established pharmaceutical models of clinical development in order to secure regulatory approval. However, exceptions can be made in rare and ultra-rare diseases when there are an insufficient number of patients for conventional trials, or when the ethics of randomising severely ill patients into randomised, placebo-controlled trials is ethically unacceptable. The conventional drug development models can also take in excess of 10 years for market approval to be reached; this may be unacceptably long for ground-breaking therapies with high potential of curative effect in grave diseases. All these characteristics make clinical research in rare genetic diseases with gene therapy challenging and require creativity and innovation from the gene therapy developers, regulators, and clinical triallists. Regulatory submissions are usually more complex and demanding and include specific requirements, e.g. biosafety submissions related to the potential release of modified organisms in the environment and many others. Regulatory agencies (FDA, EMA) provide solid frameworks and issue regular guidance to the industry to support gene therapy clinical research with the ultimate goal of facilitating the patients’ access to these medicines once they get approved. As many of the gene therapies currently under development are targeting rare diseases, this poses recruitment and enrolment challenges in the clinical setting. The practical solutions to find the right subjects involve a variety of techniques used by the trial delivery teams, such as working with patient advocacy groups, collaborating with established networks of trial sites that specialise in the given indication, and sorting complex drug or patient logistics issues across state borders and even continents to accrue the trial in a timely manner.

With the exception of oncology, the majority of gene therapy trials involve rare diseases (figures) 8 Journal for Clinical Studies

For some gene therapies, preparation of the investigational product requires complex methodologies and the necessary procedures can be quite complex. An example is viral vectors that require collection of patient cells and transfection/amplification ex vivo and reinfusion after conditioning chemotherapy. These methodologies require multiple procedures and complex logistics from the participating sites, some of which will not have the appropriate experience or equipment. In addition, shipment of gene Volume 9 Issue 6

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therapy products may be subject to special regulations and require special couriers and regulatory permits. As the volume of experience increases, the technology to produce the gene therapies will tend to become less cumbersome; however, the safety concerns at the bedside remain of special interest. The treated patients require close follow-up in the first weeks after treatment to identify early and treat promptly the side-effects and the unwanted immune responses, e.g. against viral capsid proteins that may otherwise reduce the efficacy of the therapy. Arranging for adequate testing for these patients requires proactivity and special planning. In some rare diseases that have existing treatment options, recruitment can be challenging, even if the standard of care is suboptimal. Numerous factors can influence the patient’s decision to participate in such trials. Some are simple concerns around lack of long-term experience with gene therapy. Others are more complex, like issues around exposure to certain gene therapy technologies (in vivo transfection with AAV vectors) precluding future use of similar agents. Long-term safety data collection – which can take up to 15 years – is expected in gene therapy. This is especially challenging, as patients often may lose the connection with their study investigators as their life circumstances evolve over time. To overcome the translational barriers from ‘bench to bedside’ in gene therapy, unified approaches and close collaboration are necessary from all parties. Modified clinical trial models such as various forms of adaptive trial designs are starting to become more prominent, and regulatory bodies around the world have recognised the need for flexibility in expediting the approval of promising therapeutic candidates whilst mitigating the potential risks of unregulated products. Clinical operational experts play a major role in finding the most appropriate sites to conduct trials with gene therapy, and also to respond to the specific challenges posed by the rarity of the diseases and the complex investigational treatments being studied. With consolidated collaborative efforts from all parties after decades of research and certain setbacks, it is

anticipated that gene therapy will increasingly be represented in the pool of therapeutic options for many genetic rare diseases.

Jozsef Palatka, MD Vice President of Clinical Development of Oncology, INC Research/inVentiv Health, 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 earned his medical degree from Semmelweis University of Medicine in Budapest, as well as a MS in Biomedical Engineering from University of Technical Sciences in Budapest. Email:

Daniel Mazzolenis, MD Senior Medical Director, INC Research/ inventive Health, is responsible for the nonmalignant hematology business segment, a scope that includes hereditary and acquired bleeding disorders, hemoglobinopathies, some hematologic rare diseases, and "advanced therapies" for them. Dr Mazzolenis is a Hematologist with several years of medical practice prior to joining the pharma industry, where he served as Medical Director and Product Manager for Hemophilia in major multi-national pharmas, and Country Manager and Medical Director in CROs. Dr. Mazzolenis earned his medical degree from Universidad Nacional de La Plata, and completed residencies in Internal Medicine and Hematology. He has earned post-graduate degrees in Clinical Pharmacology from the University of Buenos Aires and an MBA from the Universidad del CEMA. Email:

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Patient Safety Monitoring and Beyond: How AI is Transforming Innovation in the Life Sciences Lifecycle

Whether enabling new approaches to patient safety monitoring and clinical trials, or improving success rates for regulatory submissions, artificial intelligence (AI) offers enormous potential to transform many routine pharmaceutical processes. Market innovators in life sciences have begun to stake their reputations on the breakthroughs enabled by advanced, computeraided analysis, interpretation and extrapolation — whether that’s in the area of improved customer self-service or advanced problemsolving in such areas as health diagnosis and predictive maintenance. Examples include complex medical diagnoses — particularly in complex or baffling cases — when machine learning offers the potential to mine not just one doctor’s experience and patient notes, but unlimited archives stretching back decades and spanning the world. Vast computing resources paired with advanced mathematical algorithms are now able to combine and mine vast sources of global data and sift out significant clues as to what might be wrong and how best to treat it. This needn’t detract from a doctor’s expertise — but rather focus this or free it up for even greater impact. Utilising Pharma Big Data In life sciences, AI can be the perfect tool for making best use of the rich, multi-dimensional data in the industry. This could be for operational and/or commercial advantage, with possibilities for application right across the product lifecycle. It is conceivable that in the near future we will see AI-discovered drugs brought to market, while we can also expect to see intelligent robotics increasingly taking over routine tasks in the lab and elsewhere in product development. One of the more exciting options is AI’s taking pharmaceutical companies deeper into the realms of wellness and the proactive prevention of illness — especially self-inflicted health problems — as technology learns how to recognise warning signs and then prompt better decisions or timely interventions. Social media and web forums together with personal apps offer obvious and already well-accepted means whereby patients can submit and monitor information about themselves for purposes of analysis and reporting. Plus, life sciences companies are more and more looking at proactive ways they can harness those means within all of the legal and industry rules. AI and Patient Safety If approached responsibly and within regulatory guidelines, web and social listening offers companies a way to determine early on how their drugs are being experienced and the impacts those drugs are having. There are also important safety monitoring potential and drug feedback potential, as long as intelligent tools based on AI and machine learning are in the background, offering companies what to look for and ways of deciphering what it all means. Already, AI is being applied to identify women whose Twitter posts indicate they may have increased risk of developing two relatively rare diseases: ovarian cancer and cervical cancer. And that AI application has produced accurate alternative diagnostic insights. AI could have a strong bearing on personalised medicine too, because clear insights into data make it easier to determine which 10 Journal for Clinical Studies

sets of patients a drug might be best suited to. AI could also support a range of applications in product safety — for example, the use of algorithms to predict toxicity in clinical trial studies, which would give companies information for developing better molecules. Because — with access to the same data — machine learning can pick up on subtleties that are less obvious to a human, the potential for the use of AI in clinical trials is considerable. Wearable devices relaying data feeds from patients could mean the slightest effects would get picked up — and early trends noted, without the potential for human bias or misinterpretation — earlier than previously possible, all of which could have a bearing on drug development and improved outcomes. In some of the areas, regulators may have to take time to catch up to the potential when it comes to their willingness to accept AIenabled insights as a valid part of reporting. Tackling Regulation On a more traditional, operational basis, AI offers a path through the data complexity that has typically held back life sciences organisations from becoming more agile, innovative, and responsive. In a 2016 survey by Gens and Associates called Pursuing World Class Regulatory Information Management, around half of the companies surveyed said they were already investigating AI to streamline regulatory information management, and a further third said they were monitoring what other companies are doing in this area. One issue that will become exponentially more significant as the International Organisation for Standardization’s new Identification of Medicinal Products standards come into play is that data about pharmaceutical products has historically been created, gathered, and stored by multiple, different functions in multiple systems. Because of that, one of the challenges companies typically face is that the usefulness of those multiple systems relies on whether that created, gathered, and stored data can be combined and counted on as a definitive record of product truth. Clearly AI has a great deal to offer life sciences. The potential to turn AI-enabled insights into timely and beneficial outcomes — whether that’s accelerating market entry, successfully mining social media for real-world feedback, discovering new indications, or improving the manufacturing and supply chain process — is huge, both to drug manufacturers and patients.

Marco Anelli Marco Anelli is head of the pharmacovigilance advisory and medical affairs practice at ProductLife Group, and responsible for the coordination of all clinical and preclinical aspects of projects run internally and on behalf of clients. Drawing on a career in the pharmaceutical industry that spans 25 years, Marco provides expert oversight on a wide range of R&D activities. He has participated in and coordinated all stages of drug development, from formulation to Phase I-IV and pharmacovigilance. Email:

Volume 9 Issue 6

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FDA Guidance Recommends Diversity in Clinical Trials, but Can’t Require It The US Food and Drug Administration (FDA) frequently stresses the importance of enrolling diverse patient populations in clinical trials conducted to support product applications — both in industry guidance documents and during interactions with product sponsors. In Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies, guidance released in September 2017, the agency makes multiple recommendations for marketing submissions, from advising sponsors to “recruit diverse populations that ideally reflect the intended population,” to suggesting they “discuss how clinically meaningful differences across subgroups may contribute to differences in benefit-risk profile in certain subpopulations.” When applicable, sponsors should also “submit and publically report study demographics, including proportion by subgroup and comorbidities,” the guidance states. But the words “Contains Nonbinding Recommendations” appear at the top of each page of the 36-page document — just as they do on most pages of recent FDA industry guidance. The words, in bolded italics, suggest that sponsors have some leeway when it comes to heeding FDA guidance. And, to a large degree, they do. Industry guidance presents the FDA’s “current thinking” on issues; it typically contains recommendations for how sponsors can meet agency expectations to get products approved — but it is not legally enforceable. “It’s not that, if you don’t follow [FDA guidance], you have violated a law,” explained attorney Alan Minsk, a partner at Arnall Golden Gregory, LLP. “You don’t have to take it, but if you don’t take it, at least think about it.” FDA guidance documents often outline specific methodologies and approaches to product development that, if followed, should yield data to support a product’s safety and efficacy, the underlying standards1 on which the FDA approves or denies applications. Industry guidance “is kind of a word to the wise,” Minsk said. The agency cannot formally deny an application just because a sponsor took another route. Sponsors are free to develop alternative ways of meeting those underlying standards, but it’s up to the FDA to judge whether an alternative satisfies relevant statutes and regulations, generates results demonstrating safety and efficacy, and merits approval.2 In contrast to guidance documents, FDA regulations are legally binding. Regulations take effect only after a federal agency completes the formal rulemaking process3, which includes publishing a Notice of Proposed Rulemaking in the Federal Register and soliciting and reviewing public comments, in keeping with provisions outlined in the Administrative Procedures Act. Once it has passed through multiple levels of review and is finalised, a regulation is codified into the Code of Federal Regulations (CFR). 12 Journal for Clinical Studies

FDA Recommendations on Diversity and Clinical Trials In recent years, the FDA has frequently encouraged sponsors to report and evaluate data about the age, sex, race, and ethnicity of subjects in clinical studies, and to consider that information when assessing medical products and proposing indications. The 2017 guidance document on age-, race-, and ethnicity-specific data4 “extends” FDA policy outlined in the 2014 guidance, Evaluation of Sex-Specific Data in Medical Device Clinical Studies, for example, and “extends and complements” recommendations in a 2016 document, Collection of Race and Ethnicity Data in Clinical Trials. The FDA has recognised a lack of diversity in clinical studies. The 2014 guidance on sex data states that studies “historically” have underrepresented or excluded women subjects and that, “historically,” the proportions of women enrolled in device clinical trials have not mirrored “the underlying disease distribution in the affected population.” Similarly, the 2017 guidance notes an underrepresentation of paediatric and elderly patients in clinical trials. Accurate representation of diverse ethnic and racial groups “remains a challenge,” according to the guidance, “and inconsistent analysis and reporting contributes to a persistent lack of publicly available data on device performance in diverse ethnic and racial groups.” FDA guidance documents stress why this underrepresentation matters. For example: • Women and men may respond differently to a medical product, in part due to “intrinsic factors” such as genetics, hormones, and sex-specific physiology, but also to “extrinsic factors” such as diet, environment, and socio-cultural issues. Intrinsic and extrinsic factors may interact, too, leading to a uniquely male or female response. • Age-related comorbidities, concurrent therapies, and developmental factors can impact both device performance and how patients experience a device. As stated in the 2017 guidance, “Older patients may have age-related covariates such as characteristics of bone density, metabolism, digestion, synovial fluid, etc. that could affect the performance of medical devices.” Both the benefits and adverse events associated with a device may be age-dependent, the FDA says. • Differences in the ways a device affects a patient may also correlate with race and ethnicity. The 2016 guidance notes, for example, that mortality rates for patients receiving dialysis differ across racial and ethnic groups. Despite the FDA’s repeated calls for accurate representation of patient diversity in clinical trials, recent research suggests that most device sponsors take advantage of the “Contains Nonbinding Recommendations” notation at the top of FDA guidance documents. Volume 9 Issue 6


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Sponsor Can Reject Industry Guidance and Still Make it to Market Researchers from Yale University and the University of California-San Francisco recently concluded that sponsors evaluating the safety and efficacy of proposed devices rarely account for the potential influence of a patient’s sex, age, or race and/or ethnicity. A research team examined device labels and Summaries of Safety and Effectiveness Data (SSEDs) for each of the 42 original premarket approval5 (PMA) devices approved in 2015 by the FDA. In all, sponsors performed 82 studies (both pivotal and non-pivotal) to support the 42 approved PMA applications. The researchers collected data on the number of patients enrolled according to age, sex, and race and/or ethnicity, and also determined whether sponsors had analysed study results by age, sex, and race and/or ethnicity. If they had, the researchers looked to see whether the sponsor had identified a difference in the device’s safety or efficacy. Their findings appear in the September 2017 issue of JAMA Internal Medicine.6 Overall, sponsors analysed study results according to age, sex, and race and/or ethnicity for fewer than 20% of studies performed to support original PMA devices approved in 2015, the researchers reported. According to their findings: • Age was reported in the SSED for 65% of the 82 studies; for 50%, age was reported in the device label. Sponsors analysed study 14 Journal for Clinical Studies

data by age in just seven of the 82 studies (9%); of the seven, one found the device to be less effective in younger patients, while two found the device less effective in older patients. In device labels, six studies (7%) reported results by age. • Race and/or ethnicity was reported in the SSED for 51% of the 82 studies; for 33%, it was reported in the label. Sponsors analysed study data by race in three of the 82 studies (4%); of the three, one found the device to be less effective in non-white subjects. In device labels, one study (1%) reported results by race and/or ethnicity. • Of the 82 studies, 77 included both men and women. Sex composition was reported in the SSED for 66% of those 77 studies; for 49%, it was reported in the device label. Sponsors analysed study data by sex in 13 of 77 studies (17%). Of the 13, one study found the device to be less safe in men; one found the device to be less safe in women; and one found the device to be less effective in women. In device labels, 12 studies (16%) reported results by sex. “In my view, our most significant finding is that age data were only available for 65% of studies, sex data for 66% of studies, and any racial/ethnic composition for 51%,” cardiologist Sanket Dhruva, MD, said by email. Dhruva, one of four researchers on the team, is a Robert Wood Johnson Clinical Scholar at Yale University School Volume 9 Issue 6

Regulatory of Medicine. “All three are among the most essential characteristics to understanding the performance of a device and the patient population in whom it is tested, and should always be reported for every study used to support FDA approval of a high-risk medical device.”

FDA guidance documents and still get their products approved and marketed, would it be more effective for the FDA to write fewer guidances and issue regulations instead? Probably not, according to Minsk — in part because of science, which evolves continually.

Dhruva pointed to one of the 42 original PMA devices approved in 2015: the Impella 2.5 System, called “the world’s smallest heart pump” by manufacturer Abiomed. The FDA approved the Impella PMA application in March 2015, indicating the device for use during elective and urgent high-risk percutaneous coronary intervention (PCI) procedures. (The FDA has since extended approval to other indications.) According to an Abiomed press release, the application included “rigorous data” from two clinical trials, PROTECT I and PROTECT II. It also included “clinical and scientific supporting evidence” on 1683 patients from more than 215 publications, a medical device reporting analysis of 13,981 patients, and data from 637 high-risk US patients enrolled in an Impella registry.

“Science can change,” Minsk said; it may not be in the FDA’s best interest to issue a regulation that must be amended in six months to keep pace with science. “Every application is different. Every study can be different. For them to basically say there’s only one way to get there would be foolish and short-sighted.” As for legislating demographics, issuing a regulation requiring that all clinical studies enroll a certain percentage of subjects of a particular ethnicity, or of women versus men, would be untenable, according to Deborah Livornese, of Counsel for Arnall Golden Gregory.

Dhruva referred specifically to the larger of the two clinical trials, PROTECT II. As described in the Impella 2.5 SSED, PROTECT II assessed Impella safety and efficacy when used prophylactically in patients undergoing non-emergent high-risk PCI, comparing its use to the intra-aortic balloon pump. The primary endpoint was a composite of 10 major adverse events, including stroke, myocardial infarction, repeat revascularisation, acute renal dysfunction, and death. The sponsor ultimately halted PROTECT II early, in December 2010, after an interim evaluation of the primary endpoint identified no statistically significant differences in major adverse events between the Impella 2.5 and comparator arms. But when a subsequent data analysis found that patient outcomes with the Impella 2.5 actually improved over the longer term (at 90 days versus 30), the FDA decided to include the PROTECT II data in its review of the PMA application. Dhruva criticised the sponsor’s handling of PROTECT II data. The study enrolled 452 subjects, including patients who had additional risk factors, Dhruva said, specifically noting that some were female and/or of “advanced age.” “I note that the data for this device does include the mean age, proportion female, and proportion of racial/ethnic minorities – which is good, but there were no available data specifically on the outcomes of these groups of patients with the device at the time of approval,” Dhruva’s email said. He called outcome data on females and older patients “essential” to weighing the risks and benefits of using the Impella 2.5 in those populations. As an example, Dhruva mentioned bleeding risk, which is generally higher among women and older adults. If study data showed that women and older patients experienced higher rates of bleeding complications with the Impella 2.5, that would be an important consideration when deciding whether to use the device in women and elderly patients undergoing highriskPCI. “Even if it is determined that the benefits of using the Impella 2.5 outweigh the risks, information that risks are higher in one population may inform additional strategies to mitigate that risk,” he said, “such as duration of use of the device.” Are New Regulations the Answer? As noted, while FDA industry guidance is not legally enforceable, regulations are. If sponsors can ignore recommendations in

“That would constrain the ability to get clinical trials done because, the fact of the matter is, it’s sometimes very hard to recruit people for clinical trials,” Livornese said. REFERENCE 1. 21 CFR 860.7 outlines the rules applicable to safety and efficacy determinations for medical devices. 2. Minsk stressed that FDA guidance applies to both industry and to the agency itself. If a sponsor fulfills recommended criteria, but the FDA says their actions were inadequate and do not support approval, “it’s incumbent on the FDA to have a really good reason for that,” according to Minsk. 3. The US Administrative Procedures Act outlines the rulemaking process. 4. Publication of Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies fulfilled a commitment the FDA made in its 2014 Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data. Congress directed the FDA to develop the action plan in 2012 when it passed the Food and Drug Administration Safety and Innovation Act (FDASIA). 5. The FDA requires PMA applications for devices that pose the highest risk to patients. 6. Dhruva SS, Mazure CM, Ross JS, et al. Inclusion of Demographic-Specific Information in Studies Supporting US Food & Drug Administration Approval of High-Risk Medical Devices. JAMA Intern Med. 2017 Sep 1;177(9):1390-1391. doi: 10.1001/jamainternmed.2017.3148.

Meg Egan Auderset MS, MSW, Medical & Regulatory Writer, Clarivate Analytics Writer and editor of more than 20 years, with experience in a variety of settings in both the US and Western Europe. Currently a Medical & Regulatory Writer for Clarivate Analytics (formerly the IP & Science business of Thomson Reuters), her primary assignments include reporting on FDA advisory committee meetings and drug approvals for Cortellis and the AdComm Bulletin. Email:

Journal for Clinical Studies 15


Intellectual Property Strategies ‘Crucial’ to Protecting Future of Medical Innovation Robust intellectual property protection is essential to safeguarding the future of revolutionary biomedical innovations, which transform healthcare for millions of people worldwide. The biotechnology and medical industries are among some of the most progressive in the world with billions spent annually on creating industry-leading drugs, techniques, therapies, and technology which transcend expectation. Driving the creation of these countless medical advancements is the vast investment in research and development by thousands of leading medical researchers and firms. According to the Medical Research Council in 2015/16 its gross research expenditure, funded by Business, Innovation, and Skills budgetary allocation and contributions from other bodies, was £927.8 million compared to £771.8 million in 2014/15.1 This significantly increased sum which is spent on enhancing medical research, demonstrates the value of the biotechnology and medical industries as a multi-billion-pound commercial entity with limitless potential. It is this commercial value attributed to the medical industry that supports continuous innovation, with abundant financial returns helping to fund ongoing research and development. Realising the financial benefits also spurs on researchers and firms which plough vast sums into the initial development of revolutionary treatments, and must also be assured of a return on their investment through the subsequent financial monopoly when the product reaches the marketplace. For example, with an average cost of over £500 million spent to develop a new pharmaceutical, the aim for businesses which invest in research and development (R&D) is to make a profit when the product is marketed so as to return a dividend to investors and help fund future R&D work. However, without safeguarding the rights to a product through an effective intellectual property strategy, they could face infringement by competitors, which damages the product’s commercial exclusivity, leading to devastating financial losses.

researchers and firms involved in developing the latest industryleading drugs, therapies, medical devices and related technologies. “These transformative creations not only have an intellectual value, which could enhance the care of millions of people across the world, but also a commercial value, which is realised when the products are introduced across the pharmaceutical industry.” To help support research and progression in this field, Mr Robertson and commercial director Jayne Nation have put together some key considerations when creating an effective intellectual property strategy, along with suggestions on how to develop it to ensure maximum protection and commercial reward. On why an IP strategy is particularly vital to the biotechnology and medical industry, he said: “An IP strategy is vital to helping a company identify its strengths and weaknesses, the opportunities and threats that exist in the marketplace and from competitors, creating a framework for creating and managing the IP portfolio going forward so that it helps the company achieve its goals, and so that the company gets best value and quality for money. “Part of this is typically identifying what intellectual property it possesses, why and how it should be protected, and where it needs to be protected. “In the case of the biotech/pharmaceutical industry, intellectual property can protect a product, such as a drug, enzyme or antibody, or a method, such as a synthetic pathway, an enhanced manufacturing process, or a diagnostic test method or equipment.” To ensure the product is most effectively utilised within the pharmaceutical industry to ensure the optimal care of patients worldwide, but also to protect researchers’ intellectual property rights, Mr Robertson has offered his opinion on how best to construct an IP strategy to drive success across both the health and commercial aspects. He said: “With endless potential for innovation in this field and increasing collaboration between industry and academia, and between individual companies, a well-structured and effective strategy is vital in ensuring ownership of the rights to a discovery, and how the information can be utilised for maximum future success.

Patent attorney and partner at a leading intellectual property firm, Jim Robertson, said protecting products within this field was “crucial” in order to safeguard the future of innovation and research.

“In order to attain the greatest results through an IP strategy, it should be aligned with the aims of the business. This will allow inventors to pinpoint exactly which features they feel warrant protection, and potentially achieve the most lucrative results for the business.

Mr Robertson, who specialises in advising the biotechnology, pharmaceuticals, diagnostics and medical devices industries, said: “Nowhere is an efficient and targeted plan more productive than in the biotech industry, particularly in protecting the rights of medical

“Having a considered IP strategy in place also allows companies to focus on the most commercially lucrative aspects of their technology and brand, consequently helping to hone and further their market potential.

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Regulatory “For larger companies and groups, some with sprawling IP portfolios, or those who have previously worked with multiple IP suppliers, a first major step can simply be understanding what patents, trade marks and registered designs they own and how they fit in with the IP strategy and the current commercial products.

“A significant initial investment in research and development is required across the pharmaceutical and medical industries, where millions of pounds are spent on creating industry-leading techniques or treatments to revolutionise patient care.

“Doing this can simplify management, streamline decisionmaking, and reduce costs, particularly where the number of outside suppliers can be reduced and the quality of service increased at the same time.”

“As such, we cannot emphasise the importance of a strong and targeted IP strategy in this industry enough. Having this in place will ensure those in the medical profession receive the deserved rights to their intellectual property and also enjoy the eventual commercial benefits.

Many, however, forgo investing in intellectual property during the initial stages of development, failing to recognise the purpose and value of an IP strategy. Their failure to appreciate the unparalleled importance of an intellectual property strategy could be attributed, in part, to the initial cost.

“Putting a strategy in place also highlights the value of intellectual property as a commercial tool. In doing so, key decisionmakers are better informed about where to allocate vital funding for research and development to better achieve ongoing business goals.

On why researchers and those developing products in the pharmaceutical industry need an effective strategy, Mr Robertson said: “A professionally crafted IP strategy is a wise investment in terms of protecting your initial development, and achieving success and longevity. “Researchers will be all too aware of the expense of investing in creating a viable asset, carrying out research to enhance its marketability, and finally launching it into a competitive industry. This requires an ongoing financial commitment.

“Recognising the importance of IP and adequately protecting it can also have a beneficial impact on the value of the company which has established the drug, treatment, or equipment, which could encourage further investment by enhancing the reputation of the business. “This is particularly positive for the medical industry which is reliant on attracting external funding and grants to support the continuation of extensive research. “Ultimately, having a good and well managed IP strategy

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Regulatory demonstrates to potential investors that the business is worth investing in. “One of the first roles to undertake when developing an IP strategy is to conduct an audit of the company’s existing intellectual property, including any patents, trademarks, copyrights or designs, and comparing this against new inventions which are to be commercialised. As well as having a top-level IP strategy in place, companies need to have a strategy for each technology or product sector which focuses on the specific issues it encounters, for example protecting inventions, dealing with potential infringement of other people's patents, directing future R&D, branding and so forth. Mr Robertson said: “Having an effective plan in place from the beginning helps to reduce the likelihood of infringement of an existing patent, and reduces the risk of facing a dispute further down the line. “It can also help to prevent an invention from being targeted by potential competitors keen to profit from it, without incurring the costs of the initial financial investment. “Developing a product or drug, at great expense, and then discovering it has breached an existing patent could result in the abandonment of an invention without realising its commercial potential; finding out that the brand you have committed to selling under infringes an existing registered trademark could lead to significant and unnecessary costs.” “As part of the initial plan, an intellectual property expert will conduct thorough research, and, as appropriate, perform a freedom to operate search to help prevent this eventuality and reduce the associated risks. In the medical industry, a strategy can also help to sharpen the focus in what can often be a multi-faceted approach. “For example, the administration of a particular drug could be revolutionised through the use of a newly discovered technique, a new dosage regime, or a new piece of equipment. As a result, it is vital that the rights to this are protected as part of an IP strategy, particularly if it has significantly added value and profitability.” Dr Jayne Nation agreed. She said: “Having an effective plan in place from the beginning helps to negate the likelihood of infringement and the threat from competitors. Robust protection of these assets is needed because the investment can run into hundreds of millions of pounds, money which could be potentially wasted if someone can just copy the invention.” Mr Robertson warned, however, that lines can often become blurred as drug development travels through different channels, with external collaborators including chemists, researchers, scientists, and developers all potentially involved in the process. As a result, consideration must also be given to intellectual property rights in relation to third parties. He said: “The plan or strategy should address collaboration to ensure that the rights to the intellectual property are clearly defined in commercial agreements with third-party researchers, suppliers and collaborators, in order to avoid consequent conflicts at a later stage. The strategy should also clearly address the issue of confidentiality in working alongside outside parties, including - where and how the 18 Journal for Clinical Studies

confidential information can be used; and who owns the rights to any subsequent discoveries. “When compiling an IP strategy, prior art should also be considered to ensure the creation has space to evolve while protecting the inventor’s initial investment and market exclusivity. Prior art is anything relevant to an invention which is already in the public domain. “This can be anything from a published historic invention to discussions surrounding a use of technology that is very similar to a previous invention. By understanding the relevant prior art, patent applications can be crafted to provide the best possible protection for new inventions, whilst stepping around protection provided by prior art patents.” Dr Nation said that alongside patents and trademarks, another consideration for those creating an IP strategy is whether to keep trade secrets. “A trade secret is a form of intellectual property too but is more difficult to manage. It is an invention, knowhow or other unique creation that is considered so sensitive commercially it may be best managed by not making it transparent to the wider business community, unlike patents, where the details of the invention are published for anyone to see. However, using trade secrets to protect IP comes with significant, associated risks. “If you are planning to keep your invention or other unique creation as a trade secret, you will need a rigorously defined management process within the company that restricts access to only the most strategically important personnel. If you are considering trade secrets, it is vitally important that you seek legal advice from a specialist IP attorney and discuss the risks with your investors, management board or other senior decisionmakers.” In conclusion, Mr Robertson said: “It is imperative that the biotech/pharmaceutical industry recognises the importance of adopting effective intellectual property strategies, which can evolve with the development of world-leading products. “Continued research and development must be given support to flourish and progress unhindered; this will undoubtedly safeguard the future of the pharmaceutical industry as a whole.” REFERENCE 1. visited on October 2, 2017

Jim Robertson Patent attorney and partner at Wynne Jones IP, whose primary technical fields are based in life sciences – specialising in biotechnology, pharmaceuticals, diagnostics and medical devices.

Jayne Nation Commercial director at Wynne Jones IP. She has over 25 years’ experience in creating and developing technical innovations and managing strategic business relationships.

Volume 9 Issue 6

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The First Interactive Guidance Management System (IGMS) in the Clinical Research Industry Find out more at

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The Lay Summary – Remember the Reader As part of its Clinical Trial Transparency initiative, the EMA mandated a requirement for clinical trial sponsors to prepare a summary of the results of every clinical trial written in language understandable to lay persons (patients and others not in the pharmaceutical industry). The regulation (CTR EU No 536/2014) obliges the company to produce this summary of results for the lay audience one year after the end of the trial in the EU. This requirement was originally planned to take effect in 2018, but it seems likely that it will not now be implemented until 2019. The pharmaceutical industry is obviously aware of this coming requirement and serious discussions are occurring as to how best to respond to this challenge. Overall, CTR EU No 536/2014 is a very positive development and is a welcome chance to deliver clinical study results to the broad and crucial audience of the general public – especially patients. Few things are more important to the future of the pharmaceutical industry than informing and involving patients in the process and decisions of drug development, and by extension, in the scientific process per se. The requirement to prepare a summary of the results of every clinical study, in a form that can be understood by anyone, is a major step forwards in transparency, an opportunity to explain drug development, and hopefully to increase public awareness and understanding of the industry. However, there is a danger that this opportunity will be missed; either through lack of clarity in the requirements, or because writing for the layperson is notoriously difficult and so companies may be tempted to fulfill the letter rather than the spirit of the regulations. Confusion and misinterpretation of guidelines has happened historically. The Clinical Study Report (CSR) Synopsis ICH guidelines recommend “a brief synopsis (usually limited to 3 pages)” which was later extended to “for complex or large and important studies (e.g., to 10 pages)”. Unfortunately, few companies consider this guidance and CSR synopses of 20–25 pages are not uncommon. This likely arises from a misunderstanding of the purpose and use of the synopsis. It is mistakenly seen as an extended summary, rather than a brief description of the study for Module 2.7.6 of the CTD (where the synopses are gathered to provide a reviewer with a brief overview of all the registration studies). Many authoring teams seem unable to resist adding more and more information until the synopsis resembles the study methods and results sections of a full CSR. The lay summary describes a single study – there is no context of wider clinical development to enable the reader to properly evaluate the benefit-risk of the drug, and there is a danger that ambiguity in the CTR EU No 536/2014 regulation may result in similar misinterpretation. There are 10 suggested headings for the CTR lay summary; for some of them the information to be added is very clear and obvious, but for others, companies must make their own interpretation. 1.

Clinical trial identification (including title, protocol number, EU trial number and other identifiers).

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This section should have factual information, but how helpful it is for patients is questionable. If the title is complex, a simpler title should also be added, but care must be taken that when complex language is simplified, it does not become misleading. 2. Name and contact of sponsor. This section is self-explanatory. 3. General information about the clinical trial (including where and when the trial was conducted, the main objectives of the trial and an explanation of the reasons for conducting it). Describing objectives can be challenging. Secondary objectives can be very important, and so the company must decide what to present and how to present the facts. The methods section should be straightforward, but some companies believe that results for every single parameter should be mentioned in the methods. By itself this may be no bad thing, but as we have seen with CSR synopses, these ‘summary sections’ can mushroom into huge long lists of numbers and multi-page tables. Then there is the question of how the information is presented. It is well-known that tabular and graphical presentations are better for communicating data rapidly. Study designs can be very effectively communicated with carefully prepared, clear graphical schemes which are far superior to long passages of text. 4. Population of subjects (including information on the number of subjects included in the trial in the Member States concerned, in the union and in third countries; age group and gender breakdown; inclusion and exclusion criteria). There can be huge numbers of inclusion and exclusion criteria, and long lists of complex terms can be very difficult to understand. Which criteria should be included, if the lists are too long? 5. Investigational medicinal products used. Laypeople are unlikely to be familiar with generic names, and brand names can be different in different countries. For early phase studies, generic or brand names may not even have been allocated. 6. Description of adverse reactions and their frequency. Discussing adverse events (AEs) can be very challenging. Any potential harms should be placed into context and weighed against potential benefits of the drug, but this is very difficult to do in the trial summary when the AEs section is presented to laypeople first. Even the term ‘adverse reaction‘ can cause confusion, and the seriousness and frequency of each reaction should be explained and described. Most AEs are described in MedDRA (Medical Dictionary for Regulatory Activities) terms and so these should be explained in lay language. Underlying all of the challenges described in these sections is the more general Volume 9 Issue 6

Regulatory challenge of communicating benefit-risk information in terms that do not rely on statistical values or parameters to convince the lay audience to ‘trust‘ them. How a drug‘s AEs are described can be crucial in how they are understood, and therefore in the outcomes that result. 7. Overall results of the clinical trials. The results of the trial should be described but this can be very difficult considering that health numeracy levels (the ability to understand and interpret numbers related to health information) in the general population are even lower than those of health literacy. Technical terms such as ‘number needed to treat‘, ‘hazard ratio‘, ‘confidence interval‘, etc. are particularly difficult to explain to a lay audience, and even more difficult for them to interpret. How do we expect the lay audience to interpret and react to a table of parameters from a Phase I pharmacokinetic study? Tables and graphs that are easy for those of us in clinical research to understand and interpret due to the familiarity that comes with long and repeated exposure, may not be so straightforward to the public. How confident can we be that patients will be able to correctly interpret at first glance a shift table, Forest Plot, or Kaplan-Meier survival analysis? Presenting only the top level or main results can also be interpreted as cherry-picking so a balanced, true representation of the results must be given. Using statistical terms to explain how much ‘trust’ the reader can place in a result can increase the perception of risk (Han 2011), and lead to a reluctance to take the drug. Finally, there is the issue of what information to present. For efficacy results, a way must be found to discuss the difference between the interpretation of primary and secondary analyses, to say nothing of exploratory analyses. Giving the lay audience complex information does not help them to make decisions – especially if the information is numerical (Zikmund-Fisher 2013). It also calls into question the value of disclosing complex clinical trial results without context and explanation (neither of which is currently mandated by the regulation). Understanding the importance of increases of AEs above the general population level relies on the reader knowing what the baseline level of the population is, and being able to put this into context. How can we communicate that clinical studies are designed with statistical power such that statistically significant results for the

primary analysis indicate a clinically relevant effect, whereas for secondary analyses the interpretation is weaker and more complex? This is a challenge even for a scientifically literate audience. Safety results might appear at first glance to be easier to communicate, but there are challenges here as well. Most adverse event results are given with a percentage indicating frequency. The accuracy of these frequencies, however, is very strongly dependent on the sample size; accuracy drops sharply in small studies, but how much it drops and the relative importance of different events can be very difficult to explain. Providing guidance to a lay reader on how to interpret adverse event frequencies is not trivial, and is crucial not least because of the nocebo effect (adverse effects occurring in patients receiving placebo due to expectation rather than any treatment). The nocebo effect could become a problem for companies if the presentation of safety data is not handled with care. Since all of these complex ideas and results can only be correctly interpreted in the context of other information, the likelihood of misunderstanding and thus misinformation is very high. 8. Comments on the outcome of the clinical trial. This should be an overall summary of the results and their implications. However, it should be unbiased and should not sound promotional in any way. It is difficult to describe positive results so that they are not interpreted as promotional, but this is an excellent opportunity for companies to describe how clinically meaningful the results are. 9. Indication if follow up clinical trials are foreseen. This section should explain if and when more studies will be done on the drug. 10. Indication where additional information could be found. This section is self-explanatory, but links could also be given to more general sites, such as plain language dictionaries. These challenges are not insurmountable and have not been ignored. The EMA have ongoing consultations with industry

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and patient groups to try to improve the guidance for industry in communicating with the lay audience. There are also companies offering user testing services to allow testing of lay text with its intended audience. The continued dialogue between regulators and industry around the issues of transparency and communicating with laypeople offers the chance to develop guidelines that can lead to lay summary documents that truly aid the public’s understanding of clinical research, and improve their trust and perception of the pharmaceutical industry, rather than just add still another document to the large pile of submission requirements for clinical research. It would be a tragic waste of an opportunity if these new regulations simply lead to the addition of another overly long and hard-to-understand summary of clinical study results. Instead, everyone involved in either the writing or the designing of templates and procedures for lay summaries should invest time and resources in making sure that the resulting documents facilitate rather than hinder communication with the lay audience. The pharmaceutical industry has few opportunities to communicate directly with patients in Europe, and so it would be good to remember the reader when producing this document, and see the lay summary of the CSR not as yet another regulatory hurdle to be mechanically created and filed to gather dust, but rather as a unique chance to expand the science-public interface and perhaps improve the general understanding and acceptance of science into the bargain. REFERENCES 1.

Han PKJ, Klein WMP, Arora NK, Varieties of uncertainty in health care: a conceptual taxonomy. Med Decis Making. 2011. 31(6): 828–838 2. Zikmund-Fisher BJ. The Right Tool Is What They Need, Not What We Have. A Taxonomy of Appropriate Levels of Precision in Patient Risk Communication. Med Care Res Rev 2013;70(1): suppl 37S-49S 22 Journal for Clinical Studies

Barry Drees He received his PhD in molecular genetics at the University of California, San Francisco. Following his postdoctoral work as a fellow of the National Institute of Health, he worked as a medical writer in the pharmaceutical industry at Hoechst/ Aventis for 12 years, setting up a Phase I writing group and leading several regulatory submission teams. Barry is a frequent speaker on medical writing, statistics and other scientific communication topics for various pharmaceutical associations. He is the former Editor-inchief of “The Write Stuff”, the Journal of the European Medical Writers Association (EMWA), and was the President of EMWA 1996-1997. He is currently a Co-founder and Senior Partner of Trilogy Writing & Consulting, continuing to personally lead submission teams as well as providing training for the industry around the world.


Lisa Chamberlain James Senior Partner and Chief Executive Officer of Trilogy Writing & Consulting. Aside from management activities, she also leads client projects, with extensive experience in a variety of documents and a special interest in drug safety and patient information. After receiving her PhD in Pathology, Lisa began her medical writing career in Cambridge in 2000. Since then, she has been heavily involved in the EMWA on the Education Committee and as a workshop leader, is chair of the EMWA PV Special Interest Group, and is a Fellow of The Royal Society of Medicine.


Volume 9 Issue 6

© SGS Group Management SA - 2017 - All rights reserved - SGS is a registered trademark of SGS Group Management SA


SGS is a leading life sciences CRO providing clinical research and bioanalytical testing services. Delivering solutions in Europe and in the US, SGS offers Phase I to IV clinical trial services encompassing clinical project management and monitoring, biometrics, PK/PD modeling & simulation and regulatory & medical affairs consultancy. Clients benefit from our a wealth of expertise in regulatory and exploratory trials, viral challenge testing, complex PK/PD and biosimilars studies with a high patients therapeutic focus in Infectious Diseases, Vaccines, Oncology and Respiratory. Stay ahead in your drug development plan, contact us for reliable and adaptive clinical trial solutions.





Market Report

Regulations and Recruitment: Challenges and Experiences in Bulgaria During the preparation and conduct of clinical investigations, on both medical drugs and devices, CROs are facing a variety of regulatory and scientific challenges, leading to different initiatives to manage and balance them. Below we present our experience on several common subjects. Clinical Trials on Drug Legislation The Bulgarian legislation is in compliance with the EMA regulation. ICH E6 is implemented in the Bulgarian legislation through the Medicinal Products in Human Medicine Act (MPHMA) and through Regulation No. 31/12 Aug 2007. However, there are several specifics according to the Bulgarian legislation and the interpretation of the rules of the applicable acts is necessary with regard to the conduct of clinical trials in the Republic of Bulgaria. The misinterpretation of these rules may lead to certain discrepancies in the course of multinational trials or trials with EU sponsors conducted in Bulgaria. Currently there is a discussion about the rules of MPHMA concerning the sections on clinical trials. The suggested update will aim to unify and simplify the approval process for conducting clinical trials and optimise the regulatory framework. The most prominent changes are as follows: • The hospitals and most of the medical centres in Bulgaria are organised in a centralised healthcare system. It will become mandatory for every centre, where clinical trials are conducted, to appoint a person who will be responsible for coordination/ monitoring of the conducted trials. • Currently, the approval process requires written approval by the regulatory authorities (RA)/Bulgarian Drug Agency (BDA) and local ethics committee (EC) (in the case of a single-centre trial). When the trial is multi-centre, the approval of an additional structure is necessary – Ethics Committee for Multicenter Trials (ECMT) under the Ministry of Health (MoH). The legislation allows a multi-clinical trial to be started after RA and ECMT approval. However, based on the experience it can be said that the approval/notification of local ECs is desired, leading in some cases to additional expenses for fees. The new proposal is a single ethics committee under the authority of the Minister of Health to be created, and the local ECs to be omitted. Its purpose will be to review the submitted clinical package of documentation for all clinical trials and issue a statement. This statement will then be directly transferred to the RA. Based on that statement, the final approval for conducting the clinical trial will be given. This new procedure will shorten and simplify the approval process. • Concerning the gained popularity of CTs with narcotic INNs, the future amendment will require these CTs only to be allowed 24 Journal for Clinical Studies

in study sites that have a pharmacy with certification to handle such substances. The proposed renewal of the MPHMA is a result of the launch of Clinical Trial Regulation EU No. 536/2014, expected to come into effect in October 2018. Challenges • Regulatory audit: BDA does not provide such services, but the MoH does. The competent authority conducting an inspection of the clinical site is the Regional Health Inspectorate (RHI) under the authority of the Minister (Ministry of Health). Based on this inspection, an official document (Authorisation for Medical Activities) is issued. This document sets out the approved activities that can be conducted in the clinical site, including clinical trials, and scientific and educational tasks. The audit report from the initial inspection is kept in the study site. The official document the RHI issues is the certificate of Authorisation for Medical Activities. The latter is the one that is required and provided as an official document. • RA Deficiency Letter (DL) on submission package: can be issued only once by the RA for certain issue. Upon the response to a question being submitted, the RA cannot raise any further comments, but can discuss the issue on hand additionally. • Insurance policy/contract: In Bulgaria, the MPHMA sets insurance policy as mandatory for every type of clinical and non-interventional trial/study. The insurance policy is targeted towards the study team, especially the principal investigator, covering their professional liability for non-material and material damage of the participants caused by or in connection with the conduct of the clinical trial. Unlike most of the member states, as explained, an insurance policy is required for non-interventional studies (NIS) as well. This is additional insurance, specific to the CT, different from their mandatory professional liability insurance as a medicine practitioner. • Implementation in the current practice of the risk-based quality management of clinical trials in compliance with Regulation EU No. 536/2014 and ISO 9001:2015, especially when it comes to the design and complexity of the study protocols, data collection, monitoring, management and all relevant documentation. The focus will be on risk identification, reduction and/or acceptance. Investigators In Bulgaria, there isn’t a requirement for the duration of clinical practice of the medical practitioner in order for him/her to be Volume 9 Issue 6

Corporate Profile Ramus Medical is a contract research organisation established in 2009 and based in Sofia, Bulgaria. Ramus Medical owns an in-house clinical research centre and Phase I unit. Since 2010, Ramus Medical has built a strong portfolio – the Ramus team has successfully completed more than 40 clinical trials – BE/BA studies and NIS on drugs from the following groups: antibiotics, corticosteroids, non-steroid anti-inflammatory on medical products with different formulations, and clinical investigations on medical devices. The medicinal products being investigated by Ramus Medical have MA granting in the EU.

Ramus Medical has an experienced in-house team with strong project management skills and a keen understanding of regulatory requirements in each jurisdiction for study execution and commercialisation. We carry out clinical projects as a team. We are resultsoriented and we monitor the external situation with a mission to comply with the comprehensive global and governmental regulatory processes. Ramus Medical is building partnerships with key opinion leaders as principal investigators and dedicated research teams with good reputations. PIs working for Ramus Medical have a valuable role in designing protocols with significant positive impact on timely

ethics and governance approvals, answering medical questions, interacting with key investors to confirm their commitment to the trial and its benefits, as well as patient recruitment and provision of quality, scientifically meaningful data. The ability to meet recruitment targets is facilitated by having access to the actual patient pool available. As stakeholder in the value chain of entire drug development process, Ramus Medical contributes to managing time, costs and performance to guarantee the achievement of project objectives within the desired parameters and quality level. Usually Ramus Medical carries out the entire study, utilising years of experience in clinical development and commercialisation from planning and medical writing to the final report preparation. Depending on their requirements, the sponsor can also make use of only individual modules of our services: clinical development, launching a product or managing a portfolio across the development and product life-cycle, and clinical data capture, data management, statistical analysis, as well as readability user testing, hazardous waste management and logistics services. Ramus Medical is closely related to Medical Diagnostic Laboratory Ramus Ltd, founded in 2001. The laboratory is the largest private clinical laboratory in Bulgaria, with 15 laboratories operating in the big cities in Bulgaria. Over the years, the laboratory has provided services as safety and central laboratory for more than 300 clinical trials for Bulgarian, EU and US sponsors. The Bio-Analytical Department of Laboratory Ramus is the only one in Bulgaria with ISO/IEC 17025:2006 accreditation.  CRO and laboratories have well-designed quality systems and procedures which are capable of meeting the relevant regulatory requirements. They are certified in compliance with the requirements of the International Standard for Quality Management Systems. Ramus Medical and Medical Diagnostic Laboratory Ramus are regularly audited by sponsors. Ramus Medical have been audited by Navigant Consulting in October 2016 and inspected by the Bulgarian Drug Agency in November 2017.

Medical Diagnostic Laboratory Ramus Ltd 2–4, Angista Str. 1527 Sofia, Bulgaria Tel./Fax: +359 2 944 82 06 email:

Ramus Medical Ltd

4, Angista Str. 1527 Sofia, Bulgaria Tel./Fax: +359 2 841 23 69 email:

Dimitar Mihaylov Marketing Director

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Market Report approved as an investigator in a clinical trial. However, there is a requirement for a recognised medical speciality in the relevant field.

• Unlike the strict drug regulation regarding the clinical trials, the regulation for medical devices is not fully developed and unified in the EU.

The investigators in Bulgaria are well trained, including GCP, and have many years of experience in the clinical trial fields. The operation with documentation in the English language is not an issue, due to the general good level of English education. This ensures smoothness in communication for the needs of international trials.

• Locally, the marketing authorisation, requirement for the manufacturer, clinical trials conditions, and adverse events reporting are covered by the Medical Devices Act (MDA), as well as several more closely targeted regulations.

The common practice is for the sponsor or its representative (the CRO) to sign two separate contracts – one with the principal investigator and another with the study site. This increases the investigator’s motivation due to the direct remuneration for their trial responsibilities. Study Sites Clinical trials in the BG territory are allowed to be conducted only in medical facilities, certified by the MoH and its additional structure RHI; with local EC approval and registered by the BDA. Bulgaria is a relatively small country with a well-developed infrastructure. The conduct of a multi-centre clinical trial, even though dispersed in different BG cities, is not a particular issue. The organisation, monitoring, and SAEs reporting are usually conducted smoothly. Conducting clinical trials in a study site owned by the CRO is beneficial and improves the whole process. The full service CRO is the best opportunity for providing cost saving, simplifying the logistics, and avoiding delay, especially if the bioanalytical laboratory in site is certified under ISO 17025, and ensures quality. Recruitment One of the advantages of working in a small country is that the investigators are familiar with their patient pool. Some of the CROs in Bulgaria also maintain databases with possible healthy volunteers for certain types of CTs. Based on this, an exhaustive list of potential candidates can be relied on and the selection of a particular patient population/healthy volunteers is facilitated, and a pre-screening procedure could be initiated even before the trial itself. The recruitment and enrolment can start on time and the clinical trial can be initiated immediately after obtaining the approval, which is especially important in cases of time-sensitive trials. This also benefits the situation where the number of patients to be screened is fixed due to a pre-fixed agreement or the sponsor’s preferences. Following these politics of participant recruitment and ensuring the wellbeing of the participants during the trial, the drop-out rate is low and a follow-up process is facilitated. This is contributed by the very high trust of patients in the capabilities of their investigators. Clinical Investigations on Medical Devices Legislation The medical device manufacturing industry is growing into a major factor in the healthcare market. Thus the investigations on medical devices have become more and more popular in the last two years, particularly in BG. The increased number of such investigations showed some discrepancies and oversights in the legislation in Bulgaria, as well as in the EU – such as: 26 Journal for Clinical Studies

• The rules on clinical investigations should be in line with well-established international guidance in this field, such as the international standard ISO 14155. It implements the rules on good clinical practice for clinical investigations of medical devices for human subjects to assess the safety or performance of medical devices for regulatory purposes. • In general, the MD directives do not contain technical details but broad safety requirements, so-called essential requirements directed to the manufacturers. • The criteria for MDs classification are more difficult to define and enforce, sometimes requiring additional consultation with experts. This is particularly important due to the fact that the different classes fall under different permission conditions, having impacts on the volume of documentation, expenses for fees, approval period, etc. • There is not a clear definition or algorithm of action in the case of a mixed product – a drug used with a medical device. In such situations, the question arises as to whether the focus of the trial will be on the drug or on the device. Discussion of this problem can be found in the EMA’s Questions and Answers. • Some of the problems the CROs meet also require well-trained experts in the medical devices field in RAs and ECs. The use of a quality clinical research organisation (CRO) is recommended to avoid any contention over data quality, commonly occurring in multinational trials. For instance, some manufacturers of high-risk devices submit documentation to obtain approval to conduct clinical investigations without providing data on the full biocompatibility or finalised animal testing, committing to prepare full reports when data is available. There are cases where such applications are answered, but our experience is the RA is usually not satisfied by only a statement and requires full documentation on this item at the time of submission. In some markets, the ethics committees can be even more demanding than the RA. Despite these challenges, medical device manufacturers can conduct clinical trials more easily in Europe where currently regulatory barriers to clinical testing have less constraints. The possibility to apply and gain permission to conduct a clinical investigation in a single member state reduces the administrative burden. Also, resource-sharing is allowed. Unified criteria in EU provide the opportunity to ensure consistency regarding the assessment of the health and safety-related aspects of the investigational device. The challenges and opportunities for the CRO • The selection of investigators: They should be medical specialists (doctor or dentist) qualified for the study on hand, Volume 9 Issue 6

Market Report

having the appropriate speciality, scientific knowledge and experience in patient care. However, young specialists are often included in clinical investigations as co-investigators, benefiting the trial with an innovative point of view and enthusiasm. • The selection of facilities: the requirements for the study sites are similar to those for drug investigations. For some medical devices, there might be an additional recommendation for the study site to be similar to the facility where the device is intended to be used. • The selection of participants: • Depending on the specifics of the medical device, the investigation might need to be conducted with patients with certain pathology, not healthy volunteers, leading to even more ethical issues. • The necessity, in some cases, for preliminary training of the participants on using the medical device (in cases of CT requiring self-medication/usage) may further hamper the conduct of the study. • Additional difficulties arise for the necessity of usage of a patient’s diaries. • Some of these clinical investigations are quite prolonged and the risk of drop-outs is higher. • Additional ethical issues arise while creating the design of the clinical trial, especially when an invasive or/and surgical intervention is required. • The recruitment procedure is sometimes carried out more easily in small towns, where the healthcare system provides less innovative opportunities. While participating in a clinical investigation, the patients have a chance to use innovative drugs and devices that improve efficiency and health outcomes, but that are also cost-effective to be afforded during the normal treatment practice.

be driven by the scientific need to get valid and medically sensible results. • Frequently, the designs of clinical investigations on medical devices are less rigorous than the common CT designs on drugs. Such strongly recommended designs, for instance randomisation and blinding, are not always feasible on medical devices investigations. Another feature is the inability to fix hard endpoints and its replacement with surrogate endpoints. • For medical devices, that in their final design are intended to be used by the patients themselves, an additional stage of the investigation might be included – self-medication/ treatment/usage, to investigate their usability and appropriateness for such applications. • Adaptive designs might be suitable in several cases – if there are a small number of endpoints on which the adaptation will take place and if the timing of the primary outcome is such that there is time to implement the adaptation if required. This approach might reduce resource, decrease time to clinical investigation completion and/or increase the chance of study success. On the other hand, these designs require an experienced medical writer working closely with a statistical specialist and perhaps scientific consultation with an expert from the RA.

Rossen Mihaylov Managing Director/Owner of Ramus Medical and Medical Laboratory Ramus Rossen Mihaylov MD, PhD in Medical Science, is founder and owner of the largest private medical laboratory in Bulgaria – Ramus and Ramus Medical – full service CRO. He has more than 30 years of experience in the field of clinical trials and laboratory activities. Email:

• The selection of clinical investigation design: the choice should

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eClinical: How One Major BioPharma Company is Embracing the New World of Digital Clinical Research The major objective of pharmaceutical research & development is to bring new health solutions to people who need them. Increasing research productivity and reducing protracted timelines when bringing a new molecule to market can help achieve this goal more rapidly. Sanofi, a leading biopharmaceutical company, has prioritised clinical study optimisation as an essential step in reducing drug development cycle time.

• Increase clinical trial enrolment: The company initiated multi-channel digital solutions to increase trial awareness and accessibility by patients through social media platforms and other means. This effort also included leveraging clinical trial site and patient advocacy network relationships, and piloting ‘distributed’ (or decentralised) study approaches with the goal of bringing the clinical trial to the patient. Overall, these activities decreased the patient burden of enrolling in studies and led to improved enrolment rates.

Specifically, the company has accelerated patient recruitment in clinical studies through the utilisation of digital technologies alongside site and patient facing innovations. These digital efforts, ongoing since 2015, have led to 1) protocol simplification, 2) development of relationships with key external healthcare professionals (HCPs) and 3) improved patient partnerships.

• Optimise the entire supply chain: Sanofi has used software with predictive modelling combined with interactive response technology (IRT) parameters to identify different scenarios for production and distribution of intellectual property. This allows for early creation of a master plan to support clinical study execution, with the aim of minimising the quantity of drugs to be used.

By developing a sustainable model using quantitative and qualitative solutions, Sanofi has demonstrated that the clinical trial process can be dramatically optimised. Establishing innovative platforms and working in partnership with investigator sites along with patient groups can bring the world of digital clinical research to life.

• Utilise direct to patient (DTP) model: Sanofi is also one of the pioneers using the DTP model, which helps the company work directly with key patient groups. Overall, this approach has decreased patient burden, for example by enabling fewer visits to the hospital during trials.

Bringing a new drug to market is increasingly challenging, particularly at the development stage with longer development times, challenges in achieving clinical trial enrolment, and an increasing number of highly-complex clinical trials. Optimising clinical trials presents an opportunity to realise a reversal in these trends.

• Automate study documentation: Important steps have also been made in the automation of some study documents, first focusing on narratives leveraging content re-use and then exploring a more end-to-end approach from protocol to clinical study reports associating both content re-use and artificial intelligence.

Through the combined efforts of its research & development (R&D) teams, Sanofi has made progress each year in delivering increasingly accelerated drug development. The company’s progress on this front is the result of improving its end-to-end clinical trial process by leveraging a combination of innovative approaches across internal and external solutions. Critical opportunities were identified to reduce and reverse the industry trends at Sanofi: • Reduce protocol complexity: Through establishing a clear line of sight between ‘nice to have’ data for collection and ‘must have’ data needed for endpoint evaluation, Sanofi has identified ways to eliminate unrelated procedures, thereby reducing the complexity and costs of each study. In parallel, it has increased the eligibility of target patient populations by eliminating unnecessary inclusion/exclusion criteria through the use of e-health records (e-HRs)2, performing simulation modelling of patient prevalence and health characteristics. The use of e-HR has enhanced Sanofi’s practice since 2012 of engaging clinical trial sites and patients across the whole development-stage portfolio, helping to understand operational and procedural challenges within proposed clinical trial designs. This evolving integrated approach has led to a reduction in protocol amendments by over 50% since beginning these efforts five years ago. As a result, Sanofi’s amendment rates are now less than half of the industry average based on Tufts reported data3. 28 Journal for Clinical Studies

Embracing Digital Technology for Clinical Studies Digital innovation is revolutionising clinical studies by extending the ability to interact remotely with physicians and patients. Advances in artificial intelligence (AI), machine learning, big data and analytics offer the promise of delivering medicines with greater speed and cost-efficiency to patients around the world through shortening the timeline of development and reducing uncertainty in the process. Among the steps taken, Sanofi has integrated internal and external data sets used for modelling and simulation that include realworld e-HRs. Modelling and simulation are helping to run predictive analyses and risk identification. While improving the protocol design, the approach also helps to identify areas of the patient population that were unnecessarily restricted from clinical trials. Trial volunteers more accurately representing the patient population can be included while maintaining the integrity of clinical endpoints. This approach is now employed across the entire Sanofi development stage portfolio. By utilising e-HRs, distributed trials across an administrative framework, multi-channel recruitment and eLabels, Sanofi is leveraging the power and efficiency of digital technology to create a more practical experience for patients seeking to participate in clinical trials. Some may believe that digital technology could be disruptive to the important relationship between patients and their treating Volume 9 Issue 6

Market Report physicians. In our view, however, when used wisely, consciously and deliberately, digital technology can instead make it possible for healthcare professionals to better accommodate the needs of the individual patient, and in the case of clinical trials, increase patient recruitment rates. Sanofi has a strategic partnership with Science37 to further develop the distributed study approach to address the major barriers to trial participation, including lack of knowledge about clinical trial opportunities and geographical challenges. The “direct-to-consumer clinical trial model” as Noah Craft, cofounder and CEO of Science37 calls it, creates a clinical trial environment centred on the patient, eliminating the need to travel to a distant trial site. In this model, the study comes to participants, speeding the pace of recruitment and improving patient satisfaction while also reducing drug development timelines. Sanofi has also established strategic partnerships with key investigator sites and is expanding partnerships with patient advocacy groups across R&D. Looking at clinical trials from the patient’s point of view has led to positive transformation. These investigator and patient networks were designed with real-world input from trial sites and patient advocates to ensure that mutually beneficial partnerships would result in higher recruitment rates per site through designing studies that were logistically possible and medically meaningful. Sanofi believes that changing the environment, leveraging digital and new technologies, and building a more integrated clinical development approach around patients requires joint efforts, shared expertise and resources. Under the visionary leadership of Dr Elias Zerhouni, President, Global R&D at Sanofi, the company was one of the original TransCelerate member companies. In addition to TransCelerate BioPharma Inc, Sanofi is an active and leading contributor among selected projects from Europe’s Innovative Medicines Initiative (IMI). These consortia offer a unique forum for pre-competitive and collaborative work to form the new clinical development landscape, and maintain good levels of interactions with regulators. A common protocol template is one innovation that came about as a result of Sanofi’s participation in TransCelerate. The common protocol template initiative has created a common structure and language for clinical trial protocols. This template helps streamline protocol development time and regulatory review, as well as improving end-to-end data flow. Using one common protocol template contributes to making protocols more user-friendly for investigators and patients. The complexity of regulatory reviews is being reduced while increasing the ease of data interpretation. Study sponsors now have the opportunity to implement therapeutic area standards and increase operational efficiencies. One of Sanofi’s current collaborations with IMI is focused on developing a decentralised approach to clinical trials that would require joint efforts from all stakeholders in clinical research. IMI seeks to establish centres of excellence with gold standard practices focused on linking patients, academia, small and medium-sized enterprises (SMEs), and members of the pharmaceutical industry. It aims to do so while ensuring a fully transparent process for adoption by regulatory agencies. This project, combined with an additional project to use wearable technology to optimise data collection and study performance, are meant to be game-changers not only in the clinical development field but also accelerating the definition and adoption in Europe of best practices for telemedicine.

In conclusion, by employing the still-evolving eClinical model, Sanofi continues to expedite both patient enrolment in clinical trials and the execution of these studies to support the development of new treatments. From a patient and HCP standpoint, this means earlier innovative health solutions. These changes demand a new level of expertise to design, conduct and report clinical studies in the digital age. They also impose dramatic changes in the IT landscape for R&D with the need for higher integration. Only early implementation of integrated eSolutions allows a sponsor to adequately leverage them. However, it is clear that digital technology is opening the door to delivering trials with improved patient access and clinical site performance. REFERENCE 1. Tufts CSDD 3- CenterWatch Monthly, Aug 2017 2. The EHR4CR project (2011-2016) with a budget of +16 million Euros, has involved 35 academic and private partners (10 pharmaceutical companies) and is one of the largest of the IMI PPPs in this area. The consortium also included 11 hospital sites in France, Germany, Poland, Switzerland and the United Kingdom. It was part-sponsored by the European Commission through the Innovative Medicines Initiative (IMI). TriNetX is a network comprised of healthcare organisations representing over 84 million patients globally, biopharmaceutical companies, and contract research organisations (CROs). 3. Source: Tufts CSDD, 2015

Lionel Bascles Global Head of Clinical Sciences and Operations (CSO). Joining Sanofi in 1998, he became a member of the R&D Leadership Team in 2010 and Global Head of CSO in 2016, leading a number of strategic initiatives including the integration of Sanofi’s clinical supplies platform. He previously set up and managed the Southeast Asia and Asia Pacific Clinical Research Units between 2003 and 2006. He has experience working in Academia, Business Development, International Clinical Trials, and Project Direction & Management. Email:

Victoria (Vicky) DiBiaso Global Head of Clinical Operations Strategy & Collaboration at Sanofi. She manages an international team accountable for Sanofi’s development stage portfolio overseeing protocol optimization, global trial feasibility, competitive intelligence and their investigator and patient network partnerships. Vicky has over 20 years of global experience ranging from phase I-IV drug development in rare disease biotech and multi-therapeutic specialty large pharma. She’s worked across multiple platforms such as devices, small molecules, biologics and gene-therapies. Email:

Journal for Clinical Studies 29

Market Report

Challenges with Cash Management and Reforecasting Clinical Trials Clinical trials are becoming increasingly complex, particularly with broader scopes, globalisation, changing and expanding regulatory requirements and a greater number of players such as contract research organisations (CROs), sites, laboratories and vendors. As a result, the estimated cost of bringing a drug to market in the US is $1.3 to $1.7 billion, with the costs of conducting a clinical trial representing one of the biggest expense categories for biopharmaceutical companies.2 It’s no wonder the forecasting of clinical trials remains challenging. When you consider the inevitable changes that occur in a clinical trial, it seems from day one, it can feel as if your forecast is a moving target and reforecasting is nearly impossible. In this eBook, we discuss the consequences of poor forecasting and tools that are available to assist with accurate financial forecasting.

To help manage the cash flow more efficiently, ideally, you would be able to reforecast against actual expenses throughout the duration of the trial, particularly given the likelihood of ongoing changes. However, because of the lack of access to these actual trial data, reforecasting can be exceptionally difficult and a seemingly impossible task given the need to manually compile and evaluate the financial information. Due to the inability to monitor actual expenses and update the forecast accordingly during the trial, the variance between expected and actual costs has to be reconciled at the end of the trial. Unfortunately, there is typically an error of 50–70%, which can significantly impact profitability and margins. For life science companies in general, the variance at the end of the trial is ≥16%,1 despite nearly 70% of companies surveyed by Bioclinica stating that they will accept an error rate of only ≤10%.

Consequences of Poor Forecasting A history of poor, inaccurate forecasting for clinical trials reduces the confidence in the forecast, by you, the sponsors and investors; 31.5% of companies surveyed by Bioclinica stated that they were not confident in their ability to forecast. This ultimately affects the way that cash is managed throughout the trial. Having less cash on hand could prevent site and vendor payments, leading to site dissatisfaction. Having more cash on hand than needed will affect the ability to invest back into your organisation and drive inefficient cash flow.

The issue with these errors was highlighted by one recent trial, in which there was a >$1,000,000 discrepancy at the end of the reconciliation. Finding the funds to cover the unexpected variance compromised cash allocated for future trials. In addition, owing to the inaccuracies and storage of data across multiple locations, you are unable to use these data to forecast future trials, despite the benefit of financing R&D based on historical data. Furthermore, future forecasts are unable to account for continuous changes in the field of clinical trials3 and inevitable increasing costs for regularly budgeted items.4 Why is Forecasting So Challenging? With the track history of completed trials for the majority of the sponsors and CROs involved in drug development, why is forecasting the financial requirements for a new clinical trial so difficult? As mentioned, changes to the trial, often nearly as soon as it begins, affect expenses and payment timing. Unexpected protocol amendments, delayed subject recruitment, site or subject withdrawal and poor site performance in patient follow-up or timely data entry delay trial completion. In fact, only 10% of trials are completed on time.2 Add to this contract changes with vendors and sites, and you begin to understand why it becomes difficult to stay on top of the financial requirements and accurately reforecast the trial. Successful completion of clinical trials has been facilitated by globalisation, with access to more patients, particularly for

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Market Report more rare diseases and conditions, as well as treatment-naïve patients. However, this increased patient pool is accompanied by financial challenges, including multiple currencies, differing tax structures and amounts, governmental fees, and site costs that might have to be divided by investigator and slightly different regulations by country. In addition, compiling and reconciling reports and expenses from each of the countries can be a logistical nightmare. Other developments in clinical trials, including adaptive designs, allow for smaller sample sizes or more appropriate samples, a more efficient treatment development process and a greater chance of correctly answering your clinical question. Not only do these designs require more work upfront when developing the trial protocol, but they also create uncertainty regarding trial costs. As the trial is modified to account for accumulating data, the number of sites/patients, treatment arms and site agreements will likely change, affecting the initial forecast and requiring ongoing reforecasting. Moreover, most of the available tools to forecast and reforecast the financial requirements for clinical trials, such as Excel, require manual data entry from your EDC or other data collection methods. This pro- cess is prone to errors, exacerbating an already difficult task. Despite the knowledge that changes will occur, the specific modifications cannot be foreseen, resulting in reforecasting challenges. The lack of data transparency makes it very difficult to monitor payments in real time, particularly given the number of entities that require payments (e.g., sites, vendors, tax agencies, governments). This contributes to the retrospective request for funds at the end of the trial and renegotiation with sites after the actual expenses are calculated. What is the Solution? According to a recent Bioclinica survey, the majority of sponsors stated that a technology tool purpose-built for clinical trials would help them to improve forecast accuracy. Instead, 57% of companies currently use Microsoft Excel, which is an error-prone solution that is not scalable. It’s no wonder that most companies find it difficult to manage and forecast trials and have a lack of trust in their financial capabilities.

Now, imagine a product where you have access to actual datadriven payments that are based on pre-agreed upon data and integrated into a comprehensive forecasting solution. This system would include site-negotiated payment terms as well as expenses that seamlessly integrate with your EDC. Data entered in the EDC by the sites would be available in the financial software almost immediately, creating visibility into the data and need for payments or payment adjustments. Financial system integrated with your EDC, with automated payments

Such a system would provide actual data as they become available, with which accurate and timely payments could be made to sites, vendors and tax agencies in real time. Positive site behaviour is encouraged and reinforced because complete and accurate data entry is required before payments are issued.

Journal for Clinical Studies 31

Market Report

This would eliminate the need for manual data re-entry for reforecasting and reconciliation of actual expenses at the end of the trial. Instead, payments, actuals and variance are transparent throughout the trial lifecycle, enabling decisions regarding the trial and financial health as the trial progresses. Confidence in the forecast is restored, enabling appropriate planning of cash flow and reserves, and better, more accurate R&D plans can be established based on a history of actual data and expenses. With less required effort to determine the financial health of your trials, you can make informed, strategic decisions about the future of your trials. Conclusion The continued ability to accurately forecast the costs of clinical trials drives better decision-making and clinical trial efficiencies. Appropriate and effective tools that compile your data in one location and adapt to changes in the trials can help achieve this goal. REFERENCE 1. Grygiel A. The Struggle With Clinical Study Budgeting. Contract Pharma. Oct.11, 2011. Accessible at: issues/2011-10/view_features/the-struggle-with-clinicalstudy-budgeting/ 2. Pharma industry: Still not budgeting accurately. CenterWatch. 32 Journal for Clinical Studies

Aug. 8, 2011. Accessible at: industry-still-not-budgetingaccurately#sthash.SskmRqC3.dpbs 3. How accurate is your Clinical Supply Forecast? Clinical Trials Arena. Feb. 25,2016. Accessible at: news/supply-chain/how-accurate-is-your-clinical-supplyforecast-4821982 4. The key pillars of clinical trial budgeting: preparation and flexibility. Clinical Trials Arena. Aug. 12, 2015. Accessible at: finance/the-key-pillarsof-clinical-trial-budgeting-preparation-and- flexibility-4643547

Lorie McClain, CPA VP, Product Management, Product Development & Technology, Bioclinica Lorie brings over 20 years of financial, operational, and technology experience in the life sciences and healthcare industries. She previously held senior management roles in Information Technology at PPD and product strategy in the Health Sciences Global Business Unit at Oracle. Lorie received a Master’s in Computer Science and Information Systems, a BS in Computer Science and in Accounting from the University of North Carolina at Wilmington.

Volume 9 Issue 6

You are the person

Who called the expert

Who secured the release

Of the drug delayed in customs

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: Web:

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Pre-clinical Data Analysis Ensuring Relevant First-in-Human Clinical Trials The first-in-human trial (FIH) is an important milestone in the development of a potential new drug. It will already have successfully passed a whole range of preclinical tests, including pharmacokinetic and pharmacodynamics experiments and in vivo safety tests in animals, but there remains no way of being absolutely certain how a drug will behave when it is taken by humans. When setting the dose, there is no substitute for experience, and even then, it can be risky. It is unusual for something to go very wrong, but when it does, it puts the industry and clinical trial procedures in the spotlight. The 2006 study carried out by Parexel for TeGenero on an immunological agent at Northwick Park hospital in London is still well remembered, more than a decade on, after six men experienced organ failure. More recently, the trial run by Biotrial in Paris for Bial on a fatty acid amide hydrolase inhibitor, being investigated as a potential pain therapy that led to one death and five hospitalisations, provided more negative coverage for FIH clinical trials. Although these were just two incidents in a decade in which thousands of other trials were conducted, they were the ones that are remembered. The regulatory authorities are rightly concerned about the risk of the first exposure of humans to investigational therapeutic agents. The EMA’s ‘Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products’ was published in 2007, the year after the Parexel/TeGenero incident, and is currently being revised in the light of developments in the intervening years (draft revised version is available and will become effective from February 2018). The FDA’s guidance, ‘Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers’, dates back to 2005, and sets out a process for determining the maximum recommended starting dose that is likely to prove safe for first-in-human volunteers. That year, the FDA also recognised the exploratory IND study. These small studies, usually on fewer than 10 subjects and taking no more than a week, are designed to determine whether or not full human trials are likely to be worthwhile. Similar guidance on exploratory human studies was published by the EMA in 2008. However, there is no one-size-fits-all approach for first-inhuman trials. Every investigational drug is different, and the likely risks and uncertainties vary greatly from one to the next. Published guidelines and guidances merely describe the agencies’ current thinking, and can never be a substitute for a thorough assessment of each individual case. 34 Journal for Clinical Studies

Regardless of the care taken in designing and running a FIH trial, there remains only about a one-in-10 chance that an investigational drug being tested in humans for the first time will reach the market. This is only likely to improve with an increasing ability to predict in advance how a drug is likely to behave in humans. Great strides have been made in the ability to assess and predict pharmacokinetics and pharmacodynamics in recent years, but anticipated unexpected toxicity remains difficult, even though it is often closely related to the pharmacokinetic properties. The ability to more reliably assess the likelihood of a project’s failure before a FIH trial is commenced would be a huge asset in reducing attrition. At the heart of the problem is the reliance on animal models. Although they are required by the regulators, and do indeed give an insight into how a drug might behave in humans, in reality, human biology and biochemistry are very different from those of mice, rats or dogs, and the success of the translation of these results into human predictions is patchy at best. There is a growing realisation and acceptance among industry scientists, that animal models cannot reliably predict what will happen in humans, and that the poor attrition rate is a result of this and the similar inadequacy of in vitro lab assays. So, how can safety and efficacy predictions be improved, when the translational success of going from preclinical to clinical results is so limited? Simply relying on the preclinical studies required by the regulators is unlikely to give the best results. Those laid down by the EMA, FDA and their counterparts elsewhere have to be undertaken for legal reasons, but they should only be considered as guidance. Further preclinical studies, that give wider data on the likely behaviour of an investigational new drug in humans, should be carried out and the information they provide used to make those all-important go-no go decisions. CNS Case Study A drug recently being developed for a CNS indication provides a good example of why it is important to carefully consider the likelihood of success before embarking on a FIH programme. The FIH trial was initiated, but rapidly paused by the authorities because of an unexpected non-linearity in pharmacokinetics. The regulators, quite rightly, required this observation to be explained and an adequate investigational plan put in place before the trial could be resumed. The trial had been initiated with the usual collection of data from both in vitro and animal studies. When this was reassessed in the light of the suspension of the FIH trial, it became clear that there Volume 9 Issue 6

Therapeutics were signals in the animal toxicokinetic data that, with hindsight, showed that the non-linear behaviour in humans might have been predicted. Further data that would have been useful to inform the FIH trial were also absent. Although the high protein binding of the major pharmacologically active metabolite had been investigated, this was not the case for the parent compound. There was no explanation of the high volume of distribution or tissue affinity that was observed. And, although enzyme inhibition and induction were studied, whether the drug or the metabolite acted as an enzyme substrate were not.

This failure to explain and collect all data led to an inadequate trial design for the FIH study. The trial being stopped because of the pharmacokinetic anomaly prevented more serious safety problems, as the potential of the agent to cause serious toxic side-effects had not been adequately investigated. Further analysis of the preclinical data also indicated that it was likely to have a narrow therapeutic index. The decision whether to resume the trial could only be made after a full clinical development plan was made. This included a complete list of those in vitro and animal studies that were required, along with modelling and simulation services to aid the predictions.

Journal for Clinical Studies 35

Therapeutics Once the risk factors such as pharmacokinetics, pharmacodynamics and potential toxicities have been evaluated and a starting dose established, there are multiple other factors that will affect the trial’s likelihood of success. A good deal of care and attention must be put into the design of the trial protocol in terms of both logistics and timelines. Factors that must be considered include the number of doses that will be given to each subject, and how many participants will be dosed each day. How likely are subjects to drop out, if it is a multiperiod study? Is the design sufficiently flexible to allow changes in the light of clinical data? And, should the worst happen, how well equipped is the clinical research unit to handle unexpected adverse events? These are all questions that should be addressed in collaboration with the principal investigator and other staff from the trial site, including experts in pharmacology and clinical medicine. In most cases, the subjects recruited for a FIH trial will be healthy volunteers. There are many advantages: the recruitment speed is usually swift and cohorts can easily be scheduled, and there are no co-medications or co-morbidities to contend with. However, it is more commonplace for FIH trials of cancer drugs and those with a narrow therapeutic index to be in patient populations, and a decision to use patients instead of healthy volunteers needs to be carefully considered and justified for every individual FIH. The starting dose is perhaps the most important decision that must be made, but also one of the most challenging. It must be sufficiently low that toxicity is unlikely, but not so low as to allow relatively rapid attainment of efficient dose in early or Phase II studies. Several strategies can be applied to determining the maximum recommended starting dose, including the ‘no observed adverse effect level,’ which is also referred to as the FDA approach. Alternatives include the minimal anticipated biological effect level approach, a similar drug approach, the use of modelling and simulation, and microdosing. A case-by-case approach is usually appropriate, but caution should always be applied because of the safety implications. Once the starting dose has been given to study volunteers without incidence, attention must be turned to the dose escalation strategy. A safe multiplying factor is commonly applied, typically a factor of three for the first two or three escalation steps, a factor of two for the next two steps, and finally a factor of 1.5. Pharmacokinetic and pharmacodynamic data should be assessed throughout, and predefined criteria should support the decision to escalate to the next dose.

laboratory abnormalities while the trial is underway. Other design options will depend on the aims of the development programme and the demands of the individual agent. Alternatives include parallel, cross-over, sequential or interlocking cohorts. The decision whether to use a conventional, umbrella, adaptive or adaptive umbrella protocol must also be used. Within limits, the design should be flexible, and deliver better information more quickly and cheaply. Statistical methodologies such as the Bayesian adaptive method have flexible numbers of cohorts, and subjects within them, and simple empirical stopping rules are applied to increase performance and facilitate implementation. As an example, a FIH exploratory design was developed to establish safety, tolerability and pharmacokinetics for an investigational tyrosine kinase inhibitor. Healthy volunteers were deemed most appropriate as the biomarker of tyrosine kinase inhibition was measurable, there were no expected target-related safety issues, and high doses were not going to be necessary. The maximum recommended starting dose was calculated using both the NOAEL and MABEL methods. MABEL resulted in a lower starting dose and was chosen, and a conservative dose escalation schedule was planned in the light of the expectation, made on the basis of pre-clinical toxicology studies, that it would have a narrow therapeutic index. Sentinel groups were recommended in the high single ascending dose group, and also in all multiple ascending dose groups. The length of the in-house stay was planned based on the in vitro plasma half-life, and also, the potential for delayed toxicities occurring based on pre-clinical studies. An adaptive umbrella design with sequential cohorts was chosen, with two different oral formulations being assessed in a cross-over manner in one of the single ascending dose cohorts. There is a temptation to stick to what is known and to choose a protocol based on habit and experience, rather than applying a scientific rationale. The overall landscape of required, suitable and advisable pre-clinical studies will vary from compound type to compound type, and therapeutic indication to therapeutic indication. Filing an IND and carrying out FIH trials is an expensive and time-consuming process. Going ahead with something that will, in all likelihood, fail is a waste of time and money that could better be invested in something that is more likely to succeed.

Nariné Baririan

If an investigational drug is deemed to be particularly high risk or at high tested doses (when the safety coverage seems not to be full in terms of expected drug exposure), it can be appropriate to use sentinel subjects. By dosing a very limited number of subjects, often only one, with the active agent at the outset before the remainder of the cohort is dosed, the overall risk is much lower. Both the EMA and FDA recommend this strategy for high-risk compounds and, had it been applied, the fall-out in terms of number of patients experiencing adverse events would have been very much lower in the 2006 Parexel/TeGenero trial.

Clinical Pharmacology and PK Expert at SGS, and is part of the company’s earlyphase consultancy team which supports and advises clients in the design of studies and clinical development plan of their new compounds. She holds a degree in pharmacy and a Research Master’s degree in cellular and molecular pharmacology from the Université Catholique de Louvain (UCL). She joined SGS in 2007, after continuing her research experience by undertaking a PhD in Pharmaceutical Sciences at UCL in Clinical Pharmacology and Pharmacokinetics, which included performing her own research clinical trials in the Unité de Pharmacologie Clinique at St Luc Hospital (Brussels).

Most FIH studies are carried out in a randomised, doubleblind, placebo-controlled manner. This removes the opportunity for bias in reporting adverse events and in the assessment of


36 Journal for Clinical Studies

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Journal for Clinical Studies 37


E.coli in Urinary Tract Infections from 2000–2016 Urinary tract infection (UTI) is one of the most common infectious diseases and the most common nosocomial infection in the developed world. Complicated urinary tract infection occurs in individuals with functional or structural abnormalities of the genitourinary tract. A wide variety of organisms is isolated from patients with complicated urinary infection. E. coli is the most common organism isolated, but is isolated more frequently in women than in men1. UTIs have proven to be a serious challenge for medical professionals due to high incidence, recurrence, complications, diverse etiologic agents, and growing antibiotic resistance. They account for 10–20% of all infections treated in primary care and 30–40% of infections treated in hospitals2. Whether community or hospital- acquired, urinary tract infections are commonly caused by E. coli3. This article evaluates the prevalence of E. coli in different countries.

Material and Methods Literature Review Literature searches were performed on PubMed using urinary tract infection and E. coli as primary search terms. After this initial search, the list included articles published in the last 10 years. After the first cut, the search was limited to articles that presented data per country. In the analysis, we included at least one representing country from North America, South America, Europe and the APAC region (Table 1, Chart 1). Sample sizes of patients/specimens per country ranged from 22 to 23537. The highest % of E. coli causing cUTIs are seen in South Korea and Thailand. For South Korea, we found two articles. The first presented data from a clinical trial that enrolled Korean patients aged ≥ 18 years with cUTI or acute pyelonephritis (APN) who required

Leading pathogen


Second leading pathogen


Sample size (n)

Primary condition

Year of the study

Escherichia coli


Klebsiella Pneumoniae



cUTI including pyelonephritis


Escherichia coli


Klebsiella pneumoniae






Escherichia coli


Staphylococcus saprophyticus



Cystitis, Pyelonephritis including complicated cases



Escherichia coli








Escherichia coli


Klebsiella Pneumoniae



cUTI including pyelonephritis



Escherichia coli








Escherichia coli


Klebsiella Pneumoniae






Escherichia coli


Klebsiella Pneumoniae






Escherichia coli


Proteus Mirabilis






Escherichia coli


Klebsiella pneumoniae






Escherichia coli


Enterococcus spp.






Escherichia coli







SPAIN (16)

Escherichia coli







INDIA (17)

Escherichia coli


Klebsiella Pneumoniae





USA (18,19)

Escherichia coli







Escherichia coli


Enterococcus spp.





CHINA (20)

Escherichia coli


Staphylococcus epidermidis



Acute uncomplicated cystitis, recurrent UTI or cUTI



Escherichia coli








Escherichia coli


Enterococcus Spp.







CA UTI –Community acquired urinary tract infection


1 1


MDR – Multidrug resistant

Table 1. Table represents % of UTIs caused by E. Coli as main leading pathogen and % of UTIs caused by second leadingpathogen in prospective and retrospective studies. Table also represents primary condition patients had and the timeframe when data were collected. 38 Journal for Clinical Studies

Volume 9 Issue 6

Therapeutics The Romanian study analysed 297 diabetic patients with UTI. This was a retrospective, non-interventional study and showed that the gram-negative bacilli from the Enterobacteriaceae family were predominant, with E. coli being the most frequent (70.4%)11. One objective of the article from Turkey was to describe the epidemiology and susceptibility of pathogens (including ESBL producers) from hospital-acquired (HA) versus communityacquired (CA) urinary tract infections7. Results showed that E. coli continues to be the principal pathogen of community UTIs in Turkey. Chart 1. Chart represents per country differences in % of E.Coli caused UTIs in prospective and retrospective studies. Here we distinguished Asian countries from the rest of the world as UTIs caused by E. Coli are the most prevalent in this region.

parenteral antibiotic therapy. Baseline uropathogen needed to be present at ≥ 105 CFU/mL. A total of 271 patients were randomised, and in 185 (68%) E. coli was cultured4. The second article included a retrospective data analysis of patients diagnosed with APN. Bacteria were isolated by urine culture in 504 out of 1026 (49%) patients. E. coli was the leading pathogen causing infection in 425 patients 5. Data used for Thailand included one single-centre study that targeted patients with cUTI including acute pyelonephritis. Samples were sent for microbiology evaluation before the first dose of the drug and mandatory inclusion criteria were as follows: levels of >105 CFU/ mL uropathogens in midstream urine in women, >104 CFU/mL in midstream urine in men, or in straight catheter urine in women, were considered to be significant uropathogens in complicated urinary tract infections. A level of >104 CFU/mL uropathogens in midstream urine was considered to be significant in acute uncomplicated pyelonephritis in women. Of 22 isolated uropathogens, 16 were E. coli8. Regardless of design of the study – single-centred or multicentre trials, the data supporting E. coli as a main cause of cUTI and APN were similar.

The reviewed data prompts that the APAC region had higher levels of E. coli prevalence compared to Europe. However, the data presented for Europe had larger and similar sample sizes for all countries, which reflects better pathogen surveillance in UTI in the region. Nevertheless, the most prevalent pathogen was E. coli in all countries. Additionally available data demonstrate that the percentage of UTIs caused by the second leading pathogen was not higher than 14%. CRO Data As the next step, we compared the baseline data of patients enrolled in our prospective international trials from 2014–2016. The main inclusion criteria for patients to be screened and potentially randomised were presence of complicated urinary tract infection, including acute pyelonephritis. Both studies were designed to follow FDA Guidance for Complicated Urinary Tract Infections24. One study enrolled both indications equally and another one allowed enrolment of only 30% of patients with acute pyelonephritis. Uropathogen at screening needed to be ≥105 CFU/mL, similar to requirements from larger studies presented in the literature review. In all countries involved in clinical trials, E. coli was the most prevalent pathogen of cUTI or acute pyelonephritis (Table 2, Chart 2). In all countries, a second leading pathogen caused 4–29% of infections.

Klebsiella pneumoniae was the second leading pathogen in both countries. Rates of isolated E. coli in India, China and Pakistan were in a range from 50 to 59% 17, 20, 21. In addition to presented data for the APAC region, a recently published 30-year study in Japan shows that E. coli was the most isolated bacterium for the period 2005–2014. Whereas, in uncomplicated UTI examined over 20 years, E. coli was the most frequently isolated species accounting for 47–94% of isolates23. All studies presenting data for Europe observed at least 250 patients and the percentage of E. coli causing urinary tract infections varied from 47 to 74%. Countries with the most prevalent urinary infections caused by E. coli were: Turkey, Poland and Romania6, 10, 11. A study in Poland analysed 381 samples recovered from ambulatory adult patients with clinical symptoms of communityacquired UTI and significant bacteriuria, from 41 hospitals representing all regions of Poland10. Analysis showed that in 272 patients, the main pathogen causing infection was E. coli which was cultured in 80.6% of uncomplicated cases of UTI, compared to 65.8% in cUTI.

Table 2. Table represents % of UTIs caused by E. Coli as main leading pathogen and % of UTIs cause by second leading pathogen in industry sponsored prospective studies. Second leading pathogen varies country by country. Journal for Clinical Studies 39


Chart 2. Chart represents per country differences in % of E. Coli caused UTIs in 2 industry sponsored trials managed by us..

Prevalence is amongst the highest in South Africa and South America (Mexico, Columbia). The same can be said for the US, although the sample size is not completely representative and more data would be needed for further conclusions. However, in these countries, E. coli is seen as the main pathogen at a rate higher than 70%. Among European countries, there are no patterns that could show higher-lower prevalence within the region. Georgia, Czech Republic and Hungary are the countries with the highest prevalence of E. coli according to the data presented. In 28–71% of cases in Europe, E. coli is the main cause of complicated urinary tract infections, including acute pyelonephritis. Discussion A comparison of the literature data to our own data showed no major difference for E. coli in urinary tract infections (Chart 3). The patient population limited to complicated urinary tract infections (cUTI) and acute pyelonephritis (APN) can explain the lower percentages of infections caused by E. coli in our studies, compared to the broader patient set in retrospective epidemiology trials. Additionally, no significant discrepancies were observed comparing our own data and retrospective analysis data for Poland and Romania. The sample sizes observed in retrospective studies were larger and the prevalence of E. coli higher. This can also be explained with more strict terms for prospective clinical trials compared to retrospective studies and with the fact that E. coli is more predominant in uncomplicated urinary tract infections compared to complicated urinary tract infections10. Among all countries represented, the APAC region had the highest prevalence of UTIs caused by E. coli.



3. 4.


Chart 3. Chart represents per country differences in % of E.Coli caused UTIs in prospective (literature data and our own data) and retrospective studies.

Conclusion The percentage of UTIs caused by E. coli varies from country to country, but it remains the leading pathogen causing UTI. The APAC region has the highest prevalence of UTIs caused by E. coli. These findings do not vary significantly among data sets gathered in prospective and retrospective studies. 40 Journal for Clinical Studies



Lindsay E.N., Bradley S., Colgan, R., Rice, J.C., Schaeffer, A., Hooton, T.M. Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults, Clin. Infect. Dis. 2005, 40 (5), 643-654. DOI: Stefaniuk, E., Suchocka, U., Bosacka, K., Hryniewicz, W. Etiology and antibiotic susceptibility of bacterial pathogens responsible for communityacquired urinary tract infections in Poland, Eur J Clin Microbiol Infect Dis 2016, 35, 1363–1369. DOI: Foxman, B. The epidemiology of urinary tract infection. Nat Rev Urol 2010,7(12), 653-60. DOI: Park, D.W., Peck, K.R., Chung, M.H., Lee, J.S., Park, Y.S., Kim, H.Z., Lee, M.S., Kim, J.Y., Yeom, J.S., Kim, M.J. Comparison of Ertapenem and Ceftriaxone Therapy for Acute Pyelonephritis and Other Complicated Urinary Tract Infections in Korean Adults: A Randomized, Double-Blind, Multicenter Trial, J Korean Med Sci 2012, 27(5), 476–483. DOI: jkms.2012.27.5.476 Lee, D.G., Jeon, S.H., Lee, C.H., Lee, S.J., Kim, J.I., Chang, S.G. Acute Pyelonephritis: Clinical Characteristics and the Role of the Surgical Treatment, J Korean Med Sci 2009, 24(2), 296–301. DOI: https://doi. org/10.3346/jkms.2009.24.2.296 Filiatrault, L., McKay, R.M., Patrick, D.M., Roscoe, D.L., Quan, G., Brubacher, J., Collins, K.M. Antibiotic resistance in isolates recovered from women with community-acquired urinary tract infections presenting to a tertiary care emergency department. CJEM. 2012, 14(5), 295-305. Koksal, I., Yilmaz, G., Unal, S., Zarakolu, P., Korten, V., Mulazimoglu, L., Tabak, F., Mete, B., Oguz, V.A., Gulay, Z., Alp, E., Badal, R., Lob, S. Epidemiology and susceptibility of pathogens from SMART 2011–12 Turkey: Volume 9 Issue 6

Therapeutics 1.







8. 9.








evaluation of hospital-acquired versus community-acquired urinary tract infections and ICU- versus non-ICU-associated intra-abdominal infections, J Antimicrob Chemother 2017, 72 (5), 1364-1372. DOI: https://doi. org/10.1093/jac/dkw574 Manosuthi, W., Wiboonchutikul, W. Treatment outcomes of oral sitafloxacin in acute complicated urinary tract infection and pyelonephritis, Springerplus. 2016, 5, 410. DOI: Kiffer, C.R., Mendes, C., Oplustil, C.P., Sampaio, J.L. Antibiotic resistance and trend of urinary pathogens in general outpatients from a major urban city. Int Braz J Urol. 2007, 33(1), 42-8. Stefaniuk, E., Suchocka, U., Bosacka, K., Hryniewicz, W. Etiology and antibiotic susceptibility of bacterial pathogens responsible for communityacquired urinary tract infections in Poland. Eur J Clin Microbiol Infect Dis. 2016, 35, Issue 8, pp 1363–1369 DOI: Chiţă, T., Timar, B., Muntean, D., Bădiţoiu, L., Horhat, F., Hogea, E., Moldovan, R., Timar, R., Licker, M. Urinary tract infections in Romanian patients with diabetes: prevalence, etiology, and risk factors, Ther Clin Risk Manag. 2017, 13, 1–7. DOI: Maraki, S., Mantadakis, E., Michailidis, L., Samonis, G. Changing antibiotic susceptibilities of community-acquired uropathogens in Greece, 2005-2010. J Microbiol Immunol Infect. 2013, 46(3), 202-9. DOI: jmii.2012.05.012. Leoni, A.F., Monterisi, A., Acuña, P.G. Community acquired urinary tract infections in older adults. Rev Fac Cien Med Univ Nac Cordoba. 2017, 74(1), 10-17. Hunjak, B., Pristas, I., Stevanović, R. Uropathogens and antimicrobial susceptibility in outpatients. Acta Medica Croatica 2007, 61(1), 111-115. Trad, M.A., Zhong, L.H., Llorin, R.M., Tan, S.Y., Chan, M., Archuleta, S., Sulaiman, Z., Tam, V.H., Lye, D.C., Fisher, D.A. Ertapenem in outpatient parenteral antimicrobial therapy for complicated urinary tract infections. J Chemother. 2017, 29(1), 25-29. Doi: 9X.2016.1158937. García Viejo, M.A., Noguerado Asensio, A. Grupo de Trabajo de las Infecciones Urinarias del Grupo de Trabajo de Enfermedades Infecciosas de la Sociedad Española de Medicina Interna. Urinary tract infections in internal medicine. Rev Clin Esp. 2010, 210(11), 537-44. Mandal, J., Srinivas Acharya, N., Buddhapriya, D., Chandra Parija, S. Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant Escherichia coli, Indian J Med Res. 2012, 136(5):, 842–849. Shah, A., Justo, J.A., Bookstaver, P.B., Kohn, J., Albrecht, H., Al-Hasan, M.N. Application of Fluoroquinolone Resistance Score in Management of Complicated Urinary Tract Infections. Antimicrob Agents Chemother. 2017, 24, 61(5), pii: e02313-16. DOI: Giancola S.E., Mahoney M.V., Hogan M.D., Raux B.R., McCoy C., Hirsch E.B. Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes. Chemotherapy. 2017, 62(2), 100-104. DOI: Qiao, L.D., Chen, S., Yang, Y., Zhang, K., Zheng, B., Guo, H.F., Yang, B., Niu, Y.J., Wang, Y., Shi, B.K., Yang, W.M., Zhao, X.K., Gao, X.F., Chen, M., Tian, Y. Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study. BMJ Open. 2013,13, 3(12), e004152. DOI: bmjopen-2013-004152. Ahmad, W., Jamshed, F., Ahmad, W. Frequency of Escherichia coli in patients with community acquired urinary tract infection and their resistance pattern against some commonly used anti bacterials. J Ayub Med Coll Abbottabad. 2015, 27(2), 333-7. Koningstein, M., Van der Bij, A.K., De Kraker, M.E., Monen, J.C., Muilwijk, J., De Greeff, S.C., Geerlings, S.E., Leverstein-van Hall, M.A. ISIS-AR Study Group. Recommendations for the empirical treatment of complicated urinary tract infections using surveillance data on antimicrobial resistance in the Netherlands. PLoS One. 2014, 9(9):e86634. DOI: journal.pone.0086634.

17. Wada, K., Uehara, S., Yamamoto, M., Sadahira, T., Mitsuhata, R., Araki, M., Kobayashi, Y., Ishii, A., Kariyama, R., Watanabe, T., Nasu, Y., Kumon, H. Clinical analysis of bacterial strain profiles isolated from urinary tract infections: A 30-year study. JIC 2016, Volume 22, Issue 7, Pages 478–482 DOI: 18. FDA. Complicated Urinary Tract Infections: Developing Drugs for Treatment (Guidance for Industry) [Internet]. Silver Spring, MD: FDA, CDER; 2015 Feb. Available from: GuidanceComplianceRegulatoryInformation/Guidances/UCM070981.pdf .

Milica Cerovic, MPharm Senior Feasibility Specialist at PSI CRO AG. Before joining PSI in 2015, she worked in the pharma industry. While on faculty she was involved in several scientific projects with colleagues from Belgrade University. Email:

John Riefler, MD, MS Director, Medical Monitoring & Consulting at PSI CRO AG (USA). His MS is in microbiology and his clinical training is in internal medicine and infectious diseases. He is a Fellow, Infectious Disease Society of America (FIDSA) and Fellow, American Heart Association (FAHA). He has 29 years’ experience in clinical development in big pharma and CROs. He is also the author/co-author of 22 publications. Email:

Maxim Belotserkovskiy, MD, PhD, MBA Head of Medical Affairs at PSI CRO AG. He is a board-certified physician in internal medicine, rheumatology, anaesthesiology and intensive care, and haemodialysis, and a Certified Associate Professor of Pathological Physiology. He has more than 20 years of experience in clinical research as investigator and clinical research professional. He is also the author/co-author of more than 150 publications. Email:

Maxim Kosov, MD, PhD Director, Medical Monitoring & Consulting at PSI CRO AG (USA). He is a boardcertified physician in paediatrics and anaesthesiology and intensive care. Maxim has more than 20 years of experience in both the medical and clinical research industry and has experience across a broad range of indications. He is also the author/co-author of more than 40 publications. E-mail:

Journal for Clinical Studies 41


Updated Research Criteria for Clinical Trials Across the Alzheimer’s Disease Continuum The National Institute of Aging and Alzheimer’s Association (NIA-AA) have recently proposed a common research framework to help investigators establish a research agenda and evaluate the impact of various therapeutics in the Alzheimer’s disease (AD) continuum, and specifically to define and stage AD and facilitate research reporting. This framework was revealed at the Alzheimer’s Association International Conference (AAIC) that took place in London this past July, with an accompanying draft document posted on the Alzheimer’s Association website1. The authors were quick to point out that this update to the 2014 International Work Group (IWG) diagnostic criteria (which requires the presence of cognitive symptoms plus biomarker evidence of AD pathophysiologic processes for a diagnosis of AD), and to the 2011 NIA-AA diagnostic criteria was meant to represent a research framework to be used in observational and randomised interventional trials and not to be viewed as general clinical diagnostic criteria for use in clinical practice2. This updated framework was deemed necessary due to recent developments in conceptualising AD as being on a continuum (rather than as three separate clinical constructs of preclinical, mild cognitive impairment and dementia) occurring over long periods of time that can be accurately reflected wholly by biomarker progression commencing long before symptoms become apparent. The proposed biomarkers utilized in this research framework reflect beta amyloid deposition, tau pathology and neurodegeneration, and are considered to be valid surrogates for pathophysiologic states associated with AD. This updated framework allocates potential subjects into three biomarker classifications based on presence or absence of amyloid (A), tau (T) and neurodegenerative (N) biomarkers, and then goes on to define clinical staging in terms of both syndromal categories and numeric schemes. This brief review will attempt to summarise this research framework as well as some of the more salient issues related to implementation of this framework in clinical trials of AD therapies. AD as a Pathophysiological Construct The updated research framework hinges upon the understanding and acknowledgment that AD refers to an aggregate of pathophysiologic processes and therefore can be uniquely defined in vivo by biomarkers, and of course by post mortem by pathologic changes, but conspicuously not by clinical symptomatology. This separation of clinical symptoms from pathophysiological state represents a large departure from the antecedent NIA-AA criteria proposed in 1984 and updated in 20112,3. This shift in thinking away from AD first as a clinical-pathological construct and then as a clinical-biomarker construct (where biomarkers were used to support an AD diagnosis) represents the key feature to the updated research framework. This departure was buttressed by the awareness that dementia is not a “disease” but rather a syndrome composed of signs and symptoms that can be caused by multiple diseases, one of which is AD. In the current framework, AD is defined as a pathophysiologic construct that is uniquely and unconditionally identified by biomarkers and that only biomarkers 42 Journal for Clinical Studies

that are specific to AD proteinopathies (eg. Aβ and pathologic tau) should be considered as potential biomarkers of AD. Therefore, AD can be viewed exactingly and exclusively as a proteinopathy in this research framework. AD Biomarkers Drug developers have enjoyed an overabundance of in vivo biomarkers to choose from in order to help define disease state in AD and to track progression and treatment effects of AD therapies. Given this abundance of biomarkers, the updated research framework utilised an unbiased descriptive classification scheme to advocate for those categories of biomarkers purported to be the most useful in AD research endeavours. Specifically, the authors propose the “A/T/N” system, in which seven of the most commonly investigated AD biomarkers were divided into three binary categories based on the nature of the pathophysiology that each ostensibly measures4. In this scheme the category letter labelled “A” refers to beta amyloid biomarkers reflecting binding on amyloid positron emission tomography (PET) or low CSF beta amyloid (Aβ42) which designates the presence of beta amyloid plaque and associated pathophysiologic processes. The category letter labelled “T” refers to tau biomarkers such as elevated CSF phospho tau, or tau PET binding and reflects aggregated pathologic tau; and the category letter labelled “N” represents biomarkers of neurodegeneration or neuronal injury such as hypometabolism on [18F]-fluorodeoxyglucose–PET, atrophy as seen on structural MRI, or CSF total tau. Of note, there is both an imaging and a CSF biomarker in each of the three biomarker categories, making it possible to have complete characterisation of biomarkers using a single modality such as imaging or CSF alone. As a potential subject in a clinical trial can be either positive or negative on each of the three biomarker categories (ATN) there are eight possible biomarker profile combinations, each corresponding to a label representing a range from normal biomarkers to AD pathophysiology; to Alzheimer’s disease or nonAD pathophysiology. Using this research framework, a potential subject who has biomarker evidence of Aβ pathophysiology alone (amyloid PET or low CSF Aβ 42 or 42/40 ratio) but with a normal tau biomarker would be assigned the disease label “Alzheimer’s pathophysiology” while the term “Alzheimer’s disease” would be utilised only if there was biomarker evidence of both Aβ and pathologic tau. Of note, in this model “Alzheimer’s pathophysiology” and “Alzheimer’s disease” are not regarded as separate entities but rather earlier and later phases on the “Alzheimer’s pathophysiologic continuum” and importantly once again these labels have no regard to clinical symptoms1. Clinical Staging This does not mean that clinical symptoms are totally disregarded, as the updated research framework also provides two options for staging of clinical symptoms. The first option utilises the terms “Cognitively Unimpaired”, “Mild Cognitive Impairment” and “Dementia” to indicate the severity of cognitive impairment but importantly not to infer underlying pathology1. Each of these terms has been described in detail in the research framework and is worthy of further examination, and notably each can be Volume 9 Issue 6

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Journal for Clinical Studies 43

Therapeutics combined with the eight biomarker profiles outlined above to produce twelve independent categories that range from “normal AD biomarkers, cognitively unimpaired” all the way to “non-Alzheimers pathophysiology contributing to dementia”. For the most part, there is an effort to follow the nomenclature developed in the 2011 criteria with some notable exceptions. As an example “Alzheimer’s disease contributing to MCI” is used for subjects who are positive for both amyloid and tau biomarkers but who may be positive or negative for neurodegeneration biomarker rather than “MCI due to Alzheimer’s disease (as in the 2011 criteria)2. The authors suggest that an alternative approach to this nomenclature is to simply combine ATN biomarker profile with cognitive stage without the use of any descriptive phrases at all resulting in lables such as “A+T-N- MCI” instead of “Alzheimer’s pathophysiology contributing to MCI” or “A+T+N+ dementia” instead of “Alzheimer’s disease contributing to dementia” 1. Furthermore, the updated research framework also provides for a numeric neurocognitive staging option to be used exclusively for those subjects in the Alzheimer’s pathophysiologic continuum. This staging option avoids syndromal labels by using the numbers one through six to reflect the evolution of AD from an initial stage in which asymptomatic patients have abnormal AD biomarkers to the final stage reflecting severe dementia1. Stage 1 is defined by biomarker evidence only; Stage 2 describes the earliest detectable neurocognitive consequence of Alzheimer’s pathophysiology; Stage 3 describes neurocognitive impairment that is not severe enough to result in significant functional loss; while Stages 4 through 6 describe progressively greater functional loss1. It is important to note that the two staging systems (numeric and categorical) reflect different needs and therefore vary in several important respects, and that the numeric staging is only applicable to those in the Alzheimers pathophysiologic continuum while syndromal categorical staging includes all biomarker profiles1. Issues in Clinical Trial Implementation There is no doubt that great determination was demonstrated in this initial draft of a research framework to guide AD drug development with the lofty goals of facilitating a more precise approach to therapeutic intervention trials in which specific pathways can be targeted at precise points in the disease process and importantly targeted to the appropriate subjects most likely to benefit from treatment1. The authors proceeded rapidly and decisively, building upon the growing body of biomarker evidence while clearly making an attempt to build in flexibility to allow for future biomarker inclusion.

very intricate and cumbersome, with a resultant large number of biomarker categories and syndromal labels, arguably limiting the overall utility of the general model even when using a dichotomous approach to cutoff values for each biomarker. The addition of other potential biomarkers also increases the possibility of having an incomplete biomarker profile (especially in regard to PET imaging) and of having a higher frequency of discordance among biomarkers purportedly measuring related constructs. Discordance among biomarkers can be anticipated, as evidenced by a recent study of 144 clinical patients along the AD continuum (MCI and AD patients) who had data from both PETPiB and Aβ42 values from CSF. The percentage of discordance was reported at roughly 14% overall but fell to roughly 6% for AD patients only. Discordance in this case was mostly caused by beta amyloid positive patients who were negative for PET–PIB (80%)5. Although low rates of discordance can be easily addressed using simple rules for categorisation or more complex weighting algorithms, having discordant data from five to ten biomarkers may prove sufficiently difficult to resolve, especially in terms of assignment to cognitive status when all biomarkers are not expected to have equal contribution. Finally, and maybe most importantly, there is no reliable and valid biomarker for what many neuropathologists believe to be the most relevant outcome measure related to neurodegeneration, specifically micro-haemorrhages. Neuroimaging at this point is simply too crude to serve as a biomarker for this important measure and other biomarkers such as neurogranin and neurofilament light chain that measure synaptic degeneration/ loss and axonal injury are not sufficiently investigated to date; and like almost all markers of neurodegeneration these reflect non-specific indicators of damage across many neurodegenerative diseases. Moreover, even if a manageable panel of valid and reliable biomarkers for the AD continuum was widely agreed upon by the research community, it is important for AD drug developers to reconcile issues related to the cost and burden to both sponsor companies and to subjects (and their caregivers) with the apparent incremental increase in experimental control and internal validity that this framework might permit. Access to imaging and

The research framework is built upon the assumption that imaging and CSF biomarkers are valid proxies for pathophysiologic changes associated with the AD continuum. Arguments regarding the appropriate definition and use of the term “pathophysiology” by different medical fields aside, it is widely accepted that CSF beta amyloid levels (Aβ 42/40 ratio) and tau PET binding are valid indicators of the abnormal pathophysiologic state associated with brain fibrillar beta-amyloid and tau deposition, respectively. However, other prominent biomarkers associated with proteinopathies such as alpha-synuclein and TDP43 that play a crucial role in AD have been largely overlooked. It is acknowledged that these biomarkers have only recently become available for investigation and unfortunately may not be ready for incorporation into this research framework due to their uncertain reliability. And although the contribution of these and other possible biomarkers (e.g., vascular biomarkers) can reportedly be easily incorporated into the future ATN framework, it appears that the addition of even two to three additional biomarkers would render the framework 44 Journal for Clinical Studies

Volume 9 Issue 6

Therapeutics laboratory facilities varies widely by geographic region, national health systems and by socioeconomic status. The authors of the research framework recognise that it may not be feasible to obtain biomarkers in geographic areas without access to the facilities, or for populations less trusting of the healthcare system that are reluctant to participate in invasive studies, or even in low- and middle-income countries without adequate financial resources1. This disparity may be particularly problematic given the need to expand AD trials into underrepresented populations and regions. This need is evidenced in a recent review of five global clinical trials in AD we conducted, which suggested that the vast majority of over 3000 subjects were white and were randomised mostly from the North American and European geographic regions. In terms of cost and burden, our experience suggests that for studies requiring PET imaging most patients need to travel an average of 15–20 kilometres to reach an appropriate imaging centre. Further, when special PET ligands are required for imaging, this travel (and related costs) can be increased dramatically while the number of sites are diminished markedly, as only sites within the half-life of the tracer manufacturer can be utilised (typically sites within two hours’ drive time). In terms of costs, PET imaging considerably increases the total budget of the AD clinical trial budgets and, depending upon the frequency of scans, can account for a significant proportion of total trial costs. The adoption of this proposed research framework will also undoubtedly increase the overall costs of AD trials due to increasing rates of screen failures owing to potential subjects not meeting biomarker criterion thresholds. It would not be unexpected to have screen failure rates as high as 75–85% in studies utilising imaging and CSF biomarker criteria dependent upon specific inclusion criteria thresholds. It is possible to partially ameliorate such high screen fail rates using a hierarchic approach of patient’s eligibility factors that take into account all known and estimated screening variables. Following such a hierarchical procedure, our team has been able to reduce the screen failure rate in ongoing studies to well below the expected rate, to less than 50%6. Lastly, there may be cases where this research framework is not applicable and specifically where biomarker data may not be essential for the current investigation, and the authors of the research framework concede that there may be research studies that do not require biomarker evidence of AD to achieve the specific goals of the research programme, such as studies of cognitive decline or all cause cognitive dementia1. Conversely, should regulatory agencies and/or ethics committees fully adopt this research framework, it may prove difficult for companies to maintain that biomarker evidence is not required for any and all registration efforts. Furthermore, if biomarker data is required to define subjects for pivotal trials, it may also be reflected in eventual labelling affecting the subsequent patient group eventually served. Unfortunately, development programmes which require biomarker validation of subjects (arguable these may be more likely to have novel mechanisms of action related to biomarker-based drugs or devices) may end up only being available to large pharma who can afford these types of studies, leaving non-biomarker-based programmes to smaller companies. Access to and costs associated with biomarker acquisition and analyses may actually serve as a disincentive to small companies seeking to develop novel drugs for the AD continuum. In short, there may be numerous unforeseen practical consequences as well as far-reaching implications of a rapid and widespread adoption of this research framework that will require both careful consideration before and ongoing vigilance after implementation.


Jack CR Jr, Bennett DA, Blennow K, Carillo M, Dunn B, Elliott C, Haeberlein S, Holtzan D, Jagust W, Jessen F, Karlwash J, Liu E, Masliah E, Molineuvo JL, Montine T, Phelps C, Rankin K, Rowe C, Ryan L, Scheltens P, Siemers E, Siverberg N, Snyder H, Sperling R. 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. Draft 7-18-17. (http://alz. org/aaic/_downloads/draft-nia-aa-7-18-17.pdf).

2. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. 3. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. 4. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. 5. Mendez PC, Calandri I, Pertierra L, Allegri R, Vasquez S. What Happens When Two Alzheimer’s Biomarkers Have Discordant Results in the Same Patient. Abstract presented at Alzheimer’s Assoication International Conference July 16, 2017. London UK. 6. Babic T, Riordan H. Improving Screen Failure and Recruitment Rates in Alzheimer’s Disease Clinical Trials. Journal for Clinical Studies 2016 Vol 8 (5) Oct pp 38-40.

Henry J. Riordan, Ph.D Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. He has over 100 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology. E-mail:

Natalia E. Drosopoulou, Ph.D Senior Director of Project Management in Neuroscience at Worldwide Clinical Trials who leads the International Clinical Project Management Team. She received her Ph.D. in biochemistry, specialised in developmental neurobiology from King’s College of London. With over 16 years in the clinical research industry, Dr Drosopoulou’s experience spans from small intricate Phase I studies to large global Phase III programmes. E-mail:

Journal for Clinical Studies 45


Thinking Big: SCAPIS – The Ideal Cohort for Studies on CVD, COPD and Related Metabolic Disorders

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention are believed to be outdated because of recent changes in risk factor patterns. In this article, Cecilia Stroe, editor of JCS, looks into Europe’s largest screening study, The Swedish CardioPulmonaryBioImage Study (SCAPIS). SCAPIS will create a unique Swedish cohort for studies on CVD, COPD and related metabolic disorders at the highest international level, aiming to increase the knowledge of basal mechanisms and improve risk prediction of these diseases, and ultimately to lead to more individualised, cost-effective and better healthcare. Led by Professors Göran Bergström and Annika Rosengren, The Swedish CardioPulmonaryBioImage Study (SCAPIS) is Europe’s largest screening study. It is set to create a unique Swedish cohort for studies on CVD, COPD and related metabolic disorders at the highest international level, aiming to increase the knowledge of basal mechanisms and improve risk prediction of these diseases, ultimately leading to more individualised, cost-effective and better healthcare. According to the researchers, the risk factor patterns for myocardial infarction (MI), stroke and COPD have changed significantly during the last two decades, from an environment with high levels of cholesterol, blood pressure and smoking, to a scenario dominated by obesity, hypertriglyceridemia and diabetes. The same period of time has also seen an unparalleled development of imaging and proteomics/metabolomics/genomics (“-omics”) technologies and subsequently, the strategies for diagnosis and prevention of cardiopulmonary diseases, developed just a few decades ago, are now considered to be lacking relevance in today’s healthcare. However, these strategies have the potential to be vastly improved by using recently developed advanced imaging techniques that allow scientists to directly visualise the disease process rather than rely on the limited information provided by indirect risk factors, and by using recent developments in largescale -omics techniques, thus facilitating the identification of new biomarkers and mechanisms for disease. Prevention of premature CVD and COPD is a high priority worldwide, and researchers anticipate that better risk discrimination will lead to more cost-effective measures. They believe that the size and design of SCAPIS will ensure the ability to statistically account for age, sex and other confounding factors and provide the possibility to study subpopulations with high statistical power. The Swedish CArdioPulmonary bioImage Study (SCAPIS): objectives and design was published online by G Bergström et al. in Journal of Internal Medicine 2014. 46 Journal for Clinical Studies

Designed as a prospective observational study of a randomlyselected sample from the general population, SCAPIS is currently ongoing and approximately 40–45 participants are enrolled in it each day at six sites throughout Sweden. By the end of 2016, over 16,000 participants had been examined and the study is estimated to be completed by the end of 2018, after which quality control of collected variables will begin. The examinations were selected on the basis of their ability to provide detailed phenotypic information on subclinical disease whilst at the same time being applicable for use in a large study population. Completed in 2012, the pilot study of SCAPIS has already demonstrated the feasibility and financial and ethical consequences of SCAPIS. The pilot study was performed in the city of Gothenburg, Sweden, from February to November 2012. It had as primary goals to examine the feasibility of the study design and to estimate the consequences of pathological findings identified during the examinations, on clinical resources within the public healthcare system, and on the participants, from an ethical perspective. The only difference from the design of the main study was that the participants were recruited from areas with high versus low socio-economic status, which allowed the researchers to examine participation rates and reasons for non-participation. In total, 1111 subjects were recruited (of 2243 invited) and all main aspects of the SCAPIS design were tested. The planned time schedule was adhered to, thus verifying the feasibility of examining 5000 subjects in three years at one site. According to the paper, the overall participation rate was 49.5% (39.9% and 67.8% in areas of low and high socio-economic status, respectively). Reasons for non-participation were given as follows: inability to make contact with the subject (37.4%), too busy (15.7%), too sick (6.6%), language difficulties (7.8%), miscellaneous (6.4%) and none given (26.1%). Lack of contact and language difficulties dominated in areas of low socio-economic status. SCAPIS will recruit approximately 30,000 randomly selected men and women aged 50 to 65 years. The recruitment and examinations will be performed at six university hospitals (Uppsala, Umeå, Linköping, Malmö/Lund, Gothenburg and Stockholm). The study examinations are divided into core examinations, collected at all sites, and additional examinations, performed at one or more sites. In addition to core examinations, each site can expand on its own research interests by adding additional examinations, as long as these do not interfere with the core examinations. SCAPIS has been evaluated and approved by the ethics committee as a multi-centre study (Umeå, February 21, 2011). Volume 9 Issue 6

Therapeutics One crucial objective in the recruitment process is ensuring a reasonably high participation rate. But high participation rates have been increasingly difficult to achieve in recent years, as proved by the steady decline in rates noted in the repeated studies of 50-yearold men in Gothenburg, Sweden. The recruitment strategy used in the pilot study was designed to quantify and describe the anticipated recruitment difficulties from different social strata. As expected, researchers say, a large difference in participation rates was seen between more and less affluent areas in Swedish society (67% vs. 37%) despite an overall acceptable participation rate of 49%. Financial restraints limit the study to those who understand written and spoken Swedish, meaning that some immigrants are excluded, thus limiting the generalisability of SCAPIS to these groups in society. However, the pilot study has clearly shown significant differences in health associated with socio-economic status in Swedish society. Furthermore, the pilot study proved that subjects at risk of disease from less affluent areas will participate in the study, albeit at a lower level than those from affluent areas. And given that SCAPIS will comprise 30,000 individuals, its size is believed to be sufficient to overcome this limitation and allow important comparisons to be made between social strata. Despite the pilot study experience from Gothenburg showing socio-economic differences in risk factors, the researchers have chosen to recruit subjects based on a randomised selection of participants from the Swedish population register without stratification for socio-economic status. As explained, the main reason for this decision is that smaller socio-economic gradients are anticipated at the smaller university sites (Umeå, Linköping and Uppsala) compared to the ones located in larger cities (Stockholm, Gothenburg and Malmö). The gradients will also be qualitatively different between cities, making controlled stratification impossible. In addition, the unique Swedish PIN and availability of detailed registers (with extensive records of hospitalisations, census information, education, employment, sick leave, social welfare and income) will allow scientists to quantify and statistically compensate for variations in participation rate. In parallel with the recruitment process, virtual cohorts are going to be constructed consisting of register-based census data on hospitalisations, income, education and ethnicity in subjects aged 50–64 years in the catchment areas. The virtual cohorts will be used to gauge the representativeness of the recruited sample compared to the background population. The examinations are performed on two or three occasions within a two-week period, dependent on logistics at each study site. Core examinations that are common for all sites are performed, as well as optional examinations at one or more sites depending on the local research interest. Study data will be entered into a central database at the study site through electronic case report forms. Collaboration between SCAPIS and the Western Sweden Regional Image database (‘BildochFunktionsregistret’, Gothenburg, Sweden) will enable images generated within SCAPIS to be available both to healthcare providers for clinical follow-up and to research groups across Sweden. For SCAPIS, all university hospitals in Sweden, backed by SwedishHeart & Lung Foundation, have chosen TrialOnline,

supplied by Replior, a Swedish IT operations and development company. Relying on the tradition of early landmark population studies such as the Framingham Heart Study, several other large international cohort studies focusing on CVD and COPD have been completed, or are ongoing or planned. But compared with all these studies, the researchers say, SCAPIS has the advantage that it combines size with extensive and in-depth phenotyping and direct imaging of the disease process. In a few large-scale international studies, such as the MultiEthnic Study of Atherosclerosis, the Dallas Heart Study and the BioImage study, extensive cardiovascular and pulmonary imaging has also been performed. However, the planned size of SCAPIS is almost three times bigger than the next largest study. Besides, SCAPIS is the only study using CCTA in the total cohort, which allows direct visualisation and quantification of plaque in the coronary arteries; the direct visualisation of disease in lung and vessels is combined with detailed metabolic imaging of fat deposits on a scale not attempted in any other study; and an unbiased and randomly selected sample is recruited from the general population. Furthermore, the Swedish identification number and registers provide advantages in selection of the cohort and follow-up. In addition, because the prevalence of smoking in Sweden is relatively low (18% in the SCAPIS pilot), it is feasible to perform subgroup analyses on never-smokers. Therefore, SCAPIS is an ideal cohort to identify gene– metabolite–disease interactions, by combining the extensive phenotyping data with metabolomic/lipidomic, proteomic and genetic analyses. Associations between metabolites/metabolic pathwayrelated metabolite patterns and the presence of severe coronary atherosclerosis at baseline will also be investigated, as well as the incidence of myocardial infarction during follow-up. In order to test whether such relationships are causal or only parallel phenomena, the findings will have to be validated by identifying genetic variants strongly associated with the plasma concentration of the particular metabolite/metabolic pathway. Such metabolite-associated gene variants will then be tested for association with the presence of coronary atherosclerosis/incidence of myocardial infarction in the entire SCAPIS population. Gene–metabolite–disease interactions that can be validated in such a three-stage procedure are thought to imply a causal relationship between the metabolite/metabolite patterns and the presence of disease, indicating the existence of modifiable risk factors that could be potentially targeted in drug and lifestyle interventions for disease prevention. REFERENCES 1.

The Swedish CardioPulmonaryBioImage Study: objectives and design. J Intern Med 2014.

2. G. Bergström, corresponding author, G. Berglund, A. Blomberg, J. Brandberg, G. Engström, J. Engvall, M. Eriksson, U. de Faire, A. Flinck, M. G. Hansson, B. Hedblad, O. Hjelmgren, C. Janson, T. Jernberg, Å. Johnsson, L. Johansson, L. Lind, G. Löfdahl, O. Melander, J. Östgren, A. Persson, M. Persson, A. Sandström, C. Schmidt, S. Söderberg, J. Sundström, K. Toren, A. Waldenström, H. Wedel, J. Vikgren, B. Fagerberg, 1 and A. Rosengren Journal for Clinical Studies 47


Acne vulgaris and Associated Impact on Quality of Life Acne vulgaris or 'pimples' is a very common inflammatory skin disease affecting young adults all over the world, irrespective of race, ethnicity and geographical location. Prevalence of acne during adolescence is common enough to label it as a physiological process associated with other changes occurring during puberty, however, the underlying inflammatory processes involved classify it as a disease. Another important aspect associated with acne which affects the person psychologically and socially is the disfigurement involving the face. Psychological burden and social and emotional impairment associated with facial acne can be as devastating as that of a variety of chronic conditions such as arthritis, diabetes, epilepsy and asthma1,2. The pathophysiology of acne involves chronic inflammation of Pilosebaceous units which consist of hair follicles and sebaceous glands. The regions of the face, back and scalp are particularly known to be rich in sebaceous glands. The main physiological changes resulting in acne are: • Seborrhoea (increased sebum secretion / oily skin); • Blockage of the follicular opening by plug formation due to increased cell turnover (hyperkeratinisation); • Alteration of the quality of sebum lipids; and • Proliferation of Propionibacterium acnes (usually the normal commensals of the skin) within the plugged follicular openings of the skin. There is a simultaneous spurt in the level of androgens or sex hormones during puberty, which plays a key role. All the events together lead to appearance of pleomorphic lesions of acne vulgaris, such as open and closed comedones; (commonly known as black heads and white heads), papules, pustules and nodules. Lesions such as cysts, pseudocysts and abscesses are considered as severe and usually lead to lifelong scarring3-5. Other factors which are known to attribute to the pathology are environmental factors, such as hot and humid climate, poor hygiene, occupations associated with heavy sweating, e.g. Cooks , people working with heavy oils, people wearing heavy makeup, and consumption of diet with high glycaemic index or high fat contents. Acne represents one of the most prevalent skin pathologies, with a very high global burden of disease (GBD). During an epidemiological study conducted in 2013, acne was found to be affecting ~85% of young adults in the second and third decade of their life6. A similar percentage was observed during various other studies conducted across the developed countries, like the USA, France, the UK and others 7-10. In the tropical island of Mauritius, where hot and humid climate prevails during most of the year, a hospital-based study in 2013 showed acne to be the commonest skin pathology affecting the young age group, which was followed by fungal infections and eczema11. The psychological consequences of living with skin diseases can be significant, as skin is considered as an organ of communication 48 Journal for Clinical Studies

and plays a vital role in socialisation. Embarrassment caused by acne and associated complications such as scars and postinflammatory hyperpigmentation can have a greater psychosocial burden on the sufferer1. The array of the symptoms may range from common psychological entities such as anxiety and depression to serious suicidal tendencies in severe cases. Besides this, acne patients are very much prone to low selfesteem, low self-confidence, low self-assertiveness, embarrassment, social withdrawal or disapproval, affectation, shame, altered body image, psychosomatic symptoms (e.g., pain and discomfort), obsessive-compulsiveness, and suicidal ideation. These symptoms are found to be more commonly associated with moderate to severe acne1, 12-15. Stress has been documented to have an impact on acne manifested by young adults experiencing flaring up of acne lesions during examinations or other stressful conditions. Also, this was found to occur without any significant alteration in sebum production16,17. Acne excoree, a variant of acne with a female prevalence, is characterised by compulsive skin picking and has been associated with stress or personality disorder. In addition, various studies have shown that acne can affect patients’ functional abilities. Patients with acne are reported to show academic underachievement and higher unemployment rates compared to patients without acne18,19. Quality of Life Associated with Acne WHO defines quality of life (QoL) as the “Individual's perception of their position in the context of culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns”20. The impact of skin diseases in general, and acne in particular, on quality of life (QoL) has been well acknowledged over the last three decades1. In recent years, emphasis has been placed by psychologists and physicians on the importance of assessing the effects of acne on the patient’s quality of life21-23. It provides a valuable insight into the debilitating effects of acne on patients’ life, which patients themselves rarely address. To assess this in a standardised manner, several acne-specific quality of life (QoL) questionnaires have been developed, for example Acne Disability Index (ADI), Cardiff Acne Disability Index (CADI), Assessment of the Psychological and Social Effects of Acne (APSEA), Acne Quality of Life (AQOL), Acne-Quality of Life Index (QOLI), Acne-QoL, and Acne Q424. In clinical practice, the assessment of quality of life (QoL) allows a clinician to understand how a patient’s life is impacted by disease from the patient’s point of view and helps in selecting the most appropriate treatment for that patient. It also helps to monitor the compliance of the patients; as most of the acne treatments are associated with mild to moderate side-effects which makes it difficult for the patient to adhere to the treatment. An improvement in the scores of QoL index questionnaires can be an indication of compliant and successful treatment if they are applied before and during the course of the treatment21,25-26. Volume 9 Issue 6

Therapeutics Various factors are known to affect quality of life associated with acne apart from the severity of acne, which is probably the most influencing factor. Studies conducted all over the world have come up with some interesting findings. Age The peak incidence of acne occurs around the pre-pubertal to pubertal age. In late adolescents, above the age of 16 years, this population moves towards young adult roles and appearance is given more importance than at an earlier age. Researchers found in the studies done in France and the USA that severity of acne worsens as age advances and this affects the overall quality of life (QoL). It is proposed be attributed to increased exposure to social, emotional and occupational functioning at this age27, 28. In a study carried out in North India by Sumir Kumar et al. 29, 125 male and female subjects within the 11–30 year age group, suffering from mild to severe acne, were assessed for a quality of life questionnaire. The impact on quality of life was found to be more in the age group of 21-30 years as compared to the age group of 11–20 years, although in the latter age group the clinical severity of acne was mild to moderate only. However, above 30 years, the patients were seen to be less affected psychologically. This was in line with studies carried out by Ismail et al.30 and Priya Cinna et al.31 However, conversely, Salek et al.32 found no correlation between age and QoL in their study assessing handicap due to acne. Gender Acne most commonly involves the face and affects the appearance of the individual. Though in the present day, both men and women are equally conscious about their external appearance, various studies across the world have shown that usually women are more affected psychologically due to acne. In a study conducted by Sumir Kumar et al.29 on males and females suffering from moderate to severe acne, females were found to have high Cardiff Acne Disability Index (CADI) scores in comparison to males, indicating higherpsychological involvement. In another study carried out in schoolchildren to assess quality of life associated with acne, Jankovic et al.33 observed a significant gender difference with the Cardiff Acne Disability Index (CADI) score being more in females. This was seen as being in line with studies carried out by Ismail et al.,Cotterill et al. and Halvorsen et al., where females had higher scores in quality of life (QoL) questionnaires and were found to be more concerned about their looks30, 34-35. However, a study done by Walker and Lewis-Jones36 showed no gender differences in the Cardiff Acne Disability Index (CADI) scores obtained, and both males and females were found to be equally concerned about their acne. Severity of Acne A strong correlation between severity of acne and quality of life has been documented and confirmed in many studies conducted across the globe. Increases in the grades of acne are associated with poor quality of life questionnaires which reflect social withdrawal, low self-esteem and difficulties in relationships .. Similarly, posttreatment improvement in the grades of acne is found to be associated with improved scores on QoL questionnaires. Martin et al.37 observed that the quality of life (QoL) in facial acne correlated with the patient-reported severity and the QoL scores worsen with increasing severity. Sumir Kumar et al.29 found

that there was significant correlation between severity of acne and the Cardiff Acne Disability Index (CADI) questionnaire. Similar observations were made by Srivastava et al.38, Hassan et al.39 and Priya Cinna et al.31 during studies conducted on adolescent and adult male and female volunteers. Impact of Treatment Most acne treatments are associated with side-effects such as dryness of the skin, scaling, irritation, burning / stinging sensation and initial flaring-up of acne. With effective treatment regimens and compliant patients, usually a significant improvement in acne grades and quality of life can be seen in a clinical practice. Assessing quality of life (QoL) at baseline provides important information about patients’ psychological status with regard to the disease. In a study where an anti-acne therapy was being assessed on 111 patients, a substantial improvement in the scores on quality of life (QoL) instruments was seen after initiation of the therapy40. In a study conducted by Priya Cinna et al.31, a positive treatment history and DLQI / CADI scores were found to be strongly correlating. Quality of life (QoL) scores were better among patients who had taken treatment and this was statistically significant. This result was similar to that studied by Walker and Lewis-Jones and Martin et al. 36,37, who observed that among the 20 treated patients, 66% had overall improvement in the QoL scores. Exceptionally, in contrast, Tejada et al.41 in a study conducted in southern Brazil found that treatment had no significant impact on the improvement in the quality of life (QoL) scores. Discussion Acne vulgaris is a very common skin condition affecting young adults globally. Cosmetic disfigurement with acne can lead to significant psychosocial morbidity in this vulnerable population who are at crucial stages of physical and emotional maturity and socialisation. It can significantly affect an individual’s personality who may suffer from various psychological morbidities such as anxiety, depression, low self-esteem, social inhibition and obsessive compulsive disorder, up to suicidal intentions. Large numbers of studies have been conducted globally to study different aspects of acne and its impact on quality of life. A strong correlation has always been observed between severity of acne and poor quality of life. With few variations, factors such as age and gender have been seen to correlate well with QoL scores. Usually, therapeutic treatments are found to improve quality of life of the patients. However, during the early stages of the treatment, especially when irritating therapies such as topical retinoids are employed, the quality of life (QoL) score can deteriorate due to associated side-effects. With due counselling, such negative experiences can be eliminated. Assessment of quality of life (QoL) before commencing any treatment provides the clinician with a good insight about patient’s perception and psychological impact of the disease so as to treat them in an integrated manner. These psychological inputs help to improve the doctor-patient relationship, resulting in better therapeutic outcomes. Various practices can be inculcated in the clinical practice along with the medical treatments, such as: • Health education in secondary school to make adolescents know more about the pathophysiology of acne and the treatments available. • Spreading awareness to seek the medical treatments and the treatments available. • Emphasising the importance of starting treatments at an early stage to halt the progression of the disease and prevent complications such as scars. Journal for Clinical Studies 49

Therapeutics • Incorporate a quality of life (QoL) questionnaire in a routine clinical practice to identify the psychologically at-risk patients. • Establishing acne clinics with the provision of counsellors / psychologists. • Group discussion forums / acne support groups.


This will enable the susceptible subjects to overcome their psychosocial inhibitions and improve self-confidence, leading to an uncompromised quality of life.




1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Tan JK. Psychological impact of acne vulgaris: Evaluating the evidence. Skin Ther Lett 2004;9:1-3,9 Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: A comparison with general medical conditions using generic questionnaire. Br J Dermatol 1999;140:672-6. Layton AM. Disorders of sebaceous glands. In: Burns T, Breathnach S, Cox N,Griffiths C, editors. Rook's Textbook of Dermatology. 8th ed. Vol. 42. Oxford:Wiley-Blackwell publication; 2010. pp. 1–89.) Kubba R, Bajaj AK, Thappa DM, Sharma R, Vedamurthy M, Dhar S, et al. Indian Acne Alliance (IAA) Acne in India: Guidelines for management IAA consensus document Genetics in acne Acne and quality of life Pathogenesis of acne. Indian J Dermatol Venerol Leprol. 2009;75:S4–5. Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18:821–32. [PubMed]) Seattle WI. GBD Compare. Seattle: University of Washington; 2013  Rea JN, Newhouse ML, Halil T. Skin disease in Lambeth. A community study of prevalence and use of medical care. Br J Prev Soc Med. 1976;30(2):107– 114. [µPMC free article] [µPubMed] Wolkenstein P, Grob JJ, Bastuji-Garin S, Ruszczynski S, Roujeau JC, Revuz J. French people and skin diseases: results of a survey using a representative sample. Arch Dermatol. 2003;139(12):1614–1619.discussion 1619. [µPubMed] Johnson MT, Roberts J. Skin conditions and related need for medical care among persons 1–74 years. United States 1971–1974. Vital Health Stat. 1978;11(212):i–v. 1–72. [µPubMed] Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol. 2013;168(3):474–485. [µPubMed] Kawshar T, Rajesh J, Sociodemographic Factors and their Association to Prevalence of Skin Diseases Among Adolescents DOI: 10.7241/ourd.20133.68 Fried RG, Wechsler A. Psychological problems in the acne patient. Dermatol Ther. 2006;19:237-40 Pearl A, Arroll B, Lello J, Birchall NM. The impact of acne: A study of adolescent attitudes, perceptions and knowledge. N Z Med J 1998;111:269-71 Tallab TM. Beliefs, perceptions and psychological impact of acne vulgaris among patients in the Assir region of Saudi Arabia. West Afr J Med 2004;23:857 2004;9:1-3,9 Barak Y, Wohl Y, Greenberg Y, Bar Dayan Y, Friedman T, Shovai G, Knobler HY. Affective psychosis following Accutane (isotretinoin) therapy. Int Clin Psychopharmacol 2005;20:39- 41. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: Changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol 2003;139:897-900 Yosipovitch G, Tang M, Dawn AG, Chen M, Goh CL, Huak Y, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol (Stockh) 2007;87:135-9.) Motley RJ, Finlay AY. How much disability is caused by acne? Clin Exp Dermatol 1989;14:194-8. Cunliffe WJ. Acne and unemployment. Br J Dermatol 1986;115:386 The World Health Organization Quality Of Life assessment (WHOQOL): Position paper from the World Health Organization. Soc Sci Med. 1995;41:1403–9. [PubMed] Dreno B. Assessing quality of life in patients with acne vulgaris. Implications for treatment. Am J Clin Dermatol. 2006;7:99-106 Finlay AY. Quality of life measurement in dermatology: a practical guide. Br J Dermatol. 1997;136:305-14 Katugampola RP, Finlay AY. Impact of skin diseases on quality of life. Eur J Dermatol. 2007;17:102-6. Barnes LE, Levender MM, Fleischer AB, Feldman SR. Quality of life measures for acne patients. Dermatol Clin. 2012;30:293–300. [PubMed] Guyatt GH, Veldhuyzen van Zanten SJ, Feeny DH, Patrick DL. Measuring

50 Journal for Clinical Studies


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quality of life in clinical trials: a taxonomy and review. Can Med Assoc J. 1989;140:1441-8 Thomas DR. Psychological effect of acne. J Cutan Med Surg. 2004;8 Suppl 4:3-5 Tasoula E, Gregoriou S, Chalikias J, Lazarou D, Danopoulou I, Katsambas A, et al. The impact of acne vulgaris on quality of life and psychic health in young adolescents in Greece. Results of a population survey. An Bras Dermatol. 2012;87:862–9. [PMC free article] [PubMed] Rapp SR, Feldman SR, Graham G, Fleischer AB, Brenes G, Dailey M. The Acne Quality of Life Index (Acne-QOLI): Development and validation of a brief instrument. Am J Clin Dermatol. 2006;7:185–92. [PubMed] Kumar S, Singh R, Kaur S, Mahajan BB. Psychosocial impact of acne on quality of life in North India: A hospital-based cross-sectional study. Journal of Pakistan Association of Dermatologists. 2016;26 (1):35-39 Ismail KH, Mohammed-Ali KB. Quality of life in patients with acne in Erbil city. Health Qual Life Outcomes. 2012;10:60. [PMC free article] [PubMed] Cinna P, Durai T, Nair DG. Acne Vulgaris and Quality of Life Among Young Adults in South. Indian J Dermatol. 2015 Jan-Feb; 60(1): 33–40.doi: 10.4103/0019-5154.147784 Salek MS, Khan GK, Finlay AY. Questionnaire techniques in assessing acne handicap: Reliability and validity study. Qual Life Res. 1996;5:131–8. [PubMed] Jankovic S, Vukicevic J, Djordjevic S, Jankovic J, Marinkovic J. Quality of life among school children with acne: Results of a cross sectional study. Indian J Dermatol Venerol Leprol. 2012;78:454–8. [PubMed] Cotterill JA, Cunliffe WJ. Suicide in dermatological patients. Br J Dermatol. 1997;137:246–50. [PubMed] Halvorsen JA, Stern RS, Dalgard F, Thoresen M, Bjertness E, Lien L. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: A population-based study. J Invest Dermatol. 2011;131:363–70. [PubMed] Walker N, Lewis-Jones MS. Quality of life and acne in Scottish adolescent schoolchildren: Use of the Children's Dermatology Life Quality Index (CDLQI) and the Cardiff Acne Disability Index (CADI). J Eur Acad Dermatol Venereol. 2006;20:45–50. [PubMed] Martin AR, Lookingbill DP, Botek A, Light J, Thiboutot D, Girman CJ. Health related quality of life among patients with facial acne. 2 assessment of a new acne specific questionnaire. Clin Exp Dermatol. 2001;26:380–5. [PubMed] Srivastava S, Bhatia MS, Das P, Bhattacharya SN. A cross sectional study of quality of life and psychiatric morbidity in patients with acne vulgaris. J Pak Psychiatry Soc. 2008;5 Hassan J, Grogan S, Clark-Carter D, Richards H, Yates VM. The individual health burden of acne: Appearance- related distress in male and female adolescents and adults with back, chest and facial acne. J Health Psychol. 2009;14:1105–18.[PubMed] Newton JN, Mallon E, Klassen A, Ryan TJ, Finlay AY. The effectiveness of acne treatment: an assessment by patients of the outcome of therapy. Br J Dermatol 1997;137:563-7. Tejada CDSS, Mendoza-Sassi RA, Almeida HL, Jr, Figueiredo PN, Tejada VF. Impact on the quality of life of dermatological patients in southern Brazil. An Bras Dermatol. 2011;86:1113–21. [PubMed]

Dr Gitanjali Petkar A Dermatologist from India has been working with CIDP for more than 3 years. She has graduated with MBBS from Poona University and holds a Diploma in Dermatology. Being the Principal investigator and Medical Expert, she has a vast experience in cosmetic and pharma trials and has conducted studies for many renowned cosmetic and pharmaceutical brands. Her special areas of interest include Acne, Psoriasis, Vitiligo, Atopic dermatitis, Anti-aging and Solar Dermatoses. She is well versed with GCP and other processes of clinical research such as informed consent, protocol-report writing and pharmacovigilance. She is also actively involved in internal Dermatological trainings for CIDP group. Email:

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Improving the Performance of Clinical Trials The author suggests the course of patient recruitment and the quality of the data generated as essential indicators for the performance of clinical trials. Delayed patient recruitment is associated with high additional costs. The possible causes are analysed and as a solution to the problem it is proposed to introduce the new function of the Clinical Trial Liaison. This function has significant potential for the patient recruitment process leading to significant savings in working time and costs in conducting clinical trials. When is a clinical trial performant and how do you measure this? Several metrics systems exist to measure performance1,2,3. The most significant parameters, however, are the course of patient recruitment, how many patients complete the study, and the quality of the data generated. Sponsors invest a great deal of time and effort in the preparation of clinical trials, but patient recruitment often stays very much behind expectations. Dramatic Situation of Clinical Studies The situation of clinical trials is dramatic: • 80% of clinical studies do not reach their target of patient recruitment.4,5 • 50% of clinical study sites recruit only one or no patients at all.4,5 • 535,000 US$ are the average direct costs to implement a substantial amendment for Phase III clinical trials.6 Reasons for Bad Patient Recruitment Medically speaking, the statement: "Patient recruitment doesn’t work." just describes a symptom. The causes for this, however, can be manifold: • The wrong patient clientele is addressed. If patients eligible for the study according to the in- and exclusion criteria can’t integrate the study visits or a washout of their normal medication at the beginning of the study into their daily routines, one will not be able to win these patients for the study. • The clinical trial is not attractive to patients. Patients most often do not benefit personally from their participation in a clinical study. Therefore it is crucial whether the sponsor succeeds in designing the information to patients in a way that they can recognise the social value of the study and the possible added benefit of the medication or medical product to be approved. And it is important that the investigator can explain the study to his patients accordingly. • The clinical study is scientifically not relevant. 52 Journal for Clinical Studies

For physicians at university hospitals their scientific research has priority. Therefore they favour collaborating in studies with an interesting scientific research question that matches with their research topics and offers the prospect of the results being published. • The study sites do not fit with the study in regard to patient clientele, infrastructure or experience. Besides the number of patients with the study indication that the study sites are seeing, it is crucial how many of these patients can be recruited for the study. This not only depends on whether they fulfill the inclusion and exclusion criteria, but on various other conditions: Are the study sites experienced with patients with this indication and the infrastructure required for the study? What effort does the study participation mean for the patients? Are there unpleasant or even painful study procedures? Can the investigator motivate the patients to participate? • The study is not sufficiently paid. The study fees must be fair and correspond to the effort to be yielded, so that the study sites will be paid for the time needed to prepare for the study, even if later on they are not selected for the study. It has to be ensured that other studies, which the study sites collaborate in, are not better rewarded. • Instructions for technical devices are difficult to understand. The instructions for equipment to be used in the study must be clear and as simple as possible to be understood by the study team, and the study team must be trained in the use of these devices. It is recommended that the clinical monitors try out the equipment and the instructions, so that they can train the study team how to use them. If the instructions are difficult to understand, especially if they were written by the developers of the devices, they should be redacted by the sponsor and the redacted versions must be reviewed by the manufacturers. The study teams will not grapple with devices that do not function right away, and would rather attend another study which is less elaborate. • The study processes are difficult to integrate into the workflows of the study sites. The study teams must be able to integrate the study processes into their daily routines. It is a good investment in the success of a clinical study to deal with the study sites’ processes. In most cases, however, these are unknown to the clinical monitors. Feasibility Analysis Reconsidered So what can be done to ensure that a clinical trial recruits well, patients possibly complete the study, and that the quality of the data generated is high? Volume 9 Issue 6

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Technology Slip into the shoes of the investigators and their study teams for a moment. They usually carry out several clinical studies at the same time, are under great time pressure and have to be motivated to spend enough time for your study. The sponsor therefore should make it as easy as possible to the investigators and their study teams to recruit patients. The feasibility analysis therefore has to take the problems mentioned and their possible solutions into account. The study protocol has to be analysed with regard to the potential for patient recruitment and the operational and administrative challenges of the study. Sufficient and above all, the right questions must be asked. The study procedures and the associated time expenditure should be adjusted with the investigators and their study teams. Also, the investigators should have a plausible strategy for patient recruitment. These assessments mean a certain amount of effort, which the study sites must also be paid for. It is not sufficient to ask the investigators how many patients with the study indication they see and how many of them they are likely to recruit for the study, or whether they have the necessary infrastructure and experience and sufficient personnel resources for the study. The feasibility analysis should be started before the study protocol is final, since it can be crucial for the success of a study to account for the investigators’s concerns and suggestions in the study protocol. This doesn’t mean that the investigators write the protocol. This remains the task of the sponsor or the contract research organisation commissioned with the study conduct. Only by analysing the study protocol and a thorough feasibility analysis one can make realistic statements on which study sites are appropriate for the study and what potential for patient recruitment they really have. Clinical Trial Liaison Clinical studies are research projects. This means certain unpredictability of their course and, despite thorough preparation, challenges may arise during their conduct that must then be overcome. Therefore the investigators and their study teams need a competent contact person who can immediately answer all questions regarding the study or obligatorily takes care that these are answered in a timely manner, and who in the event of difficulties first searches for solutions with the investigational team and then with the sponsor’s study team, and who has the time to do so. The required competences of this person include analytical skills, strategic thinking, communication techniques, relationship management, and a well-founded understanding of the work of investigational teams. According to section 5.18.4 of the ICH Guideline for Good Clinical Practice E6 (R2), the clinical monitor acts as the main line of communication between the sponsor and the investigator. But the personnel resources for the monitoring of clinical trials are scarce and the clinical monitors are mainly responsible for quality control during the study course. Therefore they should not fill this role. Referring to the recently established function of the medical science liaison, who is mostly responsible for an entire therapy area and the management of the key opinion leaders (KOL), the most appropriate designation for this function is clinical trial liaison, 54 Journal for Clinical Studies

since they are responsible for the guidance of the investigational teams in a particular clinical trial. It is one of the tasks of the clinical trial liaisons to establish and maintain an open and transparent communication with the monitors as the primary contact persons of the investigational teams. The better the integration of the study team, the better the clinical trial liaisons can perform their tasks and the greater is the effect of their activity on the performance of the clinical study. There is a clear division of work into quality assurance through the monitors and supervision of the investigational team to ensure patient recruitment and resolution of the challenges which eventually arise. Often a contract research organisation is engaged for the monitoring, and the monitors form an independent team at the contract research organisation with their own project management. The clinical trial liaisons, however, must be perceived by the investigational teams as sponsor representatives. In order to be able to fulfill their tasks, they work very closely with the sponsor’s study team. Tasks and communication paths should be determined in the communication manual. Various other approaches exist to establish the function of the clinical trial liaison, among others, by various contract research organisations as well as non-profit organisations. However, most of them are limited to the aspects of supervision and relationship management, such as by PRA Health Sciences7, Therawis8 and The Medical Affairs Company9. The approaches of the two non-profit organisations, Molecular Medicine Ireland10 and the National Health and Medical Research Council of the Australian government11, also seem to include a feasibility analysis. However, the descriptions found remain very vague. Time and Cost Advantages Without a thorough feasibility analysis and supervision of the investigational team by the clinical trial liaisons, patient recruitment can be significantly delayed and the required number of cases can usually only be reached by implementing amendments to the protocol. This results in significant delays in the course of studies of up to one year. And these delays cost a lot of money because the entire study logistics must be maintained during this time and additional monitoring visits are required. As shown in Table 1, for the example of a neurological Phase III study with 375 patients at 42 sites in three countries and a duration of 31 months, additional costs of 39.5% emerged, which could have been avoided with a combination of monitoring and clinical trial liaison. Compared to the original monitoring plan, even a slight cost reduction of 3.4% could have been achieved. This result delivers calculating the study costs with our budget calculator. Deployed in addition to monitoring substantial savings in working time and costs can be achieved. Concept of Clinical Trial Site Management


Monitoring incl. feasibility analysis and site management as originally planned


Monitoring incl. feasibility analysis and site management delayed by 1 year


Clinical trial liaison incl. feasibility analysis and site management


Monitoring excl. feasibility analysis and site management


Clinical trial liaison plus monitoring


Tab. 1: Concept of Clinical Trial Site Management and their Costs Volume 9 Issue 6

Technology Ideally, patient recruitment can proceed as shown in Figure 1. The blue line is the target curve, the red line is the course of patient

recruitment without clinical trial liaison, and the green line is the course of patient recruitment when clinical trial liaison is deployed.

Figure 1: Patient recruitment with and without clinical trial liaison

Conclusion The deployment of clinical trial liaison can contribute significantly to an improved course of patient recruitment through a thorough feasibility analysis and the guidance of the investigational teams in the conduct of clinical trials. The better the communication with the clinical monitors and their integration into the student team, the greater the effect. By selecting appropriate study sites for the study during the feasibility analysis, amendments to the study protocol can be avoided and significant savings in working time and costs can be achieved. REFERENCES 1.


3. 4.

5. 6.

Nisha Berthon-Jones, Kymme Courtney-Vega, Anna Donaldson, Hila Haskelberg, Sean Emery, and Rebekah Puls: Assessing site performance in the Altair study, a multinational clinical trial, https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4412197/ Several Authors: Performance Metrics in Clinical Trials, in The Monitor Vol 26, Issue 4, August 2012, Association of Clinical Research Professionals (ACRP) Drug Development Technology: Clinical trial delays: America’s patient recruitment dilemma, features/featureclinical-trial-patient-recruitment/ Kremidas, J: Recruitment Roles, Applied Clinical Trials Vol. 20, no. 9, S. 32, September 2011 Kenneth A. Getz, MBA, Stella Stergiopoulos, BA, Mary Short, RN, MSN, Leon Surgeon, MS, Randy Krauss, PhD, Randy Krauss, Sybrand Pretorius,


8. 9.



MMedSci, MBA, MS, Julian Desmond, PhD, Derek Dunn, MMedSci: The Impact of Protocol Amendments on Clinical Trial Performance and Cost, Tufts CSDD, Sage Journals Vol 50, Issue 4, 2016 Martin Lee, MD Vice President, Global Scientific Affairs PRA Health Sciences: Engaging Clinical Trial Sites: The Role of the Clinical Trial Liaison, Trial_Sites_The_Role_of_the_Clinical_Trial_Liaison.pdf Therawis GmbH: Clinical Trial Liaison, The Medical Affairs Company: Clinical Trial Liaisons CTLs, http://www. Molecular Medicine Ireland: Clinical Trial Liaison Officer required for HRB CRCI, 15th of May 2015, clinical-trialliaison-officer-required-for-hrb-crci/ Australian Government - National Health and Medical Research Council - Department of Industry, Innovation and Science: The Good Practice Process for Site Assessment and Authorisation Phases of Clinical Trial Research Governance,

Robert Dannfeld He worked in clinical research since 2004, being self-employed since 2006. In 2011, he founded Pharmatio GmbH, a speciality service provider for performance in clinical trials. In his 14Â years in clinical research, he worked on many studies with investigators and their study teams and knows the challenges of clinical studies in practice. These experiences led to the concept of clinical trial liaison presented here. Email:

Journal for Clinical Studies 55


Gathering Substantial Data for Faster Clinical Trial Approval Pharmaceutical manufacturers have long struggled to create an efficient clinical trial process for faster next-phase approval. The root cause of most failures is a lack of necessary efficacy data to support clinical trial claims. Subpar data can be directly tied back to an inability to track and report on patient adherence to drug protocol. Adherence is an issue of utmost importance to the overall success of the clinical studies, as well as the external scientific and regulatory community. The Underlying Problem of Low Efficacy Data A study drug, no matter how chemically effective, is insignificant without substantial data for clinical validation. Tartaglia determined that 50% of drug compounds fail to demonstrate efficacy in clinical trials1, which leads to prolonged trial duration, increased study cost, and delayed approval prospects. The underlying cause of low-quality data is empirically linked to patient non-adherence to clinical medication protocol. An average trial adherence rate is estimated from 43 to 78 per cent2, and declines as complex regimen is introduced. Nonadherence can lead to toxicity and suboptimal therapy efficacy as a function of the drug’s PK/PD characteristics and subject medication utilisation patterns in between site visits. It can jeopardise subjects’ health and lead to larger samples to achieve adequate statistical power. To demonstrate, a 20 to 30 per cent decrease in medication adherence may result in increasing the patient sample size by 50 per cent to maintain sufficient statistical power, and a 40 per cent non-adherence rate would require a 200 per cent increase in the sample size to maintain significant statistical power3, resulting in increased clinical trial costs. Furthermore, the impact of non-adherence can permeate to the marketplace post-drug launch. 22 per cent of the drugs entering the US market between 1980 and 1999 required significant post-launch dose adjustments due to poor dosing during clinical trials4. Nonadherence can develop discrepant or altered data due to inaccurate dosing, which can misinterpret the drug’s efficacy during the study. Non-adherence is not only limited to the quantity of use, it also involves the quality of medication utilisation. A 2011 study by Adler and Lynch electronically monitored a one pill per day regimen, and discovered that only 34 per cent of patients managed to take their medication as prescribed5. For Phase II-IIIb field-based studies involving oral solids, non-adherence can be the result of one or a combination of the following: • Taking more medicine than prescribed, • Taking less medicine than prescribed, • Taking medication at a time of day or time intervals other than prescribed, • Taking medication in conditions other than prescribed (with or without meals, etc.). Although a prevalent issue, the silver lining is that nonadherence is mainly unintentional and can be quickly addressed. 56 Journal for Clinical Studies

A recent study by Express Scripts assessed that 70% of poor medication adherence comes from forgetfulness or procrastination in taking pills, refilling prescriptions or renewing them6. Several approaches have been introduced throughout the years to monitor patient adherence. Measurements Used for Non-adherence to Achieve Efficacy Data Pill Counts and Patient Diaries A constant challenge that pharmaceutical companies experience is the ability to supervise the subject’s medication utilisation in the outpatient setting. The methods most frequently used are pill counts at 49 per cent7 and patient diaries at 22 per cent8. Pill counts are a simple way to measure adherence that is more objective than a self-report on a patient diary. Patient diaries are a simple, practical, and inexpensive method that can be easily implemented in clinical settings. This method can also serve as a tool to identify psychosocial barriers amenable to intervention. Diaries also give a high degree of specificity regarding non-adherence. Although commonly applied in clinical trials, pill counts don’t explain utilisation patterns in between site visits, are subject to “pill dumping”, and consume staff resources that could be deployed to other value-added activities. Patient diaries, on the other hand, are limited by recall bias and vulnerable to social desirability that lead to measurable overstatements of adherence. Agot et al. reported in 2014 that self-reports and pill counts that were intended to capture consistent pill use over four-week periods had the lowest predictive values, at less than 30 per cent on average9. They elaborated that the large discrepancy found between adherence assessed through self-report or pill count and adherence assessed through drug concentrations or other biomarkers was not unique to their study. For example, in an HSV-2 suppression therapy trial, acyclovir was detected in 55% of participants’ urine, yet adherence by pill count was 90 per cent10. Adherence measured by pill count and self-report in the iPrEx trial was 93 per cent, yet a sub-study of drug concentrations showed that only 50 per cent of participants were swallowing their pills11. Pill counts upon site visits and self-reports are not accurate enough adherence measures and are retrospective ones that leave no room for proper screening and timely enrichment interventions. The use of technology has been introduced in the healthcare industry in search of innovative solutions to combat medication non-adherence. Medication Electronic Monitoring Systems (MEMS) 76 studies from 2000 to 2006 were conducted in which medication electronic monitoring systems (MEMS) were used to measure adherence. Authors reported that using MEMS allowed them to record consistency in daily dose-taking and dose-timing12. Legacy MEMS were used in packaging to time-stamp medication container openings or closings, but could not track pill counts. The data being captured only syncs at selected sites, not in real time. This limits clinical study teams to act only in retrospect instead of in a timely intervention. The healthcare industry has leveraged the advancements of technology to improve medication adherence Volume 9 Issue 6

Technology since then. Some MEMS approaches made improvements to the legacy MEMS tools, and others conceptualised a different methodology to track medication adherence. MEMS: Direct Observation Therapy (DoT) Solutions New approaches have surfaced in recent years. For example, biomarkers in the study drug which once ingested and absorbed are transported via blood to the lungs, coupled with an accompanying device that takes a post-ingestion breath sample. This provides a direct and definitive proof of the study medicine being ingested. Biomarkers are also objective and away from selective memory, unlike self-reporting patient diaries. The disadvantage is that they do not provide dosing history and results can be affected by nutraceutical interactions and formulation changes. They can only provide a snapshot of recent patient adherence. Ingesting a biomarker is also considered as an invasive approach to improving adherence. Other novel approaches include facial recognition technologies for visual confirmation of drug intake. This approach is a direct and visual observation of medication adherence. This is more convenient for the patient than having them drive to the research centre to take the medication in front of a research team member. The disadvantage to this methodology is that it may disrupt patient’s lifestyles, which can lead to the subject retention and satisfaction being compromised. These approaches can be thought of as novel direct observation therapy (DoT) solutions, which provide “proof of ingestion” and high reliability for monitoring adherence. When designing a clinical study, it should be considered that DoT solutions are not scalable into clinical settings nor do they provide information about natural patient behaviours. The researcher must evaluate if observing natural behaviour is an important factor of the study being conducted. Collecting adherence information is paramount and DoT and microchips provide higher reliability of study medicine ingestion than diaries and pill counts. However, the selected adherence monitoring approach should not conflict with subject enrolment, satisfaction and retention. Therefore, there is a growing interest in a more comprehensive and holistic approach that integrates interactive devices, software, and personalised support as a passive approach to combat medication non-adherence. MEMS: Device-enabled Adherence Platforms Pillboxes with daily alarms were initially used to combat medication non-adherence. However, this legacy MEMS tool is onedimensional. It doesn’t provide visibility to the researchers regarding dosing patterns, and it doesn’t promote patient engagement to encourage adherence. With today’s technology, a more robust integrated approach is introduced to enhance the legacy pillbox reminder approach. Medication bottles with reminders are now improved by a tracking feature for dosing patterns when the bottle is accessed. The bottle works in conjunction with a customer portal where the data is visible and research teams can present the data as meaningful analytics for benchmarking and reporting aggregated by patients, by clinical sites, etc. Improvements also feature notification setup to alert the team when the patient is showing non-adherent behaviour in real time, to enforce timely interventions. The research team can then place a call, or send text messages or emails to communicate with the patient and ask what they are experiencing, and what the reason is for not taking their dose at the scheduled time. Some solutions providers also include a mobile app to increase the patient engagement even more.

The limitation with this methodology is the assumption that the patient took a single and correct dose each time the container is opened and did not overdose. Also, since it only tracks the container opening and not the actual ingestion of the drug, the research team cannot confirm that the medication was consumed. It may also be susceptible to technical malfunction or device failure. The benefit of this is that it is a passive, non-invasive approach that goes beyond the pill by enriching patient engagement with dosing visibility and communication tools. This methodology offers a substantial correlation with clinical outcomes. The data remains objective and untampered and can be monitored in real time. It provides continuous data history instead of only providing the most recent activity. It is nothing out of the ordinary from a patient’s regular routine and observes the patient’s natural state. This also adds a layer of visibility for the research team, and allows analysis of adherence patterns over time. Improving Adherence in Clinical Trials Patient Selection The key to adherence is early and responsive intervention. It begins from subject selection, where investigators screen for subjects who are likely to be non-adherent, and those at risk can either be screened out or targeted for adherence-enhancement interventions. This strategy must be done before randomisation. FDA in 2012 stated that removing poor compliers identified after randomisation is generally not acceptable because such patients are not likely to be a random sample of the study population and because compliance itself had been linked to outcome13. The two methods of pre-randomisation screening strategies are the following: • Run-in screening – the subjects are placed on a prescribed regimen for a specified period to assess fidelity in the proxy regimen. This is a short-term adherence pre-randomisation that may predict long-term adherence after enrolment, and can eliminate 5 to 10 per cent of potential at-risk subjects14. • Test-dosing screening – the subjects are given a small dose of active agents for a short period to identify subjects who have difficulty tolerating adverse effects and candidates for exclusion based on biological response to specific agents. This method is useful for drugs that are more difficult to consume, have a high frequency of adverse effects, or have profoundly adverse effects. Patient Communication Effective communication is linked to study outcomes including subjects’ participation, recall of information, and adherence. Communication contributes to their understanding of the trial participation, study protocol, and the collaborative partnership between them and the research team. After the selection process, the clinical researcher must preemptively explain to the chosen subjects the burdens associated with the study and the imperative compliance to regimens. It goes without saying that subjects must comprehend what they are supposed to do before they can follow medical directions. Studies show that the risk of non-adherence is high when patients cannot understand basic medical instructions. A 2500-patient study by Williams et al. found that 42 per cent misunderstood common directions for taking medications15. Maintaining frequent contact by phone, email and visits is central for early intervention. It is also worth exploring the subjects’ motivation, expectations, and views Journal for Clinical Studies 57


of the research. A sense of critical involvement emphasises patient empowerment and motivates interest in participating. Leverage Novel Technologies Healthcare is embracing the digital transformation and pharmaceutical companies are gradually adapting. Once patient selection is completed and the study has been thoroughly communicated to the patients, implementing a novel technology serves as a layer of visibility for the researchers during the clinical trial. The study design varies depending on the purpose of each. Research teams need to seriously consider leveraging novel technologies for medication adherence if these conditions apply: • Studies designed to establish safety, efficacy and tolerability at different dose levels, • Therapy classes with concerns of overdosing propensity or in which the study medicine is prone to diversion, • Protocols with multi-doses, irregular, complex and/or infrequent dosing schedules; studies that require titration; adaptive studies; studies of therapies with narrow PK profile, • Studies in high-toxicity therapy classes and narrow PK profiles, • Phase II/IIIB studies where medicine ingestion is unsupervised. Faster clinical approval cannot be achieved without addressing the central problem of medication non-adherence. Addressing this issue will render substantial efficacy study data, increasing approval success rate. Integrating novel technologies, along with enriching patient selection and support strategies, is the best comprehensive approach to combat medication non-adherence. REFERENCES 1.

Tartaglia, L.A. Complementary new approaches enable repositioning of failed drug candidates. Expert Opin Investig Drugs 2006; 15:1295-8. 2. Osterberg, L., M.D. & Blaschke, T., M.D. Adherence to Medication. N Engl 58 Journal for Clinical Studies

J Med 2005; 353:487-497. 3. Smith, D. Patient Non-adherence in Clinical Trials: Could There Be a Link to Post Marketing Patient Safety? Drug Information Journal, 46 (I) 27-34, 2012. 4. Lee, J.K., Grace, K.A., Foster, T.G. et al. How should we measure medication adherence in clinical trials and practice? Ther Clin Risk Manag. 2007;3(4)685-90. 5. Adler, L.A., Lynch, L.R. et al. Medication adherence and symptom reduction in adults treated with mixed amphetamine salts in a randomized crossover study. Postgraduate Medicine Sep 2011 123(5):71-9. 6. Express Scripts Drug Trend Report: A Market and Behavioral Analysis April 2011. Available at research/dtr/archive/2010/dtrFinal.pdf 7. Gossec, L. et al. Reporting of adherence to medication in recent randomized controlled trials of 6 chronic diseases: A systematic review. Am J Med Sci 2007;334(4):248-254. 8. Swift, R. et al. Adherence monitoring in naltrexone pharmacotherapy trials: A systematic review. J Stud Alcohol Drugs 2011;72(6): 1012-8. 9. Agot, K., Taylor, D., Corneli, A., Wang, A., Ambia, J., Kashuba, A., Parker, C., Lemons, A., Malahleha, M., Lombaard, J. & Van Damme, L. Accuracy of Self-Report and Pill-Count Measures of Adherence in the FEM-PrEP Clinical Trial: Implications for Future HIV-Prevention Trials. AIDS Behav (2015) 19:743–751 DOI 10.1007/s10461-014-0859-z 10. Watson-Jones, D., Baisley, K., Rusizoka, M. et al. Measurement and predictors of adherence in a trial of HSV suppressive therapy in Tanzania. Contemp Clin Trials. 2009;30(6):504–12. 11. Amico, K.R., McMahan, V., Anderson, P.L. et al. Adherence indicators and PrEP drug levels in the iPrEx study. 18th Conference on Retroviruses and Opportunistic Infections. Boston; 2011 [abstract 95LB]. 12. Claxton, A.J., Cramer, J. & Pierce, C. A systematic review of the associations between dose regimens and medication compliance. Clinical Therapeutics. 2001;23(8):1296-1310. 13. Food and Drug Administration. Guidance for Industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. 2012. 14. Probstfield, J.L. Adherence and its management in clinical trials: Implications for arthritis treatment trials. Arthritis Care Res 1989;2(3):S48-57 15. Williams, M.V., Parker, R.M., Baker, D.W. et al. Inadequate functional health literacy among patients at two public hospitals. JAMA. 1995;274:1677–82.

Moses Zonana Moses Zonana attended Rutgers University and obtained his B.A. in Mathematics. In 2005, he earned his MBA from Harvard Business School with academic honours. With more than 15 years of executive-level experience, Zonana used his diverse expertise in healthcare, telecommunications and technology to develop the health solutions provider, Compliance Meds Technologies (CMT).


Danahlyn Tamola Danahlyn Tamola is a Florida International University alumna with a B.A. in Psychology. After several years of management experience in demanding industries, Tamola pursued her Master’s Degree in Business Administration with a concentration in Marketing, where she obtained the highest honour of Summa Cum Laude.


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Clinical Supplies

Customised Supply Solutions for Investigator-initiated Trials There is a strong, clear trend showing an increase in the number of investigator-initiated trials running across the whole pharmaceutical sector and across a wide range of therapy areas. With this growth comes an increasing global demand for IIT supplies and logistics support. This support does not always fit neatly into either commercial supply structures or sponsored clinical study supply processes. This article explores the potential benefits of utilising an outsourced or customised service designed to meet the unique drug supply needs associated with IIT programmes. Introduction Investigator-initiated trials (IITs) are an integral and increasingly important part of the clinical research landscape. Despite the many advantages for pharmaceutical and bio-tech companies in supporting such studies, it can be challenging to provide the level of service and support needed. This is particularly the case for some newer, specialist medicines which generate significant levels of interest from academics and clinicians alike, leading to a high demand and volume of potential IITs. To capture the full value of IITs while strengthening relationships with the investigator community, companies must have a flexible solution in place to address the time and resource demands required to meet the unique needs of these diverse trials and variable study populations. It is important that potentially valuable, supportive and/or revealing studies are not ‘lost to follow up’ due to practical or logistics hurdles. Most companies have a well-established and clear upstream process for reviewing and approving support for IITs. It is equally important to ensure smooth downstream systems are in place to get the studies off the ground and avoid wasted time and resource. We will focus on the latter issue in this article.

The Rise and Rise of Investigator-initiated Trials Investigator-initiated trials or studies (IIT, IIS), alternatively described as investigator-sponsored studies/trials (ISS, IST), are an important part of the research ecosystem through which independent researchers explore new uses for established or investigational medicines, novel combinations and effects in new patient populations. Such studies are on the increase and managing demand and diverse principal investigator (PI) expectations can be challenging. Pharma companies need to be careful to strike the right balance of support with supplies, advice and resources for IIT research when, by definition, they are not themselves the ‘sponsors’. Too much hands-on support could be seen to shift the IIT towards a fully pharma-sponsored study. Too little and PIs can become disheartened, or worse, take research in a direction which could be dangerous or damaging to the product and originating company reputation. Estimates for the number and growth rate of IITs running around the world vary depending on data sources. Numbers reported on, for example, are approximately flat year on year (though there are complications with search descriptors and like for like comparisons). Centrewatch reports an upward trend for IIT INDs1. A recent paper comparing global patterns of industry versus non-industry studies reports a steady growth in all studies but the proportion of non-industry has increased from 67% to 72% across the period under investigation2. Anecdotal evidence from biopharma companies is consistently reporting year-on-year growth in demand and a commensurate increase in IITs which are undertaken. Conservative estimates would suggest that there are over 10,000 ongoing IITs being supported by the top 20 pharma companies alone (minimum of 500 per company). The majority of these will not appear on registries and this could be one explanation for the contrasting data on growth and volume of IITs from different sources.

Driving factor

Why now?

Scientific and medical research in general is expanding.

Knowledge base in life sciences growing exponentially. Personalised medicine and genetic revolution.

Desire of the medical community to explore new treatments and conduct independent research.

Need to combine medical practice with formal research and publish findings. Institutional support for research ‘ranking points’.

Growth of treatment options and range of combinations.

Combination treatments (and novel schedules) much more prevalent. Rise of companion diagnostics and personalisation. Newer compounds have wider potential across more therapy areas.

Growth of comparative effectiveness research and the need for real-world evidence.

Placebo-controlled studies less acceptable. Research institutions and hospitals keen to engage with originating companies.

Insight that new drugs in development could have multiple indications.

Improved characterisation of patient populations and sub-population. Rise in use of biologics.

Willingness of industry to support IITs, share knowledge and supply drug.

Need to generate real-world evidence. New indications can support lifecycle plan. Any data which adds to the evidence base is valuable.

Table 1 Drivers of Growth of IITs 60 Journal for Clinical Studies

Volume 9 Issue 6

Clinical Supplies Overall, however, there is a clear consensus that IITs are increasing in number and importance and this increase in demand is creating pressure on resources across a range of departments in pharma companies – notably clinical development, medical affairs and regulatory. There are a number of factors driving this growth in IITs and some of these, along with the reasons behind them, are listed in table 1. Pharmaceutical company policies and procedures relating to IIT requests and support vary from company to company, but a more positive and receptive approach has emerged in recent years. A number of companies have specific portals and clear criteria to encourage and simplify the IIT support request and approval process (e.g. BMS, Sanofi). Others, notably small and growing companies, see IITs as an integral part of their relationship and transaction with the medical community and also as a way to widen their development scope and simultaneously explore multiple indications (e.g. Puma). Managing IITs – the Practicalities The first step in the effective and efficient management of IITs is the selection of which ones to support. Companies are subject to many and varied requests for IIT support, usually more than can be practically accepted or progressed. In order to manage this disconnect, pharma companies have set up and publicised clear guidelines, selection criteria and transparent processes (see links above). Whilst the increase in interest and desire to run more IITs is to be welcomed from a scientific and clinical viewpoint, it can lead to resourcing challenges and headaches for the teams tasked with making decisions and then initiating the support. Therefore, clear criteria, such as those noted in Figure 1, are helpful for all parties.

Such an outsourced service brings with it many benefits (see Table 2) – not least reassurance that IITs supplies will be handled with the same efficiency and security as industry-sponsored studies, without detracting from a focus on core business. Furthermore, a centralised outsourced approach saves time and money within the originating company (through operational and opportunity-cost savings), plus it brings economies of scale since the specialist agency can speedily and cost-effectively supply multiple sites, in multiple countries (even for unique protocols). Finally, by selecting an agency with global reach and infrastructure IIT supplies for all studies within a therapy area or all studies for a single compound can be confidently handed over, bringing with it yet more efficiencies and speed of response advantages. Benefits to bio-pharma companies

Benefits to investigators

• Saves time, money and resources.

• Dedicated attention to needs.

• Option to pool supplies and control batch consistency. • Improves service to investigators and therefore supports key customer relations. • Speeds IIT setup, execution and completion. • Ensures safe, compliant and secure supply of your product, in line with all current and emerging regulatory guidelines. • Enables responsive, just-intime, direct-to-site delivery.

• Ability to source material from all over the world. • Distribution capabilities to deliver material rapidly to sites. • Peace of mind for your study and your patients. • Guidance and advice on timelines and supply strategy. • Reassurance on medicine quality and supply chain integrity. • Accessible and responsive support on supply issues.

Table 2 Advantages of outsourcing IIT supply

IIT Supply Chain Critical Success Factors As specialist supply companies have risen to the challenge of IIT supply chain management, a number of critical success factors (CSF) have emerged. Being aware of these can help companies carefully select their outsourcing partner. In order to accrue all the benefits of outsourcing, a partner should be able to demonstrate an ability to fulfil all of these CSFs: • • • • • •

Figure 1 Factors to take into consideration when selecting which IIT request to support

The levels of support provided by the originating company of the products undergoing IITs vary, but one thing they all have in common is the provision (usually free of charge) of the investigational medicine. Due to the variability, in terms of doses needed and patient numbers, of these unique studies, coupled with their highly localised nature, supply chain needs rarely fit in the normal distribution model. This is where specialist supply companies can have a role to play. Clinical research supply specialists (such as Clinigen CTS) have designed IIT-specific services to fulfil this need.

• • • • •

Multisite warehousing and cold chain distribution. Multi-country demand management. GMP labelling and QP release capabilities. Just-in-time labelling. Global distribution synchronised with study needs and actual patient recruitment. A dedicated, experienced project manager, overseeing labelling, QP release and shipping. Identification and implementation of the ideal supply strategy. Added value to the PI communication channel. Supply of NIMPs and ancillaries. Responsive customer services support. Size and sophistication to scale up as IIT demand increases.

Conclusions IIT studies are a thriving and increasingly important part of drug development and medical advancement. As pharmaceutical companies adapt and respond to the increasing demand for IIT support, one major downstream component of the regulatory and logistics issues emerging can now be successfully and confidently outsourced – namely IIT supply chain. Expert clinical sourcing companies are developing customised solutions Journal for Clinical Studies 61

Clinical Supplies

to efficiently and effectively manage IIT supplies, giving the PI and the sponsor time to focus on other aspects of the study. Furthermore, by outsourcing to an expert, all parties have the reassurance that regulatory integrity and supply chain quality will be maintained to a level seen in sponsored and mainstream clinical research. REFERENCES 1.

2. Atal et al, Differential Globalization of Industry- and Non-IndustrySponsored Clinical Trials, PLoS One. 2015 Dec 14;10(12).

John Denier Global Head of Business Development – Clinigen - Clinical Trial Services John joined Clinigen in November 2016 and is now responsible for Global Business Development for the Clinical Trial Services team.  John’s primary responsibility is gathering client feedback to assure Clinigen is exceeding client expectations and providing offerings that provide value and support expediting Clinical trials. Prior to joining Clinigen, John spent over 20 years in the pre-clinical arena working on early stages of drug discovery. Mr. Denier holds a degree in Veterinary Science and Leadership and Communication. Email:

62 Journal for Clinical Studies

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