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Volume 11 Issue 1

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

A Unique Model to Accelerate Industry Sponsored Research In Malaysia

Adjudication in Clinical Trials A Primer

Clinical Development in Rare Diseases Graft versus Host disease

Using Selection Biomarkers and Unravelling the Resulting Data To Drive Clinical Trial Success

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Volume 11 Issue 1


Contents

JOURNAL FOR

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Your Resource for Multisite Studies & Emerging Markets

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U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITORIAL MANAGER Freya Gavaghan freya@pharmapubs.com DESIGNER Kirsty Rogen kirsty@pharmapubs.com RESEARCH & CIRCULATION MANAGER Virginia Toteva virginia@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications 50 D, City Business Centre London, SE16 2XB Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

FOREWORD

WATCH PAGES Expanding the Treatment Arsenal for Chronic Hepatitis B

Significant public health issues invariably arise, but the trajectory is not always obvious. Deborah Komlos of Clarivate discusses how such has been the case for viral hepatitis, which has been called a “silent epidemic”. In 2011, the United States (US) Department of Health and Human Services (HHS) published the first US action plan to better focus and coordinate the country’s response to the disease. The latest iteration of the plan is effective until 2020. 10 Addressing the Challenges of Clinical Trials Insurance Often thought of as a simple off-the-shelf product, clinical trials insurance can be considerably more complex, as Victoria Cockayne and Johannes Klose of Allianz explain. The process of obtaining insurance for a clinical trial can be a challenging exercise for all parties involved, be they the company electing to conduct a trial or the insurance professionals involved in arranging or providing coverage. 12 Are Graph Databases the Key Ingredient AI is Missing in Drug Discovery? The drug discovery process is hugely data-intensive, making it an ideal application for artificial intelligence (AI) and machine learning. But it isn’t as straightforward as it sounds. Gaining valuable insight can be complex. Database pioneer Emil Eifrem of Neo4j explains why graph software could be the missing link in better understanding data so that the power of AI can put it into context, and pull out the most salient information for drug discovery researchers. 14 Strategic Advantages of Integrating Regulators’ Advice into Clinical Trial Programme Design Working closely with regulators should be seen as an important strategy for successful drug development, rather than a barrier to be sidestepped or overcome. Early and frequent consultations with regulators helps to avoid surprises during all phases of clinical development, but particularly in the earlier phases. Bruno Speder of SGS discusses how integrating regulatory advice into the trial programme is an effective approach to mitigate the regulatory risk that is inherent in product development and improve the likelihood of early product approval. 16 Advancing Heart Failure Research through Innovative Clinical Trial Design

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright. Volume 11 Issue 1 January 2019 PHARMA PUBLICATIONS

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Cardiovascular disease remains public enemy number one in healthcare. Taking the top spot on the mortality scale, diseases of the heart are predicted to affect nearly 10 million people over the age of 18 by 2020 – a 25 per cent increase in just a decade. Karen Hill and Nancy Newark of Worldwide explore the many factors contributing to limited advances in heart failure discovery and treatment. REGULATORY 18 Clinical Trial Packaging: Considerations and Challenges Colin Newbould of Wasdell talks through the vital considerations when packaging drugs for clinical supply. He discusses the various challenges presented by blinding, randomisation and patient compliance before reflecting on how new practices such as just-intime labelling could help to overcome the complexities faced. He concludes that while every trial differs in how it approaches the issue Journal for Clinical Studies 1


Contents of flexibility, it is clear that flexibility is often crucial to making a trial a success.

TECHNOLOGY

20 Adjudication in Clinical Trials: A Primer

40 Industry Moves to Streamline Clinical Operations for Faster Trials

Although the main purpose of most clinical trials is to compare the efficacy and/or safety endpoints that occur in two groups, the endpoint management and adjudication process could often be considered the Cinderella of trial management. Pardeep Jhund et al. of Global Clinical Trial Partners discuss how in today’s event-driven trials, the choice of endpoints and how the endpoint adjudication process is managed can have a major impact on the success of the trial.

The need to improve efficiency and effectiveness of clinical trials has been well documented – and a new survey reveals that the life sciences industry is focusing on streamlining the clinical operations landscape to improve trial performance. Rick Van Mol of Veeva identifies the results of this survey, concluding that the industry sees unifying clinical environments as key to transforming operations, and major change is underway.

MARKET REPORT 24 A Unique Model to Accelerate Industry-sponsored Research in Malaysia The influx of industry-sponsored research (ISR) into the Asia Pacific region is continually growing due to the rising costs and complicated processes involved in drug development. Several countries within the region such as Singapore and more notably South Korea, have taken the initiative to develop and further strengthen their place as preferred destinations to conduct clinical trials. Audrey Ooi and Dr Khairul Faizi Khalid of Clinical Research Malaysia identify how Malaysia has been steadily building a comprehensive and supportive clinical research ecosystem within the country. 28 Gaps and Challenges in Malaria Clinical Research and Development Malaria has been a major global health problem of humans throughout history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years, renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility. Andrzej Piotrowski, KCR, explores the meaningful progress made in several areas in the understanding of the immunology, pathogenesis and mode of transmission of malaria. THERAPEUTICS 32 Improving Patient Outcomes: eCOA Steps up in the Fight Against Cancer By developing and bringing new oncology treatments to market, clinical researchers have an important role to play in helping reduce cancer-related mortality. But trials in this therapeutic area are not without challenges – research suggests that fewer than one in 20 adult cancer patients enroll in cancer clinical trials. Once enrolled, retaining these participants is vital. Brad Sanderson from CRF discusses the current state of oncology clinical research and how researchers can utilise the latest technology to improve the patient experience and improve outcomes. 36 Clinical Development in Rare Diseases: Graft versus Host Disease Graft versus host disease (GvHD) is a generalised immune system reaction following allogeneic hematopoietic stem cell transplantation (AHSCT) in patients with acquired and congenital hematopoietic system disorders. Vijayanand Rajendran et al. of Europital look at how the current focus is on developing and validating new biomarkers, and pursuing clinical trials of new agents which are effective, but less toxic, to develop more targeted treatments for GvHD and achieve better and safer alloHSCT treatment.

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Contents 44 Disrupting Clinical Development: How AI, the Cloud and a Modern Data Architecture are Transforming Clinical Trials Today, more than ever, pharmaceutical and biotech companies are under great pressure to run their business in a way that makes drug development processes more efficient and cost-effective. A big factor in these staggering rates is the increasing complexity of clinical trials, driven in large part by trial sponsors needing to evaluate more endpoints to demonstrate product value. Prakriteswar Santikary of ERT discusses how this is where the dynamic trio of artificial intelligence (AI), the cloud and a data lake comes in. 48 Using Selection Biomarkers and Unravelling the Resulting Data to Drive Clinical Trial Success The use of biomarkers in drug discovery and development has exploded at an unprecedented rate since the turn of the century. With recent scientific and technological breakthroughs, biomarkers

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can now be leveraged to address many questions about biological activity, safety, and clinical efficacy throughout the drug discovery and development process at a fraction of the cost and with turnaround times unimaginably less than a decade ago. Chad Clark et al. of Precision for Medicine identify how these advances are driving a paradigm shift in drug discovery and development. 52 Learning and Development for the Future As financial pressures continue to bear down on the clinical research sector, it is vital that both sponsor companies and the CROs that conduct their studies continue to invest in the development and capabilities of their staff. Martin Robinson of IAOCR examines how only through retaining competent staff will the clinical research sector be able to meet the forthcoming challenges which include increased trial complexity, the rising use of ‘big data’, and the advent of artificial intelligence in both the diagnosis and treatment of disease.

Volume 11 Issue 1


BROAD CLINICAL RESEARCH SOLUTIONS

© SGS Group Management SA – 2018 – All rights reserved - SGS is a registered trademark of SGS Group Management SA

SAFETY & EFFICACY FOR BIO/PHARMACEUTICALS SGS is providing clinical research and bioanalytical testing with a specific focus on early stage development and biometrics. Delivering solutions in Europe and in the Americas, SGS offers clinical trial (Phase I to IV) services encompassing drug development consultancy, clinical project management and monitoring, biometrics, PK/PD modeling and simulation, and regulatory and medical affairs services. Clients benefits from our wealth of expertise in First-In-Human studies, human challenge testing, biosimilars and complex PK/PD studies with a high therapeutic focus in infectious diseases, vaccines, and respiratory. Stay ahead in your drug development plan, contact us for reliable and adaptive clinical trial solutions.

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Foreword Happy New Year to all our readers – hope you all had an excellent Christmas and holiday break! With our first issue of JCS for the year, we’ve endeavoured to cover a wide range of recent developments within the industry. Our January issue covers topics ranging from challenges within clinical trials insurance, to clinical trial packaging, patient-centric trials, clinical development in rare diseases and streamlining clinical operations for faster trials. In our Watch Page section, we have a fantastic piece from Bruno Speder of SGS on the ‘Strategic Advantages of Integrating Regulators’ Advice into Clinical Trial Programme Design.’ This article looks at how to work with regulators strategically within drug development, concluding that regulatory advice can mitigate regulatory risk and improve the likelihood of early product approval. Speder looks at the guidance offered by regulators and what areas of a development programme they can cover. He explains how deciding where to seek scientific advice depends on determining where the product will be submitted for approval, so as to align the process within the requirements of each market. Pardeep Jhund and his co-authors from Global Clinical Trial Partners have contributed an editorial on ‘Adjudication in Clinical Trials: A Primer’ for our Regulatory section. This article considers the endpoint management and adjudication process in eventdriven trials, which can hugely impact the trial’s success. They note that endpoint adjudication is too often the last bit of the trial to be organised, and at times is left until after the trial has already begun. They provide an overview of the endpoint adjudication process, as well as the key elements to be considered during planning stages of the trial. In conclusion, the writers identify automated databases as being able to produce the data necessary for sponsors and CROs to carry out course corrections and keep clinical trials progressing on time. Our front cover image features the national flower of Malaysia, with ‘A Unique Model to Accelerate Industry Sponsored Research in Malaysia’ chosen as our country-specific market report for this issue. Audrey Ooi and Dr Khairul Faizi Khalid of Clinical Research Malaysia examine the growth of industry-sponsored research into the Asia Pacific, and how Malaysia has responded to this influx by building an inclusive clinical research ecosystem within the country. In the past, sponsors and CROs have found it challenging to understand

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

the requirements, processes and systems involved in conducting ISRs in Malaysia, which prolongs the time it takes for them to bring in a clinical trial. The Malaysian government is now making steps towards developing its clinical research ecosystem in response. For Therapeutics, we have an excellent feature from Vijayanand Rajendran et al. of Europital, entitled ‘Clinical Development in Rare Diseases: Graft versus Host disease.’ This article details the generalised immune system reaction following hematopoietic stem cell transplantion in patients with acquired and congenital hematopoietic system disorders, known as graft versus host disease (GvHD). They identify the development of new biomarkers as a central focus, as well as trialling new agents which are effective, but less toxic for better treatments. In our Technology section, Chard Clark et al of Precision Medicine look at ‘Using Selection Biomarkers and Unravelling the Resulting Data to Drive Clinical Trial Success.’ Recent breakthroughs in science and technology have allowed biomarkers to begin to address questions about the biological activity, safety and clinical efficacy in drug discovery and development. These developments are resulting in lower costs and turnaround times, marking an unprecedented rise in the use of biomarkers in drug discovery and development since the new century. We hope you enjoy this issue of the Journal for Clinical Studies, our first issue of the year. We look forward to continuing to bring you the latest within the clinical trials industry throughout the rest of the year and onwards. Wishing you all the best for 2019!

Freya Gavaghan, Editorial Manager Journal for Clinical Studies You may be wondering why we feature flowers on the front cover of JCS? Each of the flowers we feature on the front cover represents the national flower of one of the countries we feature an analysis on, in that issue. In this issue we have a report with a focus on Malaysia. Hibiscus rosa-sinensis is 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 Services

of Europe

• Deborah A. Komlos, Senior Medical & Regulatory Writer, Clarivate Analytics

• • Elizabeth Moench, President and CEO of Bioclinica – Patient

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

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

Recruitment & Retention

• Francis Crawley, Executive Director of the Good Clinical Practice

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

• Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) • Stefan Astrom, Founder and CEO of Astrom Research International HB

• Georg Mathis, Founder and Managing Director, Appletree AG

• Steve Heath, Head of EMEA – Medidata Solutions, Inc

• Hermann Schulz, MD, Founder, PresseKontext

• T S Jaishankar, Managing Director, QUEST Life Sciences

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Watch Pages

Expanding the Treatment Arsenal for Chronic Hepatitis B Significant public health issues invariably arise, but the trajectory is not always obvious. Such has been the case for viral hepatitis, which has been called a “silent epidemic.” In 2011, the United States (US) Department of Health and Human Services (HHS) published the first US action plan to better focus and coordinate the country’s response to the disease. The latest iteration of the plan is effective until 2020. Issued in January 2017, the current viral hepatitis action plan outlines strategies to achieve four major goals and includes indicators to help track progress. The goals are: • • • •

Advancements for Treating HBV Research and development for new viral hepatitis treatments are among strategies listed under the goals in the HHS report. The US Food and Drug Administration (FDA), a federal agency of the HHS, seeks to broaden the treatment armamentarium for HBV. It issued a new draft guidance for industry in November 2018, Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment, which is intended to assist sponsors in the clinical development of drugs and biologics to treat chronic HBV infection: from the initial investigational new drug application (IND) through the new drug application (NDA)/biologics license application (BLA) and post-marketing phases. This document is the FDA’s first version of an indication-specific draft guidance for chronic HBV infection. As explained in the guidance, currently available therapies for chronic HBV infection achieve sustained suppression of HBV DNA, with low rates of

Goal 1: Prevent new viral hepatitis infections. Goal 2: Reduce deaths and improve the health of people living with viral hepatitis. Goal 3: Reduce viral hepatitis health disparities. Goal 4: Coordinate, monitor, and report on implementation of viral hepatitis activities.

The report notes that, since 2011, federal and non-federal efforts have evolved and advanced in response to the growing threat viral hepatitis poses to public health. Despite this progress, viral hepatitis remains a serious public health threat in the US. The number of new hepatitis C virus (HCV) infections has increased rapidly, prior progress in reducing new hepatitis B virus (HBV) infections has stalled, and hepatitis-related deaths have increased, the report states. Because chronic HBV and HCV infection can persist for decades without symptoms, about half of those infected remain unaware of their infection status and are not receiving necessary care and treatment. For this reason, the HHS report notes, viral hepatitis is a leading cause of liver disease in the US and the most common reason for liver transplantation. In contrast, hepatitis A virus (HAV) produces a self-limited disease that does not result in chronic infection. While viral hepatitis can result from infection with any of at least five distinct viruses – HAV, HBV, HCV, hepatitis D virus (HDV), and hepatitis E virus (HEV) – the majority of hepatitis infections in the US are attributable to HAV, HBV, and HCV. The 2017 report mentions that a “major advance” has been the approval and widespread availability of highly effective, all-oral therapies that cure more than 90% of people with chronic HCV infection. Although both hepatitis A and B can be prevented by vaccination, there is no cure for hepatitis B. In 2016, a total of 3218 cases of acute HBV infection were reported to the Centers for Disease Control and Prevention (CDC). Since many people may not have symptoms or do not know they are infected, their illness is neither reported nor counted. The CDC estimates the actual number of acute HBV cases was almost 20,900 in 2016. As of May 2018, an estimated 850,000 people in the US have chronic HBV infection, according to the CDC, although that number may be as high as 2.2 million. Globally, approximately 257 million people have chronic HBV infection. 8 Journal for Clinical Studies

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Watch Pages

HBV surface antigen (HBsAg) loss, with or without seroconversion to antiHBsAg (HBsAb). Sustained HBV DNA suppression is associated with serum alanine aminotransferase (ALT) normalisation and improvement in liver histology, including regression of hepatic fibrosis and cirrhosis. In addition:

Effective HBV therapy reduces disease-related complications (e.g., hepatic decompensation and liver failure) and decreases risk of hepatocellular carcinoma.

Clearance of HBsAg is associated with reduced risk of hepatic decompensation and improved survival.

The FDA also advises that a limited number of secondary endpoint(s) (e.g., HBeAg loss, ALT normalisation) should be considered for testing using appropriate statistical methods for multiplicity. Biochemical serum markers such as ALT values vary between laboratories, and lack of ALT normalisation may often be confounded by presence of other chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD). Regarding a type of NAFLD, nonalcoholic steatohepat it is (NASH) the FDA issued a draft guidance for industry in December 2018, Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment.

The FDA recommends that therapies should be developed for a wide range of patients with chronic HBV infection, including paediatric populations. Because chronic HBV infection is a global disease, the FDA (under 21 CFR 312.120) will accept a well-designed, well-conducted, non-IND foreign study as support for an IND or application for marketing approval, so long as the trial was conducted in accordance with good clinical practice and the FDA can validate trial data through an onsite inspection, if necessary. The agency suggests that development programmes should include a sufficient number of US patients to ensure applicability of data to the US population. Due to the heterogeneity of the natural course of chronic HBV infection, sponsors are advised to conduct randomised and well-controlled trials to establish efficacy. In the November 2018 guidance, the FDA details which trial designs are appropriate, depending on whether the therapeutic is intended for chronic suppressive therapy or therapy of finite duration. New therapies could be evaluated in clinical trials using any of the following efficacy endpoints: •

Suppression of HBV DNA (defined as less than the lower limit of quantification [LLOQ], target not detected [TND]) on treatment – similar to currently available chronic nucleoside/nucleotide reverse transcriptase inhibitor (NrtI) therapies. Sustained suppression (more than six months) of HBV DNA (less than LLOQ, TND) off treatment, after a finite duration of therapy.

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Sustained suppression (more than six months) of HBV DNA (less than LLOQ, TND) off treatment with HBsAg loss (less than 0.05 international unit/millilitre [IU/mL]), with or without HBsAb seroconversion, after a finite duration of therapy.

The FDA welcomed comments on the HBV draft guidance by January 2, 2019, to Docket No. FDA-2018-D-3903. Comments may be submitted regarding the NASH draft guidance until February 4, 2019, to Docket No. FDA2018-D-3632.

Deborah A. Komlos Deborah A. Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis Regulatory Intelligence US module at Clarivate Analytics. In this role, her coverage centres on FDA advisory committee meetings, workshops, and product approvals. Her previous positions have included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work. Email: deborah.komlos@clarivate.com Journal for Clinical Studies 9


Watch Pages

Addressing the Challenges of Clinical Trials Insurance Often thought of as a simple off-the-shelf product, clinical trials insurance can be considerably more complex, as Allianz Global Corporate & Specialty’s Victoria Cockayne and Johannes Klose explain. The process of obtaining insurance for a clinical trial can be a challenging exercise for all parties involved, be they the company electing to conduct a trial or the insurance professionals involved in arranging or providing coverage. Firstly, there is the speed in which a client requires documentation. After many months of planning and organising the study to get to a stage where they are ready to submit to the independent ethics committee (EC), it can be a sudden realisation to a company engaging in clinical research that insurance is required and required fast! Combine this with: 1) the number of countries involved, each requiring an individual policy and certificate compliant with local regulations; and 2) a need for absolute accuracy with no room for error, and it is clear that the insurance broker and carrier have been set quite a task to turn around a company’s programme within a matter of days. This time pressure becomes even more intensified if the insurer has a technical or administrative question about the trial which hinders them from providing insurance terms as quickly as the company requires. Factors such as inadequate information when submitting the trial to the insurance company can delay the process of approval and therefore coverage for the trial. This can stretch the capabilities of an insurer, particularly when it comes to first-time testing of products/interventions in humans. Sometimes there is no protocol or investigational brochure available, meaning the insurer has not received adequate information to proceed with. Even if there is a protocol, it may not provide sufficient information about preclinical data of an investigational product or procedure and instead refers to the investigational brochure. It is a challenging task for an insurer to measure the risk adequately without this document. If missing, additional time is required to obtain it. The process can be further delayed if the sponsor has confidentiality issues, which can be resolved with a non-disclosure agreement, but, again, this adds to the time it takes for an insurer to be able to provide adequate terms for the risk.

Administering the Programme Administration of the programme can provide many hurdles too. In order to achieve a complete solution for the company, the insurer is reliant on its global network of offices, some of which may be in different time zones where immediate response to a documentation request is not always possible. Coordination of such programmes involves a high level of organisation from the lead office and invaluable cooperation from the network. This is not a challenge that is unique to the insurer, however. The company or sponsor will face many administrative and operational challenges of their own when managing the many interfaces internally and externally, such as, for example, various research and development, legal/compliance and manufacturing functions, study managers, regulators, ethics committees, internal committees, investigators and contract research organisations (CROs) and other third party service providers. A central approach to coordinate the information necessary to obtain insurance is often not in place and individual study managers are often not aware of the requirements of their country which can lead to further delays. It is no surprise, therefore, that insurers are coming under increasing pressure to find more centralised solutions for this with automatisation of the entire process being the holy grail for companies engaging in this market, but even that has its challenges. Technical Factors to Consider when Assessing Risks For example, consider the issue of risk-adequate pricing. The range of clinical trial risks is extensive. Besides the testing of drugs or medical devices by commercial sponsors, there are many investigator-initiated trials that may investigate a commercial product and/or compare non-product-based therapeutic interventions or look at other areas of research. Assessment systems centred on investigational products (nature, novelty, safety profile, route of administration, etc.) may easily struggle with such trials.

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Watch Pages Other important factors when assessing a clinical trial risk are: the scope of inclusion and exclusion criteria; completeness, accuracy and readability of the informed consent form; medical and scientific quality and performance of the investigators and trial sites; and early-phase risk management in human or dosefinding trials, (i.e. not exposing too many patients at the same time, careful selection and staggered increase of dosing ranges, allowing time for clinical observation and interpretation and not quickly exposing too many patients in short and overlapping timeframes to a broad range of single and multiple dose ranges). These risk factors are quite difficult and sometimes even impossible to be easily captured/measured by an insurer. However, they can at times be major drivers of clinical trial risk, as is evident from past high-profile clinical trial losses. Overly simplistic risk assessment systems, which only consider the trial phase and the number of patients, ignore the large spectrum of risks and are unlikely to produce risk-adequate pricing. Individual losses in the hundreds of thousands range can heavily impact profitability of clinical trial books – especially smaller ones. Considering complex and challenging upcoming new trial risks involving gene therapy or cell therapy, for example, makes it even more evident that a simple “one-sizefits-all” risk assessment and pricing approach is not the right solution. Of particular note is the fact that the sponsor themselves can significantly impact the covered risk by determining the scope of interventions which are included in the trial. Protocols can be drafted in a smart way, with particular focus on the point in time when trial inclusion starts and thereby take out interventions (which also means risk) from trial cover which are not (directly) linked to the investigational interventions of interest. Industry Growth and Improvement Lies Ahead Despite all of these challenges, it is not all doom and gloom for medical research companies seeking insurance or for those providing it. While the perfect solution to placing a multinational programme for a multicentre clinical trial does not yet exist, there are many insurance carriers out there who have the expertise to manage this and are rising to the challenge of providing consistent risk solutions to streamline the process and meet companies’ needs. Never before have medical professionals had as many choices of insurance carriers as they do today, with recent years seeing an increase in companies providing a product for this type of insurance. As companies start to look further afield with their studies,

reaching into previously unchartered territories such as China, India and the African continent, the global reach of the insurance company is key to offer a product fully able to attend to companies’ needs. Meanwhile, improvement of the whole process of conducting clinical trials in the European Union (EU) is expected in 2019 with the implementation of Clinical Trials EU directive 536/2044. The harmonisation of assessment and supervision processes across the Member States will improve both the rules relating to the insurance industry and other areas of clinical trials, and will negate the need for the sponsor and insurance company to meet the myriad different EC requirements they now have to deal with. With the global clinical trials market expected to reach USD65.2bn by 2025, according to a report by Grand View Research1, it could provide the perfect opportunity for insurance companies to develop their product offerings further, leading to more risk appetite and the incentive to invest in technology such as platforms that can provide a one-stop-shop solution for certain types of studies, an advancement that would be welcomed by everyone in the industry. REFERENCES 1.

Clinical Trials Market Size Worth $65.2 Billion by 2025. CAGR 5.7%, August 2017, Grand View Research

Dr Johannes Klose Johannes Klose is working in liability risk consulting as scientific advisor with special focus on life science industries. He has a scientific background in pharmacy (registered) and neurobiochemistry (PhD) as well as a risk management degree (ARM). He has worked in marketing / sales in the pharmaceutical industry and has 18 years’ experience as a liability risk consultant in life science corporate industrial insurance.

Victoria Cockayne Victoria Cockayne has been a clinical trials underwriter for over 10 years, starting her career at HDI Gerling Industrie Versicherung before joining Allianz Global Corporate and Speciality SE early in 2018. She has extensive experience of underwriting and coordinating large global studies for healthcare companies engaged in research and development and is dedicated to this line of business.

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Watch Pages

Are Graph Databases the Key Ingredient AI is Missing in Drug Discovery? The drug discovery process is hugely data-intensive, making it an ideal application for artificial intelligence (AI) and machine learning. But it isn’t as straightforward as it sounds. Gaining valuable insight can be complex. Database pioneer Emil Eifrem explains why graph software could be the missing link in better understanding data so that the power of AI can put it into context, and pull out the most salient information for drug discovery researchers. Pharma companies are looking to tap into powerful new technologies like machine learning to streamline labour-intensive parts of drug discovery in a bid to increase efficiencies, better control costs and bring products to market more quickly. The way knowledge is organised and represented in AI-powered systems can have a significant impact on how and what exactly can be learnt from it. Representing these relationships in a graph database can enable life scientists to spot hidden connections and shed light on cause and effect more quickly and accurately. Today most models and techniques that provide the foundations for AI systems are not optimised for detecting or traversing relationships within datasets. Graph databases, however, have shown they have the power to link complex relationships – making them the ultimate data structure to power machine learning models, as the German Center for Diabetes Research (DZD) has recently spotlighted: “[Graph technology] enables a new dimension of data analyses to fight diabetes by helping us to connect highly heterogeneous data from various disciplines, species and locations to build an invaluable body of knowledge,” according to Dr Alexander Jarasch, Head of Bioinformatics and Data Management at the DZD. “By applying modern machine learning techniques to our Neo4j graph, we are getting closer to understanding this complex disease to help diabetics and those with prediabetes.” Graph database technology provided DZD with a whole new

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measure of data analyses to help in the fight against diabetes by contributing to the connection of highly heterogeneous data from various disciplines, species and locations to create a hugely valuable body of knowledge. By applying advanced machine learning techniques to a graph database, DZD’s research team have become much closer to understanding the complexities of the disease and have moved a step forward in being able to help diabetics and those with prediabetes. As we know, medical data is highly heterogeneous by its nature, ranging from cell-level to incredibly detailed data, often contained within the same study group. All too often, researchers want to link either end of the scale – the meeting point between different data sets – which is where the compelling results tend to sit. But this can be a gargantuan challenge. In addition to this data complexity, researchers are also looking at huge amounts of data, often running into exabytes, which need to be distilled. Trawling through such large amounts of data, which put in perspective is the equivalent of more than 25 million whitepapers, is pretty much impossible for human teams. Working out how multiple researchers can access and collaborate on the data is also a challenge. With data at this scale, which often comes in an unstructured format, data needs to be turned into a valuable research ingredient as quickly as possible – not just simply initially analysed and stored. Deep data mining and pattern detection with graph technology can provide a path to invaluable insight. Graph software also has the innate power to collaboratively filter data. Collaborative filtering is the process of filtering information, using the information gathered by many users. Collaborative filtering is actually a technique used by recommendation engines. Information or patterns can be filtered via data sources, viewpoints, multiple agents and so forth. This approach allows research teams to work on data at the same time.

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Three Big Issues Traditional databases struggle to cope with three of the biggest issues in the life science sector – heterogeneity, complexity and scale. This is why we need to reconsider the way data has been historically modelled. Traditional SQL and relational databases find the volume and the unstructured nature of the data extremely difficult to handle. Scientists need diverse quality data to develop new drugs. When data is missing or there is insufficient data to feed AI algorithms to train and test accurate models, this makes it an impossible goal. In addition, this data is often stored in disparate database silos across different departments and formats, creating yet another bottleneck to research advancement. The Novartis Institutes for BioMedical Research, the research arm of Novartis, has shown how it has harnessed the power of graph technology to get over these hurdles. Novartis has used graph software to help create a system of scalable biological knowledge. This isn’t just about connecting huge amounts of heterogeneous data – it is also about enabling researchers to create a query for a particular kind of triangular relationship. These nodes are made up of chemical compounds, specific biological entities and diseases as described in specific research literature. The system needs to use uncertainty in key links as part of the query. Graph technology allows the system to capture the strength of the relationship between the medical research text by encoding it in the properties of a graph and connecting or joining the dots between these terms. This then provides a foundation for later queries that link the literature to observed chemical or biological data. Results can be tested by removing links and monitoring how results differ. Pharma, animal health and agrichemical giant Monsanto is another example. It has been working to get better inferences out of its plant genomics pipeline data. Before it recognised the power of graph technology it used relational databases, which resulted in millions of rows of data, which was a difficult read and made connecting relationships extremely difficult and timeconsuming. www.jforcs.com

Monsanto’s research teams wanted a tool that would enable it to provide an entire tree of ancestors from a single plant. They tested graph technology and can now process arbitrary-depth trees at what approximates to scale-free performance. This can not only be done quickly, but they can now analyse the ancestry of one million plants, instead of just one plant, in minutes. The graph tool has totally changed Monsanto’s research horizon. One of the graph software applications it developed, for example, touched every seed in its pipeline. The research time observed a 10x performance increase in this application, and a particular data scientist was able to replace one month of manual number-crunching with three hours of analysis using the graph-based system. Discovering Hidden Patterns These companies, amongst others, are exploring new frontiers in what can be achieved in graph-powered AI, which is essentially an intelligent system of connections. This relationship-first approach to data puts it in real context and provides a foundation for accurate, smart predictions and ultimately informed decision-making. This is helping life sciences make real advances that will contribute to the discovery of therapies in the future.

Emil Eifrem Emil Eifrem is CEO and co-founder of Neo4j. Emil famously sketched out what today is known as the property graph model on a flight to Mumbai in 2000. Since then Emil has devoted his professional life to building and evangelising graph databases, and is a frequent conference speaker and a well-known author and blogger on NoSQL and graph databases.

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Strategic Advantages of Integrating Regulators’ Advice into Clinical Trial Programme Design Working closely with regulators should be seen as an important strategy for successful drug development, rather than a barrier to be sidestepped or overcome. Early and frequent consultations with regulators helps to avoid surprises during all phases of clinical development, but particularly in the earlier phases. Integrating regulatory advice into the trial programme is an effective approach to mitigating the regulatory risk that is inherent in product development, and improving the likelihood of early product approval. The first step in deciding where to seek scientific advice is to determine where the product will be submitted for approval; both European and US regulators have created tools to assist developers in tailoring research and development programmes to meet regulatory needs and align the process with the specific requirements and preferences of each market. If the product is destined for both European and US markets, the typical approach is to seek scientific advice first from regulators in the market in which the product will be submitted, as a successful request for scientific advice from one regulator typically produces a stronger submission in other jurisdictions. The scientific guidance offered by regulators, be it from the European Medicines Agency (EMA), US Food and Drug Administration (FDA), or national authorities, can cover many aspects of a development programme, such as: • • • • • • • •

Has the correct and most appropriate animal model been chosen? And if there is no pre-defined animal model, is the proposal appropriate? Has the first-in-human (FIH) starting dose been calculated accurately? Is the manufacturing process well defined and appropriate? Has the investigational medicinal product (IMP) been classified correctly? Is it chemical, biological, a vaccine, an advanced therapy medicinal product (ATMP) or herbal? Has the appropriate comparator been selected for the patient studies? Will this be a placebo or another treatment? Are the trials sufficiently statistically powered? Are there sufficient data available to start a paediatric trial? Can certain aspects of the trials, such as a thorough QT/QTc (TQT) or drug-drug interaction, be replaced by modelling and simulation studies?

Scientific advice meetings can be conducted face-to-face, via teleconference or video conference, or entirely in writing. Face-to-face meetings tend to be the most productive, with a less formal atmosphere that offers the opportunity to combine exploratory questions seeking specific guidance and informal negotiations, in which all parties can discuss their respective 14 Journal for Clinical Studies

needs and preferences to build a mutually agreeable path toward product approval. The actual requests and responses can be multidisciplinary, and focus on a broad range of questions from product quality to acceptance of novel study designs, pharmacokinetic/ pharmacodynamic modelling, biomarkers, hard versus surrogate endpoints, or any other scientific question. Advice is also available on quality, non-clinical and clinical issues and paediatric issues, in parallel with other organisations and stakeholders such as the World Health Organization, payers, patients and academic researchers. National European authorities offer a cheaper alternative to seeking advice from the EMA (typically fees may be ~€4000, compared to up to €90,000), and it can be faster and easier to schedule these advisory meetings. However, it should be noted that national body advice does not often reflect a pan-European perspective, and may be driven by individual national agency opinion or scientific expertise. The EMA provides guidance reflecting the pan-EU perspective, and will assist the sponsor in ensuring that the development is aligned with the expectations of the Committee for Medicinal Products for Human Use (CHMP). It also offers financial incentives for small and medium-sized enterprises to seek scientific advice early and often, that can be up to a 100% fee reduction; and larger companies seeking advice on products with orphan designation or products intended for paediatriconly use can also benefit from these. In the United States, the FDA is committed to multiple iterative meetings with sponsors during the preclinical and clinical phases of development. The Prescription Drug User Fee Act (PDUFA) sets fees for scientific advice, but also incorporates fee waivers and reductions at the new drug application (NDA) and biological licence application (BLA) stages for products with priority, fast-track status, breakthrough designation and new molecular entities, as well as products that face significant barriers to innovation. The clear message from both European and US regulators is that it is never too early to seek scientific advice to reduce the risks and maximise the likelihood of product approval to ensure the success of clinical development. Whether the questions deal with broad issues of study design and appropriate indication/ study population, or more focused issues of chemistry, manufacturing and controls for a new product class, early agency consultation is better. As the cost of development of new drugs continues to rise, and attrition throughout the clinical phases remains high, there should be no reason to increase the risk of failure through a lack of discussion and planning with the regulators. Case Study: The Importance of Discussing Non-clinical and Manufacturing Strategy Before Initiating a Phase I Trial A US biotech company with an innovative diabetes treatment contacted SGS for advice on its non-clinical and manufacturing Volume 11 Issue 1


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plan, as well as its FIH study outline, and to assist in a scientific advice meeting with a European national authority. SGS reviewed the available in vitro and in vivo non-clinical data alongside the proposed GMP manufacturing plan. A number of questions for the agency were prepared, and the briefing book developed. An innovative study design based on an approach usually used in oncology was also prepared. During the scientific advice meeting the following items were discussed: • • • •

The validation of the testing strategy and analytical steps in the manufacturing programme, particularly the testing of an adventious agent; Approval for the GLP non-clinical programme, in particular the choice of animal model, as there was no ‘standard’ animal model available for this type of compound; Design of the Phase I trial, where the ‘oncology-based’ design was validated by the regulator; Agreement by the regulator that the FIH study can be

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performed in patients. The successful advice allowed the company to start its nonclinical programme quickly and assured a smooth approval of the FIH trial.

Bruno Speder Bruno Speder is Head of Clinical Regulatory Affairs & Consultancy at SGS Clinical Research. He is a pharmaceutical engineer and has over 10 years’ experience in drug development. He is also a member of the advisory board of several biotech companies and a guest lecturer on clinical research in the honours programme of Ghent University. Email: clinicalresearch@sgs.com

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Advancing Heart Failure Research Through Innovative Clinical Trial Design Cardiovascular disease remains public enemy number one in healthcare. Taking the top spot on the mortality scale, diseases of the heart are predicted to affect nearly 10 million people over the age of 18 by 2020 – a 25 per cent increase in just a decade.1 Heart failure is one of the more serious cardiovascular conditions, amassing a 23 per cent readmission rate and resulting in death within five years across 50 per cent of cases.2 It includes a complex set of diseases that typically are treated in the US by cardiology subspecialists. From a research perspective, heart failure should be ripe for progress. However, statistics and treatments have remained relatively static for decades. Many factors contribute to limited advances in heart failure discovery and treatment. The fact that several drugs for heart failure have shown detrimental effects on long-term outcomes, despite showing beneficial effects on shorter-term surrogate markers, has led regulatory bodies and clinical practice guidelines to seek mortality/morbidity data for approving/ recommending therapeutic interventions for heart failure. However, it is now recognized that preventing heart failure hospitalization and improving functional capacity are important benefits to be considered if a mortality excess is ruled out. Yet the value proposition for heart failure research is not lost on the industry. In sync with current initiatives to lower healthcare costs and improve clinical outcomes, better therapies are needed to move the needle on unacceptable heart failure statistics. It’s a priority that sits at the heart of the research community’s mission to improve the quality of life for healthcare’s most important asset: patients. Heart Failure Clinical Trial Challenges: A Deeper Look Heart failure clinical trials are inherently complex due to the variability in patients’ conditions and the intricacies of a disease with numerous causes. A patient’s clinical course is often marked by repeated hospitalisations, rapid disease progression, and death. Consequently, clinical trials must account for multiple risks; there are numerous pitfalls for sponsors that lack heart failure study experience.

that enrolment must often occur when patients present in an emergency setting. The question then becomes: How does the trial design address the needs of patients and families who present in an emergency room (ER) with an acute episode? Unlike studies conducted solely in clinical settings, acute heart failure studies require 24/7 coverage and must account for the nuances of busy ER workflows. Trials must work parallel to ER processes and not hinder the course of patient care. For example, study teams must be experts in handling informed consent thoroughly and delicately, giving patients and their families the information and time necessary to make informed decisions, even within the dynamics of an emergency situation. While there is often some tension between adherence to study protocols and supporting the needs of families, these strains are intensified with heart failure recruitment and retention. Strategies for Better Clinical Trial Design Recognising the many opportunities offered by successful heart failure trials, health authorities are increasingly open to alternative, innovative clinical trial designs that uphold safety and improve results. Current movements point to greater treatment effect, smaller sample sizes, better characterisation of patient

Depending on the aim of a heart failure trial, patient recruitment and retention becomes increasingly challenging. Clinical trials designed to test efficacy in stopping disease progression may encompass patient samples that represent more stable conditions. However, clinical trials often must involve acute, decompensated patients if the study goal is to reduce patients’ need for emergency care. Within these situations, investigators must identify patients most likely to have an acute event. Partnering with heart failure specialists whose historical data indicates a strong heart failure population can produce some enrolment wins in a more controlled clinic environment. The reality, however, is 16 Journal for Clinical Studies

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subgroups targeted for more intensive therapy, and increased information capture to enhance understanding of outcomes. One way to tighten the belt on mammoth cardiovascular clinical trials is to combine a Phase II and Phase III programme into one fluid, adaptive clinical trial. This way, the study can leverage existing patient enrolment for safety and efficacy data review, as well as re-evaluate the sample size based on the Phase II period treatment effect. This parallel effort reduces timeframes between the Phase II and III trials and health authority discussions. Consequently, this approach can reduce costs, recruitment needs and the overall duration of a trial. Partnering with a contract research organisation (CRO) experienced with innovative heart failure clinical trials can improve success rates by implementing best practices that include: •

Effective site selection that considers more than just the expertise of the principal investigator and their staff, but also the experience of the ancillary services that will support the protocol schedule of assessments. Trial design that includes an operational strategy for 24/7 coverage not only from investigators but also from medical monitors (to answer provider questions) and from ancillary services (such as echocardiogram or cardiac catheterisation services). Methods for reducing the burden of a trial on the clinical site. These might include customised training materials and reference tools, such as “pocket protocol” cards to help onsite staff quickly and easily identify study protocols. Processes to improve experiences for patients and families. Offering a concierge service that can help with transportation needs, meals, or even arranging for follow-ups from a visiting nurse have proven effective for patient retention. Recruitment that considers retention during screening and enrolment. This includes trying to determine upfront whether a patient is likely to be compliant and reliable throughout the course of the trial. Important questions include: Does the patient have a history of medication or therapy nonadherence? Where does a patient live in proximity to the clinical site? Does the patient have reliable transportation?

Great opportunity exists to advance heart failure trials and improve quality outcomes for all stakeholders. Going forward, however, it’s important that the industry start setting aside www.jforcs.com

traditional approaches to these complex research undertakings. Researchers must take advantage of innovative and emerging best practices to bring new discovery to market and to give heart failure patients new options for better outcomes. REFERENCES 1.

Mozaffarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2016 update: a report from the American Heart Association [published online ahead of print December 16, 2015]. Circulation. 2. Centers for Medicare & Medicaid Services. Hospital Quality Initiative Outcome measures. https://www.cms.gov/medicare/quality-initiativespatient-assessment-instruments/hospitalqualityinits/outcomemeasures.html

Karen Hill Karen Hill is senior vice president of global project management at Worldwide Clinical Trials and is responsible for global project management within the cardiovascular and metabolic division. She has more than 25 years of experience in the contract research organisation (CRO) industry and currently heads up an experienced global team who are focused on working on both large cardiovascular outcome trials, as well as other phase II–IV studies in cardiovascular and metabolic indications. Email: karen.hill@worldwide.com

Nancy Newark Nancy Newark, R.N., is executive director of project management for the cardiovascular therapeutic area at Worldwide Clinical Trials and is responsible for oversight and leadership for cardiovascular and metabolic clinical trials. She has over 30 years’ experience in the CRO and clinical research industry and served as a registered nurse in cardiology and critical care transport. Email: nancy.newark@worldwide.com

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Regulatory

Clinical Trial Packaging: Considerations and Challenges Packaging pharmaceutical products in accordance with environmental considerations and marketing authorisation requirements can be an extremely difficult process. It requires experience, knowledge, highly trained staff and well-run facilities. Packaging products for a clinical trial brings even further complexities, making it perhaps the most demanding packaging work within the industry. The high risks associated mean staff working with such products must have a full understanding of the regulations when it comes to providing packaging for trial drugs. The process can also be made more complex when numerous products are being packed for different markets and clinical sites. In such cases, a thorough understanding of clinical protocol is vital, and all staff need to have full knowledge of each study design. In this article, Colin Newbould, director of regulatory affairs and QP services at the Wasdell Group, talks through the vital considerations when packaging drugs for clinical supply. He discusses the various challenges presented by blinding, randomisation and patient compliance before reflecting on how new practices such as just-in-time labelling could help to overcome the complexities faced. Guidance on Blinding and Randomisation Managing the process of blinding and randomisation across multiple trial sites, which are often in different countries, can be challenging. To help the industry understand the complexities and adopt a uniform approach to the packaging of pharmaceutical products, the World Health Organisation (WHO)1 published guidance on the matter in 2002. The guidelines offered clarity on packaging for clinical trials, highlighting the key differences from commercial-stage packaging, such as aesthetics vs usability, high vs low volume and the variances in storage and logistics when a product is not being created for market. Blinding and randomisation are vital considerations in the development of trial packaging. Blinding involves more than ensuring patients, trial staff and physicians cannot differentiate between placebos and the active drug; packagers must also maintain accurate records of the processing, packaging, testing and distribution of placebo drugs, which can be accessed quickly if there is an emergency. These records require input from staff across the manufacturing, quality and distribution departments, and capture all actions undertaken in the process, as well as any deviation from procedures or issues encountered. These documents form the proof of correct manufacture once completed. The blinding of the trial drugs and their packaging makes these processes particularly 18 Journal for Clinical Studies

challenging compared to commercial products. Storing and tracking accurate records and comprehensive data necessitates a reporting and data storage system that can receive input from different users without preventing effective security and the validity of data. This is another intricate logistic that needs to be addressed. Masking the identity of a product is a highly complicated practice. For example, if the product was an injectable in a doubleblinded study, those administering the drug should not be able to differentiate between placebo and the active drug. Therefore, the trial sponsor would have to create pre-filled syringes with two identical liquids that behave in very different ways. In cases such as these, the packaging must be also identical to provide the vital results. Given the wide range of formats and materials that can be used, this requires a vast library of designs. It is also important to match the packaging in comparator studies. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)2 emphasises that modifying packaging or implementing repackaging is an efficient approach, yet this generates a vast amount of waste. Randomisation is another important step in clinical trial packaging. Randomisation prevents selection bias between patient groups which could lead to inaccurate results and compromise the entire study. It is mostly used in later-stage clinical trials, which means that companies often have to deal with larger volumes3 while ensuring that the drug products can be distributed to sites in such a way that conceals the nature of each. Ensuring Adherence Another important aspect to consider when a clinical trial is being conducted is patient compliance. The WHO stated that1 clinical packaging has got a significant role to play in compliance, in addition to providing necessary information to trial staff. The guidelines state that the packaging should allow for simple and safe administration, in order to ensure patient compliance. Missed dosages, for example, can impact the outcomes of the trial but this can be managed, in part with effective packaging. For example, information specific to the patient, such as when the medicines need to be taken, can be added to packaging designs. In addition to this, trials that include an elderly patient population should have tablets that are easily accessible and contain clear instructions that help the patients to take their medication regularly and on time. Packaging such as this will become increasingly important as smart technology and virtual trials become more common. Smart technology includes wearable devices such as the Apple watch, smart devices (mobile phones Volume 11 Issue 1


Regulatory and tablets), and home sensors such as Amazon’s Alexa. These allow real-world data (time, movements) to be captured and recorded for use in a trial. Smart technology in conjunction with trial-specific apps make the running of trials increasingly possible outside of a medical or clinical research organisation environment, and more possible from the patient’s home. Patient compliance and ease of access of the trial medicines then becomes key, with clear and straightforward access provided by the trial packaging key to ensure that patient compliance is achieved. ‘Just-in-time’ Packaging Investing in clinical trials is a calculated risk for many companies and anything that extends the duration of the trial adds more cost. One way of negating this cost is to ensure that trial supplies are ready, packaged and shipped to trial sites as efficiently as possible. It is not always possible to have products packaged and stored away awaiting demand in a clinical trial. Packaging largely differs depending on the conditions of the trial and the product itself. For example, the shelf life and stability of a solid dosage form when compared to a liquid formulation highlights the difficulty in being prepared in practice. Small molecule drugs can often endure temperature changes whilst in transit and are easier to store than large molecule products, which usually need cold-chain transportation and storage. As more and more biotech products are being used, this is an important consideration. In addition, the ability to more accurately forecast supply is imperative during clinical research. Deciding on the exact number of placebos, comparators and doses needed for each site is complicated and time-consuming. Although trials try to establish the ideal participation rate, it is unusual for patient targets to be met. It is also unlikely that all patients will continue through until the end of the trial. These contributing factors make it hard to determine the demand for drugs that the trial will generate and therefore exactly how many doses will need to be packaged up and stored. At sites where enrolment rates differ from those that are expected, it is vital that supplies are provided in a flexible manner. To make sure that supplies are packaged, randomised and blinded, it is crucial to understand when flexibility will be needed long before the trial begins. This requires considerable expertise and infrastructure. In order to ensure that this process is as simple as possible, many companies adopt a ‘just-in-time’ supply chain strategy where partially packaged products are held and finalised for specific trial dates for a short amount of time. By adopting this tactic, the drug products can be delivered to the site within a matter of days. This requires implementing a clinical protocol design that can use partially finished packaging. Adopting this protocol means that labelling can be left until the last minute. At this late stage, the correct language, patient numbering information and expiration date can be added to the label. This allows for changes in country authorisation, patient recruitment and expiration dates. Yet, in the absence of the full information needed for the label, companies need to ensure that they can still adequately track and identify medicines. Wider Considerations Batch size is another central consideration as the volumes of products needed for trials are often much smaller. Efficient packaging relies on companies being able to provide packaging to scale as and when it is needed. Packaging design is also key in clinical trials. Overall, most packaging designs for clinical trials are quite simple and easily 19 Journal for Clinical Studies

blinded. However, this becomes more complex during later-phase trials, especially in Phase III. It is important to consider how the commercial packaging will appear so that the pharma company can gather feedback from staff and patients involved in the trial. To give one example, if the medicine is designed for young children, the bottle must be childproof. Such issues need to be addressed as early as possible to ensure that mistakes in the packaging are not repeated on a commercial scale later down the line. Despite serialisation regulations not applying to clinical trials at this time, many regional regulators have also developed their own tracking and serialisation processes specifically for trials, in order for drugs to be tracked from the factory to the pharmacy. This is to support near-commercial packaging for later-phase trials, offering the manufacturers the chance to ensure that their designs have enough space to include information such as serial numbers. Knowledge of local regulations and geographic reach is also extremely useful for teams working on clinical trials. If medicines are packaged at a central place, which can happen with ‘just-intime’ packaging, a clear understanding of the various regional regulations is vital. Conclusion Every trial differs in how it approaches the issue of flexibility. However, it is clear that flexibility is often crucial to making a trial a success. Expert packagers can offer the guidance and support that is needed to make sure that the drug products reach the right places when they need to. Compliance is also highly important when it comes to planning clinical trials. This is because it helps to ensure patient safety, but it is also due to how compliance can prevent expensive delays. If it is implemented well, adopting the ‘just-in-time’ process may help to reduce the amount of time and resources needed to repackage products. It also allows companies to improve efficiency during the trial and can ultimately help to bring products to market more quickly. REFERENCES 1.

http://www.who.int/medicines/areas/quality_safety/quality_assurance/ GuidelinesPackagingPharmaceuticalProductsTRS902Annex9.pdf 2. http://www.ich.org/fileadmin/Public_Web_Site/Training/GCG_-_ Endorsed_Training_Events/APEC_LSIF_FDA_prelim_workshop_ Bangkok__Thailand_Mar_08/Day_2/Manufacture_and_Import.pdf 3. http://www.who.int/medicines/publications/druginformation/issues/ WHO_DI_31-2_Placebo.pdf 4. https://www.ncbi.nlm.nih.gov/pubmed/26908540

Colin Newbould Colin Newbould, director of regulatory affairs and QP services at the Wasdell Group. As the director of regulatory affairs and QP services at The Wasdell Group, Colin is responsible for developing and implementing the company strategy to ensure world-class compliance, effective processes and customer satisfaction. Along with his position as director of QP services, he is also one of Wasdell’s QPs for certification to the European market. He has over 20 years’ experience in the pharmaceutical industry and having previously held management positions at PCI Pharma Services, Penn Pharmaceutical Services and Catalent, Colin also has expertise in facility design and startup, high potent manufacturing, managing supply chain quality, risk management and continuous improvement. He holds a BSc in chemistry with analytical chemistry and toxicology and is a current management committee member of the Pharmaceutical and Healthcare Sciences Society (PHSS) and has previous terms with the Pharmaceutical Quality Group (PQG). Volume 11 Issue 1


Regulatory

Adjudication in Clinical Trials: A Primer

Although the main purpose of most clinical trials is to compare the efficacy and/or safety endpoints that occur in two groups, the endpoint management and adjudication process could often be considered the Cinderella of trial management. Too often, endpoint adjudication planning is the last bit of the trial to be organised, at times even after the trial has begun. In today’s event-driven trials, the choice of endpoints and how the endpoint adjudication process is managed can have a major impact on the success of the trial. Endpoint adjudication is the process by which an independent, blinded expert committee reviews clinical events that occur during the trial. These are assessed – adjudicated – against a set of predefined criteria to classify the events. Endpoint adjudication is usually managed in an electronic system which provides efficiency, accountability and documentation of the entire process. When a quality, systematic and standardised clinical event committee (CEC) process is incorporated into a clinical trial, it can enhance the validity of trial results. In this article we will give a brief overview of the endpoint adjudication process, and the key elements that should be considered when the trial is in the planning stages. What is Endpoint Adjudication and When is it Necessary? Endpoint adjudication is used when the outcomes of interest are made up of clinical events. When a clinical event occurs in a trial, the onsite investigator will have an opinion as to what type of event the patient has had. However, if you were to ask a different doctor for an opinion about what the event was, a different answer might be obtained. Therefore, if one relies solely on investigatorassignation of outcome events in a clinical trial, there is a risk of introducing a significant degree of variability into the results. There are multiple reasons for the variability in reporting between physicians: differences in medical training; geographical differences in the management of disease and availability of diagnostic tests; differences in healthcare systems; and of course, bias, as often the investigator is also the treating physician. In multi-centre and multi-country studies, this effect may be amplified. A centralised and standardised adjudication process reduces such variability in adjudication outcomes by limiting the number of individuals tasked with classifying the potential endpoint events and by ensuring that those individuals have special expertise in the relevant clinical area(s) of interest. This enhances consistency and improves the accuracy of results. Endpoint adjudication can be used to assess both efficacy outcomes such as myocardial infarction and safety outcomes such as the occurrence of angioedema. Centralised endpoint adjudication should improve the reliability of outcomes data, so it is particularly useful when events of interest are more subjective, e.g. hospitalisation for heart failure or when sub-categorisation of endpoints is needed, for example a sub-type of myocardial infarction or stroke.

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There are increasing regulatory requirements for centralised adjudication. For example, for several years such centralised adjudication has been mandated in trials examining the CV safety of new treatments for type 2 diabetes mellitus. In addition to adjudication of events, the endpoint committee can also be used to help identify events. They may recognise potential new events in source documentation and flag these. In addition, CECs can be used to review serious adverse events for unreported potential endpoint events and thus ensure that this process is done independently of the sponsor. What is a Clinical Event Committee (CEC)? A CEC is a group of independent experts tasked with reviewing and adjudicating all the events of interest in the clinical trial. The CEC perform blinded assessment of clinical event data and decide if the event under scrutiny meets pre-specified clinical event definitions. The event definitions are established in advance of trial commencement and are detailed in a CEC charter document that is available for review by regulatory agencies. The CEC results are used purely for trial analyses and are not fed back to the site investigators. Who is in a CEC? A CEC is made up of a variable number of subject matter experts and a CEC chairperson. Members should have clinical expertise in the endpoints of interest and ideally have CEC experience. If a broad range of endpoints must be assessed, then subject matter experts from varying specialties may be required. It is most important that the selected chairperson has CEC experience and leadership ability. The chairman’s knowledge of adjudication becomes particularly important during committee meetings where adjudication disagreements are discussed. Trial details must be specified up front to ensure that members are able to commit for the full duration of the study and have sufficient capacity to meet the workload and timeline requirements. Event volume can often be large, so the number of committee members as well as member availability must be taken into consideration, with redundancy built in to account for illness and vacation time. The CEC members must be free of conflicts of interest and cannot act as trial investigators. Selection of CEC members can be performed by the sponsor or, as is more often the case, by a clinical research organisation (CRO) or a specialist adjudication organisation. The sponsor usually must approve the committee after selection. How do CECs Make Decisions? There are several different CEC workflows that can be utilized, however, the one most resistant to bias is parallel adjudication. Each outcome event packet is randomly assigned to a pair of adjudicators. Each adjudicator reviews and adjudicates the package independently. If the answers given by each adjudicator are in agreement, then the event is considered adjudicated or “classified.” If there is discord between the reviewer outcomes, then the event is sent to a committee meeting for a group decision to be made. Minor disagreements such as event dates can often be dealt with before they reach full committee meetings (e.g. by both reviewers re-examining the event data and ensuring that the discord is not the result of a simple transcription error).

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Journal for Clinical Studies 21


Regulatory Why You Need to Plan for Centralised Adjudication in Advance The decision to use centralised adjudication must be made at the trial planning phase. A CEC expert should be engaged during trial design. Critical decisions regarding types of endpoints used in the primary and secondary outcomes should ideally be made in advance and after discussion with an expert, as errors in endpoint selection are difficult to rectify later. In addition to the definition of events, one of the most crucial aspects of endpoint adjudication is defining the workflow, from gathering the required site documents, to translation and presentation of the event data to the CEC for adjudication. These workflows should be designed in parallel with the CEC charter and aligned with the overall trial design and collection of trial documentation. The adjudication operation can involve multiple stakeholders (e.g. CRO, CEC, study sites) and it is important that the various steps and procedures involved in the process are defined early on to ensure workflows are correct. In addition, real-time, prospective adjudication is now considered the gold standard and allows live metrics to be utilised in assessing trial progress. Gone are the days of waiting until the trial finishes and adjudicating all the events at the end. When adjudication is performed in real time, it is easier for sites to act on CEC requests for more information. In addition, other trial committees, such as the executive committee or the data safety monitoring board, rely on timely adjudication to perform their functions and run the trial efficiently. There is no one-sizefits-all approach to the CEC and the CEC workflow as it must be tailored to the trial design. Key Elements to be Considered when Planning for Adjudication Who will manage the process? It is important that the CEC remains independent from the sponsor. Ideally, sponsors should engage the services of a specialist adjudication provider or a CRO with adjudication capabilities in the early stages of trial design. What software systems will be implemented? Gone are the days when it was practical to use paper-based methods to manage endpoint adjudication. Just as central adjudication

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reduces the possibility of bias, a software environment that manages the process from collection to final adjudication reduces procedural discrepancies that can introduce important data variances, leading to inaccurate outcomes. There are two elements to consider in the software used to support the endpoint adjudication process. 1. The ability to collect data from investigator sites in a way that reduces errors and increases accuracy. 2. The ability to enable process controls and oversight that provide for early warnings about process, CRO and adjudication performance. Whatever the system, it must allow CROs and sponsors alike to trace every aspect of process evolution, from collection, deidentification, dossier aggregation and adjudicator voting to CEC management. When a single integrated system follows the data from cradle to final outcome, it enables the types of metrics sponsors and regulators have been expecting for years: • • •

The ability to evaluate site performance. The capacity to run QC on the adjudication process. The means to compare individual adjudicators to their peer group within and across protocols.

Finally, with advanced system capabilities enabling fully auditable communications between stakeholders (e.g., adjudicators and trial managers), it is now possible to compile the most complete record of every endpoint process, eliminating guesswork and reducing reconciliation processes significantly. This in turn can have enormous benefits to patients and sponsors alike. CEC charter The CEC charter describes all the key activities of the endpoint process. It should include standard operating procedures for the entire process, including endpoint definitions, data capture overview, committee workflow and decision-making rules, dossier compilation responsibilities, key stakeholder roles and responsibilities, and in the case of the CEC, a description of CEC member requirements. It is a critical document that needs input from all stakeholders involved in the process.

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Regulatory

Identifying key stakeholders Endpoint workflow can be complex and involve multiple stakeholders: site investigators; site research personnel; CEC coordinators; translators; adjudicators; site monitors; project managers. Each project may have variations on these key roles. Key personnel should be identified early, and roles specified in the charter. Event definitions Careful consideration needs to be given to event definitions. Ideally these need to be as clinically meaningful and as objective as possible. With cardiovascular endpoints, there are standardised definition documents that can be used as outlines for event definitions. If there are no standardised event definitions, the definitions need to be carefully drafted to ensure they are not ambiguous. If an event definition is ambiguous and open to interpretation, it can introduce further variability into the results. An example of an ambiguous definition might be an event definition including the phrase “kidney failure.” This is too open to interpretation, and ideally key levels of creatinine or eGFR (estimated glomerular filtration rate) should be used within the definition. Similarly, the components of any definition utilised for a trial should be obtainable for review by the CEC. For example, since cardiac biomarkers (particularly Troponin) are central to the FDA-recommended definition of an acute myocardial infarction event, then for trials where acute myocardial infarction (AMI) is an endpoint of interest, there should be a reasonable expectation that, for most suspected AMI events, relevant biomarker measurements will be available to the adjudicators. Summary Prospective endpoint adjudication is now considered the gold standard in assessing trial progress. When done correctly, tried and true workflows and event definitions ensure consistency and reproducibility and thus the reliability of final results in clinical trials. Process matters in endpoint adjudication. From consistent data collection and de-identification, to performance metrics and oversight, long-term adjudication functions benefit greatly from www.jforcs.com

systems that can QC and follow the data from event trigger to final outcome. Such automated databases can produce quality reporting and visible metrics that provide the key constituencies including sponsors and CROs with the data necessary to do course corrections and keep clinical trials on track in real time.

Pardeep Jhund Dr Pardeep Jhund is a cardiologist and cofounder of Global Clinical Trial Partners. He has a specialist interest in heart failure and clinical trials. He has been a member or chair of a number of adjudication committees for academic and industry-sponsored trials over the past 20 years.

Michael Macdonald Dr Michael MacDonald is a cardiologist and co-founder of Global Clinical Trial Partners. He has 15 years’ experience in the management of the endpoint adjudication process from charter development to adjudication. In addition, he has chaired and been a member of numerous committees for trials with both academic and industry sponsors across multiple disease areas.

Abraham Gutman Abraham Gutman founded AG Mednet in 2005 and leads the company’s mission to improve, automate and expedite outcomes in clinical trials by ensuring quality and compliance within drug, biologic and device trials. Abraham holds a BA in Computer Science from Cornell University and an MSc in Computer Science from Yale University. Journal for Clinical Studies 23


Market Report

A Unique Model to Accelerate Industrysponsored Research in Malaysia The influx of industry-sponsored research (ISR) into the Asia Pacific region is continually growing due to the rising costs and complicated processes involved in drug development. Several countries within the region such as Singapore and, more notably, South Korea, have taken the initiative to develop and further strengthen their place as preferred destinations to conduct clinical trials. One such initiative is the establishment of specific entities that focus on nurturing and expanding the existing clinical trial ecosystem within the individual countries. With over 20 years of experience in conducting late-phase trials, the Malaysian government is no exception. In the last six years, Malaysia has been steadily building a comprehensive and supportive clinical research ecosystem within the country. This includes the creation of Clinical Research Malaysia (CRM), a non-profit company wholly owned by the Ministry of Health (MOH).1 This review will present CRM as a unique business model, established to create a thriving and comprehensive ecosystem for ISRs in Malaysia and how this business model may be relevant and replicated in Asian countries that are looking to focus on attracting ISRs. Clinical Research Malaysia – Addressing the Need for a Unique Business Model Previously, sponsors and CROs have found it challenging in understanding the requirements, processes and systems involved in conducting ISRs in Malaysia. As a result, the time taken for them to bring in a clinical trial would have been prolonged. As Malaysia gears itself to increase the volume of ISRs into the country, the government is continually taking steps to develop its clinical research ecosystem. To this end, developing mechanisms to ensure that these studies are performed and managed efficiently from its inception has been a main focus. One such example is a “centralised support service”1 that should facilitate the business and administrative aspects of clinical trials.2 Tang et al. determined that a focused research infrastructure is able to facilitate rapid development of trials (faster trial progress from institutional review board (IRB) approval to activation by 1.1 months and from activation to first enrolment by 0.3 months in ISRs) as well increased patient accrual rates.3 Though the infrastructure studied focuses on oncology trials, some of its components such as a “capitalist” research model, enrolling patients from early-phase trials into subsequent later-phase trials, parallel processing for trial approval and a decentralised staffing model can be extended to government and research institutions to cultivate a thriving clinical trial ecosystem. In the Asia Pacific region, other countries have also established similar entities to further advance their clinical research industry. Two 24 Journal for Clinical Studies

examples are the formation of the South Korea National Enterprise for Clinical Trials (KoNECT) and Singapore Clinical Research Institute (SCRI). KoNECT was established to nurture the country’s clinical trial infrastructure and capabilities4 while SCRI is dedicated to enhancing the standards of clinical research capabilities in Singapore. Creation of CRM Acknowledging the significant growth of the drug development industry, the Malaysian government ensured the National Key Economic Area (NKEA) encompassing the healthcare industry included the creation of a supportive ecosystem to grow clinical research.1 Its focus is to allow for the conduct of more efficient and higher quality trials by increasing the number of clinical research centres, developing a larger pool of certified investigators and improving approval timelines.5 Therefore, CRM was established in 2012 to effectively increase the speed, reliability and delivery of outcomes for all stakeholders involved in clinical research. Its vision is to highlight Malaysia as a preferred global destination for clinical research by improving the local ecosystem to support the growth of ISRs within the country.1 As a non-profit company that is wholly owned by the Malaysian MOH, it is governed by a board of directors that include the Minister and Secretary General of the MOH, the Director of the National Clinical Research Centres and representatives from the Pharmaceutical Association of Malaysia and university hospitals. The management team of CRM follows that of a corporate entity headed by a CEO and senior leadership team comprising finance, human resources, business development and clinical operations. Challenges Within the Malaysian Clinical Trial Ecosystem Prior to CRM Before the establishment of CRM, the country faced several challenges that dampened the conduct of ISRs. These included long-drawn-out hiring and asset acquisition processes that involved complicated and fractionated government bureaucracy, poor transparency of funds management and a lack of activities to increase the number of talented and trained human resource, as well as adequately set-up trial investigation sites. There was also no clear research pathway to develop the potential interests of existing investigators and support staff, and a need to ensure that the pool of experienced principal investigators (PIs) was maintained through proper succession plans. Further, there was a need to manage the whole national clinical research ecosystem under one centralised body. This entails collaborating with various stakeholders within the clinical research ecosystem, such as sponsors and contract research organisations (CROs), private and public doctors from universities, health clinics and hospitals, as well as the regulatory agencies and ethics committees, under a single point of contact to facilitate the processes of end-to-end activities involved in conducting ISRs.1 Volume 11 Issue 1


Market Report CRM as a Unique Working Model The detailed objectives of CRM as discussed in a prior article1 are to locally improve capabilities at trial sites and of human resource required to run trials which conforms to international quality and standards, establishing high quality feasibility assessments and investigator selection mechanisms and ensuring speedy and transparent administrative processes, especially in the management of the clinical trial budget. CRM is also tasked to initiate and grow collaborations locally and internationally to bring in investments by global pharmaceutical and CRO companies and address the lack of awareness of and interest in clinical research among the healthcare fraternity and the public.

Malaysia’s research ecosystem, these individual databases have led to inaccuracies, which have misguided and delayed feasibility approaches. Examples of the dynamic changes are movements (e.g. promotions, transfers or retirements) of investigators within the healthcare setting, changes in regulatory environment, site staffing or person in charge, and resources leading to change in site capabilities. A centralised feasibility service, on the other hand, allows for a single point of contact that capitalises on CRM presence in all 33 major clinical research centres nationwide, which enables it to

As a whole, the objectives of CRM are to leverage Malaysia’s distinct advantages such as its diverse and large clinical trial-naïve population, its low clinical trial density,6 low health costs6 and competitive approval timelines compared to its counterparts in Asia. Part of its objectives is to also develop the existing infrastructure for the country’s clinical research centre (CRC) network, which is an extensive network of research centres, housed within various MOH hospitals.7 Strategies There are five pillars that constitute CRM’s strategies toward accomplishing its objectives. These are to grow the numbers of PIs and sites conducting ISRs, to increase the volume of ISRs, collaborate with stakeholders, create awareness of CRM and develop human capital. Overall, the strategies allow CRM to centralise the management and optimise and mobilise resources quickly and efficiently. Being an entity under the MOH facilitates CRM’s initiatives and activities with private healthcare facilities, regulatory agencies such as the National Pharmaceutical Regulatory Agency (NPRA), which is its main stakeholder, and ethics committees. It also gives CRM access to the large CRC networks and its investigator database, the Medical Research Ethics Committee (MREC), the Medical Device Authority (MDA) and various other MOH components. Through its government affiliations, CRM is able to work with university hospitals and their individual institutional review boards (IRBs), the Malaysian Investment Development Authority (MIDA) and other important government agencies that have roles in developing a healthy clinical trial ecosystem within the country. Complimentary Feasibility Studies In an effort to attract global sponsors and CROs into Malaysia, CRM offers a range of services to support and facilitate their needs in conducting ISRs. One of the key core services that CRM offers is providing feasibility studies and investigator matching at no cost to sponsors and CROs. A clinical trial feasibility is a process of evaluating the possibility of conducting a particular clinical trial in a particular geographical region with an objective of running a trial at an optimum timeline, cost and patient accrual rates. The centralised feasibility service by CRM functions as a single point of contact for sponsors and CROs. It capitalises on a comprehensive updated internal database of investigators, enables outreach to a wider range of investigators and sites, and leads to streamlined communications, which reduces delay and confusion on the ground. Prior to having a centralised feasibility management service in Malaysia, sponsors and CROs had to conduct feasibility assessments individually by relying on their own internal databases, which are based on their company’s experiences with previous feasibility studies.8 Additionally, due to the dynamic nature of www.jforcs.com

Figure 1: The figure shows the difference between sponsor/CRO-investigator contact without and with a centralised feasibility point of contact like CRM. Without a centralising entity, sponsors and CROs work within their internal databases of investigators (and investigation sites) restricting their reach to a large pool of clinical research resources. Comparatively, having a centralising entity such as CRM with its capabilities and connections with the various public and private institutions, allows both sponsors and CROs to have a wider reach to investigators and investigation sites.

have a comprehensive database that is frequently updated, which ultimately reduces delay for ISRs initiation (Figure 1). On a nationwide perspective, a centrally managed feasibility structure is an attractive alternative to sponsors and CROs looking to enhance efficiency and width of a feasibility outreach, avoid redundant processes and promote a more accurate assessment of Malaysia’s capabilities. Consultation and Management of Clinical Trial Budget CRM is authorised by the Malaysian government to act as a trustee in managing the budgets of clinical trials conducted in the country by receiving and executing its disbursement. It ensures that payments are made to the relevant parties involved in the conduct of clinical trials and that they are made in a fair and transparent manner. The majority of investigators conducting clinical trials are in the government sector, and according to the General Orders of Journal for Clinical Studies 25


Market Report the Malaysian Government,9 investigators who are government officers shall not receive money paid directly to them (from sponsors/CROs) derived from their clinical trial activities. In light of this, CRM legitimises the transfer of the trial funds by managing the trial budget and channelling the investigators’ fees to the relevant investigators. Placement of Study Coordinators CRM recruits and provides training for its study coordinators (SCs) who are then placed at trial sites nationwide to assist investigators with ISRs. At the start of 2018, there were about 110 study coordinators. To ensure that these SCs continuously maintain a high standard of professionalism, frequent trainings related to clinical research such as Good Clinical Practice (GCP) refresher courses, protocol deviation workshops and recruitment trainings are conducted for them. Review of Clinical Trial Agreement and Non-disclosure Agreement CRM also assists investigators, sponsors and CROs by reviewing and advising on clinical trial agreements (CTAs) and non-disclosure agreements (NDAs). CRM’s experienced legal officers ensure that all agreements made in relation to the conduct of clinical trials in Malaysia comply with the applicable laws, regulations and guidelines of the Malaysian government. This has significantly reduced the duration of the CTA reviewing process from three months to 14 days.1 Outcomes The outcomes of bringing together the various touch points involved in ISRs speak to the success of CRM’s unique model. In financial terms, the investment value cumulatively from CRM’s inception in 2012 to 2017 has reached more than RM240 million, which is 42% of its 2020 target.

Figure 3: The number of requests for full feasibilities received by CRM from sponsors and CROs from 2014–2017

also recognised CRM’s capability and timeliness in reverting a feasibility assessment and have therefore approached CRM in most of their enquiries. Conclusion Compared to the current standard working model of ISRs wherein individual sponsors and CROs attempt to conduct clinical trials without a centralised organisation, CRM offers a new paradigm as well as value proposition. The uniqueness of CRM is that it forms an overarching collaborative force between all the different stakeholders involved in the clinical trial ecosystem – sponsors, CROs, government bodies, regulatory agencies, ethics committees, institutional research facilities and private healthcare facilities.

Between 2014 and 2017, there was more than 400% growth in sponsors and more than 200% growth in CROs that have utilised CRM’s services (Figure 2). By the end of 2017, there were 1110 new and ongoing ISRs and more than 1900 skilled jobs (versus

Figure 2: Both charts show the growth of number of sponsors and CROs that have used any of CRM’s services from 2014–2017.

the 1000 set) created in the clinical research industry before the projected 2020 timeline. These numbers far surpass the KPI set for CRM.10 The reported number of full feasibilities received by CRM from sponsors and CROs showed an increasing trend from 2014 to 2017 with more than a twofold growth (Figure 3). Besides offering this service on a complimentary basis, sponsors and CROs have 26 Journal for Clinical Studies

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Market Report Through its various strategies and activities, the model allows for an integrative approach to transform the ISR industry into a business model with an efficient business management perspective and added dimensions such as marketing and business development, all within a framework that is supported by a country’s legal and ethical framework. As the target year 2020 approaches and as CRM continues to expand and gain experience, it offers a working model that may be replicated in other countries within the region that seek to build an efficient and thriving clinical research ecosystem. REFERENCES 1.

Ooi AJA & Khalid KF. Malaysia’s clinical research ecosystem. Appl Clin Trials. (2017). http://www.appliedclinicaltrialsonline.com/malaysia-sclinical-research-ecosystem. 2. Rahman S & Majumder MAA. Managing clinical trials in Asia: issues, threats, opportunities and approaches. South East Asia J. Public Health (online). 2(2), 80-84 (2012). 3. Tang C, Hess KR, Sanders D, Davis SE, Buzdar AU, Kurzrock R, Lee JJ, Meric-Bernstam F & Hong DS. Modifying the clinical research infrastructure at a dedicated clinical trials unit: assessment of trial development, activation, and participant accrual. Clin. Cancer Res. 23(6), 1407-1413 (2016). 4. Chee D, Park MS & Sohn J-H. New initiatives for transforming clinical research in Korea. J Med. Dev. Sci. 1(2), 27-32 (2015). doi:10.18063/ JMDS.2015.02.003. 5. Performance Management and Delivery Unity, Malaysia. Healthcare NKEA fact sheet. http://etp.pemandu.gov.my/upload/NKEA_Factsheet_ Healthcare.pdf visited on 30 November 2018. 6. Frost & Sullivan. Asia: preferred destination for clinical trials. (2016). 7. Sim A & Astudillo D. Working with Clinical Research Malaysia to move Malaysia forward. Ann. Clin. Lab. Res. 3(333), 1 (2015). 8. Khalid KF, Ooi AJA & Tay WC. How a centralized feasibility service attracts sponsors and contract research organizations to Malaysia. Presented at Drug Information Association (DIA), Chicago, Illinois (2017). 9. Government of Malaysia. General Orders Chapter D, Clause 5. (1993). 10. Clinical Research Malaysia. Annual Report (2017).

Audrey Ooi Audrey Ooi is currently the Associate Manager of Business Development at Clinical Research Malaysia (CRM). She graduated from Monash University with a Bachelor of Medical Bioscience and went on to obtain a Master Degree in Medical Science from the University of Malaya. She has an extensive experience in various areas of medical writing, project management and stakeholder engagement. Email: audrey.ooi@clinicalresearch.my

Dr. Khairul Faizi Khalid Dr. Khairul Faizi is currently the Head of Business Development at Clinical Research Malaysia (CRM). He graduated with honors from Moscow Medical Academy. Dr. Khairul joined the pharmaceutical industry in 2012 and worked with Astra Zeneca (AZ) and Boehringer Ingelheim (BI) in the areas of medical affairs and clinical trials. He received the Country Presidents Award twice and the Asia Area Vice Presidents Award while at AZ and the Best Diabetes team in SEA and South Korea during his tenure with BI. Email: khairulfaizi@clinicalresearch.my

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Market Report

Gaps and Challenges in Malaria Clinical Research and Development Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes, called "malaria vectors". It has been a major global health problem of humans through history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years, renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility (Alan F et al., 2016). Introduction In 2016, there were an estimated 216 million cases of malaria in 91 countries, an increase of 5 million cases over 2015 (WHO, 2018). Six plasmodial species present a significant health threat for humans, being responsible for almost 90% of all infections and for most of the 445,000 deaths that occur annually; most are in African children under five years of age. P. falciparum is the most prevalent malaria parasite on the African continent, responsible for most malaria-related deaths globally. P. vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa (Naing et al., 2014; WHO Key facts, 2018). P. ovale, P. curtisi, P. ovale wallikeri, and P. malariae are much less common causes of significant disease. Recently, P. knowlesi has emerged as a local but important cause of disease (including severe disease) in Malaysia and other areas of southeast Asia (Ahmed and Cox-Singh, 2015). Most deaths in 2016 were in the African Region (91%), followed by the South-East Asia Region (7%) and the Eastern Mediterranean Region (2%). The South-East Asian region contributes 2.5 million cases of malaria each year to the global burden, of which 80% is reported from India (WHO, 2018). Current Malaria Treatment and Drug-resistance Artemisinin-based combination therapies (ACTs) are the treatment of choice for uncomplicated malaria caused by the P. falciparum parasite. By combining two active ingredients with different mechanisms of action, ACTs are the most effective antimalarial medicines available today. Their administration over a three-day period, however, is associated with important problems of treatment adherence, resulting in markedly reduced effectiveness of currently recommended antimalarials under real-world settings. WHO currently recommends five ACTs for use against P. falciparum malaria. The choice of ACT should be based on the results of therapeutic efficacy studies against local strains of P. falciparum malaria (WHO Overview of malaria treatment, 2018). Among these combination therapies, only one (artemether-lumefantrine) is available as a child-friendly tastemasked formulation. The plasticity of the mosquito and the Plasmodium parasite has led to increasing resistance to antimalarial medicines and insecticides. Resistance to artemisinin-based combination therapies has been detected in five countries in South-East Asia (Greater Mekong sub-region). The spread of these strains to Africa 28 Journal for Clinical Studies

or the Indian subcontinent could be a major setback in the fight against malaria (Hemingway et al., 2016). Recently, the first case of artemisinin-resistant P. falciparum on the African continent was documented (Lu et al., 2017). Current artemisinin-based combination therapy (ACT) must be taken once or twice daily over a period of three days. Several studies suggest that patients often do not complete the full course of treatment, which can lead to incomplete cure and the appearance of drug-resistant pathogens (Bruxvoort et al., 2014). The prophylactic drug treatments against malaria are often too expensive for most people who live in endemic areas. Malaria prevention in pregnant women relies on long-lasting insecticidal nets (LLINs), and, in Africa, intermittent preventive treatment during pregnancy (IPTp). Increasing resistance of malaria parasites to sulfadoxine-pyrimethamine, the only drug endorsed for IPTp, and increasing mosquito resistance to pyrethroids used in LLINs, threaten the efficacy of these proven strategies. Over 100 million women and their babies are at risk of malaria in pregnancy each year (Rogerson and Unger, 2017). In Africa, mosquitoes are rapidly developing resistance to the four insecticides that are used to treat bed nets and spray houses. Bed nets treated with insecticide are among the more effective and widespread low-cost measures. Most countries distribute them free. Everywhere in Africa there are mosquitoes that have become resistant to pyrethroids, the chemicals used in two-thirds of house sprayings and the only type used to treat bed nets (The Economist, 2015). A WHO-coordinated five-year observational study concluded, however, that long-lasting insecticidal nets (LLINs) still provide a significant level of protection against malaria, even where mosquitoes are resistant to pyrethroids (Kleinschmidt et al., 2018). Another critical step in reducing the infectious burden of the disease is related to current malaria tests, which cannot detect either the low-level blood-stage infections of any malaria species or the dormant liver stages of P. vivax and P. ovale. A highly sensitive point-of-care field test is needed to rapidly detect lowdensity parasitemia and identify all infected individuals, enabling immediate treatment (Graves et al., 2016; Hemingway et al., 2016). Addressing the Gaps in Malaria Treatment There are over 100 products in the research and development pipeline that will benefit regional elimination and global eradication goals. These range from innovative diagnostics, medicines, vaccines, and vector control products to improved mechanisms for surveillance and targeted responses. Many of these promising products are expected to be introduced within the next ten years (Hemingway et al., 2016). Research-and-development spending on malaria drugs, vaccines, and basic research more than quadrupled between 1993 and 2013, reaching US$550 million annually (The Economist, 2015). Investments in basic research and product Volume 11 Issue 1


Market Report development (2014–2016) averaged annually $215 million for drug development (32% of total malaria R&D); $142 million for vaccine development (21%); $135 million for basic research (20%); $35.3 million for vector control products (5%); and $19 million for diagnostics (3%) (PATH, 2018). The overall goal of new medicines is twofold. First, it is important to have new medicines available that are active against emerging resistant strains of the parasite. Second, as part of the malaria elimination, simpler courses of treatment would be useful. The development of a single-dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionise population-based interventions in the context of malaria elimination campaigns (Mischlinger et al., 2016). Currently, there are at least four new medicines that have reached clinical Phase II, where they have been shown to be active in curing malaria: OZ439, a third-generation endoperoxide; KAE609, an inhibitor of the parasite sodium channel PfATP4; KAF156, a next-generation antimalarial compound belonging to the novel class of imidazolopiperazines; and DSM265, an inhibitor of the parasite dihydroxyorotate dehydrogenase (DHODH). All four products, which have been discovered within the last decade, are fully active against primary clinical isolates, including the recently characterised artemisinin-resistant strains. They are all relatively fast-acting compounds, but, in contrast to artemisinin, all compounds have long half-lives and show potential to give coverage for over a week from a single dose. The challenge moving forward is to identify the best possible combinations (Hemingway et al., 2016). OZ439, or artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins (McCathy et al., 2016). Artefenomel is a front-runner candidate for inclusion in a new antimalarial combination with ferroquine. The combination is being specifically formulated for children and to allow for oncedaily dosing. Achieving an equivalent efficacy and safety profile in fewer doses than current three-day ACT regimens is a major challenge. In partnership with Sanofi, MMV is aiming to overcome that challenge. The combination is currently in a Phase IIb trial, which is expected to be completed in the fourth quarter of 2018 (Fraisse, 2018). Advances in automation and phenotypic assay screening techniques have aided the discovery of innovative compounds effective against both asexual and sexual stages of P. falciparum. Spiroindolone KAE609 (Cipargamin) and related compounds bind the P-type Na+-ATPase (PfATP4) expressed on the parasite plasma membrane. This disrupts sodium homeostasis, thus blocking asexual blood-stage development and transmission to the mosquito (Spillman et al., 2013). Cipargamin is seven times more potent than artesunate and 40 times more potent than 4-aminoquinolines. Results from a recent Phase II clinical trial conducted among Thai patients indicated a clearance half-life of 0.90 h for P. falciparum and 0.95 h for P. vivax. The promising profile of KAE609 will be evaluated further in upcoming early phase trials, with potential to become a broad range antimalarial for treatment of multidrugresistant P. falciparum malaria (Nicholus et al., 2014). KAF 156 has the potential to clear malaria infection, including resistant strains, as well as to block the transmission of the malaria parasite. As demonstrated in a Phase IIa proof-ofwww.jforcs.com

concept trial, the compound is fast-acting and potent across multiple stages of the parasite's lifecycle, rapidly clearing both P. falciparum and P. vivax parasites. A recently started Phase IIb study will test multiple dosing combinations and dosing schedules of KAF156 and a new, improved formulation of the existing antimalarial lumefantrine, including the feasibility of a single-dose therapy in adults, adolescents and children. As children are the most vulnerable to malaria, the goal of the study is to include them in the clinical trial as quickly as possible, following safety review of the data generated in adults (Novartis, 2017). DSM265, a dihydroorotate dehydrogenase (DHODH) inhibitor acting against the liver (schizont formation) stage, is proving to be promising as a one-dose (400 mg) malaria cure in a Phase I trial in healthy volunteers, with an encouraging safety profile. DSM265 is currently in the clinical developmental stage (Phase II) in Peru (NCT02123290). Its activity against uncomplicated P. falciparum and P. vivax parasites is being assessed in adult patients using a single-dose treatment (400 mg). Although DSM265 showed robust results in Phase I trials, further studies are needed to predict its safety for use in pregnant women (Phillips et al., 2015). Another antimalarial medication in Phase II clinical stage, AQ13, a next generation 4-aminoquinoline (4-AQ) compound was comparable to artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria and able to clear infection within a week (Ousmane et al., 2017). Development of Malaria Vaccine The development of effective malaria vaccines has been a major goal of the malaria research community for many decades. In 2006, the global Malaria Vaccine Technology Roadmap established the goal of developing an 80%-effective vaccine against P. falciparum malaria by 2025 that would provide protection for longer than four years (WHO, 2006). The new Technology Roadmap updated in 2012 outlines that by 2030, vaccines should be developed that provide at least 75% protective efficacy against clinical malaria, reduce transmission of the parasite, and can be deployed in mass campaigns (WHO, 2013). RTS,S/AS01 is the falciparum malaria vaccine candidate that is most advanced in development, globally (Phase IV). RTS,S/ AS01 is based on the circumsporozoite protein (CSP) combined with hepatitis B surface antigen to prevent hepatocyte infection of sporozoites. Although RTS,S/AS01 was approved by the European Medicines Agency for active immunisation of children aged six weeks to 17 months against malaria, the WHO did not recommend the inclusion of RTS,S/AS01 in the Expanded Programme of Immunisations (EPI). While RTS,S demonstrates that a malaria vaccine is possible, an ideal candidate to support global eradication efforts would need to have a higher efficacy (WHO, 2015). In April 2014, the World Health Organization announced that the new RTS,S malaria vaccine (Mosquirix) would be tested on a large scale in Kenya, Ghana and Malawi, with 360,000 children to be vaccinated between 2018 and 2020. In 2015, EMA approved Mosquirix as the world's first malaria vaccine for use outside the EU among children aged six weeks to 17 months (EMA, 2015). In clinical trials, Mosquirix only proved to be partially effective, and the vaccine needs to be administered in a four-dose schedule. Nevertheless, Mosquirix presents a meaningful step towards the eradication of malaria and could save many lives (Rigall, 2013). Journal for Clinical Studies 29


Market Report Another malaria vaccine called Sanaria® PfSPZ-CVac was 100% effective in US clinical trials and 48% effective in trials run in Mali, exhibiting a previously unseen level of sustained efficacy in that region. GSK RTS,S (Mosqurix) is not expected to be as successful as PfSPZ, but it is further ahead in development as PfSPZ has only just cleared Phase II clinical trials (Bhavsar, 2017). The product development pipeline for malaria has never been stronger, with promising new tools to detect, treat, and prevent malaria, including innovative diagnostics, medicines, vaccines, vector control products, and improved mechanisms for surveillance and response. There are at least 25 projects in the global malaria vaccine pipeline, as well as 47 medicines and 13 vector control products. In addition, there are several next-generation diagnostic tools and reference methods currently in development, with many expected to be introduced in the next decade (Hemingway et al., 2016). Challenges from Malaria Clinical Trials in Africa and Other Endemic Regions Several promising vaccines, drugs, diagnostics and devices have been discovered and carried to the phase of clinical testing. It is essential to conduct these trials in those very countries where the diseases are most prevalent. Yet, the basic infrastructure is often lacking. There may be a weak or inadequate, outdated legal and regulatory environment as well as scarce human expertise in Africa and other endemic regions. In addition to this, ethical oversight is often absent or inadequate (Djimbe, 2006). Conducting clinical trials is also a challenge in countries like India or the Greater Mekong sub-region (GMS) (CNM, 2013). Malaria is endemic in regions that are inaccessible, have poor health facilities and are typically inhabited by tribal / nomadic populations. Meeting GCP requirements at these sites is often not feasible; for example, obtaining informed consent is difficult in low-literacy patients. Maintaining uniformity in patient care across the country also presents a challenge. Western Cambodia, located along the borderline with Thailand, is notable both for its sizable mobile and migrant population (MMP), who carry the bulk of malaria burden in GMS, and historically beginning a frequent point of origin for drug resistance in P. falciparum. This results in excluding patients from research studies because of the difficulty in conducting follow-up or “treatment failures”. The combination of low malaria incidence, a mobile and remote participant pool and high rates of participant ineligibility due to mobility and recrudescence creates several barriers to effective field research (Leang et al., 2016; Peto et al., 2016). Recruiting sufficient participant within the scheduled timeframe is rarely feasible and results in delays and cost overruns. It also increases the distances that each staff member need to cover to meet their quota. Field staff are therefore based permanently or temporarily in remote locations equipped with sample storage capacities and then spend extensive periods of time travelling, sometimes under harsh weather conditions, in order to conduct recruitment and follow-up activities. The transportation of biological samples is similarly complicated by long distances and the high temperatures, humidity and unpredictability of the rainy seasons (Canavati et al., 2017). In Africa, clinical trials are usually conducted in communities with little or limited access to healthcare facilities and, even if health facilities are present, they often suffer from limited resources, such as personnel, infrastructure and medical 30 Journal for Clinical Studies

supplies. Given the diversity of ethical review committees (ERCs) in Africa, there is a high likelihood of diverse decisions if the same study protocols are submitted to these committees, particularly in a growing number of multicentre studies. The need to harmonise ethical review processes is urgent. Harmonisation could first focus on procedural aspects of the ethical review process and subsequently address substantive aspects of ethical review, which could be more challenging than the former. A participatory approach to include all interested stakeholders is critical for harmonisation to be acceptable to African ERCs and also to be effective in terms of improving the quality and timing of the review process without compromising on science. Capacity building for the committee members is of equal importance, as it is crucial that ethical committees reviewing protocols are adequately knowledgeable about all established national and international guidelines (Mganwoka et al., 2013). Investigators should make a collaborative effort to develop a policy of supporting healthcare for the community where trials are being conducted and this policy should be communicated to sponsors during the planning stage. Increasing the effectiveness and efficiency of healthcare services is important everywhere, but particularly in developing countries with limited resources (Smith et al., 2002). Clinical audits are an example of a useful tool in improving clinical care that should be adopted by African investigators. Career development and job security are required to attract and retain African scientists to ensure there is a critical mass of competent, skilled personnel available to support these centres in the long term. Meaningful progress has been made in several areas in the understanding of the immunology, pathogenesis and mode of transmission of malaria. This progress, together with a sharp increase in interest and funding from the scientific community and various international funding agencies carries much hope for a brighter future in the fight against this life-threatening disease. REFERENCES 1.

Cowman AF, Healer J, Marapana D and Marsh K. Malaria: Biology and Disease. Cell 2016; 167: 610-624 2. WHO, Malaria key facts. WHO 2018: www.who.int/news-room/factsheets/detail/malaria visited on 23 Oct 2018 3. Naing C, Whittaker MA, Nyunt Wai V and Mak JW. (2014). Is Plasmodium vivax malaria a severe malaria?: a systematic review and meta-analysis. PLoS Negl. Trop. Dis. 8, e3071. 4. Ahmed MA and Cox-Singh J. (2015). Plasmodium knowlesi - an emerging pathogen. ISBT Sci. Ser. 10 1, 134–140. 5. WHO, Overview of malaria treatment. WHO 2018 www.who.int/ malaria/areas/treatment/overview/en/ visited on 23 Oct 2018 6. Hemingway J, Shretta R, Wells TNC et al. Tools and Strategies for Malaria Control and Elimination: What Do We Need to Achieve a Grand Convergence in Malaria. PLoS Biol 2016; 14(3): e1002380 7. Lu F, Culleton R, Zhang M, Ramaprasad A et al. Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa. NEJM 2017;376(10): 991-993 8. Bruxvoort K, Goodman C, Kachur SP and Schellenberg D. How Patients Take Malaria Treatment: A Systematic Review of the Literature on Adherence to Antimalarial Drugs. PLOS ONE 2014; 9(1): e84555 9. Mischlinger J, Agnandji ST and Ramharter M. Single dose treatment of malaria - current status and perspectives. Expert Rev Anti Infect Ther 2016;14(7):669-678 10. Rogerson SJ and Unger HW. Prevention and control of malaria in Volume 11 Issue 1


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12.

13. 14.

15.

16. 17.

18.

19.

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21.

22. 23. 24.

pregnancy - new threats, new opportunities? Expert Rev Anti Infect Ther 2017;15(4):361-375 Kleinschmidt I, Bradley J, Bellamy Knox T et al. Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: a WHO-coordinated, prospective, international, observational cohort study. The Lancet Inf Dis 2018;18(6):640-649 Graves PM, Gelband H and Garner P. Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission. Cochrane Database Syst Rev 2015; 2:CD008152 Breaking the fever – Malaria Eradication. The Economist 2015. www. economist.com visited on 23 Oct 2018. PATH, Bridging the gaps in malaria R&D: An analysis of funding— from basic research and product development to research for implementation. PATH 2018: www.malariavaccine.org visited on 23 Oct 2018 McCarthy JS, Baker M, O'Rourke P, Marquart L et al. Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother 2016; 71(9):2620–2627 Fraisse L. Artefenomel (OZ439) plus ferroquine. MMV 2017: www. mmv.org visited on 23 Oct 2018 Spillman NJ, Allen RJ, McNamara CW, Yeung BK et al. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe 2013; 13(2):227-237 Nicholus JW, Sasithon P, Phyo AP, Reuangweerayut R, Nosten F, Podjanee J et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Eng J Med 2014;371:403–410 Novartis and Medicines for Malaria Venture launch patient trial in Africa for KAF156, a novel compound against multidrug-resistant malaria. Novartis 2017: www.novartis.com visited on 23 Oct 2013 Phillips MA, Lotharius J, Marsh K et al. A longduration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Translat Med 2015;7(269):296ra111 Koita OA, Sangaré L, Miller HD et al. AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial. The Lancet Inf Dis 2017; 17(12): 1266-1275 Malaria vaccine technology roadmap 2006. WHO 2006: www.who.int visited on 23 Oct 2018 Malaria vaccine technology roadmap. Update 2013. WHO 2013: www. who.int visited on 23 Oct 2018 WHO 2015. Meeting of the Strategic Advisory Group of Experts on immunization, October 2015 –conclusions and recommendations. Wkly Epidemiol Rec 2015; 90:681–699.

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25. EMA 2015. First malaria vaccine receives positive scientific opinion from EMA. www.ema.europa.eu visited on 23 Oct 2018 26. Riggall L. Mosquirix: The World’s First Malaria Vaccine. PI Media 2017: https://pimediaonline.co.uk visited on 23 Oct 2013 27. Bhavsar NC. A New Malaria Vaccine Was 100% Effective in Clinical Trials. Futurism 2017: https://futurism.com visited on 23 Oct 2018 28. Djimbe A. Multicentre partnerships for clinical trials in Africa. The Third European and Developing Countries Clinical Trials Partnership, 8-11 October 2006, Stockholm, Sweden 29. CNM. Cambodia malaria survey 2013. Phnom Penh National Centre for Parasitology and Malaria Control (CNM); 2013, p.2013 30. Leang R, Canavati S, Khim N et al. Efficacy and safety of pyronaridineartesunate for the treatment of uncomplicated Plasmodium falciparum malaria in western Cambodia. Antimicrob Agents Chemother 2016; 60:3884-3890 31. Peto TJ, Kloprogge SE, Tripura R et al. History of malaria treatment as predictor of subsequent sublinical parasitaemia: a cross-sectional survey and malaria case records from three villages in Pilin, western Cambodia. Malar J 2016; 15:240 32. Canavati SE, Quintero CE, Haller B et al. Maximizing research study effectiveness in malaria elimination settings: a mixed methods study to capture the experiences of field-based staff. Malaria J 2017; 16:362 33. Mwangoka G, Ogutu B, Msambichaka B et al. Experience and challenges from clinical trials with malaria vaccines in Africa. Malaria J 2013, 12:86 34. Smits HL, Leatherman S, Berwick DM: Quality improvement in the developing world. Int J Qual Health Care 2002, 14:439–440.

Andrzej Piotrowski Andrzej Piotrowski, MD, PhD, is a Medical Monitor at KCR, internationally operating CRO. During his medical advisory work for the pharmaceutical industry, Andrzej Piotrowski has specialised in a broad range of therapeutic areas, including immunological diseases, pulmonology, vaccines and contraception. He has also longterm experience as a clinician in neuroimaging diagnostics. At KCR, Mr Piotrowski is responsible for medical oversight of clinical study projects, as well as coordinating and performing activities related to medical monitoring. Email: pr@kcrcro.com Journal for Clinical Studies 31


Therapeutics

Improving Patient Outcomes: eCOA Steps up in the Fight Against Cancer Breast cancer is the most commonly occurring cancer in women worldwide and the second most common cancer overall. With the World Cancer Research Fund revealing that there were over 2 million new cases in 2018,1 it seems an appropriate time to shine a spotlight on clinical research into this prevalent disease. According to the World Health Organization (WHO), cancer is the second leading cause of death globally, with around one in six deaths due to cancer. It estimates that the disease has been responsible for approximately 9.6 million deaths in 2018.2 In 2017, the World Health Assembly passed the resolution Cancer Prevention and Control through an Integrated Approach (WHA70.12),3 which urges governments and WHO to accelerate action to achieve the targets specified in the Global Action Plan and 2030 UN Agenda for Sustainable Development to reduce premature mortality from cancer. By developing and bringing new oncology treatments to market, clinical researchers have an important role to play in helping reduce this cancer-related mortality. But trials in this therapeutic area are not without challenges. In fact, research suggests that fewer than one in 20 adult cancer patients enroll in cancer clinical trials.4 Once enrolled, retaining these participants is therefore vital. With this in mind, Brad Sanderson from CRF Health, a CRF Bracket company, discusses the current state of oncology clinical research and how researchers can utilise the latest technology to improve the patient experience and improve outcomes. What is the current state of the oncology clinical trials market? It is a competitive and ever-evolving landscape, meaning it’s an

32 Journal for Clinical Studies

exciting time for pharmaceutical companies who want to play their part in creating and advancing therapies that will shape the course of future, much-needed, cancer treatment. According to recent figures, almost 11,000 cancer clinical trials are underway in the US5 and with as many as 600 oncology-related treatments in the pipeline, the next decade will hopefully see a number of new medicines introduced to market which will extend the lives of cancer sufferers. What are the challenges in collection of patient-reported outcomes for patients in oncology clinical trials? The associated symptoms of the disease, and side-effects of treatment, place a huge burden on cancer patients. These symptoms, such as pain and fatigue, make it at times difficult or impractical for them to provide regular reports on their symptoms, side-effects and ability to conduct activities of daily living, and can make clinic visit attendance difficult. Even if they are able to travel, long journeys and waiting time can prove strenuous for participants, adding considerable burden to their involvement in the trial. For some patients, flexibility around visit dates and the ability to complete certain assessments, such as patient-reported outcomes measures (PROMs) away from clinic may be important. In addition to this, making sure patients keep track of their concomitant medications and treatments can also be a challenge for oncology researchers. Tracking these medications during a clinical trial is an important element of understanding treatment effects. That said, asking a patient to write down the supplemental medications they take can be problematic as they may not always remember what they take, how often they take it, or its official name. Traditionally, patients are asked about concomitant

Volume 11 Issue 1


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Journal for Clinical Studies 33


Therapeutics what we’d call the ‘parking lot syndrome’ – when patients fill out the questionnaire in the parking lot just before an appointment. eCOA provides helpful reminders, alerting patients as to when to input data and notifying them if they miss anything. It also provides alerts to sponsors and site teams if there is data missing from a participant, meaning they can follow up and ensure it is obtained promptly. By completing data entry in a timely manner, data quality is improved as patients are less likely to forget or mis-report activity. By improving the timeliness of data entry, sponsors can also ensure the data is contemporaneous, helping them meet the ALOCA principles as required by the FDA in its PRO Guidance.8

medication during site visits but this could be weeks after they have taken the medication. Clearly this could lead to missed and/ or incorrect data. Why is the patient experience so important in oncology research? While involvement in oncology studies often provides access to latest treatments, drugs, specialist equipment and better access to specialist oncologists that might not otherwise be available, it’s important to remember that many of the participants may be very ill, facing reduced life expectancy, or uncertainty around life expectancy. They may also have complex treatment programmed and numerous other medications to take, so it’s vital that participation in a clinical trial does not add any additional burden or stress to the challenges they are already facing. Creating patient-centric trials has been high on the agenda for the pharmaceutical industry for many years now, with researchers realising the benefits to be gained from patient-focused study designs. The FDA are publishing new guidances on patient-focussed drug development in response to the requirements outlined in the US 21st Century Cure Act.6 By adopting a patient-centric approach to a clinical trial, sponsors and CROs can ensure that the study fits in with the participants’ lives and not the other way around, improving their study experience. Understanding the patient perspective and improving their overall study experience sounds obvious but this should be at the heart of the development process. Identifying what would be valuable for the patient by working with them, as well as patient representatives and associations, and incorporating their suggestions into the trial development process is a logical step. It is likely to result in improved compliance and retention which, in turn, will result in higher quality data capture and maximise the value of PROs in a timely and cost-effective manner.

As previously mentioned, as their condition progresses or during certain cycles of treatment, patients may experience increasing burden due to the disease and its treatment. For studies utilising eCOA, patients unable to complete the questionnaire at the site can use the technology to reschedule visits, re-activate incomplete or interrupted visits so that patients can pick up where they left off, and also add unscheduled visits for patients who may need additional time at the site due to a change in their diagnosis. In addition, eCOA allows patients to elect a caregiver role on their device, meaning that if necessary, a caregiver can input data on their behalf using observer-reported outcomes (ObsRO), and this user-entry clearly marked within the eCOA data. Caregivers will be provided with on-device training to ensure they feel comfortable with the process and are able to report the data confidently in line with the study protocol, in order to maintain compliance. eCOA solutions are also intuitive and extremely user-friendly, delivering an outstanding user experience compared to traditional paper-based collection methods. By transforming the way patients submit their data, making it easy and time-efficient for them, they stay invested in the study, improving retention rates and increasing compliance. Without these options provided via eCOA, which all reduce burden for the patient, the likelihood of poor data quality, participant drop-outs, or site challenges greatly increases. In turn, study teams put at risk their ability to collect high quality, defensible data that they can feel confident about. How do you feel technology will influence oncology clinical trials over the next 5–10 years? New solutions will continue to evolve and impact on the speed and accuracy with which oncology clinical trials are able to be conducted. Paper-based processes really are no match for e-solutions in terms of

How can new technologies, such as eCOA and eConsent, help improve the patient experience? The advantages of using new technologies such as electronic data collection methods during oncology clinical trials are very clear, with industry leaders among the first to adopt eCOA. Inside the primary care environment, oncology patients believe that the use of eCOA to report symptoms positively affects their clinical care.7 Improving the patient experience is one of the biggest benefits eCOA solutions provide. Firstly, eCOA lends itself to daily life more than traditional paper-based questionnaires. It is cumbersome to carry around paper and a pen for the duration of the study, and it is easier to misplace or forget about. This can often result in 34 Journal for Clinical Studies

Volume 11 Issue 1


Therapeutics

speed, simplicity and cleanliness of data collection. Perhaps the biggest opportunity within patient onboarding in the coming years is the advent of eConsent within the clinical trial environment. eConsent provides a huge opportunity to improve patient comprehension of study procedures before embarking on a clinical study which may reduce the risk of drop-out. Additionally, eConsent enhances the traceability of consent across clinical studies and provides a clear and secure QA trail that provides robust support for GCP regulatory requirements. Furthermore, specifically relevant to oncology trials, is the flexibility with which eConsent can manage the completion of multiple consent forms with relative ease. This could include consent forms for biopsy, imaging, etc, which, if not appropriately signed, may result in a sponsor not being able to use the data as planned. The continued introduction of innovative wearable technologies will also play its part, as these solutions offer new means of data capture by allowing researchers to passively monitor and collect information about a person’s physical activity and movement, such as step-count or sleep patterns. All stages of a clinical trial, from recruitment through to monitoring, will benefit from the adoption of electronic solutions. Not only will communications be much smarter and faster but by utilising technology which is familiar with patients and fits in with the participants’ everyday lives, outcomes will be of higher quality, resulting in lower cost for sponsors and CROs, and much quicker time to market for new treatments in the fight against cancer. REFERENCES 1.

https://www.wcrf.org/dietandcancer/cancer-trends/breast-cancerstatistics 2. World Health Organisation (2018) Cancer: Key Facts. Retrieved from http://www.who.int/news-room/fact-sheets/detail/cancer www.jforcs.com

3.

World Health Assembly (31 May 2017) Cancer prevention and control in the context of an integrated approach. Retrieved from http://apps.who. int/medicinedocs/documents/s23233en/s23233en.pdf 4. Unger, J. M., Cook, E., Tai, E. & Bleyer, A. (2016). The role of clinical trial participation in cancer research: barriers, evidence, and strategies. American Society of Clinical Oncology Educational Book, 36, 185-198. 5. ClinicalTrials.gov (2018). National Institute of Health - U.S. National Library of Medicine: ClinicalTrials.gov. Retrieved from https://goo.gl/e8RWaQ 6. U.S. Department of Health and Human Services Food and Drug Administration (2009). 21st Century Cures Act. Retrieved from https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/ significantamendmentstothefdcact/21stcenturycuresact/default.htm 7. Seow, H., King, S., Green, E., Pereira, J. & Sawka, C. (2011). Perspectives of patients on the utility of electronic patient-reported outcomes on cancer care. Journal of Clinical Oncology, 29(31), 4213-4214. 8. U.S. Department of Health and Human Services Food and Drug Administration (2009). Guidance for Industry PatientReported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Retrieved from https://www.fda.gov/downloads/drugs/guidances/

Brad Sanderson Brad Sanderson is a Senior Scientific Advisor, Head of Health Outcomes at CRF Health. He is based in London, United Kingdom. Brad is Senior Scientific Advisor – Head of Health Outcomes at CRF Bracket. Within this role he leads the Health Outcomes discipline and seeks to advance the company’s scientific and technical expertise in eCOA. Brad has over 15 years of industry experience in research across pharma, bio-tech and digital health. Email: media@crfhealth.com Journal for Clinical Studies 35


Therapeutics

Clinical Development in Rare Diseases: Graft Versus Host disease Graft versus host disease (GvHD) is a generalised immune system reaction following allogeneic haematopoietic stem cell transplantation (AHSCT) in patients with acquired and congenital haematopoietic system disorders (e.g. lymphoid malignancies, dysmyelopoietic syndrome, bone marrow aplasia, etc.)1. GvHD is considered to affect approximately 0.5 in 10,000 people in the European Union (with a prevalence of around 26,000) and is thereby designated among rare diseases 2. Symptoms of GvHD were first described at the begining of the twentieth century by Murphy, but the underlying pathophysiology was not discovered until in the late 1950s; Simonsen differentiated the acute and chronic forms and introduced the name of graft versus host disease in the 1960s3.

a cut-off of 100 days6. Recently, due to different techniques for processing stem cells and administration of several adjuvant drugs during transplantation, manifestation of GvHD became more diverse and ’classic forms’ are often overlapping. It is reasonable to differentiate GvHD according to its existing features in whole, rather than its set of time or duration. In 2014, the National Institute of Health (NIH) released updated consensus criteria of both acute and chronic GvHDs7 as: Acute form – defined by the classic features (sunburn-like rashes, blisters on skin, diarrhoea, abdominal pain, blood in stool, nausea, vomiting, jaundice, dark urine, elevated serum bilirubin level, systemic infections, abdominal cramps) and manifested generally within 100 days after haematopoietic cell transplantation (HCT). A hyperacute form can develop within the first two weeks. Accidentally, the symptoms can return or persist more than 100 days post-HCT as late-phase ’acute’ GvHD.

Etiology and Pathogenesis The exact pathophysiology in the background of GvHD still remains incompletely understood. The main events can be characterised into three phases: tissue damage, called the afferent phase, followed by T-cell priming in the efferent phase, and then disease manifestation, as the effector phase. There are some determinants (risk factors) in the afferent phase4:

Chronic form – main features are skin thickening and rashes, joint pain and swelling, dry eyes, blurred vision, sore and pain in mouth, ocular, digestive and respiratory symptoms, diarrhoea, fatigue, and icterus8.

donor-recipient disparity, such as human leukocyte antigen (HLA) diversity, gender difference, other conditions e. g. multiparous female donors ineffective transplant conditioning/prophylactic regimen increased age (affecting either the recipient or the donor) pre-transplant comorbidities (e.g. peptic ulcer, obesity, diabetes, prior malignancy, cerebra-vascular disease, etc.)

The diagnosis of GvHD is based on clinical features (see above) and histologic confirmation: tissue biopsy (skin, gut, liver). There are no individual biomarkers yet for clinical application, but some serum proteins are possible options for diagnosis and prognosis of GvHD10:

• • • •

During the efferent phase, reactive T-cells in the graft recognise difference in histocompatibility antigens of recipient tissues, which activates the immune system and promotes secretion of inflammatory cytokines (predominantly IL-2 and IFN-gamma), enhance T-cell expansion, induce cytotoxic T-cells and natural killer cell responses and prime additional mononuclear phagocytes producing TNF-alpha and IL-1. The inflammatory cytokines initiate excessive production of chemokines, thus recruiting effector cells into target organs. Mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharides that leak through the intestinal mucosa damaged during the initial phase1. This kind of cytokine ’storm’ drives the systemic inflammatory response leading to the effector phase reaction: expansive tissue injury and apoptosis, persisting inflammatory condition which, together with the activated cells drive the destruction and necrosis in the host body, complicated with general immune system dysregulation and organ dysfunction5. Clinical Manifestation and Diagnosis Historically, classification of GvHD was based on onset of symptoms and was divided into acute and chronic forms by 36 Journal for Clinical Studies

Overlap of acute and chronic form can also develop with features of both chronic GvHD and acute GvHD9.

• • •

soluble IL-2-receptor-alpha (sIL-2Rα) concentrations are increased in aGVHD TNF receptor-1 reflects inflammation, correlates with clinical outcomes Hepatocyte growth factor (marker of epithelial apoptosis associated with intestinal and hepatic GvHD damage) have been suggested as a confirmatory tool for the diagnosis of acute GvHD at the onset of clinical symptoms and to provide prognostic information independent of GvHD severity ST2 (suppression of tumorogenicity 2) receptor is a member of the interleukin-1 receptor family) correlated with an increased risk of non-relapse mortality and resistance to treatment of acute GvHD REG-3-alpha (regenerating islet-derived 3-alpha) is expressed by regenerating cells in the gastrointestinal epithelium (especially Paneth cells), and its concentration increases in the bloodstream as a result of GvHD-associated epithelial mucosa injury

In all suspected cases, differential diagnosis of clinical features should be considered, e.g. rash (caused by drugs), diarrhoea (infections), hyperbilirubinemia (biliary sludge, drugs), etc11. Clinical Management (Prevention and Treatment) Presently, neither acute nor chronic GvHD can be 100% prevented, Volume 11 Issue 1


Therapeutics but there are options to reduce the risk and balance the symptoms of the persisting disease. There are practical guidelines for risk stratification and treatment, but unfortunately they are not integrated or used on a global basis12,13,14. Classically acute GvHD affects the skin, liver and gastrointestinal tract. McMillan et al. have set up a scoring system for acute GvHD patients to estimate response to initial therapy, survival and transplant-related mortality. This system incorporates the nature of basic disease, stage and grade of initial manifestation of GvHD in each organ, the extent of affected organs and transplant characteristics (donor type, graft sources, preparative therapy)15. Prevention of GvHD starts with proper graft selection, and careful preparation of the cells planned to be engrafted, in addition to the inevitable modulation of host immune reactions by aggressive immunosuppression. Treatment of GvHD is still challenging. The basis of firstline therapy in both forms (acute/chronic GvHD) is immunosuppressants with corticosteroids. Response rate is around 50%, primarily depending on initial disease severity16. Recent therapeutic guides suggest use of antibody treatment in addition to immunosuppression with cyclosporine and methotrexate. Administration of antilymphocyte or antithymocyte globulins, CD52 monoclonal antibodies or adhesion molecule blockers (e.g. LFA-1, or Campath-1H for acute GvHD) are options for secondline treatments17. Monoclonal antibodies such as alemtuzumab, dacluzimab, infliximab (preferably in gut manifestations), antithymocyte globuline or mycophenolate mofetil, extracorporal photopheresis, sirolimus, pentostatin or mesenchymal stem cells (also preferably administered in gut manifestations) can alleviate steroid-refractory acute GvHD cases18. Cytokine inhibitors (e.g. pentostatin) can be a promising treatment option, especially in patients above 60 years or younger patients with isolated gastrointestinal tract involvement19.

is expected to alleviate their negative effect on graft versus host disease22. A Phase III clinical trial with inolimomab together with etanercept failed to improve the dismal prognosis of severe steroid-refractory acute GvHD or to cure steroid-resistant acute GvHD23. Itacitinib Itacitinib is an orally bioavailable inhibitor of Janus-associated kinase 1 (JAK1) enzyme. JAK-dependent cytokines are related to the pathogenesis of a number of inflammatory and autoimmune diseases. By blocking signalling and then cell proliferation in JAK1-expressing pathologic cells, itacitinib could reduce tumour growth and induce apoptosis in animal xenograft models either in monotherapy or in combination with cytotoxic agents such as gemcitabine24. The combination of itacitinib together with corticosteroids is currently being investigated in a Phase III trial (GRAVITAS-301) as a first-line treatment of acute GvHD patients25. Defibrotide Defibrotide is composed of oligonucleotides. Preclinical studies confirmed that it enhances PGI2 release from vascular walls and can relieve ischemia by improvement of local tissue oxygenation and platelet function via its ability to deaggregate platelet clumps26. Defibrotide has been approved for the treatment of hepatic veno-occlusive disease following haematopoietic stemcell transplantation. Defibrotide may also protect the cell linings of blood vessels, which are damaged in patients undergoing stemcell transplantation27. A Phase II, prospective, randomised, openlabel study was initated in 2017 with defibrotide added to standard of care immunoprophylaxis for the prevention of acute GvHD in adult and paediatric patients28.

Prognosis and Complications Outcomes of either form of GvHD are highly variable; symptoms may range from mild to life-threatening. Time for resolution of acute GvHD is generally 4–6 weeks but may even last for years or may be permanent in some patients20. The prognosis or outcome of GvHD depends both upon the severity and extent of the symptoms and the effectiveness of treatment15. Clinical Development in GvHD Over the last years, the progress in understanding the pathophysiology of this immune-based process helped redefine graft versus host reaction and opened new possibilities for novel preventive and therapeutic approaches. The evolution in the field of immunology widened the horizons for haematopoietic stem cell transplant, leading to the availability of different stem cell sources for potential graft and incorporation of novel conditioning regimens21. There are few randomised controlled trials focusing on management of steroid-refractory GvHD. Recently, a number of novel pharmacotherapies have been under investigation for the treatment of GvHD. These are some of the most promising treatment options: Inolimomab Inolimomab is a mouse monoclonal antibody investigated for treatment of severe, steroid-resistant acute GvHD. It targets the alpha chain of the IL-2 receptor, and is expected to bind to these cells and consequentially stop their multiplication, which www.jforcs.com

Journal for Clinical Studies 37


Therapeutics Human plasma-derived alpha-1 proteinase inhibitor Alpha-1 proteinase inhibitor, also known as alpha1-antitrypsin (A1AT), is a natural protein derived from human blood that blocks the action of a group of enzymes called serine proteases. A1AT is approved for the treatment of congenital A1AT deficiency with symptoms of emphysema29. A1AT treatment may improve symptoms in patients who develop GvHD and do not respond to treatment with corticosteroids and cyclosporin. Serine proteases, which include neutrophil elastase, trypsin and proteinase-3, help to break up proteins in the body and have an important role in the processes of inflammation and cell death that are triggered in GvHD30. By blocking their action, A1AT is expected to improve the symptoms of the condition and reduce organ damage. In 2015 a Phase I/II trial was initiated in GvHD patients and was completed in 2017, however results have not been published yet31. Ibrutinib Ibrutinib was developed as a targeted therapy to block two enzymes: Bruton’s tyrosine kinase (Btk), which plays an important role in B cells, and interleukin-2-inducible T-cell kinase (ITK), that stimulates T-cells. Both B and T-cells in the host are involved in GvHD. Ibrutinib is approved by the EMA for the treatment of chronic lymphocytic leukaemia and lymphoma with 17p deletion, Waldenström's macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma. By blocking Btk and ITK, ibrutinib is expected to reduce the activity of both types of cells and improve the symptoms of GvHD. Ibrutinib is currently investigated in combination with corticosteroids in subjects with chronic GvHD32. Begelomab Begelomab is a CD26+ receptor antibody; its target is a multifunctional membrane-bound glycoprotein presented on a wide variety of cells, and known to play a key function in T-cell biology (marker of T-cell activation, antigen presenting cell and T-cell interaction) and linked to signalling pathways33. It was previously investigated in animal models by Hatano et al.34, where CD26-mediated co-stimulation was found to induce vigorous secretion of inflammatory cytokines, and blocking CD26 cells by humanised anti-CD26 monoclonal antibody was found to reduce development of xenogeneric GvHD (x-GvHD). Blocking activity of CD26 receptors with specific monoclonal antibodies would reduce the quantity of activated T-cells and reduce attacks of the recipient’s organs. Murine-derived CD26 antibody was thought to be favourable in patients with GvHD, as early studies indicated efficacy in patients who do not respond to corticosteroids, but a Phase III study was terminated because of its insufficient rate of accrual34,35. Arsenic trioxide Arsenic trioxide (ATO) is a small-molecule compound with antineoplastic activity and has been previously approved for the treatment of acute promyelocytic leukaemia36. The mechanism of action of ATO is not completely understood. ATO promotes degradation of some promyelocytic leukaemia-associated proteins and induces apoptosis in tumour cells37. Potential benefits of ATO in chronic GvHD events (in first-line therapy) when added to standard therapy with corticosteroids, with or without cyclosporine, are being investigated in a prospective, national, multicentre, non-randomised Phase II study. It is expected that ATO may alter and reduce the duration of corticosteroid therapy and improve the outcome of patients with GvHD38. 38 Journal for Clinical Studies

Conclusion GvHD generally develops in allogeneic HSCT patients and is characterised by severe, potentially life-threatening complications. Several guidelines are used by different transplant centres but, to date, there is no standardised regimen. As for primary treatment, immunosuppression using steroids remains the first line of intervention, but nearly half of cases prove steroidrefractory. The list of alternative agents are abundant with variable effectivity, and new therapeutic options are being investigated. Despite the existing therapies and efforts exerted in research to develop new therapies, GvHD is still partially preventable or curable, and it is a progressive condition with poor prognosis. Both acute and chronic forms of GvHD cause remarkable medical, social, and quality of life problems, as well as a significant rise in healthcare-related costs. The current focus is on developing and validating new biomarkers, and pursuing clinical trials of new agents which are effective, but less toxic, to develop more targeted treatments for GvHD and achieve better and safer alloHSCT treatment. REFERENCES 1.

Reddy, P. & Ferrara, J. L. M. Immunobiology of acute graft-versus-host disease. Blood Rev. 17, 187–94 (2003). 2. Prevalence of GvHD was adapted information of Committee for Orphan Medicinal Products (COMP), estimated and assessed on the basis of data from the European Union (EU 28), Norway, Iceland and Liechtenstein (Eurostat 2017). 3. Simonsen, M. Graft Versus Host Reactions. Their Natural History, and Applicability as Tools of Research. in 6, 349–467 (Karger Publishers, 1962). 4. Holtan, S. G. & MacMillan, M. L. A risk-adapted approach to acute GVHD treatment: are we there yet? Bone Marrow Transplant. 51, 172–175 (2016). 5. Ferrara, J. & Mineishi, S. Graft Versus Host Disease. Curr. Med. Chem. Endocr. Metab. Agents 5, 539–545 (2005). 6. Lee, S. J. Classification systems for chronic graft-versus-host disease. Blood 129, 30–37 (2017). 7. Shulman, H. M. et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol. Blood Marrow Transplant. 21, 589–603 (2015). 8. Cooke, K. R. et al. The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease. Biol. Blood Marrow Transplant. 23, 211–234 (2017). 9. Holtan, S. G. et al. Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors. Blood 128, 2350–2358 (2016). 10. Budde, H. et al. Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines. Ann. Hematol. 96, 1127– 1133 (2017). 11. Matsukuma, K. E., Wei, D., Sun, K., Ramsamooj, R. & Chen, M. Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD). J. Gastrointest. Oncol. 7, S21-31 (2016).

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Therapeutics

12. Majhail, N. S. et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 21, 1863–1869 (2015). 13. Sung, L. et al. Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Support. Palliat. Care 7, 7–16 (2017). 14. Martin, P. J. et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 18, 1150–63 (2012). 15. MacMillan, M. L. et al. A Refined Risk Score for Acute Graft-versusHost Disease that Predicts Response to Initial Therapy, Survival, and Transplant-Related Mortality. Biol. Blood Marrow Transplant. 21, 761– 767 (2015). 16. Westin, J. R. et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Adv. Hematol. 2011, 601953 (2011). 17. Poritz, L. S. et al. Monoclonal antibody to lymphocyte function associated antigen-1 improves graft-versus-host disease. Dis. Colon Rectum 41, 299–309 (1998). 18. Garnett, C., Apperley, J. F. & Pavlů, J. Treatment and management of graft-versus-host disease: improving response and survival. Ther. Adv. Hematol. 4, 366–78 (2013). 19. Ragon, B. K. et al. Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant. 53, 315–325 (2018). 20. Ali, N., Adil, S. N., Shaikh, M. U. & Masood, N. Frequency and Outcome of Graft versus Host Disease after Stem Cell Transplantation: A Six-Year Experience from a Tertiary Care Center in Pakistan. ISRN Hematol. 2013, 232519 (2013). 21. Baron, F. et al. Anti-thymocyte globulin as graft- versus -host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 102, 224–234 (2017). 22. Bay, J.-O. et al. Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies. Transplantation 80, 782–8 (2005). 23. van Groningen, L. F. J. et al. Combination Therapy with Inolimomab and Etanercept for Severe Steroid-Refractory Acute Graft-versus-Host Disease. Biol. Blood Marrow Transplant. 22, 179–182 (2016). 24. Li, J. et al. Abstract 779: Blockade of the IL-6/JAK/STAT3 signaling pathway inhibits pancreatic tumor cell growth in 3D spheroid cultures and in xenograft models. Cancer Res. 75, 779–779 (2015). 25. EU/3/17/1964 | European Medicines Agency. Available at: https:// www.ema.europa.eu/en/medicines/human/orphan-designations/ eu3171964. (Accessed: 25th October 2018) 26. Niada, R., Porta, R., Pescador, R., Mantovani, M. & Prino, G. Cardioprotective effects of defibrotide in acute myocardial ischemia in the cat. Thromb. Res. 38, 71–81 (1985). 27. Fulgenzi, A. & Ferrero, M. E. Defibrotide in the treatment of hepatic veno-occlusive disease. Hepatic Med. Evid. Res. Volume 8, 105–113 www.jforcs.com

(2016). 28. An Open-Label Study of Defibrotide for the Prevention of Acute Graftversus-Host-Disease (AGvHD), https://clinicaltrials.gov/ct2/show/ NCT03339297?term=Defibrotide&rank=5 29. European Medicines Agency, Alpha 1-Proteinase Inhibitor (Human) AralastTM Product Information., https://www.ema.europa.eu/en/ medicines/human/EPAR/respreeza 30. Santangelo, S. et al. Alpha-1 Antitrypsin Deficiency: Current Perspective from Genetics to Diagnosis and Therapeutic Approaches. Curr. Med. Chem. 24, 65–90 (2017). 31. Medicines Agency, E. Public summary of opinion on orphan designation Human plasma-derived alpha-1 proteinase inhibitor for the treatment of graft-versus-host disease (2015). 32. ClinicalTrials.gov Identifier: NCT03474679. A Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) 33. Dang, N. H. & Morimoto, C. CD26: an expanding role in immune regulation and cancer. Histol. Histopathol. 17, 1213–26 (2002). 34. Hatano, R. et al. A Novel Function of CD26-Mediated Costimulation in the Cytotoxic Activity of Human CD8+ T Cells in Xenogeneic Chronic Graft-Versus-Host Disease (cGVHD) and GVL Mice Model. Blood 114, (2009). 35. ClinicalTrials.gov Identifier: NCT02411084. Study of BEGEDINA® 36. CHMP. Trisenox,INN-arsenic trioxide. 37. Iland, H. J. & Seymour, J. F. Role of Arsenic Trioxide in Acute Promyelocytic Leukemia. Curr. Treat. Options Oncol. 14, 170–184 (2013). 38. Filipovich, A. H. et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease: I. Diagnosis and Staging Working Group Report. Biol. Blood Marrow Transplant. 11, 945–956 (2005).

Dr. Emília Balogh, MD, PhD Dr. Emília Balogh, MD, PhD, Clinical Research Physician, Europital. Experienced Clinical Pharmacologist, Pulmonology specialist and Scientific Researcher with 22 years overall experience as Medical Doctor, including 6 years as consultant Pneumonologist, 15 years in Clinical Research in Academic Centers and Pharma Industry, in addition to 3 years as GCP inspector with the Hungarian Health Authority and EMA. Email: info@europital.com

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: info@europital.com

Dr. Mohamed El Malt, MD, PhD Oncology surgeon and expert scientific researcher with more than 33 years of experience as a medical doctor, including 18 years of clinical research and drug development experience in academic medical centers, pharma and CRO as investigator, project leader and medical director, in addition to 15 years of experience as general and oncology surgeon. Email: info@europital.com

Journal for Clinical Studies 39


Technology

Industry Moves to Streamline Clinical Operations for Faster Trials The Need for Better Visibility and Faster Trial Execution The widespread move to unify clinical environments is being driven by application and process silos that have resulted from the steady adoption of function-specific clinical technologies over the past decade. Stand-alone e-clinical applications, including EDC, eTMF, RTSM, and CTMS, are now the norm. And newer, purpose-built applications such as study start-up are gaining traction.1 Faced with a landscape of disparate systems and processes, over three-quarters (77%) of those surveyed find better visibility across their clinical trial processes a top driver for unifying clinical applications. Other primary drivers include faster study execution (67%), improved study quality (62%), and increased productivity (51%).

Top Drivers for Unified Clinical Operations

On average, companies use four applications to manage their clinical studies, and more than one-third (38%) use at least five applications. While such applications have been critical to modernising clinical processes in key areas, they have also created common operational challenges with application and system silos. Integrating multiple applications (74%) is the top challenge reported by both sponsors and CROs, followed by reporting across multiple applications (57%) and managing content and data across them (56%).

Biggest Challenges with Clinical Applications 40 Journal for Clinical Studies

However, the survey shows that organisations extensively using standardised operational metrics and KPIs to measure trial performance have fewer challenges than their peers across key trial processes, most notably study performance metrics and reporting (44% versus 66%, respectively), as well as visibility into TMF status (32% versus 45%, respectively). In addition, organisations using metrics are four times more likely to have programmes in place to unify their clinical applications than those not using metrics (47% versus 12%, respectively). CROs Leading Adoption, but Struggle with Collaboration While there is significant overall momentum towards unifying clinical systems across the sector, CROs are more active than sponsors in adopting purpose-built clinical applications. This is particularly true in study start-up (33% of CROs versus 17% of sponsors) and CTMS (66% versus 54%). This momentum is consistent with these organisations’ focus on improving study visibility (77%) and execution (67%), which were the two top drivers cited by CROs for unifying clinical applications. Other leading drivers raised were improved study quality (62%) and increased productivity (51%). The biggest challenge that CROs struggle with is collaboration. One-third (33%) cite this as an issue, compared to 30% of sponsors. Moving to unified systems and processes will make it easier for CROs, sponsors, and sites to work together and share information throughout the course of a trial. This is contributing to CROs’ move toward advanced clinical applications. The overwhelming majority (91%) therefore now have initiatives planned or underway to unify their clinical applications for improved trial performance. Increased Shift to eTMF Applications to Optimise TMF Processes With the focus to improve clinical operations, companies are looking for more advanced, purpose-built systems to impact visibility, collaboration, and compliance. The survey reveals that adoption of eTMF has grown significantly, and it is now the second most commonly used clinical system at 66%. In fact, the number of organisations now using eTMF applications has quadrupled since 2014, with half of sponsors (50%) using purpose-built eTMF applications, versus 13% in 2014 and 31% in 2017. This increase is matched by a sharp decline in the use of content management systems and file shares. This signals a shift away from general-purpose methods – typically used in "passive" TMFs – toward a mature, active TMF operating model in which TMF processes and information are managed in real time. These active TMF solutions have a positive impact on inspection readiness and trial performance. Automated document exchange and tracking replace iterative, paper-based processes, study progress is made visible to all stakeholders, and centralised oversight and use of metrics enable a constant state of inspection readiness.2 Volume 11 Issue 1


Technology CROs’ use of eTMF applications has more than doubled since 2014. More than half (54%) of CROs now use purpose-built eTMF applications, versus one-fifth (21%) in 2014 and 42% in 2017. This increase has been matched by a 16% decline in general-purpose content management systems and file shares. CROs have made significant progress in modernising trial processes by adopting purpose-built eTMF applications. Those CROs that use advanced eTMF applications report having greater visibility into TMF status and fewer challenges, including with study partner collaboration. This new model, and the emergence of modern systems to support it, are helping to drive change in the industry. Sponsors and CROs are now looking to optimise TMF processes in order to improve inspection readiness (70%), visibility (61%), and automated tracking and reporting (57%).

Top Drivers of eTMF Optimization

Looking at CROs in particular, their adoption of modern systems is driven by the need to be always inspection-ready (69%), automate document tracking and reporting (62%), and save costs (52%). Streamlining Study Start-up Now a Major Priority Organisations are also looking at upstream processes as an area of significant potential, focusing on study start-up and leveraging study start-up applications as major priorities. It is estimated that 70% of studies run more than one month behind schedule, costing sponsors between $600,000 and $8 million per day of delay.3 With as many as 11% of sites failing to enroll a single patient, and another 37% failing to meet enrollment targets, poor site selection can increase the cost of trials by at least 20%.4 Consequently, 83% of organisations say they have initiatives underway, or will within the next year or so, to improve study start-up processes. Top drivers for improving study start-up include faster study start-up times (63%), improved site feasibility and site selection outcomes (48%), and better visibility into site performance (44%). In particular, speeding study execution has become a top priority for CROs, especially as sponsors continue to outsource study start-up processes. Findings show that nearly 80% of CROs are taking steps to improve study start-up (66%), reduce spreadsheets and manual processes (45%), improve collaboration with study partners (45%), and improve site feasibility and site selection outcomes (45%). This supports the fact that an increasing number of CROs are making technology investments to improve trial efficiency.5 Easier collaboration among trial partners is one of the top three most important drivers for enhancing study start-up processes. Almost half of CROs (45%) say collaboration during study startwww.jforcs.com

up continues to be an area of improvement, compared to 30% of sponsors. Research from Tufts CSDD shows that the initial stages of the site initiation process, such as site contracting and budgeting, account for most of the cycle times. As more global trials are conducted, challenges with country selection, initiation, and regulatory compliance add to these cycle times.6 Correspondingly, more than half of CRO respondents (59%) report site contract and budgeting among the most challenging study start-up processes that limit their organisations’ ability to speed clinical trials, followed by site identification and selection (41%) and IRB/ethics committee planning and approval (38%). Opportunity to Improve Clinical Trial Performance with CTMS With the amendments in 2016 to ICH E6 (R2) GCP guidelines, companies are now required to document the rationales for their chosen trial strategies, including the use of systems and processes.7 This may be contributing to survey respondents’ desire to improve the use of CTMS in their trial operations. Nearly all (99%) have challenges with core trial management processes, such as study performance metrics and reporting (51%), study and site management (49%), and resource management (45%). The majority (84%) also report significant deficiencies with their current CTMS applications. Most have CTMS applications that cannot fully support a range of key functions, including governance and oversight (89%), resource management (88%), and issue and task management (86%). They see improving the CTMS as a way to gain greater visibility Veeva 2018 Unified Clinical Operations Survey Key Findings • •

Nearly all (99%) respondents report the need to unify clinical operations, and 87% say their organisations have, or plan to have, initiatives in place to do so. All respondents say they want to improve the use of CTMS in study operations. Drivers are greater visibility (70%), more proactive risk mitigation (65%), and better study analytics and reporting (61%). Organisations have made progress in modernising trial processes with purpose-built applications such as eTMF, ensuring a constant state of inspection-readiness (70%), increased visibility and oversight (61%), and improved collaboration (42%). Consistent with the aim to improve study execution, study start-up is a priority. Most (83%) organisations have programmes to speed study start-up (63%), streamline contract approval cycles (48%), and improve site selection (44%). Organisations that use metrics (77%) report fewer challenges with clinical operations, and are four times more likely to have programmes in place to unify their clinical applications than those not using metrics. Those that have programmes in place to unify their clinical landscapes are also more likely to use operational metrics to measure performance, manage risk, and implement process improvements. CROs are leading sponsors in adoption of purpose-built clinical applications. This is particularly true in start-up (33% of CROs versus 17% of sponsors) and CTMS (66% versus 54%).

Journal for Clinical Studies 41


Technology

(70%), more proactive risk identification and mitigation (65%), and improved study analytics and reporting (61%).

2.

Industry Moving Toward Unified Clinical Landscape There is universal recognition of the importance of a unified clinical landscape in improving trial performance, and most companies are now working toward this goal. The industry sees a significant opportunity to run more efficient and effective trials by increasing visibility, quality and speed of execution.

3.

The majority of challenges faced by sponsors today in managing clinical trials still stem from the siloed nature of processes and applications, which makes visibility across the end-to-end trial life cycle difficult. Adoption of newer, more advanced, cloud-based applications is already having a measurable impact on visibility, collaboration, and compliance. Rationalising systems, eliminating silos and manual processes, and having best-in-class applications on a single clinical platform are now critical to unifying clinical operations.

6.

With the growing complexity of trials and the ongoing need to improve compliance and leverage insight across the full trial life cycle in order to accelerate time to market, the industry sees unifying clinical environments as key to transforming operations – and major change is well underway. REFERENCES 1.

Markets and Markets, eClinical Solutions Market, Global Forecast to

42 Journal for Clinical Studies

4.

5.

7.

2020, 2016 Veeva 2017 Clinical Operations Survey, Benefits of an eTMF by Type of eTMF Temkar P, Accelerating Study Start-Up: The Key to Avoiding Trial Delays, Clinical Researcher, February 2017 Lamberti MJ, Wilkinson M, Harper B, Morgan C, Getz KA, Assessing Study Start-up Practices, Performance, and Perceptions Among Sponsors and Contract Research Organizations, Therapeutic Innovation & Regulatory Science, DOI: 10.1177/2168479017751403 tirs.sagepub.com Pharmaoutsourcing.com. The Increasing Shift of Clinical Trials to CROs. May 2015. Temkar P. Accelerating Study Start-up: The Key to Avoiding Trial Delays. Clinical Researcher. February 2017 Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2), 2016

Rik Van Mol Rik Van Mol is vice president of R&D strategy, responsible for the Veeva Vault R&D suite of applications in Europe. He has nearly 20 years of experience in business/IT consulting and regulated content management in the life sciences sector. Rik’s experience has been built on assisting clients through complex transformational programmes across the life sciences value chain, including clinical, regulatory, and manufacturing/ supply-chain areas for some of the world’s largest companies. Email: rikvanmol@veeva.com Volume 11 Issue 1


The Box is Just the Base! MLM Kit Building® Customized kit building Global supplies FDA/EMA-compliant central lab

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MLM Medical Labs® is one of the leading Central Labs for clinical trials in Europe. For further information please contact Dr. Katja Neuer at kneuer@mlm-labs.com or visit us at www.mlm-labs.com Heat test

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Technology

Disrupting Clinical Development: How AI, the Cloud and a Modern Data Architecture are Transforming Clinical Trials Today, more than ever, pharmaceutical and biotech companies are under great pressure to run their business in a way that makes drug development processes more efficient and cost-effective. But the costs and time needed to commercialise a new drug continue to escalate – currently exceeding eight years and $2 billion.1 A big factor in these staggering rates is the increasing complexity of clinical trials, driven in large part by trial sponsors needing to evaluate more endpoints to demonstrate product value. Clinical trial sponsors face increasing challenges based on the need for more complex study protocols and larger digitised data sets to support the next medical breakthrough. Couple this with the geographic growth of clinical trials – many spread across multiple countries to target just the right patient populations – and it’s no wonder that we’ve reached a point where humans are struggling to keep up. And it’s not just increasing data volume that keeps trial sponsors awake at night. Data velocity, data variety and data veracity are problems as well. Against this backdrop, the clinical trials industry needs disruption more than ever before. This is where the dynamic trio of artificial intelligence (AI), the cloud and a data lake comes in. Disruption Begins with a Cloud-based Data Lake In clinical development, speed to market is key. And trial efficiency is paramount when it comes to bringing drugs and therapies to the market faster. In this regard, AI, supported by a scalable, cloudhosted data lake that enables real-time ingestion, integration and curation of structured, unstructured and binary data presents a huge potential to disrupt practically every stage of the clinical development process (Table 1).

that are usually not interoperable, a data lake architecture provides a strong foundation to bring this data together and integrate it in one place. This integrated view of data, available and easily accessible in the data lake, enables real-time trial monitoring so clinical research teams can assess study and programme risks preemptively and evaluate study performance based on key metrics. From a commercial point of view, a data lake provides the foundation to create data products at the therapeutic level, allowing pharmaceutical and biotechnology companies to predict how a treatment will perform in the market, based on claims/ EMR data and comparisons to similar marketed products, market trends and competitor activity. Such an infrastructure enables trial sponsors to select sites, primary investigators and patients quickly via analysis, enabling data-driven decision-making. A data lake also allows clinical trial teams to focus on research and analysis versus data wrangling, data ingestion, and vendor integration. And, a data lake opens up new possibilities and frontiers for how to manage data in the life sciences industry and provides an integrated experience for clinical development. Improving Clinical Trial Efficiencies through AI Let’s review a few concrete use cases of how AI, the cloud and data lake – the dynamic trio – can disrupt key clinical trial processes to improve efficiencies, reduce cost, and accelerate the time to market of life-savings drugs and therapies. Protocol Development Any transformation of clinical trials needs to start with protocol development. Traditionally, clinicians and researchers design protocols based on past expertise, relying on repetition of previous trial designs or even unproven strategies. Applying AI to big data that is readily available in a data lake has the potential to shape insights from masses of real-world data (RWD) into protocol design. RWD (claims data, prescriptions data, etc.) can be used to assess and develop trial objectives, inclusion and exclusion criteria, endpoints, and procedures that work in the real world.

How today's technologies are disrupting and improving clinical trials

A scalable, cloud-based data lake solution can optimise clinical development and deliver outcomes by streamlining the steps of the entire clinical data journey (from data capture to statistical analysis and all data transformations in between) and unifying disparate data sources from multiple data silos and applications. Since clinical development teams use various vendors’ systems 44 Journal for Clinical Studies

For example, an AI platform can analyse large data sets from multiple sources and recognise patterns and trends measured against a predetermined set of parameters or rules. It can then provide one or more actionable hypotheses or recommendations faster than dozens of researchers could recognise or handle alone. Culling from millions of data points in near real time from a data lake, AI algorithms can flag missing informed consent documents, patterns of missing site visits or medications, and potential errors or clinical data outliners. It can even identify potential fraud by specific sites. AI-driven protocol designs can make clinical trials more intelligent in numerous other ways (Table 2). And, AI can provide pharmaceutical researchers with additional, predictive data that can help to determine whether taking a drug will result in a Volume 11 Issue 1


Technology These features are particularly important for studies involving a relatively small number of volunteers, such as those for orphan diseases, where every data point is critically important. VA can also verify completion of care tasks such as taking blood pressure and attending investigative site visits, all of which ensures trial sponsors that patients are being compliant with the protocol. This consistent compliance delivers more reliable and higher quality data.

How AI-driven protocol designs make clinical trials more intelligent

positive or negative outcome and whether trials will be successful or not. Patient Recruitment / Retention Patient recruitment is at the very heart of clinical trials. For a trial to be successful, the right patients must be selected from the very start, and supported through trial completion. Recruiting and retaining patients come at a huge cost – patient recruitment takes up over a quarter of the funds allocated to a clinical trial. But, on average, 50% of investigative sites under-enroll (it’s common that half of all sites will enroll only one or no patients at all) and 85% of trials fail to retain patients.2 So it comes as no surprise that 80% of all clinical trials don’t finish on time or on budget.3 Each day a clinical trial is delayed costs the sponsoring pharmaceutical company millions. So, the fundamental question is – how can trial sponsors and physicians quickly find and keep the right patients in clinical trials? The answer may be found in the use of AI and big data. By extracting pertinent electronic medical record (EMR) information, sifting through physicians’ notes, reading binary data from images and medical scans and comparing them to a study’s inclusion and exclusion criteria, AI can more efficiently and effectively identify appropriate patients for clinical trial enrolment. And, during trials, AI can help by predicting which patients are at risk of dropping out. Patient Engagement Advancements in AI are enabling smart speakers (Alexa, Google Home, etc.) to deliver more human-like responses than ever before, and users around the world are finding themselves engaging with these devices in a natural, conversational manner. Sponsors who leverage this voice assistant (VA) technology, along with data from a data lake, enable patients to have real-time conversational experiences (CX) that can simplify their routine interactions as they participate in clinical trials. This CX represents a paradigm shift in clinical trials. For example, instead of having to call or go to the investigative site, clinical trial patients can pose questions about various aspects of the trial through their smart speaker and receive a human-like response from the data stored in the data lake. Making this kind of virtual and humanistic training available during lengthy trials is really helpful for patients. This is primarily because they feel better supported and as a result, become more engaged. VA can also help sponsors collect better quality data over the duration of their studies. The ability for patients and study organisers to set reminders and prompts minimises missing data entries, and ensures that data are collected at appropriate times. www.jforcs.com

Many clinical trials require patients to complete questionnaires on either paper diaries, electronically via smartphones, tablets or desktop applications, or through a caregiver. Patients with manual dexterity problems, e.g., advanced arthritis and Parkinson’s disease, or those who are visually impaired, may not be able to participate due to these constraints. VA can now provide options for these patients. By incorporating AI-enabled smart speakers into their trial planning, pharma can expand the pool of possible clinical trial participants and achieve two objectives: meeting patient enrolment sooner and serving patients who may not otherwise have access to clinical trials. The use of voice assistants is not the only way AI can improve patient engagement in clinical trials. Technologies such as telehealth, digital apps, mobile coaching solutions, and wearables allow for real-time engagement, communication, and support in patient-centric trials. Patients use these devices to send feedback on treatment and symptoms, manage medication intake, and share information with researchers. This reduces or eliminates the need to travel to sites, which, in turn, improves patient engagement and compliance while reducing site costs. Study Monitoring and Real-time Trial Insights Running AI and predictive algorithms on a cloud-hosted data lake can help researchers better flag and predict clinical trial risks, including those related to site management, patient adherence, safety and adverse event monitoring, and the impact of disease and treatments on clinical trial patients. AI can help improve the quality, reliability, and safety of clinical trials by generating the knowledge needed for better decision-making during clinical trial monitoring. Sponsors can use AI on top of a data lake to predict the health of studies throughout their lifecycles with regard to time, cost, and quality. Developing predictive models in conjunction with historical data can provide the foundation for determining clinical trial success and avoiding potential risks, which can accelerate the timeline from protocol submission to regulatory approval, resulting in reduced cost and faster time-to-market. Virtual Trials Imagine a situation where participating in a clinical trial does not require travel to a clinical research facility or a doctor’s office. Mobile devices (phones, watches, apps, etc.) are the link to the study and how patients report information and adverse events. Wearable sensors record data such as body temperature, heart rate, and blood glucose levels in near real time, which are sent automatically to the study’s electronic data capture (EDC) system, and then routed to the data lake for immediate ingestion, curation and integration. The study personnel visit patients at home for drug administration and follow up. When a visit is approaching, the patient’s mobile device provides automated reminders, allowing the patient to reschedule the appointment within a timeframe permitted by the study protocol. And that’s just the beginning of what the future is likely to hold for virtual clinical trials and how we can better engage patients. Journal for Clinical Studies 45


Technology

Virtual trials will take full advantage of the cloud, modern data architecture and AI so that practically every stage of the clinical trial process is conducted from the comfort of the patient’s home. Conclusion As the adage goes, “Why fix it if it’s not broken?” However, in this case, it is broken, hence we must fix it. Less than 10% of trials end on time3 and the costs to develop new drugs are sky-rocketing. But, as the examples outlined here demonstrate, the use of dynamic trio – AI, the cloud and a data lake – can help reverse these trends and enable pharmaceutical companies to optimise every stage of the clinical trial process, resulting in more efficient clinical development and faster time to market. Recognising these benefits, however, will be a journey, rather than a destination. Pharmaceutical and biotech companies that have an open data culture and an appetite for cloud and modern data architecture with a strong data governance programme embedded throughout the data lifecycle will have a head start in bringing AI to reality and disrupting the clinical development industry.

46 Journal for Clinical Studies

REFERENCES 1. http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_

cost_study 2. https://vertassets.blob.core.windows.net/download/64c39d7e/ 64c39d7e-c643-457b-aec2-9ff7b65b3ad2/ rdprecruitmentwhitepaper.pdf 3. https://vertassets.blob.core.windows.net/download/64c39d7e/ 64c39d7e-c643-457b-aec2-9ff7b65b3ad2/rdprecruitmentwhitepaper. pdf

Prakriteswar Santikary, PhD Prakriteswar Santikary, PhD, Vice President, Global Chief Data Officer, ERT., has over 20 years of experience in building distributed systems, platforms, and applications using techniques of modern data architecture, distributed computing, and cloud computing. In his current role, Prakriteswar leads the development and execution of ERT’s global data architecture, advanced analytics, and master data management strategy to ensure ERT’s pharmaceutical customers meet their clinical development objectives. Volume 11 Issue 1


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Journal for Clinical Studies 47


Technology

Using Selection Biomarkers and Unravelling the Resulting Data to Drive Clinical Trial Success Introduction The use of biomarkers in drug discovery and development has exploded at an unprecedented rate since the turn of the century. With recent scientific and technological breakthroughs – including genomics, advanced cellular and tissue profiling, and complex imaging – biomarkers can now be leveraged to address many questions about biological activity, safety, and clinical efficacy throughout the drug discovery and development process at a fraction of the cost and with turnaround times unimaginably less than a decade ago. These advances in precision medicine are driving a paradigm shift in drug discovery and development as innovators are now focusing on programmes with narrow indications, shorter development times, and lower costs.1

of an investigative compound. Importantly, surrogate biomarker endpoints may also allow for assessment of treatment effects at earlier times than the clinical endpoint of interest, enabling studies with an adaptive design. Over the past five years, there has been a marked increase in the number of clinical trials citing a biomarker-guided precision medicine design.3 Notably, according to a recent report, drugs developed using a precision medicine design were more likely to reach the market. This higher likelihood of commercial launch was found across all therapeutic areas, with the most significant difference in oncology (see Figure 1).1

Biomarkers play a key role in characterising the biological pathways and processes that drive response and potentially define patient populations. In fact, as targeted therapies and immunotherapies proliferate, biomarkers are increasingly relied upon for patient selection and for determination of eligibility for clinical trials. Treatment selection biomarkers are of particular interest in contexts such as cancer, where treatment effects are heterogeneous and where efficacy may be variable, the risk of toxicity is potentially significant, and/or the cost of the treatment is high.2 However, having a biomarker strategy is only part of the equation. As assay technologies have been refined and their costs have significantly decreased, many development teams find themselves overwhelmed with biological data and completely under-resourced to capitalise on the tens of millions of data points they have created. To address this gap, biomarker data processing is increasingly recognised as the new frontier in the practical application of a biomarker strategy in drug development. In this article, we discuss biomarker use in clinical trials, as well as the importance of a proactive biomarker data processing strategy to ensure valuable insights are not lost in the morass of data.

Adapted from TrialTrove | Pharmaintelligence, 2018. Data: 2012–2017. Adapted from The Economist Intelligence Unit. The Innovation Imperative: The Future of Drug Development Part I: Research Methods and Findings.

In particular, the use of biomarkers as inclusion or exclusion criteria for clinical trial enrolment (also known as “selection biomarkers”) may be a powerful predictor of success. In a BIO industry analysis that examined clinical development success rates from 2006 to 2015, programmes that utilised selection biomarkers had higher success rates at each phase of development. This analysis revealed that the use of selection biomarkers led to a threefold increase in the likelihood of progressing all the way through to approval (see Figure 2).4

Biomarkers in Clinical Trials The primary objective of biomarkers is to generate informative data and enable better decision-making throughout the course of drug development. In general, biomarkers can be grouped into four categories: 1. Markers of toxicity in pre-clinical safety studies 2. Diagnostic markers of clinical safety and efficacy 3. Biochemical or pharmacodynamic markers associated with the compound’s mechanism of action 4. Markers of disease progression or reversal Evaluating biomarkers in clinical trials and integrating speciality lab data – such as flow cytometry, gene expression profiling, and immunosequencing – with pharmacokinetics, safety lab, imaging, and clinical data can provide a broader foundation for assessing the pharmacodynamic effect, safety, and efficacy 48 Journal for Clinical Studies

Adapted from David W Thomas, Justin Burns, John Audette, Adam Carroll, Corey DowHygelund, Michael Hay. Clinical Development Success Rates 2006–2015. (2016) A BIO Industry Analysis white paper. Volume 11 Issue 1


Technology Selecting Appropriate Biomarkers When selecting biomarkers for a clinical trial, clinical relevance is a key driver. Specific biologic or genomic profiles can be used to differentiate patients. This can lead to a subset of patients more likely to respond based on safety or efficacy. Clinical relevance is one factor to weigh in selecting the right biomarker; there are also practical considerations to evaluate (see Figure 3).

clinical study may fall under the purview of both the Centers for Medicare & Medicaid Services in the form of the Clinical Laboratory Improvement Amendments (CLIA) and the US Food and Drug Administration. In addition, some states may have additional laws governing in-state clinical laboratories or the analysis of their residents’ samples, regardless of where the analysis is conducted. If multiple biomarkers are to be used to stratify patients in a clinical trial, the complexity of the study may increase, requiring greater planning and the need for specialised translational science teams to help design and execute these novel programmes. Success of these programmes will depend on upfront planning of assay selection, sample handling and processing methods, global logistics, and timing such as real-time patient selection assays. Managing Vast Amounts of Biomarker Data There is a broad spectrum of biomarker assays available, from targeted genomic panels to high-content or high-throughput experiments, with applications ranging from characterising mechanism of action and guiding dosing to optimising study design and enriching study populations. Technologies are evolving in tandem and large volumes of data are now being generated at unprecedented rates. To further complicate the diversity and complexity of biomarker assays, the resulting data are often generated in different formats, making data harmonisation, interpretation, and accessibility difficult.

Translating a Biomarker to a Clinical Study The translation of predictive biomarkers to the clinic requires a cross-functional team that includes scientists, clinicians, biomarker experts, regulatory personnel, and assay developers.5 When developing a biomarker strategy and method or assay, sponsors will need to balance the need to simplify sample preparation procedures and minimise the number of samples required with the need to maximise the amount of useful, high-quality data collected. Key practical issues that should be considered when planning to use a biomarker to determine eligibility for a clinical study include:6 •

Sample Collection Considerations. Where possible, the collection method should utilise non-invasive or minimally invasive techniques. The amount of specimen needed for analysis, and potential reanalysis, should be minimised. In addition, the collection and preservation methods should be technically and logistically feasible within the context of a clinical study.

Assay Considerations. If an assay needs to be developed, it is important for the team to build adequate time into the clinical trial timeline. The lead time required can vary greatly depending on the platform chosen, as well as the complexity of the assay.

Sample Analysis Considerations. Turnaround time can have a significant impact on recruitment and other clinical trial activities. While using a local laboratory may decrease turnaround time, it may also come with the risk of greater variability resulting from different methods, instruments, validation standards, and quality control processes which can have a significant impact on the success of the study. Especially for eligibility decisions, having assays validated in a centralised testing lab are usually preferred.

Regulatory Considerations. Sponsors should keep in mind that in the United States, predictive biomarkers used to balance arms of a study or to select patients for enrolment into a

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In order to optimise the value of generated biomarker data, drug developers and clinical researchers must be able to rapidly and efficiently interrogate data within and across platforms, trials, geographies, and even companies. This interrogation capability informs hypothesis rule-out, as well as generation of new hypotheses which can be used to shape a drug development programme. In addition, to better harness the collective intelligence of the company, drug developers and clinical researchers need to be able to distribute information seamlessly within and across relevant organisations. Historically, due to resource limitations and lack of appropriate technology, there has been no efficient way to leverage the volumes of data being generated throughout a drug development programme. According to a survey by Forbes, nearly 80% of scientists’ time is spent collecting, cleaning, and organising data sets.6 Clearly, if all of these data could be made accessible for visualisation, large-scale analytics, and sharing, drug developers and clinical researchers would benefit from a significant multiplier effect in value generated and insights gained. A prerequisite to productive data interrogation and analysis is a harmonised data set that is quality-controlled and correctly mapped together, transforming millions of data points into actionable insights. Today, sponsors can leverage cutting-edge technology solutions to harmonise disparate sources of biomarker data and warehouse them in near real time for effective onstudy decision-making, as well as downstream use. Technology solutions also exist for organising these data as part of end-ofstudy activities and regulatory submission. These technologies enable tighter integration between clinical operations and biomarker data, facilitating go/no-go decision-making between trial phases and potentially leading to shorter timelines, reduced costs, and faster approvals. A number of industry trends, including partnerships, licensing agreements, and combination therapies, underscore the critical Journal for Clinical Studies 49


Technology importance of being able to share data within and across both platforms and organisations. Those organisations that are able to provide access to complex, organised biomarker data sets will be well-positioned to detect and convey signs of positive biological response in early-phase trials. Selecting a Biomarker Data Management Platform Drug developers who are contemplating the use of biomarkers for their trials should consider a biomarker data management platform, and ask: • • • • • •

Does the platform have a centralised database for storage and access to all speciality lab data, regardless of which or how many labs are providing data? Does the platform include assay-specific workflows and quality control parameters, as well as a capability to incorporate custom workflows? Does the platform have data reconciliation capabilities to expedite time-consuming reconciliation activities between LIMS and EDC? Does the platform include plug-in modules for translational research/biomarker data management? Can the platform generate submission-ready data sets that comply with Clinical Data Interchange Standards Consortium (CDISC) standards and can be adapted to regulatory shifts? Is the platform compatible with other software tools (e.g., GraphPad Prism)?

To handle the complexity and throughput of biomarker assays and make data actionable, the biomarker data management platform should also be able to simultaneously integrate and deliver multiple workflows with dynamic reporting. The technology solution should also enable sponsors, translational researchers, and clinical trial teams to visualise and analyse biomarker data through user-friendly, intuitive web-based tools so they can harvest insights from all available data sources to inform their decision-making (see Figure 4).

The use of biomarkers to predict and select likely-to-respond patient populations is a transformational aspect of today’s drug development process and is reducing both the time and cost of development. By successfully reducing time and cost, innovators are capable of bringing novel therapeutics to patients at an unprecedented pace. All of these advancements are bringing the promise of precision medicine to fruition. REFERENCES 1. 2.

3. 4.

5.

6.

Carroll A. Utilizing selection biomarkers in clinical trials: is this the future of drug development? Biomarkers in Medicine 2016;10(9). Janes H, Brown MD, Pepe MS. Designing a study to evaluate the benefit of a biomarker for selecting patient treatment. Stat Med 2015;34(27):35033515. The Economist Intelligence Unit. The Innovation Imperative: The Future of Drug Development Part I: Research Methods and Findings. David W Thomas, Justin Burns, John Audette, Adam Carroll, Corey DowHygelund, Michael Hay. Clinical Development Success Rates 2006-2015. (2016) A BIO Industry Analysis white paper. Available at https://www.bio. org/sites/default/files/Clinical%20Development%20Success%20Rates%20 2006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf. Marton MJ, Weiner R. Practical guidance for implementing predictive bio-markers into early phase clinical studies. Biomed Res Int 2013;2013:891391. Press G. Cleaning Big Data: Most Time-Consuming, Least Enjoyable Data Science Task, Survey Says. March 23, 2016. Available at https://www.forbes.

Chad Clark Chad Clark is president and a life science executive at Precision for Medicine, focused on the implementation of biomarker driven clinical programs. His industry expertise includes combining advanced technologies, strategic program design, and operational excellence to help life sciences companies effectively accelerate research initiatives through biomarkers and advanced informatics. Clark’s previous experience spans the execution of phase I–IV global clinical trials, specialty lab services, translational sciences, risk management, and patient support initiatives.

Scott Marshall, PhD

Conclusion In order to maximise the benefit of using selection biomarkers and other biomarkers in drug development, sponsors will increasingly need to contemplate logistics related to biomarker programmes, ensure the viability of these programmes globally, and then leverage technology platforms that enable them to optimise the data they collect. As drug developers and clinical researchers strive to deliver on the promise of precision medicine, technology-based solutions for biomarker data management will become a prerequisite for clinical trial operations. To unlock the full potential of biomarker data and bridge the gap between translational research and clinical medicine, these technologies will need to be supported by a multidisciplinary team of translational informaticians, programmers, data managers, and innovative data scientists. This combination of cutting-edge technology and biomarker expertise can facilitate efficiency, flexibility, and even compliance, reducing clinical trial costs and bringing novel therapies to the patients most likely to benefit from them. 50 Journal for Clinical Studies

Scott Marshall PhD, Managing Director Translational Informatics and Diagnostic Sciences at Precision for Medicine, has extensive industry expertise across the pharmaceutical and biotech space – Dx regulatory submissions, translational informatics, biomarker R&D – with a focus in precision medicine-guided efforts as well as strategy development and medical device/ diagnostic development. Globally responsible for translational informatics R&D efforts at Precision for Medicine, Marshall has led the development of novel methodologies for patient stratification and biomarker guided clinical trial design.

Cliff Culver Cliff Culver, Senior Vice President, Precision Medicine Group at Precision for Medicine, is a corporate strategy executive specializing in the development of software platforms for the life science industry at Precision for Medicine. Culver’s particular focus is on increasing the efficiency of preclinical and clinical contract research & development operations. He has prior experience as founder, advisor, and general manager in rapidly scaling technology-enabled businesses. Volume 11 Issue 1


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Journal for Clinical Studies 51 Journal for Clinical Studies 51


Technology

Learning and Development for the Future As financial pressures continue to bear down on the clinical research sector, it is vital that both sponsor companies and the CROs that conduct their studies continue to invest in the development and capabilities of their staff. Only through retaining competent staff will the clinical research sector be able to meet the forthcoming challenges which include increased trial complexity, the rising use of ‘big data’, and the advent of artificial intelligence in both the diagnosis and treatment of disease. Competent staff are also essential for the continuing protection of patients and integrity of data.

The concept behind a risk-based approach to learning and development is that it is targeted at high-risk areas and therefore has the maximum impact for each learning intervention by preventing non-compliance. This ultimately supports the protection of patients and data integrity. Using a dynamic approach and regularly reassessing risks helps keep staff capabilities contemporary and relevant, particularly with respect to the use of new technologies and methodologies. The first step in a risk-based framework is to conduct a risk analysis. A risk can be defined as a threat and those risks which have both a high impact and a high probability of occurring are the ones which should be targeted as a priority. Risk tends to be associated with high complexity (for example complex studies or processes), and novelty (such as a new disease area, emerging or relatively untried technology, new organisational structures). Risks can also include known undesirable outcomes from past experience such as problems encountered with certain types of study or results based on historical trend analysis of data. Risks can be grouped in clusters such as those pertaining to patient safety, data integrity, regulatory compliance and may also include operational metrics such as quality standards and project overruns in terms of cost and time. The second stage is to identify the possible root causes of risks. There are various tools and techniques available for root cause analysis such as the cause-and-effect diagram (for example Ishikawa), the interrelationship diagram, and the current reality tree. The cause and effect diagram is helpful when identifying possible causes for a specific problem, particularly when a team’s thinking has become stagnated and an impasse has been reached. An interrelationship diagram shows graphically the cause-andeffect relationships that exist among a group of potential threats. It is best used when helping to identify the potential causal relationships that might lie behind a recurring issue (i.e. a threat that keeps manifesting itself) despite previous attempts to resolve it. A current reality tree depicts the current situation in a series of dependent logical cause-and-effect relationships. It starts with the symptoms, i.e. the apparent threats (sometimes known as undesirable effects) and drills down to one or a few core root causes. Current reality trees are best used when there are number of threats which may have common or similar root causes which may result in system-wide problems. The third stage is to decide what part learning and development can play in dealing with these fundamental problem areas. The ultimate goal is to prevent the risks occurring. Depending on the nature of the threat and its root cause(s), various learning interventions can be used. These may include case study analysis (perhaps of the actual threat itself), coaching, focus groups, problem-solving techniques and training courses either faceto-face or by webinar. Lastly the effectiveness of the learning intervention needs to be assessed. The ultimate goal is to prevent the threat occurring so any measure of effectiveness should involve an assessment of whether the threat has occurred, or if it has, to what extent. If the threat has manifested itself despite the implementation of the learning intervention (and any other preventive measures), a back-up plan should be deployed to contain the threat.

The Digital World of Clinical Research

Organisations must use their resources effectively and efficiently in developing their staff. Tools to train and develop staff must be used in a targeted way so that the outcomes support the business needs of the organisation. It is undeniable that learning and development costs money and time and takes people away from their frontline jobs. It is very important that money spent on these activities produces results in the shape of satisfactory performance and supports the drive for constant improvement. Learning and development interventions can be targeted using a combination of two approaches; one applies risk analysis as its basis and the other uses a competency-based methodology. The concept of risk management is now well established in the clinical research sector. A risk-based approach to monitoring was described in the FDA’s Guidance for Industry (Guidance for Industry, Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring, August 2013), in response to the FDA’s opinion that not all studies are equal in terms of complexity and risk to patients. The aim was to focus sponsors’ monitoring efforts into those areas that will pose the greatest risk to patient safety and data integrity. Many sponsors and CROs now use a risk-based approach to monitoring. In Europe, the European Medicines Agency (EMA) had a similar standpoint. Their view was that the practices of the day were not proportionate or well adapted. The EMA’s position was presented in their Reflection Paper on risk-based quality management in clinical trials (September 2013). In this document the EMA outlined a risk management process summarised by the illustration below.

It is a dynamic system which involves identifying risks, planning and implementing control measures, then reviewing, communicating, and reassessing risk. Applying such a methodology to the design and delivery of training would seem to present a logical extension to the use of this model. 52 Journal for Clinical Studies

One of the advantages of taking a risk-based approach to learning and development is that it avoids wasting time and money on repetitive and redundant training, particularly if it involves Good Volume 11 Issue 1


Clinical Trial Supply

Organized By

New England2019 FREE PLACES rese

rved Director for VP / /C Executiv -level es

��th & 27th March 2019, Boston, MA

“We have built on last year’s success conference and are returning with full force to Boston with the aim of supporting trial sponsors and solution providers across New England to ensure trials are deliv ered on time, partnerships are improved and supply chain uncertainties are resolved." This year we will be looking at those issues which are affecting companies in the Boston-Cambridge hub, such as but no limited to: ways to move beyond the theory; harnessing the power of technology to design a functioning Direct to Patient (DtP) supply chain, discovering how to incorporate gene therapies within your supply chain and blockchain: a discussion of practical applications for clinical supply chain and life-sciences.

Outlining challenges in the import and export of IMP's to guarantee drugs reach their destination and avoid delays at border control Designing and implementing a quality management system to improve how your clinical supplies are administered Blockchain: a discussion of practical Blo applications for clinical supply chain and life-sciences Integrating different IRT systems across your internal CMS to reduce error and

Georgia Mitsi, Senior Director, Search & Evaluation, Digital Healthcare, Sunovion Pharmaceuticals Troy Petrillo, Supervisory Consumer Safety Officer, FDA Barrett Glasser, Director Supply Chain Integrator, Takeda Kell IRT Specialist, Clinical Supply Janel Kelly, Capabilities, Biogen James Krupa, Director, Clinical Supplies Team Lead, Shire Matthew Leets, Transportation and Trade Management Analyst, Sanofi

www.arena-international.com/ctsnewengland/ Secure your place today by quoting reference code - MK-IKAD 53 Journal for Clinical Studies

Volume 11 Issue 1


Technology Clinical Practice as a subject area. This is because of a mistaken belief that it is a regulatory requirement to have GCP training annually or that investigator sites must routinely have GCP training as part of the study setup activities. Redundant GCP training is frustrating for the investigator and their site staff and diverts the sponsor’s valuable resources from more productive activities. The time could be better spent on targeting learning activities on those high-risk areas which could compromise patient safety, as well as regulatory and protocol compliance. There is no doubt that using a new investigator site is a potential risk for a sponsor. However, a risk assessment in the form of pre-training competence check of the site staff on what they already know about GCP would allow learning activities to be targeted on those areas and individuals where knowledge was weak, so filling the competence gaps. For study-specific training for both sponsors’ staff and investigator site staff, the learning should be focused on those parts of the protocol which have the biggest impact on subject safety and data integrity. Any complex sections of the protocol (e.g. investigational product dose adjustment) or case record form (CRF) should also be the subject of a risk-based approach. In terms of the CRF, analysing trends in data errors can highlight the ‘high-risk’ data fields and learning activities can be targeted in these specific areas. The introduction of new regulations often poses a threat of potential non-compliance. A risk-based approach to regulatory training targets those areas of the legislation where the threat of non-compliance is greatest. The same principles apply to SOP training when new procedures are implemented and efforts should be focused on those parts of the process which are complex or significantly different from previous practice. A risk-based approach to learning and development should be a dynamic system and the results should be analysed and the learning activities refined or refocused as necessary. By using a riskbased approach to learning and development, outcomes can be targeted and designed specifically for managing and preventing risks. This enables the learning interventions to be designed in a logical and constructive way. It also empowers the learners, in that they can see the relevance of the learning activities in preventing risks occurring, improving their performance and increasing their confidence. Applying a risk-based methodology allows the effects of learning activities to be more readily measured from an organisation’s perspective. An end assessment can include whether or not the risk manifested itself, the effect on incidents of noncompliance, reduction in errors and the savings of cost and time. We have examined the use of a risk-based approach to learning and development. Closely aligned to this philosophy is the concept of using competence as a basis for developing people. Competence can be defined as “the ability of an individual to demonstrate knowledge, skills and behaviours”. The word competence is seldom found in regulations governing clinical research. Guidelines and regulations deal broadly with the issue by requiring that “Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task”. (The Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2)), principle 2.8). Education, training and experience are important but this is not the whole picture. Substandard training and narrow, poor quality experience can all have a negative effect on the ability of an individual to perform their job. The key aspect of whether someone can fulfil their role in clinical research is directly related to their competence – i.e. the possession of the required and observable skills, knowledge and behaviours. Unfortunately a search through clinical research regulations and guidelines for the word “competence” produces a scant return. FDA 21 CFR mentions it in the context of IRB membership (56.107) and in the use of foreign data, relating to the competence of investigators (314.106). The ICH GCP Guideline E6 (R2) mentions competence only once, in connection with the www.jforcs.com

documentation of a medical laboratory to perform the required tests. As covered in the introduction to this article, new innovations in the clinical research environment are putting increasing demands on the requirement that people are competent. A skill set that was valid ten years ago is not necessarily fit for purpose today. Set against this background, there is a shortage of trained new talent coming into the clinical research sector. This seems to be an international problem, particularly in the USA and Europe. A scan of the job vacancies for clinical research positions will reveal that the overwhelming majority require previous experience, commonly at least two years’ worth. Many new graduates in biological sciences complain they cannot find work in clinical research because they lack work experience, so that breaking into this sector of the job market proves a frustrating exercise for them. From industry’s perspective, the situation is not very satisfactory as organisations are constantly playing catch-up in trying to acquire enough experienced and skilled people to meet their resource demands. Because of the time-pressured environment of clinical research and the shortage of experienced staff, the irony is that there seems to be a reluctance for companies to invest time and money into training new graduates, as the need is for people who can ‘hit the ground running’ with little or no extra staff development. The conventional picture of training involves attending a course, either face-to-face, online, or completing an e-learning course using a self-directed approach. Depending on how the training is designed and conducted, these methods can result in a passive experience or irrelevant experience for the so-called learner. A certificate of attendance may be obtained, or completion of a multiple-choice questionnaire may be required in order to obtain a certificate. However, a certificate of attendance of training is verification only that the person physically attended the training course. Without learning through active participation, there is no guarantee that any new skills will have been acquired. The important factor in any training activity is to have very clear goals of what should be learned either in knowledge, skills or behaviours – in other words, competence-based learning outcomes should be used. This enables people to demonstrate their new areas of competence after taking part in a learning activity. The learning intervention should be relevant for the person, their level of competence and their job role which, in turn, should be linked ultimately to their organisation’s business goals. The most important benefit in staff development of using a risk-based approach combined with a learning system based on competence is the positive impact on patient safety and its use as a tool in the protection of the rights and well-being of clinical trial subjects. Focusing on this key aspect helps put the learning activities in context and gives them an underlying theme, making it relevant for the learners, the organisation itself and of course the clinical trial subjects.

Martin Robinson Martin Robinson is 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: mrobinson@iaocr.com Journal for Clinical Studies 54


20th Annual

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