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Volume 11 Issue 6


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


Attracting Clinical Research to Malaysia With a Centralised Feasibility Platform Addressing Regulatory Challenges in Clinical Trials of Cannabis-related Drug Products Phase III Clinical Trials A Fate Decider in the Drug Development Patient Pioneers The Patient and Site-centricity Movement


ADVANCED CLINICAL RESEARCH SOLUTIONS LIFE INSPIRED, QUALITY DRIVEN 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 therapeutics. Stay ahead in your drug development plan, contact us for reliable and adaptive clinical trial solutions.









Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITORIAL MANAGER Ana De Jesus DESIGNER Jana Sukenikova RESEARCH & CIRCULATION MANAGER Virginia Toteva 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: Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS



Ensuring Appropriate and Reliable Data is Collected for Conclusive First-in-human/Phase I Trials

The purpose of clinical trials is to find answers to a research question by generating data to prove or disprove a hypothesis. By their very nature, first-in-human (FIH) and most Phase I trials are exploratory, and are conducted without a statistical hypothesis; and so their aim is to obtain reliable information on the safety, tolerability, pharmacokinetics and mechanism of action of a drug. Nariné Baririan at SGS explores how there are four main steps in clinical data processing, including data management and data analysis. 8

The Changing Face of Oncology Endpoint Monitoring

Oncology trials have always relied on tumour response to gauge the efficacy of the drugs they assess. The traditional primary endpoint for an oncology trial is tumour response, with studies focused on quantifiable signs of a shrinking malignancy and disease-free or overall survival. While researchers can obtain objective, definitive data on a patient’s response and disease progression, Dr. Anthony T. Everhart at Signant Health questions whether these “hard endpoints” offer developers – and regulators – the whole story in a world of patient-centricity and value-based reimbursement. 10 Clinically Important Endpoints to Measure Heart Failure How treatments affect aspects of life that are most important to patients is a priority for the US Food and Drug Administration (FDA) as it seeks ways to facilitate and accelerate drug development programmes. Deborah Komlos at Clarivate Analytics looks at how this topic was the basis of a public workshop held in July 2019, during which the FDA sought stakeholder input on clinical endpoints for trials in heart failure that could be used to support FDA approval of drugs. REGULATORY 12

How to Prepare for an Inspection and Establish a Culture of Readiness

Preparing for a regulatory inspection can be daunting – but it doesn’t have to be. The stress of an inspection can be lessened by building inspection-readiness practices into daily operations. Rik Van Mol at Veeva Europe demonstrates how a strong preparation process that readies your entire organisation for a successful inspection helps build and maintain an inspection-ready culture. 14 Addressing Regulatory Challenges in Clinical Trials of Cannabis-related Drug Products

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 6 November 2019 PHARMA PUBLICATIONS

The past few years have witnessed a burgeoning global interest in the development of therapies related to cannabis (Cannabis sativa L.) and its components, including cannabidiols (CBD) and other active constituents of cannabis. Aman Khera, Barry J. Dussault Jr and Henry J. Riordan at Worldwide Clinical Trials summarise the recent trends in clinical trials and point out the most common and salient regulatory and operational pitfalls in an effort to overcome shifting regulatory challenges inherent in the conduct of controlled clinical trials of cannabis-related drug products. 18 The MDR: The Clock is Ticking The European Union (EU) Medical Device Regulation (MDR) is the biggest challenge to the medical device industry in over 20 years. With the new regulations come more stringent requirements, which must be met for the product to obtain a CE mark and be commercially available in the EU. Dr. Sergio Perez at Kolabtree shares insight into the MDR and what it means for medical device manufacturers. Journal for Clinical Studies 1

Contents MARKET REPORT 22 Attracting Clinical Research to Malaysia with a Centralised Feasibility Platform A feasibility study is a crucial part of the clinical trial planning process. It enables sponsors and contract research organisations (CROs) to identify relevant clinicians who may be interested in a particular study as well as providing information on a site’s infrastructure and pool of eligible patients. Noorzaihan Mat Radi, Dr. Bee Ying Tan and Audrey Ooi at Clinical Research Malaysia examines the role of CRM’s centralised feasibility service in attracting sponsors and CROs to Malaysia. 26 Subgroups, Study Design, and the Impact of the Biosimilar Extension Rule In advance of a prospective pivotal biosimilar safety and efficacy trial, researchers reviewing the data from the Phase III clinical trial of the reference molecule noted that approximately 20% of participants showed only a partial response to the molecule. With further analysis suggesting that these partial responders might constitute a clinically plausible and distinct subgroup, Michael F. Murphy, Aleksandra Bibic and Hazel Gorham at Worldwide Clinical Trials use this data to explore the potential for excluding subjects or otherwise adjusting and accounting for presumptively prognostically important variables. THERAPEUTICS 28 The Need to Finally Get It Right with Universal Influenza Vaccines January 2018 marked the centennial of the 1918 influenza worldwide pandemic, which served as a stark reminder that the need for a universal influenza vaccine is paramount. Jaime Polychrones at Clarivate Analytics outlines how more than 100 years after the deadliest influenza outbreak in modern history – one that killed one-fifth of the world’s human population – there is still no vaccine available to protect people from most or all strains of influenza each influenza season. 32 Functional Service Provision and Full Service Outsourcing Models Have Key Roles to Play in Outsourced Drug Development as Clinical Trials Evolve The relative merits of the functional service provision (FSP) and full service (FS) outsourcing models have been debated repeatedly over at least the last ten years. There is a place for both in the outsourced market although, over time, there have been shifts between them in terms of market share. Andrew MacGarvey at PHASTAR analyses the pros and cons of the FS and FSP model, exploring whether hybrid is the compromise that will deliver the optimum outsourcing strategy. 34 Phase III Clinical Trials: A Fate Decider in Drug Development A Phase III clinical study evaluates the safety, efficacy and related parameters of experimental therapy against a standard therapy in a large human population to assure that it is fit for the intended purpose. Mr Chandan, Dr. M P Venkatesh and Dr. T M Pramod Kumar at JSS College of Pharmacy put forward a thesis on how a Phase III clinical trial may compare the effectiveness of a new treatment intervention with the present standard of care, if experimental therapy shows significant activity in any disease condition during the Phase II trial.

resulting in repeated episodes of spontaneous inflammation affecting multiple organs and manifesting as recurrent fever, mucocutaneous lesions, serositis and osteoarticular symptoms. Owing to their relatively recent identification and their low incidence rates, Bhanu Priya, Ivana Kocsicska and Mohamed El Malt at Europital discuss why it is believed that clinical cases are currently underdiagnosed and increased clinical awareness is required. TECHNOLOGY 44 Retooling Risk-based Management Using AI As a clinical trial monitoring technique, risk-based monitoring (or RBM) has become the R&D industry’s de facto monitoring approach to achieve quality data, patient safety, protocol compliance, and efficiency. Moving away from 100% source data verification (SDV), RBM approaches emphasise critical data and processes and are designed to manage potential differences in the quality and experience of clinical trial sites. Sandra H. Blumenrath at DIA Global looks at how recent debates have focused on how technology can support improvements in compliance, quality, and consistency. 46 Patient Pioneers: The Patient- and Site-centricity Movement The patient-centricity movement has been inspired by the empowerment of patients and patient advocacy groups through the internet, social media and new technology. This has caused a paradigm shift in the clinical research industry with protocol developers now viewing mobile nursing as an almost essential ingredient to the success of their trial. Helen Springford at Illingworth Research Group assesses whether patients could avoid site visits but still be safely involved in a clinical study. 48 Driving Clinical Trials Forward: The Benefits of Establishing a Strategic Partnership for Flow Cytometry Targeted therapies for use in clinical studies, such as those in immunooncology (I-O), are the future of pharmaceuticals. Critically assessing the efficacy and safety of a targeted molecule in I-O trials is essential. Li Zhou Ph.D., Christina D. Swenson Ph.D., Karen J. Quadrini Ph.D., Thomas W. Mc Closkey, Ph.D., and Krista D. Buono Ph.D. at ICON delve into flow cytometry being a sophisticated technology that can provide specific information on how biologics and other targeted therapies interact with living cells on a cellular level in clinical trials. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 52 Transforming Healthcare – How Curative Therapies will Disrupt the Market The shift to curative treatments promises to transform the entire healthcare ecosystem. Patients whose conditions were previously managed through ongoing, long-term medication can now be cured through specific courses of treatment. However, while this might transform their lives, it also has a disruptive effect on the wider market. Craig Wylie, Thomas Unger, Ulrica Sehlstedt, Vikas Kharbanda, Rebecka Axelsson-Wadman and Satoshi Ohara at Arthur D. Little observe how curative therapies can shift payers’ expenditure, increasing the importance of first-mover advantage for pharmaceutical companies, and changing care models for healthcare providers.

38 Clinical Development in Rare Diseases: Autoinflammatory Syndrome ”Autoinflammatory” is a term used to describe a group of diseases that cannot be classified as immunological disorders. Autoinflammatory syndromes are a set of genetically diverse but clinically similar conditions caused by an exaggerated innate immune system response 2 Journal for Clinical Studies

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Foreword The festive season is drawing ever closer and here at JCS, we are thrilled to bring you our sixth and final issue of the year! We’ve curated leading research and industry developments from across the world, covering topical areas of interest such as the changing classifications of MDR (Medical Device Regulations) and the evolutionary elements of oncology end point monitoring. As part of our exclusive market report feature, Noorzaihan Mat Radi, Dr. Bee Ying Tan and Audrey Ooi at Clinical Research Malaysia examine how attracting clinical research to Malaysia with a centralised feasibility platform is deemed useful for site selection processes. The team explores how a feasibility study is a crucial part of the clinical trial planning process and how it allows sponsors and contract research organisations (CROs) to identify relevant clinicians. Before the implementation of a centralised feasibility system, pre-feasibility is needed for preliminary, higher-level assessments which allows sponsors and CROs to make decisions at a national and global level. They show how offering complimentary, centralised feasibility management to CROs provides information on a site’s infrastructure and pool of eligible patients, enabling companies to meet regulatory and ethical conditions in Malaysia. In our regulatory section, we have an article by Aman Khera, Barry J. Dussault and Henry J. Riordan at Worldwide Clinical Trials entitled ‘Addressing Regulatory Challenges in Clinical Trials of Cannabis-Related Drug Products’. They explore the intersection between cannabis-based chemicals being used to treat a variety of therapeutic indications and the subsequent burgeoning global interest in the development of therapies related to cannabis (Cannabis sativa L.) and its components, including cannabidiols (CBD). The feature investigates how the increase in clinical trials reflects public interest in both medicinal and recreational use of cannabis and comes at a time of dynamic fluctuations in both state and federal regulations. This review summarises the recent trends in clinical trials and points out the most common and salient regulatory and operational pitfalls to overcome shifting regulatory challenges inherent in the conduct of controlled clinical trials of cannabis-related drug products. For therapeutics, we have featured a piece on ‘Phase III Clinical Trials: A Fate Decider in the Drug Development’ by Mr Chandan, Dr. M P Venkatesh and Dr. T M Pramod Kumar at JSS College of Pharmacy. The article determines whether a Phase III clinical trial may compare the effectiveness of a new treatment intervention with the present standard of care, pointing out that if experimental therapy shows significant activity in any disease

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

condition during the Phase II trial, advance clinical trials for comparing the experimental treatment efficacy can be made for the disease in comparison with standard or control treatment. The team highlights the need to incorporate a review of the accessible proof, as well as a suitable clinical setting with all the required facilities, when conducting Phase III trials. In technology, Helen Springford at Illingworth Research Group evaluates how the patient-centricity movement has been inspired by the empowerment of patients and patient advocacy groups through the internet, creating a paradigm shift in the clinical research industry. Titled ‘Patient Pioneers: The Patient- and Site-centricity Movement’, the article shows how replacing site visits with appointments at home not only allows for flexibility by revolving around the patient’s needs, but also frees up hospital time to recruit more patients, whilst hitting enrolment targets. Springford concludes that an effective partnership between site personnel, third-party research nursing companies, pharmaceutical companies and patients is critical for the success of a truly patient-centric approach. Finally, in logistics & supply chain management, Craig Wylie, Dr. Thomas Unger, Dr. Ulrica Sehlstedt, Rebecka Axelsson Wadman, Satoshi Ohara and Vikas Kharbanda at Arthur D. Little look at ‘Transforming Healthcare – How Curative Therapies will Disrupt the Market’. The team investigates whether a shift to curative treatments will disrupt the entire healthcare ecosystem, with payers’ expenditure drastically changing from ongoing, long-term and relatively low-cost drugs to large, front-loaded therapy costs. They conclude that this will create a streamlined care model for healthcare providers soon. That rounds off our sixth edition of the year – we look forward to seeing you in the New Year! Ana De-Jesus, Editorial Co-Ordinator 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, and so the cover depicts the Hibiscus rosa-sinensis, the national flower of Malaysia. I hope this journal guides you through the maze of activities and changes taking place in the clinical research industry worldwide.

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

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

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

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

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

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

of Europe

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

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

Services & 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

4 Journal for Clinical Studies

Volume 11 Issue 6

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Ensuring Appropriate and Reliable Data is Collected for Conclusive First-in-human/Phase I Trials The purpose of clinical trials is to find answers to a research question by generating data to prove or disprove a hypothesis. By their very nature, first-in-human (FIH) and most Phase I trials are exploratory, and are conducted without a statistical hypothesis; and so their aim is to obtain reliable information on the safety, tolerability, pharmacokinetics and mechanism of action of a drug. Various data are captured from FIH trials, and despite their exploratory character, these data need to be relevant, accurate and appropriately analysed to obtain meaningful results that are useful for future clinical development. There are four main steps in clinical data processing:

(e)CRF: (electronic) Clinical Research Form, TLFs: Tables, Listings and Figures

Data Planning The first step is the planning of the data at an early stage when developing the study design / protocol / case report form (CRF). The clinical team must evaluate which measurements need to be taken, when exactly in the study these will be carried out, for how long and how frequently. These questions concern all the assessments within the FIH, such as patient safety, drug tolerability, and pharmacokinetics (PK) and pharmacodynamics (PD). Often, planning is not very targeted since the only supporting information available at this stage is preclinical data with human predictions; moreover, there is no precise statistical endpoint. Data Collection Once the study starts, data are collected by the operational staff of the Research Unit on an ongoing basis. Any use of inappropriate methodology or non-adherence to protocol / manuals / CRF may have a critical influence on data reliability and can introduce unintended bias to the results. Therefore, it is critical that staff overseeing the study are fully trained and aware of the importance of their work and the precision needed in the detail of both the timing and methodology of data collection. It also goes without saying that the staff cannot overlook the safety and care of the study subjects. The relatively high-risk 6 Journal for Clinical Studies

nature of FIH studies and the absence of therapeutic benefit for participants brings with it the ethical obligation to limit the number of exposed subjects, stressing even more the need for good quality data capture and handling. Data Management Clinical data management (CDM) is the process of collecting, cleaning, coding and managing subject data in compliance with the appropriate regulatory standards. The primary objective of CDM processes is to provide good quality data and gather the maximum data for analysis. To meet this objective, best practices (the use of software, standard automatic process, electronic CRFs, electronic data review) should be adopted. Data Analysis At the end of the trial, the data must be analysed to “become resultsâ€?. If appropriate methods of analysis are used with the appropriate data, it will be possible to interpret results and come to a conclusion. In the case of FIH studies, the conclusion should allow a decision to proceed or not to the next phase of development, and to give initial indications on how to design the next study. As with many aspects of clinical design, ensuring meaningful data are achieved is enhanced with the experience of the clinicians undertaking the studies. It may be the case that protocols need to be adaptive and flexible to meet the objectives of the studies, especially in FIH and early phases which are exploratory. Two scenarios are outlined below which demonstrate this: •

Scenario 1: A substantial amendment was introduced, and study conduct changed because of inappropriate PK data planned in an initial version of the study protocol

During a complex FIH study, including both single ascending dose (SAD) and multiple ascending dose (MAD) parts, the PK sampling until 24h needed to be analysed before the next dosing in the SAD escalation part. This time point was based on a predicted human short half-life of the compound, and the next dosing was fixed to start 14 days after the preceding dose. The starting dose was very low and, in most subjects, the plasma drug concentrations were very low or even non-quantifiable. As such, PK parameters (including half-life) were not relevant; therefore, the 14-day interval was sufficient but perhaps in this instance, unnecessary. Interestingly, with the third and fourth doses, the 24h PK sampling period proved to be too short, and so the half-life could not be estimated correctly (as it was longer than predicted in the protocol). The protocol was amended after the fourth dose, and additional subjects were included to repeat the third and fourth doses with PK sampling up to 72h and 96h post-dose, Volume 11 Issue 6

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respectively, before escalating to the fifth and final dose in the SAD part. This scenario highlights the fact that FIH trials are exploratory, with PK as one of the primary objectives, and that PK data/ assessments cannot always be precisely planned in the initial protocol. Therefore, an adaptive approach can be used with careful and tailored PK data review steps. •

Scenario 2: After a specific adverse event (AE), the safety data collection method was changed after two MAD groups to obtain the necessary information on drug/dose relationship, severity and actions to be taken during further clinical development

During a Phase I MAD study, frequent gastrointestinal (GI) events were observed in the first two dose groups, increasing with the higher dose. As usual protocol, and as foreseen by the CRF, the date/time and severity of this AE was reported by the clinical site. However, since it was a frequent AE, related to dose, and might occur multiple times in the same subject, it became of interest to know if vomiting/diarrhoea only occurred once in each subject or multiple consecutive times and if so, how often and within what time frame. The observational staff suggested starting collecting details for each particular GI AE, i.e. a separate record for each vomiting/diarrhoea episode for each subject. No amendment to the CTP or other actions related to the CRF were needed, but only a modification to the way data were collected in the clinical pharmacology unit. This event reinforces the need for specific and detailed safety information to be collected. Clinical sites should be reactive and

ready to adapt the data collection process in response to ongoing observations to ensure that the data collected are as useful as possible. In summary, high-quality data are needed in all clinical studies including exploratory FIH. These should meet the protocolspecified parameters and comply with the protocol requirements. However, the unpredictability of the studies mean that clinicians must be flexible and adaptive to ensure as much data as possible available to assist in the progression of a drug through the development process.

Nariné Baririan Nariné Baririan is a Clinical Pharmacology Expert at SGS, and is part of the company’s early phase consultancy team which supports and advises clients in the design of studies and clinical development plans of their new compounds. She holds a degree in pharmacy and a research master’s degree in cellular and molecular pharmacology from the Université Catholique de Louvain (UCL). She joined SGS in 2007, after continuing her research experience by undertaking a PhD in Pharmaceutical Sciences at UCL in Clinical Pharmacology and Pharmacokinetics. Nariné is an active member of the Belgian Association of Phase I Units (BAPU) and Association Française de Pharmacologie Translationnelle (AFPT).

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The Changing Face of Oncology Endpoint Monitoring Oncology trials have always relied on tumour response to gauge the efficacy of the drugs they assess. But in a world of patientcentricity and value-based reimbursement, do these “hard endpoints” offer developers – and regulators – the whole story? The traditional primary endpoint for an oncology trial is tumour response, with studies focused on quantifiable signs of a shrinking malignancy and disease-free or overall survival. Many trials use RECIST, or the Response Evaluation Criteria in Solid Tumours, for example. By measuring tumours, via CT, MRI or X-ray at baseline and throughout the study, researchers can obtain objective, definitive data on a patient’s response and disease progression. What this doesn’t tell us is how well the drug was tolerated, and whether the patient believed the burden of treatment was worth the result – information that is becoming crucial to developing successful drugs and getting them approved. Limitations of the Traditional Approach In 2001, the Institute of Medicine published Crossing the Quality Chasm1, a seminal report that named patient-centricity as one of the six goals a healthcare system should fulfil in order to deliver quality care. Medicine should revolve around the patient, respect patient preference and put the patient in control. There is a growing body of evidence2 that the systematic monitoring of symptoms, as part of routine clinical care, can result in significantly better outcomes and it has become generally accepted that patient reporting can improve communication, drive satisfaction and ease symptom management 3. This, combined with a shift towards a value-based approach to care and reimbursement, means patient-reported outcome (PRO) measures have never been more important. Oncology, which has traditionally relied on tumour response, has been slower to include PROs. In fact, between 2010 and 2014, only three of the 40 cancer4 treatments approved for use in the USA received any PRO-related labelling.

necessarily indicate what is of primary concern to the patient, or tell us how patients manage their cancer, cope with their symptoms or deal with treatment. The field is also lacking consensus on how best to embrace the opportunities of these “soft” endpoints. A recent study in paediatric oncology6 identified barriers to implementation in practice, that equally apply to research, which included inadequate time, insufficient staff, logistics, and a lack of financial resources. Another important barrier is tension between different stakeholders. While clinicians worry payors could misinterpret PRO data, those who develop the performance measures have concerns over the quality of data clinicians collect. The Future of Oncology Endpoints Whatever the challenge, improving patient-centredness in oncology is growing in focus. For decades, the scientific community has been on a mission to battle cancer, and, in large parts, it has been successful. People are living longer after a diagnosis of cancer than ever before. It means that today’s oncology therapies don’t just have to treat cancer, but also offer tangible quality of life benefits. Regulators and payors want developers to prove not just efficacy, but value of care, and the traditional fee-for-service model is shifting to value-based reimbursement. As such, real-world data on whether today’s sophisticated, yet expensive, cancer therapies improve overall quality of life and value of care is in demand. This information can only come from the patients themselves. The collection of PROs in oncology research, then, offers a “two birds, one stone” solution to future approval considerations as well as a solid step towards the development of patient-centred, valuebased cancer treatments. Joining the Dots: Building the Big Data Picture Knowing what to collect is the first step. A study in pancreatic cancer7 identified a battery of meaningful patient-collected data points. These centred on themes including overall general health and physical ability, as well as satisfaction with caregivers, services and care organisations.

Limitations of Patient-reported Outcome Measures in Oncology While the benefits of PROs are generally accepted, there is still, in oncology, uncertainty around what to measure and how to collect it. The US’ Food and Drug Administration (FDA) defines a PRO as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else”. 5 To date, PRO-related endpoints in cancer clinical trials have centred around health-related quality of life (HRQoL). While these provide information of value to the clinician, they do not 8 Journal for Clinical Studies

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Watch Pages out outliers and potential data quality issues as and when they arise. Integrating systems such as eCOA with eConsent helps to build the strong site-patient relationships that boost engagement, reduces dropouts and delivers meaningful PRO data. Augmenting Not Replacing Hard Endpoints Ultimately, embracing “soft” oncology trial endpoints is not about replacing the “hard” measure of tumour response. The ultimate goal of any cancer therapy will always be to shrink or kill malignant tumours. But by collecting and centralising all available information, from tumour imaging and clinician-assessed response, to caregiver and patient-reported outcomes, sponsors have everything they need to develop patient-centred therapies and get them approved. Adherence is another important consideration – no matter how efficacious a treatment is, it won’t work if patients aren’t taking it. Trials can collect endpoints on treatment plans, intentional or unintentional barriers to compliance, as well as a patient’s motivation to follow the regimen. What’s more, PROs can inform regulators on patient satisfaction and experience by asking trial participants to comment on the use and effectiveness of, and trust in, new therapies. Looking at unmet needs and treatment preferences, such as side-effect versus symptom burden, is also useful for proving value. Collecting all this information in a systematic manner, so that it not only informs drug development and boosts patient-centricity but is also robust enough to support the approval process, requires the utilisation of cutting-edge clinical trial technology. eCOA software can incorporate relevant, validated instruments that collect the right data at the right time, whether that be from patients, clinicians or caregivers. Daily symptom diaries allow patients to record how they feel at any given time, rather than be expected to remember the good days and the bad at their next appointment. Adherence trackers provide vital information on compliance and motivation issues. Validated PRO information can offer developers deep insights into how their treatments work and impact on the everyday lives of the patients who take them. And it also provides them with the robust evidence of patient-centric value-based care that regulators are increasingly asking for. Analytics Provide Data Quality Confidence In CNS studies, sponsors have used cutting-edge software to bring all this information together and utilised data analytics to monitor the quality of both patient- and clinician-reported outcomes. This has given them the oversight they need to ensure the quality of the data collected and that their clinical trials succeed or fail on the merit of the therapy and not the reliability of the data. There is a huge opportunity here for oncology to follow suit. Gold standard technology providers can ensure data integrity and boost patient engagement across today’s increasingly complex, global cancer trials. They can help researchers to identify and secure validated instruments and design patient-centric protocols, can improve data consistency by ensuring all raters receive gold standard training, and boost data quality with real-time analytics that root


Crossing the Quality Chasm: A New Health System for the 21st Century. (2001). 20Files/2001/Crossing-the-Quality-Chasm/Quality%20Chasm%202001% 20%20report%20brief.pdf 2. Stepanski, E. (2016). Incorporating Routine Patient-Reported Outcomes Assessment into Cancer Care: Building Momentum. https://www. 3. Bacsh, E et al. (2014) Patient-reported outcome performance measures in oncology. 4. Gnanasakthy, A, DeMuro, C, Clark, M, Haydysch, E, Ma, E and Bonthapally, V. Patient-reported outcomes labeling for products approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014). J Clin Oncol.2016;34(16):1928-1934. 5. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labelling Claims. (2009). https://www.fda. gov/regulatory-information/search-fda-guidance-documents/patientreported-outcome-measures-use-medical-product-development-supportlabeling-claims 6. Schepers, SA et al. (2016). Healthcare Professionals' Preferences and Perceived Barriers for Routine Assessment of Patient-Reported Outcomes in Paediatric Oncology Practice: Moving Toward International Processes of Change. 7. Gerritsen, A. (2016). Developing a core set of patient-reported outcomes in pancreatic cancer: A Delphi survey. pubmed/26886181

Anthony T. Everhart Todd Everhart, MD, FACP, is the internal medicine leader at Signant Health. Dr. Everhart is board-certified in internal medicine and a fellow of the American College of Physicians with over 23 years of experience in the practice of medicine and over 12 years of experience in clinical development. Prior to joining Signant Health, Dr. Everhart held positions of Vice President, Medical Affairs and Vice President, Medical Informatics at Chiltern and Covance, and consulted independently in the areas of medical monitoring, medical data review, data analytics, and physician adoption of technology. He has worked in all phases of clinical development in numerous therapeutic areas including allergy & immunology, cardiovascular, hematology & oncology, infectious disease & HIV, neurology, ophthalmology, psychiatry, respiratory, and rheumatology.

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Clinically Important Endpoints to Measure Heart Failure How treatments affect aspects of life that are most important to patients is a priority for the US Food and Drug Administration (FDA) as it seeks ways to facilitate and accelerate drug development programmes. This topic was the basis of a public workshop held in July during which the FDA sought stakeholder input on clinical endpoints for trials in heart failure that could be used to support FDA approval of drugs. The meeting focused on endpoints related to symptoms (e.g., dyspnea, fatigue) and physical function (e.g., walking, exercising, other activities of daily living). The need to assess mortality effects of drugs under development for heart failure was also discussed. “There’s something beautiful about an endpoint that involves symptoms – and that is, that the patient can figure out if they feel better,” said Ellis Unger, MD, director, Office of Drug Evaluation-I, Office of New Drugs, Center for Drug Evaluation and Research (CDER), FDA. The “benefit-risk calculus” is affected greatly by whether patients can tell if they are deriving a treatment benefit, he said. They can notice such benefit for symptomatic endpoints (e.g., dyspnea, fatigue), but not for “hard" endpoints such as hospitalisation prevention or death. According to Eldrin Lewis, MD, MPH, FAHA, associate professor of medicine at Harvard Medical School, despite the FDA’s issuance of its December 2009 final Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, which he called a “very comprehensive” document, the use of patient-reported outcomes (PROs) for regulatory requirements and to measure changes in outcomes has not occurred on a regular basis. Lewis explained that often a considerable amount of emphasis is placed on mortality. As patients progress through their natural history, however, they become more symptom-sensitive instead of survival-sensitive. PROs or health status encompass “the entire spectrum between symptom status and overall quality of life,” Lewis said. “Sometimes we get caught up in the terms when we really should just focus on how to do best for our patients,” he added. New FDA Guidance on Heart Failure Drugs The recent meeting in July was prompted by the FDA’s issuance of the Draft Guidance for Industry: Treatment for Heart Failure: Endpoints for Drug Development in June. In particular, the agency was interested in soliciting feedback regarding four high-priority topics: • Identify endpoints related to symptoms or physical function of clinical importance, including an approach to quantifying hospitalisation. • Understand when the nature, magnitude, and clinical importance of an endpoint may justify deferral or omission of outcomes studies. • Identify the risk of mortality that should be ruled out in outcome studies and whether the acceptable upper bound should be 10 Journal for Clinical Studies

influenced by a drug’s demonstrated benefit and risk. Discuss the pros and cons of capturing all-cause events versus cause-specific events, and the need for adjudication of events.

This guidance has two purposes: 1) to make it clear that an effect on symptoms or physical function, without a favourable effect on survival or risk of hospitalisation, can be a basis for approving drugs to treat heart failure; and 2) to provide recommendations to sponsors on the need to assess mortality effects of drugs under development to treat heart failure. Functional/wellbeing outcomes of interest could be more important to the patient than the traditional hospitalisation/ mortality outcomes, said Scott Solomon, MD, the Edward D. Frohlich Distinguished Chair, professor of medicine at Harvard Medical School, and senior physician at Brigham and Women’s Hospital. For example, at the end stage of disease, a patient may forego duration of life for quality of life (QOL). It would be easy if mortality was the only measure in clinical trials, Solomon said, but there are many aspects that patients care about besides the hard outcomes. How to better incorporate those aspects into trials and how to convince payers that these kinds of benefits are worth paying for need consideration, he said. One of the patient representatives speaking at the July meeting was Rhonda Monroe, who overcame numerous challenges relating to heart disease with considerable hard work (e.g., cardiac rehab, surgery). Monroe, who is African American, commented that this demographic is disproportionately affected by heart disease/heart failure and its members often do not recognise the symptoms. For example, patients do not perceive fluid retention as related to heart disease; instead, they think it is due to standing too long or eating too much salt. She advised that, if clinical trials are to be based on symptoms, clear education is needed about what symptoms are, so that patients are relating those symptoms to their disease state. Monroe said she is grateful for all the work being done in the heart failure field, including to establish guidelines. “But if [a therapy] never comes to market because of litigation or I can’t ever access it because my payer won’t cover it, then it’s fruitless,” she said.

Deborah Komlos Deborah Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis suite of life science intelligence solutions 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:

Volume 11 Issue 6

spanning the globe. China: strategic partner Teddy Clinical Research Laboratory since 2019. North America: well established partnership with Cenetron since 2015. Europe: full coverage through MLM Medical Labs since 2012.

MLM Medical Labs is one of the leading central labs for clinical trials in Europe. For 25 years we have been supporting clinical trials phase I-IV with full laboratory services, kit building and logistics. For further information please contact Dr. Katja Neuer at or visit us at

MLM Medical Labs GmbH Dohrweg 63 41066 Mรถnchengladbach Journal for Clinical Studies 11 Germany


How to Prepare for an Inspection and Establish a Culture of Readiness Preparing for a regulatory inspection can be daunting – but it doesn’t have to be. The stress of an inspection can be lessened by building inspection-readiness practices into daily operations. This can be paired with a strong preparation process that readies your entire organisation for a successful inspection. This approach will ensure inspections run smoothly with little disruption to day-to-day operations.

Document Preparation Inspection-readiness begins and ends with your TMF. A welldeveloped TMF plan includes the roles and responsibilities of internal and external partners across the study, document content requirements, instructions for inspections, and the type and frequency of quality checks. It is a living document that should be reviewed and updated on a regular basis to ensure the TMF is fully leveraged to enable a constant state of inspection-readiness for your organisation.

Roles and Responsibilities Passing an inspection is a team effort, so it’s important to call out some of the key roles. The core team is responsible for defining, reviewing, and implementing procedures outlined in the standard operating procedure (SOP). This codifies the roles, procedures, and training your organisation will enact ahead of an announced inspection.

An active TMF operating model ensures a constant state of inspection-readiness. Incorporate active TMF management practices into daily operations by submitting or creating all TMF documents in a timely and contemporaneous manner. Apply quality control checks to ensure they are accurate and complete. Each action should be traceable and auditable for inspectors to review.

Essential team members include:

Before a planned inspection, the following list is a good starting point for the documents that inspectors will be reviewing.

• • •

A leader with the authority to coordinate and direct staff at all levels, and with strong project management skills Quality assurance and regulatory team members who are well prepared to provide documents outside of the TMF Functional area contacts involved in the development of the SOP. These individuals will also act as liaisons for their respective departments during an inspection

Team Expectations Both study staff and non-study staff will need to be ready to be interviewed on inspection day. Organisations should identify primary interviewees and backups for each department. Equally important is the ancillary support staff who will support with logistics on the day. This team may require less intensive training than interview personnel but should still be prepared. Consider who the inspector will meet on the day, as well as specialised staff you may need to call on. This could include an eTMF driver or a TMF liaison. Leadership endorsement is essential to build and maintain an inspection-ready culture. Ongoing and consistent communication from executives is critical in making sure that everyone is aware of the benefits of incorporating inspection-readiness practices into daily operations. Make it a practice to gather feedback from internal and external study teams. This can be done during study planning, training sessions, or pre-defined times throughout the study. Involving all stakeholders regularly in the process will increase trust, improve collaboration, and maintain high-quality documentation practices throughout the study. 12 Journal for Clinical Studies

• •

Study-related documents – preferably final versions without annotations Charts and reports – you may be able to anticipate the type of information your inspectors will look for, such as data on contemporaneousness of file submission; create these charts and reports beforehand and be ready to explain the results Previous findings – it’s likely that inspectors will want to see the resolution plan for past issues; include complete responses and documentation about corrective and preventive actions (CAPA) taken Non-study-related documents – the inspector may want to review non-TMF-related materials such as company SOPs, IT system security, validation documentation, etc.

If your organisation uses an eTMF, you will need to consider the inspector’s access to these files. Restrict the inspector’s access to files only needed for the inspection. Include details on how these permissions will be validated before the inspection, and the plan for revoking access once the inspection has concluded. Training inspectors to navigate an eTMF should take no more than 15-20 minutes. Have this training ready even if you plan to have an eTMF driver present for the duration of the inspection. Your eTMF vendor may have best practices or tips to help you organise documents more efficiently or present your processes in the best possible light. Communication Plans All key stakeholders should be aware of preparation activities and their role as soon as an inspection is announced. Volume 11 Issue 6

Regulatory Establish and monitor key performance indicators to drive inspection-readiness and inform proactive decision-making. Design reports to help identify issues before they become problems, and use KPIs to assess TMF timeliness, quality, and completeness. Checking these on a regularly scheduled basis will enable your organisation to identify and resolve issues proactively, before an inspection occurs. Unannounced inspections are a critical reason for having an SOP in place and all staff trained. Be clear on what absolutely must happen if inspectors show up unannounced. Start with the communication procedure and include who is responsible for getting the inspectors settled and the organisation ready at a moment’s notice. Planned inspections can be more defined in their set-up, with organisations able to plan every step of the way. The following timeline serves as a guide for the day of inspection with who should be involved and when. • • •

• • •

Arrival – who needs to be notified when an inspector arrives and through what means Announcement – how the inspection will be announced to the entire organisation Core inspection team – what information is needed by the core inspection team while the inspection is being conducted and who is responsible for delivering that information Liaisons and ancillary staff – how liaisons will communicate with the inspectors, their departments, and the core inspection team Post-inspection – similar to arrival communications, identify who should be notified upon the departure of inspectors Inspection results – how inspection results will be communicated and to whom

Training Content and Procedures Everyone needs to know how to conduct themselves in the event of an inspection. Position inspections as a normal, important activity that requires everyone’s collaboration to be successful. Even small things like renaming the “inspection war room” to the “inspection preparation room” can help reduce tension. Training should include regulations, the company's processes, and information about the construct of the TMF. All new team members should receive this training as part of their onboarding process. Just as a “fire drill” helps everyone in a building to prepare for an emergency, conducting internal audits and mock inspections ensures your organisation is ready for an inspection. Leverage these activities to identify areas where processes and/or performance can be enhanced or improved. Compose answers to anticipated questions; the core inspection team should come up with questions inspectors are likely to ask and how these questions should be answered. Determine how to present information in a positive, collaborative light, and help interview candidates practise their answers (without oversharing). Inspectors are sometimes said to shoot rapid-fire questions to see how prepared you are, and as a way to measure awareness and transparency. Anticipate what these questions might be and

practise your response. Allow individuals to hone their responses as needed without losing the key points. Mock inspections serve an important purpose by gauging how prepared your organisation is for an actual inspection. The person playing the role of the inspector is ideally someone who has experience as an auditor/inspector, and ideally is unfamiliar to the team. Start from the first interaction and include any procedures that security or reception must follow when inspectors announce themselves. A mock inspection should cover everything contained in the SOP, including how the inspector is received, how ancillary staff fulfil their roles, the communication procedures throughout the day, and access to all necessary documents. Take the opportunity to use the observations and findings from the mock inspection and make changes as necessary. Day of Inspection Checklist Be thoughtful about the physical needs of both the inspector and your preparation team so that they can all perform their jobs smoothly. It’s important that the inspector is comfortable while working with your team. Inspectors should be given their own working space. Do not put inspectors in a room where confidential materials may be visible. Make sure restrooms are conveniently accessible. Equip the room with anything the inspector may need; consider a computer with internet access and a phone, and be prepared to source anything else the inspector may need. Indicate what type of refreshments are appropriate to provide. In some cases, you may need to be careful to avoid the appearance of bribery. Provide a welcome packet which includes basic, nonstudy information, such as a site map and contact information for specific people and their roles. Don’t forget about your internal team; select a room for the preparation team that is adequately close to the inspectors’ room and provides privacy. Plan for Change Remember, an ounce of prevention is worth a pound of cure. Be prepared to modify any step in this plan to accommodate any necessary regulatory changes in a timely manner. It is better to incorporate changes when needed rather than risk citation for failure to comply during an inspection – planned or otherwise.

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 valuechain, including clinical, regulatory, and manufacturing/supply-chain areas for some of the world’s largest companies. Email:

Journal for Clinical Studies 13


Addressing Regulatory Challenges in Clinical Trials of Cannabis-Related Drug Products The past few years have witnessed a burgeoning global interest in the development of therapies related to cannabis (Cannabis sativa L.) and its components including cannabidiols (CBD) and other active constituents of cannabis; and many such cannabis-related drug products are currently in various stages of development. There has also been great headway made in exploring ways that cannabis-based chemicals may be used to treat a variety of indications across several therapeutic indications, including but not limited to PTSD, anxiety, chronic pain, epilepsy, and movement and rare disorders. A cursory review of suggests that well over 100 clinical trials of cannabis-based therapies have been completed, are currently underway, or are pending recruitment globally; an upsurge that is replicated when reviewing other clinical trial registries such as the EU Clinical Trials register. This increase in clinical trials reflects the general public interest in both medicinal and recreational use of cannabis, and comes at a time of dynamic fluctuations in both state and federal regulations. This review will attempt to summarise the recent trends in clinical trials and point out the most common and salient regulatory and operational pitfalls in an effort to overcome shifting regulatory challenges inherent in the conduct of controlled clinical trials of cannabis-related drug products. An Evolving Landscape The past few years have been characterised by diverse opinions and feedback from state and federal regulatory bodies regarding cannabis use and cannabis-based medications. Of note, Congress passed the Agriculture Improvement Act of 2018 (known as the 2018 Farm Bill) which among other things established a new category of cannabis classified as “hemp” – defined as cannabis and cannabis derivatives with extremely low (no more than 0.3 per cent on a dry weight basis) concentrations of the psychoactive compound delta-9-tetrahydrocannabinol (THC)1. The 2018 Farm Bill also removed hemp from the Controlled Substances Act, which means that hemp is no longer considered a controlled substance under federal law; however, the FDA Commissioner at the time also issued a clear statement on the status of cannabis-derived compounds. The FDA, much like other global regulatory agencies, stands firm on the foundation that producers are not able to make therapeutic claims regarding cannabis or its derivatives until they have gone through the standard drug development journey, and have been approved via the established regulatory pathways, just as with any other product2. Many people use the term cannabinoid products and cannabis-related drug products interchangeably. To clarify the term “cannabinoids” is used often to categorise a wide variety of types of molecules that have an effect on human cannabinoid receptors, including endocannabinoids (produced endogenously in humans), phytocannabinoids (plant-based), and synthetic analogs of both groups. Of note, the cannabis plant produces over 100 different cannabinoids but the most prevalent and well understood are THC and CBD. To date, the FDA has approved three cannabinoids or cannabis-related drug products for medical 14 Journal for Clinical Studies

treatment with a fourth currently under review. The synthetic product dronabinol and nabilone are approved to treat nausea and vomiting associated with cancer chemotherapy. Dronabinol is also approved to treat loss of appetite and weight loss in people with acquired immunodeficiency syndrome (AIDS) and contains synthetic THC, while nabilone contains a synthetic substance with a similar chemical structure. In 2016, the FDA approved Syndros, a liquid form of dronabinol and more recently, in 2018, the agency approved Epidiolex (cannabidiol or CBD) oral solution for the treatment of seizures associated with two severe forms of epilepsy. This approval was the first non-synthetic, cannabisderived medicine for rare types of epilepsy such as LennoxGastaut syndrome and Dravet syndrome, in patients two years of age and older3. The drug is known as Epidiolex and is made from cannabis grown in the United Kingdom. Auspiciously prompted by the recent approval of Epidiolex, the Drug Enforcement Agency (DEA) announced that “finished dosage formulations” of CBD with THC below 0.1% would be considered a Schedule 5 (which is the least regulated) drug as long as the medications have been approved by the FDA. This downgrading of a type of cannabis product from its original Schedule 1 classification was a first for the DEA and allowed Epidiolex to be distributed through traditional pharmaceutical channels. Without this change, physicians would not have been able to freely and easily prescribe this medication. Significantly, this rescheduling affects more than Epidiolex and has paved the way for other sponsor companies to follow a similar pathway to market. In May 2019, the FDA held a public hearing, the purpose of which was to clarify the FDA’s stance regarding the use and testing of cannabisrelated drug products, to understand the public’s questions and concerns regarding these policies, and to put manufacturers of CBD-based products making unsubstantiated claims on notice that they will continue to receive warning letters from the agency and that action may be taken, noting that “selling unapproved drug products with unsubstantiated therapeutic claims is a violation of the law, and puts patients at risk”. Although a minority of speakers supported a prohibition of cannabis-based products, most speakers endorsed a sanctioned regulatory pathway that would lead to uniform labelling and quality standards for cannabis-based drugs4. Current Regulatory Pathways To avoid any confusion regarding apposite regulatory pathways for cannabis-related drug products, it is imperative to specify that in order to progress a cannabis derived product through the drug development journey, the pathways established by regulatory authorities for non-cannabis derived must first be adhered to, whether this be the NDA(b)(1) route or the NDA 505(b)(2) route. In all of these pathways, it is essential to note that robust trial data which demonstrates safety and efficacy must be presented. As with all medicinal compounds, it is highly recommended to seek early and frequent engagement with the FDA when developing these products, and to seek advice on the clinical development of such a programme. Appropriate regulatory designations are also applicable, which include, but are not limited to, the Orphan Drug Designation (ODD) pathway, rare disease paediatric disease Volume 11 Issue 6

Regulatory vouchers, and priority review/fast track and breakthrough designations. It is also advisable to take advantage of the early engagement mechanisms that are available to sponsor companies through the type-B FDA meetings; such as a pre-IND meeting where the opportunity exists to ask the FDA questions regarding the development of the product before an IND is submitted. Through such interactions, sponsor companies can receive clear and explicit guidance from the agency regarding requirements for their specific compound. The FDA have also provided detailed information and guidance on the specific data requirements that are necessary to develop a drug that is derived from a plant such as cannabis through its updated Guidance for Industry on Botanical Drug Development5. After pre-IND meetings, and as with other drug development journeys, an IND application is submitted to the appropriate division in the Office of New Drugs in CDER, depending on the therapeutic indication under review. A complete and thorough evaluation of the safety of the product, as well as the quality (CMC) data, will be undertaken; and the timelines for approval (“no objection�) are 30 days unless the product is placed on clinical hold until such time any outstanding questions are resolved to the satisfaction of the FDA. Once the IND approval is in place, sponsor companies can then begin navigating the complex pathway to getting the study drug to investigational sites in the various states. A complicated array of state-by-state legal differences and challenges, each impacting study conduct in different ways, has been the norm for US studies. These state edicts also interrelate with not one but several federal agencies. For example, all

scheduled substances are subject to DEA regulations; the lower the scheduled number, the more restrictive the regulations. For Schedule 1 substances (the most restrictive of all and which currently includes cannabis and its derivatives), the request for approval to use such substances in clinical studies (which has to be made separately to the DEA) can only be initiated once an IND has been approved6. For any medical research to be performed with cannabis, the cannabis product must be provided by a DEA-registered source (such as a sponsor company) or by the National Institute on Drug Abuse (NIDA), which is part of the National Institutes of Health. When provided by NIDA, the cannabis supplied is research-grade. The DEA is responsible for overseeing the cultivation of such cannabis supplied for medical research and has contracted with universities to grow cannabis for research at a secure facility in order to ensure uniformity in potency and compositions. However, some research sites have opined that the NIDA-supplied cannabis can be of varying quality and have been critical of federal control of cannabis for research7. This has resulted in an effort by the DEA to increase the number of bulk growers. Although the exact requirements vary from state to state, there are some generalities that can be noted regarding the conduct of research involving Schedule 1 compounds. First, sponsor companies conducting such research must have DEA approval to import materials into the US (if needed) and/or then across US state lines. All US investigational sites participating in a clinical trial of a Schedule 1 substance are subject to a DEA inspection prior to trial activation, regardless of previous clinical trial experience with Schedule 1 compounds. Any company or

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Regulatory requirements for cannabis-related drug products, including the assignment of the correct drug code prior to importation and distribution, which is dependent upon the source of the cannabis and the exact ratio of THC/CBD.

facility (including any third-party vendor companies) that handle study drug or test Schedule 1 substances also require DEA licensure, and any site researchers conducting trials of Schedule 1 substances have to prepare and submit a research protocol to the DEA that includes details regarding the security provisions for storing and dispensing the substance. Local DEA officials have the jurisdiction to perform a preregistration inspection of the facility where the proposed research will take place. DEA security requirements include storing cannabis in a safe, a steel cabinet, or a vault which cannot be easily removed from the site and which has controlled access (key card or otherwise) to the storage facility. It is very likely and/or expected that the inspections and diligence could also be initiated at the state level in addition to the federal level. Furthermore, a robust supply chain for the investigational product is also subject to international controls. In 2018, the Who Health Organization (WHO) Expert Committee on Drug Dependence (ECDD) recommended that preparations predominantly containing cannabidiol and not more than 0.2% THC not be under international control8. An endorsement by the United Nations is being considered next year and would effectively remove certain restrictions on the control of CBD, perhaps easing the complexity of undertaking clinical research from an international perspective. Operational Considerations In order to conduct an investigational clinical trial of cannabisrelated drug products, careful consideration must be given to the management of the controlled investigational product (IP) as well as to the myriad regulations that as previously noted vary by country and even from state to state within the US. It is important to not only consider that approvals have to be obtained, but that the logistics in running these studies are both cumbersome and convoluted9. For sponsor companies seeking to develop cannabis-related drug products, it is imperative to plan the trial well in advance of study conduct and to allow for extended startup timelines – as much as one full year as operational success requires comprehensive preparation and strategy to manage the strictly controlled processes for shipment, delivery, diversion control, dispensation, and accountability. Pre-planning is particularly essential in order to avoid inevitable delays in startup activities associated with the import of a controlled substance as most (if not all) companies conducting cannabinoid research may choose to incorporate outside of the United States (US) due to the ambiguity surrounding cannabinoids at the federal level. Of note, the US has specific approval, shipment, import and licensing 16 Journal for Clinical Studies

To increase the chances for seamless study conduct of clinical trials in the US involving cannabis and its derivatives, there are a number of recommendations that can be made. First, it is recommended to begin the DEA Schedule 1 application (which is protocol-specific at the site level) as early as possible as it could take at least three months and perhaps as much as twice this long to obtain the necessary approvals. If possible, the use of sites that have experience in this process at their state and local levels may help to expedite this process. As noted above, sites should also fully expect to be inspected at the state level as well following the DEA application but prior to, and as a condition of, DEA approval. Prior inspections for previous Schedule 1 studies may obviate the need for this inspection; however, sites should assume an inspection will take place for each and every protocol. During this inspection, state authorities may examine the site carefully to assess storage conditions, floor plan, presence of crawl space, and that a diversion plan is in place. The IP manufacturer and the distributor (if different) must also have a licence in place at the state level in order to be able to import the IP into the state to which the IP is being shipped. If not already in place, it is recommended that this process begin as early as possible to remove it from the critical path for study start-up procedures. Principal investigators must have DEA authorisation in the state in which they practice, in order to prescribe, dispense, administer, and conduct research with controlled substances with a separate licence requirement for Schedule 1 studies. Importantly, the address to which the drug will be shipped must exactly match that on the investigator’s licence. Some states may also have a separate state-issued controlled-substance licensing requirement for prescribing, dispensing, or administering controlled substances, while other states may have a separate state-controlled substances authority that requires practitioners to obtain a separate registration, in addition to the licence granted by their respective board. Federal registration is also required and the authority for granting federal registrations is vested in the DEA. The DEA registration for practitioners is predicated on licensure or authorisation by the competent state authority. Once approved, a certificate of DEA registration is issued by the DEA in the category of “Practitioner”. Schedule 1 controlled substances require a separate DEA “Researcher” registration. The DEA also performs an investigation/audit of a site prior to granting the DEA “Researcher” registration which is only valid for one year. Finally, although it may not be a specific state or federal requirement, it is strongly recommended that each site implement a study-wide drug diversion plan. The purpose of such a plan is multi-faceted and should outline the minimum requirements at the site level for the storage, security and accountability of study drug; as well as provide guidance as to potential signs of study-drug diversion in both subjects and site staff. This policy should guide the sites as to the appropriate steps to be taken in case of suspected or confirmed study drug diversion, including reporting of the event to the authorities. Similar plans are commonly used in opioid use disorder studies to help prevent diversions of the study drug, and this heightened level of diligence will be helpful and appreciated by auditors and state/federal officials who may inspect the site. The plan should Volume 11 Issue 6

Regulatory outline the measures designed to help manage the potential for diversion by subjects and site staff. Minimally, this is through employment of a meticulous drug accountability regimen at each site. It is only when the study drug is carefully tracked that it can be identified as missing in the first place. All members of the site staff that come in contact with study drug should be required to read and acknowledge the policy by wet-ink signature, with the original signed diversion plan filed in the study trial master file10. Summary It is an interesting yet vexing time to undertake clinical trials designed to determine the efficacy and safety of cannabis-related drug products. There appears to be a confluence of fluctuating state laws regarding the medicinal and recreational use of cannabinoids with evolving federal attitudes towards research seemingly buttressed by heightened public interest and calls for rigorous well controlled clinical studies. Until recently, evidence was mostly based on anecdotal reports, as this research was very difficult if not impossible to conduct, due to the restrictions placed on the use and availability of these compounds for clinical research. Recent developments in state, federal and international guidance, paired with increased numbers of trials with rigorous results, suggests that the current regulatory challenges can now be successfully addressed with careful preparation and planning that will ease the regulatory pathway to approval of this much needed class of compounds.

Act [news release]. Washington, DC; September 27, 2018: DOJ Office of Public Affairs. 4. Scientific Data and Information about Products Containing Cannabis or Cannabis-Derived Compounds; Public Hearing MAY 31, 2019 https://www. 5. Botanical Drug Development: Guidance for Industry December 2016 https:// botanical-drug-development-guidance-industry 6. DEA Drug Scheduling 7. 8. WHO Expert Committee on Drug Dependence medicines/access/controlled-substances/ecdd/ecdd/en/ 9. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. Washington (DC): National Academies Press (US); 2017 Jan 12. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. 15. Challenges and Barriers in Conducting Cannabis Research. NBK425757/ 10. Dussault, B. and Riordan, H. (2015). Methodological Issues in Design and Conduct of Opioid Use Disorders Studies. Journal for Clinical Studies Vol 7 (4) July pp 36-38.


Aman Khera


Aman Khera is Global Head of Regulatory Strategy at Worldwide Clinical Trials. Ms Khera has over 22 years’ industry experience in providing global strategic direction in regulatory affairs. She has led a wide variety of regulatory projects providing regulatory strategy and development services for a variety of client sponsor companies in many therapeutic indications. Ms Khera is well versed in developing comprehensive regulatory strategies. Her career is built on helping client sponsor companies achieve their end-to-end regulatory strategies from study submission to commercialisation.



Agriculture Improvement Act of 2018: Highlights and Implications. https:// Agency is expediting work to evaluate regulatory policies related to cannabis and cannabis-derived ingredients like CBD (FDA; 07/23/19) FDA warns company marketing unapproved cannabidiol products with unsubstantiated claims to treat cancer, Alzheimer’s disease, opioid withdrawal, pain and pet anxiety    FDA-approved drug Epidiolex placed in Schedule V of Controlled Substances


Barry J. Dussault Barry J. Dussault, Jr., MBA is Executive Director, Neuroscience, and Franchise Lead for Pain/Analgesia at Worldwide Clinical Trials. Mr Dussault has worked in all phases of drug development, for both sponsors and CROs over the course of his 20+ year career. In addition to pain and analgesia, he has specialised in trials of addiction and opioid dependency. Email:

Henry J. Riordan Henry J. Riordan, Ph.D. is Executive Vice President of Scientific Solutions at Worldwide Clinical Trials. Dr. Riordan has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years. He has over 100 publications, including coauthoring two books focusing on innovative CNS clinical trials methodology. Email:

Journal for Clinical Studies 17


The MDR: The Clock is Ticking

The European Union (EU) Medical Device Regulation (MDR) is the biggest challenge to the medical device industry in over 20 years. It affects every medical device manufacturer that supplies the EU market. With the new regulations come more stringent requirements, which must be met for the product to obtain a CE mark and be commercially available in the EU. Here Dr. Sergio Perez, MDR expert and freelancer at online platform for research scientists Kolabtree, shares insight into the MDR and what it means for medical device manufacturers. Among the reasons for the new regulation were some highprofile incidents. This included a hip replacement recall in 2010, in which wear of metal-on-metal devices led to particles entering patients’ blood and soft tissue. Another incident, in 2012, involved a French firm, which had been using industrial grade – rather than medical grade – silicone. This resulted in a high number of women suffering from ruptured breast implants, although poor record-keeping meant it was not clear exactly who received such an implant, worsening the situation. In addition, there is a growing number of medical devices available on the market – current estimates are around 500,000 different devices available in Europe. Advances in technology also mean that we now have devices performing more invasive and critical functions. These factors, combined with the incidents, showcased that the Medical Devices Directive (MDD) was no longer fit for purpose and that new regulation was required to keep patients safe. Officially titled Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, the MDR was announced in May 2017. It came with a threeyear transition period and will come into force on May 26, 2020. The MDR applies to all medical devices on the market and even established products that were CE marked under the previous regulation require recertification. The MDR comes with numerous differences from its predecessor, the MDD, such as changes to; device classification rules, traceability, clinical evaluation and post-market surveillance. Time is now running out, as we are drawing closer to when the new regulation is introduced. If a company does not comply with the MDR, the stakes are high – it could lose its right to market the product. As a result, businesses are now familiarising themselves with the regulations, so that they can implement the necessary processes and procedures for compliance. The extent of the MDR means that a structured, well-managed and well-communicated approach is ideal. But, before manufacturers can implement the changes, they must understand exactly what is needed. Changing Classifications One of the first steps for medical device manufacturers is to review their product range to establish what will be needed for each device or product family. Medical devices are classified into four groups: 18 Journal for Clinical Studies

Class I, Class IIa, Class IIb and Class III, according to risk. While the MDR doesn’t change the nomenclature of the categories, it does bring changes on which devices fall into each group. The fact that certain products have been moved into a higher class is likely to cause difficulties, particularly if a product is moved to a higher class. The change of class affects other areas of the regulation and, if the device is moved into a higher class, will come with more stringent requirements. For example, the manufacturer may need to provide additional data on an existing medical device if a device moves from Class IIa to III, where a clinical investigation is needed to justify certain clinical claims. In addition, products that were previously not classified as medical devices under the MDD, are under the MDR. Eye contact lens solution and liposuction equipment, for example, are included and manufacturers of these will therefore need to comply with the regulation. Clinical Evaluation Reports Under both the MDD and the MDR, medical device manufacturers are required to provide a technical file that includes all documentation and information on the product’s function, intended use, history, complaints, clinical evaluation, biological evaluation and traceability, etc. Part of the technical file, the CER, includes all clinical data, so it can be analysed to see if safety and performance requirements are complied with. It should include the clinical evidence to support that the product conforms to the essential requirements in MEDDEV 2.7/1 Rev. 4 Annex 1. Alongside this, it should describe other aspects of the device and instructions on how to use it. However, the contents of the CER will vary, depending on the nature of the device under evaluation and its history. CERs begin during research and development (R&D) and are a mandatory part of CE marking. However, it is an ongoing process that does not stop there, with post-market data forming an essential part. Compiling these reports is a time-consuming process, often taking several months, or more, if additional data needs to be obtained. Besides, CER is not an isolated process, it is closely linked with other areas such as risk management and marketing. Clinical evaluations have four stages. The first is to define the scope, at which point the manufacturer has to specify which products are covered by the CER and how it is intended to be used, and document any claims. The next stage is to identify pertinent data, before appraising each individual data set for validity, relevance and weighting. The penultimate stage is to analyse the data, drawing conclusions on whether essential requirements are met, including those on performance and safety. They should also identify any uncertainties, risks and unanswered questions and whether these Volume 11 Issue 6


will be assessed during post-market surveillance (PMS). Once this is complete, the manufacturer will then finalise the CER.

to be reported but must find ways to seek relevant information themselves.

Changes to Equivalence The general safety and performance requirements in the MDR require the manufacturer to evaluate clinical data either from the medical device under evaluation or an equivalent device.

The PMS must be central to the manufacturer’s quality management system (QMS). For many businesses, the changes to PMS will mean setting up new processes and procedures to collect the data needed on things like vigilance, side-effects and incidents, feedback and complaints, literature and more. They will then have to document their findings and implement necessary changes.

Previously, it was far easier to claim equivalence. But under the MDR, the medical device manufacturer must consider three factors to prove a product is equivalent: biological, technical and clinical. Technical equivalence means it must be used in the same conditions, with the same deployment method and operational principles. It must have similar design, specifications and properties, such as porosity, surface texture and tensile strength. Clinical equivalence means it is used to treat the same condition, for the same purpose, at the same location in the body and for the same group of the population. It will achieve similar performance, too. Biological equivalence covers the use of materials and substances that will be in direct contact with the patient. Biological safety, under ISO 10993, is also important here. If a business is now unable to claim equivalence to another product on the market, depending on the type of claim, they may have to perform further research, such as clinical investigation for clinical claims, an extremely expensive and time-consuming process, or remove the claim from their product. Post-market Surveillance (PMS) The CER is not complete once the product has achieved its CE mark. It is an ongoing, continuous process throughout the duration of the product’s lifecycle, including post-market. The MDR also brings changes to post-market surveillance, in that businesses must now take proactive steps, rather than a passive approach, to gathering information from their post-market devices. Medical device manufacturers therefore cannot sit and wait for a complaint

In some cases, post-market clinical follow-up (PMCF) will be required. This involves ongoing, proactive collection and evaluation of clinical data, to evaluate safety and performance and manage risk. The MDR lays out that every medical device manufacturer must have a person responsible for regulatory compliance (PRRC). The PRRC will take responsibility for meeting PMS and vigilance requirements. Smaller manufacturers are not required to have a full-time, in-house PRRC, but they must be able to access them whenever needed. Traceability While the MDD did not have a specific focus on traceability, the MDR describes a completely new set of requirements. Every device requires a unique device identification (UDI) displayed clearly on the label and/or packaging. The UDI consists of a unique series of characters that can be used to identify a specific device, including who made it, what device it is and a production identifier for the device itself. The data will be stored in the EUDAMED database, the central European database on medical devices, which aims to improve transparency. The UDI must be available in formats that can be both machineand human-read. Many medical device manufacturers will need to purchase scanning technology for their production lines to manage traceability, another investment of time and money. Journal for Clinical Studies 19


The traceability change does not just affect manufacturers, but everyone in their supply chains. Distribution partners must also ensure that they comply with the traceability requirements. Skills and Communication Communication across the entire enterprise will be essential, for example with the marketing team, who will need to be aware of exactly what they can claim about a product. Communication with production, risk management experts and many other areas of the business are also important. As the clock ticks and we approach the May 2020 deadline, businesses are seeking more help with MDR compliance. While

some larger businesses are fully equipped to deal with the extensive changes described above, many are not. Small and medium enterprises in particular are less likely to have the knowledge in house and require help from external experts. Companies that require additional help with developing their strategies or processes can turn to freelance experts, who can share insight based on their experience in other roles. For example, to share an overall idea of the meaning of the regulations and what steps a business will need to take, help you with a CE strategy or with your technical documentation. In addition, experience working with a notified body can be extremely valuable. Accessing freelance skills is straightforward, with the rise of online platforms like Kolabtree. Preparing for the MDR is no small feat. The extensive changes are challenging for all medical device manufacturers operating within the EU market. However, to avoid future incidents like the hip replacement and breast implant scandals, they are an essential step to ensuring patient safety. To be sure they are ready for the changes when they come into full force, companies should assess where they are at currently and what steps they need to take, to plan and implement an overarching strategy.

Dr. Sergio Perez Dr. Sergio Perez is a professional with more than 8 years of experience providing scientific and regulatory support to different key areas within the pharmaceutical and medical device industry. He has been extensively involved in the elaboration of scientific material to be provided to HCP and more recently in the implementation of the MDR requirements and the elaboration of the technical file for class I and class II medical devices.

20 Journal for Clinical Studies

Volume 11 Issue 6

Corporate Profile Ramus Corporate Group

is a union between Ramus Medical and Medical Diagnostic Laboratory Ramus. Ramus Medical is a full service contract research organisation based in Sofia, Bulgaria. Medical Diagnostic Laboratory Ramus is the biggest private laboratory in Bulgaria. Since 2018, the new member in the group has been the Medical Centre Ramus. Since 2010, Ramus Medical has built a strong portfolio as the Ramus team has successfully completed more than 45 clinical trials. These include BE/BA studies and NIS on drugs from the following groups: antibiotics, corticosteroids, non-steroid anti-inflammatories and medical products with different formulations, as well as clinical investigations on medical devices. The medicinal products being investigated by Ramus Medical have MA granted in the EU. , fast, correc t! Safe


to Cito



The Ramus corporate group also includes the Medical Centre Ramus, which includes a Clinical Pharmacology unit for Phase I BA/ BE studies. Ramus Medical have an experienced in-house team with strong project management skills and a keen understanding of regulatory requirements in each jurisdiction, for both study execution and commercialisation.

These can include clinical data capture, data management and statistical analysis, as well as readability user testing, hazardous waste management, and logistics services. Ramus Medical is closely related to the Medical Diagnostic Laboratory Ramus Ltd, founded in 2001. The laboratory is the largest private clinical laboratory in Bulgaria, with 17 laboratories operating in big cities in Bulgaria. The laboratories are fully equipped and work with analysers, consumables and reagents of the highest quality. The lab participates regularly in all national external systems for quality control, as well as in many international ones. Over the years the laboratory has provided services such as safety, and a central laboratory for more than 350 clinical trials for Bulgarian, EU and US sponsors. The Bio-Analytical Department of Laboratory Ramus is the only one in Bulgaria with ISO/IEC 17025:2006 accreditation.   The CRO and laboratories have well-designed quality systems and procedures which are capable of meeting the relevant regulatory requirements. They are certified in compliance with the requirements of the International Standard for Quality Management System. Ramus Medical and Medical Diagnostic Laboratory Ramus are regularly audited by sponsors. Ramus Medical were audited by Navigant Consulting in October 2016, and inspected by the Bulgarian Drug Agency in November 2017.

We carry out clinical projects as a results-oriented team, monitoring the external situation to achieve our mission of complying with the comprehensive global and governmental regulatory processes. Ramus Medical is building partnerships with key opinion leaders, such as principal investigators and dedicated research teams with good reputations. PIs working for Ramus Medical have a valuable role in designing protocols, having a significant positive impact on timely ethical and governance approvals, answering medical questions, interacting with key investors to confirm commitment to the trial, benefiting patient recruitment and providing quality, scientifically meaningful data. The ability to meet recruitment targets is facilitated by having access to the actual patient pool available. As stakeholder in the whole value chain of the drug development process, Ramus Medical contributes to managing time, costs and performance to guarantee the achievement of project objectives within the desired parameters and quality level. Usually Ramus Medical carries out the entire study, utilising years of experience in clinical development and commercialisation – from planning and medical writing to the final report preparation. Depending on the requirements, the sponsor can also make use of individual modules of our services in clinical development, launching a product or managing a portfolio across the development and product life-cycle.

Medical Diagnostic Laboratory Ramus Ltd

26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel/Fax: +359 2 944 82 06 email:

Ramus Medical Ltd

26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel./Fax: +359 2 841 23 69 email:

Dimitar Mihaylov Marketing Director

Journal for Clinical Studies 21

Market Report

Attracting Clinical Research to Malaysia with a Centralised Feasibility Platform A feasibility study is a crucial part of the clinical trial planning process. It enables sponsors and contract research organisations (CROs) to identify relevant clinicians who may be interested in a particular study.1-4 It also provides information on a site’s infrastructure, human resources and pool of eligible patients.1-4 Such information would help these companies strategise to meet timeliness, sample size requirements and regulatory and ethical conditions, as well as plan for potential challenges. As clinical research involves multiple stakeholders, the presence of a single point of contact can improve communication, simplify processes, and reduce delays.5,6 This centralised approach is particularly useful for feasibility and site selection processes.6 In Malaysia, Clinical Research Malaysia (CRM), a not-for-profit government-owned organisation established in 2012 to nurture an ecosystem that supports industry-sponsored research in the country, offers sponsors and CROs a one-stop contact point for feasibility requests, access to the public hospital network of investigators, and other services. This review will present the role of CRM’s centralised feasibility service in attracting sponsors and CROs to Malaysia. The Importance of Rigorous Feasibility Studies Pre-feasibility is information that is collected for preliminary, higher-level assessments which allows sponsors and CROs to make decisions at a national and global level. Such enquiries include general questions on standard of care, drug registration status, epidemiology, and estimated patient pool of a particular therapeutic indication. A full feasibility study is a complete documentation of individual sites which may include a confidential disclosure agreement, protocol synopsis and site assessment questionnaire. About 35% of delays in clinical trials are attributed to patient recruitment, with one in five investigators unable to recruit a single patient.4 As non-active or under-performing trial sites can increase the cost of conducting a clinical trial by 20% or more,7 rigorous feasibility studies conducted in multiple centres are recommended.8 But conducting thorough feasibility assessments and selecting appropriate sites may be time-consuming, and delay in these preliminary processes will jeopardise study milestones.7 Therefore, if feasibility processes in individual countries can be centralised with a single point of contact for sponsors and CROs, delays and redundancies may be avoided.5,6 Leveraging the Strength of Nationwide Access to Public Hospitals One of the challenges in conducting feasibility studies is maintaining an updated database of principal investigators. The 22 Journal for Clinical Studies

bulk of studies in Malaysia are conducted in government hospitals where doctors are transferred periodically. Therefore, data built on individual company databases can be outdated, thus misguiding and delaying feasibility approaches. In Malaysia, CRM is the common link for various stakeholders which include sponsors, CROs, private and public doctors from universities, health clinics and hospitals, as well as the regulatory agencies and ethics committees. It is a centralised governmentowned body that manages and overlooks Malaysia’s entire clinical research ecosystem.9 The detailed objectives of CRM are discussed in a prior article.10 As a single point of contact for sponsors and CROs and with presence in 33 clinical research centres within public hospitals throughout the country, CRM is vital in streamlining and accelerating feasibility studies in Malaysia. Evolving to Offer Complimentary, Centralised Feasibility Management As CRM receives a variety of enquiries (Table 1) including prefeasibility and full feasibility requests across all clinical therapeutic areas from both sponsors (pharma, medical device, biotech) and CROs worldwide, the Ministry of Health, Malaysia through CRM, established a centralised feasibility service. This service, which is offered complimentary to sponsors and CROs, capitalises on a comprehensive updated internal database of investigators, and enables outreach to a wider range of investigators and sites. Previously, the sponsors and CROs conducted their own feasibility assessments and contacted individual sites on their own.11 Separate databases, based on a company’s own experience, may not always be updated, and information such as transfer of clinician, changes in site personnel, and regulatory changes may be missed.11 A centralised process leads to centralised knowledge of the research environment which benefits CROs and sponsors engaging the service. A central database which incorporates data on a site’s performance and experience in recruitment and compliance provides more insight into how the site may perform in future trials.1,7 And as a single point of contact, the standardised processes lead to streamlined communications which reduces delay and confusion on the ground. As a result, the turnaround time is shorter than if a sponsor or CRO were to approach individually. As CRM has a strong network and good rapport with investigators, and is familiar with ground-level capacities of sites, poor site selection is less likely. Sites are mapped according to disease to enable the right sites to be approached for a specific patient pool in future. The sites are also mapped to track Volume 11 Issue 6

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Journal for Clinical Studies 23

Market Report investigators who were overwhelmed, conducting competing trials, or transferred to ensure that only available investigators are contacted for upcoming trials. Such data would help narrow down the investigators who will give positive responses, thus reducing the time needed for feasibility studies. When the feasibility team at CRM receives a feasibility questionnaire, a thorough analysis based on CRM’s central intelligence database is done (Figure 1). The questionnaire is then forwarded to relevant investigators. The process from the time CRM is approached to conduct a full feasibility assessment to the time CRM sends the completed questionnaire back to the company would take 5–10 working days. Pre-feasibility enquiries would take between one and five days, depending on the complexity of the questions.

companies. The one-stop national feasibility model improves efficiency and timelines, as well as reducing the financial, administrative, and human resource burden of sponsors, CROs and investigators. Sponsors and CROs are becoming more interested in Malaysia after the introduction of centralised feasibility, with full feasibility requests received by CRM increasing between 2015 and 2018 (Figure 2). There was also a five-fold increase in sponsors and an almost three-fold increase in CROs using CRM’s services in 2018 compared to 2014 (Figure 3). The majority of these companies are international companies (85%).5,11 Rise in the use of Clinical Research Malaysia’s services, particularly for clinical trial feasibility assessments

Optimising Feasibility in Clinical Trials with Clinical Research Malaysia’s Centralised Process

Figure 2. The increase in full feasibility requests received by Clinical Research Malaysia from sponsors/CROs

Figure 3. Growth in the number of CROs/sponsors using Clinical Research Malaysia feasibility services

In addition, feasibility assessments are complimentary, thus contributing to the overall cost-effectiveness of conducting a trial in Malaysia.

Figure 1. Clinical Research Malaysia Clinical Trial Full Feasibility Process

In addition, the feasibility specialists help interested potential investigators to address the queries and submit the completed feasibility questionnaire to the enquiring company. They provide technical consultation and organise meetings between investigators and CROs. Information is also compiled when investigators reject feasibility requests to understand their reasons for doing so. Centralised Service; a Key Attraction for Sponsors and CROs A centralised feasibility management service is a key attraction for sponsors and CROs,5 as the information from feasibility studies determines the suitability of Malaysia for a particular trial and promotes the capability of the sites to new international 24 Journal for Clinical Studies

Conclusion Clinical Research Malaysia’s model as a one-stop national centre is a primary factor for the expansion in Malaysia’s clinical research industry in the last few years. The growth in sponsors and CROs is made possible through a centralised feasibility team coordinating and overseeing communications with sites. Thus, on a nationwide perspective, a centrally managed feasibility structure is an attractive alternative for sponsors and CROs looking to enhance the efficiency and width of a feasibility outreach, avoid redundant processes and promote a more accurate assessment of Malaysia’s capabilities. REFERENCES 1. 2.

Johnson, O. An Evidence-Based Approach to Conducting Clinical Trial Feasibility Assessments. Clin. Invest. (Lond.). 5(5), 491–499 (2015). Orsmond, G.I. & Cohn, E.S. The Distinctive Features of a Feasibility Study: Objectives and Guiding Questions. OTJR. (Thorofare N J). 35(3), 169–77 Volume 11 Issue 6

Market Report 3.

4. 5.




9. 10.


(2015). Arain, M., Campbell, M.J., Cooper, C.L. & Lancaster, G.A. What is a Pilot or Feasibility Study? A Review of Current Practice and Editorial Policy. BMC. Med. Res. Methodol. 10, 67 (2010). Rajadhyaksha, V. Conducting Feasibilities in Clinical Trials: An Investment to Ensure a Good Study. Perspect. Clin. Res. 1(3), 106-9 (2010). Khairul, F.K., Ooi, A.J.A. & Tay, W.C. How a Centralized Feasibility Service Attracts Sponsors and Contract Research Organizations to Malaysia. Poster presented at the 53rd Drug Information Association Annual Meeting, Chicago US: Jun 18–22, 2017. Arenz, D., Siepmann, T. & Cornely, O.A. Centralized Management of Clinical Trial Feasibility Requests: A Single Center Database Analysis from 2008 to 2015. Clin. Invest. (Lond.). 6(1), 867–874 (2016). Temkar, P. Accelerating Study Start-Up: The Key to Avoiding Trial Delays. Clinical Researcher, 1 February 2017. Available at https://acrpnet. org/2017/02/01/accelerating-study-start-up-the-key-to-avoiding-trialdelays/, visited on 5 July 2019. Turner, C.L., Kolias, A.G. & Hutchinson, P.J. Feasibility Studies, Clinical Trials and Multicentre Collaboration. Acta Neurochir. (Wien). 159(1), 11–12 (2017). Society of Clinical Research Professionals Malaysia. A Guide to Conducting Clinical Trials in Malaysia (1st edition) 2016. Ooi, A.J.A & Khalid, K.F. Malaysia’s Clinical Research Ecosystem. Appl. Clin. Trials. 26(4), (2017). Available at http://www., visited on 5 July 2019. Ooi, A.J.A & Khairul, F.K. A Unique Model to Accelerate IndustrySponsored Research in Malaysia. Journal for Clinical Studies. 11(1), 24–27 (2019).

Noorzaihan Mat Radi Noorzaihan, M.D., obtained her medical degree from Universiti Kebangsaan Malaysia (UKM) in 2014. She currently works at Clinical Research Malaysia as a Senior Feasibility Specialist. She has been involved in the clinical research industry for more than 3 years. Her specialty is in feasibility study where she has been liaising with doctors and pharmaceutical companies and Clinical Research Organizations.

Dr. Bee Ying Tan Bee Ying Tan obtained her Ph.D. from the School of Pharmaceutical Sciences, Universiti Sains Malaysia. Her research interests are in pharmacoeconomics and outcomes research, which includes evaluations of clinical safety and efficacy, comparative effectiveness, epidemiology, health services research and clinical research. She has published more than 10 peer-reviewed articles and abstracts. She is also a reviewer for an international peer-reviewed journal. She is currently a feasibility specialist at Clinical Research Malaysia.

Audrey Ooi Audrey Ooi is currently the Acting Head of Business Development at Clinical Research Malaysia. She graduated from Monash University with a Bachelor of Medical Science and went on to obtain a Masters Degree in Medical Science from the University of Malaya. She has extensive experience in various fields within the healthcare and clinical research industry including medical writing, corporate communication, project management and stakeholder engagement.

Journal for Clinical Studies 25

Market Report

Subgroups, Study Design, and the Impact of the Biosimilar Extension Rule In advance of a prospective pivotal biosimilar safety and efficacy trial, researchers reviewing the data from the Phase III clinical trial of the reference molecule noted that approximately 20% of participants showed only a partial response to the molecule. Further analysis suggested that these partial responders might constitute a clinically plausible and distinct subgroup. The subgroup had a higher body weight, suggesting that levels of exposure might be less than optimal. They all experienced a longer duration of the condition that the reference molecule was intended to address, suggesting more disease severity and perhaps comorbidities that might limit treatment response. All participants within the subgroup had previously demonstrated an inadequate response to at least one other biological, lending credence to this assumption. Finally, they all had a history of a specific and common comorbidity, which plausibly could be associated with partial response. Presumptively, this subgroup would degrade detection of efficacy in a planned equivalence study of the reference molecule against a biosimilar if included in the randomisation process.

Further review indicated that the proposed subgroup’s response to the reference molecule was quantitatively, not qualitatively, different from the overall result of the randomised population. Specifically, the presumptive subgroup did respond in a manner consistent with all other participants in the trial; they simply responded to a significantly lesser degree. While a quantitatively, rather than qualitatively, different response could favour the legitimacy of the subgroup by conventional guidance, other factors undermined such an identification. As noted, subgroup identification occurred post hoc, so there was no randomisation within the subgroup of both observed and unobserved variables that might be prognostically important. Moreover, while the neutralising antibody data suggested the possibility of a biological basis for the subgroup, no biological basis for the distinctive response patterns had been identified a priori based on non-clinical data, i.e., it was not identified as a concept at the time of study design. Further, a review of extant literature for both the reference molecule and other compounds used in this indication identified no other clinical study with a subgroup of non-responding or partially responding subjects exhibiting these same clinical characteristics. The absence of both an a priori hypothesis, as well as the absence of a comparable subgroup in existing clinical literature, attenuated enthusiasm for the exclusion of subjects in a pivotal study.

Based upon these data, the potential for excluding subjects or otherwise adjusting and accounting for presumptively prognostically important variables was considered. These considerations highlighted two important questions regarding the optimal design of a pivotal Phase III study: First, did the hypothesised subgroup constitute a properly defined subgroup based upon established clinical and biostatistical conventions? Identification of this subgroup occurred after the analysis rather than as a part of the randomisation schema as an example of limitations. Second, would excluding potential participants who fit into this subgroup limit the indications for which the molecule ultimately would be approved?

Finally, a further analysis of the data established that two-thirds of individuals in the proposed subgroup ultimately did respond positively to the reference molecule when the dosage was increased. In fact, when given a higher dosage of the reference molecule, the majority of subjects in the proposed subgroup ceased to be partial responders by protocol-mandated criteria. The underlying characteristics shared by the partial responders – the higher body weight, the demonstrated inadequate response to at least one other biological, and so on – persisted, but increasing the dosage of the reference molecule created the response profile comparable to the overall sample from which the subgroup had been extracted.

Proper and Improper Subgroups: Revisiting Oxman and Guyatt While methods of evaluating the propriety of a given subgroup were promulgated by Oxman and Guyatt as early as 1992, questions about these methods continue to provide rich fodder for discussion within the analysis and interpretation of randomised clinical trials.1-2 As an approach to the systematic evaluation of the subgroup, at the level that would inform a subsequent change in a prospective clinical trial, the hypothesised subgroup was examined against the existing literature regarding subgroup identification and interpretation. Then, the subgroup was considered in light of general rules for subgroup creation, analysis, and accommodation within the design of a Phase III trial.

In, Out, or Accommodate? Analysis of the existing data concluded that the characteristics initially attributed to the identified subgroup were insufficiently robust to warrant exclusion from participation in a Phase III trial. Indeed, including individuals with these characteristics in a Phase III trial would be beneficial from several perspectives. Including members of this subgroup would facilitate patient identification and accrual. Moreover, the greater the diversity of the participant pool – within the broad parameters of the trial – the more fully researchers would be able to understand the efficacy of a molecule mapped against variations in clinical phenotype. Greater diversity in disease presentation would permit an exploration of the molecule’s impact on disease characteristics, including comorbidities, and on eventual patient outcomes. Researchers might still need to design the trial with risk stratification in mind, but risk stratification is an accepted convention for evaluating treatment outcome in patient subsets when uncertainty in the response profile has been suggested.

The initial review raised concerns about the predictors identified as defining the proposed subgroup. The biostatistical model, as such, was not present in its entirety for the evaluation, and evidence of potential multicollinearity (i.e., two or more variables explaining the same variance in outcome) could be inferred at least on a clinical level. Furthermore, antibodies that effectively neutralised the reference molecule were found in 12.7% of those demonstrating partial response – compared to 2% of the broader group – which bolstered the possibility of a biological basis for subgroup identification. 26 Journal for Clinical Studies

A Counterintuitive Solution While all these considerations argued for inclusion of this hypothesised subgroup, the final recommendation counterintuitively Volume 11 Issue 6

Market Report When an approach to the prospective development of safety and efficacy evidence exists that is both sanctioned by regulators and could maximise trial sensitivity by excluding a subgroup of patients who might, in theory, demonstrate partial response, then the shortest distance between development and market authorisation recommends that exclusion. REFERENCES 1.

recommended excluding these subjects. Why? Because the Phase III trial being designed would be a potentially pivotal study comparing the reference molecule to a potential biosimilar. Two concepts in biosimilar development must be taken into account when considering the inclusion or exclusion of a hypothesised subgroup: The first is the principle of extrapolation; the second is the involvement of a sensitive patient population. Extrapolation is a scientific and regulatory principle that refers to the approval of a biosimilar for use in an indication held by the reference product but not directly studied in a comparative clinical trial with a biosimilar. Extrapolation of efficacy and safety data from one indication to another may be considered if biosimilarity to the reference product has been shown by a comprehensive comparability programme including safety, efficacy, and immunogenicity and there is sufficient scientific justification for extrapolation. A sensitive patient population is one that represents an appropriate disease model for confirming biosimilarity in a comparative clinical trial between the potential biosimilar and the reference product. Because these concepts have been embraced by the regulatory agencies that would be reviewing the trial data, there was no need to determine whether – or how – to accommodate a hypothesised subgroup of partial responders in the design of this pivotal study.3-4 If the biosimilar demonstrates outcomes consistent with the existing reference biological under prespecified criteria, the sponsor can then seek approval for the biosimilar to be used among subgroups for which the reference molecule is already approved. The Shortest Distance Between Two Points is a Straight Line Ultimately, when it comes to weighing the impact on trial design and operations of a preidentified and plausible (but unconfirmed) subgroup of patients, there are many factors to consider. Does the subgroup constitute a valid subgroup based upon a spectrum of wellestablished criteria? It is important to dig into the data to discover the answer to that foundational question because the answer will drive subsequent considerations. If the subgroup does constitute a potentially valid subgroup based upon biological, clinical, and biostatistical constructs, how will clinical trial methodologists accommodate it in the Phase III trial design? Even more importantly, must they accommodate the subgroup into the trial design given the overall intended objective? Depending on the kind of molecule of being tested, it may be more – or less – important to address questions of generalisability and subgroup accommodation. It is crucial for trial designers to evaluate the propriety of preexisting data, including potential subgroups identified or hypothesised to exist, when considering the design of a proposed registration study. At its foundation, these analyses represent an adjudication process that balances multiple, occasionally conflicting, demands for study sensitivity, clinical meaningfulness, and eventual commercial utilisation. Also crucial is the ability to execute the programme with efficiency, thus reducing overall timelines and expenditures.

Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med. 1992;116:78–84. doi: 2. Oxman AD, Guyatt G, Green L. When to believe a subgroup analysis. Users' Guide to the Medical Literature. A Manual for Evidence-Based Clinical Practice, 2002:553-65. 3. U.S. Department of Health and Human Services/Food and Drug Administration (2015). Scientific considerations in demonstrating biosimilarity to a reference product: Guidance for industry. Retrieved from 4. European Medicines Agency. Committee for Medicinal Products for Human Use (2015). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues. Retrieved from https://www.ema.europa. eu/en/documents/scientific-guideline/guideline-similar-biologicalmedicinal-products-containing-biotechnology-derived-proteinsactive_en-2.pdf.

Michael Murphy Michael Murphy, M.D., Ph.D is a Chief Medical and Scientific Officer at Worldwide Clinical Trials. He emphasises translational research and strategic consultation regarding methodologies for interventional and observational research. He is boarded in adult psychiatry, with a pharmacology doctorate. He trained at Tulane University, Stanford University, and Mt. Sinai School of Medicine. Email:

Hazel Gorham Hazel Gorham, BSc, Ph.D., is Senior Director. Project Management at Worldwide Clinical Trials. Dr. Gorham has over 20 years of clinical research experience in the pharmaceutical and CRO industries across a wide range of roles, including CRA, project management, and developing and implementing clinical development strategies for biosimilars and complex generics. Email:

Aleksandra Bibic Aleksandra Bibic, M.D., is Medical Director of Medical Affairs at Worldwide Clinical Trials. Dr. Bibic has experience supporting research efforts surrounding Alzheimer’s disease, angina, CKD, Gaucher's disease, diabetes type 1, haematological cancer, hearing loss, leukaemia, lupus, MS, osteoarthritis pain, pemphigoid, psoriasis, and acromegaly. She also has experience working with biosimilars. Email:

Journal for Clinical Studies 27


The Need to Finally Get it Right with Universal Influenza Vaccines January 2018 marked the centennial of the 1918 influenza worldwide pandemic. It served as a stark reminder that the need for a universal influenza vaccine is paramount. More than 100 years after the deadliest influenza outbreak in modern history – one that killed one-fifth of the world’s human population – there is still no vaccine available to protect people from most or all strains of influenza each influenza season. Since 1918, there have been three other pandemics – in 1957, 1968, and as recently as 2009 – with minor epidemics every other influenza season. The Centers for Disease Control and Prevention (CDC) estimates that during the last influenza season (2018–2019), 36,400–61,200 people in the United States (US) alone died from influenza.1 Globally, influenza accounts for an estimated 291,000–646,000 deaths per season. The vaccines are seasonal, so their contents and effectiveness change annually for each hemisphere. In the past 10 years, influenza vaccine effectiveness (VE) has fluctuated in the range 19–60% in the US, with the 2014–2015 season demonstrating the lowest VE due to a change in the circulating A/H3N2 influenza viruses between strain selection and vaccine administration, according to the CDC.2 The World Health Organization (WHO) recognises that most routine childhood vaccines for other diseases are effective for 85–95% of recipients.3 This poses the question: Why is there no influenza vaccine as effective as those vaccinations for a virus that has been around for hundreds or, presumably, thousands of years? The answer is complicated but simple at the same time: Influenza viruses evolve – and fast. Understanding influenza Influenza viruses present in three types in humans: A, B, and C. Humans and animals can be infected with influenza A, while only humans can be infected with influenza B and C. The C type is rare, presenting more mild disease symptoms, and not included in current seasonal vaccines. Influenza B is responsible for about 20% of influenza cases, usually occurring in local outbreaks, and it has generally stable proteins. Influenza A is the virus type responsible for most influenza infections and the root of most epidemics and pandemics, such as the four pandemics in modern history. Influenza A virus surface proteins frequently change, so the human body considers them foreign antigens. Minor changes to these proteins are called “antigenic drifts”, and major changes are deemed “antigenic shifts”. The more changes in surface protein, the less the body’s immune system can protect against them, thus rendering the current vaccine options less effective for influenza A types not included in the vaccines. Influenza includes two surface glycoproteins – haemagglutinin, which helps the virus enter host cells, and neuramidase (N), which helps the virus spread among cells. Haemagglutinin structure is 28 Journal for Clinical Studies

3-dimensional illustration highlighting features exhibited by an influenza virus: surface proteins, hemagglutinin, and neuraminidase, Photo courtesy of CDC/Douglas Jordan, Dr. Ruben Donis, Dr. James Stevens Dr. Jerry Tokars, Influenza Division

composed of a “head” and a “stalk”. Influenza vaccines usually generate antibodies against the head due to their variability. Since the stalk is more preserved, research is largely focused on developing a universal vaccine that targets the stalk rather than haemagglutinin. Influenza A viruses are divided into subtypes based on which of the two proteins is present on the surface of the virus (H = 18, N = 11). Even further, the viruses are broken down into two subtype strains, H1N1 and H3N2, that are currently found in humans and are included in seasonal influenza vaccines. Influenza B viruses do not have subtypes but are categorised based on lineage and strain. Two lineages – B/Yamagata and B/Victoria — are present in currently circulating influenza B viruses. The viruses are also categorised by host of origin, geographical origin, strain number, and year of isolation. Seasonal Influenza Strain Selection and Vaccine Development The WHO assembles technical consultations twice a year to recommend the viruses for inclusion in seasonal influenza vaccines. In February, the consultation considers which strains to include in the northern hemisphere influenza season; in September, it considers strains for the southern hemisphere vaccine. Once the consultations are complete, the WHO announces its recommendation for which viruses to include in the vaccines. The influenza vaccine for each season usually contains different viruses, but often circulating strains in one hemisphere could influence the selection in another hemisphere. The WHO recommendations are then used by national public health and regulatory authorities and vaccine manufacturers Volume 11 Issue 6

Therapeutics responsible for developing and producing influenza vaccines to determine which strains to include and begin production. This process must occur annually for each hemisphere as circulating influenza viruses continually evolve. Even with this system in place, the WHO faces obstacles when selecting strains, and the US Food and Drug Administration (FDA) relies on the WHO’s decision for recommending US vaccine components. For example, in March 2019, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened to recommend strains for inclusion in the 2019-2020 trivalent and quadrivalent vaccines for the influenza season in the northern hemisphere. The committee supported the WHO’s recommendations; however, at the time of the meeting, the WHO had not yet determined which A(H3N2) strain should be recommended for inclusion in the vaccine. Multiple co-circulating influenza A(H3N2) virus groups and one antigenically distinct group of A(H3N2) had increased in proportion to other influenza A viruses in recent months before the meeting, causing uncertainty about the match. The VRBPAC delayed its decision for the A(H3N2) strain until later in the month when the WHO announced its selection; the panel ultimately agreed with all of the WHO’s recommendations. In September 2019, the WHO made recommendations for which strains to include in the influenza vaccine for the 2020 southern hemisphere influenza season. The selection included a change in two of the four strains from the March 2019 northern hemisphere selection, signalling a potential mismatch in the vaccine virus components for the 2019–2020 northern hemisphere vaccine. The southern hemisphere selections are largely made based on current circulating strains, so if different viruses are circulating, the vaccine viruses could be outdated. Unfortunately, manufacturers and approval bodies need six to eight months to make these vaccines publicly available. This significant delay is an opportunity for influenza viruses to evolve and circulate in unpredictable patterns, thus causing a mismatch in the circulating strain and the vaccine components. This game of catch-

Photo by whitesession

up has led to worldwide uncertainty about influenza vaccines and, in some cases, vaccine hesitancy, which leads to fewer individuals receiving the vaccines. Fewer vaccines in circulation often leads to lower VE. The only solution to break this cycle is a vaccine that targets all influenza viruses. Global Clinical Studies for a Universal Influenza Vaccine Pharmaceutical companies and researchers worldwide have been studying the safety and efficacy of potential universal flu vaccines for decades, attempting development using various methods. The universal influenza vaccine that has reached the furthest stage in development so far is M-001 from BiondVax Pharmaceuticals Ltd. M-001 is designed to provide protection against all human influenza virus strains – seasonal and pandemic. This vaccine contains no influenza viruses; it is a peptide vaccine that contains nine viral epitopes that are common to the 4000 influenza viruses in the National Institutes of Health (NIH) database. M-001 proved to be safe and immunogenic to a wide range of strains in six earlier clinical trials.4 The vaccine is currently under evaluation in two later-stage clinical trials: 1. A pivotal randomised, modified double-blind, placebocontrolled Phase III trial in about 12,000 participants in Europe to determine safety and efficacy of M-001 administered twice in older adults and the elderly (≥50 years) in two cohorts: the first for two influenza seasons and the second for o ne; and 2. A double-blind, randomised, placebo-controlled phase II trial in 120 participants, sponsored by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), to assess the safety, reactogenicity, and immunogenicity of two doses of M-001 followed by seasonal quadrivalent influenza vaccine. Results for the NIAID-sponsored trial are expected at the end of 2019, and BiondVax Pharmaceuticals expects results for the pivotal trial by the end of 2020 after enrolling the rest of the participants for the 2019–2020 influenza season.

Negative-stained transmission electron microscopic image showing recreated 1918 Influenza virions that were collected from supernatants of 1918-infected Madin-Darby Canine Kidney (MDCK) cell cultures, Photo courtesy of CDC/Dr. Terrence Tumpey

Following M-001 are many other potential universal influenza vaccines in Phase I and II development. GlaxoSmithKline plc (GSK) was in Phase I development with its investigational supraseasonal universal influenza vaccines (SUIVs; GSK3816302A), unadjuvanted or adjuvanted, in healthy adults in a randomised, parallel-assignment study. After Phase I results showed that while the vaccine provided cross-protection, multiple-dose boosting effect was not as strong as expected and it would likely not offer Journal for Clinical Studies 29

Therapeutics longer-term protection.5 GSK is now focusing on a collaborative effort with PATH to study the safety and immunogenicity of a liveattenuated universal flu vaccine (cH8/1N1 LAIV) followed by an inactivated universal flu vaccine (cH5/1N1 IIV) in a randomised, parallel-assignment, observer-blind Phase I trial in healthy adults aged 18–39 years. FluGen, Inc, is studying an influenza vaccine (H3N2 RedeeFlu; M2SR) for protection against influenza A disease for all A subtypes. The sponsor reported positive results from a double-blind, placebocontrolled, human challenge Phase II trial, sponsored by the US Department of Defense, in which the vaccine demonstrated protection against a highly mismatched influenza virus. This could address the issue of “seasonal drift” as it stimulates antibody and T-cell responses. NIAID is supporting development of this vaccine as well, according to FluGen. US Efforts to Develop a Vaccine NIAID mentions four approaches currently in development for a universal influenza vaccine:6 1. A vaccine that would produce antibodies targeting the haemagglutinin protein stem; 2. Four subtypes of haemagglutinin would be incorporated into one vaccine made from noninfectious virus-like particles that promote an immune response but cannot replicate or cause disease; 3. An investigational DNA-based vaccine (a DNA “prime”) followed by a licensed seasonal influenza vaccine (“boost”) that could improve potency and durability of seasonal vaccines; and

4. A vaccine that contains antigenic peptide sequences to share among many different influenza strains. In August 2018, NIAID announced its strategic plan for development of the universal vaccine.7 As part of its goal, the institute published the key criteria it expects from a universal flu vaccine. It should: • Be ≥75% effective; • Provide protection against group 1 and 2 influenza A and B viruses; • Provide durable protection for at least one year; and • Be suitable for all age groups to receive. Then in September 2019, NIAID announced the creation of the Collaborative Influenza Vaccine Innovation Centers (CIVICs) programme.8 The programme is designed to connect research centres in the effort to create a broadly protective influenza vaccine. NIAID is providing up to $51 million for first-year funding to support the programme over seven years. NIAID has awarded these centres to the Icahn School of Medicine at Mount Sinai, Duke University, and the University of Georgia (UGA). These centres will collaborate with other universities and research institutes to address this need. UGA’s programme is also focusing on vaccine research for high-risk populations. Since April 2019, NIAID has been recruiting patients for an openlabel Phase I study to evaluate the dose, safety, tolerability, and immunogenicity of an influenza H1 stabilised stem ferritin vaccine, H1ssF_3928 (VRCFLUNPF099-00 VP), in healthy adults. The vaccine is designed to focus the body’s immune system on a portion of the

Results from a hemagglutinin inhibition (HI) test, Photo courtesy of CDC/Robert Denty 30 Journal for Clinical Studies

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Therapeutics exposure to those seasonal viruses to determine whether the vaccine is efficacious. The use of human challenge trials, in which healthy participants are intentionally exposed to a specific influenza strain after vaccination, is one approach to address this issue. These trials are not considered natural exposures, however, and they could potentially mask the process of a natural infection, some experts have suggested. In addition to the complexity and cost of clinical trials in the US, manufacturing is a major challenge. Adherence to current good manufacturing practice (CGMP) regulations is essential for products seeking FDA approval. To meet these standards, sponsors need time and funding to support CGMP evaluations. Large private companies are more likely to have these resources, while public and smaller private bodies could face significant delays. This is where NIAID’s support and funding has changed the landscape for universal influenza vaccine development.

3D graphical representation of a generic influenza virion’s ultrastructure, Photo courtesy of CDC/Douglas Jordan

virus that is minimally variant between strains, thereby teaching the body to produce protective immune responses against multiple subtypes. The study will consist of five experimental arms: two arms will evaluate two separate doses (20 mcg and 60 mcg intramuscular [IM] H1ssF 3928) in patients aged 18–40, and three will evaluate one dose (60 mcg IM H1ssF 3928) in three different age groups of adults aged ≥41 years. In the US, the FDA requires real-world clinical trials involving thousands of participants, which are expensive and difficult to execute. When the seasonal nature of the virus is factored in, this complicates the process even further if researchers are relying on

With government agencies, non-governmental organisations, and private organisations committing to universal influenza vaccine development, novel approaches and human clinical trials showing effectiveness in large populations must be on the horizon. The threat of another influenza epidemic is the undercurrent to worldwide research to ensure 1918 is not repeated. REFERENCES 1.

2018-2019 U.S. Flu Season: Preliminary Burden Estimates. Centers for Disease Control and Prevention Web Site. burden/preliminary-in-season-estimates.htm 2. Seasonal Flu Vaccine Effectiveness. Centers for Disease Control and Prevention Web Site. htm#figure 3. Six Common Misconceptions About Immunization. World Health Organization Web Site. detection/immunization_misconceptions/en/index2.html 4. BiondVax Announces Rights Offering in Support of Ongoing Pivotal, Clinical Efficacy Phase 3 Trial of the M-001 Universal Flu Vaccine and Scale Up of Manufacturing Process. (2019). BiondVax Pharmaceuticals Ltd Web Site. 5. Our Pipeline. GlaxoSmithKline plc Web Site. research-and-development/our-pipeline/#pipeline-changes 6. Universal Influenza Vaccine Research. National Institute of Allergy and Infectious Diseases Web Site. 7. Erbelding EJ, Post DJ, Stemmy EJ, et al. A universal influenza vaccine: The strategic plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis. 2018;218(3):347–354. 8. NIH Forms New Collaborative Influenza Vaccine Research Network. (2019). National Institutes of Health Web Site.

Jaime Polychrones Jaime Polychrones is a medical & regulatory writer for the Cortellis suite of life science intelligence solutions at Clarivate Analytics. Her previous roles include writing and editing for books, online magazines, educational coursework, and government regulatory publications. Her primary assignments at Clarivate include reporting on FDA drug/device advisory committee meetings and drug approvals. Email: Photo courtesy of CDC/Donnald A. Berreth

Journal for Clinical Studies 31


Functional Service Provision and Full Service Outsourcing Models Have Key Roles to Play in Outsourced Drug Development as Clinical Trials Evolve The relative merits of the functional service provision (FSP) and full service (FS) outsourcing models have been debated repeatedly over at least the last ten years. There is a place for both in the outsourced market although, over time, there have been shifts between them in terms of market share. Recent developments have seen hybrid models come into the market as service providers seek to both align their products with customer wishes and also gain competitive advantage. The pros and cons of each model are well known. Proponents of the FS approach point to the convenience of the ‘one-stop-shop’, simplified contractual arrangement, the integrated team, and the potential for cost savings both in efficiency gains and through increased bargaining power, particularly if a sponsor awards several programmes of studies to a single provider. Supporters of FSP will point to access to specialist providers, similar cost savings from efficiencies, flexibility in terms of team size, and the plug-and-play nature of functional contracts. The downsides of each tend to be the flipsides of the list of the advantages above: for ‘one-stop-shop’ read generalist vs specialist support; for specialist providers, read the need for staff to complete repetitive tasking. The arguments for and against each model are well worn. To a certain extent, the models shape the fabric of companies offering them. Specialist companies attract talented technicians because of their reputation within their field and their investment focus. Recruitment teams can identify strong candidates more readily because they become expert in the specialism. They have extensive networks, often stemming from the company’s management team. That same management team typically features technical experts with deep expertise. It is not hard to see why such businesses become function-centric and why sponsors consider FSP not only when looking for volume provision, but also when they are grappling with a difficult problem. FS companies offer a different proposition for candidates. These companies are typically larger than their FSP counterparts – the largest CROs are all FS. For some, working in a big company is very attractive. Once established within a large company, a candidate can seek out more varied opportunities – perhaps having a career change within the same employer. Staff in FS companies can see more of the clinical trials process going on around them – they may feel more part of the overall team. The larger CROs deliver more of the ‘mega’ trials and these can drive excitement within the working environment. For specific roles, such as project management, the remit is wider than typically seen in the specialist setting. Sponsors may be drawn to large FS CROs when outsourcing large programmes of work or individually big studies. Making the Choice – FSP, FS, (or Hybrid)? Sponsor companies have seen successes with both approaches and neither shows any sign of disappearing. However, if you are new to outsourcing, or are coming across your first big program of work, what are the considerations that shape your decision between the two, and is hybrid the compromise that will deliver the optimum outsourcing strategy? 32 Journal for Clinical Studies

Moreover, it is when examining the detail that the focus on the pros and cons of a methodology is strongest. Where the work product involves a high volume of functional expertise, FSP can deliver efficiencies which translate to significant cost savings. Where a study might be difficult to recruit for, a FS provider with their established strong site network can help reduce the risk of missing a deadline. And it is perhaps the complexities of clinical studies that have led to some FS providers offering a hybrid approach. Sponsors want to have access to both options. Any outsourcing strategy must work for both sponsor and service provider. Where outsourcing involves FS or FSP services, it is normal for the sponsor to work through a procurement group. Before any outsourcing decision, it is essential that the study team correctly inform the procurement group as to their needs. The first key consideration is the nature of the package to be outsourced and how much of the work will be delivered or overseen by the sponsor. At the extreme ends of the scale, this might be a virtual company outsourcing a single, but complex, study as opposed to a major biopharma company outsourcing a large volume of programming work. In these situations, it might seem obvious that an FS approach is correct in the former case and FSP in the latter. However, if the biopharma budgets on a study or therapy area (TA) basis, it can become more challenging to operate a successful FSP model. If the study sponsored by the virtual company has complex needs and involves their only product, maybe specialist advice will reduce the risk of failure? The desired operational model, the budgeting structure, and the contractual arrangement must all be aligned. Only then can the other elements come into play. The first consideration calls for an introspective review and in the real world, the package or packages of work will not always be as clear cut as those examples above. It may be difficult to model how the budgets may break down, it may not be obvious what impact shifting timelines will have on resource availability, and the question as to the level of expertise required may be open. At this stage, there may be several outsourcing strategies that appear feasible. Where the sponsor is seeking to outsource a programme of studies, it may not be evident as to which methodology is the better fit. At this stage, the buyer’s operational team must give input and advice as to the nuances of the work and how these will influence the choice of service. The buying team needs to understand how the programme may develop based on the success or failure of component trials. If a submission is involved, the benefits of one integrated team working to the deadline versus functional teams with the flexibility to grow at busy times can be debated. Is global reach more important than therapeutic expertise; is therapeutic expertise more important than domain knowledge? For smaller companies, the decision might be based more on how much oversight they can provide or how much vendor management they can cope with. It is only after considering the work in detail that the buying team can make an informed decision. The Changing Climate In recent years, there has been a shift away from FSP as a costsaving device. There have been new entrants into the market and Volume 11 Issue 6

Therapeutics the emphasis has been on staff augmentation. The mood is changing somewhat: Sponsors are expecting domain expertise from their FSP providers and quality and innovation feature as much as cost in requests for information. The trends toward patient-centricity and data-driven portfolios have focused minds on quality and more in-depth understanding of study design and analytics. The introduction of machine learning and artificial intelligence into study conduct has changed the game again. Domain expertise is becoming more and more critical. The requirement for highly specialist domain knowledge would suggest the expertise provided under the FSP model is now more important. Sponsors still require the flexibility that FSP brings and will continue to need access to a high number of resources but that will not be enough in the longer term. They will require access to the expertise that comes with specialist providers. This interesting shift leads to the final consideration. Sponsors need to be building relationships with those companies that can help them deal with new techniques and new technologies. They need to assess where the very best domain knowledge resides and build links with those providers. The FS approach will still provide a large proportion of services for some sponsors, but the complexity of the drug development environment has driven up the demand for specialist providers. Such companies have turned to FSP to scale operations and retained groups dedicated to project-based deliverables to retain the credibility needed to win business. Sponsors can derive value from both the FS and FSP models. Some FS providers have recognised this and offer a hybrid approach – deploying FSP for components of the drug development process. However, FSP as part of a hybrid model does not deliver the benefits outlined above. Where FSP sits in the FS environment, management, recruitment, and investment are not targeted solely towards the area of specialism. An FSP business unit might have a director, but they will sit on a board bringing together the various players involved in FS delivery. The FS company will attract a different group of candidates. Where FS companies are attempting to establish specialist units, they must consider these factors. Sponsors, in turn, must account for them when selecting a hybrid model. On the flipside, FSP providers may offer to run a FS approach by acting as the single point of contact and even offering to hold the central contract. A sponsor adopting this approach must assess the associated risks. FS companies have the expertise to manage complex contracts, understand the complexities of site payments, have experience of the logistics involved with running a successful study and how to contract appropriately with those third-party providers. An FS provider working with integrated processes can simplify life for the sponsor when agreeing on the contract. There are a great many studies that utilise FSP in part and then use one CRO for the remainder of the work. Companies have grown used to this way of working. As study design has evolved and the amount and types of data have increased, the demand for specialist FSP has increased. While a drive for cost savings drove the growth of early FSP arrangements, now a desire for access to specialist expertise plays a significant part too. Considerations for All Models of Clinical Trials Management These are some of the areas a sponsor must consider when deciding between an FS approach or bringing in FSP for some services. There will be others, especially when the sponsor examines the detail of any package of work. A sponsor can establish key considerations from the project risk assessment. The market shares of FS and FSP tell us there is a place for both methodologies. We may not have seen the end of the current cycle which is seeing a trend back towards the FSP approach. It will be

interesting to see if the introduction of new techniques coupled with the increasing complexity of drug development will help to power the FSP market to new heights. FSP itself must evolve if that is to happen. If access to expertise is the driving force, then it seems likely specialist companies will underpin such growth. FS companies may respond; we have already seen specialist divisions established within the larger CROs. It is likely we will see further acquisitions of specialist firms as the mid-size and mega CROs seek to meet the demand for expertise. While these changes occur, it will be more difficult for those charged with procuring services to have a clear view of the best option. Certainly, sponsors will need to look past the marketing of these products and gain a real understanding of the expertise on offer. The implication of this is that smaller companies will need to have access to independent expertise to guide the procurement process and preferably oversight during the study conduct. We have seen the introduction of regulations emphasising the importance of vendor oversight. As in-study tasks become more technical (think artificiaI intelligence, machine learning, new statistical techniques), such monitoring becomes more challenging but also more critical. Perhaps, in the past, there has been an option to ‘throw a study over the fence’, bring in a FS provider at the beginning, and then wait for the final report sometime later. Things have moved on and the need for specialist advice has seen demand for FSP grow. The work involved in submissions has increased too. For large companies, access to FSP on the volume side has proven very successful and saved money. It is easier for the FS companies to establish FSP for volume services and most have responded with some element of staff augmentation services. Various providers from outside the life sciences sector (for example consultancy firms and recruitment companies) have entered the market to deliver under the staffing model. For the sponsor, the volume of work might be the most important consideration when weighing FS against FSP. Where FSP is procured to deal with a large quantity of work, the risk assessment is different versus the case where FSP is procured for access to expertise. It is this area where we will see companies seeking to differentiate and specialist providers grow to meet the demand. Conclusion FSP and FS both have roles to play in outsourced drug development and neither appears to be under threat in the medium term. The nature of clinical trials is evolving, and as regulatory and perhaps political factors shape drug development there may be a swing towards one or the other. Procurement groups will typically work over three-year cycles, occasionally five. These run times will protect them against shifting models which, unless there is a profound change in approach, would take several years to play out.

Andrew MacGarvey Andrew MacGarvey is Managing Director for PHASTAR. He began his career in statistical programming some twenty years ago and subsequently held various technical roles in contract research organisations. He has served on several boards and has worked in both the UK and the USA in leadership roles with a focus on growing businesses. Andrew is responsible for the operational delivery at PHASTAR as well the oversight of Quality Assurance, Finance, Administration, and Human Resources. He holds an MBA from the University of Newcastle and is currently completing a Law degree.

Journal for Clinical Studies 33


Phase III Clinical Trials: A Fate Decider in the Drug Development Introduction A Phase III clinical study evaluates the safety, efficacy and related parameters of experimental therapy against a standard therapy in a large human population to ensure that it is fit for the intended purpose. A Phase III clinical trial may compare the effectiveness of a new treatment intervention with the present standard of care. If experimental therapy shows significant activity in any disease condition during the Phase II trial, advance clinical trials for comparing the experimental treatment efficacy can be made for the disease in comparison with standard or control treatment. An assortment of trial outlines might be reasonable, as indicated by the standard of care treatment for the specific disease. Those that are most acceptable are controlled trials that contrast the new agent with a standard single agent or a standard regimen in addition to the test agent to the standard regimen alone.1 In most cases, therapy moves into Phase III trials only after it meets the objectives of Phase I and II trials as depicted in Figure 1.

The aim of this study is to provide a comprehensive review of the conduct of Phase III trials, failures of Phase III trials and to delve into the failures of Phase III trials. Discussion Phase III studies involve the participation of a large number of patients in different locations. Therefore the design, conduct, reporting and management of the trial is not as easy as earlier trials. On the other side, the experimental therapies that are eligible for Phase III trials may not show the results as anticipated earlier, which creates trouble for the sponsors, investigators and patients. Requirements for the conduct of Phase III studies include: • •

Dosage schedule explored in the Phase II studies. Human participants who are suffering from the disease or a condition for which the drug is intended to be treated or used; a suitable clinical setting with all the required facilities. Qualification requirements: Phase III clinical trials must incorporate a review of the accessible proof to demonstrate regardless of whether clinically essential sex or race/ethnicity contrasts in the reaction to the intervention are normal.1

Figure 1

A far more noteworthy test is the advancement of a Phase III trial strategy that will permit fusion of test treatment into a regular regimen, apparently substituting at least one of the conventional medications incorporated into the standard regimen.2 This is otherwise called the "pre-marketing stage" since it really measures a patient’s reaction to the medication. Studies in this stage are costly, tedious and troublesome trials to plan and run, particularly in treatments for chronic medicinal conditions.3 Trials of chronic disease conditions regularly have a short follow-up time for assessment; in respect to the timeframe, the intervention may be utilised as a part of practice. The high rate of disappointment in late phases of advancement is driving a considerable weight on the pharmaceutical business. Expenses are rising since disappointments happen later and regularly after being developed in Phase III. In 2013, PhRMA evaluated that biopharmaceutical makers burned through $10 billion to run 1680 clinical trials including 644,684 patients.4 FDA's exploration demonstrated that, of 313 new molecular entities (NME) submissions made in 2013, just 151 were endorsed, and about half fizzled in light of the fact that they couldn't indicate efficacy. Over 40% fizzled, the study found, since they had safety and efficacy problems.5 34 Journal for Clinical Studies

Investigators should consider the accompanying conditions when arranging a Phase III clinical trial and incorporate the appropriate expected gathering table data in the protocol document:1 •

Earlier information unequivocally demonstrates that the therapy will indicate huge clinical or general wellbeing contrasts among sexes, as well as racial and ethnic subgroups. For this situation, the proposed Phase III trials essential question(s) to be tended to and configuration should particularly oblige these distinctions.

Prior information neither unequivocally aids nor nullifies the presence of noteworthy clinical or general wellbeing contrasts among groups. In such cases, the Phase III trial must incorporate adequate and suitable sexual orientations, racial, or potentially ethnic subgroups, all with the goal that substantial investigation of the intervention consequences for subgroups can be performed. In any case, the trial won't be required to give high measurable energy to each subgroup.1

a. Design The trial's design must be based on the present condition of information about expected contrasts. Phase III clinical trials are Volume 11 Issue 6

Therapeutics required to give substantial investigation to quantify contrasts of clinical or importance in intervention effects based on gender or racial/ethnic subgroups where proof supports contrast.1 It is typically controlled or uncontrolled, unblinded, single-blinded or twofold blinded, and members are grouped out to treatment group by randomisation. In these trials, new treatment might be compared with existing regimen or placebo. b. Conduct Generally the investigations are led in various medical centres and facilities across the nation, or world in case of a global clinical trial. These trials incorporate patients of various ages and ethnicities, and both genders. This enables investigators to apply the outcomes to an expansive number of individuals. Phase III trials are directed in huge patient populaces (normally, the quantity of subjects runs from 1000 to 3000). Studies include the assessment of different parameters like dose response relationship, or to investigate the medication's utilisation in more extensive population areas, in various phases of illness, or in mix with another medication. For drugs expected to be directed for longer-term therapy, studies including stretched out exposure to the medication are customarily led in Phase III, despite the fact that they might be begun in Phase II.6 The example and profile of any adverse responses must be researched and extraordinary highlights of the drug should be investigated.7 c. Types Phase III clinical trials studies are divided into two types:

Roughly 70% of Phase II trials are unsuccessful. In spite of the fact that this rate may appear to be high, disappointment in an early stage is relied upon to some degree, as these seem to be "exploratory" trials, however the level of Phase III trials that fall flat is around 50%, as these may be "confirmatory". Hypothetically, if early-stage trials give the important criteria to move a drug discovery programme to Phase III testing, generally, few Phase III trials should flop; however, that isn't the case.5,10 Product candidates that show up deficiently safe or effective at one phase may not continue to the following phase. Approximately nine out of 10 drugs/biologics that are tried on humans are never submitted to FDA for approval.11 Typically, data is submitted to the FDA for authorisation after Phase III testing. As of late, there has been developing enthusiasm for investigating options necessities for Phase III testing before drug endorsement; for example, depending on various sorts of information and invalidated surrogate endpoints. Reasons for the Failure In an abnormal state examination, most experimental therapies were stopped in Phase III because of insufficient efficacy (44%) or safety issues (24%). This information proposes that the majority of negative results likely reflects the natural properties of the investigational drug.12 The most significant reasons for the failure of Phase III trials include:13

The second-most reduced stage progress achievement rate was found in Phase III in contrast with the different phases of a clinical trial. This is critical, as most organisations who support Phase III trials acknowledge they are the longest and most costly trials to execute.

1. Fundamental science – Animal models that don't interpret or are not by any stretch of the imagination identified with human disease, poor comprehension of target ailment science, or medications that are just ineffectual. 2. Clinical study design – Changes in patient definitions (consideration criteria and rejection criteria) from Phase II to Phase III, unfeeling results measures or Phase II surrogate endpoints that are not affirmed by Phase III endpoints. Wrong examination configuration can undermine the capacity to indicate adequacy or the sample size might be too small. 3. Dose selection – The dosage might be unseemly for Phase III. This can happen when investigators or sponsors wind up being overenthusiastic about Phase II results and hurry to Phase III without completely investigating measurement findings. Lacking remedial files may likewise prompt problematic dosing. 4. Information gathering and investigation – False positive signs from Phase II and excessively hopeful presumptions about changeability and treatment contrasts may bring about such issues as missing information, diminished down inclination, rater predisposition, mistakes in estimation strategies, or improper factual techniques. 5. Operational execution – Data trustworthiness issues or Good Clinical Practice (GCP) infringement may become an integral factor if the protocol hasn't been composed enough. What's more, surprising varieties in enlistment or dropouts can come about, as can protocol varieties, missing information, or accidental unblinding of subjects.13

The degree of Phase III clinical trial disappointments is the single measure of increases in speculation for R&D. The speculations for discovery and improvement come toward the finish of the procedure, and if those trials flop, all the capital contributed up to that point is lost. The whole early advancement process, along these lines, is intended to lessen that vast and costly crucial trials disappointment that directs the approval and sales.5, 10

A noteworthy supporter of the high disappointment rate is deficient Phase II programmes that give imperfect data to the "go/no-go" choice to move to Phase III and the plan of the Phase III trials. Lacking Phase II programmes can be insufficiently planned, do not contain the full supplement of studies, fail to join endpoints that give constrained or deluding data with respect to the adequacy of the test specialist, or are dishonorably executed. The particular difficulties change with the therapeutic area.14

1. Phase IIIa, conducted after the demonstration of efficacy but prior to regulatory submission. 2. Phase IIIb, conducted after regulatory submission but prior to approval and launching. d. Significance of Phase III Clinical Trials The outcome of the Phase III clinical trial is most significant in the drug development process. It gives information related to the additional safety and efficacy data in a large population, usage in any other condition than those specified in early studies, and applicability of the investigational treatment in a special population. The information obtained determines how the compound is best prescribed to patients in the future. e. Failures of Phase III Clinical Trials Compliant with past investigations of drug development phase progress achievement rates, we observed Phase II achievement rates to be far lower than other stages. Phase I and III rates were significantly higher than Phase II, with Phase I marginally higher than Phase III.9

Journal for Clinical Studies 35

Therapeutics Strategies to Overcome the Failures13 •

Applying more meticulousness to the general advancement process – Applying more thoroughness to the improvement procedure holds potential for getting rid of likely disappointments, thus lessening Phase III failure rates. Satisfactory Phase II testing – Many Phase III trials come up short in view of a principal absence of comprehension of the mode of activity of NMEs. Racing to get the chance to reach Phase III without satisfactory comprehension of basic segments is dangerous and all the more frequently prompts harmful surprises in Phase III. This proposed approach in Phase II might not bode well, however it likewise holds potential for lessening late disappointments. Improving Phase III investigation design – Strategies for progress would incorporate well-defined protocol and improvement, and additionally use of displaying and reproduction, versatile trial plans, and biomarkers. De-risking Phase III execution – Pharmaceutical organisations and CROs should use information from various sources and lead continuous observation of the nature of information being gathered, which binds this to a legitimately arranged risk-based protocol check system. Ensure completeness and clarity of submissions for regulatory agencies – Pharmaceutical companies should seek advice from regulators during the drug development process. FDA offers sponsors and applicants the opportunity to schedule formal meetings at critical points in the development and regulatory process to discuss the plan and identify areas of concern that may need adjustment.

Pharmaceutical organisations should look for guidance from regulators during the drug development process. FDA gives an opportunity to the sponsors and applicants to plan formal gatherings with a basic focus on development and regulatory procedures to examine the arrangement and recognize areas of worry that may require change. Regulatory agencies and their countless projects that both succeed and come up short can convey noteworthy advantage to supporters who tune in and gain from it, using their wealth of specialist experience and knowledge.13 Various organisations have curated accepted procedures and dependable guidelines to help guarantee achievement, Pretorius noted, citing AstraZeneca’s “5R” approach, which involves ensuring that Phase III work is designed to confirm “Right Target, Right Tissue, Right Safety, Right Patients, and Right Commercial Potential”. A sixth R is “Right Culture”, he adds, in which groups are willing to admit failure early on and to evaluate test data in an open way.15 Significance of Phase III Failure Phase III includes all the investments made for the drug development process, i.e. from the target identification of the preclinical phase to the Phase II clinical trial. Examples of Phase III clinical trial failures are given in Table 1. Case Studies In case 1 (refer to Table 2), a Phase III trial randomised over 1500 patients to receive placebo or Semagacestat for 18 months.16 The primary outcomes were the change in cognition from baseline to month 18 in the ADAS-cog and ADCS-ADL, which are measures of cognition and function, respectively. The trial was terminated before completion because patients taking Semagacestat experienced decreased cognitive functionality over the course of the trial compared to those taking a placebo.16 Treatment with Semagacestat was associated with decreases in blood concentrations of amyloidbeta, but was also associated with a statistically significant dose36 Journal for Clinical Studies

Table 1

Table 2

related decline in primary outcomes including activities of daily living, global functioning, cognitive functioning, and quality of life, compared to placebo. Patients taking Semagacestat had more adverse events including infections, skin cancers, and total cancers compared to placebo. In fact, patients receiving Semagacestat had at least double the risk of developing skin cancer compared to patients receiving placebo. In case 2 (refer to Table 3), a Phase III study randomised over 15,000 participants with coronary artery disease, history of stroke, diabetes, or peripheral artery disease to receive either torcetrapib or placebo in addition to a statin. The primary outcome measure was the time to first occurrence of a major cardiovascular disease event (e.g., heart attack, stroke); other outcomes measures included cholesterol levels and blood pressure. Although HDL-C increased and LDL-C decreased significantly among those receiving torcetrapib compared with those receiving placebo, the drug was not shown to be effective and proved to be dangerous. Patients who received torcetrapib were 25% more likely to suffer a major adverse cardiac event, and were 58% more likely to die from any cause, than those taking the placebo (both results were statistically significant). The torcetrapib group also showed a significant increase in blood pressure.17 The trial was halted three years earlier than expected because of these compelling and unexpected safety concerns.18

Table 3

Statistical Analysis The information about the failures that occurred at the Phase III stage during 2012 to 2016 was collected by various resources; raw data was segregated (year / company) and was subjected to statistical analysis (Figures 2 & 3). The Phase III trials that were conducted during 2014 had a higher failure rate compared to other time periods and the studies sponsored or conducted by Eli Lilly had suffered more failures than other companies during this period. Most of the drugs failed to show the expected efficacy and safety at the Phase III trials. Conclusion The proper conduct and execution of the Phase III clinical trial, with special emphasis on design, management and reporting, is critical for the success of the drug development process. There is a need to consider all the related aspects from the beginning of the clinical development process to minimise the failure at a late stage, and to achieve this, industries have taken a step forward to understand Volume 11 Issue 6


Figure 2

Figure 3

the reasons and root causes which have a significant role in these failures. Additionally, a novel strategy is essential, which includes considerations to the regulatory and ethical aspects of conduct and to prevent the failures associated with it. REFERENCES 1.

CTEP, DCTD, NCI., A Handbook for Clinical Investigators Conducting Therapeutic Clinical Trials., Version 1.2 on 21/08/2017) 2. Francis Jay Mussai, Christina Yap, Christopher Mitchell and Pamela Kearns., Challenges of clinical trial design for targeted agents against pediatric leukemias., Front. Oncol., 06 January 2015 https://doi. org/10.3389/fonc.2014.00374 (Accessed on 25/07/2017) 3. Speight TM, Holford NH., Avery’s drug treatment, IVedition , WileyBlackwell., page no : 430-434 4. Battelle Technology Partnership Practice & Pharmaceutical Research and Manufacturers of America (PhRMA)., Biopharmaceutical IndustrySponsored Clinical Studies: Impact on State Economies., March 2015 (Accessed on 29/08/2017) 5. Leonard V. Sacks, Hala H. Shamsuddin, Yuliya I. Yasinskaya, Khaled Bouri, Michael L. Lanthier, Rachel E. Sherman. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA. 2014; 311(4):378–384. https://jamanetwork. com/journals/jama/fullarticle/1817795 (Accessed on 15/10/2017) 6. ICH Harmonized Guideline Tripartite General Consideration for Clinical Trial E8; Current Step 4 version dated 17 July 1997 fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/ Step4/E8_Guideline.pdf (Accessed on 10/09/2017) 7. National Drug Authority; Ministry of Health, The Republic of Uganda., Guidelines for the conduct of clinical trials. medicinedocs/en/d/Js19724en/ (Accessed on 20/08/2017) 8. Guidance for investigators., Conduct of identical phase 3 studies http://www. (Accessed on 23/08/2017) 9. Biotechnology Innovation Organisation (BIO), Biomedtracker, Amplion.,Clinical Development Success Rates 2006-2015.,2016.https:// Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016. pdf(Accessed on 26/10/2017) 10. StopkeE, Burns J., New drug and biologic R&D success rates, 2004- 2014. Parexel’s Bio/PharmaceuticalR&DStatisticalSourcebook 2015/2016.

11. DiMasi, J.A., H.G. Grabowski, and R.W. Hansen., Briefing: Cost of Developing a New Drug (November 18, 2014) [Presentation]. 2014, Tufts University. RD_cost_study_-_Nov_18,_2014..pdf (Accessed on 10/10/2017) 12. Hwang TJ, Carpenter D, Lauffenburger JC, et al., Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results. JAMA Intern Med. 2016 Oct 10. doi: 10.1001/jamainternmed.2016.6008. (Accessed on 15/10/2017) 13. Agnes Shanley., Preventing Phase III Failures., Feb 01, 2016, Pharmaceutical Technology , Volume 2016 Supplement, Issue 1, page no: 24-27 http://www. (Accessed on 25/10/2017) 14. Anastassios D. Retzios, Ph.D., Why Do So Many Phase 3 Clinical Trials Fail? Bay Clinical R&D Services, 2417 Canyon Lakes Drive, San Ramon, California 94582 Research_links/Why%2 Pivotal%20Clinical%20Trials%20Fail%20-%20 Part%201_v12L_a.pdf(Accessed on 06/11/2017) 15. David Cook, Dearg Brown, Robert Alexander, Ruth March, Paul Morgan, Gemma Satterthwaite &Menelas N. Pangalos.,Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework, Nature Reviews and Discovery, 13 419-431, May 2014. articles/nrd4309 (Accessed on 08/08/2017) 16. Doody, R.S., et al., A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med, 2013 July 25. 369(4): p. 341-50. https:// (Accessed on 17/08/2017) 17. Barter, P.J., et al., Effects of torcetrapib in patients at high risk for coronary events. N EnglJ Med, November 2007. 357:2109-2122, http://www.nejm. org/doi/full/10.1056/NEJMoa0706628#t=article (Accessed on 18/08/2017) 18. Berenson. A., Pfizer Ends Studies on Drug for Heart Disease. The New York Times, 2006. html?_r=2&th&emc=th&oref=slogin& (Accessed on 19/08/2017)

Mr. Chandan Mr. Chandan M.S has completed his Masters in Pharmacy in Pharmaceutical Regulatory Affairs from JSS College of Pharmacy, Mysuru. He is currently working as a Regulatory Specialist at Alcon Laboratories (India) Pvt. Ltd. He is a keen learner and a regulatory professional with a passion for learning about healthcare product regulations across the globe.

Dr. M P Venkatesh Dr. M P Venkatesh is an Assistant Professor for the Department of Pharmaceutics at JSS College of Pharmacy, Mysuru. He has over 13 years of research & teaching experience. He has guided 38 M.Pharm candidates, mentored 5 PhDs and authored 17 International and 78 National publications in reputed journals. He has attended various national and international conferences and is currently working on clinical and drug regulations.

Dr. T M Pramod Kumar Dr. T M Pramod Kumar is a Professor and Principal at JSS College of Pharmacy, Mysuru. He has over 26 years of research & teaching experience. He has guided 8 PhDs and 58 M.Pharm candidates, as well as guiding 7 PhD scholars and 6 M.Pharm students and has authored 59 International and 72 National publications in reputed journals. He has completed 9 research projects from various external funding agencies. His area of expertise is formulation of transdermal systems and regulatory aspects of medical devices.

Journal for Clinical Studies 37


Clinical Development in Rare Diseases: Autoinflammatory Syndrome ”Autoinflammatory” is a term used to describe a group of diseases that cannot be classified as immunological disorders [auto-immune, allergic, or immunodeficient]1. The term was first mentioned by Michael McDermott and Daniel Kastner and colleagues, coined to describe the monogenic periodic fever syndromes when it was first proposed in 19992,3. Today, it has become an encompassing term to include diverse conditions that involve not only the disorders of the innate immune system but also polygenic, metabolic and storage disorders4. Autoinflammatory syndromes are a set of genetically diverse but clinically similar conditions caused by an exaggerated innate immune system response resulting in repeated episodes of spontaneous inflammation affecting multiple organs and manifesting as recurrent fever, mucocutaneous lesions, serositis and osteoarticular symptoms5,6,7. It is characterised by absence of pathogens, autoantibodies or antigen specific T cells and with no evidence of adaptive immune dysregulation2. It is genetically driven with resultant activation of the inflammasome and cytokine excess. Affected individuals often have first- or second-degree relatives with similar features5. In 2013, a study estimated the incidence to be 2.83 patients per million people in Sweden. The prevalence of a given disease can vary from 1:1000 people (Sweet's syndrome) to 1:1,000,000 (Marshall’s syndrome) and vary between populations. Owing to their relatively recent identification and their low incidence rates, it is believed that clinical cases are currently underdiagnosed and increased clinical awareness is required8. Concept of Autoinflammatory The innate immune response acts with immediacy to danger or pathogen signals, termed pathogen-associated molecule patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs)5. Inflammasome pathway can lead to its constitutive activation, producing inflammation in the absence of a trigger. In fact, inflammasomes are so critical to the pathogenesis of autoinflammatory syndromes that these are also referred to as inflammasomopathies. Inflammasomes belong to the family of pattern recognition receptors and are an integral part of the innate immune system. These multiprotein complexes can sense not only pathogen-associated molecular patterns but also intracellular molecules released from injured host cells7. PAMPs and DAMPs activate intracellular inflammasomes to set forth an inflammatory cascade of effector molecules. For example, as depicted in Figure 1, Nod like receptor protein3 (NLRP3) inflammasome is a cytosolic scaffold of proteins triggered by multiple signals including microbial products, endogenous substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines leading to the activation of NLRP3 gene and the inflammasome. NLRP3 inflammasone complex consists of a protein component which is NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD) is the binding component and pro-caspase1. The pro-caspase1 gets activated to caspase1 with resultant unopposed cytokine activation such as IL-1, IL-18, TNF-α, IL-6, IL-17, type 1 interferons (IFN-α and IFN-β), and the complement system5. 38 Journal for Clinical Studies

Activation of inflammasomes produces an inflammatory response by activating caspase. Caspase activation also leads to pyroptosis, a specific form of programmed cell death, which also releases pro‑inflammatory molecules and further potentiates the inflammatory cascade. Activating mutations in genes coding for any component of the inflammasome pathway can lead to its constitutive activation, producing inflammation in the absence of a trigger7.

Figure 1: Illustrated above is the formation of an inflammasome complex. NLRP3 inflammasone complex consists of a protein component which is NLRP3, ASC (apoptosisassociated speck-like protein containing a CARD) is binding component and procaspase1 and it gets activated to caspase1, which in turn activates the pro-cytokines and chemokines to their active form.

Genetics of Autoinflammatory Disorders The spectrum of systemic autoinflammatory disorders has been evolving continually over the last decade9. The initial classifications were based on the clinical phenotypes. However, with increasing understanding of the pathogenesis, new classification systems are being based on the underlying molecular defects7. Today, 30 genes have been linked to autoinflammatory diseases8, and comprise both hereditary and multifactorial disorders7. As genetic testing is used more regularly and increasing numbers of patients are screened, there is widening of clinical phenotypes. Numerous attempts to classify autoinflammatory disorders have been made. However, until we understand the inheritance patterns as well as the influence of the environment, epigenetic factors and their interactions, any classification modality will remain arbitrary4. McGonagle and McDermott proposed a ‘continuum model’ for immunological Volume 11 Issue 6

Therapeutics diseases in 2006, integrating autoinflammatory disorders into a spectrum ranging from monogenic autoinflammatory disorders to monogenic autoimmune diseases and later this model was expanded to include polygenic disorders and other diseases that may have both an autoinflammatory and autoimmune component9.

The below Tables 1–4 provide information about the gene responsible and onset time of episodic and multisystemic; Episodic – affecting bone and joints; Persistent and multisystemic; Persistent and affecting the skin – autoinflammatory disorders10,11.

Tabl e1 : Epi s odi candmul t i s y s t e mi c r onym Ac

Na me

Aut oi nf l a mma t or ydi s or de rg r oup

Ge ne

Ag eofons e t

Fi r s tye a ro fl i f e

AGS( i nc l ude s s ub c l a s s i f i c a t i o n sAGS1 7 )

Ai c a r di Go ut i e r e ss yndr o me

I nt e r f e r o nme di a t e d Aut o i nf l a mma t o r yDi s e a s e s

TREX1( AGS1 ) , RNASEH2 A ( AGS4 ) , RNASEH2 C( AGS3 ) . I FI H1( AGS7 ) , DSRAD( AGS6) , SAMHD1( AGS5 ) , RNASEH2 B ( AGS2 )


Aut o i nf l a mma t i o n&PLCG2 a s s o c i a t e d Ant i b o dyDe f i c i e nc ya ndI mmune Dy s r e g ul a t i o n

PLCG2 a s s o c i a t e d

PLCG2mut a t i o n

I nf a nc y


De f i c i e nc yo fAde no s i neDe a mi na s e2/ Fe ve rwi t hEa r l yOns e tSt r o ke

ADA2de f i c i e nc y


I nf a nc y–e a r l y c hi l dho o d


Fa mi l i a l Co l dAut o i nf l a mma t o r y Syndr o me( NLRP3 AI Dmi l d)

Cr yo pyr i na s s o c i a t e dPe r i o di c Syndr o me s( CAPS) NLRP3 a s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e s( NLRP3 AI D)


I nf a nc y, b utaf e w l a t e ri nc hi l dho o do r a do l e s c e nc e


Fa mi l i a l Me di t e r r a ne a nFe ve r

Pyr i na s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e s( PAAD)


I nf a nc y, t ounde r2 0 ye a r s

MA, MKDs e ve r e

Me va l o na t eAc i dur i a( MA) , Me va l o na t eKi na s eDe f i c i e nc ys e ve r e

Me va l o na t eKi na s eDe f i c i e nc y( MKD) MVK

Bi r t ho ri ne a r l y i nf a nc y

Me va l o na t eKi na s eDe f i c i e nc yMe va l o na t e mi l d/mo de r a t e , k i na s ede f i c i e nc y Hype r i mmuno g l o b ul i ne mi aDwi t h ( i nc l ude sHI DS) Pe r i o di cFe ve rSyndr o me

Me va l o na t eKi na s eDe f i c i e nc y( MKD) MVK

I nf a nc y

Muc k l e We l l s Syndr o me ( MWS )

Muc kl e We l l sSyndr o me( NLRP3 AI Dmo de r a t e )

Cr yo pyr i na s s o c i a t e dPe r i o di c Syndr o me s( CAPS) NLRP3 a s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e( NLRP3 AI D)

I nf a nc y


NLRC4 a s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e , NLRC4 a s s o c i a t e dMa c r o pha g e Ac t i va t i o nl i keSyndr o me( NLRC4 MAS)

NLRC4 a s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e s , NLRC4( a kaSCAN4 , CARD1 2 ) Ma c r o pha g eAc t i va t i o nDi s e a s e s

I nf a nc y, e a r l y c hi l dho o d-s o mea t b i r t h

NLRP1 2 a s s o c i a t e d di s e a s e

NLRP1 2 a s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e /NLRP1 2 As s o c i a t e dPe r i o di c Fe ve rSyndr o me/Fa mi l i a l Co l d Aut o i nf l a mma t o r ySyndr o me2( FCAS2 ) / Gua de l o upePe r i o di cFe ve r

NLRP1 2 a s s o c i a t e d Aut o i nf l a mma t o r yDi s e a s e , ( Mo na r c h1 )


Ne o na t a l /e a r l y i nf a nc y


Pyo de r maGa ng r e no s uma ndAc ne/ Pyo g e ni cSt e r i l eAr t hr i t i s , Pyo de r ma Ga ng r e no s uma ndAc neSyndr o me

Pyo g e ni cDi s e a s e s


1 1 0ye a r so fa g e


Pe r i o di cFe ve r , Apht ho usSt o ma t i t i s , Pha r yng i t i s , a ndCe r vi c a l Ade ni t i s/ Ma r s ha l l Syndr o me

I di o pa t hi c

Cur r e nt l yunk no wn. Nog e ne t i c t e s t i nga va i l a b l e

Ea r l yc hi l dho o d-2 5ye a r so fa g e

PLCG2 a s s o c i a t e d

He t e r o z yg o usg e no mi c de l e t i o nswi t hi nt hePLCG2 g e ne

I nf a nc yunde r6 mo nt hs

Ge ne r a t i o no fI nt r a c e l l ul a rSt r e s s ; Co ng e ni t a l Si de r o b l a s t i cAna e mi a s ( CSAs )


Ne o na t a l pe r i o do r pr i o rt o3mo nt hso f a g e

S LC2 9A3 r e l a t e d

SLC2 9A3

I nf a nc y

I nt e r f e r o nme di a t e d Aut o i nf l a mma t o r yDi s e a s e s


I nf a nc y, c hi l dho o d o ra do l e s c e nc e

TNFa s s o c i a t e dAut o i nf l a mma t o r y Di s e a s e s , Pr o t e i nFo l di ng


By3ye a r so fa g e

Ma c r o pha g eAc t i va t i o nDi s e a s e s


I nf a nc yt oe a r l y c hi l dho o d.


SI FD S LC2 9 A3




PLCG2 a s s o c i a t e dAnt i b o dyDe f i c i e nc y& I mmuneDys r e g ul a t i o n/Fa mi l i a l At ypi c a l Co l dUr t i c a r i a Co ng e ni t a l s i de r o b l a s t i ca na e mi awi t h i mmuno de f i c i e nc y, f e ve r s , a nd de ve l o pme nt a l de l a y SLC2 9A3Spe c t r umDi s o r de r/ H. s yndr o me Spo ndyl o e nc ho ndr o dys pl a s i awi t h I mmuneDys r e g ul a t i o n/Ro i f ma n I mmuno s ke l e t a l Syndr o me/Ro i f ma nCo s t aSyndr o me Tumo urNe c r o s i sFa c t o r( TNF) As s o c i a t e d Pe r i o di cSyndr o me/Fa mi l i a l Hi b e r ni a n Fe ve r Xl i nke dFa mi l i a l He mo pha g o c yt i c Lympho hi s t i o c yt o s i s ; Xl i nke d Lympho pr o l i f e r a t i veSyndr o meType2– MAS


Journal for Clinical Studies 39


40 Journal for Clinical Studies

Volume 11 Issue 6

Therapeutics Clinical Presentation of Autoinflammatory Syndrome Autoinflammatory diseases are characterised by intense episodes of inflammation8. There is no one clinical symptom, but rather a set of clinical symptoms occurring repeatedly which suggests its diagnosis, and the differential remains broad and includes infectious, rheumatologic and oncologic/lymphoproliferative causes, as well as immunodeficiencies. The longer the period of repeated, stereotypical episodes, especially with fevers and systemic features affecting skin, mucosa, eyes, musculoskeletal, gastrointestinal and nervous systems, the greater the likelihood of an AD4. Further, there is often a delay in recognising that the clinical features follow a pattern. With the extending clinical spectrum of autoinflammatory syndromes, we now know that some of these may have continuous fever or no fever at all. Other clues include childhood onset, positive family history and raised laboratory markers of systemic inflammation during the episodes4,7. Clinical features that are most predictive in making a diagnosis are (a) age of onset; (b) presence, magnitude, and duration of fever; (c) duration of attacks; (d) rash or urticaria; (e) distinguishing features (e.g., serositis, arthritis, organomegaly, ocular, or neurologic involvement); (f) ethnicity; and (g) family history of similar illness5. The skin rash of autoinflammatory syndromes is asymptomatic, longer lasting, symmetrical and does not respond to antihistamines. Other cutaneous features that can point toward autoinflammatory syndrome include a recurrent cellulitis‑like eruption, neutrophilic dermatoses‑like lesions (such as inflammatory nodules, ulcers or pustules), leukocytoclastic vasculitis‑like purpura, and aphthous ulcers7. Since the penetrance of the mutations is not 100% and de novo mutations may occur, a negative family history does not exclude a particular diagnosis. A family history of amyloidosis, chronic renal disease and deafness would strengthen the possibility4. The site provides a comprehensive chart with systemic findings and characteristics. To diagnose AD, it is important to understand that not every patient will manifest with all the listed symptoms and to perform diagnostic tests, genetics and other evaluations11. Lab Values and Diagnostic Methods Advances in understanding the pathogenesis and genetics of these disorders have led to testing, which may ultimately diagnose one of these rare disorders. A complete clinical evaluation is necessary to characterise features that are most diagnostic and it is also important to exclude possible infectious, neoplastic, or autoimmune diseases. Once a differential diagnosis is considered, confirmation may ensue by either an empiric trial of known effective therapy or the identification of a genetic mutation5. Laboratory test values and acute phase reactants are going to be elevated in all the patients, especially during attacks, thus providing limited value for disease differentiation. Inflammatory markers may remain persistently elevated, although typically lower than during attacks, in between episodes12. However, changes in acute-phase reactants can occur quite quickly following initiation of therapy, and monitoring these levels consistently can help anticipate disease flares13. Biopsies have a limited role in evaluation of patients for autoinflammatory syndromes beyond their use in determining whether symptoms are related to malignancy or infection. A skin biopsy of rashes can identify neutrophilic infiltrates, but will not differentiate between the various autoinflammatory syndromes. Numerous studies have demonstrated that between 30% and 40% of patients who meet phenotypic classification of an autoinflammatory condition do not have a definable genetic mutation. Findings from other studies record that the likelihood of identifying a genetic mutation associated with an autoinflammatory condition varies depending on the patient population, patient ethnicity, or presence of a family member with a genetic mutation. Thus, it is important to consider genetic results in the context of the patient’s symptoms12.

Current Therapies The optimal therapies for autoinflammatory diseases should be effective at both decreasing chronic inflammation and preventing acute flares, but safe enough to be used for extended periods of time in these lifelong disorders14. It is important to note that all medications used to treat autoinflammatory disease are designed to disrupt normal signalling pathways in the innate response, thus increasing the risk of infection. Other potential concerns regarding increased risk of malignancy due to perturbation of naturally occurring cancer surveillance processes, a risk observed in conditions such as rheumatoid arthritis but not studied in great detail in the autoinflammatory conditions. Monitoring the response can be a challenge in these patients, and health-related quality of life and functional scales provide an important clue into patients’ perception of their health and may indicate the need for involvement of ancillary services to improve these domains13. Results from different therapeutic interventions can provide diagnostic data, for example., including incorporation of “hard stops” or “dose pushes”. While waiting for genetic testing results, practitioners could escalate doses of a drug for a two-week period and if symptoms respond to therapy, it could indicate certain disease and if there is no response, that could also eliminate certain autoinflammatory diseases12. Dosing frequency of these drugs should be driven by clinical phenotype and disease severity and adjusted to deliver symptom relief and improved quality of life13. Interleukin-1 inhibitors: Inhibition of the proinflammatory effects of IL-1 offers significant improvement in the symptoms of autoinflammatory conditions. Anakinra, rilonacept and canakinumab belong to this class. Clinical trials have repeatedly demonstrated that this class of medications can effectively manage the symptoms and improve the quality of life. These medications may have the potential to reduce the possibility of complications associated with autoinflammatory diseases such as hearing loss and amyloidosis. TNF-α inhibitors: Stems from the use of etanercept in patients with TRAPS. Case reports also have documented etanercept efficacy in patients with FMF, CAPS, and HIDS. Scattered reports of adalimumab and infliximab efficacy have been reported in FMF patients as well. Colchicine: For almost a half-century this has been the mainstay of therapy for patients with FMF. In up to 70% of patients, colchicine use results in cessation of febrile attacks while an additional 25% have a reduction in the severity and frequency of attacks. A small number of FMF patients (5%–10%) have no response to colchicine; in patients unresponsive or unable to tolerate it, IL-1 inhibitors offer a potential option. By far the most important benefit offered by colchicine is the reduced risk of amyloidosis. Clinical Development The future of therapeutic options for autoinflammatory disorders is optimistic. There is a steady stream of agents in development that target components of the proinflammatory pathway, critical to driving the autoinflammatory phenotype13. Some of the current clinical studies include a Phase II study of Tranilast (antiallergic drug) for treatment of CAPS; the MAMBA study, a dietary interventional study to know the influence on gut microbiota and Bechet’s syndrome; a Phase I study of IZD334 (inhibitor of the NLRP3 inflammasome) in patients with CAPS115. As per canakinumab recommendations for CAPS patients, it can be started after a course of routine vaccination, and no vaccination involving live vaccines should be administered during the therapy. Canakinumab is effective for patients with CAPS aged as young as 44 days old and has no effect on the ability to produce antibodies against standard childhood non-live vaccines16,17. Canakinumab treatment is associated with substantial glucocorticoid dose reduction or Journal for Clinical Studies 41

Therapeutics discontinuation in patients with JIA18 and for rapid disease control in patients with active TRAPS19, Schnitzler syndrome, Steroid Refractory Pyoderma Gangrenosum and Periodic Fever Syndromes15. Rilonacept helps to maintain inflammatory remission in patients with DIRA20. Studies demonstrating the involvement of ATP, potassium efflux, uric acid, or reactive oxygen species in the activation of the inflammasome point to a role for drugs targeting purine receptors (P2X7 inhibitors), potassium channels (glyburide like compounds), or uric acid levels (uricosuric agents). Drugs with membrane-stabilising functions or antioxidant properties might also be successful in blocking steps upstream of the inflammasome. The identification of heat shock protein chaperones in the inflammasome complex suggests a role for drugs targeting molecules that might affect inflammasome stability or function. The complex mechanisms of lysosomal IL-1β release or signal transduction pathways of IL-1 receptor signalling also provide a number of potential therapeutic targets, which could have effects on cytokine-mediated inflammation. Finally, biologic agents targeting downstream cytokines, such as IL-6, might also have a role in the therapy of autoinflammatory diseases. These drugs offer novel options for additional blockade of inflammatory signalling14. Conclusion ADs commonly arise as a result of mutations to genes that encode inflammasome components7. The additional causative mechanisms leading to exacerbated autoinflammation in both mutated and nonmutated pathogenic genes increase the complexity of manifestation of autoinflammatory diseases and their evolution. In this regard, indepth genetic studies using massively parallel sequencing techniques, epigenetic genome-wide profiling studies could be of great value as they would provide information of non-genetic landscapes for the better understanding of pathogenesis. Overall, the identification of such epigenetic dysregulation will allow us to relate the environmental contribution to autoinflammatory syndromes21. Clinical awareness of AD is lacking and it is believed that, at present, many cases go undiagnosed. The importance of controlled, functional inflammation for homeostasis cannot be ignored. Thus, therapeutic inflammasome inhibition needs to be balanced against the beneficial contribution of inflammasomes to innate immunity. As the mechanisms governing inflammasome regulation continue to evolve, so too will additional targets and therapies to regulate inflammasome activity during disease and most importantly, quality of life8,13. REFERENCES 1.

Galon J, Aksentijevich I, Mcdermott MF, O’Shea JJ, Kastner DL: TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol 2000; 12: 479-86. 2. Galeazzi M, Gasbarrini G, Ghirardello A et al. Autoinflammatory syndromes. Clin Exp Rheumatol. 2006;24(1 Suppl 40):S79-85. 3. Canna SW, Goldbach-Mansky R. New monogenic autoinflammatory diseases – A clinical overview. Semin Immunopathol 2015;37:387-943. 4. Dedeoglu F, Kim S. Autoinflammatory Disorders, in Pediatric Allergy: Principles and Practice (Third Edition), 2016. 5. Cush JJ. Autoinflammatory syndromes. Dermatol Clin 2013;31:471-80. 6. Zeft AS, Spalding SJ. Autoinflammatory syndromes: fever is not always a sign of infection. Cleve Clin J Med. 2012 Aug;79(8):569-81. 7. Gupta V, Ramam M. Monogenic Autoinflammatory Syndromes in Children: Through the Dermatologist's Lens. IJPD. 2018;19(3); 194-201. 8. Kenealy S, Creagh EM. Autoinflammatory Diseases: Consequences of Uncontrolled Inflammasome Activation. EMJ Allergy Immunol. 2018;3[1]:106-113. 9. Pathak S, McDermott MF, Savic S. Autoinflammatory diseases: update on classification diagnosis and management. Journal of Clinical Pathology 2017;70:1-8. 10. Grateau G, Hentgen V, Stojanovic KS, Jéru I, Amselem S, Steichen O. How should we approach classification of autoinflammatory diseases? Nature Reviews Rheumatology 2013 Vol: 9 (10):624. 11. "Comparison Chart for symptom search of autoinflammatory syndrome" cited 42 Journal for Clinical Studies

from 12. Spalding S. Overview of Autoinflammatory Syndromes cited from www. 13. Spalding S. Treatment of Autoinflammatory Conditions: Current Options and Future Directions. cited from 14. Hoffman HM. Therapy of autoinflammatory syndromes. J Allergy Clin Immunol. 2009;124(6): 1129–1140. 15. 'Clinical trials for Autoinflammatory Syndrome' cited from 16. Kuemmerle-Deschner Jasmin B, Haug I. Canakinumab in patients with cryopyrin associated periodic syndrome: an update for clinicians. Ther. Adv. Musculoskel Dis. 2013;5(6):315–329. 17. Brogan P, Hofer M, Kuemmerle-Deschner J et al. Efficacy, safety, and post-vaccination antibody titer data in children with CAPS treated with Canakinumab. Pediatr Rheumatol Online J. 2015;13(Suppl 1):P1. Published 2015 Sep 28. 18. Ruperto N, Brunner HI, Quartier P et al. Two randomized trials of Canakinumab in systemic juvenile idiopathic Arthritis. N Engl J Med. 2012;367:2396–2406. 19. Gattorno M, Obici L, Cattalini M, Tormey V, Abrams K, Davis N, Speziale A, Bhansali SG, Martini A, Lachmann HJ. Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): An open-label, phase II study. Ann. Rheum. Dis. 2017;76:173 178. 20. Garg M, de Jesus AA, Chapelle D et al. Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017;2(16) 21. Álvarez-Errico D, Vento-Tormo R, Ballestar E. Genetic and Epigenetic Determinants in Autoinflammatory Diseases. Front Immunol. 2017;8:318. Published 2017 Mar 22.

Dr. Bhanu Priya Basavaraju Bhanu Priya Basavaraju, MD, PhD is a Clinical Research Physician at Europital. She is a Clinical Pharmacologist and Research Physician with in-depth knowledge of clinical trials, research methodologies, safety aspects, GCP and regulatory requirements. In addition she also has handson experience. Email :

Dr. Ivana Kocsicska Dr. Ivana Kocsicska, MD is a Research Physician with 8 years of experience as a Medical Doctor, including 4 years of Clinical Research experience in Pharma and CRO in addition to 4 years of Clinical Practice experience. She also has in-depth knowledge', with hands-on experience in a variety of Therapeutic Areas including, but not limited to Oncology, Gastroenterology, Inflammatory Diseases, Neurology and Anesthesia. Email :

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

Volume 11 Issue 6


April 7-8 • Boston, MA

Carl June

Prof. of Immunotherapy, Perelman School of Medicine

Crystal Mackall

Director, Stanford Center for Cancer Cell Therapy

Peter Emtage Head of R&D

Caron Jacobson Medical Director

David Miklos Professor

Tickets are currently at the cheapest rate.Prices increase in January 2020. Go to to register and see the full agenda.

Revolutionizing patient outcomes in cancer therapies ALTERNATIVE CELL THERAPIES STREAM Delve into the innovative research that is shaping cancer targeting therapies in the race to develop off-the-shelf solid tumor targeting cell therapies.

COMMERCIALIZATION, REGULATION AND SAFETY STREAM International views on regulation and reimbursement, best practice for long term safety trials, novel data on toxicities in oncological cell therapies and how the translation of science is influencing clinical trials |


Identify novel methods for homing, infiltrating and overcoming suppression in the tumor microenvironment

Increase efficacies in “off the shelf” CAR-T therapies with checkpoint inhibitor combination therapies

Discover new technologies for the identification of novel biomarkers

VEIN-TO-VEIN STREAM Address the challenges of manufacturing cell therapies head on.

Journal for Clinical Studies 43


Retooling Risk-based Management Using AI As a clinical trial monitoring technique, risk-based monitoring (or RBM) has become the R&D industry’s de facto monitoring approach to achieve quality data, patient safety, protocol compliance, and efficiency. Moving away from 100% source data verification (SDV), RBM approaches emphasise critical data and processes and are designed to manage potential differences in the quality and experience of clinical trial sites. Regulators have long encouraged a risk-based approach, and, indeed, regulations now require a risk-proportionate approach to clinical trial (CT) design and conduct. However, organisations have faced challenges in successfully implementing and scaling RBM throughout the entire R&D process, and to make things even more difficult, there is no one-size-fits-all solution to overcome these challenges. On the other hand, CT monitoring has not fully taken advantage of technologies that could improve the quality and efficiency of sponsor oversight of clinical investigations. Therefore, recent debates have focused on how technology can support improvements in compliance, quality, and consistency – arguing that certain technological advancements, such as process automation and artificial intelligence, may be able to enhance the risk-based monitoring experience and lead to more precise decisionmaking in clinical monitoring. Humans versus Algorithms Strategies to reliably implement a streamlined RBM process essentially revolve around the central question of what requires a human versus what can be handled by a computer algorithm. In other words, how many steps or checks can we automate effectively and accurately, and what tasks should be handled by a person rather than a computer engine? Increasingly, centralised monitoring has become the core of riskbased monitoring. Here, a team of monitors (or clinical research associates, CRAs) reviews aggregate data from an ongoing trial using data analytical and visualisation tools to identify and correct issues with study site performance, patient safety, and other areas of risk. Although the rationale behind central monitoring is sound, many of the key monitoring processes currently rely on disparate tools that are based on the manual review of visualised data. What’s more, process execution is often complex and lacks standardisation across sites and functions, leading to inconsistencies. Automated workflows could reduce the manual review burden of central monitors and improve anomaly detection, providing a more efficient and possibly more standardised approach to risk management than the traditional, manual approach. In this scenario, manual review by a central monitor would only be necessary once clinically significant data are detected, engaging the expertise and attention of CRAs where they are most needed. 44 Journal for Clinical Studies

Automated Evaluation AI tools like predictive analytics, machine learning, and natural language processing (NLP) can, in theory, evaluate CT data and raise alerts whenever manual data reviews are needed or CT subjects don’t meet a study’s I/E criteria. Such process automation requires “supervised learning,” in which information from repeated observations of central monitor activities is fed into a machine learning algorithm to train the model (i.e., an artificial neural network comprised of several algorithms designed to recognise patterns). For effective process automation and supervised learning, structured data on all the study and subject level oversight elements are key so that the information processed by AI tools can, when necessary, quickly lead to an appropriate escalation to a medical monitor. The management of risk in CTs requires numerous time-intensive risk assessment-related checks that do not need a human monitor mining the data – if it is clear what to look for. With I/E criteria, for example, the task might be to find evidence of certain medical history or adverse events within a specified time frame. Since these are parameters that are reported across study sites, it is possible to write an algorithm and apply a rule engine using the massive amounts of incoming data to produce real-time evaluation results with much greater accuracy than a monitor can. With this approach, monitors would no longer carry the responsibility of performing timeconsuming checks by sifting through all the data manually; instead, their attention can be focused on analysing the evaluation results, looking for trends among subjects who no longer meet inclusion criteria, and engaging with study sites more deeply and critically. Similarly, automated data processing like this can be used to evaluate whether a subject is trending toward specified primary and secondary study endpoints. Once a pattern is identified, the central monitor can then work with the study’s medical team to determine next steps and apply this decision across study sites in a timely and efficient manner. Why Automate RBM? There are arguably multiple benefits to workflow automation and the use of technologies in RBM, ranging from reducing review time and cost to increasing accuracy, consistency, and — ultimately — patient safety. Automation proponents frequently provide the following benefit examples: •

Reduced review time and cost: Ensuring protocol compliance, patient safety, and data integrity and quality involves costly onsite visits and multiple time-consuming data reviews, including informed consent forms (ICFs), case report forms (CRFs), investigational product (IP) activities and logs, adverse event/serious adverse event (AE/SAE) compliance, safety data, and protocol compliance. For many data review activities, however, automation can reduce the review time from days to only a few hours, leaving more time for other important tasks, such as the review of standard operating procedures (SOPs) and good clinical practices (GCPs). With an automated RBM process, Volume 11 Issue 6




individual tasks also become scalable across study sites without the need to hire additional staff. Increased consistency: The experience and background of individual monitors and the level of accuracy with which monitoring tasks are performed on any given day can vary significantly. Process automation using engine rules can centralise the monitoring process by enabling consistent reporting across study sites, irrespective of the location of monitors. Increased patient safety: Producing more accurate evaluation results faster leads to much earlier signal detection, which in turn makes patients safer.

Meaningful CRA Roles Site monitors (or CRAs) are key to the entire site monitoring process, regardless of the level of automation. Although CRAs will not become redundant with process automation, their required skill set and range of responsibilities will most certainly change. CRAs have traditionally been involved with substantial amounts of quality verification onsite and in person and have thus been trained to perform a slew of cumbersome and time-intensive tasks, including drug reconciliation, essential document inspection, and SDV as well as real-time data reviews, ensuring compliance, and tracking key risk indicators (KRIs). However, CRAs have received very little or no training on how to engage with sites. With the application of new technologies and automation models, the knowledge and expertise of CRAs can be leveraged more meaningfully by taking cumbersome tasks off the CRA’s plate and freeing up valuable time and resources to shift their focus to areas that impact patient safety and data quality more directly. These areas include critical processes and adherence to protocol, SOPs, and GCP, to name just a few. For example, although onsite visits will become less frequent with automation, site contact and the need to build relationships and promote GCP will increase significantly. By taking over some of the workload, process automation also opens the door for training opportunities that upskill the role of CRAs, preparing monitors to adjust their engagement with sites based on unique needs and risks.

The Future of RBM Clinical trial systems and protocol designs are becoming increasingly more complex. Successful RBM that ensures patient safety, data quality, and operational efficiency depends on an integrated approach to risk assessment and monitoring throughout the entire R&D process. If done properly, automated centralised monitoring can facilitate early signal detection by streamlining the monitoring process and overcoming silos across sites and functions. Using KRIs and triggers, predictive analytics and machine learning can identify site- and subject-level risks quickly and accurately, and reveal issues with protocol compliance, eligibility, and enrolment. Successful, future clinical trials will involve RBM that is moving towards a simpler, more streamlined approach to risk assessment, removes subjectivity, and is tailored to each study site. Process automation and a transformed role of site monitors could be the linchpin of faster, more precise decision-making in clinical monitoring without compromising quality and safety.

Sandra H. Blumenrath A biologist by training, Sandra H. Blumenrath, PhD, MS, serves as science writer for the Drug Information Association (DIA) in Washington, DC. Dr. Blumenrath brings extensive experience in scientific research, education, and communication to her role at DIA, where she produces scientific and healthcare-related content for a variety of audiences. She graduated with a Master's of Science from the University of Copenhagen, Denmark, and earned her PhD at the University of Maryland, College Park, USA. Prior to joining DIA, Blumenrath worked as a scientist, educator, and content developer at the University of Maryland, the Howard Hughes Medical Institute (HHMI), and the American Association for the Advancement of Science (AAAS). Email:

Journal for Clinical Studies 45


Patient Pioneers: The Patient- and Site-centricity Movement Could patients participate safely in a clinical trial and hardly ever visit the study site in person? Surely this is achievable with modern technology and the support of dedicated research nurses whose passion is putting patients first. If that can be accomplished, then why stop there? New tech and skilled photographers can perhaps take clinical imaging and videography to the patient’s home too. Reducing the burden on both patients and their investigative sites can enable hospitals to enrol more quickly and participate in a greater number of studies, giving even more patients access to potentially life changing new drugs. The patient-centricity movement has been inspired by the empowerment of patients and patient advocacy groups through the internet, social media and new technology. This has caused a paradigm shift in the clinical research industry, with protocol developers now viewing mobile nursing as an almost essential ingredient to the success of their trial. Research is seeing an objective shift, making participation in a clinical study easier for patients by replacing site visits with appointments at home, school or work that, where appropriate, fit around the patient – relieving some of the burden on worklife and family. This demonstrates a duty of care to patients while at the same time providing sites with extra resources, freeing up their hospital time to recruit more patients, often allowing them to meet enrolment targets faster. The benefits to a sponsor and CRO partners are many; primarily, however, the early completion of a trial can mean longer patent protection for the drug and of course earlier access to much-needed medicines for patients. Let it be clear, clinical research still requires skilled site staff and the specialist equipment needed for assessment in many trials. An effective partnership between site personnel, third party research nursing companies, the pharmaceutical companies themselves and patients is critical for the success of a truly patient centric approach. Patient advocacy groups, along with social media, are also driving this movement, allowing both the patient and their families to take more control by providing additional information and support which would not have previously been available. This development has made patients, families and research question and challenge why we conduct clinical trials as we do… with the old adage “we always have” no longer an appropriate answer. The Solution? The solution seems simple: specialist GCP (Good Clinical Practice) trained research nurses delivering where appropriate, and the protocol allows, visits away from the research site. Vital signs, blood draws, IMP administration, urine sampling and ECGs can all be performed in a safe, convenient location for the patient when delivered by a suitably qualified research nurse, while visits which require specialist equipment remain at 46 Journal for Clinical Studies

the clinical site, for example MRI scans. The visits which could be appropriate for this service can be identified at the protocol development stage as part of the proposed schedule of events. One example of this is the administration of a subcutaneous infusion given to patients in their homes by utilising research nurses who were contracted to visit patients twice daily, in the morning and evening. The logistics of this can be challenging but achievable with a sponsor who is determined to show compassion to their patients and appreciates the sacrifices involved in participation. Imagine a family with two children suffering from a rare disease travelling from their home in Reykjavik, Iceland to a site in another country every two weeks. This example seems extreme but is not an uncommon situation for parents of children with orphan diseases to encounter. It’s an impossible decision: put your child and family through the stress of travelling regularly to receive treatment or do nothing, receive no additional treatment. This was mitigated by finding, recruiting and training a local research nurse, eliminating a significant number of round trips by visiting the children in their own home and enabling parents to continue working and children to attend school. For a sponsor, this can save a huge amount of money by avoiding having to pay for regular, often business class airfares for the study duration. For the family, it avoided the burden of participation becoming overwhelming which avoided the children ultimately dropping out of the trial. Another example of the service playing it’s part is in the distressing condition Epidermolysis Bullosa (EB), whose sufferers are mainly children living with a rare disease that means they are highly susceptible to contracting infection in their lesions. The nature of the disease makes it extremely difficult for EB sufferers to travel; even a trip to a nearby site may require specialist transport, chaperones, and much logistical planning. Research nurses visiting patients in their home reduced stress and kept the children as safe and pain-free as possible. Nurses trained in wound care expertly soaked off and re-dressed lesions which form on patients’ paper-thin skin, with experience in paediatric trials and the skilled sensitivity required to manage such fragile participants. Furthermore, one of the endpoints in the study was image-based and the nurses were able to use specialist calibrated cameras to monitor the wounds and further prevent the need for site visits. Clinical photographers performed ongoing quality control, advising nurses if images need to be retaken and permitting the relevant data to be collected without having to repeat visits. This innovative approach enabled the sponsor to minimise patient travel, while maximising the time which research nurses have with patients, capturing key data and benefiting all stakeholders. Sites received CRF data directly from the nurse, as well as access to high-resolution images per subject, while families experienced as little impact as possible on their daily lives. The condition means they already have much to deal with and we believe this approach benefited all involved. Volume 11 Issue 6

Technology This service has impressed families and sponsors alike. In one example, a sponsor was struggling with children dropping out of a rare disease study. The protocol required children to attend weekly hospital visits. This can lead to a major loss of time at school, loss of earnings for their parents due to lost time from work, and general inconvenience. The sponsor adjusted the protocol to allow 75% of all visits to be conducted within the child’s home, rather than them having to attend the hospital. Research nurses visited the children in their homes three out of every four weeks for a two-year treatment period. After the two years, not one child had dropped out of the study. Parents and their children were delighted with the rapport built up, and it meant the loss of school time, loss of earnings of parents, and general inconvenience was kept to a minimum.

These examples highlight how taking care of patient needs boosts recruitment and supports retention, while the integrity of robust high-quality data increases the likelihood of a successful study and shortens time to market. Still not convinced? Take it from the patients themselves. The comments below were from patients and their families participating in a multi-centre global Duchenne Muscular Dystrophy study. All are speaking about how research nurses aided their ability to contribute to this study. •

“The fact that we do not have to travel to site every time we do analytical work is already very comfortable and good for the patient.”

“Our son was more relaxed having bloods taken at home; he found it a lot easier only having one nurse and not lots of people in the room, with time to make sure he was ok and relaxed. I found it a lot less stressful as we would need to travel a great distance to hospital and have to pull over to put “magic cream” on his arms. It’s more of a relaxed experience with yourself.”

“The home delivery service was excellent, impeccable both for the punctuality and for the professionalism and availability. The nurse also proved very understanding with the problems of the child who was happy about this feeling reassured by this attitude. The service was very efficient as was the nurse we met. She was very timely and always behaved well with my son. In practice, the service was perfect.”

“My opinion about the nursing service was that it was all perfect. The nurse with her work and with the family, we are pleased and wish this service success in future.”

“My experience with our nurse who took care of the home samples for the trial was certainly positive. She is a person who makes herself loved by parents and especially by the child who willingly accepted samples that are notoriously unpleasant at the age of nine. The nurses’ joy, patience and willingness to play and involve the whole family was very good and we are happy that among many doctors, nurses and therapists, there was also our nurse we saw regularly.”

There is also the rise of the virtual clinical trial, which technology has made much more achievable. ‘Siteless’, or centralised studies run the risk of becoming impersonal and detached, however: patients often decide to enrol on trials in order to have more access to healthcare professionals, not less. Patient materials, advertising campaigns, apps and other support mechanisms mean nothing if patients become disengaged or feel abandoned, and ultimately discontinue involvement. In a hybrid approach, research nurses can provide that highly valuable faceto-face engagement, building a rapport with their patients, helping to navigate them through the study, and increasing their likelihood of compliance. Patient advocacy is becoming more than just a buzz word and it will drive the future of clinical research as patients and their families become more empowered with greater access to information and support. It should be acknowledged that technology will play an increasingly important part of clinical care including research, but can we or should we ever replace the human touch? The introduction of specialist trained clinical research nurses enables the smoothest possible clinical trials experience for patients and families. This approach also gives the patients a single point of contact who they see regularly and build a relationship with, resulting in a more realistic view of the patient’s views and needs, something technology alone could never deliver. Thus, perhaps pioneering patients is about empowerment and ensuring we can offer a truly patient-centric solution, by offering seamless clinical research solutions involving sites, technology, nurses and – most importantly – the patients.

Helen Springford Helen Springford was promoted to Chief Operating Officer at Illingworth Research Group in June 2019. She has over 25 years experience within the clinical trials arena. Having spent five years as a research nurse managing over 25 cardiology clinical trials in hospital and subsequent to that, seven years in clinical project management within both a CRO and big pharma setting, Helen truly appreciates the importance and difference a patient-centric approach can make. Email:

Journal for Clinical Studies 47


Driving Clinical Trials Forward: The Benefits of Establishing a Strategic Partnership for Flow Cytometry Targeted therapies for use in clinical studies, such as those in immuno-oncology (I-O), are the future of pharmaceuticals. Critically assessing the efficacy and safety of a targeted molecule in I-O trials is essential. Flow cytometry is a sophisticated technology that can provide specific information on how biologics and other targeted therapies interact with living cells on a cellular level in clinical trials. With laser technology and single cell analysis, flow cytometry precisely measures how specifically and efficiently a targeted therapy binds to its intended cellular receptor. In this way, flow cytometry can measure the proportion of available target receptors to which a drug candidate binds. This assessment may correlate with a study drug’s therapeutic potential and clinical efficacy. Flow cytometry can also determine how treated cells or test subjects are responding to treatment by measuring the presence of other molecules in biological matrices, such as blood or tissue samples. These capabilities make flow cytometric assays invaluable for characterising and evaluating preclinical research, demonstrating proof-of-concept, and monitoring patient outcomes in clinical trials. Many standardised flow cytometric assays have been validated for common tests, and may be off-the-shelf, for example quantifying specific intracellular biomarkers, cytokines and immune cells such as T, B and natural killer lymphocytes. However, detecting the presence of molecules, such as bi-specific monoclonal antibodies or checkpoint inhibitors, studied in a number of I-O trials, that target specific receptors, requires custom flow cytometric assays specific to these molecular targets. In addition, global studies are now common and, regardless of where and when they are done, require an infrastructure of laboratories capable of ensuring comparable results for study tests, including those for flow cytometric assays. Global capabilities require significant investment, not only in sample collection and transportation monitoring, but also expertise and quality control experience to create and maintain. Given the cost, time and expertise needed to develop and qualify robust flow cytometric capabilities internally, many sponsors find strategic partnering the best solution. A partner with the scientific expertise, global resources and mission commitment required to effectively develop and uniformly execute flow cytometry can help drive successful clinical trials forward, while increasing the overall efficiency of a pharmaceutical sponsor’s drug development programme.   This article outlines best practices in developing and implementing flow cytometric assays for clinical study samples, as well as the benefits of adopting a strategic partner to perform these complex assays.  A Customised Approach to Flow Cytometry Customised assays used in research and early clinical trials are major factors in improving targeted therapy development efficiency. Because of the specificity of these customised assays, 48 Journal for Clinical Studies

they can powerfully predict the performance potential of targeted compounds ‘in vivo’, and precisely measure performance in clinical trials. Three types of custom flow cytometry assays and how they can be used to predict and assess targeted therapy performance are detailed below. 1. Receptor occupancy assays – The potential effectiveness of drugs and biologics can be assessed using receptor occupancy (RO) assays, which measure how efficiently the compound binds to cell surface receptors. The classic approach to RO cytometric assays is to develop two monoclonal antibodies that bind to a target protein: one that is non-competitive, meaning it binds to all target receptors even if they are already occupied by the test compound; and one that is competitive, meaning it only binds to target receptors not occupied by the test compound. Both antibodies are tagged with different fluorochromes.   When added to a cell sample that has been treated with the test compound, the non-competitive antibody attaches to all target receptors, and these can be counted using flow cytometry to determine the total number of potential receptor positive cells in the sample. The competitive antibody binds only to unoccupied target receptors and dividing this number by the number of total target receptors reveals the proportion of receptors bound by the test compound (see Figure 1). 

Figure 1. Determination of Receptor Occupancy Using Competitive and Non-Competitive Antibodies. A cell membrane receptor serves as target for two different antibodies, one that is non-competitive ( ) and one that is competitive ( ) for the epitope recognised by the test drug ( ). A saturating dose of unconjugated test drug can be used as a pretreatment to bind all the target epitopes and determine maximal binding. Ideally, this binding is similar to that obtained with the non-competitive antibody.

An alternate method involves sequentially treating the test sample with tagged competitive antibodies and antibodies that bind to the target compound bound to receptors, directly measuring bound and unbound receptors (see Figure 2). In general, the higher the proportion of receptors bound, the greater the potential efficacy of the compound. Running RO tests on samples treated with different concentrations and exposure times in drug development and preclinical trials can generate useful pharmacodynamic information on which compounds are likely to be successful. Flow cytometric RO tests in clinical trials can be used to Volume 11 Issue 6

Technology custom flow cytometric assays and performing standardised assays, many sponsors choose to outsource these functions to experts. Regardless of whether assay design and execution are outsourced or undertaken internally, a close working partnership between product researchers, clinical study design and operations, regulatory and flow cytometry experts is essential for success.

Figure 2. Receptor Occupancy Assay Experimental Design Using A Direct Detection Approach. A cell membrane receptor serves as target for an antibody that is competitive ( ) for the epitope recognised by the test drug ( ). Wherever free target epitopes exist, competitive antibody will bind. Unconjugated bound study drug can be detected with a secondary antibody ( ). A saturatinf dose of unconjugated test drug can be used as a pretreatment to bind all target epitopes and determine maximal binding. Free venus bound receptor is quantitated and percent receptor occupancy is determined.

inform go/no-go decisions in early clinical trials and determine dosage levels in later trials to assess clinical effectiveness. An analysis of clinical trials using flow cytometry between 2006 and 2018 found that these methods were most often used in Phase I, I / II, and Phase II studies. Since every target of a test compound is receptor-specific, a customised RO assay is required for every compound tested. 2. Immunophenotyping assays – Binding a targeted compound to one cell type may trigger intracellular reactions that affect other immune cells and the immune response, which can be potentially dangerous. Therefore, immunophenotyping assays must be run concurrently with RO tests to detect these effects. Immunophenotyping involves identifying a range of markers for immune activity in blood or tissue samples. These include the presence and quantification of sample characteristics including white blood cell types, T cells and B cells with specific biomarkers. Like RO assays, these tests use antibodies tagged with fluorescent molecules that bind to specific molecular targets, allowing cells to be identified and counted by type. Many of these assays are standard and commonly used, though custom assays for identifying specific antigens may also be required. 3. Functional assays – Functional assays seek to characterise not only the presence of specific immune cells and factors, but also how they are affected by a candidate compound. Subjects are treated with the compound, and flow cytometry is used to assess changes before and after stimulation in immune cell subpopulations. For example, intracellular cytokine production can be measured, which can provide an indication of magnitude of response. This gives additional insight into the pharmacodynamics and potential efficacy and side-effects of candidate compounds.

Communication, early, often and ongoing – Open communication about the goals, methods and technical details of an assay programme between developers and test experts is critical to matching assay approaches to specific study needs. Whether the need is for consistent execution of a panel of previously determined standardised assays; refinement, validation and execution of an existing custom assay; or conceptualising and developing new custom assays, establishing early on a common understanding of the requirements for the assay makes the entire process easier and more efficient. Because clinical development programmes are iterative, with details and goals shifting as results and evidence accumulate, ongoing communication and collaboration are needed to ensure that assays address changing needs. For example, as a compound advances through clinical trials, adjustments to the assay protocol or interpretation framework are required when differences exist between the health of populations used to develop the assay and the disease indication of the study population. Also various state and national guidelines, typically those promulgated by the US Food and Drug Administration and the New York State Department of Health, must be considered depending on whether the assay will be used for research only, clinical trials or clinical treatment. For portfolios with multiple products, it is helpful to take a strategic communication approach throughout all product development stages. This can ensure that tests run during early development provide the necessary information to inform clinical trial design, and inform decisions about which candidates or programmes have the best chance of success.   Robust and use-appropriate assay method validation process – Demonstrating the scientific integrity of a study, not to mention winning regulatory approval, requires the presentation of methodologically and statistically reliable clinical evidence. Because flow cytometric assays provide much of the evidence supporting product development, test programmes must be designed to ensure they address relevant research and clinical questions in a way that will pass scientific and statistical scrutiny. It is also necessary to ensure assays are characterised for the intended use of the results, such as for exploratory, clinical diagnostic for patient management during a trial, or as a companion diagnostic test for drug treatment.

Taken together, these three types of flow cytometric assays are powerful tools for developing targeted therapies. However, they do entail highly technical processes and clinical experience which are presented below. Best Practices for Developing and Implementing Flow Cytometric Assays in Clinical Development Programmes Due to the complexity and highly technical nature of developing

Journal for Clinical Studies 49


Keep in mind that the evidence threshold differs in the development process, according to the context of use for an assay, with its stringency increasing as patient risk increases. For example, assays with exploratory endpoints may be validated for use across laboratories and study sites with an initial demonstration of 20 to 30 per cent variation in precision for standard cell samples.   At the other end of the patient risk spectrum, however, flow cytometric assay requirements are more stringent. Any assay used to support patient treatment decisions, whether in clinical trials or in vitro diagnostic tests for monitoring clinical treatment, must undergo a more rigorous assessment across test laboratories. In these cases, the observed variation in results from an assay should be lower, as achieved by using increased sample sizes and postcollection time points. For all flow cytometric methods to be implemented in clinical trials, validation processes should include: •

A detailed plan including experiment outlines and goals, such as timeline and specific types of cells or phenotypes that will be identified; intended assay use and any associated acceptance criteria; descriptions of assay methods employed; and any equipment, reagents, test cell lines or other standardised supplies needed. Quantitative assessments of assay characteristics, including feasibility for measuring theoretically relevant variables; biologic variability across sample sources when needed; precision of measurement; stability of results over time and across sites; and statistical validation of results. Documentation of all processes, methods, instrumentation and materials sufficient to reproduce results.

Note that determining an appropriate assay for a particular clinical application is as much an art as it is a science. Experts 50 Journal for Clinical Studies

with extensive experience developing, optimising and validating complex cell-based methods that can troubleshoot issues as they arise are an invaluable asset for moving development programmes and clinical trials forward. Robust data reporting, analysis and validation process – Similarly, demonstrating assay data integrity and significance are essential for showing study scientific integrity and passing regulatory muster. Details of data collection methods, raw data results and statistical frameworks, assumptions and calculations should be outlined to ensure reliability, and developed and documented to ensure they meet requirements. Quality control – Documenting quality control is critical for demonstrating assay reliability. Aspects that must be documented include:   • Process quality control. This includes ensuring appropriate sample collection, timely transportation, and any necessary temperature or other environmental control required to ensure sample integrity. It also includes ensuring processes for preparing and analysing samples are uniform at laboratories around the world. • Fluorescence quality control. This entails ensuring that fluorescent tags necessary for identifying cells or cellassociated biomarkers are consistent over time and across instruments, whether in the same laboratory or globally, and that antibodies for attaching them to targets are specific and reliable. • Customised assay quality control. Ensures that assays and processes – such as any special cell line, sample preparation and quantitative or qualitative evidence – required to measure or demonstrate a particular effect are developed, and scientifically and statistically validated as needed. Volume 11 Issue 6

Technology these partnerships can aid in developing high-value products at lower cost and in less time than developing a comparable internal capability. Contributions to this article were made by members of ICON’s R&D Department: Li Zhou Ph.D., Christina D. Swenson Ph.D., Karen J. Quadrini Ph.D., Thomas W. Mc Closkey, Ph.D., and Krista D. Buono Ph.D. REFERENCES 1.



Benefits of Adopting a Strategic Flow Cytometry Partnership Ensuring that the highly technical aspects of flow cytometric assays are suitable for specific development purposes is both valuable and difficult – particularly for sponsors with limited experience developing targeted therapies. Because many sponsors do not have the ability to develop custom flow cytometric assays in house, a strategic relationship with an experienced partner can assist sponsors to capitalise on the benefits of flow cytometry. Partners build on scientist-to-scientist relationships and have established regional laboratories and sample handling capabilities for supporting basic research and global clinical trials. Moreover,







Lee JW, Devanarayan V, Barrett YC, Weiner R, Allinson J, Fountain S, Keller S, Weinryb I, Green M, Duan L, Rogers JA, Millham R, O Brien PJ, Sailstad J, Khan M, Ray C and Wagner JA. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res 2006; 23:312328. doi: 10.1007/s11095-005-9045-3. Cunliffe J, Derbyshire N, Keeler S and Coldwell R. An approach to the validation of flow cytometry methods. Pharm Res 2009; 26:2551. https://doi. org/10.1007/s11095-009-9972-5. Green CL, Brown L, Stewart JJ, Xu Y, Litwin V and Mc Closkey TW. Recommendations for the validation of flow cytometric testing during drug development: instrumentation, J Immunol Methods, 363: 104-109, 2011. O’Hara DM, Xu Y, Liang Z, Reddy MP, Wu DY and Litwin V. Recommendations for the validation of flow cytometric testing during drug development: II assays. J Immunol Methods 2011; 363(2):120-134. Wood B, Jevremovic D, Bene MC, Yan M, Jacobs P and Litwin, V. Validation of cell-based fluorescence assays: practice guidelines from the ICSH and ICCS - part V - assay performance criteria. Cytometry B Clin Cytom 2013; 84(5):315–323. Stewart JJ, Green CL, Jones N, Liang M, Xu Y, Wilkins DEC, Moulard M, Czechowska K, Lanham D, Mc Closkey TW, Ferbas J, van der Strate BWA, Hogerkorp CM, Wyant T, Lackey A and Litwin V. Role of receptor occupancy assays by flow cytometry in drug development. Cytometry Part B: Clinical Cytometry 2016; 90B:110-116. Green CL, Stewart JJ, Hogerkorp CM, Lackey A, Jones N, Liang M, Xu Y, Ferbas J, Moulard M, Czechowska K, Mc Closkey TW, van der Strate, BWA, Wilkins DEC, Lanham D, Wyant T and Litwin V. Recommendations for the development and validation of flow cytometry based receptor occupancy assays. Cytometry Part B: Clinical Cytometry 2016; 90B:141-149. Quadrini KJ, Hegelund AC, Cortes KE, Xue C, Kennelly SM, Ji H, Hogerkorp CM and Mc Closkey TW. Validation of a flow cytometry based assay to assess C5aR receptor occupancy on neutrophils and monocytes for use in drug development. Cytometry Part B: Clinical Cytometry 2016; 90B:177-190. Selliah N, Eck S, Green C, Oldaker T, Stewart J, Vitaliti A and Litwin V. Flow cytometry method validation protocols. Current Protocols in Cytometry 2019; 87, e53. doi: 10.1002/cpcy.53.

ICON’s R&D Department Contributions to this article were made by members of ICON’s R&D Department: Li Zhou Ph.D., Senior Research Scientist; Christina D. Swenson Ph.D., Medical Writer; Karen J. Quadrini Ph.D., Senior Research Scientist; Thomas W. Mc Closkey, Ph.D., Director, Cell Biology Research & Development; and Krista D. Buono Ph.D., Senior Research Scientist ICON’s R&D Department, located in Farmingdale, NY, develops and validates fit-for-purpose flow cytometric biomarker assays and qualifies client developed assays for use in clinical trials. The scientific team, with over 75 years of combined experience, works closely with ICON partners to provide complex flow cytometry assays that reduce cost, enhance quality and expedite drug development. Email: Email:

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Logistics & Supply Chain Management

Transforming Healthcare – How Curative Therapies will Disrupt the Market The shift to curative treatments promises to transform the entire healthcare ecosystem. Patients whose conditions were previously managed through ongoing, long-term medication can now be cured through specific courses of treatment. This transforms their lives – but, as this article explains, it also has a disruptive effect on the wider market, shifting payers’ expenditure, increasing the importance of first-mover advantage for pharmaceutical companies, and changing care models for healthcare providers. The combination of scientific advances, increasing patient expectations, emergence of new technologies and growing concerns around cost are driving an unprecedented level of change, encompassing whole healthcare systems across the globe.

Therapeutic, for patients with inherited retinal diseases (IRDs). Cell therapies • Genetically re-engineering cells, such as CAR-T and stem cell treatments.

The number of curative treatments is increasing. Analysis of the clinical trials pipeline undertaken by Arthur D. Little shows that approximately five per cent of all drugs currently registered as active in are potentially curative1. The highest share of potentially curative treatments can be observed in Phase I (the earliest testing phase), which indicates that we will see a significant increase in the number of curative treatments reaching the market over the next 10 years.

One key part of this is the shift towards curative treatment for conditions that were previously considered chronic or untreatable. Essentially, patients that previously had to rely on ongoing medication can now be cured through a specific, time-limited course of treatment, which transforms their lives. This will disrupt the entire healthcare ecosystem. With curative treatments, payers’ expenditure drastically shifts from ongoing, longterm and relatively low-cost drugs to large, front-loaded therapy costs. Revenues for therapy providers will also shift, focusing around when they are introduced to the market. This transformation will lead to a number of consequences for patients, policy-makers, payers, providers, and pharma companies alike. In this article, we will take a deeper look at what those consequences are, and what can be done to address them. What are Curative Therapies? Our definition of a curative therapy is a time-limited treatment that removes the symptoms of a disease through permanent (or semipermanent) correction of the underlying condition. In contrast, a pill that a patient needs to take for the rest of their life to manage symptoms or disease progression is not curative. From our analysis, we have defined three archetypes of curative treatments: • •

Biology-modifying drugs • A good example of this is the hepatitis C virus (HCV) treatment Sovaldi, created by Gilead Sciences. Gene therapy • Gene therapy addresses underlying causes of a disease by correcting the missing or mutated genes. It can be divided into somatic and germ-line therapy, with the latter treatment curing not only the current patient, but also their future offspring. Examples include Luxturna from Spark

52 Journal for Clinical Studies

Implications for Care Provision Curative treatments have the potential to lower the overall impact and cost that particular diseases have on healthcare systems, as they eliminate the need for long-term chronic care. This will change the way we treat patients and impact how healthcare providers organise care and its delivery. The sales and upfront cost profiles of these new treatments will have an immense impact on payers and providers. It will demand the development of new models for payment and reimbursement in order for their introduction to be affordable. This impact is already being seen. Many one-payer health systems have observed significant increases in drug spending directly attributable to the introduction of Sovaldi, which costs $84,000 for a three-month course of treatment. For budgetary reasons, England’s National Health Service (NHS) tried to delay its availability (along with next-generation therapy Havoni) to patients, and looked to cap the annual number receiving the treatment. In the US, some state Medicaid programmes and private health insurers restricted access to curative therapies, which has led to warnings from federal officials and lawsuits from patients. Medicaid programs in 29 states2 said Sovaldi was the first or second most costly pharmaceutical outlay that they had to make. While payers recognise that drugs such as Sovaldi lead to bigger medical Volume 11 Issue 6

Logistics & Supply Chain Management savings later on – for example, if hepatitis C is left untreated, it can lead to cirrhosis, liver failure or liver cancer – its immediate financial impact has a profound impact on the current budgets of insurers and payers. And this is for a drug that is relatively low cost compared to some curative treatments. In contrast, imagine the cost and operational impact for a cancer centre if multiple expensive curative treatments were introduced in the same year. This higher variability in costs makes it increasingly difficult to plan and budget, aspects that are key to healthcare systems given that they are under continuous cost pressure. Implications for Pharma Companies The revenue models for curative treatments are radically different from those for existing drugs. Traditionally, new therapies tend to show a modest bump in sales when introduced, which then stabilises and remains steady until patent expiration. This delivers predictable revenues and requires stable, ongoing drug production. Curative therapies, however, are one-off treatments. Once a patient has been treated, they will not require any further treatment. That means peak sales will appear earlier and be higher than for traditional therapies, as the populations of eligible patients will all be treated in a short spaces of time. However, sales will then drop off much faster once this pentup demand has been met. Figure 1 below compares revenues for a traditional therapy versus a curative one.

Figure 2: Sales for hepatitis C curative treatments (2013–2018)

the leading treatment for new patients. While this has managed to gain AbbVie a strong long-term market position, the company clearly missed out on the lion’s share of treatment revenues. The unusual sales profile shown in Figure 2 had a clear and unexpected effect on Gilead’s share price. Even though investors understood that Sovaldi was a curative treatment, shareholders weren’t expecting the peak and consequent drop in sales, which led to the share price slumping as sales naturally slowed down. This demonstrates that pharma companies will need to anticipate this issue and either educate the market or, more likely, try to balance product portfolios to counteract potential large swings in sales.

Figure 3: Gilead share price movement

Figure 1: Revenue curves for traditional vs curative treatments (illustrative)

This new model represents a clear break from typical pharma sales profiles, which will, in turn, impact the way the pharma organisation needs to be set up and function. Manufacturing needs to be able to deliver large-scale production in the short term, but once the peak has passed, it needs to be scaled down to more modest, “steady-state” production volumes. The same is true for marketing and sales. This also affects competitive products. When there is already unmet demand, the first mover really does have a significant advantage. It can effectively eliminate any market opportunities for competitors by curing the backlog of patients either waiting for treatment or receiving chronic care. The only remaining need will then be from newly diagnosed patients. Case study: Sovaldi A recent example of the shift in sales patterns is Sovaldi, which was launched in 2013. This is the first curative treatment that effectively cures 99 per cent of hepatitis C virus cases. When competitors entered the market in 2014, a large share of patients had already been treated. Based on its successful record, Sovaldi was the natural first choice for prescribing to new patients. To demonstrate the importance of first-mover advantage, when AbbVie launched its first hepatitis C drug about 12 months later, sales were disappointing. However, in 2018, it launched a significantly improved follow-up drug, Mavyret, which is currently

Key Factors to Consider in Anticipation of Curative Therapies Curative therapies have the potential to disrupt the healthcare market, and most importantly, to dramatically improve the lives of patients struggling with significant, long-term conditions. In order to control this disruption and maximise their positive impact, a number of questions need to be addressed by treatment providers, care providers, payers and policy-makers. Payers and Policy-makers In a world of limited resources, tough decisions need to be made. While curative treatments have the potential to reduce costs down the line, they are increasingly expensive, which adds to the accelerating overall cost pressure on healthcare systems. What diseases should be treated over others, what curative treatments should be funded, and for whom? These are ethical questions that need to be answered, and the answers will have significant impact on patients and their health. The timing of costs also needs to be controlled, with the financial impact of new treatments evened out to reduce cost volatility. There are a number of potential payment model options that could be used, either alone or in combination, to address this: •

Survival/outcomes-based payment – The treatment is only paid for when successful. This shifts part of the risk of unsuccessful treatment to pharma companies, effectively lowering the risk that payers will have to fund both an expensive treatment and continued treatment for a chronic condition. Interim payments – Payments are spread out over longer periods. This aligns the cost profile much more closely to that of a chronic/long-term treatment and reduces the immediate cost for payers. Journal for Clinical Studies 53

Logistics & Supply Chain Management •

Companion diagnostic-based payment – Treatments are only approved when a companion diagnostic has shown that the patient is highly likely to respond to the treatment. This also serves to limit the number of patients subjected to ineffective treatments, which, by extension, also reduces costs for payers.

approval and be first on market. If first approval is possible, but they face competition, they should assess how they can accelerate time to market to beat rivals. If first approval is not a possibility, they need to be prepared to significantly revalue potential market revenues, move away from the project, or know for sure that the product is superior to the competition.

If the payer is a private insurance company, its models for calculating risks and costs, as well as for pricing, will need to be changed, as past actuarial data will no longer be accurate.

Pharma companies also need to rethink their reimbursement models. The greater the certainty that a treatment will be curative, the greater its worth, and this enables it to command higher prices. If a specific patient type is responsive, the company needs to ensure that there are diagnostics in place to demonstrate this. It will need to charge more if it knows the treatment is going to work and reduce long-term costs, or leverage the use of contingent payments to allow care providers to pay over time or when results have been achieved. This makes it hard for anyone else to break into the market.

In addition, payers and policy-makers will need prior warning when new curative treatments are about to hit the market, so that they have time to accurately plan, budget, and adapt policies. Care Providers Care providers are facing a multitude of changes due to the increase in curative treatments. They will need to shift their organisations and infrastructure from chronic care and surgery to curative treatments. Care providers will need to shift their financial models, as well as their operating models, to better account for swift changes in standards of care. A key component here is training of staff – as new treatments are introduced more often and for shorter time spans, training models will need to be adapted to focus on faster learning and higher degrees of staff specialisation. Pharma Companies Ensuring first-mover advantage is key for any pharma companies that operate in fields in which curative treatments can potentially be introduced. They need to focus on market intelligence and build portfolio decision-making models that take into account the unique properties of curative treatments. They will need to understand if the new treatments they are developing are curative, if products being developed by competitors are curative, what their own time to market is, and whether they can gain first regulatory

54 Journal for Clinical Studies

Companies will also require a proactive approach to portfolio management. They must understand the timing of revenues and plan for dealing with revenue cycles that are radically different from the pharma industry standard. Finding a way to balance revenue either through portfolio management, business/price model changes, or financial planning could help avoid large shareprice fluctuations. Factoring companies could become important players in the industry by financing peak manufacturing costs, and then taking upfront revenue and paying it out to the pharma company over time, thus helping to manage peaks in costs and revenue. Case study: Luxturna • Luxturna (voretigene neparvovec) from Spark Therapeutic is the first FDA-approached gene therapy for patients with inherited retinal diseases (also called inherited retinal degeneration, or IRD) caused by mutations in both copies of the RPE65 gene. • Patients suffering from IRD risk partial or complete blindness,

Volume 11 Issue 6

Logistics & Supply Chain Management •

• •

• •

and while current treatments can help slow down the advancement of IRD, they cannot stop disease progression. Luxturna carries a list price of $850,000 (or $425,000 per eye) – a high cost for payers to bear despite there being a limited number of patients. In order to address this, Spark set up a payment agreement with Harvard Pilgrim Health Care, the first health plan to cover the treatment. Under its terms, Harvard Pilgrim Health Care will only need to pay for patients that are successfully treated. The outcomes-based contract pays Spark in full only if the drug works after 30 months, with an interim payment based on preliminary effects at 30–90 days. Before being treated, patients will need to undergo genetic testing to confirm the gene mutation, and it must be confirmed that the patient has enough viable retinal cells to restore or preserve vision.

Insight for the Executive An increase in curative treatments will lead to tremendous clinical progress and drastically improved quality of life for affected patients. It will also, however, put significant pressure on healthcare systems, as well as change revenue models for pharma companies providing such treatments. High initial sales caused by the treatment of large backlogs will lead to distinct first-mover advantages and large fluctuations in production volumes. In order to prepare for this major change, there are a number of concrete items that policy-makers and executives in the healthcare industry must focus on: •

New payment and reimbursement models need to be put in place. Pharmaceutical companies developing curative treatments need to engage with care providers, policy-makers, and payers to develop financial models that are sustainable for all parties. Engaging with payers and providers early on will also help them plan and prepare for implementation of new treatments. In order for patients to fully benefit from the new developments, healthcare provider operations need to be able to accommodate rapid changes in care practices. Training, education, facilities management, and executive decision-making processes will all be impacted. Policy-makers, payers, and care providers should start to build up better analytical capabilities tailored to assessment of new curative treatments and their implications. These must focus on quantifying the value of the new therapies, in terms of both the value to patients (improved quality of life, increased lifespan) and the financial side (the upfront cost of treatment versus the long-term costs of managing the disease, as well as the cost of treating medical issues caused by the disease). Models for quantifying and analysing treatment impact should then be used to make qualified decisions around treatment funding and prioritisation of healthcare spend in order to balance expectations around

treatment access with overall cost and value. Pharmaceutical companies need to review their drug pipelines, portfolio management practices, and launch plans (marketing, sales, manufacturing) to accommodate the different properties of curative treatments so that they can proactively push for first-mover position or adapt their strategies if that isn’t possible.

Developing these new capabilities across the healthcare system will be essential to ensuring that new therapies can be brought to market and implemented in clinical practice in an efficient and sustainable manner, prioritising high-value treatments to the benefit of patients.

Craig Wylie Craig Wylie is a Managing Partner in the New York office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice. Email:

Dr. Thomas Unger Thomas Unger is an Associate Director in the San Francisco office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice. Email:

Dr. Ulrica Sehlstedt Ulrica Sehlstedt is a Managing Partner in the Stockholm office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice. Email:

Rebecka Axelsson Wadman Rebecka Axelsson Wadman is a Principal in the Stockholm office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice. Email:

Satoshi Ohara Satoshi Ohara is a Partner in the Japan office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice. Email:

Arthur D. Little

Arthur D. Little has been at the forefront of innovation since 1886. We are an acknowledged thought leader in linking strategy, innovation and transformation in technology-intensive and converging industries. 

Vikas Kharbanda Vikas Kharbanda is a Partner in the Dubai office of Arthur D. Little and a member of the Healthcare and Life Sciences Practice.

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