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Volume 10 Issue 2


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


Clinical Trials Downunder

Australia and New Zealand – A Competitive Region

Immune Mediated Inflammatory Diseases And Unmet Medical Need

Clinical Development in Challenging Cancers Ovarian Clear Cell Carcinoma

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Part 2: Considerations for Planning and Conducting Clinical Trials

Dr. Lisa Chamberlain James, Senior Partner Master Skills — Laser focus, unwavering tenacity, infectious charm

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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 Orla Brennan 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 FDA Efficacy Recommendations Vary for Hypogonadotropic Hypogonadism Drugs

This article, written by Meg Egan Auderset at Clarivate Analytics, describes how the new draft industry guidance from the US Food and Drug Administration (FDA) underscores the importance of randomised, double-blind, placebo-controlled trials to establish the efficacy of drugs to treat male hypogonadotropic hypogonadism when it is caused by obesity or another acquired condition. The draft guidance also asserts the potential importance of patient-reported outcome (PRO) instruments to such efficacy determinations, since they offer “direct evidence of how patients feel or function.” 10 Ensuring Launch Success in Rare Disease Areas by Creating a Value Story A number of trends (both in science and on the regulatory front) bode well for the development and availability of drugs to treat rare diseases. The authors Cinzia Dorigo and Mariah Baltezegar at Syneos Health say that they believe that a company’s ability to appreciate the thoughts, values, and preferences of patients and caregivers will be a primary differentiator for launch success for products to treat rare diseases. 12 Clinical Trials in Russia – Report on Q3 of 2017 The Russian MoH approved 158 new clinical trials of all types including local and bioequivalence studies during Q3 2017, demonstrating a 34% decrease in comparison with the same period last year. Igor Stefanov at Synergy Research Group compares how clinical trials in Russia have changed between 2016 and 2017. 14 Combined Studies Under the New EU Clinical Trial Regulation The key aim of the new EU Clinical Trial Regulation, which is currently planned for implementation in mid-2019, is to boost clinical research in the European Union (EU). Bruno Speder at SGS Clinical Research discusses that the major impact will be a new authorisation process which will involve a single submission via the EMA portal, with a two-step approval procedure. REGULATORY 16 Paediatric Melanoma and the Pharmaceutical Industry

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.

The age of paediatric melanoma used to be a theoretical discussion, but has become a real-life challenge due to arbitrary age limits decreed by regulatory authorities. Metastasised melanoma is today treated effectively with drug combinations. And young patients? Thirteen European Medicines Agency (EMA) paediatric investigation plans (PIPs) and one Food and Drug Administration (FDA) "Written Request" demand monotherapy studies in paediatric melanoma. Klaus Rose at Klausrose Consulting discusses the conundrum of paediatric trials and the ways forward.

Volume 10 Issue 2 March 2018 PHARMA PUBLICATIONS

20 A Review of FDA’s Updated Guidance for Developing Drugs to Treat Early Alzheimer’s Disease There has been a renewed interest in clinical trials of drugs to treat early Alzheimer’s disease, owing partially to recent advances in the

Journal for Clinical Studies 1

Contents understanding of pathophysiological processes that occur well before the emergence of clinical symptoms. Henry J. Riordan and Natalia E. Drosopoulou at Worldwide Clinical Trials reveal to the readers how the Food and Drug Administration (FDA) has responded to this shift and recently issued draft guidance to assist sponsor companies in the development of drugs for the treatment of the stages of sporadic Alzheimer’s disease. MARKET REPORT 24 Clinical Trials Down Under Australia and New Zealand – A Competitive Region The Australian clinical trials landscape has developed considerably over recent years with over 1000 new clinical trials commencing each year in the pharmaceutical, biotechnology and medical device space. An estimated 6900 skilled professionals are involved in the conduct of Australian trials. Growth in the sector has been remarkable, especially in the medical devices trials area. Suzanne Williams at Mobius Medical Pty Ltd concludes that Australia plays a substantial part in global, multi-centre studies, which comprise approximately one-third of all trials undertaken. 28 Russian Clinical Trials Market in 2017 Following on from the last article featured by Svetlana Zavidova from the Association of Clinical Trials Organizations (ACTO) in the July 2017 JCS on clinical trials in Russia. This article continues the topic of the previous article whereby Svetlana presents the market report of Russia for the 2017 and reveals that during the year, the number of local registration clinical trials has radically decreased. 32 Developing Talent for the Future of Clinical Research Clinical research is a rapidly evolving and dynamic environment and the sector is undergoing significant changes on a number of fronts. The wider use of technology, rapid advances in the diagnosis and treatment of diseases such as cancer, and other emerging health technologies such as data analytics, and the use of artificial intelligence in diagnostics are having a significant impact on the way that clinical trials are conducted. Martin Robinson at IAOCR discusses how pharma companies are attempting to capitalise fully on the data they collect from each study by having an increasing number of trial objectives and consequently, clinical studies are becoming more complex than ever before. 36 How to Rescue a Clinical Trial, If You Must Conducting a clinical trial is a huge and complex undertaking, and there are, more often than not, challenges. And in an undertaking as scientifically and logistically complex as a pharmaceutical trial, there’s a lot that can go wrong. In fact, almost 50% of Phase III trials fail. They fail because the drug did not work or because the design of the trial was fatally flawed. But they can fail for other reasons, too, such as poor execution. Karen Chu and Dr Sy Pretorius at PAREXEL claim that fortunately, troubled trials can often be rescued. THERAPEUTICS 40 Clinical Development in Challenging Cancers: Ovarian Clear Cell Carcinoma (OCCC) Ovarian clear cell carcinoma (OCCC) is a rare histological subtype of epithelial ovarian cancers (EOCs), with an incidence, among 2 Journal for Clinical Studies

Volume 10 Issue 2


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Contents EOCs, of 4–12% in western countries and a higher ratio of over 20% in Japan. Histologically, EOCs are classified into serous, mucinous, endometroid, clear cell and undifferentiated subtypes. David Winkler at Europital discusses the fact that ovarian cancer is already the leading cause of death among gynaecological malignancies in the US; in addition, the OCCC subtype presents a lower response rate to traditional platinum-based chemotherapy and is generally associated with poorer prognosis across all stages compared to other EOC subtypes. 46 Immune Mediated Inflammatory Diseases (IMIDs) and Unmet Medical Need Our immune system is extremely complex and is of great value for our health. HIV and its destruction of the immune system is clear evidence. Many researchers have long lived with the virtue of understanding the autoimmune disease specifically on a molecular level. The IMID acronym might not be as popular as the names of the conditions it represents, such as rheumatoid arthritis, psoriasis, and Crohn’s disease. Dr Jim Khalifa and Aleksandra Bibic of Worldwide Clinical Trials consider most of these conditions are debilitating and sometimes life-threatening. TECHNOLOGY 50 Why the Need for Centralised Content Management is on the Rise Despite the advances in electronic content management over the past decade, many of the biggest global life sciences companies still manage their local translations in a highly fragmented way. Not only does it lead to a rise in costs, but it also comes with risks to safety and slows down product speed-to-market. However, there is a smarter approach to take, as outlined by Jason Arnsparger of AMPLEXOR. 52 How Integrated Technology Benefits Patients and Investigators in Diabetes Clinical Trials Doctors are warning of the ‘absolute pandemic’ of diabetes. In the US alone, 100 million are diagnosed with diabetes, with many millions more undiagnosed or unaware of their condition. It is not surprising that pharmaceutical companies are heavily investing in this area. Researchers are, therefore, adopting technology to elevate their clinical trials for better data, reduced burden on patients, and increased patient safety. In this article, Jill V. Platko at CRF Health explores how connected technology and electronic solutions can be integrated specifically into diabetes clinical trials to meet the needs of clinicians and patients. SPECIAL SECTION 54 Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Part 2: Considerations for Planning and Conducting Clinical Trials Nonalcoholic fatty liver disease (NAFLD) is a widespread cause of chronic liver disease (CLD) and liver-related morbidity and mortality, and is the most common cause of CLD in North America. This paper, the second in a two-part series by Dr Mark DeLegge of NASH Focus Group addressing nonalcoholic steatohepatitis, provides an overview of these important diseases.

4 Journal for Clinical Studies

Volume 10 Issue 2










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Foreword We are seeing a record number of newly diagnosed skin cancers worldwide, with the incidence of melanoma increasing at a faster rate than almost all other cancers. The medical community must enhance its efforts to increase its training of new healthcare personnel who are capable of diagnosing and treating this record number of patients with skin cancer. We must also try to increase the access to our limited number of dermatologists and provide novel ways of patient education such as through skin selfexaminations, total body photography, and improved education for our children. By providing easier access to skin examinations, we will increase our chances of detecting melanoma in its earliest and most curable form. According to the Surveillance Epidemiology and End Results data, melanoma is the sixth most common fatal malignancy in the United States, responsible for 4% of all cancer deaths and six of every seven skin cancer-related deaths Incidence rates vary throughout Europe as well, with the highest rates seen in Switzerland, Norway, Sweden, and Denmark compared with those countries in southern Europe. MacKie et al. hypothesise that this latitudinal gradient may be related to sun-exposure behaviours, and in particular to the tendency for Northern Europeans to vacation in sunny climates, resulting in intense, intermittent sun exposure. A Swedish study reported 46,337 melanomas diagnosed during the period from 1960 through 2004, clearly revealing an increase in the incidence of melanomas of the trunk and lower limb. Primary melanomas of the trunk and lower limb have been associated with intermittent, high-intensity sun exposure, as opposed to head and neck melanomas, which appear to be associated more with chronic, long-term sun exposure. In the Regulatory Section, Dr Klaus Rose of Klaus Rose Consulting in his article on paediatric melanoma and the pharmaceutical industry discusseses how the age of paediatric melanoma used to be a theoretical discussion, but has become a real-life challenge due to arbitrary age limits decreed by regulatory authorities. In the Therapeutics Section, continuing on the cancer discussion, Vijayanand Rajendran & David Winkler from Europital address the topic of clinical development in challenging cancers: 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

ovarian clear cell carcinoma (OCCC). They demonstrate that the clinical management of OCCC remains to be a significant challenge for clinicians till this day. This specific subtype of EOCs is not only primarily chemoresistant but is genetically heterogenous, and no effective therapy has yet been identified to overcome this obstacle. Our main destination in our Market Report Section is where Suzanne Williams of Mobius Medical Pty Ltd features the article on clinical trials down under. Is Australia and New Zealand still a competitive region to conduct your clinical trials? Technology is in the forefront of clinical trials. Jason Arnsparger of AMPLEXOR discusses why the need for centralised content management is on the rise. Despite the advances in electronic content management over the past decade, many of the biggest global life sciences companies still manage their local translations in a highly fragmented way. Not only does this lead to a rise in costs, but it also comes with risks to safety and slows down product speed-to-market, and Jill V. Platko of CRF Health explains how integrated technology benefits patients and investigators in diabetes clinical trials Welcome to the second issue of JCS in 2018. The DIA European Meeting is in the horizon. To everybody attending the event, I wish them a successful meet. I hope you all like the articles and features in this issue. My team and I are working hard to present more exciting articles in the next issue of JCS. Till then, enjoy your spring days, and see you in summer. 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 the country focus is Australia & New Zealand. Golden Wattles are the national flower of Australia, 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, Clarivate Analytics

• • 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 6 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 10 Issue 2

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FDA Efficacy Recommendations Vary for Hypogonadotropic Hypogonadism Drugs Improvement in signs and symptoms is important when seeking approval of testosterone products intended for hypogonadotropic hypogonadism that occurs without intrinsic hypothalamic and pituitary damage. New draft industry guidance from the US Food and Drug Administration (FDA) underscores the importance of randomised, double-blind, placebo-controlled trials to establish the efficacy of drugs to treat male hypogonadotropic hypogonadism when it is caused by obesity or another acquired condition. The draft guidance also asserts the potential importance of patient-reported outcome (PRO) instruments to such efficacy determinations, since they offer “direct evidence of how patients feel or function.” Male hypogonadism is marked by low concentrations of serum testosterone. There are two forms of hypogonadism, differentiated by serum concentrations of gonadotropins, the hormones that stimulate the gonads – in men, the testes. In hypergonadotropic hypogonadism, which is related to testicular function, concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are elevated. In hypogonadotropic hypogonadism, which is related to hypothalamic and pituitary function, FSH and LH concentrations are low or normal. The 2018 draft guidance pertains only to hypogonadotropic hypogonadism. Released in January 2018, the FDA’s Establishing Effectiveness for Drugs Intended to Treat Male Hypogonadotropic Hypogonadism Attributed to Nonstructural Disorders focuses particularly on efficacy endpoints and criteria for enrolling subjects in clinical trials. It distinguishes “classic” hypogonadotropic hypogonadism – which is caused by intrinsic damage to the hypothalamus or pituitary gland – from hypogonadotropic hypogonadism that occurs in the absence of such damage. As explained in the draft guidance, classic hypogonadotropic hypogonadism can occur following pituitary resection or can be caused by congenital conditions that affect sexual development (e.g., Kallmann syndrome). Males with classic hypogonadotropic hypogonadism “are clearly testosterone deficient,” the FDA states. Puberty may be delayed and development impaired. A boy’s voice might not deepen, for example, or his penis and testicles remain immature. For men, symptoms can include erectile dysfunction, infertility, and decreased muscle mass and body hair, according to the Mayo Clinic.1 As the guidance notes, some men develop hypogonadotropic hypogonadism after “normal” puberty and sexual development, and absent intrinsic hypothalamic or pituitary damage. (The many comorbidities associated with male obesity, for example, include reduced serum total testosterone with low or normal gonadotropins.) 8 Journal for Clinical Studies

Unlike patients with classic hypogonadotropic hypogonadism, these men often experience “non-specific” symptoms – such as low energy and depression – that “cannot definitively be attributed to the low testosterone concentrations”, the FDA states. For patients not interested in preserving fertility, testosterone replacement therapy (TRT) is a standard treatment for all forms of hypogonadotropic hypogonadism. Under the FDA’s draft guidelines, however, it is simpler to establish a testosterone drug’s efficacy when it is proposed for classic hypogonadotropic hypogonadism than when the condition was caused by a non-structural disorder. To demonstrate efficacy for the classic form, a sponsor must show only that a treatment “reliably” raises serum testosterone concentrations to the normal range for a healthy young man. In the absence of intrinsic hypothalamic and pituitary damage, it is “unclear” whether such reduced concentrations are “inappropriately low” and that raising testosterone concentrations leads to clinical benefit, according to the FDA. Because of these uncertainties, the agency does not accept serum testosterone as a valid surrogate endpoint for these patients, but advises sponsors to design clinical trials that link increased serum testosterone to improvements in how patients feel, function, or survive. The draft guidance presents FDA recommendations for clinical trials of drugs for hypogonadotropic hypogonadism caused by nonstructural disorders. Points related to efficacy endpoints include: •

Randomised, double-blind, placebo-controlled trials should demonstrate that the drug increases serum testosterone and provides “clinically meaningful improvement” in at least one sign or symptom.

PRO instruments can be central to efficacy determinations. The agency notes, however, that it is “not aware” of existing PRO instruments that are adequate for regulatory use to evaluate patient improvement in signs or symptoms of hypogonadism, but that it is willing to evaluate instruments for their suitability. When creating or choosing an instrument, the FDA advises sponsors to consider recommendations in the agency’s guidance document, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.2

If using biomarkers to establish evidence of clinical benefit, they must be established surrogate endpoints for how patients feel, function, or survive.

For drugs that improve spermatogenesis, efficacy could be established by demonstrating improved fertility outcomes; changes in semen parameters alone would be insufficient. For drugs that do not impact spermatogenesis or that have an Volume 10 Issue 2

Watch Pages adverse effect, efficacy could be established by demonstrating improvement in other signs or symptoms of hypogonadism. Recommendations related to patient enrolment include: •

Enroll subjects who have clinical and laboratory evidence of hypogonadotropic hypogonadism, including: • • • •

Low serum total testosterone concentrations in the morning on at least two days (separated by at least three days). Low free testosterone concentrations in the morning on at least two days (separated by at least three days). Serum FSH and LH not exceeding the upper limit of the reference range. Normal serum prolactin concentration and normal thyroid function tests.

The trial population should not have intrinsic damage to the hypothalamus, pituitary glands, or testes, but should be “well defined” in terms of the underlying associated condition, symptoms, and signs.

Recent FDA Review of Products for Hypogonadism FDA-approved TRT products are available in a variety of formulations, including topical gels and solutions, buccal systems for the gums, transdermal pellets, and injections. To date, the only approved testosterone therapy that is orally administered is methyltestosterone, a synthetic derivative of testosterone that is associated with serious hepatic adverse events and, for that reason, not widely used. In the first 10 days of 2018, the FDA asked its Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) to review new drug applications (NDAs) for two oral products proposed as TRT for male hypogonadism, including hypogonadotropic hypogonadism; neither received the committee’s overall support. On January 9, the BRUDAC considered Clarus Therapeutics’ NDA 206089 for Jatenzo (oral testosterone undecanoate capsules). Of the 19 advisory committee members who voted, only nine agreed that the proposed drug’s overall benefit/risk profile supported its approval as a TRT. The other 10 cited clinically significant cardiovascular events (e.g., elevated blood pressure, increased heart rate) associated with Jatenzo use as their reason for voting “no.” The BRUDAC did not contest Jatenzo’s efficacy, however. The sponsor’s submission included the results of study CLAR-15012, a three-month pivotal Phase III trial; to meet the primary efficacy endpoint, at least 75% of subjects had to achieve testosterone Cavg in the normal range (252-907 ng/dL) and the lower bound of the corresponding 95% confidence interval (CI) had to be at least 65%. Results showed 87.4% of subjects within the Cavg normal range, and the lower bound of the 95% CI was 81.3%. This was the second time the BRUDAC met to consider the Clarus application. In September 2014, a joint meeting of the BRUDAC and the Drug Safety and Risk Management Advisory Committee (DSaRM) discussed the same NDA (but with a different proposed trade name, Rextoro). The committees voted 17-4 against the drug’s overall benefit/risk profile, citing concerns that the easyto-use oral formulation could be widely misused. The BRUDAC and DSaRM also advised the FDA to seek more data from Clarus (e.g., dose titrations, dietary concerns) and recommended additional study to evaluate cardiovascular risk.

On January 10, the BRUDAC voted 13-6 against the overall benefit/risk profile of Lipocine Inc’s Tlando (oral testosterone undecanoate capsules). Again, the committee did not question the efficacy of the proposed product, but expressed concerns about its cardiovascular safety. Members called for additional safety data, particularly regarding a potential increased risk for adverse cardiovascular events, as well as Tlando’s effects on blood pressure, lipid parameters, and hematocrit. The outcomes of these latest BRUDAC meetings reflect ongoing FDA concerns about testosterone products and cardiovascular risk. Previous agency actions include: •

The FDA announced in January 2014 that it was investigating a potential risk for stroke, heart attack, and death in men taking FDA-approved testosterone products, citing the published results of two observational studies linking testosterone therapy with increased risk for cardiovascular events. In March 2015, the FDA announced its conclusion that testosterone use carries “a possible increased cardiovascular risk”, and instructed manufacturers of approved prescription products to update product labelling. In October 2016, class-wide labelling changes for all prescription testosterone products focused on the risks associated with testosterone (and other anabolic androgenic steroids) abuse and dependence, including heart attack and heart failure.

REFERENCES 1. 2. symptoms-causes/syc-20354881

Meg Egan Auderset, MS, MSW Meg Egan Auderset is a 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, her primary assignments include reporting on FDA advisory committee meetings and drug approvals for Cortellis and the AdComm Bulletin, as well as editing several publications. Email:

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Ensuring Launch Success in Rare Disease Areas by Creating a Value Story A number of trends (both in science and on the regulatory front) bode well for the development and availability of drugs to treat rare diseases. Currently, there are hundreds of requests under consideration by the US Food and Drug Administration (FDA) for orphan drug status.1 However, given continued pressure on payers to curb healthcare spending, launch success will still depend upon having a strong value story — one that resonates with all stakeholders. Drug companies are, of course, practised in developing evidence dossiers that address the needs of regulators, payers, and prescribers, but have less experience in incorporating insights from patients and caregivers in their development work. Taking this step for therapies treating rare diseases is every bit as important as in other therapeutic areas, but even more challenging because of the scarcity of patients. We believe that a company’s ability to appreciate the thoughts, values, and preferences of patients and caregivers will be a primary differentiator for launch success for products to treat rare diseases. Fortunately, patient awareness, understanding and involvement in clinical development are becoming more sophisticated, making it less challenging for drug developers to seek their perspectives. In fact, a project supported by the Innovative Medicines Initiative in the EU is designed to educate and train patients so that they can be more effective partners in clinical development. And, we’ve observed that many sponsors now hold regular meetings with patient advocacy groups to gather feedback for consideration in their development plans. In the current environment, it is essential that a patient-centric approach is taken early in development so that work starts with the end in mind. In fact, it is never too early in the development cycle to consider what will be required for commercial success. There’s a tool that is commonly used to ensure these activities are planned for at the start of a clinical trial — the Integrated Medical Plan (IMP). The IMP is a best practice for ensuring that the development strategy will be successful is to create an IMP that incorporates the Medical Affairs Evidence Plan as well as the Clinical Development Plan. The IMP should be in place from the start of first-in-human (FIH) trials and extend all the way through commercialisation to define what evidence needs to be collected. While the Clinical Development Plan outlines what regulators will need, the broader IMP addresses the needs of other stakeholders. The IMP should specify why, where, when, and how the drug will be used — in other words, it will lay out the value story. It should then identify the evidence needs for the key stakeholders and any existing evidence gaps that will drive operational plans to gather the necessary evidence. These are critical steps in being ready for successful commercialisation. There are many mechanisms for identifying the evidence needs of each stakeholder group, but at a basic level, it involves asking a set of key (but different) questions to each group that are then effectively answered in the value story. The IMP is an ideal place to store the pertinent information you gather for each of your key stakeholders. It is necessary to gather patient information like this across geographies as views may vary from region to region. For example, research should allow marketers to devise answers to the following questions from patients/caregivers: 10 Journal for Clinical Studies

• • • • • • •

Why do I need this medicine? What do I need to understand about how this medicine works? Is your drug more efficacious than the alternatives? What side-effects may I suffer and how will they be managed? How long do I need to take this medicine? What support will I be offered to manage my illness more effectively? Can I afford this medicine?

In the end, it will be necessary not only to answer these questions for patients and caregivers, but also to have the evidence to substantiate those answers. Patient and caregiver ability to digest data and to make informed decisions about their care is improving, a phenomenon that will be advantageous to those companies that cater to patient and caregiver information needs. Taking the time to map out evidence needs in this way significantly increases a company’s chances for a successful launch. Developing an IMP requires an interdisciplinary approach within sponsor companies and a collaborative approach with patient communities and advocacy groups. And, making best use of the insights gathered to speed development will require greater cooperation between all stakeholders. REFERENCES 1. Reports/BudgetReports/UCM488554.pdf

Cinzia Dorigo Cinzia Dorigo leads the Syneos Health Rare Disease Consortium, which focuses on an effective strategic implementation for the successful delivery of rare and ultra-rare disease studies. She has 18 years of experience in rare and ultra-rare clinical development, including extensive experience in early-phase, adaptive study design and paediatric rare disease studies. Email:

Mariah Baltezegar Mariah Baltezeger co-leads the Syneos Health Rare Disease Consortium. For nearly 20 years, she has functioned in various clinical research capacities. Her breadth of experience has given her a unique perspective on the needs of rare disease development, including integration of patient advocacy groups in the development process, managing advocacy groups, patient, site and sponsor relationships and developing focused strategies for programme and study success. Email:

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Clinical Trials in Russia – Report on Q3 of 2017

The Russian MoH approved 158 new clinical trials of all types including local and bioequivalence studies during Q3 2017, demonstrating a 34% decrease in comparison with the same period last year. The main contribution to the total number of studies was made by multinational multi-centre clinical trials (MMCT); the number of these studies decreased from 89 studies in Q3 2016 to 65 in Q3 2017, representing a 27% decrease from last year’s figure. The number of bioequivalence studies (BE) significantly decreased from 72 studies in Q3 2016 to 43 in Q3 2017, representing a 40% decrease from last year’s figure. The number of local clinical trials (LCT) decreased from 80 in Q3 2016 to 50 in Q3 2017, representing a 38% decrease from last year’s figure. The share of bioequivalence studies decreased from 30% to 27% of the total number of clinical trials approved in Q3 2017. The share of the local clinical trials was almost identical, 33% in Q3 2016, compared to 32% in Q3 2017, and the share of multinational multi-centre clinical trials was 41% of the total number of trials approved during Q3 2017 (37% in Q3 2016). The geographic origins of sponsors changed in comparison with last year. 56% of the total number of new studies in Q3 2017 were sponsored by foreign companies, which received 89 study approvals (61% in Q3 2016). The share of studies of local manufacturers increased from 39% in Q3 2016 to 44% in Q3 2017, and amounted to 69 studies. Clinical trials in Russia in Q3 2017 were sponsored by companies from 22 countries. The largest number of trials (69) were initiated by Russian sponsors. American sponsors with 30 new studies secured the runner-up place; they were followed by Indian and Swiss sponsors with 11 studies each, then by French sponsors with six new studies. The group of leaders is concluded by German sponsors (five studies), Sweden and Belgium (each having four studies), and Spain (three studies). Other sponsors included: Macedonia and Portugal (two studies each), and BosniaHerzegovina, Croatia, Denmark, Japan, Jordan, Republic of Korea, New Zealand, Slovenia, Turkey, Ukraine and the United Kingdom each started one new study in Q3 2017. All Clinical Trials by Phase The number of Phase I clinical trials decreased by 52% compared to Q3 2016: from 23 studies to 11 new studies in Q3 2017. The number of Phase II trials increased by 26% compared to Q3 2016 from 23 studies to 29 new studies. The number of Phase III trials decreased from 115 to 66 studies, 43% less than in Q3 2016. The number of Phase IV trials increased slightly in comparison with Q3 2016 from eight to nine studies in Q3 2017. If we look specifically at Russian clinical trials by phase, then the share of Phase III trials in Q3 2017 is 57% of the total number of studies, the share of Phase II trials is 25%, of Phase I trials is 10%, and the share of Phase IV studies accounted for 8%.

III studies and 1717 subjects are planned to be enrolled in Phase IV studies. The minimal number of subjects in a single study is seven; the maximum number is 448. The Top Five: Sponsors, Sites and CRO № 1 2 3 4 5

Company Name AbbVie Inc Eli Lilly and Company Novartis Merck & Co. AstraZeneca

No. studies (1) 7 5 5 4 4

№ 1 2 3 4 5

Company Name Biocad North Star Sotex Pharmasyntez Obnovlenie Pharmaceutical Company

No. patients 264 382 286 280 373

Table 1. Top 5 International Study Sponsors in Q3 2017

No. studies 6 6 4 4 3

No. patients 789 300 804 561 105

Table 2. Top 5 Russian Study Sponsors in Q3 2017 №

Site Name


1 2 3 4 5

Medical Center Probiotec

Serpukhov, Moscow region

Clinical Hospital N2, Yaroslavl


Ecosafety Ltd.


Bioeq Ltd.


6 6 5

Road Clinical Hospital at the station Yaroslavl of Russian Railways




Regional Clinical Cardiology Center, Ivanovo




Federal North-West Medical Research Centre named after V.A. Almazov




Russian Oncological Scientific Center named after N.N. Blokhin



No. studies 7

Table 3. Top 5 Russian Research Sites (BE and Phase I studies) in Q3 2017 №

Site Name



First Moscow State Medical University named after I.M. Sechenov



First St. Petersburg State Medical University named after I.P. Pavlov




Research Institute of Oncology named after N.N. Petrov




Russian Oncological Scientific Center named after N.N. Blokhin




Moscow State University of Medicine and Dentistry




Clinical emergency hospital named after N.V. Solovyov, Yaroslavl




Volgograd Regional Clinical Oncology Center



No. studies 13

Table 4. Top 5 Russian Research Sites (Phase II–IV studies) in Q3 2017

The number of subjects planned to be enrolled in Phase I–IV trials launched in Q3 2017 is 11,652, less than in Q3 2016, when 22,226 subjects were planned to be enrolled. 531 subjects are planned to be enrolled in Phase I trials; 1832 in Phase II trials; 7572 in Phase 12 Journal for Clinical Studies

Volume 10 Issue 2

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No. studies 13

Site Name


First Moscow State Medical University named after I.M. Sechenov



Russian Oncological Scientific Center named after N.N. Blokhin




Research Institute of Oncology named after N.N. Petrov



4 5

Bioeq Ltd. First St. Petersburg State Medical University named after I.P. Pavlov

Saint-Petersburg Saint-Petersburg




Table 5. Top 5 Russian Research Sites (all studies) in Q3 2017

№ 1 2 3 4 5

CRO Name OST RUS Quintiles PSI Synergy Research Group iPharma

No. studies 3 3 3 3 2

No. patients 378 293 275 164 440

Table 6. Top CROs in Russia in Q3 2017

Therapeutic Areas of Russian Clinical Trials in Q3 2017 The largest number of studies were initiated in therapy (22 new studies); and is followed by oncology (21 new studies), infectious diseases (17 new studies), rheumatology (12 new studies), haematology (12 new studies), neurology (eight studies), paediatrics (seven studies), traumatology and orthopedics, surgery and endocrinology (six studies each). Clinical Trials Results The U.S. Center for Drug Evaluation and Research (CDER) of the FDA approved 41 new drugs during Q3 2017; nine of them are new molecular entities (NME); other approvals concern new dosages, combinations or manufacturers. Nine of 41 drugs were (or are being) studied in clinical trials involving Russian sites. Table 7 shows the drugs which were approved by the FDA in Q3 2017 that were (or are being) studied in clinical trials in Russia.

Drug (active ingredient)



Tremfya (guselkumab)

Janssen Biotech


Benlysta (belimumab)

GlaxoSmithKline LLC


Mavyret (glecaprevir/pibrentasvir)

Abbvie Inc


Lynparza (olaparib)

Astrazeneca Pharms


Tracleer (bosentan)

Actelion Pharmaceuticals Ltd


Aliqopa (copanlisib)

Bayer Healthcare Pharms


Trelegy Ellipta (fluticasone furoate/ umeclidinium/vilanterol)



Verzenio (abemaciclib)

Eli Lilly and Co


Fiasp (insulin aspart)

Novo Nordisk Inc

Drug (active ingredient)



Bavencio (avelumab)

Merck Serono Europe Ltd


Dupixent (dupilumab)

Sanofi-Aventis groupe


Symtuza (darunavir/cobicistat/ emtricitabine/tenofovir alafenamide)

Janssen-Cilag International N.V.

07/20/2017 07/20/2017

Tecentriq (atezolizumab) Lacosamide Accord (lacosamide)

Roche Registration Ltd Accord Healthcare Ltd

07/20/2017 07/20/2017 07/20/2017 07/20/2017 07/20/2017 07/20/2017 07/20/2017 07/20/2017

Bydureon (exenatide) Gazyvaro (obinutuzumab) Humira (adalimumab) Keytruda (pembrolizumab) RoActemra (tocilizumab) Signifor (pasireotide) Sovaldi (sofosbuvir)

AstraZeneca AB Roche Registration Ltd AbbVie Ltd

Vimpat (lacosamide)

Merck Sharp & Dohme Ltd Roche Registration Ltd Novartis Europharm Ltd Gilead Sciences International Ltd UCB Pharma S.A.


Elebrato Ellipta (fluticasone furoate/ umeclidinium/vilanterol)

GlaxoSmithKline Trading Services

09/14/2017 09/14/2017

Tremfya (guselkumab)

Janssen-Cilag International N.V.

Trelegy Ellipta (fluticasone furoate/ umeclidinium/vilanterol)

GlaxoSmithKline Trading Services


Cyltezo (adalimumab)

Boehringer Ingelheim International GmbH


Benlysta (belimumab)

Glaxo Group Ltd


Tasigna (nilotinib)

Novartis Europharm Ltd


Firazyr (icatibant)

Shire Orphan Therapies GmbH

Table 8. New Drugs Approved by EMA in Q3 2017 and Tested in Russian Sites


Excluding BE studies.


Positive opinions on new generic, hybrid and biosimilar medicines are not included.

Table 7. New Drugs Approved by FDA in Q3 2017 and Tested in Russian Sites

During Q3 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMA) gave positive recommendations on 28 new drug applications (2), six positive recommendations on new generic medicines and two for new biosimilar medicines. A negative opinion was adopted for six drugs. 20 of the drugs which received positive opinions were (or are being) studied in clinical trials in Russia. Table 8 represents those drugs which were, or are being, studied in clinical trials in Russia in Q3 2017.

Igor Stefanov Igor Stefanov graduated from the Moscow Aviation Institute in 1989. After the collapse of the Soviet Union, he received an MBA degree in Economics at the Moscow International University in 1993 and went into the business consulting area, developing and implementing localisation strategies for the Fortune 500 companies in Russia, comprising Big Pharma representatives including Pfizer, J&J, GlaxoSmithKline, Roche and others. Prior to joining Synergy Research Group in January 2007 as CEO, Igor served as General Manager for SmartLock, the Russian hi-tech biometric company, and was recognised as an entrepreneur of the month by the Russian edition of Forbes magazine in 2005. Email:

Journal for Clinical Studies 13

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Combined Studies Under the New EU Clinical Trial Regulation The key aims of the new EU Clinical Trial Regulation 536/2014, which is currently planned for implementation in mid-2019, are to boost clinical research in the European Union (EU). Its major impact will be a new authorisation process which will involve a single submission via the EMA portal, with a twostep approval procedure: the first step assessing the scientific portion; and the second assessing the local requirements of the application file. The Regulation has mainly been developed to improve the competitiveness of the EU in late-phase clinical research, however early-phase clinical research (Phase I/IIa) has several specificities which are not covered by the new Regulation 536/2014, potentially introducing additional challenges. Combined Studies There is a growing tendency to obtain a first indication of efficacy early on in a drug’s development. This has led to so-called ‘combined’ studies, where the single ascending dose (SAD) and multiple ascending dose (MAD) part in healthy volunteers (HV) is supplemented by a patient cohort, in which a limited number of patients are included to make a first assessment of the efficacy of the drug. These data are used to make early go/no-go decisions and to support the design of Phase II trials. In the EU, the HV part of such studies is often conducted in countries with competitive Phase I timelines and a well-developed clinical research infrastructure, such as Belgium or the UK. One of the complexities of these studies is that they may require treatment-naive patients. Depending on the indication, these can be difficult to find in Western Europe, but more easily in Eastern Europe countries. The problem is that clinical trial authorisation (CTA) approval timelines in Eastern European member states are much longer than those where the HV part of the study will be conducted, ranging from 60 to 90 days, depending on the country.

after submission, which is much longer than the 15 days’ approval for the HV part that is available under current national law under Directive 2001/20. The upshot is that this will reduce the EU’s competitiveness to perform these trials. The risk is that sponsors will conduct the HV part as a single-centre study in the EU (taking advantage of the short timelines some MS would still offer for such studies), but will conduct the patient part outside the EU, or decide to perform the full study outside the EU. However, the Regulation does leave room for manoeuvre. It is indeed possible to submit a combined proof of concept (PoC) protocol as a single-country study in the country where the HV part will be conducted. As the trial is approved, a sponsor can start the study, and then add the ‘patient part’ countries as additional countries. Adding these will take between 52 and 83 days under the new Regulation, depending on the length of validation and the questions. This will allow sponsors to maintain the current advantage of being able to start such a study quickly. However, this can entail some risk, as although it is allowed under the Regulation, it is not within the “spirit” of it. An applicant choosing this approach could run the risk that the member state being added as an additional country might not be agreeable to the trial, as they would have to accept the conclusion of the assessment of part I, despite the fact that they would be responsible for the full patient part. When choosing this strategy, it would be advisable to discuss this upfront with the concerned member state. Figure 1 shows a combined FIH/PoC study conducted in three countries, Belgium (HV), Romania and Poland (patients). Three scenarios are presented: the first gives the approval timelines and

Under the current Directive 2001/20/EC, this is not an issue as each country individually approves the study, so it is possible to start the HV part quickly in a country with short Phase I timelines, and by the time the countries where the patient part will be undertaken have approved the trial, the HV part has been finished, and the trial can proceed to the patient part. This makes the EU a competitive region to perform such studies, combining quick study start with good patient recruitment. Under Regulation 536/2014, this will no longer be possible, as the full trial will be approved at the same time for all the countries. It will, therefore, be impossible to take advantage of countries with short approval timelines to start the study, while the study is still under review in the countries where the patients will be included, but which have longer CTA approval timelines. Under the new Regulation, the approval will be available between 60 and 106 days 14 Journal for Clinical Studies

Figure 1: Approval timelines for combined protocol with patient proof of concept part Volume 10 Issue 2

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the date of the start of the study (as first-patient-first-visit) under the current Directive; the second scenario does the same but under the new Regulation, when all countries are included in the initial application; and the third scenario gives the approval timelines and study start when Belgium is included in the initial application, and Poland and Romania are the additional countries. Conclusion While the new Regulation 532/2014 will be beneficial for larger latephase trials, it might have a negative impact on the performance of combined studies, where it could delay the start-up timelines. However, from a regulatory viewpoint, the choice of country in which to conduct Phase I studies is not only dependent on timelines but also on a good infrastructure for scientific advice.

Bruno Speder Bruno Speder is Head of Clinical Regulatory affairs at SGS Clinical Research, a leading CRO focused on infectious diseases, oncology and respiratory diseases. He is a pharmaceutical engineer and has almost 10 years of experience in drug development. He is a member of the advisory board of several biotech companies, and guest lecturer on the subject of clinical research in the honours programme of Ghent University.

Journal for Clinical Studies 15


Paediatric Melanoma and the Pharmaceutical Industry The age of paediatric melanoma patients used to be a theoretical discussion, but it has become a real-life challenge due to arbitrary age limits decreed by regulatory authorities. Metastasised melanoma is today treated effectively with drug combinations. And young patients? Thirteen European Medicines Agency (EMA) paediatric investigation plans (PIPs) and one Food and Drug Administration (FDA) "Written Request" demand monotherapy studies in paediatric melanoma. Two such studies were terminated in 2016 because adolescents could no longer be recruited into monotherapy inferior to established adult combination therapy. Four monotherapy studies in minors with solid tumours, including melanoma, continue recruitment. Not in Tuskegee, Alabama, nor the infamous Willowbrook state school, but worldwide in clean, well-organised hospitals committed to the highest standards of medical ethics. How long will this gruelling theatre continue? Paediatric melanoma is intriguing. Several strains of societal, medical and legal thinking entwine this term. "Paediatric" means in children, but what are children? In the stone age, young men's capacity to kill in combat, young women's capacity to get pregnant, and young Amazons' strength and pinpoint accuracy played a role; passage from childhood to adulthood required a ceremony, still perpetuated now in religious ceremonies, but replaced in secular societies by the date of birth. Melanoma means black, but not all melanomas are black. Genomic differentiation of conventional adulttype melanoma from spitz nevus, spitzoid melanoma, and melanoma from giant congenital nevi is possible1. The regulatory quest for more paediatric studies entered the arena of international drug development in 1997 with the first US paediatric law which offered rewards for industry-sponsored paediatric studies by "paediatric exclusivity"; six monthsâ&#x20AC;&#x2122; added protection against generic competition2. Since 2007, the EMA has approved drugs in adults only with an EMA-approved PIP2, unless the targeted disease is PIP-exempted3,4. The theory behind these laws is the concept of children as "therapeutic orphans", which from 1968 on claimed that paediatric warnings in US drug labels denied children the use of many drugs5. The American Academy of Pediatrics (AAP) took this thought up, referring to unexpected toxicities of antibiotics in the 1950s6,7 and demanded separate pharmacological testing of drugs in children of all ages8. The AAP thoughts made it into politics, laws, and regulatory demands2,9, justified by concern for child health. The FDA defines children as 0â&#x20AC;&#x201C;169, the EMA as <18 years2. The flaw in the "therapeutic orphans" concept and paediatric laws is that newborns' and babies' absorption, distribution, metabolism, excretion (ADME) are very different. Babies mature. Roughly after the first year of life, children need dose-finding, not separate proof of efficacy. Antibiotics, monoclonal antibodies and cytotoxics work the same before and 16 Journal for Clinical Studies

after a birthday. The "therapeutic orphans" concept blurs legal age and physiological maturity3. Most patients with "paediatric melanoma" are teenagers with the bad luck of a cancer that occurs more often in older persons11. The median age of "paediatric melanoma" patients in a 29-year German registry was 16 years; differentiation between spitzoid versus non-spitzoid melanomas was available only in a small subgroup12. Advanced diagnostics and resulting treatment options1 were/are not available in this otherwise rich country. FDA/EMA activities in paediatric melanoma claim clinical concern for underage melanoma patients, but demand paediatric studies drug by drug. Rare diseases are excluded from FDA mandatory requirements, so in melanoma the FDA could only use the voluntary pathway2,13. Actually, it was a bit more complex. In 2008, a first "paediatric" ipilimumab dose-escalation study was initiated by the US National Institute of Cancer (NCI) in patients aged 1â&#x20AC;&#x201C;21 years: children, adolescents, young adults14. In 2011, ipilimumab was FDAapproved for melanoma15. Also in 2011, the EMA issued an ipilimumab melanoma PIP16. In 2014, the FDA issued an ipilimumab written request (WR), requesting four paediatric studies13. The first FDA WR study corresponds to the NCI study initiated in 2008 and to the first PIP-demanded study: the developer negotiated with both authorities and provided the NCI with ipilimumab in 2008 when it was still experimental14. The study was finalised in 2016 and published17. But since 2011, since ipilimumab was FDA-approved, this study had ceased to be experimental or Phase I, and it never was paediatric. From 2011 on, children, adolescents, young adults were recruited into a dose-escalation study with an approved drug; adolescents and young adults were exposed to initial subtherapeutic doses14. The second ipilimumab WR/PIP study recruited 14 patients18, and was terminated in 2016 because meanwhile the combination of ipilimumab + nivolumab had been FDA-approved. Since 2015, the centres could no longer recruit patients into this inferior monotherapy19. The study was reported in 2017, without mentioning that or why it had been terminated20. The EMA has issued 13 melanoma PIPs: twelve for systemic treatment, one (talimogene) for local injection into tumour tissue (Table 1). Four international industry-sponsored monotherapy studies continue recruitment wordwide in solid tumours, including melanoma (4, Table 2), triggered by PIPs the developers had to commit to. Otherwise, the EMA would have blocked adult approval. Thus, the EMA has so far blackmailed six companies to initiate and sponsor international studies that deter young melanoma patients from combination treatment [ipilimumab + nivolumab, dabrafenib + trametinib, or vemurafenib + cobimetinib21]. These medically senseless studies harm at least the melanoma patients. There is no clinical benevolence in this murderous obsession with paediatric studies, but massive conflicts of interest behind authorities' and paediatric researchers' humane disguise. Volume 10 Issue 2

Regulatory ones, turning this into the demand for even more medically senseless studies27. Parts of paediatric academia became corrupted by industry funds, channelled through regulatory decisions. The pharmaceutical industry, science, academia, and institutional review boards/ ethics committees have so far failed to intellectually process this massive abuse of patients. The faster drug development is progressing, the more the "therapeutic orphans" concept runs foul of clinical reality.

The introduction of clinical studies as a base for drug approval in 1962 rocked traditional scholarly medicine, where eminent clinicians instructed colleagues what to prescribe. This placid world was partially replaced by impersonal data of pivotal studies. Both the pharmaceutical industry (then still the chemical industry) and the American Medical Association protested against this new approach22. Both survived, grew, and became even more powerful pillars of healthcare and health economy. Regulatory authorities transited from dusty administration into science-based drug assessment. But something went wrong for children. When Shirkey characterised children as "therapeutic orphans", the medical profession was still in shock and awe, pulled out of its traditional comfort zone by the new pharmaceutical law2. Shirkey was the first chairman of the AAP Committee on Drugs23. Drug development was new. Unexpected toxicities of antibiotics in preterm newborns6,7 were inflated into demands for separate pharmacological testing in children of all ages8. The AAP guidelines listed risk categories in paediatric research, types of potential patients, and many operational details8. The age of children clinically cared for by paediatricians was assumed to be the same age range where drugs need special approval. The following decades were good for paediatric clinical pharmacology24, with much industry-sponsored research. European paediatric researchers admired US paediatric clinical pharmacology, including industry funds flowing into academic research. They wanted something comparable25 and partnered with the regulatory authorities26. FDA/EMA strengthened their standing in public perception. There is no a clear black-and-white picture. Not all paediatric researchers were dishonest. But the sudden flow of research funds was welcome. An entire "industry" developed in paediatric academia that performs, to this day, medically senseless, regulatorily demanded paediatric studies. Representatives of paediatric oncology and paediatric rheumatology became very vocal in publicly supporting research opportunities offered by paediatric legislation27,28. Funds from pharmaceutical companies, channeled by regulatory decisions, became a key pillar of paediatric oncology and rheumatology, in oncology accompanied by pseudo-scientific political pamphlets that ruthlessy exploit parents' pain and despair over having lost loved

Paediatric melanoma serves here as a gravitational lens to reveal the characteristics of EMA/FDA-demanded studies in minors. The thirteen melanoma PIPs (Table 1) reflect the abundance of innovative anti-melanoma compounds. Each PIP demands separate studies in underage (and sometimes young adult) patients, pretending that anti-cancer compounds that work in adults might work differently in younger patients. This is simply wrong. Babies grow. After a year, toddlers' ADME is comparable to adults10. From then on, pharmacokinetic (PK) and dose-finding studies are medically justified for young patients, not randomised efficacy studies. The abundance of innovative anti-melanoma compounds with resulting PIP-triggered studies made it the first disease where this patient abuse was addressed29. Twenty adolescents in two studies that were terminated too late were banned from effective therapy. We don't know how many melanoma patients are currently participating in the ongoing studies (Table 2). More melanoma PIPs will translate into physical studies until this gruelling theatre is stopped. In paediatric melanoma, high-tech diagnosis and treatments1 could and should alleviate the shock of parents and patients hit by a horror diagnosis. Instead, it has become a killing field for unleashed bureaucracy that, in the name of science and child health, deters young patients with a lethal disease from adequate treatment. Our societal framework allows regulatory dinosaurs to terrorise young patients and the pharmaceutical industry. Let's not get this wrong. There are no more white knights in the pharmaceutical industry than in the defence, real estate or financial business. The market is brutal, like the jungle. But while the jungle's beautiful orchids are available only to those who live there (or to the rich who in the past could afford their transport to posh residences), orchids are affordable today, thanks to science, technology and transport. The market and science enable development of life-saving drugs. But we can always do better. One key requirement will be to deter regulators' megalomania. REFERENCES 1. 2. 3. 4. 5. 6. 7.

Pappo AS 2014: Pediatric Melanoma: The Whole (Genome) Story. Am Soc Clin Oncol Educ Book. 2014:e432-5 Hirschfeld S, Saint-Raymond A: Pediatric Regulatory Initiatives. Handb Exp Pharmacol. 2011;205:245-68 doi: 10.1007/978-3-64220195-0_12. Rose K, Walson PD: Do Pediatric Investigation Plans (PIPs) Advance Pediatric Healthcare? Pediatr Drugs 2017, Dec;19(6):515522 Rose K, Walson PD: Do the European Medicines Agency (EMA) Decisions Hurt Pediatric Melanoma Patients? Clin Ther 2017, 39(2), 253-265 Shirkey H. Therapeutic Orphans. The Journal of Pediatrics 1968;72(1),119-120. Reprinted in Pediatrics 1999;104(3) (Suppl), 583-584. Burns LE, Hodgman JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. N EngI J Med. 1959;261:1318-1321 Silverman WA, Andersen DH, Blanc WA, Crozier DN. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial


8. 9. 10.

11. 12.

13. 14. 15. 16. 17.


19. 20.

regimens. Pediatrics. 1956;18:614 Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, Committee on Drugs. American Academy of Pediatrics. Pediatrics 1995 Feb;95:286-94 Karesh A. Pediatric Drug Development: Regulatory Expectations Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology - drug disposition, action, and therapy in infants and children. N Engl J Med 2003, 349, 1157-67 Rose K, Grant-Kels JM. Most adolescents' melanomas are conventional malignant adult-type melanomas. Eur J Cancer. 2018 Feb 20 Brecht IB, Garbe C, Gefeller O, Pfahlberg A, Bauer J, Eigentler TK, Offenmueller S, Schneider DT, Leiter U. 443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Eur J Cancer. 2015 May;51(7):861-8 Ipilimumab Written Request 2014. https://www.fda. gov/downloads/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/UCM571258.pdf Phase I Study of Ipilimumab (Anti-CTLA-4) in Children and Adolescents With Treatment-Resistant Cancer. https:// Ipilimumab Prescribing Information https://www.accessdata. EMEA-000117-PIP02-10 GB/document_library/PIP_decision/WC500108733.pdf Merchant MS, Wright M, Baird K, Wexler LH, RodriguezGalindo C, Bernstein D, et al. Phase 1 trial of Ipilumamb in pediatric patients with advanced solid tumors. Clin Cancer Res. 2016 Mar 15;22(6):1364-70 Phase 2 Study of Ipilimumab in Children and Adolescents (12 to < 18 Years) With Previously Treated or Untreated, Unresectable Stage III or Stage lV Malignant Melanoma. https://clinicaltrials. gov/ct2/show/NCT01696045 FDA ipilimumab clinical review 125377/supplement 87 https:// Process/DevelopmentResources/UCM572924.pdf Geoerger B, Bergeron C, Gore L, Sender L, Dunkel IJ, Herzog C, Brochez L, Cruz O, Nysom K, Berghorn E, Simsek B, Shen J, Pappo A. Phase II study of ipilimumab in adolescents with

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21. 22. 23. 24. 25. 26. 27.



unresectable stage III or IV malignant melanoma. Eur J Cancer. 2017 Nov;86:358-363. Hilts PJ. Protecting America's Health. The University of North Carolina Pres, 2004 Wilson JT. An update on the therapeutic orphan. Pediatrics. 1999 Sep;104(3 Pt 2):585-90. Kearns GL. The Pursuit of Pediatric Clinical Pharmacology: Perspectives from a Current Journey. J Pediatr Pharmacol Ther 2009;14:10–16 Assael BM. Therapeutic Orphans: European Perspective. Pediatrics 1999;104;591 Choonara I, Dunne J. Licensing of medicines. Arch Dis Child. 1998 May;78(5):402-3. Vassal G, Rousseau R, Blanc P, Moreno L, Bode G, Schwoch S, Schrappe M, Skolnik J, Bergman L, Bradley-Garelik MB, Saha V, Pearson A, Zwierzina H. Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. Eur J Cancer 51, 218-24 (2015) Ruperto N, Vesely R, Saint-Raymond A, Martini A, for the Paediatric Rheumatology International Trials Organisation (PRINTO). Impact of the European paediatric legislation in paediatric rheumatology: past, present and future. Ann Rheum Dis 72, 1893-6 (2013) Rose K. European Union pediatric legislation jeopardizes worldwide, timely future advances in the care of children with cancer. Clin Ther. 2014 Feb 1;36(2):163-77

Klaus Rose Klaus Rose studied medicine, Latin languages and psychology. After postgraduate clinical training in Germany and England he joined the pharmaceutical industry. He was Global Head Paediatrics Novartis 2001–2005 and Global Head Paediatrics Roche/ Genentech 2005–2009. Since 2011 he has been independent, advising on paediatric drug development, speaking at conferences, and publishing. Email:

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Journal for Clinical Studies 19


A Review of FDA’s Updated Guidance for Developing Drugs to Treat Early Alzheimer’s Disease There has been a renewed interest in clinical trials of drugs to treat early Alzheimer’s disease (AD) owing partially to recent advances in the understanding of pathophysiological processes that occur well before the emergence of clinical symptoms, but also to the recent failures of trials of diseasemodifying drugs aimed at later stages of the disease. The Food and Drug Administration (FDA) has responded to this by recently issuing draft guidance to assist sponsor companies in the development of drugs for the treatment of the stages of sporadic Alzheimer’s disease (AD) that occur before the onset of overt dementia, collectively referred to as “early AD”1. This updated guidance outlines the FDA’s current thinking regarding the selection of patients with early AD for entry into clinical trials, and the appropriate endpoints for clinical trials of these populations, and represents a major revision from former draft guidance issued in February 20132. This review will highlight the more salient aspects of this guidance that may impact drug developers, and will make comparisons to prior FDA guidance as well as recently updated European guidance. Two major departures in thinking about early AD come in the new-found appreciation of changes in cognition as being meaningful in terms of clinical benefit in and of themselves, and with that a rejection of the longheld dichotomy of function and cognition in respect to demanding dual-outcome measures; and in the growing role that biomarkers have in both reflecting the pathophysiological changes in early stages of disease when there may be no discernible functional impairment nor cognitive abnormality, and as an indicator of drug activity and possible surrogate for clinical outcome. Diagnosis of Early AD The updated FDA guidance demands that enrolment in any efficacy trial in AD, including early AD, be based on consensus diagnostic criteria reflecting a contemporary understanding of the pathophysiology and evolution of AD with a focus on objective tests and, when appropriate, history and physical examination designed to determine the presence or likely presence of AD, and to exclude other conditions that can mimic AD. As these pathophysiological changes precede the development of clinical findings and progress on a continuum, the updated guidance reflects staged diagnostic criteria. This represents a major departure from previous FDA guidance which supported various sets of criteria related to the diagnosis of mild cognitive impairment (MCI), and particularly the amnestic subtype to help identify those patients who are most likely to progress to dementia, citing examples of both research criteria for prodromal AD published by the International Working Group for New Research Criteria for the Diagnosis of AD3; as well as for MCI due to AD by the National Institute on Aging – Alzheimer’s Association working group4. Importantly, the updated guidance does not address any specific diagnostic frameworks such as these nor endorse any specific nomenclature, but rather categorises stages of early AD based on the presence of pathophysiological changes, neuropsychological abnormalities, and functional impairment as in the below table: 20 Journal for Clinical Studies

The updated guidance argues that is essential to accurately distinguish these four conceptual categories, even in the presence of a single continuous disease process in order to inform the selection of appropriate outcome measures. As such, drug developers must identify both the stage of AD defined for study eligibility as well as the stage of AD anticipated for the majority of the enrolled patient population at the time of primary outcome assessment for all proposed and completed studies, which may differ for studies of long duration. It is also fully expected that biomarkers will play a role in the identification of patients with early AD and the updated guidance speculates that it would be unusual to encounter a proposed clinical trial that does not include in the enrollment criteria some biomarker evidence of disease. The implications of demanding such biomarkers were reviewed in a prior article by the authors, who point out the practical issues related to the cost and burden to both sponsor companies and to subjects (and their caregivers) as well as the theoretical possibility of having an incomplete biomarker profile or some degree of discordance amongst biomarkers for patients making accurate classification problematic5. Outcome Measures The updated guidance stresses that the outcome measures must be appropriate for the stage of illness and outlines several broad possibilities for each stage but interestingly does not name any single outcome measure. This represents a major departure from past guidance which suggested that patients with prodromal AD or MCI due to AD were likely to have relatively mild but noticeable impairments in their daily functioning, and therefore it was important to demonstrate that a drug favourably affects these deficits, in addition to showing an improvement in cognition and named the Clinical Dementia Rating scale, specifically the Clinical Dementia Rating – Sum of Boxes as an example of a suitable outcome measure; although open to others. The proposed categories of outcome measures related to each stage of early AD are as follows: Stage 1: The updated guidance submits that for Stage 1 patients, a clinically meaningful benefit cannot be measured as there is no clinical impairment to assess. As such an effect on various biomarkers alone may serve as a primary efficacy measure, and in principle serve as the basis for an accelerated approval should the biomarker effects be found to be reasonably likely to predict clinical benefit, with an appropriate post-approval requirement for confirmation. Of note, a pattern of treatment-related effects across multiple biomarkers would increase the persuasiveness of the putative effect. Volume 10 Issue 2

Regulatory Stage 2: The updated guidance opines that it may be difficult to establish a clinically meaningful effect on cognition in a reasonable period of time for Stage 2 patients where there is no functional impairment but subtle cognitive dysfunction. Nonetheless, the FDA will consider strongly justified arguments that a persuasive effect on neuropsychological performance may provide adequate support for a marketing approval if the magnitude of the effect is large or if a pattern of beneficial effects was demonstrated across multiple individual tests. Conversely, the persuasiveness of showing significance on a single cognitive test that is not supported by consistent findings on other tests would be less persuasive. Prior guidance advocated the use of an accelerated approval mechanism to consider an effect on an isolated cognitive measure based on a single primary efficacy measure for a marketing approval2. Notably, no single cognitive test or cognitive domain is mentioned in the updated guidance. Any considerations in terms of magnitude or pattern of effect must also take into account the relationship between cognitive measures and biomarkers, as well as changes to the evolution of more severe cognitive deficits and functional impairment. Should the cognitive effects be judged as “inherently clinically meaningful” then approval is possible. However, should these cognitive effects be found to be reasonably likely to predict clinical benefit, then an accelerated approval is possible with an accompanying postapproval requirement for a separate study to confirm the predicted clinical benefit. Understandably, a discussion with the agency would be required early in the development process. A pattern of beneficial cognitive effects can be established by comparing z-scores corresponding to each individual cognitive domain. Clinically significant effects would be those that approach a 0.5 z-score improvement, a cutoff that is generally acknowledged by clinicians to reflect true changes in cognition not due to variability or chance. This z-transformed data also permits a shape or profile analysis that can help determine if treatment differentially affects one cognitive domain versus another, or if all domains are affected equally 6. Stage 3: Unlike prior stages, patients in Stage 3 may have mild but noticeable impairments in functioning and therefore the updated guidance suggests that although it is generally acceptable to include neuropsychological measures of unknown clinical meaningfulness, it is imperative to demonstrate improvements in functional deficits. Although no specific functional outcome measure is named, the updated guidance suggests that the outcome measure should be an integrated scale that adequately and meaningfully assesses both daily function and cognitive effects as a single primary efficacy outcome measure. The development of novel approaches to a truly integrated outcome measure using real-world measures such as ease of financial transactions and adequacy of social conversation are encouraged. Alternatively, independent measures of function and cognition can also be utilised to support a claim but once again, none are named. Additional Assessments and Biomarkers The updated guidance suggests that a time-to-event or survival analysis (such as the time to the occurrence of a clinically meaningful event or impairment of daily function) can be used as a primary efficacy measure in early AD trials. In the past, this type of analysis was typically seen in the context of later stage early AD patients that utilised time to conversion from MCI to AD as a primary outcome measure. It is difficult to argue against the meaningfulness of this outcome measure but it is recognised that some change in a specific function or a composite measure may prove to be more

advantageous than any single dichotomous variable in terms of study duration and sample size. Notoriously, many prior studies using such dichotomous outcomes greatly overestimated MCI conversion rates to AD and therefore significantly underestimated study duration resulting in a number of long and costly failed trials. The updated guidance acknowledges that it is challenging to provide supportive evidence that a drug has an established clinically meaningful benefit based solely on biomarker evidence, as biomarkers in AD are not well enough understood to provide strong evidence of a persistent effect on the course of AD. As such, there is no consensus as to which specific biomarkers are most appropriate to support clinical findings in early AD trials, and inadequate information on which to establish a hierarchy of biomarkers as secondary outcomes. This differs from prior guidance, which at least theoretically allowed for approval based on the use of a biomarker as a single primary surrogate efficacy measure considered under accelerated approval if the biomarker was likely to predict ultimate clinical benefit2. Prior guidance was also willing to consider the argument that a positive biomarker secondary outcome measure in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in AD based, of course, on widespread agreement in the research community that the chosen biomarker reflects a pathophysiologic process that is fundamental to the underlying disease2. There is also no mention in the updated guidance that a comparison of the rate of change based on slopes between active treatment and control could provide support for a claim of disease modification. Rather, consistent with past guidance, the updated guidance continues to support the use of randomised-start or randomised-withdrawal trial design as the most convincing approach to demonstrating a persistent effect on disease course. Comparisons to Revised EMA Guidance In relation to the almost simultaneously released European Medicines Agency (EMA) guidance on the clinical investigation of medicines for the treatment of Alzheimer’s disease, the updated FDA guidance on early AD differences differs with respect to several salient areas including disease nomenclature (with EMA embracing the terms prodromal AD/MCI due to AD and preclinical AD) and the acceptability of efficacy endpoints for these two populations. In preclinical AD, the population is essentially asymptomatic (as in FDA Stage 1) and the presence of AD pathology is measured by biomarkers (both Aβ and Tau markers). European regulators continue to remain open in regard to the diagnostic criteria for prodromal AD/MCI due to AD, instead suggesting that efforts be focused on detecting a homogeneous group of patients with a defined rate of progression to AD dementia7. Similar to FDA guidance which recognises that patients with later-stage early AD and patients with AD in the earliest stages of dementia may not differ significantly, EMA guidance also acknowledges that the clinical characteristics of patients with prodromal AD/MCI due to AD may overlap with those at the milder end of the AD dementia spectrum, with similar levels of cognitive impairment and biomarker levels. Thus, the selection of patients with early AD for long-term interventional trials should not be unnecessarily subdivided, and subjects with prodromal AD/MCI due to AD and mild AD may be studied together7. European guidance also acknowledges the challenges of having co-primary endpoints of cognition and function, due mainly to the limitations of currently available scales that may be prone to ceiling effects and recommend that sponsors demonstrate the clinical relevance of their results. EMA guidance also call for the use of more sensitive item scoring for MCI-specific scales and/ Journal for Clinical Studies 21

Regulatory or investigating only those domains that have been shown to be consistently impaired in this population; as well as the use of composite scales that have a combined assessment of cognition and its impact on daily functioning as a single primary endpoint, provided that this does not hinder demonstration of the significant contribution of both domains to treatment effects. Further, EMA guidance recommends that measures of instrumental activities, executive functions and health-related quality of life be included as secondary endpoints7. Although novel outcome tools sensitive to small neuropsychological changes in Preclinical AD are currently being developed, the EMA concedes that there is no "gold standard" as yet for the assessment of treatment effects in this population. And unlike the updated guidance from the FDA, which suggests that time to the occurrence of a clinical meaningful event during the progressive course of AD (such as a meaningful impact of daily function) could serve an acceptable primary efficacy measure in clinical trials in early AD, the EMA supports the use of time to event analysis as a complementary measure in order to support the relevance of a chosen outcome measured. As the main goal of treatment in the at-risk population remains prevention of cognitive impairment, as no biomarker can yet be considered a valid surrogate endpoint, the event of interest must be of clear clinical importance such as onset of cognitive impairment. While US regulators have remained largely silent on issues surrounding primary prevention designs, previously citing very large sample sizes and following patients possibly until death, EMA guidance notes that prevention trials will likely require relatively large sample sizes and long study durations, typically of at least three years7. However, given the dearth of scientific information on prevention no firm recommendations are provided. Reconciling the disparities between US and European guidance may be challenging for sponsor companies designing and conducting international clinical trials as part of a development programme being submitted to both FDA and European regulatory agencies simultaneously. Obviously some degree of harmonisation of clinical diagnostic criteria and acceptable outcomes is needed at a minimum, and the adoption of the updated FDA guidance would need to be aligned with the corresponding recent EMA guidance (and vice versa) in order to facilitate and expedite the potential approval of new drugs for early AD. REFERENCES 1.




Early Alzheimer’s Disease: Developing Drugs for Treatment. Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER). February 2018. Clinical/ Medical Revision 1. Draft Guidance for Industry. Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). February 2018. Clinical/Medical. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ and Scheltens P (2010). Revising the Definition of Alzheimer’s Disease: A New Lexicon, Lancet 248 Neurol, 9(11):1118-27. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC,

22 Journal for Clinical Studies

5. 6. 7.

Snyder PJ, Carrillo MC, Thies B and Phelps CH (2011). The Diagnosis of Mild Cognitive Impairment due to Alzheimer’s Disease: Recommendations From the National Institute on Aging - Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease, Alzheimer’s Dement, 7(3):270-9. Riordan H and Drosopoulou N (2017). Updated Research Criteria for Clinical Trials across the Alzheimer’s Disease Continuum. Journal for Clinical Studies, Vol 9 (6) Dec pp 42-45. Riordan H (2017). Constructing Composites to Optimize Cognitive Outcomes. Journal for Clinical Studies. Vol 9 (2) April pp 40-45. European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease. Committee for Medicinal Products for Human Use (CHMP). Feb 22 2018.

Henry J. Riordan, PhD Henry J. Riordan is the 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. Email:

Natalia E. Drosopoulou, PhD Natalia E. Drosopolou is the Executive Director of Project Management and Franchise Area Lead in Neuroscience at Worldwide Clinical Trials. She received her PhD in Biochemistry, specialised in Developmental Neurobiology from King’s College of London. With over 19 years in the clinical research industry, Dr Drosopoulou’s experience spans from small intricate Phase I studies to large global Phase III programmes with a special emphasis in AD trials. Email:

Volume 10 Issue 2


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Journal for Clinical Studies 23

Market Report

Clinical Trials Down Under Australia and New Zealand – A Competitive Region The Australian clinical trials landscape has developed considerably over recent years, with over 1000 new clinical trials commencing each year in the pharmaceutical, biotechnology and medical device space. In 2015 approximately 1360 clinical trials commenced, representing an estimated $1.1billion of direct expenditure. An estimated 6900 skilled professionals are involved in the conduct of Australian trials1. Growth in the sector has been remarkable, especially in the medical devices trials area, with a 10% p.a. growth year on year (2012–2015), significantly above the global average. Interestingly, Australia plays a substantial part in global, multi-centre studies, which comprise approximately one third of all trials undertaken1. Figure 1 represents a global comparison of numbers of registered clinical trials per capita. Australia beats Germany, UK and USA according to the World Health Organisation figures plotted against population (2017–2018), and per capita, New Zealand conducts more clinical trials than the UK and USA combined2.

According to a recent publication from the Australian and New Zealand Clinical Trial Registry, appraising the decade 2006 through 2015, a total of 5.2 million people have participated in its registered trials in Australia. Clinical trials in the region have crossed multiple types of interventions, including drug treatments (47 per cent), surgery (4 per cent), medical devices (10 per cent), behavioural therapies (10 per cent) and prevention strategies (11 per cent). Cancer has been the most frequently studied health issue in Australian clinical trials registered between 2006 and 2015, with 1870 trials (18 per cent of the total) selecting this category, followed by mental health with 1229 (12 per cent) and cardiovascular conditions with 1034 (10 per cent)3. 24 Journal for Clinical Studies

Globally, markets compete for clinical trials activity (especially industry sponsored) due to the contribution to the local healthcare systems and economy. Australia has long been considered as a serious competitor in innovation, quality of research outputs, expeditious timelines and aggressive enrolment, and has a pool of highly regarded key opinion leaders. The Regulatory Environment Australia The Australian Register of Therapeutic Goods (ARTG) contains all medicines, devices and diagnostics which are approved for use in a specified indication. To supply a therapeutic product to a person or persons that is not listed on the register, or is intended for a purpose other than specified in the ARTG, is an offence. TGA have a number of mechanisms in place to enable the safe and monitored supply of products which are not in the ARTG. In an emergency setting, or for compassionate use, TGA provides a special access scheme whereby a physician can apply for case by case use of an unapproved product. The authorised prescriber route is utilised when a physician can make a case for using a particular good in a cohort of patients. There is also a scheme for personal importation of products, via application directly to TGA. When it comes to clinical trials, Australia has arguably one of the most pragmatic and expeditious regulatory systems in the world with its clinical trial notification (CTN) scheme permitting the supply of unapproved goods in a clinical trials setting. This pathway eliminates the burden of the requirement of regulatory and competent authority approvals. The TGA has successfully been running its clinical trial notification scheme (CTN) for decades, and it is seemingly only improving in recent years with the online portal handling submissions and acknowledgments seamlessly. TGA allows the responsibility for reviewing and approving clinical studies to be firmly held with an appropriately constituted human research ethics committee. Following HREC approval, each institution then reviews the legal and site-specific documents and, if all is correct and above board, provides governance (or institutional) approval. Once the essential documents, including HREC and institutional approval are in place, the sponsor simply submits an online form containing details of the sites, investigational product(s) and high-level details to TGA with AUS$350. Two to three days later, TGA provides an acknowledgment letter permitting the supply of the product in the clinical trial setting. The Clinical Trials Jurisdictional Working Group recently began to develop a national dataset on clinical trials and activity in Australia. The National Aggregate Statistics (NAS) 2015–16 report on startup timelines (defined as initial application to ‘first patient in (FPI)’) estimated that 62% of trials started within 120 days (four months)3. Volume 10 Issue 2

Market Report New Zealand New Zealand’s population is only 4.7 million but it certainly packs a mighty punch as a location for conducting clinical trials. The speed with which studies can be initiated in the very many clinical research centres throughout the two major islands is arguably the fastest in the world, due to slick, sensible and efficient ethics and governance processes. Broadly, Medsafe, New Zealand’s regulatory authority, operates a different set of requirements depending on whether the clinical trial is for a pharmaceutical, genetic material or a medical device. Approval from the Director General of Health (DGH) is mandated prior to the commencement of a clinical trial involving a new medicine or gene therapy. The Standing Committee on Therapeutic Trials (SCOTT) undertakes a scientific assessment of applications and makes the appropriate recommendation to the Director General of Health. Similarly, the Gene Technology Advisory Committee reviews trials that involve the introduction of nucleic acids, genetically manipulated microorganism or viruses or cells into human beings, and provides recommendation to the DGH4. Medical device trials are exempt from the requirement for DGH approval, but, as with all trials, do require ethics approval from a duly constituted Health and Disability Ethical Committee (HDEC) as well as institutional approval2. Timelines are expeditious with respect to initiating device trials (often less than four weeks in the experience of the author) and extremely competitive for other trials (less than eight weeks in the experience of the author). Cost-effectiveness In a White Paper produced by Frost & Sullivan in 2016, it was estimated that in early-phase clinical trials, Australia is 28% cheaper than the US before tax incentives, and 60% cheaper after tax incentives6. Many factors contribute to this, the most important being speed to clinical data and study completion. Other factors include high-quality data and therefore faster data cleaning and database lock, reasonable rates for service and, as the huge difference in the savings above suggests, the government’s tax incentive scheme for R&D. The Australian Government’s R&D Tax Incentive gives companies with an annual aggregated turnover of less than A$20 million a 43.5% refundable tax credit, and companies with an annual aggregated turnover of more than A$20 million a 38.5% non-refundable tax credit on eligible R&D expenditure. The R&D Tax Incentive is specially designed to make access to tax benefits more efficient and more predictable. Unlike similar programmes in other countries, there is no requirement for companies in Australia to demonstrate year-onyear growth in their R&D expenditure in order to claim a tax benefit. There is also no requirement for intellectual property from eligible R&D projects to be held in Australia. This recognises the inherent value of the research and development process itself, regardless of the eventual ‘location’ of ownership of the resulting intellectual property. Above all, the R&D Tax Incentive provides a globally competitive incentive for both home-grown and foreign-owned companies to conduct R&D activities in Australia. In fact, a recent report by global accounting firm KPMG placed Australia among the top ten most competitive locations for R&D investment7. Specialised Infrastructure and Initiatives A substantial range of factors determine choice of location when planning a clinical strategy and delivery of individual clinical trial objectives. The weight of each factor alters depending on the trial and sponsor type; for example, overall cost may be less of a driver for multinational pharmaceutical companies whilst it is a critical aspect for small to medium-sized or startup companies.

As already discussed, it is old news that speed to FPI thanks to Australia’s CTN scheme and New Zealand’s efficient review processes attracts overseas sponsors time and time again. From the personal experience of the author, human data, critical for investment presentations and fundraising, can be gathered from the antipodean sites before a USA FDA investigational device exemption (IDE) submission is even made and accepted. These early data can support the IDE and expedite the regulatory approval process in some cases, meaning that the FDA study can start sooner. Additionally, so long as demographic similarities to the European population can be illustrated, Australia and New Zealand can provide data for CE Mark studies gaining approval and market access for the sponsor into Europe. The region’s key opinion leaders (KOL) are highly regarded across the globe with excellent reputations and respected research outputs. As such, data is accepted by a number of international regulators including FDA and EMA. Australia and New Zealand tend to hold their own in complex or rapidly changing disease areas, trials involving biologics, complex trial designs and first-in-human work. These trials often require state-of-the-art health institutions, keen KOL involvement, especially in the early stages, and extremely high quality data output, especially safety reporting. Australia and New Zealand’s capabilities in these areas are strong relative and emerging markets, and tend to compete well with North America and Western Europe. Australia boasts several world-class Phase I units in all of its major cities and the speed and quality of early phase data is well known in many disciplines, including oncology. In the private sector, a dedicated, not-for-profit human research ethics committee, Bellberry Limited, is improving time to FPI year on year, achieving an average turnaround of approximately 20 days8. The Australian government appreciates the advantage of attracting clinical research to the region and, as such, has a vast number of departments, working groups, and internationally based Australian Trade and Investment Commission offices (Austrade) developing initiatives to continue the growth of its market share in clinical research activities. Three major initiatives have been progressing since 2011, when the Clinical Trials Action Group (CTAG)9 produced a report identifying three major areas to work on: • • •

Improving the speed of ethics and site approvals, Standardising and reducing costs associated with clinical trials, Improving patient recruitment.

The sector has strived to concentrate on these areas and timelines (to FPI), in the author’s opinion, have improved markedly in the last five years. In addition, myriad webbased search tools are available to Australians when searching for relevant trials to participate in (e.g., https://www. In 2017, some A$7 million of committed funding was promised to an initiative entitled Encouraging Clinical Trials in Australia, aimed at streamlining clinical trial administrative and operating systems in each Australian state and territory10. Challenges So there has to be a downside, doesn’t there? If anything seems too good to be true, someone is leaving something out, right? OK, yes. Two things need to be addressed in order for this article to be believable. Journal for Clinical Studies 25

Market Report There is a single, frustrating, costly, time-consuming problem. Australia and New Zealand are quite literally on the other side of the planet from the vast majority of other countries heavily involved in clinical trials. It is a whopping 23 hours flying time from London, 15 hours from West Coast USA and a good eight hours to Asian hubs (to Sydney). For sponsors wishing to include Australia/NZ in early-phase device trials, involving surgical procedures and the need for clinical engineers and even physician proctors to be present at cases, it is wholly unattractive. Local CROs are trying to address this by offering case support and, at times, this does alleviate the burden. However, for US companies, often European destinations with a streamlined regulatory system may win over. In addition to the prohibitive travel time and cost, it can be frustrating doing business with a country that is literally asleep during your working day. Like New Zealand, Australia has a tiny population of approximately 24.7 million (similar to Madagascar) and a land mass similar in size to the USA (Figure 2). As a result of the relatively small populations, patient numbers can make competitive enrolment challenging, especially if compared to emerging countries for whom enrolment is rarely an issue. This can make some trials, which are troublesome to recruit for, expensive to run in Australia if fixed site set-up fees are directly compared to meeting patient recruitment targets.

The last major reason for avoiding Australia at all costs is the monumental array of deadly critters (Figure 3). On the list as THE most dangerous creatures in the world include snakes (e.g. Eastern brown snake), spiders (funnel-web), jellyfish (box jellyfish), sharks (e.g. great white), and octopi (blue-ringed octopus)11. Even the rivers are deadly, many in the Northern Territory inhabited by 1,000kg crocodiles.

Conclusion Volumes of data and comprehensive reports suggest that Australia and New Zealand are extremely healthy in the clinical research arena, drawing in significant dollars for healthcare, and 26 Journal for Clinical Studies

providing seriously ill patients access to cutting-edge therapeutic goods in clinical trials settings. It is encouraging that the [Australian] government continues to create new, and build on existing, initiatives to ensure timelines from submission to first patient in are reduced, site management costs are streamlined, and recruitment tools (for patients) are plentiful, well advertised and user-friendly. The region continues to be an attractive option for global pharma and the medtech. industry wishing to explore overseas markets for their clinical development strategies, ensuring high quality and timely initiation of trials. REFERENCES 1.

Clinical Australia: the economic profile and competitive advantage of the sector. MTP Connect and LEK Consulting, June 2017 visited on 11 February 2018 2. World Health Organisation/trial search visited on 18 February 2018 3. Clinical Trials in Australia 2006-2015 â&#x20AC;&#x201C; ANZCTR visited on 15 February 2018 Australia2006-2015.pdf 4. Health Research Council of New Zealand visited on 10 February 2018 5. Medsafe Guideline of the Regulation of Therapeutic Products in New Zealand visited on 15 February 2018 regulatory/Guideline/GRTPNZ/Part11.pdf 6. Australia: Preferred Destination for Early Phase Clinical Trials. Frost & Sullivan White Paper 2016 7. KPMG. Competitive alternatives: KPMGâ&#x20AC;&#x2122;s guide to international business locations costs. 2016 edition visited on 12 February 2018 aspx?id=886 8. Bellberry Limited visited on 15 February 2018 http://www.bellberry. 9. Clinical Trials Action Group Report visited on 15 February 2018 andHealthTechnologies/ClinicalTrialsActionGroup/Pages/ Library%20Card/Clinical_Trials_Action_Group_Report.aspx 10. National Disability Insurance Scheme 31 March 2017 Quarterly Report visited on 13 February 2018 h29/h92/8800925974558/COAG-DRC-Report-2016-17-Q3-v10.0Final.pdf 11. Australian Geographic visited on 12 February 2018 http://www.

Suzanne Williams Suzanne Williams graduated from Manchester University, UK in 1993 and, for the next ten years, held monitoring and management clinical roles in the UK, USA and Australia at ICON and then later with Searle, Pharmacia, Pfizer and Roche. Between 2003 and 2006, Suzanne ran a successful consulting business providing independent contract clinical research services. From there, she joined the team at an Australian medical device company and successfully CE Marked their left ventricular assist device in under two years. Suzanne went on to co-found Mobius Medical Pty Ltd, a boutique CRO offering clinical trials monitoring, data management & biostatistics and electronic data capture services to the medical device startup, and biotech/pharma companies all over the world. Email:

Volume 10 Issue 2

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Journal for Clinical Studies 27

Market Report

Russian Clinical Trials Market in 2017

This article continues the topic of the Russian clinical trials market, put into the spotlight in the July issue1 of The Journal for Clinical Studies. The results of 2017 proved rather unexpected. To a lesser extent, this pertained to multinational clinical trials conducted in Russia, where the market remained more or less stable. But during the year, the number of local registration clinical trials radically decreased. General Stats The total number of approvals for conducting clinical trials issued by the Russian Ministry of Health (MoH) went down by 22% compared to 2016 – 700 approvals vs. 897 (Diagram 1). Multinational clinical trials (MCTs) were least affected – 281 approvals a year vs. 302 in 2016 (7%). Bioequivalence studies by local sponsors dropped by 11.2% (151 approvals vs. 170). The number of efficacy and safety local trials by Russian sponsors decreased by 24.4% (149 approvals vs 197). Local trials of foreign sponsors declined dramatically indeed. Thus, the number of efficacy and safety trials plummeted by 41.5% (48 trials vs. 82 in 2016), whereas the number of approved bioequivalence studies for drugs of foreign make dropped by 51.4% to 71 vs. 146.

practice for more than 20 years. Given that the said amendments were adopted back in 2014 and took effect starting on January 1, 2016, as was earlier mentioned, we’ve long been forecasting a lesser number of local trials, but the market demonstrated strong inertness and we saw real changes only in 2017. As we can remember, the most dramatic fall occurred in the sector of local trials by foreign sponsors. This is also explicable, since most local trials are conducted for the sake of drug registration in Russia. Starting in 2016, a new rule has been effective in Russia: to get a new drug registered, foreign companies must now pass the manufacturing site inspection by the Russian inspectorate, for conformity to the Russian GMP (the same measure actually paralysed the pharmaceutical market of Turkey). After such a “bottleneck” was created, this predictably caused a sharp decline in the registration of new outlandish drugs and took a toll on the number of locally conducted trials of such drugs, which is quite understandable: why invest in trials when the very registration is in question? Thus, under the impact of one positive factor (the repeal of redundant trials) and one negative factor (the requirement to pass the Russian GMP inspection), the Russian market of clinical trials lost ground in 2017 due to a considerable reduction in the number of local trials. Local Clinical Research: What is Studied? It would be interesting to look at the market of local clinical trials in Russia. Diagram 2 shows the structure of local trials by foreign and Russian sponsors

Diagram 1: Data from

As a result, the ratio of various trial types notably changed. And whereas during three recent years we could see a gradual slide in the share of MCTs, which reached the level of 33.7% in 2016, last year this sector won back more than six percentage points, to reach 40.1% of all trials. Given the skeptical attitude of the expert community towards local trials which surged dramatically in Russia in the wake of the implementation of the new law “On circulation of medicines”, the rebounding of MCTs is rewarding. What’s the reason for such radical changes in the market composition? First of all, starting on January 1, 2016, amendments to the law “On circulation of medicines” that had long been awaited by manufacturers of generics, finally came into force. The requirement to produce the results of the so-called “studies of therapeutic equivalence” was cancelled for a number of pharmaceutical forms of generics – for most injectable dosage forms, gaseous substances, liquids, etc. Furthermore, no reports on trials are to be now produced for drugs containing substances that have been used in medical 28 Journal for Clinical Studies

Diagram 2: Data from

We see generics accounting for the largest share of local trials (54.2% in total local trials by foreign sponsors and 28.2% in total trials by national sponsors). It should be mentioned that these data do not include bioequivalence studies, i.e. in this case the matter regards the so-called trials of “therapeutic equivalence” of generics to reference products. They certainly lack full equivalence: the average number of participants involved in such trials is 203 persons for foreign medicines and 115 for domestic drugs. Just as a reminder: local trials are a condition of new medicinal product registration in Russia; hence the need for this type of trial. The trials of biosimilars and biobetters account for another 14.1% in the local trials of Russian sponsors. Foreign companies did not conduct this type of trials in Russia last year. The trials of new combinations of generics also account for a considerable share of local trials by foreign sponsors – 10.4%. Similar trials of Russian drugs account for only 2.7%. Volume 10 Issue 2

Market Report The trials of original products represented by small molecules and biological products account for 8.3% and 4.2% in the structure of local trials conducted by foreign sponsors (four and two drugs, respectively). Two other trials were vaccine studies. One may ask why there are so few trials of original foreign drugs. The reason is that most pharmaceutical companies try to come to Russia with MCTs and very rarely agree to local trials (unless Russia was included in the MCT). We see a lot more trials of original drugs in the sector of Russian sponsors. The trials of drugs created on the basis of small molecules account for 14.8% (22 trials); biological products account for another 8.7% (13 trials) and vaccines – for 4% (six trials). We’d like to reassure scientific skeptics, though: despite this seeming abundance of original Russian developments, most of them are of little value for the world of science. The most exciting sector of trials is conventionally classified as “other”. The share of foreign sponsors in these trials was 10.4% in 2017 (five trials); the share of Russian sponsors stood at 12.1% (18 trials). This category includes herbal medicines, drugs of animal origin, homeopathic products, surprise combinations of old wellknown substances and similar studies. To give you some examples, in 2017 motherwort and mint herbal medicines, cattle liver, bladder and ovary extractions (humors) as well as combinations of charcoal with aluminum oxide and similar developments were included in this category. We separate post-registration trials as a special category. Some may regard this approach as a deviation from the general classification. Yet it was important for us to see what kind of drugs are explored for registration purposes; that’s why we separated from them those trials which do not pursue such goals. That’s enough about local trials, since we are mainly interested in MCTs and the role of Russia in their conduct. International Clinical Research in Russia: Phases and Therapeutic Fields Most MCTs conducted in Russia are Phase III studies. In 2017 they accounted for 69% (194 trials). Almost a fourth (24% or 67 MCTs) are Phase II trials. Phase I and IV studies accounted for 2% (six protocols) each. We should remember that in Russia they ban trials of first-phase drugs made abroad, with healthy volunteers involved. Accordingly, patients with specific diseases (most often oncological patients) take part in MCTs of Phase I. The logic of this restriction is not quite clear, but dura lex sed lex. The remaining 3% are trials where Phases (I/II, II/III etc.) are combined.

It’s also interesting to look at the number of patients recruited in Russian centres. Cardiac and cardio-vascular patients take the lead here. The original plan called for the inclusion of 264 patients in the trials approved for 2017, on average. The average pool for pulmonology studies was 180 patients, and for endocrinology studies was 171 patients. The average pool for all MCT types was 96 patients. Approval Deadlines ACTO2 annually monitors timeframes for the conduct of clinical trials. The data are gathered, based on the survey of ACTO member companies. For the second year in a row, the survey is conducted together with another business association, AIPM3. As a result, the monitoring includes the data of companies conducting more than 90% of MCTs in Russia. The average time for getting approvals for trials in 2017 was 95 days (three days shorter than in 2016). This timeframe was calculated on the basis of all applications, regardless of whether requests or comments were sent by expert bodies or not. If any request was questioned for some reason in the process of expert evaluation, the average time for trial approval would extend to 116 days. Without comments, the average time of passing the official procedure was 69 days in 2017. The average time of an investigational medicinal product (IMP) import permit was 14 days (vs. 13 days in 2016), whereas it took 20 days to get a permit for the export of biological samples (vs. 19 days a year before). The applicant had to wait about 42 days for obtaining an approval of significant protocol amendments, and 26 days for other approvals (to prolong clinical trial, to enroll additional patients or to include new sites). In Diagram 3 you may see the dynamics of obtaining the key approvals needed for a clinical trial to commence in Russia, starting in 2005. You may see the stabilisation of timeframes in four recent years. The total time for getting a clinical trial approval and the permit to export biological samples (the latter can be done in parallel with getting the IMP import permit, so the times are not summed up in this case and we use the longest period for our calculations) is less than 120 days.

Let’s review the breakdown of MCTs conducted in Russia by key therapeutic areas (Table 1).

Diagram 3: Data from timeframes monitoring of ACTO

Geographic Distribution One undisputed advantage of Russia is that it spans huge territories and there is a large number of medical institutions participating in clinical trials here. Hospitals and clinics taking part in clinical trials must be accredited by MoH. As of February 2018, the register of accredited medical institutions includes 1343 organisations.

Table 1: Data from

The most active regions are: Central Russia (Moscow, Yaroslavl, Ryazan) and North-West (St. Petersburg, Arkhangelsk). Thus, during 2017 the clinics of the Central Federal District took part in 284 approved MCTs, and the clinics of the Northwestern Federal District in 242 MCTs. The Volga Federal District ranks third in Journal for Clinical Studies 29

Market Report terms of active participation in MCTs (the Nizhny Novgorod region, Tatarstan, the Samara and Saratov regions). This region accounted for 193 of MCTs approved in 2017. It is followed by the Siberian Federal District (Novosibirsk, Kemerovo and Tomsk). Last year, clinics from this region participated in 166 new MCTs. The Ural Federal District (Sverdlovsk and Chelyabinsk regions) is the outsider of the top five most active regions – 107 approved MCTs in 2017. It should be noted that the Siberian and Ural Federal Districts significantly increased their profile in MCTs, whereas the activity of clinics from other regions, Moscow in the first place, declined in 2017. Historically, most trials are conducted in the biggest Russian cities, Moscow and St Petersburg. In 2017, St Petersburg ranked first, shooting slightly ahead of Moscow which was the leader in 2016 (see Diagram 4). This region accounted for 236 MCTs approved during the year. Moscow was very near, only five trials behind the northern capital. Yaroslavl, which was fifth a year before, ranked third in 2017, with the Nizhny Novgorod and Novosibirsk regions as well as the Republic of Tatarstan following next, slightly behind. The top 10 also included Kemerovo and Chelyabinsk regions, which notably improved compared to 2016. While the Chelyabinsk region improved its performance by five trials only (53 MCTs vs. 48 a year before), the Kemerovo region conducted 22 trials more than in 2016 (65 vs. 43).

This high competition between different regions of Russia is a positive factor. Trials are not concentrated solely in the two capital cities, Moscow and St Petersburg. And we are happy that the year 2017 shows clear signs of the trend towards greater propagation of MCTs all over Russia, including in Siberia and the Urals. This is good news for patients, because even residents of remote regions have access to MCTs. This is also good news for business, since high competition between clinics enables the choice and eventually enhances the quality of trials conducted. Main MCT Market Players in Russia Diagram 6 shows the top 10 pharmaceutical companies sponsoring MCTs conducted in Russia during 2017. For the fifth year in a row, the leader is Novartis (prior to 2013 ACTO had not run the stats) which last year obtained 25 MCT approvals, followed by Merck & Co. and AstraZeneca (17 new MCTs each). But if Merck & Co. also ranked second a year before, AstraZeneca staked a place among the three leaders, having risen from position 7–8 which it shared in 2016 with AbbVie. GlaxoSmithKline, ranked third in 2016, dropped to the 5–6 position in the rating, initiating only 12 new MCTs in 2017. Pfizer and Novo Nordisk (ranked nine and 10 in 2016) dropped out of the top 10 in 2017. On the other hand, Sanofi and Eli Lilly, absent from the top 10 a year before, came back to this enviable club.

Diagram 4: Data from

Diagram 5 shows the top 10 regions by the number of approved MCTs in 2017 per 1 mln. population. The breakdown is totally different here, with the Yaroslavl region topping the list (like a year before) (59 approved MCTs in 2017 per 1 mln. population), followed by the Tomsk region, which was ranked fourth in 2016. St Petersburg and Smolensk, ranked second and third a year before, lost one rank each, whereas Arkhangelsk, Omsk and Kemerovo regions were absent from the top 10 in 2016 but were included in 2017.

Diagram 5: Data from 30 Journal for Clinical Studies

Diagram 6: Data from

Diagram 6 also shows when trials were conducted by the sponsor independently, and when CROs were involved. We should make reservations, to be sure: ACTO taps the MoH Register of CT Approvals for statistics, which does not always reflect the fact of CRO involvement in trials, especially when the sponsor is in charge of the regulatory part (getting MoH approvals). As per the MoH Register, about 48% of MCTs in Russia are conducted by local business units of sponsors, and the rest via CRO. Most likely, the share of the latter is slightly higher in actual practice. In Diagram 7 you may see the top 10 CROs in terms of MCT approvals they got in 2017. The leader is IQVIA (former QuintilesIMS) with 27 MCTs. It has to be mentioned that QuintilesIMS (still earlier named Quintiles) has topped the ranking for four years in a row already. Only in 2013 was it outstripped by Parexel. PPD and PRA Health Sciences shared second and third positions in 2017 (both were responsible for 14 MCTs). We can also mention the stability of both companies in the Russian market; in 2016 and 2015, PPD took the second position and PRA Health Sciences took the third position in the rankings. We suppose that, given the merger of INC Research and inVenitive Health into Syneos Health, as well as the merger of Covance and Chiltern International, the rankings will be different next year. Volume 10 Issue 2

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District in 2017. The standing of key players in the Russian MCT market – sponsors and CROs – changed little during the past year. REFERENCES 1. 2. 3. Association of Clinical Trials Organizations, Russia Association of International Pharmaceutical Manufacturers, Russia

Svetlana Zavidova

Diagram 7: Data from

General Conclusions As we review the results for 2017 in the Russian market of clinical trials, we can mention a tangible decrease in the number of trials in the local CT sector. This led to a higher share of MCTs in the general market composition. Generally, this trend is perceived as positive by the expert community. Meanwhile, the past year was rather stable for MCTs. The timeframes for getting approvals remained almost unchanged. We may also notice a slightly different territorial distribution of MCTs in favour of the Ural Federal District and the Siberia Federal 31 Journal for Clinical Studies

Svetlana Zavidova is the Executive Director of the Association of Clinical Trials Organizations (ACTO) since its establishing in 2007. ACTO is a non-commercial organization of sponsors (pharmaceutical companies) and CROs engaged in clinical trials in Russia. Svetlana is a lawyer by education and has more than 20 years’ experience in non-commercial sector and more than 15 years in clinical trials market. She specialized in analysis of regulation of pharmaceutical market, has a broad experience in the elimination of harmful administrative barriers. Email:

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Developing Talent for the Future of Clinical Research Clinical research is a rapidly evolving and dynamic environment and the sector is undergoing significant changes on a number of fronts. The wider use of technology, rapid advances in the diagnosis and treatment of diseases such as cancer, and other emerging health technologies such as data analytics, and the use of artificial intelligence in diagnostics are having a significant impact on the way that clinical trials are conducted. The move towards more patient-centric trials, and changes in methodology such as the use of risk-based monitoring and adaptive trial design, are continuing to evolve the way that clinical research is conducted. The search for new markets and treatment-naïve patient populations, and the need to drive down costs, have seen an increasing number of studies in emerging geographical areas such as China and India. Pharma companies are attempting to capitalise fully on the data they collect from each study by having an increasing number of trial objectives. Consequently, clinical studies are becoming more complex than ever before. Regulatory changes have also had their impact. There is, quite rightly, increasing pressure on trial sponsors to be transparent about the design and outcomes of trials in terms of publishing results. One example is that the European Medicines Agency has launched a new version of the European Clinical Trials Database (EudraCT) - EudraCT V10.1 This version marks the final step of a process through which summary clinical trial results will be made publicly available through the EU Clinical Trials Register (EU CTR). Because of all these developments, what we might call human factors are ever more critical to the success of the conduct of any clinical trial. Used in this sense, the term ‘human factors’ refers to how people perform at work, collectively and individually. Are they carrying out their work activities efficiently and effectively? Are they motivated and engaged? Are they communicating effectively? Are they ready and equipped for the challenging and dynamic environment that is clinical research?

R&D spend continues to grow at an annual rate of 7–8%2 and so the demand for talented people in the clinical research sector continues to increase. To fail to develop the global clinical research workforce, in the face of such innovations, is to stagnate at best, and at worst, to move backwards. In order to keep pace with this rapidly changing landscape, a fresh approach to the development of human talent is required. This article will look at three aspects of growing the talent the sector needs; development of the individual, organisational capability and the development of a new generation of leadership for the clinical research sector. The Use of Competencies as Performance Standards Many employers still have the bad habit of hiring or promoting people based solely on the number of years’ experience, without regard to whether or not the individual is suited to their new position. Experience does not necessarily guarantee competence and may even lead to complacency, either by the individual themselves or the organisation they work for. An experienced but incompetent person can make errors like any novice, and potentially jeopardise the integrity of a clinical trial and put patients at risk. These people may struggle in their new role, particularly if it carries significant responsibility. The organisation itself can also be damaged, and teamwork and morale may also suffer. Objective criteria such as competence should be used to help select, develop and retain talent. Competence can be defined as the ability of a person to demonstrate knowledge, skills and behaviours. In order to thrive and prosper, organisations need to adopt a competence-based approach when selecting and developing their staff. A competency is a performance standard which is used to measure competence. Competencies define the skills, knowledge or behaviour required to perform a specific job role effectively and to the correct quality standards. Competencies for specific job roles can be arranged in frameworks. These are designed to map competencies to job descriptions or roles. They are part of an array of performance standards which can be used to help organisations and individuals to assess and manage individual and collective work performance. These frameworks are applicable to any organisation in the clinical research sector, from the largest to the smallest. Pharmaceutical companies, CROs, small biotech companies, individual investigator sites and investigator networks – all can make use of them. Competency Frameworks in Clinical Research The development of a competency framework starts typically with having a job description. The roles of a clinical research monitor and investigator are described comprehensively in the ICH Guideline for Good Clinical Practice E6(R2) in sections 5.18 and 4 respectively3. These descriptions can form the solid foundations for developing competency frameworks for these roles. There are various options for developing competency frameworks. One method is to align competencies in related clusters which cover the broad responsibilities of the job role in question. The descriptor of each specific competency is created and it is also helpful to provide examples of how the competency can be demonstrated. Competency frameworks should cover both the technical and nontechnical requirements of a job role. A sample of a competency framework for a clinical research monitor may resemble something like the example below.

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Competency frameworks can be used for: • • • • • • • • •

Hiring staff with the relevant skills, Selecting contractors and sub-contractors, Demonstrating the capabilities of organisations such as CROs and investigator sites, Conducting objective performance appraisals and assessments and delivering performance feedback, Setting professional working standards, which can be used in combination with SOPs and working practice guidelines, Selecting individuals for promotion, succession planning and career mapping, Identifying learning and development needs of individuals, teams and organisations, Creating focused training and development interventions, Workforce capability audits.

Verifying Competence – Accreditation In many other industries where health and safety is an issue, people working in those sectors are certified or accredited to fulfil their roles. There are plenty of examples where this applies. For the operation of pleasure craft there is an International Certificate of Competence (ICC),4 and the International Institute of Business Analysis (IIBA)5 has a system of accreditation for business analysts, to name but two of numerous examples. The clinical research sector is very unusual in this respect, in that although the guidelines and regulations require that individuals should be “qualified by education, training, and experience”3, there is no requirement for certification or accreditation and certainly nothing that demands proof of competence. This loophole in the regulations could be closed by using standard competency frameworks together with an accreditation system which involves assessing individuals’ competence against these standards. The system can be made robust by having the assessment system independently verified by organisations that are themselves regulated within internationally recognised qualifications and credits frameworks. Naturally, nobody wants to add to the bureaucratic load of clinical researchers. However, so much is at stake regarding the health, wellbeing and rights of clinical trial subjects that it is vital that there is some system for verifying that individuals working in clinical research are fully capable of doing their jobs. Using a 33 Journal for Clinical Studies

competence-based approach can result in cost savings in terms of using a specific and targeted approach to identifying and meeting training needs, rather than the outdated ‘shotgun’ approach where everyone is put through the same training irrespective of their individual performance gaps. It is also a much more cost-efficient way of developing the badly-needed new talent the sector is crying out for, particularly regarding the requirement for CRAs. Taking a Holistic Approach – Organisational Development As well as individual accreditation, it is vital that organisations support their staff by having systems and processes in place that enable their employees to develop and grow so that they feel engaged and have fulfilling work. As a minimum requirement, organisations should have job descriptions in place. Employee engagement should be an organisational priority. Many organisations have a mission, a vision and a number of values. Without meaningful implementation, these statements are sometimes represented merely by words on posters displayed round the office or on a website. Ideally the vision, mission and values, together with the organisation’s business objectives, should underpin all staff development and be communicated to each individual from the first day of their employment. These concepts should not only reinforce appraisal systems but also staff learning and development activities, so that employees can see the relevance of their work to the objectives and overall success of their organisation. In a fully functional and healthy organisation there should be development plans in place to address competence gaps. Competence assessment should be an ongoing process that occurs regularly and is linked to the organisation’s performance management processes and key performance indicators. Just as with individuals, there is the possibility of an accreditation model being used holistically by looking at the workforce as a whole, or even a section of an organisation. This could be applied to any size of organisation from all sectors of the clinical research community. There could be an independent assessment of the processes, procedures and practices of how an organisation develops its staff in line with its role within the clinical research sector. Leadership Development As well as individual competence and workforce capability, it is also vital that an organisation’s leadership is fit for purpose. Incompetent leaders and managers can have a significant effect on organisational Volume 10 Issue 2

Market Report performance, including employee turnover which can be damaging, particularly if an organisation is losing its most competent staff to its competitors. A survey conducted by the Chartered Management Institute6 revealed that 47% of people felt they were in a badly managed workplace, leading them to leave their job. Replacing staff is costly, as the accountancy firm PricewaterhouseCoopers reported when it revealed that the cost of hiring a new person to replace an existing employee who is performing optimally, is equal to that person’s annual salary6. There are other aspects to leadership development. The clinical research enterprise is international and today’s and tomorrow’s leaders will need to cope with the demands of increasing globalisation. Some of today’s managers will become tomorrow’s leaders and proper succession planning needs to be in place. Leaders need to be able to handle organisational change, including mergers, and head up new types of organisations as clinical research continues to evolve. Flexibility and agility are the order of the day and leaders should be constantly updating their skills to cope with the dynamic nature of clinical research in the 21st century. Leadership is arguably one of the most difficult challenges in the workplace. There is no single magic formula that leaders can use to get their team totally motivated all the time and continuously achieving outstanding performance. A person who excels in operations may not necessarily make the transition to leadership. Many people in leadership roles in clinical research have come up through the traditional scientific route. They may have had no opportunity to reap the benefits of participating in a structured leadership development programme with defined learning outcomes based on core leadership competencies. Such a programme should focus on business and organisational strategy finance and commercial skills, corporate governance and ethics, leading organisational change, and leading people. Summary Developing individual and organisational capabilities using a competence-based approach will help secure a clinical research sector which is fit for the future. Some of the benefits of individual accreditation include: • • • • •

Consistency across the sector globally, Reduction of vendor oversight costs for pharmaceutical company sponsors, Driving up quality and increasing the speed and efficiency in the way that trials are designed and conducted, Reduction in errors, regulatory findings and the costs of corrective actions, Reduction in repetitive and redundant training, e.g. GCP training.

In addition, by taking a holistic approach to workforce competence, by embedding values and giving context to employees’ work, the potential benefits are: • • •

Increased staff engagement, Decreased staff turnover – often a key performance indicator for contract research organisations, Attraction and retention of talented people for the clinical research sector.

In order to reap the full benefits of individual and organisational competence, dynamic and inspiring leaders need to be developed. By using a competence-based approach to developing leaders, the clinical research sector will be able to meet the challenges of an 34 Journal for Clinical Studies

increasingly complex, demanding and uncertain environment. The fast-changing political, technological, social and scientific landscape means that it is impossible to predict the future with any certainty. Developing leaders that can influence and shape the environment and lead dynamic, robust and agile organisations is vital to the successful future of the clinical research sector. REFERENCES 1. 2. 3. 4. 5. 6. The 2017 Avoca Industry Report, Evaluating and Managing Risk in Clinical Trials www./ uploads/2017/09/2017-Avoca-Industry-Survey-Report.pdf ICH Guideline for Good Clinical Practice E6(R2), www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Efficacy/E6/E6_R2__Step_4_2016_1109.pdf. Pages/what-is-the-icc.aspx Schueler P. and Brendan B. (eds), Re-Engineering Clinical Trials, 2015, Elsevier Press, ISBN: 978-0-12-420246-7

Martin Robinson Martin Robinson is the Co-founder and Executive Vice President of IAOCR Martin has worked across the international biopharmaceuticals industry for nearly 30 years and his extensive experience includes setting up a number of clinical research business ventures. Using his clinical operations and workforce development expertise, he is a leading expert in clinical research competence, at an individual and organisational level. Email:

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How to Rescue a Clinical Trial, if You Must Conducting a clinical trial is a huge and complex undertaking; there are, more often than not, challenges. And in an undertaking as scientifically and logistically complex as a pharmaceutical trial, there’s a lot that can go wrong. In fact, almost 50% of Phase III trials fail.1,2 They fail because the drug did not work or because the design of the trial was fatally flawed. But they can fail for other reasons, too, such as poor execution. Fortunately, troubled trials can often be rescued. Why do Bad Things Happen to Good Trials? Even a well-designed trial can veer off track in a variety of ways. No two studies are alike, but trials that go awry tend to run into common problems, such as: Timeline issues: Slow or inadequate patient enrolment is often due to recruitment challenges, sub-optimal site selection, and/or fatigue on the part of patients and investigators – possibly because a protocol demands the collection of too many (often non-essential) data points. Also, if the standard of care changes while a trial is in progress, patients may no longer be interested in enrolling or may drop out. Insufficient resources: Trials can falter if the sponsor or its CRO misjudge resource requirements and do not have enough clinical research associates (CRAs) to devote to the study, or they use subcontractors who don’t have enough experienced resources in the right places. Additionally, the sites themselves may not have sufficient trained personnel and study coordinators to support the trials. Or they may simply not have enough time, due to other responsibilities. Poor data quality: Serious protocol violations such as the unblinding of study arms, disclosure of confidential patient data, enrolment of ineligible patients, or lack of informed consent can seriously jeopardise a trial’s findings. And even minor protocol deviations, such as rescheduled study visits or incomplete collection of data points, can raise major questions about the integrity and quality of a trial’s data. If patient samples or study drugs are improperly handled and stored, matters can get worse.

The European Center for Pharmaceutical Medicine (ECPM) organised a seminar in September 2014 entitled “Why Do Clinical Trials Fail?” Based on presentations delivered by various experts at the seminar, we grouped the drivers behind Phase III failures into six categories:3 1. Basic science 2. Clinical study design 3. Dose selection 4. Data collection and analysis 5. Operational execution 6. Other (such as insufficient assessment of current standards of care) Trials that are in trouble due to basic science, clinical study design and dose selection are more challenging to rescue (if they can be salvaged at all). But often trials troubled by data collection and analysis or operational execution can. In these cases, PAREXEL has seen an 80–90 per cent success rate with appropriate interventions. Use Metrics to Spot Trials in Distress … And in Need of Rescue The best way to avoid having to rescue a trial is to do a good job of planning and executing it. But when things go wrong (as they often do), the first line of defence is early detection. PAREXEL uses many types of leading metrics, available in real time via the MyTrials platform, to alert us to a trial that is not proceeding as it should. Three examples of key metrics are: Cycle Times: If site startup or patient enrolment cycle times are lagging (planned versus actual), you need to find out why. If a chart of cycle times shows the line for “actual sites initiated” is starting to diverge significantly from the line for “planned sites initiated”, your trial may be heading off the rails. Budget: Multiple changes in the scope of a trial or significant timeline delays (e.g., due to sluggish patient enrolment) add costs and raise red flags. Quality: The number of protocol deviations and violations being reported – site-by-site and overall – provides a snapshot of the quality of data collection.

It is best to benchmark metrics not only against a trial’s original plan, but also against the internal database, tracking the same metrics for thousands of completed studies, matched on key aspects.

Once you have nailed down the nature and scope of a trial’s problem, the next step is to decide how best to fix it. The intervention required may be small and targeted, or large and comprehensive.

Overall, perhaps the single biggest driver of risk in clinical trials (presuming the drug works) is their increasing complexity. In the decade from 2002 to 2012, the average number of endpoints included in a pivotal trial nearly doubled, and the average number of procedures that a trial participant underwent rose from 106 to 167 – an increase of 58 percent.1

Small, Targeted Interventions can Often Prevent Big Problems Sometimes a problem can be handled with minimal disruption. For example, if the CRO cannot enroll enough patients, and does not have representation in countries that are deemed attractive for the relevant patient population (say, for example, Bulgaria, Poland or South Korea), the sponsor can subcontract a regional or global CRO to set up additional sites in these places. Or if a regulatory deadline is looming but the existing CRO is badly lagging in collecting data on a key endpoint, such as reading imaging scans in a breast cancer trial, the sponsor may enlist another CRO to collect retrospective data and complete the task in time for the planned database lock.

Complexity in a system tends to increase inefficiency; the greater the number of variables, the greater the probability those variables will burden a trial with conflicting demands and lead to disarray. Because more can go wrong, more will.2 36 Journal for Clinical Studies

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Another scenario where targeted tactics can rescue a trial is when the therapeutic standard of care changes while a study is in progress. I recently took part in revitalising a client’s Phase III oncology trial after an enrolment slump. A competing product had been approved for national reimbursement halfway through our client’s trial and quickly became the “gold standard” treatment. With a fully reimbursable medicine now an easy option, patients were far less motivated to enroll in the research study. The best way to avoid having to rescue a trial is to do a good job of planning and executing it. But when things go wrong (as they often do), the first line of defence is early detection. We tackled the problem with several interventions, starting with an outreach programme to better engage patient advocacy groups (PAGs). PAGs often run disease education programmes in hospitals at the point of care, and we worked with them to distribute educational materials that explained the societal benefits of participating in clinical research, as well as some of the extra patient evaluations, physician contacts and increased data collection that comes with being part of a study. We also increased the trial’s social media presence on PAG websites.

We submitted a minor protocol amendment, devised by statisticians, that loosened ever so slightly the trial’s overly strict prescription for follow-up visits (an inflexible 30-/60-/90-day visit plan was triggering too many protocol deviations), enabling the study sites to adhere to a more reasonable, real-life schedule. Finally, we bolstered the physician referral system by establishing relationships with key opinion leaders in the field. The result of these targeted interventions to increase and sustain enrolment in the trial allowed the sponsor to complete the pivotal study in a timely fashion, despite a shifting therapeutic and reimbursement landscape. Recognising the problem early (by tracking metrics) was crucial to solving it. For Large Interventions, Time is of the Essence When corrective and preventive actions won’t solve a problem, a complete switch of CRO provider is required. This is not common – but when a trial is in serious trouble, it may be the only option. A large intervention that includes switching CROs costs money and time, and can easily add three or four months of do-over work. Delays may result in the disillusionment and withdrawal of PIs, sites Journal for Clinical Studies 37

Market Report and patients. And it could delay market entry, placing projected revenue at risk and incurring higher competitive risks. So, it’s critical the receiving party gets its arms around the problem and puts new processes in place as fast as possible. The trick is applying the right resources (adequate CRAs in the relevant geographies) and expertise (i.e., therapeutic area specialists who need little ramp-up time to grasp the protocol design and the condition’s idiosyncrasies). In these cases, only a CRO with sufficient scale can streamline the process and minimise the hand-off’s impact on the overall product development timeline. A complete CRO transition involves both retrospective clean-up work and prospective work, all of which must be scoped out in advance and delivered within budget. Salvaging an Oncology Programme We were recently asked to salvage an oncology programme with four ongoing trial protocols. The sponsor had identified data quality issues and determined that a CRO switch and 100% re-monitoring was required. We assessed the resource requirements first. We assembled a team of 17 CRAs with oncology backgrounds in two weeks, conducted an intensive CRA training meeting, and coordinated data management with another CRO. After assessing and quantifying all known data, we prioritised tasks by project and by site, setting up a triage system (whom, how and when to contact) for the transfer of documents, data, and questions and answers – all with tracking. We scheduled visits to all sites, enlisting the sponsor’s support for site commitment, and sent CRA teams (one CRA served as team coordinator on each team) to sites with specific assignments for task prioritisation and completion. Weekly team meetings with the sponsor and data contractor, project leader, clinical operations leader, and CRA team coordinators allowed us to handle emerging issues and revise priorities as needed. This full-blown rescue effort met the sponsor’s aggressive timeline goals, and data from the programme supported the NDA submission. Optimising a Safety Trial for a Flu Vaccine When one of our clients asked us to take over a post-authorisation safety study (mandated by the EMA) of a flu vaccine, we assembled a cross-functional team to analyse options for optimising the flagging trial. We removed superfluous non-safety endpoints to decrease costs, shaved eight months off the overall patient recruitment timeline by targeting recruiting efforts more tightly and adding a country with a more sophisticated way of identifying patients in need of a flu vaccine, and increased physician participation by modifying data collection procedures — from requiring electronic data capture (EDC) only with on-site monitoring to allowing EDC plus paper options and remote monitoring for critical variables only — aligning the study more closely with clinical practice. Refining the trial on multiple fronts led to cost savings, faster enrolment and greater physician participation. Rescues Require Readiness, Expertise and Resources In any intervention, from small to large, readiness, expertise and resources are among the most important factors. Additionally, expert project management and planning drive successful rescues. Sponsors can prepare for inevitable hiccoughs by monitoring leading metrics and detecting problems early. A problem tackled early is always easier to remediate than one that has festered. Targeted corrective and preventive action can get a trial back on track. When it can’t, and a new CRO must be engaged to take over all or parts of a project, that CRO must have resources available in all the areas they are needed: CRAs, regulatory specialists, and so on, in the geographies where they are needed. 38 Journal for Clinical Studies


The Large Pharmaceutical Company Perspective, Michael Rosenblatt, M.D. N Engl J Med 2017; 376:52-60, January 5, 2017, DOI: 10.1056/NEJMra1510069 In defense of chaos: the chaology of politics, economics and human action, Samuels LK, Cobden Press, 2013 Phase III Trial Failures: Costly, But Preventable, Alberto Grignolo and Sy Pretorius. Applied Clinical Trials, Aug 01, 2016

Karen Chu, Pharm D. In her role as Corporate Vice President for Clinical Research Services, Karen has the responsibility as the Global Head for Clinical Operations. Karen responsibility includes the oversight of site management and functional lead role within Clinical. Prior to PAREXEL’s acquisition of APEX International Clinical Research Co., Ltd., Ms. Chu joined APEX in 2005 as the Executive Director for all clinical operations including Project Management, Clinical Operations, Data Operations & Statistical Analysis, Medical and Regulatory Affairs at APEX. In 2013, Karen transitioned to a global responsibility as the Worldwide Head for Project Support and Planning and Records Management while support the Asia Business. In addition, she has extensive experience with clinical trials both globally and in the APAC region, as well as a unique understanding of the diverse regulatory landscape in the AsiaPacific region. Email:

Dr. Sy Pretorius Dr. Sy Pretorius is the Chief Scientific Officer at PAREXEL and has been with PAREXEL for the past twenty-one years in a variety of roles and countries. On a dayto-day basis, Sy collaborates closely with biopharmaceutical and medical device clients in designing and optimizing drug / device development strategies and plans, as well as finding, evaluating and purchasing assets. As a member of the PAREXEL senior executive team, Sy is responsible for the overall leadership of a number of PAREXEL business units – these include our Global Early Phase business (responsible for Phase I and II clinical development), Global Medical Services (therapeutic area expertize, global medical writing and pharmacovigilance operations), Quantitative Clinical Development (modeling and simulation), as well as the Genomic medicine unit. Sy is absolutely passionate about drug development and leads several company-wide forums and initiatives focused on clinical trial innovation and further expanding PAREXEL’s capabilities and service offering. Sy is a Medical Doctor (M.B.,Ch.B) with Masters degrees in Clinical Pharmacology (M.Med.Sc), Business Administration (MBA) and, most recently in the Management of Drug Development (MS) from the University of Southern California (USC). Sy has and continues to publish and present extensively. Email:

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Clinical Development in Challenging Cancers: Ovarian Clear Cell Carcinoma (OCCC) Ovarian clear cell carcinoma (OCCC) is a rare histological subtype of epithelial ovarian cancers (EOCs), with an incidence, among EOCs, of 4–12% in western countries1–3 and a higher ratio of over 20% in Japan4,5. Histologically, EOCs are classified into serous, mucinous, endometroid, clear cell and undifferentiated subtypes. Ovarian cancer is already the leading cause of death among gynaecological malignancies in the US6; in addition, the OCCC subtype presents a lower response rate to traditional platinum-based chemotherapy and is generally associated with poorer prognosis across all stages compared to other EOC subtypes2,4,7–9. In 1973, the World Health Organization (WHO) strictly defined ovarian clear cell carcinomas (OCCCs) as lesions characterised by clear cells growing in solid, glandular, tubular, papillary or microcystic patterns or combinations thereof, as well as hobnail cells lining tubules and cysts10. Current Clinical Management The peak age group of incidence of EOC is 55–64 years11. OCCC generally presents as an observable pelvic mass12–14, and is associated with endometriosis1,4,15,16 and an increased risk of thromboembolic complications4,15,17,18, and more than half of patients are diagnosed early in Stage I2,18. Although chemoresistence is a significant challenge in OCCC management, no specific first-line treatment has been established to address this, and standard EOC treatment is used, which is summarised in Figure 1. Primary management is based on initial surgery19,20 with a goal of optimal cytoreduction, followed by adjuvant chemotherapy. Surgical interventions include total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy; however, there is currently no strong evidence that systematic nodal dissection improves survival21. In a meta-analysis, which included 835 patients with stage III and IV ovarian cancer, the incremental increase in chemotherapy cycles in the neoadjuvant setting was associated with a decrease in median overall survival compared to initial surgery22. Chemotherapy historically comprised a combination of cisplatin plus cyclophosphamide23, and later, cisplatin-paclitaxel doublet, due to evidence of superiority in effectiveness24. Finally, carboplatin was found to be an equally effective, but safer, alternative to cisplatin25, thus the current standard of care comprises carboplatin-paclitaxel combination. Several studies concluded that the use of VEGF (Vascular Endothelial Growth Factor) inhibitor bevacizumab, in addition to platinum-based chemotherapy, is beneficial to patients in late stages (III and IV), for patients with recurrent diseases, as well as patients 40 Journal for Clinical Studies

in early stages with a high risk of recurrence26,27. Bevacizumab has been approved as first-line treatment, in the mentioned settings, by EMA28 and FDA29. Additionally, since December 2016, three different target therapy agents from the PARP (Poly ADP-Ribose Polymerase) inhibitor group were granted approval by FDA in second-line treatment: rucaparib30, niraparib31 and olaparib32. While niraparib and olaparib were also approved by EMA33,34, rucaparib is pending approval. Theoretically, PARP inhibitors express most effectiveness in cells with deleterious BRCA mutations, thus the indication of rucaparib is restricted to these cases; niraparib and olaparib showed benefit to PFS (progression-free survival) regardless of BRCA status35,36. Although patients with identified germline BRCA1/2 mutations showed increased response to olaparib and niraparib treatment, the observed effect on patients without BRCA mutations can be explained by other deficiencies of the HR (homologous recombination) system in cancer cells, leading to susceptibility to PARP inhibition37–39. As these agents primarily demonstrated effectiveness in platinum-sensitive EOCs, and taking into consideration the lower BRCA mutation rates in the clear cell subtype40, their role in the management of OCCC is yet to be confirmed.

Figure 1: Overview of approved treatment options in EOC

Therapeutic Challenges OCCC is known to be less sensitive to platinum-based front-line chemotherapy and is associated with a worse prognosis. Crotzer et al. (2007)41 retrospectively analysed 51 patients with OCCC and concluded that OCCC is particularly chemoresistant and advocated for more active research on target identification. Another aspect in the clinical management of OCCC is the lack of effective chemotherapy for recurrent disease after front-line treatment with platinum-based chemotherapy. It was reported after a retrospective study in 75 OCCC patients42 that the response rate for various regimens in the setting of second-line chemotherapy for recurrent platinum-resistant OCCC was only 1%, and suggested that recurrent or resistant OCCC is extremely chemoresistant, and there is only a small benefit of long treatment-free periods in OCCC patients. Conventionally, the OCCCs were considered as a homogenous subtype of EOC at the molecular level until 2011, when Tan et al.43 Volume 10 Issue 2

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Therapeutics subjected 50 archival OCCCs to high-resolution microarray-based comparative genomic hybridisation analysis that revealed OCCC are indeed genetically heterogenous, and can be further subdivided into distinct patterns of copy number aberration. Based on this, two distinct genomic subgroups of OCCCs (cluster-1 and cluster-2) that did not significantly differ in terms of their clinicopathological and histological features were identified. Subsequent survival analysis revealed that patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs 65 months, P=0.009) and subsequent multivariate analysis revealed that genomic cluster was an independent prognostic factor for PFS. Distinction of OCCC from high-grade serous carcinomas (HGSCs) was a diagnostic challenge. In 2006, Kato et al.44 presented that hepatocyte nuclear factor-1beta (HNF-1beta) was significantly upregulated in OCCC, and proposed HNF-1beta as an excellent biomarker for OCCC. This was later confirmed by Kobel et al.45, by examining 133 OCCC samples. However, a specific antibody for HNF-1beta was not developed and its potential as a therapeutic target in such tumours of high expression remains unexplored. Various studies were conducted to understand carcinogenesis in OCCC, and multiple OCCC-specific genetic mutations and altered protein expressions were identified, leading the way to the discovery of molecular pathways that could shed light on potential therapeutic targets. Unlike serous ovarian cancers, OCCCs show low frequency of BRCA1 and BRCA2 mutations, but harbour important alterations in AT-rich interactive domain 1A (ARID1A), phosphatase and tensin homolog (PTEN), and phosphatidylinositol4,5 -bisphosphate 3-kinase catalytic subunit α (PIK3CA) mutations46.

line chemotherapy in recurrent or advanced ovarian clear cell carcinomas, with no results to date49. PD-1 Inhibition Multiple molecules were developed inhibiting interaction between Programmed Cell Death Ligand 1 (PD-L1) and PD-1. PD-L1 may be expressed or overexpressed by tumour cells, leading to decreased T-cell response from the immune system and subsequent decreased anti-tumour activity. By inhibiting this interaction, anti-tumour activity may be increased. It is notable that in previous studies examining the safety and efficacy of PD-1 receptor antibody Nivolumab50 and PD-L1 antibody Avelumab51, in refractory or recurrent ovarian cancer patients, best results were achieved in patients with the OCCC subtype52. Although no OCCC-specific study has started as of now, it may be a promising direction toward target therapy in the treatment. A recent Phase II study is recruiting patients with recurrent OCCC comparing Durvalumab to any second-line standard chemotherapy53. Multi-kinase Inhibitors ENMD-2076, a multi-kinase inhibitor, with effect demonstrated on Aurora-A kinases, VGFRs, FGFRs and other targets, is examined in a Phase II clinical study for OCCC treatment54. The study concluded with 40 patients and demonstrated a PFS of 20% after six months. However, patients with ARID1A loss demonstrated better results, despite loss of ARID1A being a negative prognostic factor55. Although additional molecular profiling for interpretation of results is still underway, further research will not be continued by the current manufacturer to demonstrate efficacy of ENMD-2076 as a monotherapy56.

Here, we will discuss some of the key pathways and agents tested with clinical studies in recent years. Clinical Development in OCCC Published results from recent clinical studies of OCCC patients are seen in Table 1, while there are several other ongoing clinical trials. mTOR Inhibitors mTORC1 (mammalian target of rapamycin complex 1) was shown by immunohistochemical analysis to be more frequently activated in OCCC than in serous adenocarcinomas (86.6% versus 50%)47. Additionally, various studies have shown that ovarian CCCs often exhibit genetic alterations in one or more components of the PI3K/ AKT/mTOR signalling pathway46. VEGFR Inhibitors The most successful VEGFR inhibitor, bevacizumab, an antiangiogenic humanised monoclonal antibody that inhibits the binding of both VEGFR-1 and VEGFR-2 is already approved in the treatment of ovarian cancers. Recently Sunitinib, an oral multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) pathways was evaluated by a Phase II study in 30 subjects with persistent or recurrent OCCC. Five (16.7%) patients had PFS ≥ 6 months (90% CI: 6.8%, 31.9%). Two (6.7%) patients had a partial or complete response (90% CI: 1.2%–19.5%). The median PFS was 2.7 months and the median overall survival was 12.8 months, and it was concluded that Sunitinib demonstrated minimal activity in the second- and third-line treatments of persistent or recurrent clear cell ovarian carcinoma48. Nintedanib, which is also an inhibitor of FGFR (fibroblast growth factor receptor) and PDGFR (plateletderived growth factor receptor) in addition to VEGFR is examined in a Phase II study comparing efficacy to standard second42 Journal for Clinical Studies

Table 1: Overview of recent OCCC-specific studies with published results

Conclusion As demonstrated, the clinical management of OCCC remains to be a significant challenge for clinicians to this day. This specific subtype of EOCs is not only primarily chemoresistant, but is genetically heterogenous and no effective therapy has yet been identified to overcome this obstacle. Even the promising results of some of the newer treatment options for EOCs, like the PARP inhibitors, cannot be extrapolated to OCCCs due to the difference in tumorigenesis and genetic mutations. It can be observed that current clinical studies do not routinely focus on stratification by histological subtype and therefore the advancements in overall EOC management often overshadow the fact that OCCC treatment, especially in an advanced setting, is still unresolved. To facilitate the advancement of OCCC management, further genetic research is needed to define the potential target points for emerging future treatment options and the currently ongoing Volume 10 Issue 2

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Therapeutics clinical studies need to be more focused on examining the effects of the experimental treatments based on histological subtypes. The question also arises if there is a need to define a separate first‑line treatment protocol for OCCC management based on the high ratio of platinum-resistant diseases. There have been minor improvements in recent years to the treatment of advanced OCCC, but the results need to be further verified on larger patient groups. There are also some promising pathways waiting to be explored, like the PD-1 checkpoint inhibition or the potential benefit from PARP inhibitor therapy. REFERENCES 1.


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Vijayanand Rajendran, MD Vijayanand Rajendran is the Senior Clinical Research Physician at Europital. Qualified physician with over ten years of clinical and research experience. Hands-on experience in safety monitoring of Phase I-IV trials in a variety of therapeutic areas including oncology, haematology, respiratory, gastroenterology and the musculoskeletal system. Email:

David Winkler, MD David Winkler is a Clinical Research physician at Europital. Skillful pharmaceutical physician with over 5 years of clinical and drug safety experience. Extensive knowledge in medical/safety review and postmarketing adverse event reporting with a strong clinical background in orthopaedics, trauma surgery and patient care in general. Handson experience in medical management and monitoring of phase I–IV clinical trials in diverse therapeutic areas. Email:

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

Journal for Clinical Studies 45


Immune Mediated Inflammatory Diseases (IMIDs) and Unmet Medical Need Our immune system is extremely complex and is of great value for our health. HIV and its destruction of the immune system offer clear evidence. Many researchers have long lived with the virtue of understanding the autoimmune disease specifically on a molecular level. The IMID acronym might not be as popular as the names of the conditions it represents, such as rheumatoid arthritis, psoriasis, and Crohn’s disease. Most of these conditions are debilitating and sometimes lifethreatening. History and Background In the early 1980s, a series of parallel studies from several laboratories shed some light on the importance of cytokines in the process of immune disease. These studies showed that human leukocyte antigen molecules on the cell surface, especially the class II molecules involved in antigen presentation, are upregulated in some autoimmune diseases such as thyroiditis and rheumatoid arthritis, leading to speculation that the molecules augmenting major histocompatibility complex class II might be important pathogenic factors in autoimmunity1. Initially, interferons were the only cytokines known to regulate major histocompatibility complex expression. Hence, it was appealing to start studying cytokines at the height of disease activity such as the synovium in rheumatoid arthritis. This was made possible via cloning of cDNAs of cytokines such as interferon-beta, interleukin-2 (IL-2)2, tumour necrosis factor-alpha (TNF-alpha), lymphotoxin3, and IL-64. Rheumatoid Arthritis (RA) Rheumatoid arthritis is considered one of the most common autoimmune diseases, resulting in the destruction of the joints, long-term disability and shortened lifespan. Interleukin-1 (IL-1) has been viewed as having major importance in inflammatory arthritis. Experimental work has shown that if TNF-alpha was blocked using specific antibodies, IL-1 production was ceased. Accordingly, TNFalpha was identified as a major pro-inflammatory cytokine and was considered a “master regulator”. Moreover, further work has shown that TNF blockade led to the reduction of other inflammatory cytokines such as GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), IL-6, and IL85,6. Thus, TNF-alpha blockade, through the inhibition of several pro-inflammatory cytokines, has become a therapeutic possibility for rheumatoid arthritis. Clinical data have shown that anti-TNF therapeutic agents were very effective in the treatment of rheumatoid arthritis with remarkable and rapid improvement in pain, fatigue, and mobility. Additionally, there was a remarkable inhibition and possible healing of bone erosion and loss of cartilage, as assessed radiographically. Most importantly, there was a significant improvement in physical function that was sustained for a duration of more than two years in patients with moderate to severe impairment7, thus emphasising the value of anti-TNF therapy even at a late stage of the disease. 46 Journal for Clinical Studies

Moreover, the availability of some of these agents as selfadministered subcutaneous injections increased the choices that patients have in terms of route of administration. In fact, a significant number of patients went under treatment for more than five years without loss of efficacy and, in many of these patients, it was possible that reducing the dose of corticosteroids was required to control the disease8. However, the simultaneous reduction of the pro- and anti-inflammatory molecules may very well provide an explanation for the lack of restoration of homeostasis in the cytokine network and the fact that the sustained remission of the disease is relatively rare. It is also noteworthy to state that anti-TNF therapy involves the risk of inducing a lupus-like disease. Hence, risk-benefit analysis is essential, in addition to careful monitoring during treatment with anti-TNF therapeutics. Additionally, infusion reactions, injection site reactions, and increased incidence of lymphoma are adversely related to the treatment. Relatively speaking, significant joint protection was documented with TNF inhibitors including antibodies and antibody-like receptor fusion protein, and accordingly a justification for the significant sales of TNF blockers, despite their substantial costs. Other Autoimmune Diseases TNF inhibitors have been therapeutically successful in the treatment of several autoimmune diseases such as ankylosing spondylitis, psoriatic arthritis, psoriasis, sarcoidosis, amyloidosis, Bechet syndrome, and vasculitis. Thus, the potential of future indications remains to be seen. Although these patients’ populations are comparatively small, IMID patients usually suffer severe debilitating disease complications. Ulcerative colitis (UC) is a perfect example; although chronic UC affects more people in the United States than multiple sclerosis or cystic fibrosis, general awareness of the disease is much lower. UC is characterised by inflammation and ulceration of the inner epithelium of the colon, leading to complications such as weight loss, severe bloody diarrhoea, fatigue, and frequent abdominal pain. Disease management for some of these patients would include surgery; colectomy. Additionally, for other patients the condition may lead to serious complications, such as colorectal cancer. Clinical judgement has shown that tissue protection was also present in Crohn’s disease9 patients when treated with TNF inhibitors, even with minimal anti-inflammatory effect. For instance, in many cases, conventional systemic therapy for both psoriasis and psoriatic arthritis are either ineffective, are poorly tolerated, or are unable to maintain long-lasting remission. Biologic agents such as etanercept and infliximab have been used for plaque psoriasis. Meanwhile, adalimumab has also been used for psoriatic arthritis. The most efficient method for advancing lupus therapy through clinical trials is to study promising agents in highly enriched Volume 10 Issue 2

Growth needs space We expanded our premises to a third building, making our working area 2400 m2. MLM Kit Building was launched and we became even more flexible in providing sampling kits. Currently we are running over 130 studies in parallel and our dedicated team grew to over 50 people.

Staying dynamic for your trials!

Building 61 since 2016

Building 63 since 2012

Building 57 since 2017

MLM Medical Labs is one of the leading Central Labs for clinical trials in Europe. For further information please contact Dr. Katja Neuer at or visit us at

MLM Medical Labs GmbH Dohrweg 63 41066 Mรถnchengladbach Journal for Clinical Studies 47 Germany

Therapeutics populations performed by experienced, preferably academic centres involved in its design. Metrics need to be reevaluated from scratch. Consideration should be given to prevention, induction, maintenance, flare reduction and using a combination of agents that would be disease-modifying, damage-preventive and cost-effective. Therapeutics and Unmet Needs In spite of the fact that long strides have been made in the treatment of autoimmune diseases, many hurdles still exist on the road to finding a cure. Immunogenicity is an important aspect of treatment. High doses of infliximab (anti-TNF) alone or in combination with methotrexate has been proven to be less immunogenic. The combination of other anti-TNF agents and methotrexate has been shown to be superior to monotherapy in studies with both soluble TNF receptor fusion proteins (etanercept) and a fully human monoclonal antibody (adalimumab). All therapeutics for IMIDs have identical goals; to gain rapid control of inflammation, prevent tissue damage, improve quality of life (QoL) and, if possible, achieve long-term disease remission. As these goals are rarely met in each patient with traditional treatments, presumably due to failure to address the underlying immunopathology, targeted biological therapy has been revolutionary. Other biologics such as rituximab and abatacept have been successful in patients with an inadequate response to anti-TNF alpha therapy. However, multiple complications have been reported with biological treatment, such as TB reactivation, infection, increased incidence of congestive heart failure, lymphoma, solid malignancy, and the development of antinuclear antibody. Additionally, serious adverse events have been reported and long-term safety data is needed. Moreover, concurrent treatment with two biologics has led to serious infection. There are several unaddressed concerns related to the agents used in the management of these conditions, ranging from the appropriate use, to per-patient and aggregate costs, to utilisation management, to managing site of care, to incorporating these agents into the current information data systems, to which patients are appropriate for a certain therapy. No doubt, IMID is an area of high unmet medical need. Biologics may fill a gap in that need; as many IMID patients have only experienced partial or perhaps no response to other available therapies10. Method of delivery or mode of administration of the treatment is a unique area for innovation and creativity. Some of the IMID treatments are administered in physician offices or other healthcare provider locations via intravenous infusion at periodic intervals. This would allow patients to choose from a wide selection of infusion-delivery sites and definite convenience that ensures compliance. Additionally, in-office infusions, unlike at-home treatments, are administered under the supervision of a healthcare professional who can monitor the patient’s progress, response, and compliance. Moreover, this allows for instant dose adjustment if needed according to any weight changes. Thus, patient management may be dependent on formularies that accommodate both infusion and injectable treatments in 48 Journal for Clinical Studies

order to satisfy patient differences with regard to preference, comfort, and the extent to which the treatment is efficacious. Patient access to current innovations in treatment is still a challenging matter. Education of both healthcare professionals and patients can play a vital role in the practicality of office-based infusions of these critical therapies. Basically and simply said; getting the right drug to the right patient. Partnerships with professional organisations can also be a major contributor in ensuring patient access to treatment. Patientadvocacy groups, such as Arthritis Foundation, the Crohn’s & Colitis Foundation of America, and the National Psoriasis Foundation, are major players in the field. Additionally, manufacturers usually provide patient assistance programmes to assist patients of lower incomes receive the required treatment10. Efficiency and uniqueness are clearly exemplified in IMID therapeutics as, in some instances, a biologic that has been developed for one condition may show the same efficacy for other inflammatory conditions. However, that remains an important question that requires an answer via extensive research for several years to come. The fact here is that it is always about bringing the highest scientific standards to ultimately help patients10. Conclusion Future frontiers are expected. IMID research is about to become a public health priority. Recent research has shown patterns of comorbidity between IMID diagnoses and increased risks for other disease such as liver, renal, and cardiovascular disorders, as well as lymphoma. Additionally, patients with IMID diagnoses were found to be high consumers of healthcare in general. As a result, the healthcare is witnessing a heightened value in biologics, evidenced by the rapid growth that has been predicted for the near future. Several bio-therapeutics for multiple indications will be approved within the next few years, since new products are being developed and existing products are being approved for new indications. Accordingly, there will be an increasing demand for patients and physicians to understand the long-term benefits of these therapeutics, from cross-disease potential to compliance. As WCT has been involved in many IMID trials, we have participated in several discussions related to unmet needs in this patient population. Billions of dollars have been spent on these trials and our ultimate goal has always been to help our sponsors to effectively design their trials in order to develop the optimum therapy for these devastated patients and improve their quality of life. Several Questions Remain Unanswered 1. Why is there a difference in response to TNF blockade? Good responders, low responders, and non-responders? Is it genetic or acquired? 2. What are the other therapeutics that can be added to anti-TNF to increase the therapeutic benefit but not the side-effects? 3. Etiology of some of the side-effects of anti-TNF treatment is not well understood, such as: • The induction of antibody response against doublestranded DNA • Severe infections • Possible demyelination Volume 10 Issue 2

Therapeutics 4. The reason for the superior effectiveness of multiple anticytokine therapies that block TNF, IL-1, IL-6, or IL-15 in comparison to the partial effectiveness of anti-immune therapies (anti CD4, CD7, CD5, or CD52)? 5. Would it be possible to block the initial production of TNF in the pathological tissue itself? 6. Is there a possibility of finding a cure? How far are we? REFERENCES 1.

2. 3. 4. 5.

Bottazzo, G.F., Pujol-Borrell, R., Hanafusa, T. & Feldmann, M. Role of aberrant HLA-DR expression and antigen presentation in the induction of endocrine autoimmunity. Lancet 2, 1115-1119 (1983). Taniguchi, T. et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 302, 305-310 (1983). Pennica, D. et al. Human tumor necrosis factor: precursor structure expression and homology to lymphotoxin. Nature 312, 724-729 (1984). Yasukawa, L. et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6 gene). EMBO J. 6. 2939-2945 (1987). Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in

rheumatoid arthritis. Annu. Rev. Immunol. 14, 397-440 (1996). Haworth, C. et al. Expression of granulocyte-macrophage colonystimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur. J. Immunol. 21. 2575-2579 (1991). 7. Elliott, M.J. et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 36, 1681-1690 (1993). 8. Van Dullemen, H.M. et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129-135 (1995). 9. Feldmann, M. & Maini, R.N. TNF defined as therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nature Medicine, Volume 9, Number 10, October 2003. 10. Marquardt, J. I.M.I.D. Spurs Innovations, Tough Payer Questions. Biotechnology Healthcare-February 2006. 6.

Jim Khalifa, M.D. Dr Khalifa has more than 25 years of experience in clinical research and drug development in the pharmaceutical and biotechnology industries. He has managed several clinical programmes from inception in multiple therapeutic areas including inflammation, neuroimmunology, neurology, endocrinology, cardiovascular, urology, women's health, respiratory disorders, rare diseases, and oncology. Throughout his career, Dr Khalifa has been responsible for the submission and approval of 11 NDAs (new drug applications). Jim brings a tremendous wealth of experience to any organisation. He has held several executive leadership positions with major pharmaceutical companies. Prior to his work in the pharmaceutical industry, Jim was in clinical practice in New Jersey and New York. He was trained in internal medicine and neurology at Linden Medical Center in New Jersey and is Internal Medicine Board eligible. Jim received his medical degree from Alexandria University, Egypt and continued his medical education at Harvard Medical School. He also received his EMBA from the University of Science in Philadelphia. Dr Khalifa has received several awards for his achievements in clinical research. Very well-known professional organisations worldwide have recognised his work. Jim is also a member of several humanitarian organisations such as the World Health Organization, Doctors without Borders, and the Boston Cure Project. Email:

Aleksandra Bibic, M.D. Aleksandra brings 11 years of experience in working in the pharmaceutical, biotech, and CRO industry, as well as six years of experience as a general practitioner. Her work spans many therapeutic areas, including CNS, cardiology, endocrinology – diabetes, haematology (anticoagulation), nephrology, pain, SLE, dermatology and psoriasis. She has worked on several projects, including rare diseases, acromegaly pemphigus and Gaucher’s disease. Her experience encompasses all Phases of clinical trials, from first-in-human to post-marketing studies. She has extensive experience in drug safety and operational activities. Email:

Journal for Clinical Studies 49


Why the Need for Centralised Content Management is on the Rise Despite the advances in electronic content management over the past decade, many of the biggest global life sciences companies still manage their local translations in a highly fragmented way. Not only does this lead to a rise in costs, but it also comes with risks to safety and slows down product speedto-market. Competition in the life sciences sector has never been tougher, and for organisations to succeed requires a combination of business agility and control. Agility allows organisations to get their product to market more quickly, and control ensures that they never fall foul of local market requirements. However, despite being an industry which is subject to stringent, diverse and frequently changing regulation, life sciences has a tendency to manage content for international markets in an inefficient and error-prone way. For example, it’s not uncommon to manage patient information and labelling and packaging in a manual, decentralised, and case-by-case way. When content on packaging or labelling needs to change, each country must oversee its reviews. Visibility is quite limited, and the correct master content and relative status of each country’s version are not always clear. Where affiliates are involved, the line of sight is further blurred. It’s a situation that has become unsustainable. The life sciences market has been a slow adopter of advanced content management technology, preferring traditional ways of managing processes and content because of the comfort factor associated with hands-on checks, or viewing content development and translation as an afterthought. But the volumes of patientfacing content manufacturers and distributors are required to maintain for each product, in each market, is increasing exponentially. Not only are companies advancing into modern technologies, making more products, and expanding into more countries and emerging markets; safety and regulatory requirements they must adhere to are multiplying and changing all the time. The result is increased risk of incomplete or inaccurate information that leads to late-market introduction because compliant labelling or patient literature isn’t ready. Lengthy Update Cycles There are many different factors that can drive a change to labelling, including changes to product safety information, new or changed local regulatory requirements, and ongoing product updates due to an increase in the agile development methodology. 50 Journal for Clinical Studies

To illustrate the challenges, take an extreme example. A company with 1000 distinct labelling deliverables distributed to international markets requiring translations in 50 different languages could face endless cycles of updates as changes are absorbed, approved and rolled out to each country. It’s not unusual for a major update cycle, impacting all labelling, to take up to two years, tripling the size of the team involved, if this is managed manually and in a highly dispersed, siloed or non-centralised manner. By the end of this highly protracted process, new changes are likely to be needed. The situation is becoming more, rather than less, challenging. Increased focus on improving patient safety internationally means countries that once accepted English as the language for product labelling and instructions for use, now require local translations. Similarly, organisations can no longer get away with imposing the most commonly spoken versions of a language (such as Spanish); they’re now expected to reflect each market’s variations – so that Mexico, for instance, gets its own translation. This is increasing the workload associated with creating compliant patient information. It is becoming overwhelming, and an inhibitor to the agility companies seek to maintain their competitive position in a dynamic yet highly regulated global market. Adding to the market’s dynamics are the continued elevated levels of merger and acquisition activity, which are further intensifying the demands on content management – as brand names, copyright details, and corporate identity change. These changes must be reflected across all external content and often require re-submission and registration with different international notified bodies – a process that can take many months in some countries. Complexity, Risk of Error and Costs are All on the Rise If content is not managed in a structured, centralised way, complexity, risk of error, and inflated costs can grow exponentially. This situation is magnified if responsibility for local versions is left to in-country distributors or affiliates, and can lead to retrospective labelling, a common burden for companies marketing drugs internationally. It happens where content is developed in local languages and must be translated into English for verification, corrected, and then translated back into the local language, and sense-checked to ensure its meaning has not been distorted along the way. Failure to produce correct, compliant labelling and other patient information can delay market entry, or worse, result in costly product recalls, or pose a threat to patient safety. Mistakes can lead to reams of pre-printed content (e.g., stack upon stack of instructions-for-use leaflets sitting in warehouses, ready to ship out with products) having to be pulped. Volume 10 Issue 2

Technology Wanted: A Systematic, Centralised Approach to International Packaging and Labelling After decades of making do with the old ways of managing international labelling, the realisation is finally dawning that things can’t continue – a manual approach is unsustainable, risky and highly inefficient. Continuing to treat packaging, labelling, and regional translations as an afterthought at the end of a long and complex research and development process is potentially undermining all the investment that has gone before. In the meantime, everything points to the need for life sciences companies to adopt a systematic, centralised approach to international packaging and labelling, to reduce labour, shorten time cycles, reduce risk and cost, and substantially improve market agility. So, what does best practice in global labelling look like? Establish Content Ownership Centralised content management begins with content ownership, which should be brought under a single team - for instance, technical communications. Appointing someone to own all content (including translated versions) brings clarity and an opportunity to drive change from a single focal point. As an extension of this single point of focus, it makes sense to have a single, unified content asset database which is hosted centrally. For the sake of simplicity and ease of access, it is advisable to host this in the cloud (by way of a software-as-a-service model), to allow authorised teams ease of access anywhere in the world. The right system provider will have several data centres across different geographic regions, to ensure distance is no barrier to the system’s performance and that latency is minimised. This added advantage of using an externally hosted content management system is that companies don’t need to manage, administer or support the technology themselves (it’s all done for them). The right provider will be able to provide guidance on setting up good internal processes to ensure teams get the most from the centralised approach to global information and achieve international consistency. Given the very specific and complex needs of global life sciences content management, it is worth looking for a system that has been designed specifically to cater to the nuances of this highly regulated environment and provides a fit-for-purpose workflow for rigorous quality assurance and traceability that will be needed. A system that can manage content at a component level, rather than at a document level, is recommended. This allows approved components (e.g., associated with warnings, instructions or disclaimers), or other digital assets such as logos or symbols, to be simply plugged into different types of output. This ready repurposing reduces the overall scale of the task and the risk of mistakes being introduced each time changes are required. Measuring ROI on Centralisation The benefits of centralising and streamlining global information are well proven. Major international labelling updates involving thousands of different pieces of output have been shown to shrink from two years to six months. Desktop publishing costs can be halved across all languages, thanks to automated publishing made possible through a centralised content management system.

The typical international content lifecycle meanwhile can be reduced from 28 weeks to as short a time as nine weeks, through content modularisation and concurrent rather than sequential content development. Moreover, centralised, automated management of content has become the standard methodology in most industries now – from banking to the legal sector. It’s much easier to visualise, verify, trace and audit, and it’s many times more efficient and confidenceinspiring than ad-hoc, distributed processes which depend heavily on manual actions. Agile organisations can keep pace with markets because they can adapt and respond quickly to the environment around them. In life sciences, centralised, systematic control of global product information is the best way of achieving this.

Jason Arnsparger Jason Arnsparger is Program Manager at AMPLEXOR Life Sciences and has been in the localisation industry, focusing on life sciences, for 13 years. He works with life sciences companies to define, develop and implement strategic processes and systems to streamline the product development and localisation life cycle. Before joining AMPLEXOR, he worked at a leading medical device company, where he led the way in developing the localisation process and continuous process improvements. Jason has a B.A. in Modern Languages, is a certified Project Management Professional from the Project Management Institute, is a certified Six Sigma Green Belt, and is training for his Six Sigma Black Belt certification. Email:

Journal for Clinical Studies 51


How Integrated Technology Benefits Patients and Investigators in Diabetes Clinical Trials Doctors are warning of the ‘absolute pandemic’ of diabetes. In the US alone, 100 million are diagnosed with diabetes, with many millions more undiagnosed or unaware of their condition. In July 2017, the Centers for Disease Control and Prevention (CDC) reported that more than 100 million Americans have diabetes or prediabetes1. By 2035 it is predicted that diabetes will be the seventh leading cause of death, affecting more than 592 million people worldwide2. Given these statistics, it is not surprising that pharmaceutical companies are heavily investing in this area. Researchers are, therefore, adopting technology to elevate their clinical trials for better data, reduced burden on patients, and increased patient safety. This article explores how connected technology and electronic solutions can be integrated specifically into diabetes clinical trials to meet the needs of clinicians and patients. Connected Devices Clinical research is changing due to the Internet of Things (IoT) and the Internet of Medical Things (IoMT). New data from Juniper Research predicts the number of connected IoT devices will reach over 46 billion in 20213. IoT connected devices currently include standard smartphones, tablets and bluetooth speakers. While 5G is not expected until 2020, this low-bandwidth technology has the potential to be included in devices with IP addresses and battery lives of up to ten years, designed to passively collect and transmit data as required. 5G's speed and capacity will therefore enable an even more connected future. IoMT connected medical devices can be defined as wireless, wearable or implantable digital technologies used in healthcare and clinical research to passively collect biometric data about a patient’s health. These devices may be regulated or not. For example, Class I, II, and III regulated medical devices include glucometers, spirometers, weights, scales, and implantables, while unregulated devices include activity trackers, smartwatches, cardiac monitors and body temperature devices. As noted, these devices are collectively part of the IoMT network, and can be applied to clinical trials in several beneficial ways, including the capture of better quality data. Integrating Technology into Diabetes Clinical Trials Diabetes is a complex condition for patients to manage, with significant impact on patients’ daily lives. Managing the condition can involve a variety of demanding tasks including taking regular measurements of blood glucose, monitoring the nutritional value of meals and tracking insulin usage. Diabetes clinical trials typically seek to capture this data, as well as expecting participants to complete a variety of additional patient-reported outcomes, often while having to alter their normal established routine to align with the study protocol. It is difficult for patients to remember to report everything at the right time and this increased complexity can lead to higher patient burden and risks, resulting in additional worry and lower compliance within the study. The key to optimising data collection is to understand the patient perspective and how each activity affects their everyday life. Managing diabetes clinical trials can similarly be a challenge to the investigators if patients are not reporting data accurately, as they use 52 Journal for Clinical Studies

this data to closely monitor patients’ wellbeing. A 1984 publication concluded that, “Two thirds of the subjects had reported values (on paper) in such a manner as to obscure hyper- and hypoglycemia, leading to misleading clinical impressions about the fluctuation in metabolic control4.” This leads to the conclusion that paper collection impacts data quality and therefore also impacts monitoring patient safety. Robust and intuitive systems for use in diabetes clinical trials are needed to capture clinically relevant data, decrease patient burden and increase patient safety. Developing an Effective Electronic Solution A leading provider of patient-centred eSource and electronic solutions for the life sciences industry, CRF Health, identified a need for a diabetes solution that not only caters to the clinical team and sponsors’ needs for accurate data collection, but is also relevant to a patient’s symptoms and typical daily routine, thereby limiting any additional burden to the patient. The company implemented a project to identify what constitutes a good electronic solution. The process took the following stages: 1. Collect feedback from sponsors and patients a. Client interviews to gather requirements and challenges b. Online survey of diabetic patients 2. eDiary design for collecting ePRO data in trials 3. Test and refine the eDiary design a. Diabetes focus group testing 1. Revisions based on focus group b. Independent usability testing 1. Revisions based on usability testing c. Second round of independent usability testing 1. Revisions based on second round of usability testing 4. Final eDiary solution Let’s take a deeper dive into the process: Collecting Feedback from Sponsors and Patients While designing this solution, feedback from sponsors on previous studies was used to identify the specific challenges associated with capturing patient data in diabetes populations. Input was also gathered from the intended users of the solution: the patients. An online survey was used to assess aspects of diabetes patients’ daily routines. The survey was completed by patients from a diabetes support group, with a wide mix of ages, sexes and type I and type II diabetes. eDiary Design, Testing, and Refinement The feedback from sponsors and patients was used to implement the design and layout of the initial diary (CRF Health’s TrialMax Touch® software for handheld devices). This alpha version of the solution was then tested in focus groups formed of members of a diabetes support group, providing hands-on user testing data. This feedback was used to update the content, design and layout of the diary. Once the diary had been refined, it was sent to an independent third party for usability testing with diabetes patients. The purpose Volume 10 Issue 2

Technology was to determine how suitable the tailored eDiary was and to ensure it fit in with the daily routines of diabetic patients. The feedback was used to further refine the diary and a final round of testing was done to gather evidence that proved the intended population deemed the product intuitive and easy to use. The patients from this study expressed a preference for the integrated electronic diary over traditional paper and electronic reporting methods, as they found it to be less burdensome, and given the option, they would choose to use it in a clinical trial setting. Final eDiary Solution The solution developed to minimise burden incorporates a handheld device, a bluetooth-enabled wireless glucose meter (MyGlucoHealth) which allows data transfer to the diary, and a site management software tool (see Figures 1 and 2). • • •

The home-based eDiaries are integrated with a glucometer, allowing for the automatic capture of glucose readings (Figure 1) The diary indicates what tasks have been accomplished for the day and what still needs to be done Reports for investigators are available in near real time because of automated data sending

of the data values. Date and time stamps of the reading and the device serial number are also transferred, providing evidence of the timeliness of the data and an attributable source. Once the eDiary receives the values from the glucometer, the values can automatically be sent to the ePRO database for review by the site personnel or study team. This allows very close to real-time monitoring of the patient’s status and permits timely intervention for safety or compliance concerns. Patient experience is key. The patient should be able to report meals, blood glucose, insulin and hypoglycemic symptoms and events. The devices should have well-designed user interfaces for a pleasant user experience, with reminders, prompts and notifications to encourage reporting to boost compliance and complete data. A good system should also deploy common diabetes instruments, such as pre-approved questionnaires that can be deployed electronically. From a site perspective, a system should allow near real-time view on the patient’s wellbeing including glycemic control and hypoglycemic events, as well as insulin use, to allow follow-up on patient compliance. The Electronic Revolution By utilising sophisticated wireless biometric sensors and devices, real-time patient readings can be collected and seamlessly uploaded to cloud-based platforms, for data aggregation, reporting and analysis. This in turn leads to improved data quality and study efficiency, meeting the needs of the trial sponsor. From a clinical trial perspective, electronic solutions and connected devices result in cleaner, faster data and better management of the patient. REFERENCES 1. 2.

Figure 1: Data transfer from MyGlucoHealth meter to the diabetes diary

3. 4., visited on 29 November 2017., visited on 13 December 2017., visited on 29 November 2017. Mazze, R. S., Shamoon, H., Pasmantier, R. et al. Reliability of Blood Glucose Monitoring by Patients with Diabetes Mellitus, The American Journal of Medicine. 77: 211-217 Published August 1984

Jill V. Platko, PhD Dr. Jill V. Platko is a Senior Scientific Advisor and expert in electronic Clinical Outcome Assessment (eCOA) systems at CRF Health. She has more than 16 years of experience in biology-based scientific research and has lead projects for renowned institutions such as: Cornell University, Genome Therapeutics Corporation, Whitehead Institute Center for Genome Research, and Massachusetts General Hospital. Figure 2: Reporting available to investigators via TrialManager® with automatic data sending

The benefits of this solution include higher data quality because the removal of paper leads to a reduction in errors. In addition, engagement and compliance are enhanced because of the patientcentric design. Finally, because patients can submit data from home via the eDiary, the investigators are able to effectively monitor the data. This provided a real-time picture of the patient and the ability to react (for instance, adjusting the insulin dose). Key Considerations When Using eCOA in Diabetes Trials The wireless integration of eDiaries with medical devices results in more accurate data by removing the need for manual transcription

Before joining CRF Health, Dr. Platko was an Associate Director at Covance within the Global Health Economic and Outcomes Research group for 2 years. Prior to that, she was a Senior Scientific Advisor at PHT Corporation. In these roles, she provided scientific guidance and review of clinical trial protocols to determine eCOA data collection design and project complexities. Before joining PHT in 2007, Dr. Platko served as Lead Business Analyst on the Autism Consortium Informatics Team and DNA Laboratory Manager within the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital.

Journal for Clinical Studies 53

Special Section

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Part 2: Considerations for Planning and Conducting Clinical Trials Editor’s Note: This paper is the second in a two-part series addressing non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. In Part 1, Dr Mark Delegge provided an overview of these important diseases. In Part 2, he discusses considerations when planning and conducting clinical trials for new treatments in these therapeutic areas. Introduction As indicated in the Editor’s Note, this paper is the second in a two-part mini-series addressing nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. After introducing these diseases in Part 1 in the previous issue of this journal, this paper addresses considerations for the future of clinical trials in these therapeutic areas. Topics covered include trial design, biomarker and liver biopsy considerations, and efficacy outcome endpoints.

In past clinical trials, TZDs improved hepatic histology in patients with NASH, although their favourable effect on steatosis was greater than their impact on other histological variables such as inflammation, ballooning, or fibrosis. Their favourable effect on liver histology and liver biochemistries disappeared upon their discontinuation, suggesting that long-term treatment is needed to maintain therapeutic benefits.7 The PIVENS trial compared the impact of vitamin E, pioglitazone or placebo on the diagnosis of biopsy-proven NASH. Vitamin E therapy compared with placebo was associated with a significantly higher rate of improvement in NASH (43% vs. 19%; P = 0.001) after 96 weeks. However, the difference in the rate of NASH improvement with pioglitazone compared with placebo did not reach the pre-specified 0.025 level of significance (34% vs. 19%; P = 0.04).8

Clinical Trials A multitude of new molecular entities have been evaluated for the treatment of NASH. A few will be reviewed here. Insulin resistance is nearly universal in patients with NASH, and some studies have therefore evaluated insulin sensitisers in humans: these employed biguanides (metformin) and thiazolidinediones (pioglitazone and rosiglitazone). Metformin’s anti-diabetic action is likely related to decreased hepatic gluconeogenesis, decreased glucose absorption, and increased insulin sensitivity by facilitating glucose uptake and utilisation.1 In addition, its stimulatory effect on AMP-activated protein kinase or modulation of hepatic TNFα expression may offer benefits. A Cochrane database analysis showed that metformin leads to normalisation of serum aminotransferases in a significantly greater proportion of patients with NAFLD compared with dietary modification.2 The NASH Clinical Research Network performed the Treatment of NAFLD in Children (TONIC) trial, which evaluated the impact of metformin, vitamin E, or placebo on liver function, testing abnormality improvement and histology in a multicentre trial of paediatric patients diagnosed with NAFLD by biopsy. Neither liver function test abnormality nor histology were improved with the use of metformin or vitamin E as compared with placebo.3,4

Vitamin E (RRR-α-tocopherol) is a lipid-soluble antioxidant that is able to scavenge free radicals and avoid lipid peroxidation. A metaanalysis reported that vitamin E supplementation might improve transaminase levels in patients with NASH, which confirms the therapeutic potential of vitamin E.9 The potential benefit of vitamin E was demonstrated in the PIVENS trial described in the previous paragraph.8 Conversely, the TONIC trial failed to demonstrate any impact of vitamin E on paediatric patients diagnosed with NASH.3 The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid [OCA]) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. The Phase II FLINT trial evaluated the impact of OCA on the diagnosis of biopsy proven NASH.10 OCA was statistically significantly superior to placebo for the primary outcome of improved liver histology, as well as the secondary endpoint of fibrosis improvement by at least one stage. Additionally, statistically significant OCA treatment effects were demonstrated on the major histological features of NASH, including steatosis, lobular inflammation, and hepatocellular ballooning. Post-hoc subgroup analyses found that the histological improvements were consistently greater in patients with more advanced disease and at greatest risk of progressing to liver failure and death. A large Phase III trial is currently underway, with completion forecast for 2021.

Thiazolidinediones Thiazolidinediones (TZDs) are a class of oral anti-diabetic medications that improve insulin resistance by acting as selective peroxisome proliferator-activated receptor (PPAR)-γ agonists. Rosiglitazone and pioglitazone are the second generation TZDs that are currently available for clinical use. They redistribute fat from muscle and liver to adipose tissue and thereby improve peripheral (skeletal muscle) and hepatic insulin sensitivity.5 In addition, they increase circulating levels of adiponectin, which is produced exclusively by the adipose tissue and has insulin sensitising properties.6

Elafibranor is an agonist of the peroxisome proliferator-activated receptor-alpha and receptor-gamma that play key roles in fatty acid transport, oxidation, glucose homeostasis, and anti-inflammatory activities. A Phase II international, randomised, placebo-controlled, multicentre study evaluated the efficacy of elafibranor for treating NASH. A total of 276 patients with biopsy-proven NASH but not cirrhosis were randomised to elafibranor 80 mg, elafibranor 120 mg, or placebo. Patients were followed every two months for a year, and an end-of-treatment biopsy was performed.11 There was no difference between the elafibranor groups and placebo in the primary outcome (reversal of NASH). A post-hoc analysis used a more stringent

54 Journal for Clinical Studies

Volume 10 Issue 2

Special Section outcome where NASH resolution was defined as disappearance of ballooning and either no or mild inflammation. In this analysis, the 120-mg elafibranor group had a significantly higher resolution of NASH without fibrosis progression than did placebo (19% vs 12%). Elafibranor was well tolerated, with the only significant sideeffect being a mild, reversible increase in serum creatinine. A large Phase III trial is currently underway, with completion forecasted for 2021. Other new molecular entities are focused specifically on the inflammatory cascade and/or inhibiting fibrosis. Cenicriviroc is a chemokine blocker impacting receptors 2 and 5. In a Phase II study, Cenicriviroc was able to show an improvement in fibrosis with no worsening of inflammation. A Phase III clinical trial looking specifically at fibrosis improvement in NASH has begun. Selonsertib is an apoptosis signal regulating kinase inhibitor (ASK-1 inhibitor). In a Phase II study, this new molecular entity was shown to inhibit fibrosis. Selonsertib is currently enrolling in a Phase III trial. A thyroid receptor hormone B-agonist has recently completed a Phase II trial where it achieved its primary outcome. A Phase III trial is planned. There are numerous other compounds in pre-clinical, Phase I, and Phase II trials that are beyond the scope of this paper. Considerations for the Future of NAFLD/NASH Clinical Trials  The majority of multicentre, interventional clinical trials in NAFLD/ NASH have been conducted in the past 15 years, starting with the landmark PIVENS trial in 2003 that was funded by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).8 However, as of 2017, of the approximately 87 interventional trials that have been conducted or are currently active, over 80% have been initiated in the past five years alone, which is indicative of the increased attention being paid to the unmet medical needs and growing incidence and awareness of NAFLD and NASH globally. Overall study initiation trends are shown in Figure 1.

Figure 1: Initiated Industry-sponsored NASH/NAFLD Trials by Start Year (n=87)

Many of these trials, 16 of which are in Phase II, are actively enrolling with a target accrual of over 13,000 patients. The three largest trials are in Phase III, aiming to recruit over 12,000 patients combined at over 1200 sites globally. Because of the size of Phase III trials needed to show a statistically significant treatment effect and the time over which this effect can be seen, it is expected that future Phase III trials in this space will be equally large in terms of site and patient volumes. Study Design Considerations: Adaptive Trials Clinical trials are designed with regulatory milestones in mind regarding safety and efficacy outcomes, while being mindful of cost and ultimate acceptability by both principal investigators and patients who become clinical trial participants. Many drug and

device development pathways follow a standard Phase I-III process. Although traditionally this has provided successful drug approval pathways and robust data production, the time and cost of these pathways can be prohibitive and may not meet the needs of new molecular entities in certain disease spaces, such as NASH. Adaptive designs may be useful when developing NMEs for NASH. This approach, which has become acceptable within clinical trials, evaluates a medical device or drug by observing participant outcomes (and possibly other measures, such as side-effects) on a prescribed schedule, and allows modification of the trial protocol based on those observations.12 The adaptation process continues throughout the trial, as pre-determined in the trial protocol. Modifications may include drug dosage, sample size, and patient selection criteria. The aim of an adaptive trial is to identify drugs or devices more quickly that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies.13 The adaptive design model works well within the NASH clinical space where multiple new molecular entities are hypothesised to work on one or more of the pathophysiologic pathways. Efficacy Outcome/Endpoint Measures The 2012 guidelines from the American Association for the Study of Liver Disease and the 2009 European Association for the Study of Liver Disease position statement on liver biopsy recommend liver biopsy as an endpoint for all clinical trials.14,15 Therefore, to date, liver biopsy has been the mainstay for monitoring NAFLD progression when repeated biopsies are performed.16 A more recent (2016) publication from the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) noted that “the resolution of the histological lesions defining NASH is now accepted as a surrogate endpoint, particularly in clinical trials.”17 Histology findings are an accepted surrogate for hard clinical endpoints such as mortality, but the most relevant histological features are a matter of debate.18,19 The US Food and Drug Administration (FDA) recently endorsed endpoints for clinical trials of potential NASH therapies. Reversal of NASH without evidence of progression to advanced fibrosis is now defined as the endpoint for Phase IIb and Phase III trials in individuals with NASH and early-stage fibrosis.20 While a reduction in the nonalcoholic fatty liver disease activity score could be used as an endpoint in clinical trials, it is unclear whether patients with lower scores have a reduced risk of developing advanced fibrosis. Endpoints for clinical trials involving NASH cirrhosis are currently based on the model for end-stage liver disease and Child-Turcotte-Pugh scores (for classification of the severity of cirrhosis), in addition to the hepatic venous pressure gradient.20 These approaches offer a starting point to develop treatments. Liver Biopsy Considerations To achieve consistency in histology interpretation in NASH clinical trials, a central reading process consisting of a pathologist specifically experienced in NASH histology assessment is recommended. The same pathologist should be evaluated over time to ensure interpretation consistency. A formal adjudication process should be in place to resolve any inconsistencies in interpretation: similar adjudication processes have been used for other disease states such as central reading of endoscopy for inflammatory bowel disease.21 Some limitations of liver biopsy are due to variability of the disease process itself, as with all other forms of chronic liver disease. This Journal for Clinical Studies 55

Special Section is compounded by the sampling limitations of biopsy with only 1/50,000 of the liver volume captured at biopsy. NAFLD, while a diffuse process of the liver, can have differences due to the location of the samples under evaluation. It is important that pre- and poststudy biopsies are done in a similar fashion and from the same region of the liver.22 Transport of tissue slides and blocks between multiple sites can make tissue sample management complex. In addition, slide preparation can vary between local pathologists. The ideal situation is to have tissue samples be sent in ‘block’ form to a central site for slide preparation. These slides are digitally imaged for review by the central readers. Biomarkers in Clinical Studies Probably the most urgent need in the field of NASH is the discovery of biomarkers that would help diagnose and monitor disease progression.23 To date, the FDA has not endorsed any biomarker as an alternative for liver biopsy histology as the primary outcome for NASH clinical trials. Therefore, biomarkers and scoring systems are usually considered secondary or exploratory endpoints in clinical trials. Attempts have been made to create algorithms to predict which patients with NASH as a potential diagnosis should receive a liver biopsy for definitive diagnosis.24 Serum biomarkers for staging of fibrosis include combinations of either direct markers, which are mainly complex proteins from myofibroblasts and extracellular matrix remodelling, or indirect markers, which are detectable via simple biochemical tests and can be used to estimate the severity of disease. These diagnostic algorithms (scoring systems) have also been adapted to take account of risk factors for metabolic syndrome, helping to provide more accurate estimates of the severity of NAFLD.25 A combination of serum biomarker and bedside transient elastography (bedside liver stiffness text) analyses appears to offer initial approaches to assessing NASH, but their applicability for follow-up analyses has yet to be established. Most imaging methods are unable to directly visualise the combination of fibrosis and inflammation, or accurately assess liver disease progression. Promising exploratory results have been recorded from molecular and targeted magnetic resonance imaging studies of small molecules that bind to fibrillary collagen, or other extracellular matrix proteins. These may have potential in tracking changes in fibrosis, offering promising new and non-invasive tools for quantitative measurement of fibrogenesis. This may enable validation of next-generation biomarkers, helping in assessment of the efficacy of potential antifibrotic therapies.26

assessment model, multiparametric MRI was superior to transient elastography in predicting the presence of NAFLD prior to liver biopsy.30 Multiparametric MR has also been shown to be predictive of future liver-related outcomes.27 Feasibility Considerations: Competition for Study Participants Although the number of potential NAFLD and NASH clinical trial participants is theoretically large enough to support such trials, it is expected to become increasingly difficult to enroll these patients. The burden on sites is expected to increase since there will likely be greater competition from pharmaceutical companies to recruit principal investigators at the most experienced sites, and a need to expand into geographic regions and sites that have patients but less direct experience in NAFLD/NASH clinical trials. One potential and paradoxical advantage for clinical trial participant recruitment in this therapeutic area is the lack of currently available pharmacological treatments: clinical trial participation therefore offers considerable benefit to patients in allowing access to potential new therapies. Investigational sites with NAFLD/NASH expertise generally have clinical trial experience in this area dating back to the PIVENS trial and, more recently, the FLINT trial, in addition to the influx of pharma-sponsored trails over the last five years. As the research landscape grows more crowded, studies will become more complex and targeted with regard to patient eligibility: patient populations that are most likely to show benefit will be of great interest. Figure 2 shows geographic regions that have some experience of participation in these trials. As can be seen, to date the US has accumulated the bulk of the experience in NASH/NAFLD clinical trials. However, it is unlikely that the experienced US-based investigational sites will be able to accommodate all future trials, due to limited availability of patients and site resources. This presents an opportunity for other physicians with patient populations and clinical interests in NASH/NAFLD around the world to participate in clinical trials that have the potential to offer novel treatments to patients while also increasing understanding of the disease itself.  

Figure 2: NASH/NAFLD Trials to Date by Country

More recently, work in multiparametric MRI scanning has been provocative and impressive. The sensitivity of this technology to both fibrosis and inflammation offers a non-invasive approach with the potential to enrich the population of NASH patients volunteering for NASH trials and reducing the number of unnecessary biopsies.27,28 It has been reported that 50–60% of patients who have liver biopsy for NASH trial inclusion are subsequently excluded from clinical trial participation based on the biopsy results. This is a significant inconvenience and medical risk for patients and a substantial cost burden to any clinical trial. As noted earlier, given that it is an invasive procedure with a 0.5% complication rate and a 0.01% mortality rate, liver biopsy is not suitable as a screening test.29 There is also a mounting body of evidence that a needle liver biopsy that results in a tissue sample that is a tiny portion of the liver (as mentioned previously, around 1/50,000 of the total mass of the liver) may be subject to significant sampling variability. In a cost 56 Journal for Clinical Studies

Anonymised Patient Data Mining Diverse methodologies exist for anonymised patient data mining. These include electronic medical records (EMR), prescription data, and direct information from patients. The EMR is a timetable recording of patient health information, generated by multiple encounters in a multitude of healthcare settings (e.g., clinic, hospital, and emergency room visits). The dramatic advancement and availability of health information technologies offers tremendous opportunities for clinical research.31–33 EMR is fairly well established in the US, but many countries have yet to adopt this approach. Prescription data may be of value to identify concentrations of NASH patients, especially as treatment options expand. Linking EMRs with clinical trials has been demonstrated to increase the recruitment rate of patients.34 The ability to access Volume 10 Issue 2

Special Section EMR information can allow very precise questions to be asked about a disease state including disease prevalence in a region, physicians caring for patients with these diseases, current therapies, hospitalisations as a result of the disease, and procedures performed. A funnel plot can be created that allows the overall incidence of a disease in a region to be captured and further analysed by a study’s inclusion and exclusion criteria to generate a more reliable estimate of how many patients are truly available for participation in a given clinical trial. Safety-related Assessments  Lastly, but certainly not of least importance, attention must be paid to safety considerations and assessments. It was noted previously that there is a correlation between the presence of NASH and hypertension, hyperlipidaemia, and obesity, which alerts us to the need for specific safety assessments: in addition to being efficacious, it is imperative that any drug developed for NASH does not increase cardiovascular risk, and, ideally, reduces it.35 One important goal in Phase IIb and Phase III trials, therefore, is to demonstrate that important cardiovascular parameters (e.g., LDL-cholesterol, HDLcholesterol, triglicerides, apolipoprotein, coronary calcification scores) are not negatively impacted. It is also important to demonstrate stability of metabolic parameters (HbA1C, fasting insulin and glucose, fasting free fatty acids) during Phase IIb and Phase III trials. Cancer risk is best monitored during longer-term Phase IV post-marketing studies. Monitoring should also occur for drug-induced liver injury, behavioural adverse events such as depression (depression scores should be tracked during treatment), and other off-target unexpected effects. Concluding Comments  NAFLD and NASH are being diagnosed globally with increasing frequency. The global prevalence of NAFLD is estimated to be 25% – 30%. It is predicted that approximately one-third of patients with NAFLD will ultimately be diagnosed with NASH. NAFLD and NASH often present clinically as incidental findings on laboratory (elevated liver function tests) or radiographical (steatosis or fibrosis) testing without specific clinical symptoms. The definitive diagnosis of NASH requires a liver biopsy with specific histologic findings of steatosis, fibrosis, inflammation, and hepatocyte ballooning and degeneration. From a demographic perspective, there are certain patient characteristics which are risk factors for developing NASH, e.g., type 2 diabetes, obesity, hypertriglyceridemia and polymorphism in the PNPLA3 gene. However, we do not have a reliable non-invasive biomarker of NASH including serum and/or imaging biomarkers. Multiparametric MRI appears to be very promising in achieving this goal. Liver biopsy, with its associated cost, morbidity, and mortality, does not allow it to serve as a reasonable screening tool for NAFLD or NASH. There are currently no commercially available, regulatoryapproved pharmacologic agents available for the treatment of NASH. There are some therapies being used off-label. As of writing this paper, four Phase III trials are ongoing or getting ready to begin, and a number of Phase I and Phase II trials and pre-clinical work in progress. These clinical trials face similar challenges for enrolment. Patients are usually asymptomatic and may be reluctant to participate in a clinical trial. The lack of a sensitive and specific biomarker to diagnose NASH or to monitor its response to therapy has led to the requirement of one or multiple liver biopsies over the course of a clinical trial. Patients with elevated liver function tests or abnormal imaging studies suspicious for NASH are subject to a liver biopsy

only to have a > 50% likelihood of not having a histologic diagnosis of NASH which would allow them to enter a given clinical trial. This is disappointing and frustrating for both patients and primary investigators. Most patients with NAFLD and NASH are not currently receiving their medical care from hepatologists but rather from endocrinologists and primary care physicians. Anonymised patient data-mining can determine where patients with NASH or risk factors associated with NASH are located and who are their treating institutions and physicians. This can monumentally improve the identification of productive NASH geographic locations and investigators. Raising the awareness of NASH with these physician groups and encouraging early diagnosis and referral to hepatologists is critical for appropriate patient treatment and monitoring, and for creating a large enough pool of patients for clinical trials involving NMEs. Given the significant impact of NAFLD and NASH on the long-term health of patients, development of NMEs is imperative. Pharmaceutical companies, contract research organisations, clinicians, researchers, and patients need to partner at a very high level to ensure the timely development of approved NMEs for commercialisation and treatment of these diseases. REFERENCES 1.

Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135(1):48-58. 2. Angelico F, Burattin M, Alessandri C, Del Ben M, Lirussi F. Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007(1):Cd005166. 3. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659-1668. 4. Alkhouri N, Feldstein AE. The TONIC trial: a step forward in treating pediatric nonalcoholic fatty liver disease. Hepatology. 2012;55(4):12921295. 5. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106-1118. 6. Riera-Guardia N, Rothenbacher D. The effect of thiazolidinediones on adiponectin serum level: a meta-analysis. Diabetes Obes Metab. 2008;10(5):367-375. 7. Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46(2):424-429. 8. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. New England Journal of Medicine. 2010;362(18):1675-1685. 9. Ji HF, Sun Y, Shen L. Effect of vitamin E supplementation on aminotransferase levels in patients with NAFLD, NASH, and CHC: results from a meta-analysis. Nutrition. 2014;30(9):986-991. 10. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 11. Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150(5):1147-1159.e1145. 12. Gallo P, Chuang-Stein C, Dragalin V, et al. Adaptive designs in clinical drug development--an Executive Summary of the PhRMA Working Group. J Biopharm Stat. 2006;16(3):275-283; discussion 285-291, 293278, 311-272. 13. Kairalla JA, Coffey CS, Thomann MA, Muller KE. Adaptive trial designs: a review of barriers and opportunities. Trials. 2012;13(1):145. 14. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Journal for Clinical Studies 57

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Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005-2023. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372-384. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344-353. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388-1402. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis. 2012;32(1):3-13. Kleiner DE, Bedossa P. Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists. Gastroenterology. 2015;149(6):1305-1308. Lassailly G, Caiazzo R, Pattou F, Mathurin P. Perspectives on treatment for nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1835-1848. Ahmad HA, Gottlieb K, Hussain F. The 2 + 1 paradigm: an efficient algorithm for central reading of Mayo endoscopic subscores in global multicenter phase 3 ulcerative colitis clinical trials. Gastroenterol Rep (Oxf). 2016;4(1):35-38. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62(1 Suppl):S65-75. Tapper EB, Lok AS-F. Use of liver imaging and biopsy in clinical practice. N Engl J Med. 2017;377:756-768. Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):666-675. Bedossa P, Patel K. Biopsy and noninvasive methods to assess progression of nonalcoholic fatty liver disease. Gastroenterology. 2016;150:1811-1822. e1814 . Pavlides M, Banerjee R, Sellwood J, et al. Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease. J Hepatol. 2016;64:308-315. Eddowes PJ, McDonald N, Davies N, et al. Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2018;47:631-644. Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2(2):165-173. Blake L, Duarte RV, Cummins C. Decision analytic model of the diagnostic pathways for patients with suspected non-alcoholic fatty liver disease using non-invasive transient elastography and multiparametric

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magnetic resonance imaging. BMJ Open. 2016;6(9):e010507. De Moor G, Sundgren M, Kalra D, et al. Using electronic health records for clinical research: the case of the EHR4CR project. J Biomed Inform. 2015;53:162-173. Prokosch HU, Ganslandt T. Perspectives for medical informatics. Reusing the electronic medical record for clinical research. Methods Inf Med. 2009;48(1):38-44. Turisco F, Keogh D, Stubbs C, Glaser J, Crowley Jr WF. Current status of integrating information technologies into the clinical research enterprise within US academic health centers: strategic value and opportunities for investment. J Investig Med. 2005;53(8):425-433. Embi PJ, Jain A, Clark J, Harris CM. Development of an electronic health record-based Clinical Trial Alert system to enhance recruitment at the point of care. AMIA Annu Symp Proc. 2005:231-235. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology. 2015;61:1392-1405.

Mark H. Delegge, MD Mark H. Delegge is a Board-certified gastroenterologist with more than 20 years of academic practice at a US medical university, including oversight of a research enterprise. He currently serves as the Clinical Lead of the NASH Focus Group, part of IQVIA’s GI Center of Excellence. He has more than seven years of drug development experience working with Baxter Healthcare, including nonclinical and Phase I-IV clinical trial design and global regulatory package submissions. He has more than 100 co-authored publications in peer-reviewed journals and 30 book chapters, and is a former editor for Digestive Diseases and Sciences. Dr Delegge has multiple educational degrees, including his Bachelor of Science from University at Albany, SUNY; Doctor of Medicine at Universidad Autónoma de Guadalajara; Doctor of Medicine at University of Maryland Baltimore; Internal Medicine at The University of Connecticut Health Center; and Gastroenterology Fellowship at Medical College of Virginia. Email: Volume 10 Issue 2

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News UK Biobank Expanded to Cover Mental Health with Help from NIHR Researchers

transparency. This means all clinical trials they fund or support will be registered and the results reported.

Mental health information on more than 150,000 people is now available in the UK Biobank for research into mental health disorders, thanks to work supported by the NIHR. UK Biobank is a national and international health resource that is tracking the health and wellbeing of 500,000 volunteers. These volunteers have undergone tests and provided blood, urine and saliva samples, and detailed information about themselves.

In a joint statement, nine major funders including Médecins Sans Frontières, the Bill & Melinda Gates Foundation, the Indian Council of Medical Research, the Norwegian Research Council, the UK Medical Research Council and the Wellcome Trust committed to develop and implement policies that require all trials they fund, co-fund, sponsor or support to be registered in a publicly-available register. They also agreed that all trial results would be disclosed within specified timeframes on the register or by publication in a scientific journal. Around half of clinical trials carried out around the world have gone unreported, according to several studies, often because the results are negative. These unreported trial results leave an incomplete and potentially misleading picture of the risks and benefits of vaccines, drugs and medical devices, and can lead to use of sub-optimal or even harmful products.

Academic and industry researchers can use Biobank data to understand why some people develop particular diseases and others do not, with the aim of improving the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses Until now, UK Biobank had limited data on mental health disorders. To remedy this, researchers supported by the NIHR Maudsley Biomedical Research Centre developed and undertook an online mental health questionnaire with 157,366 Biobank participants. Professor Matthew Hotopf, Director of the NIHR Maudsley Biomedical Research Centre, who chaired the expert working group that developed the questionnaire, said, “Our study suggests that UK Biobank could be a powerful tool for mental health research, and since it is open to all health researchers for work in the public good, we hope to inspire both existing and new users of UK Biobank.”

“Research funders are making a strong statement that there will be no more excuses on why some clinical trials remain unreported long after they have completed,” said Dr Marie-Paule Kieny, Assistant Director-General for Health Systems and Innovation at WHO. The signatories also agreed to monitor compliance with registration requirements and to endorse the development of systems to monitor results reporting.

Source: National Institute of Health Research

Source: JCS Staff Writer

Three-month Course of Chemotherapy as Effective as Six Months Following Surgery for Bowel Cancer

Australia NHMRC Clinical Trials Centre Partners with Medidata to Digitize Cancer Research

New research published in The Lancet Oncology has shown that many patients receiving chemotherapy following surgery for bowel cancer may only need three months treatment rather than the six months currently given.

Medidata announced that the National Health and Medical Research Council Clinical Trial Centre (NHMRC CTC), University of Sydney, will now use Medidata’s unified platform and analytics for all major new studies starting in 2018.

An international clinical trial, funded by an NIHR and MRC partnership, has evaluated the effectiveness of a three-month course of adjuvant oxaliplatin/fluoropyrimidine combination chemotherapy for colorectal cancer versus the standard six-month treatment regimen. One of the main side effects of oxaliplatin chemotherapy is nerve damage affecting the hands and feet (peripheral neuropathy) which can be long-lasting and result in worse quality of life. The SCOT study also showed three months chemotherapy results in less peripheral neuropathy. The SCOT study, led by the Cancer Research UK Clinical Trials Unit in Glasgow, recruited 6,088 patients with high-risk stage II or stage III colorectal cancer from 244 centres across Europe, Australia and New Zealand. They received either a three or six month course of chemotherapy and were followed up for a minimum of three years.

The agreement will result in the NHMRC Clinical Trial Centre consolidating multiple electronic data capture (EDC) solutions to the Medidata eClinical platform. This includes the use of Medidata Rave eCOA/ePRO and Medidata Rave EDC, which enable the NHMRC Clinical Trials Centre to manage and ingest the widest array of clinical trial data, with the potential to include sensors, mobile apps, genomics and RWE (Real World Evidence). NHMRC Clinical Trial Centre will also improve data quality and risk reduction in randomization and trial supply management with a single source of data from Medidata Rave RTSM. These solutions allow streamlined collaboration for researchers across sites and simplify how patients involved in the trials can report their data.

After three years, 76.7% of patients who received treatment over three months were disease free compared to 77.1% of patients treated over six months. Patients treated over three months had fewer side effects and reported a better quality of life as well as reduced peripheral neuropathy.

The NHMRC Clinical Trials Centre has earned an outstanding reputation for contributing to major advances in clinical care via their high-quality, collaborative clinical trials research. NHMRC Clinical Trials Centre trials focus on investigating anti-cancer treatments, novel therapeutics for cardiovascular disease and diabetes, and driving new standards of care in perinatal disease. Source: Market Insider

Source: National Institute of Health Research

“No More Excuses” As Major Global Research Funders Take Strong Lead on Clinical Trial Transparency Some of the world’s largest research funders and NGOs today agreed to adopt the WHO’s strong standards on clinical trial 62 Journal for Clinical Studies

App-based Self-acupressure Benefits Women with Menstrual Pain Can acupressure achieve a sustained reduction in menstrual pain? Is an app-based self-care program particularly attractive to young women? These questions addressed in a new study by researchers from Charité - Universitätsmedizin Berlin, the results of Volume 10 Issue 2


which have been published in the American Journal of Obstetrics and Gynecology. The researchers wanted to evaluate whether in a group of women suffering from severe menstrual pain, aged between 18 and 34, self-acupressure would be more effective at achieving a sustained reduction in menstrual pain than usual care alone (e.g. pain medication and hormonal contraceptives). A total of 221 participants were randomly assigned to one of two treatment groups, both of which received a study app and short introduction. Acupressure-based features - with instructions on how to administer self-acupressure shortly before and during menstruation - were only made available to the intervention group. One advantage of an appbased intervention is its ability to provide visual descriptions of the pressure points users need to target in order to achieve the desired effect. It can also send regular reminders. Additionally, the app was used to collect all study-related data. Source: News Medical Lifesciences

Sellas’ NeuVax + Herceptin Combination Treatment Shows Significant Effect in Breast Cancer Trial Sellas Life Sciences Group has reported a positive interim data from the prospective, randomized, single-blinded, controlled Phase 2b independent investigator-sponsored clinical trial (IST) of trastuzumab (Herceptin) +/- nelipepimut-S (NeuVax™) in HER2 1+/2+ breast cancer patients in the adjuvant setting to prevent recurrences. A pre-specified interim analysis, conducted by an independent Data Safety Monitoring Board (DSMB) of the efficacy and safety data for the study in an overall population of 275 patients as well as the two primary study target patient populations (node-positive and TNBC) after a median follow-up of 19 months, demonstrated a clinically meaningful difference in median disease-free survival (DFS) in favor of the active arm (NeuVax + Herceptin), a primary endpoint of the study, with hazard ratios of 0.67 and 0.61 in the intent to treat (ITT) and modified ITT (mITT) populations (i.e., those who received at least one dose of vaccine or control) as well as a 34.9% and 39.5% reduction in relative risk of recurrence in the active versus control arms in the ITT and mITT populations, respectively.

Tumors in these women show low levels of expression of HER2, as measured by immunohistochemistry (IHC), i.e., at a level of either 1+ or 2+ and, hence, these patients are not considered candidates for Herceptin. Patients who are hormone receptor-negative and HER2 1+/2+ by IHC are currently defined as ‘triple-negative’ breast cancer (TNBC) patients. Source: Company News

Number of Clinical Trials in India May Surge by 2018–19 As per reports of, 1.4% of global clinical trials are done in India, while the country has 16% of the world’s population and carries 20% disease burden in the world. However, the number of clinical trials in India is expected to grow by 2018–19 as a result of regulations for clinical trials in India becoming more stable and predictable, according to Dr Chirag Trivedi, President, Indian Society for Clinical Research (ISCR). “In 2010, more than 500 clinical trials were done in India, and later the number dropped to less than 200 per year because there were said to be many uncertainties and ambiguities and regulations were not conducive to conduct clinical researches, with which the companies did not want to deal. In 2013, new regulations were introduced due to which major changes took place and clinical trials nosedived. Over the years, many efforts were made into making the regulations more rationale and balanced by the government. The timeline for the approval of clinical trials research has been reduced by the Central Drugs Standard Control Organization (CDSCO). Initially, it used to take 6 months for any proposed clinical trials research to get approved. “So, by the time the trials body used to get the approval to conduct clinical research in India, globally similar trials had already been conducted in that time period resulting in India losing out its competitive edge. Since the timelines are defined now, this will help in introducing new trials and if they become successful, those molecules then subsequently can be introduced for our patients in India,” said Dr Trivedi. Source: ET Health World Journal for Clinical Studies 63

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Worldwide Clinical Trials

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Jcs volume 10 issue 2 march 18  
Jcs volume 10 issue 2 march 18