JCS Volume 12 Issue 6 by Senglobal

Volume 12 Issue 6

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

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Regenerative Medicine Hype and Hope or Safety and Efficacy? Psychedelics Make a Comeback To Treat Mental Health Conditions For Paediatric Participants Patient-centric Trials Must Be Family-centric Minimising Risk and Maximising Efficiency By taking a Strategic Approach to Comparative Trial Supply

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Contents

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker BUSINESS DEVELOPMENT Keith Martinez-Hoareaux keith@pharmapubs.com EDITORIAL MANAGER Ana De Jesus ana@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Virginia Toteva virginia@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications J101 Tower Bridge Business Complex London, SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

FOREWORD

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Psychedelics Make a Comeback to Treat Mental Health Conditions

The FDA has approved only two products to treat TRD, and several companies are evaluating products with psychedelic properties as a new approach to previously untreatable mental health conditions. Jaime Polychrones at Clarivate shows how psychedelics are being explored worldwide, with Johns Hopkins opening the Center for Psychedelic and Conscious Research in the US and in the UK, the Imperial College opened the Centre for Psychedelic Research. 8

Combating COVID-19 Cold Chain Challenges

As the world continues to react to the impact of the global pandemic, by far the most significant challenges currently for pharmaceutical cold chain logistics are the ongoing repercussions relating to COVID-19. Adam Tetz at Peli BioThermal addresses the current challenges within cold chain logistics operations and outlines what steps must be taken to meet cold chain requirements. 10 Practical Implications of Undertaking Clinical Trials during the COVID-19 Pandemic Faced with the coronavirus pandemic, restrictions and everfluctuating situations have necessitated changes to ongoing and future clinical trials. Nariné Baririan at SGS explains why practical and harmonised actions have been required to ensure the necessary flexibility in trial facilities, and adaptations to regular procedures have been needed to maintain the integrity of the trials. REGULATORY 12 New FDA Guidance on Endpoints for Demonstrating Effectiveness of Drugs for Treatment of Opioid Use Disorder Use and abuse of opioid products has increased alarmingly over the last 20 years, along with deaths due to overdose. Now commonly referred to as the “opioid crisis”, the number of opioid-involved overdose deaths in the US increased 90% from 2013 to 2017. Christine K. Moore and Henry J. Riordan at Worldwide Clinical Trials look at new FDA guidance on endpoints for demonstrating effectiveness of drugs when treating opioid use disorder. 14 The Importance of Global Collaboration for Successful Paediatric Development

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 12 Issue 6 December 2020 PHARMA PUBLICATIONS

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The paediatric population which needs treatment is small compared to the adult population, hence the necessity for global drug development. Paediatric legislation is not global, so collaboration to achieve agency alignment is the only route to global drug development. Harris Dalrymple, Mark Sorrentino, and Dr. Martine Dehlinger-Kremer at PRA Health Sciences explore the similarities and differences in paediatric legislations in the US and the EU. MARKET REPORT 20 Regenerative Medicine: Hype and Hope or Safety and Efficacy? Regenerative medicine, and the underlying stem cell technology on which it is based, offers considerable hope to patients suffering from Journal for Clinical Studies 1

Contents trauma and chronic disease. Despite this, regenerative medicine can be highly controversial. Professor Peter Hollands shows why regenerative medicine claims relating to safety and efficacy are often disputed, because it is still in its infancy. 22 The Role of eConsent in Remote Trials Today’s clinical trials demand flexible approaches and solutions. The drive to make trial participation more convenient and more inclusive for patients living greater distances from sites, has led sponsors to design trials requiring fewer site visits, increasing what can be accomplished by the patient while at home. Neetu Pundir at Signant Health examines the role of eConsent in remote trials. THERAPEUTICS 26 Clinical Development in Inflammatory Diseases: Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by an inflammatory polyarthritis that preferentially affects the small joints. RA is a "multicausal" disease. Dr. Peter Benedek, Dr. Vijayanand Rajendran and Dr. Mohamed El Malt at Europital aim to give a summary on RA and its treatment with emphasis on the new treatments currently under development. 30 For Paediatric Participants, Patient-centric Trials Must Be Family-centric Clinical research in paediatric patients has long been the subject of ethical debate, focusing on topics as varied as a minor’s ability to make an autonomous decision to participate in a clinical trial, to what age a child can be to provide true assent to participate in a clinical trial. Juliet Moritz at Illingsworth Research explains why patient-centric trials must be family-centric for paediatric participants. 34 Precision Medicine: Targeted Therapy in Paediatric Oncology Patients Targeted therapy depends on targeting unique receptors or proteins in the malignant cells, thus leading to fewer chemotherapy-induced adverse effects. Subhajit Hazra and Sara Ahmed Zaki demonstrate how to achieve the highest benefit from the targeted therapy, to focus on developing the diagnostic tools to identify the highest priority targets in each patient. TECHNOLOGY 38 Artificial Intelligence and Machine Learning Combine to Streamline Data Management in Clinical Trials Technology advances are becoming more and more sophisticated, particularly in data management for clinical trials. But despite how advanced these technologies become, clinical trials depend on quality, accuracy, and comprehensive clinical trial data. Jennifer Bradford at PHASTAR outlines why accurate clinical trial data is necessary to ensure safety and efficacy standards, to pass regulation.

Sigmund at SSS International Clinical Research GmbH provide a solution for dealing with the data flood in clinical studies. 44 Advancing Clinical Trials through Artificial Intelligence: A Legal Perspective The current health crisis and the pharmaceutical industry’s subsequent efforts to develop new treatments and vaccines for COVID-19 have brought the complexities of clinical research and development to the forefront of public attention. Vincenzo Salvatore and Vivian Grace Chammah at BonelliErede examine how artificial intelligence can be beneficial for clinical trials. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 46 Minimising Risk and Maximising Efficiency by taking a Strategic Approach to Comparative Trial Supply Widely acknowledged to be a prerequisite for formulary listing and even successful licensure, comparator drugs and co-therapies are used within an estimated two-thirds of clinical trials. Nicholas Griffin at Almac Clinical Services evaluates how to minimise risk and increase efficiency, when taking a strategic approach to comparative trial supply. CARDIOVASCULAR SAFETY 50 A New Twist in The Brief History of The Cardiac Safety Regulations: An Update of the ICH- E14 and S7B 2000 Q&A Revision Cardiac toxicity of pharmaceuticals, primarily drug-induced proarrhythmia and the risk of sudden cardiac death, emerged as a primary public and regulatory drug safety concern. Boaz Mendzelevski at Cardiac Safety Consultants Ltd looks at new guidance designed to establish an infallible scientific and regulatory process to ensure the cardiac safety of new drugs in development. 54 Assessing Cardiac Safety in Oncological Drug Development Advances in the development of anticancer drugs have decreased mortality rates for many cancers and increased patient survival. However, concerns have been raised about possible long-term effects of these new anticancer agents, such as cardiovascular toxicity. Alexandre Durand-Salmon and Joe-Elie Salem at Banook Group show why assessing cardiac safety is imperative in drug development. 58 Commentary: On the Revised ICH E14 and S7B Q&As The International Council on Harmonisation (ICH) released a new set of questions and answers (Q&As) for ECH E14 and ICH S7B in August 2020. On October 15 and 16, FDA hosted a webinar on the Q&A document. Dr. Robert Kleiman and Borje Darpo at ERT provide commentary on the revised ICH E14 and the S7B Q&As and what this may mean for drug developers.

40 Dealing with the Data Flood in Clinical Studies Managing clinical trials requires the coordination of many processes and mastering of large amounts of information under huge time pressure. In addition, increasingly complex regulatory requirements must be met, and the team must be ready for audits or inspections at any time. Dr. Lars Behrend, Sebastian Weis, and Dr. Michael 2 Journal for Clinical Studies

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Foreword As we move into the new year, our focus moves away from COVID-19 and onto cardiovascular safety. A hot topic for 2021, cardiovascular safety has emerged as a primary public and regulatory drug safety concern. Cardiovascular safety concerns have been raised during the last decade for some medicinal products that have been approved for the long-term treatment of cardiovascular diseases and metabolic diseases. While cardiovascular safety protocols are needed to treat cardiovascular diseases, just how good are we at identifying cardiovascular risks of new drugs? According to Boaz Mendzelevski at Cardiac Safety Consultants Ltd, cardiac toxicity of pharmaceuticals, primarily drug-induced proarrhythmia and the risk of sudden cardiac death, are all common factors that are associated with cardiovascular toxicity. So, what can be done to solve this? Boaz looks at new guidance to establish an infallible scientific and regulatory process, while ensuring the cardiac safety of new drugs in development. Assessing cardiac safety is imperative for streamlining the drug development process. Advances in the development of anti-cancer drugs have decreased mortality rates for many cancers and increased patient survival. Alexandre Durand-Salmon and Joe-Elie Salem at Banook Group analyse the concerns that have been raised about the possible long-term effects of these new anti-cancer agents, such as cardiovascular toxicity. Perhaps Dr. Robert Kleiman and Borje Darpo at ERT might have the solution, with their detailed commentary report on the revised ICH E14 and the S7B Q&As and what this may mean for drug developers. Speaking of drug development, drug developers must also seek to minimise risk and maximise efficiency by taking a strategic approach to comparative trial supply. After all, comparator drugs and co-therapies are used within an estimated two-thirds of clinical trials. Nicholas Griffin at Almac Clinical Services shows how comparator drugs and co-therapies provide sponsors with the ability to demonstrate a study drug’s enhanced efficacy and tolerability over the best performing alternative. A core driver for the growing popularity of comparative trials is the increasingly competitive global drug development marketplace, which has seen a surge in new drug launches. In particular, the paediatric population has seen the necessity for global drug development. Paediatric legislation is not global, so collaboration

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

to achieve agency alignment is the only route to global drug development. Harris Dalrymple, Mark Sorrentino, and Dr Martine Dehlinger-Kremer at PRA Health Sciences explore the similarities and differences in paediatric legislations in the US and the EU. Clinical research in paediatric patients has long been the subject of ethical debate, focusing on topics as varied as a minor’s ability to make an autonomous decision to participate in a clinical trial, to what age a child can be to provide true assent to participate in a clinical trial. Juliet Moritz at Illingsworth Research explains why patient-centric trials must be family-centric for paediatric participants. Enhancing and improving support for paediatric patients and their guardians better positions trials for optimal participation, but it is not the only factor to take into consideration. To deliver the best patient experience, targeted therapy in paediatric oncology patients can be used. Subhajit Hazra and Sara Ahmed Zaki demonstrate how to achieve the highest benefit from the targeted therapy, by focusing on developing the diagnostic tools to identify the highest priority targets in each patient. Lastly, creating a better patient ecosystem relies on the coordination of many processes and mastering of large amounts of information under huge time pressure. Conducting clinical trials means that complex regulatory requirements must be met, and the team must be ready for audits or inspections at any time. Dr. Lars Behrend, Sebastian Weis, and Dr. Michael Sigmund at SSS International Clinical Research GmbH provide a solution for dealing with the data flood in clinical studies. I hope you all enjoy your festive season and I look forward to welcoming you back in the new year, with more enthralling articles to be included in JCS. You may have noticed that we have changed the theme of the front cover picture of the JCS Journal. We started JCS with the unique goal of highlighting emerging countries and thoroughly analysed these countries as a clinical trial destination. Hence, we featured the national flower of one of the countries highlighted in that issue. Although we remain committed to bringing you a market analysis of emerging clinical trial destinations, JCS will now focus on therapeutic and regulatory aspects throughout 2020. The front cover picture will represent one of the therapeutic focuses that we have in this issue. Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies

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

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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Catherine Lund, Vice Chairman, OnQ Consulting

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Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

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

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Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

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Stefan Astrom, Founder and CEO of Astrom Research International HB

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Elizabeth Moench, President and CEO of Bioclinica – Patient Recruitment & Retention Francis Crawley, Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

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Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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Hermann Schulz, MD, Founder, PresseKontext

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T S Jaishankar, Managing Director, QUEST Life Sciences

4 Journal for Clinical Studies

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Psychedelics Make a Comeback to Treat Mental Health Conditions In January 2020, the World Health Organization (WHO) published a fact sheet naming depression as a “leading cause of disability worldwide” and stating that “more than 264 million people of all ages suffer from depression.”1 Drug treatments for depression, post-traumatic stress disorder (PTSD), and other mental health conditions have been largely successful in the past few decades. However, some patients initially diagnosed with major depressive disorder (MDD) who prove resistant to those treatments have few options after treatments have failed. The US Food and Drug Administration (FDA) considers patients with treatment-resistant depression (TRD) as those who have MDD and, “despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment.”2 The FDA has approved only two products to treat TRD, and several companies are evaluating products with psychedelic properties as a new approach to previously untreatable mental health conditions. In the US, Johns Hopkins opened the Center for Psychedelic and Conscious Research to contribute to this exciting field; in the UK, the Imperial College opened the Centre for Psychedelic Research. Such prestigious institutions, as well as other major investors throughout the past decade, have fuelled the conversation and brought psychedelics back to the drawing board. Ketamine to Treat TRD In 2009, the FDA approved a new indication for Eli Lilly and Company’s Symbyax (olanzapine and fluoxetine hydrochloride), a product already approved by the FDA for the acute treatment of bipolar depression. It became the first drug approved to treat patients with TRD. A decade later, a second drug was approved for patients with TRD. This marked the beginning of a new outlook on a type of product virtually banned from being researched in the 1970s due to the “War on Drugs”. On March 5, 2019, the FDA opened the door for the use of psychedelics as viable treatments with the approval of Spravato (esketamine), an s-enantiomer of ketamine provided as a spray by Janssen Pharmaceuticals. The new drug application (NDA) was granted fast track and breakthrough therapy designations. On February 12, 2019, the FDA convened a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee during which the panellists voted overwhelmingly to support the NDA. They agreed the product could contribute to a shift in the mental health treatment landscape to allow for more regulatory reviews of these types of products at the FDA. Psilocybin to Treat TRD Multiple companies are evaluating psilocybin for the treatment of 6 Journal for Clinical Studies

mental health disorders. Psilocybin is a hallucinogenic chemical found in specific mushrooms and is a schedule I substance under the Controlled Substances Act (CSA), according to the Drug Enforcement Administration (DEA).3 A search on ClinicalTrials.gov turns up more than 10 US-based clinical trials evaluating psilocybin for the treatment of mental health conditions. The FDA granted breakthrough therapy designation to COMP360, a synthesised formulation of psilocybin isolated from psilocybin mushrooms and a partial agonist for multiple 5-hydroxytryptamine (5-HT) receptors developed by COMPASS Pathways. The sponsor is evaluating COMP-360 for the potential treatment of TRD in a Phase IIb study in 20 sites across Europe and North America. The study also aims to determine the optimal dose of COMP-360 by investigating three doses. In another Phase II study, conducted in collaboration with Sheppard Pratt Health System, COMPASS Pathways is evaluating psilocybin in patients with TRD. The primary outcome measure of both studies is the rating on the Montgomery Asberg Depression Rating Scale (MADRS). PTSD Treatment with MDMA Perhaps the most notable research in this arena comes from studies conducted by the Multidisciplinary Association for Psychedelic Studies (MAPS) that evaluate the use of 3,4-methyl enedioxy methamphetamine (MDMA), in combination with psychotherapy, as a treatment for PTSD. In August 2017, the FDA granted MDMA breakthrough therapy designation for the treatment of PTSD and came to an agreement with MAPS on its Phase III protocol designs after completing the Special Protocol Assessment (SPA) process. MDMA is also a schedule I substance. In June 2020, MAPS published long-term follow-up results of its six Phase II studies of MDMA-assisted psychotherapy for the treatment of PTSD, which the sponsor stated is the “most comprehensive analysis yet published of the safety and durability of treatment outcomes following MDMA-assisted psychotherapy for PTSD.”4 Most study participants received benefit from this treatment for ≥12 months after treatment sessions. In addition, 56% of the participants no longer met the diagnostic criteria for PTSD two months after their last session. MAPS has completed one randomised, double-blind, placebocontrolled Phase III study, and another is in progress. MAPP1 evaluated the efficacy and safety of MDMA-assisted psychotherapy versus psychotherapy with placebo in participants diagnosed with at least severe PTSD. MAPP2, which is still recruiting, is assessing the efficacy and safety of manualised MDMA-assisted psychotherapy for the treatment of PTSD of moderate or greater severity. In May 2020, MAPS announced promising news about MAPP1 based on an analysis conducted by an independent data monitoring committee.5 The first 60 out of 100 patients provided information that supported the assumption that there is a ≥90% probability that the study will Volume 12 Issue 6

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discover statistically significant results after all participants have been treated. MAPP2 is expected to complete in 2021. Pending positive final results, MAPS plans to seek FDA approval for MDMA-assisted therapy for PTSD by 2022. DEA Scheduling Despite emerging enthusiasm for research on psychedelics to treat mental health conditions, drug developers still face regulatory complications with DEA scheduling. They are required, under the CSA, to register with the DEA and provide extensive information about their research and qualifications. In a DEA press release in 2018, Acting DEA Administrator Robert W. Patterson said the agency is committed to supporting these “new and innovative” research opportunities.6 Some states have decriminalised plants and fungi containing psychedelic compounds, which falls in line with the evergrowing number of states decriminalising or legalising cannabis. As the lingering stigma from past generations of medical treatment standards dissipates, individuals with mental health conditions might finally have the option to find reprieve from their severe TRD and PTSD. REFERENCES 1. 2.

Depression. World Health Organization Website. https://www.who.int/ news-room/fact-sheets/detail/depression FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at a Certified Doctor’s Office or Clinic. Food and Drug Administration Website. https://www.fda.gov/news-events/ press-announcements/fda-approves-new-nasal-spray-medicationtreatment-resistant-depression-available-only-certified Psilocybin. Drug Enforcement Administration Website. https://www.dea.

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gov/factsheets/psilocybin Press Release: MDMA-Assisted Psychotherapy May Have Lasting Benefits for PTSD, Results Published in Psychopharmacology. Multidisciplinary Association for Psychedelic Studies Website. https://maps.org/news/media/8190-press-release-mdma-assistedpsychotherapy-may-have-lasting-benefits-for-ptsd,-results-publishedin-psychopharmacology Press Release: Interim Analysis Shows at Least 90% Chance of Statistically Significant Difference in PTSD Symptoms After MDMAAssisted Psychotherapy. Multidisciplinary Association for Psychedelic Studies Website. https://maps.org/news/media/8154-press-releaseinterim-analysis-shows-at-least-90-chance-of-statistically-significantdifference-in-ptsd-symptoms-after-mdma-assisted-psychotherapy DEA Speeds Up Application Process for Research on Schedule I Drugs. Drug Enforcement Administration Website. https://www.dea.gov/ press-releases/2018/01/18/dea-speeds-application-process-researchschedule-i-drugs

Jaime Polychrones Jaime Polychrones is a medical & regulatory writer for the Cortellis suite of life science intelligence solutions at Clarivate. 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: jaime.polychrones@clarivate.com

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Combating Covid-19 Cold Chain Challenges

As the world continues to react to the impact of the global pandemic, by far the most significant challenges currently for pharmaceutical cold chain logistics are the ongoing repercussions relating to COVID-19. This is in relation to the cold chain requirements necessary to support the high number of vaccines currently being trialled globally, some of which are expected to make it through successfully to the approval stage and be utilised in response to the pandemic. Consequently this will have a significant impact for cold chain logistics, which is going to affect the whole industry. This is because a lot of these vaccines to begin with, especially within the clinical trials stage, are likely to be in a deep frozen format, which is not typical for many approval stage biologic drug products as they are distributed. More often, it is the refrigerated temperature range that makes up the majority of the transport temperature requirements within the sector. If we consider the vaccines being developed currently and some subset of those will make it to the approval stage, these vaccines will then need to be manufactured at a rate of millions of doses per week. This mass manufacturing of vaccines is most likely to take place within manufacturing centres worldwide, at key locations including Western Europe, the United States, Japan and China. At that stage we are going to see a critical crunch of the volume versus the capacity within both the clinical trial period and then the subsequent worldwide distribution of approved vaccines. We already have to address the current challenges within cold chain logistics operations, where air transport capabilities are down because so few passengers are flying due to the pandemic. As a response from the airline industry, we are seeing a number of passenger jets being converted to cargo jets because fewer passenger planes are flying. The demand for air cargo capacity is expected to rapidly rise due to the development of COVID-19 vaccines. The demand will increase significantly when it comes to the distribution of the vaccine during the clinical trials, which is expected within the next 12 months. These developments are going to have a major impact within the industry and cold chain packaging manufacturers probably will not be in a position to manufacture enough packaging necessary to meet the entire demand. Therefore, what we expect to see within the sector is a lot of multiple sourcing via different packaging vendors. This will be necessary to meet the demands of the different pharmaceutical manufacturers as they try and distribute vaccines during both the clinical trial phase and the approved phase. 8 Journal for Clinical Studies

This is also true for COVID-19 therapies being developed by major pharmaceutical manufacturers which also demand tight temperature transportation requirements. With such specific therapies being deployed to help fight the active disease in seriously ill patients, this additional requirement will put extra pressure on the already restricted resources and challenges for cold chain logistics. It is predicted the pandemic will continue to cause shockwaves throughout our industry for the next two to three years. Rapid Response In response, innovative temperature-controlled packaging products are being adapted at unprecedentedly rapid rates to support pandemic clinical trials and ensure the global distribution of successful COVID-19 vaccines. We’re seeing major logistics providers building giant freezer farms around the world, which are capable of super-cooling millions of vials of COVID-19 vaccine once it is approved. Consisting of a total of 100s of deep freezers, each capable of holding 48,000 vials of vaccine to temperatures as low as -80 Celsius, it is the latest development aimed at getting high volumes of vaccines distributed worldwide. This demonstrates how companies are starting to build out the capacity and infrastructure necessary to successful distribution of COVID-19 vaccines. As highlighted by the conversion of passenger planes to cargo planes to ensure, we have more cargo capacity available. On the ground there will be more of these deep freeze/ blast freezer farms that will be established at major distribution points worldwide. The current cold-chain storage and transportation is not sufficient to meet this demand but that is not surprising given that you have several billion people that will need to be vaccinated against COVID-19. It will take time to scale up when it comes to managing manufacturing and distributing a vaccine, or likely several approved vaccines. In response, organisations operating within the cold-chain logistics sector are actively innovating, researching and developing technologies that had not been developed before to assist with this challenge. Some cold-chain packaging manufacturers are actively developing and converting products to provide a dry ice capacity in support of the Operation Warp Speed project and meet the needs of pharmaceutical companies. It is likely that deep frozen and frozen (-20°C, -35°C, -50°C, -65°C, -80°C) will be required for the shipment of vaccines during the clinical trial and approved for wide immunisation stages. When it comes to what is available at the clinics and hospitals where the patients will be treated, there is likely limited freezer Volume 12 Issue 6

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capacity, especially at deep frozen temperatures (-65°C and -80°C). It is expected the coronavirus vaccines will move to require refrigerated or frozen (-20°C) temperature, once it gets to an approved stage and the vaccines are being mass-produced and distributed by air and ground. The clinics, hospitals and other healthcare providers will have refrigeration and standard frozen equipement at the point of administration to patients, but likely won’t have blast freezers. So, the pharmaceutical manufacturers are expected to invest significant effort to have the approved COVID-19 vaccine require refrigerated temperature, rather than being deep frozen. That temperature difference will change what is required for manufacturing and transportation via truck or air to what is required for storage en route to what is required in terms of storage at designated healthcare locations when the vaccine is administered to patients. www.jforcs.com

Adam Tetz Adam Tetz is the Director of Worldwide Marketing at Peli BioThermal and has more than 25 years of marketing experience. He is responsible for telling the story of Peli BioThermal to our worldwide audiences. His areas of responsibility include brand identity, product launch and communication strategy. Prior to Peli BioThermal, Tetz held positions in product management and marketing communication across a variety of industries, including medical software, financial software, information services and professional consulting services. He holds an MBA in Marketing from the University of Saint Thomas, a BA in Advertising from the University of Minnesota and is a veteran of the United States Coast Guard. Email: adam.tetz@pelican.com

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Practical Implications of Undertaking Clinical Trials during the COVID-19 Pandemic Faced with the coronavirus pandemic, restrictions and everfluctuating situations have necessitated changes to ongoing and future clinical trials. Practical and harmonised actions have been required to ensure the necessary flexibility in trial facilities, and adaptations to regular procedures have been needed to maintain the integrity of the trials, as well as ensuring the rights and safety of trial participants, and the safety of clinical trial staff. The pandemic has seen announcements from pharma companies, clinical research organisations (CROs) and universities about delays in the enrolment of patients to trials, as well as terminations and temporary pauses of clinical trials. These effects have impacted clinical research, irrespective of indication, and could lead to implications for data collection and analysis going forward. Phase I studies with healthy volunteers (HV) were particularly affected due to the lack of certainty in respect of the health status of the participants during the early stages of the pandemic. Additionally, with hospitals devoting their entire activities to COVID-19, access to Phase I units was severely restricted, if not impossible. Regulatory Support As the implications of the pandemic began to become apparent, the European Medicines Agency (EMA) published its first version of “Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic”, which has subsequently been revised, with version 3 being the most recent (dated April 28, 2020). The guidance included the following key recommendations from the EC: • • •

• • • • • •

Absolute priority should be given to clinical trials for the prevention or treatment of COVID-19 and COVID-19-related illnesses. The feasibility and immediate necessity of starting a new clinical trial should be critically assessed. Sponsors should consider in their risk assessment whether the following measures could be applied during COVID-19: conversion of physical visits into phone or video visits, temporary halt of the trial, interruption or slowing down of recruitment, closing of sites, transfer of trial participants to investigational sites away from risk zones, use of local laboratories. Priority is given to substantial amendment applications to existing clinical trials necessary as a result of COVID-19. Alternative ways of obtaining re-consent (for reasons related to COVID-19) should be considered during the pandemic. Changes in the distribution of the investigational medicinal products (IMP), alternative shipping and storage arrangements may be necessary. Cancelling or postponing of on-site monitoring visits by preferring online tools. On-site audits should be avoided or postponed. Consider Guidance on the Implications of Coronavirus Disease (COVID-19) on Methodological Aspects of Ongoing Clinical

10 Journal for Clinical Studies

Trials published by the CHMP Biostatistics Working Party, dated March 25, 2020, to manage protocol deviations related to COVID-19. At approximately the same time, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) published its own guidance, “How Investigators and Sponsors Should Manage Clinical Trials During COVID-19” (March 19, 2020). The FDA also released its guidance “Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency” in March 2020, which was subsequently updated on July 2. Any guidance from the regulatory authorities will be updated depending on the evolution of the pandemic and new available scientific data. Managing a Clinical Pharmacology Unit As with many similar facilities, when the pandemic struck Belgium in March, the SGS Clinical Pharmacology Unit (CPU) reduced its activities to an absolute minimum. Recruitment and start-up of trials/cohorts was completely put on hold. To safely restart clinical trial activities, a thorough risk implementation plan was put in place and was based on the instructions and guidelines from the Belgian government, local and regional regulatory authorities, the ZNA Stuivenberg Hospital to which the CPU is attached, and also SGS global policy. This allowed activities to be undertaken, with internal guidance in place to ensure measures were adopted to avoid any potential spread of the SARS-CoV-2 virus, to ensure the safety of trial participants and staff at all times, and to ensure the quality and integrity of data from the trials. Similar to the regulatory guidance from the EMA, MHRA and FDA, this internal guidance remains adaptable to the changing effects and consequences of the pandemic. Ensuring precautions to minimise the potential risk of SARSCoV-2 virus infection into the unit could be implemented led to some standard activities being redesigned and additional measures being put in place. From a practical point of view, activities and procedures have been amended for staff and visitors to the facility. Common hygienic and preventive measures were set up for the subjects and visitors, such as ensuring regular handwashing was practised, sanitising of hands with alcohol gel, face masks became compulsory at all times, and physical distancing of 1.5 metres was introduced. To reduce the risk of potentially infected subjects accessing the site, intake interviews were conducted by telephone prior to the screening visit, using structured questionnaires. Additionally, each reception area in CPU was equipped with a device to measure the temperature of people entering the facility. In place of the standard screening process volunteers and subjects would have normally undertaken prior to a study, all are Volume 12 Issue 6

Watch Pages

now provided with an informed consent form (ICF) document along with the facility COVID-19 procedure documents via email, so that they can read through them prior to arriving at the unit. Instead of admitting all subjects of one cohort at the same time, subjects now receive individually scheduled appointments, and follow a “one-way” system at the unit, moving through the facility in a set flow to reduce the risk of encountering another subject. There is only one staff member in each interview/examination room with each participant. During monitoring and data collection, the length of time each monitor spends in the monitoring room is limited to the minimal amount possible. The SGS unit is fully equipped with eSource monitoring and collection, allowing most relevant data to be reviewed remotely. For the wards at the SGS Phase I unit, careful consideration was given to ensure all safety precautions were taken and the potential risk of COVID-19 infection was minimised. The wards were reorganised to reduce bed capacity by half; and specific attention was paid to toilets, bathrooms and dining/recreation rooms, to ensure the disinfection of fixed furniture and to limit simultaneous occupancy. Where there is suspicion of COVID-19 infection or a study protocol requires testing, the SGS CPU can perform COVID-19 testing in-house or before admission, with results available within 45 minutes. Additionally, quarantine measures were developed for handling cases with suspected COVID-19. This would involve any subject being quarantined within the CPU unit, and a nasal swab taken to test for COVID-19. They would remain quarantined until the test result is available, and if negative, the subject would be allowed to return to the rest of the group to further participate in the trial. In the case of a positive result, the subject would undergo extended quarantine within the CPU, and a mutual decision by the investigator and sponsor would need to be made to evaluate the subjects’ safety and data integrity of the trial. www.jforcs.com

Clinical Activities Going Forward Clinical trials are an essential tool in medical research, and their continuation in the future must be ensured. The COVID-19 pandemic has obliged CROs to explore ways that trials are designed and conducted, and how they could be adapted. What is clear is that lessons must be learned from the last six months, so that the highest quality of clinical trials conduct, and the safety of volunteers and research staff, are ensured. Most sponsors have looked to restart early-phase study activities, so that product development timelines are not delayed further. Going forward, activities are looking to return to “normal”, although it is expected that re-prioritisation of product pipelines by sponsors is likely, and Phase I units should be ready to welcome these trials. What the long-term effects of this COVID-19 pandemic on clinical research will be is unclear, although COVID-19 risk assessments will likely be part of common practice for some time to come. Although these may be updated according to the most recent scientific information as and when appropriate, some general approaches such as social distancing and enhanced hygiene measures are expected to be in place for a long time.

Nariné Baririan Nariné Baririan joined SGS in 2007 and is currently the company’s Clinical Pharmacology Expert, and serves as part of SGS’s Clinical Pharmacology Unit (CPU) and consultancy/ experts team that supports and advises clients in study design and clinical development plans of new compounds. She holds a degree in pharmaceutical sciences, a research master’s degree from UCL (Belgium) in cellular and molecular pharmacology, as well as a doctorate in pharmaceutical sciences from UCL and St Luc Hospital (Brussels). She is an active member of the Belgian Association of Phase 1 Units (BAPU) and Association Française de Pharmacologie Translationnelle (AFPT).

Journal for Clinical Studies 11

Regulatory

New FDA Guidance on Endpoints for Demonstrating Effectiveness of Drugs for Treatment of Opioid Use Disorder Use and abuse of opioid products has increased alarmingly over the last 20 years, along with deaths due to overdose. Now commonly referred to as the “opioid crisis”, the number of opioid-involved overdose deaths in the US increased 90% from 2013 to 2017.1 The first wave of this rising trend began in the 1990s, related to the increased prescribing of opioids. By 2010, the second wave of overdose deaths was largely due to heroin overdose, and in the past decade or third wave, heroin overdose deaths were replaced by synthetic opioids, namely illicit fentanyl. Nearly 70% of the 67,367 US overdose deaths in 2018 involved an opioid.2 Each of these three overlapping waves has been associated with a different form of opioid, with a fourth possible wave predicted given the recent increase in the widespread use of cocaine and psychostimulants alongside opioids.3 Although the US accounts for one-quarter of estimated drug-related deaths worldwide, similar trends have also been noted in Europe.4 Led by the US Dept of Health and Human Services (HHS) and in conjunction with its operating divisions including the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and the Substance Abuse and Mental Health Services (SAMHSA), a five-point Opioid Strategy was put in place in April 2017 to 1) improve patient access to addiction prevention and treatment, programs 2) improve availability of overdose-reversing drugs especially in high-risk populations, 3) strengthen public health data reporting, 4) support cutting-edge research advancing pain and additional treatments, and 5) advance the practice of pain management to enable access to high-quality, evidence-based pain care.5 Similar initiatives in Europe have focused on reduction of public supply; improved prevention, treatment and rehabilitation programmes; decriminalisation; and provision of medications for opioid use disorder (MOUD).4 The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) introduced important strategies to address overdose prevention in 2018 that included increasing awareness about overdose risk, providing effective drug treatments, and improving throughcare between prisons and communities. A second set of responses focus on the prevention of fatalities when overdoses occur.6 As part of the five-point Opioid Strategy to improve access to prevention and treatment in the US, FDA finalised a new policy in 2019 to encourage widespread innovation and development of new buprenorphine treatments for opioid use disorder (OUD) that may result in less misuse, abuse, or accidental exposure than previously marketed formulations.7 The guidance details the types of studies the FDA recommends for buprenorphine depot products and includes considerations for trial design and recommended and novel efficacy endpoints related to buprenorphine.8 More recently (October 2020), the FDA released finalised guidance intended to help advance the development of new treatments for 12 Journal for Clinical Studies

OUD, addressing the clinical endpoints acceptable for demonstrating effectiveness.9 Historically, endpoints in clinical trials evaluating effectiveness of medications for OUD for purposes of FDA approval have generally used changes in drug use patterns as an endpoint; in this guidance, expansion of primary and secondary endpoints to include measures important to patients, their families, clinicians, and the public are encouraged. Trials for treating OUD are typically randomised, blinded, controlled trials and can be either superiority or non-inferiority designs. For treatments intended for use as initial therapy, patients should be new to treatment and the trial should generally include a standard-of-care non-pharmacologic treatment. For prevention of relapse, patients already stable on other treatments for OUD should be studied and seen at frequent intervals, using an approved therapy as a comparator.9 Newly-initiated patients are considered more difficult to treat than clinically stable patients, so substantial evidence supporting effectiveness in patients new to treatment would typically also support approval for treatments in clinically stable patients, but not vice versa.9 Reduction in drug-taking behaviour (drug use patterns) are most often used as an endpoint – the recommended primary efficacy endpoint is the proportion of responders, where “responder” is commonly pre-defined by abstinence or no detected or self-reported use during the specific assessment window, very frequently assessed and utilising both urine drug tests and self-report (a grace period may be incorporated). As with previous guidance on analgesic drug development, efficacy analyses should compare percentage of responders and include cumulative responder curves and graphic displays of individual patient responses.10 Other endpoints that may be meaningful and should be considered as primary or secondary for inclusion in FDA-approved labelling include adverse outcomes of OUD, change in proportion of patients meeting DSM-V diagnostic criteria disease status (e.g., change from moderate or severe to remission at baseline to the end of the trial can be used as a primary or secondary efficacy endpoint), and other changes in drug use patterns (e.g., fewer usage per day or per occasion provided it can be measured and shown to predict clinical benefit). Guidance asserts that reductions in adverse outcomes related to OUD continue to be desirable endpoints for study and encourages the use of various and novel adverse event-related outcomes such as overall or overdose mortality, need for emergency intervention, and hepatitis C virus infection/reinfection. Sponsors are free to propose other adverse outcomes as well and can even evaluate several adverse endpoints in the same trial, selecting one as the primary endpoint and one or more as secondary endpoints, or even combining outcomes in a composite or summary scale. Supportive data regarding baseline rates of the adverse outcomes would be required in determining sample size and trial duration estimates.9 Volume 12 Issue 6

Regulatory Of note, guidance emphasises that very frequent measurements will provide more assurance of a substantial reduction in drug use, whereas infrequent drug use measurements result in greater uncertainty about the true magnitude of reduction in drug use. For this reason, absence of positive urine drug tests, absence of selfreported drug use, and attendance at frequent scheduled observations for these measures are components of a complete abstinence response definition; abstinence is no longer defined as no detected or self-reported use during a specific assessment time period.9 Guidance also permits the utilisation of drug use patterns other than abstinence to define clinical response to treatment, as long as sponsors specify how the change in drug use pattern will be created and measured as a priority, as these may be difficult to validate. For example, changes in drug use patterns such as fewer occasions of use per day or reduced amount of use per occasion are notoriously problematic to track with confidence and may/may not be associated with clinical benefit. Therefore, in addition sponsors should attempt to gather supportive data from longitudinal prospective observational studies as well as other realworld evidence to make the association that the reduction in drug use is associated with and even portends clinical benefit.9 Expectedly this new guidance promotes patient-reported outcomes (PROs) from both patients and family members for change in how patients feel or function (e.g., improvement in sleep or mood) by encouraging the development of new PROs on other domains to use as secondary outcomes, provided the magnitude of change in the trial representing clinical sustained benefit has been determined.9 For example, the development of a fit-for-purpose valid outcome for measuring a reduction in the intensity of the urge to use opioids could serve as an important secondary endpoint in trials that utilise drug use patterns as a primary endpoint. Additionally, it would be important to determine how craving reductions correlate with sustained clinical benefit with the goal of determining how long reductions in craving need to be maintained in the trial setting in order to predict a sustained clinical benefit. Finally, the collection of additional clinically meaningful outcome measures that may demonstrate clinical benefit of drugs for treating OUD, such as reduction in hospitalisations or improvements in the ability to resume work, school, or activities is also encouraged, even though these types of outcomes typically require large subject numbers and longer time periods than typical registration studies.9 Guidance supports their inclusion even if not intended to support a regulatory decision, noting that these outcomes could provide the basis for inclusion in labelling. Importantly, retention in treatment as a standalone endpoint is not recommended, as various trial design features can promote incentives to remain in treatment even in the absence of meaningful clinical benefit. As always, if these types of novel endpoints are planned, guidance strongly encourages early discussion with regulators in the drug development process. Of course, regardless of the outcome measure(s) chosen for inclusion, the demonstrated clinical benefit of a product will be weighed against its risk of serious adverse events. In addition, if the product has abuse potential (which is the case with currently available MAT), FDA will further evaluate risk of diversion and potential risks to both patients and non-patients, particularly in children. REFERENCES 1.

National Center for Health Statistics. National Vital Statistics System, Mortality. Data Brief, Number 329, November 2019. Accessed October 9, 2020. https://www.cdc.gov/nchs/data/databriefs/db329_tables-508.pdf#4 Centers for Disease Control and Prevention. Opioid Overdose: Understanding the Epidemic. Three Waves of Opioid Overdose Deaths. Accessed October 9, 2020. https://www.cdc.gov/drugoverdose/epidemic/

www.jforcs.com

10.

index.html Centers for Disease Control and Prevention. 2019 Annual Surveillance Report of Drug-Related Risks and Outcomes — United States Surveillance Special Report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Published November 1, 2019. Accessed October 9, 2020. https:// www.cdc.gov/drugoverdose/pdf/pubs/2019-cdc-drug-surveillance-report.pdf Alho H, Dematteis M, Lembo D et al. Opioid-related deaths in Europe: strategies for a comprehensive approach to address a major public health concern. International Journal of Drug Policy. 2020;76:102616. US Dept of Health and Human Services. Strategy to Combat Opioid Abuse, Misuse, and Overdose. A Framework Based on a Five Point Strategy. Accessed October 9, 2020. https://www.hhs.gov/opioids/sites/default/files/2018-09/ opioid-fivepoint-strategy-20180917-508compliant.pdf European Monitoring Centre for Drugs and Drug Addiction. Perspectives on Drugs. Preventing Overdose Deaths in Europe. Accessed October 9, 2020. https:// www.emcdda.europa.eu/system/files/publications/2748/POD_Preventing%20 overdose%20deaths.pdf FDA in Brief: FDA finalizes new policy to encourage widespread innovation and development of new buprenorphine treatments for opioid use disorder. Feb 06. 2019. Accessed October 9, 2020. https:// www.fda.gov/news-events/fda-brief/fda-brief-fda-finalizes-new-policyencourage-widespread-innovation-and-development-new-buprenorphine U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Feb. 2019 Clinical/Medical. Opioid Use Disorder: Developing Depot Buprenorphine Products for Treatment Guidance for Industry. Accessed October 9, 2020. https://www.fda.gov/ media/120090/download U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Oct. 2020 Clinical/Medical Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment Guidance for Industry. Accessed October 9, 2020. https://www.fda. gov/regulatory-information/search-fda-guidance-documents/opioid-usedisorder-endpoints-demonstrating-effectiveness-drugs-treatment-guidanceindustry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Feb. 2014 Clinical/Medical. Analgesic Indications: Developing Drug and Biological Products Guidance for Industry.

Christine K. Moore Christine K. Moore, PhD is Vice President, Scientific Solutions: Neuroscience at Worldwide Clinical Trials. Dr Moore has been involved in industry drug development and commercialisation of treatments for CNS indications for the past 20 years, with nearly 50 publications. She has been a part of several analgesic and addiction programmes, designing and writing clinical development plans and numerous protocols as well as commercialisation efforts for an atypical opioid for pain and addiction. Email: christine.moore@worldwide.com

Henry J. Riordan Dr. Riordan is the Chief Development Officer at Worldwide Clinical Trials. He 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 120 publications, including co-authoring two books focusing on innovative clinical trials methodology. Email: henry.riordan@worldwide.com

Journal for Clinical Studies 13

Regulatory

The Importance of Global Collaboration for Successful Paediatric Development Global Agency Collaboration – Tools and Processes FDA and EMA Parallel Scientific Advice The parallel scientific advice programme provides a mechanism for FDA and EMA to exchange their views on scientific issues during the development phase of new products concurrently with sponsors. These interactions aim to provide a deeper understanding of the bases of regulatory decisions, optimise the development programme, and minimise unnecessary testing replication or unnecessarily diverse testing methodologies.

Introduction The paediatric population which needs treatment is small compared to the adult population, hence the necessity for global drug development. Paediatric legislation is not global, so collaboration to achieve agency alignment is the only route to global drug development. Paediatric development is largely driven by US and EU legislation, which have similarities and differences that must be navigated for successful drug development. Several tools and processes have been implemented to facilitate inter-agency collaboration to achieve this. Paediatric Legislations in the US and the EU – Similarities and Differences The US authorities have been working on the conditions for paediatric drug development programmes since 1979. The requirement for a paediatric study plan (PSP) for new products became mandatory under the 2003 Pediatric Research Equity Act (PREA),1 which, together with the Best Pharmaceutical for Children Act (BPCA),2 govern paediatric development in the US. PREA requires companies to ascertain the safety and efficacy of new medicinal products as well as amendments in children unless a waiver is granted or the product is exempt from PREA, and an initial PSP must be submitted to the FDA for medicines falling under PREA. Accordingly, with the exceptions of waivers or deferrals, marketing applications for new products and amendments (for new indications, dosage forms, and formulations) need to contain paediatric data. In 2006, the EU followed suit, and the Pediatric Regulation 1901/20063 came into force on January 26, 2007. This introduced a system of obligations and incentives for the paediatric evaluation of new drugs and amendments. For new products, paediatric investigation plans (PIPs) must be submitted to the European Medicines Agency (EMA) no later than upon completion of adult human pharmacokinetic studies. For approved products no longer covered by patent, the PIP, which can lead to paediatric use marketing authorisation (PUMA), is optional. An overview of paediatric legislation in the US and EU is shown in Table 1. The FDA’s paediatric legislative pillars, BPCA and PREA, together ensure adequate efficacy and safety data for labelling. However, the lag between adult and paediatric approval is still around nine years.4 The needs of paediatric-specific diseases are stark, especially for neonates and premature infants as well as for cancer and genetic diseases. Progress is being made gradually. In the last decade we have seen the implementation of paediatric extrapolation, adoption of innovative clinical trial designs, exploration and acceptance of real-world evidence, and the establishment of paediatric clinical trial networks. 14 Journal for Clinical Studies

For paediatric developments, engaging the EMA–FDA parallel procedure before submitting the iPSP and PIP will facilitate global alignment of the development programme. This may be particularly beneficial for first-in-class medicines or medicines presenting an innovative approach. Scientific advice agreed by the Scientific Advice Working Party (SAWP) and endorsed by the Committee for Human Medicinal Products (CHMP) is considered important in the Pediatric Committee (PDCO) PIP assessment. There is close collaboration between the SAWP and the PDCO, the latter being involved in paediatric scientific advice, including the parallel scientific advice with the FDA. Paediatric Cluster Meetings Paediatric cluster meetings were established in 2007 and are monthly teleconferences held between the FDA, EMA, Health Canada, the Japanese Pharmaceutical and Medical Device Agency, and the Australian Therapeutic Goods Agency. The objective is to support global development plans by exchanging information on products and general issues, and to seek a harmonised approach to the fullest extent possible, whenever possible reaching consensus on their requirements for individual paediatric plans. More than one approach may be possible but the aim is to avoid unnecessary studies. Between August 2007 and March 2019, information had been exchanged on 517 products, with 172 discussions on general topics.5 The most frequently discussed topics are shown in Figure 1. Non-product discussions addressed meetings/workshops, joint publications, and regulatory actions. Between 2014 and 2017, convergence was achieved for 73% of the issues discussed. From 1997 to 2017, over 650 products in the US were labelled with additional information gathered from paediatric trials. Since

Figure 1: Clinical trial topics discussed during paediatric cluster meetings (2007–2016) Volume 12 Issue 6

Regulatory EU

Descrip�on

PIP

PUMA

Applicable Regula�on

Regula�on (EC) No 1901/2006 and as amended 1902/2006

Scope Applicable product classiﬁca�ons

Mandatory Drugs, biologics (including orphan products): new products, new indica�ons, or pharmaceu�cal forms that qualify for or are protected by a supplementary protec�on cer�ﬁcate (SPC)

Exemp�ons

• Gene�cs • Hybrids • Tradi�onal herbal products • Biosimilars • Well established use • “Class waiver” products • Likely to be ineffec�ve or unsafe • Condi�on only occurs in adults or a paediatric subset • Does not represent significant therapeu�c benefit over exis�ng treatments for paediatrics

Regula�on (EC) No 1901/2006 and as amended 1902/2006 Op�onal • Already authorized • No longer covered by SPC or patent that qualiﬁes for a SPC • Products indicated exclusively for use in the paediatric popula�on Not applicable, op�onal scope

Grounds for waiver (par�al or full waivers)

Not applicable

PREA

BPCA

PREA and FDASIA 2012

BPCA and FDASIA 2012

Mandatory Drugs, biologics and biosimilars involving new ac�ve ingredient, indica�on, dosage form, dosing regimen, or route of administra�on

Op�onal Drugs, biologics (including biosimilars, orphan products, and oﬀ-patent products)

• Orphan designated products* • Generics • Dietary (including herbal) supplements

Dietary (including herbal) supplements

• Evidence strongly suggests product would be ineffec�ve or unsafe • Necessary studies impossible or highly impossible • Does not represent significant therapeu�c benefit over exis�ng therapies for paediatrics and not likely to be used in a substan�al number of paediatric pa�ents • Not possible to develop an age-appropriate paediatric formula�on • Only required for indica�on that will be under review • One iPSP for each indica�on • Within 60 days of End of phase 2 (EOP2) mee�ng • If no EOP2, at least 210 days prior to planned NDA/BLA filing

Not applicable

Scope

• Derived from adult indica�on within the same condi�on • One PIP may cover more than one condi�on/ indica�on

Condi�on/indica�on exclusive to paediatric use

Timing

End of Phase 1 (adult pharmacokine�c data)

Instrument

PIP

iPSP

Key rewards and incen�ves

• Six-month extension to supplementary protec�on cer�ﬁcate • For orphan products an addi�onal two years of market exclusivity • Free paediatric scien�ﬁc advice

• Automated access to centralized procedure • Eight years data + two years of market protec�on • Par�al exemp�on from submission fees and post-authoriza�on fees for one year

None

Related to the en�re moiety. The FDA may request studies for a diﬀerent indica�on including an indica�on not approved in adults • Determina�on of exclusivity is based on completed reports for all studies listed in the wri�en request (WRI) • The FDA has up to six months to review reports to make a ﬁnal determina�on • The FDA’s decision on exclusivity determina�on should be made no later than nine months before the pa�ent or exclusivity expira�on or paediatric exclusivity will not be granted • Proposed paediatric study request (PPSR) issued by the sponsor to the FDA • WR issued by the FDA • Addi�onal six months of exclusivity to an exis�ng patent on the en�re moiety • Priority review status for paediatric applica�ons/ supplements

Table 1: Regulatory requirements for PIP, PUMA, PREA, and BPCA

the implementation of the EU Pediatric Regulation, 238 medicines and 39 pharmaceutical forms for use in children were authorised between 2007 and 2015.6 Between 2007 and 2016, 425 specific products were discussed, the majority in oncology (Figure 2), illustrating its importance in paediatrics and the need for global development plans. The paediatric clusters face some challenges. Individual divisions have varying levels of paediatric expertise and international experience. The different laws in each region have impacts: PREA requires certain matters to be studied, BPCA www.jforcs.com

provides incentives for doing more, and the EU legislation requires earlier commitment to paediatric plans. This is important as the paediatric cluster aims to avoid the fragmentation of paediatric development so anticipating proactively is essential to avoid missed opportunities and learnings. The cluster is also responsible for ensuring that the appropriate paediatric and other subject matter experts are in attendance. The paediatric cluster has had succeses. One example is related to the patient population for a product intended to treat medulloblastoma. The sponsor proposed to the EMA newly Journal for Clinical Studies 15

Regulatory

Figure 2: Drug Indications discussed during paediatric cluster product discussions (2007–2016)7

diagnosed and relapsed/refractory patients with medulloblastoma and to the FDA relapsed/refractory patients with medulloblastoma only. As an outcome of the cluster discussion, the FDA requested the sponsor to study both patient populations.8 The collaboration between the agencies has also resolved discrepancies regarding the timing of paediatric trials. For a drug to be used as an add-on to insulin to treat Type 1 Diabetes Mellitus (T1DM), the EMA’s initial position was that trials should start once efficacy and safety data were available in adults as the drug was an add-on drug and the first in its class to be studied in children with T1DM. The FDA’s position was that it would be sufficient to have interim adult data in T1DM and paediatric PK/PD T1DM data, based on the significant unmet need, i.e., many children with T1DM do not achieve glycaemic control on insulin alone. Following discussion in the cluster meeting, the EMA aligned with the FDA on an earlier timing of the paediatric programme.8 These examples demonstrate how important a global approach is to develop much-needed medicines for children. Key contributors to this are the paediatric cluster teleconferences together with initiatives such as joint working groups, workshops and expert meetings for extended discussions, joint publications, and the development of global paediatric trials networks. The EMA and European Commission (EC) action plan on paediatrics published in October 2018 envisages a strengthening of cooperation amongst decision-makers. The plan foresees enhanced integration of paediatric cluster activities to ensure knowledge and information exchange between PDCO and the paediatric regulatory cluster. This will also increase transparency of EMA/FDA paediatric cluster discussions to better inform sponsors about them and to increase openness for all relevant stakeholders regarding outcomes of non-product-related interactions. A progress report for the action plan on paediatrics will be published in 2020.9 Common Commentary The Common Commentary, pertaining to paediatric development plans which have been submitted to both FDA and EMA, are under review by both agencies, and have been discussed at the cluster, was launched in 2012 to inform sponsors of issues considered for some products, showing a commitment to a more collaborative approach with industry. The Common Commentary informs sponsors in writing of products discussed where the FDA and EMA have come to an agreement on the proposal at the paediatric 16 Journal for Clinical Studies

cluster meeting, although this is non-binding and not regulatory advice. Between 2012 and 2015, 25 products were considered. Products for oncology (n=10) and gastroenterology (n=9) were the most frequently discussed; the remaining therapeutic areas were cardiology (n=2), and one each for neurology, dermatology, inborn errors, and antimicrobial. In addition, the two agencies have collaborated to publish manuscripts and editorials pertaining to development of products for the treatment of ulcerative colitis, Crohn’s disease, and type 2 diabetes mellitus. Common Commentary – Impact on Paediatric Cancer Drug Development Common Commentaries directly influenced 26 paediatric oncology drug development plans.10 Those discussions focused on toxicity, non-clinical data versus adult patient experience and suggested monitoring plans, eligible patient populations, planned indication, and study design. Common Commentaries were issued for eight oncology products (Table 2), recommending global collaborative studies in many cases. Initial Common Commentaries resulted in parallel scientific advice in some cases. Currently, two of these drugs have approved paediatric labelling and the others have ongoing paediatric trials in view of approval for paediatrics. Following the implementation of the Research to Accelerate Cures and Equity (RACE) for Children Act, an increase in the development of drugs for paediatric cancers is expected. For those developments, collaboration will be essential due to the small subpopulation of children with cancers.

Table 2: Examples of FDA EMA Common Commentaries 2012–201611 Volume 12 Issue 6

Regulatory

Table 3: Comparison of specific PSP and PIP template structures

Common Commentary – Impact COVID-19 Pandemic Another example of collaboration between agencies relates to the development of an initial PSP/PIP for the prevention or treatment of COVID-19, with the FDA and EMA both providing procedural assistance to sponsors who anticipate submission of development plans for such agents. On June 2, 2020, these agencies published a Common Commentary streamlining administrative processes and facilitating efficient submission of iPSPs/PIPs for drugs and biological products for COVID-19.12 There are many similarities between the iPSP and PIP templates (Table 3). However, due to differences in legislation, a single template cannot meet the needs of both agencies. www.jforcs.com

Given the necessity to generate data to enable safe and effective use of products to treat and prevent COVID-19, the two agencies have agreed to encourage early submission of iPSPs/PIPs (no difference in timelines). Furthermore, the agencies will meet as needed to facilitate the product development for children. This shows an encouraging flexibility by the agencies, achieved through close collaboration. 1.

The iPSP template is included in FDA’s draft guidance for industry, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans, which when finalised will represent FDA’s current thinking on the topic. Journal for Clinical Studies 17

Regulatory 2.

https://www.ema.europa.eu/en/documents/template-form/ template-scientific-document-part-b-f_en.doc

Ongoing Progress to Intensify Collaboration for Paediatric Drug Development Relevant Molecular Targets in Paediatric Cancers In March 2018, the EMA and EC held a workshop with patients, academia, healthcare professionals, industry, and FDA representatives to discuss how to better apply the paediatric regulation to boost development of medicines for children. One of the 21 actions following the meeting was to establish a framework for collaboration with EMA/PDCO and the FDA’s Oncology Center of Excellence (OCE) to assess relevant molecular targets in paediatric cancers. The progress report of the paediatric action plan will be published in 2020. For the time being, the EMA and FDA review paediatric oncology programmes on a monthly basis via the paediatric cluster. Furthermore, both agencies have been represented in the ACCELERATE steering committee since 2019 and are actively engaged in the organisation of paediatric strategy forums addressing needs in children with malignancies. The relevant molecular targets13 in paediatric cancers is not envisioned to restrict flexibility and is another example of international collaboration. It was constructed by the OCE with the National Cancer Institute (NCI) and input from international experts in an open public meeting on April 20, 2018 at the FDA. The target list is continuously reviewed in semi-annual public workshops, with the possibility of recommendations for additions and deletions through internal and external advice panels.

18 Journal for Clinical Studies

ICH E11 (R1) The FDA, EMA, and other global regulatory authorities and industry representatives participated in the addendum to the International Council for Harmonization (ICH) E11 guideline, “Clinical Investigation of Medicinal Products in the Pediatric Population”. The addendum aims to advance paediatric research with clear, compatible guidance specific to global development of paediatric medicines and provides clarification and current regulatory perspectives on paediatric drug development and commonality of scientific approaches for paediatric programmes. ICH E11A Paediatric Extrapolation This new ICH Guideline proposes harmonisation of methodologies and strategies to incorporate paediatric extrapolation into overall drug development plans. This should improve the speed of access to new medicines for children while limiting the number required for enrolment in clinical trials. The draft is to be published in 2020. Further Collaboration and Alignment Needed The major challenge facing paediatric drug development is that children are generally healthy and therefore study populations are limited. Current legislation in the US and EU does not support prioritisation of disease based on unmet medical need, or a datadriven process that can equitably identify and prioritise drugs for clinical trials. Consequently, concerns regarding execution of the paediatric trials that are part of agreed paediatric development plans have been expressed.14 In 2013, the EMA held a workshop to discuss studies required under the paediatric regulation for several new drugs for T2DM.

Volume 12 Issue 6

Regulatory At that time, 16 PIPs (comprising 31 studies) had been agreed across the glucagon-like peptide-1 analogues, dipeptidyl peptidase 4 inhibitors, and sodium-glucose co-transporter 2 inhibitors, of which none had been successfully progressed due to insufficient numbers of patients. There is a need for a rational, collaborative, and data-driven approach to identifying and prioritising drugs for studies that are within the scope of legislative requirements, and for selecting and prioritising the best potential drugs to move forward. Working together with regulators, sponsors, patient advocates, and academic experts across company portfolios will better inform and facilitate prioritisation of developments. Regulators will continue to discuss coordinated approaches to minimise unnecessary trials and to optimise trial design, safety, and conduct so the limited paediatric populations available are enrolled only in ethically-implemented, scientifically-important trials. Innovative approaches to data generation, data sharing, and the use of preexisting data through innovative analytical strategies could be part of the solution. Conclusion Collaboration is essential for successful global paediatric drug development. To ensure adequate availability of drugs for children, the following will be paramount: • • • • • •

Regulatory collaboration to seek alignment Engagement with other stakeholders beside regulators Education on regulatory science and procedures Continued and collaborative discovery of efficient pathways to ensure safe and effective medicine development Strategic and creative approaches Emboldened approaches to public health

Discussions with the agencies could be established to shape paediatric development programmes, optimising development plans. One could envisage piloting an interaction with the agencies to further support global alignment, including: • • •

Use the paediatric cluster teleconferences as platform Output as non-binding Common Commentary providing recommendations for streamlined PIP/PSP/PPSP addressing children’s needs and regulatory requirements Option for trilateral discussions with the applicant and both agencies at the same time.

The agencies systematically collaborate using their experience to support paediatric assessment. Discussion of initial development plans and a coordinated international scientific review is paramount for the efficient evaluation of new agents and for developing medicines meeting the children’s needs. Ongoing harmonisation of paediatric science and research is fundamental to make paediatric product development easier and faster in order for children to obtain the medicines they deserve. REFERENCES 1. 2. 3. 4. 5.

US Congress. Pediatric Research Equity Act amending Section 505B of the Federal Food, Drug & Cosmetic Act (Public Law 108- 155). 2003 US Congress. Best Pharmaceuticals for Children Act Amending Section 505A of the Federal Food, Drug & Cosmetic Act (Public Law 107-109). 2002. European Parliament and the Council of the European Union. Regulation (EC) No. 1901/2006 on medicinal products for pediatric use. 2006. Yao, L. (2017). Current state of pediatric drug development. Available at https://www.fda.gov/media/107592/download US Food & Drug Administration. International Collaboration / Pediatric

www.jforcs.com

8. 9. 10.

11. 12.

13. 14.

Cluster. 2020. Available at https://www.fda.gov/science-research/ pediatrics/international-collaboration-pediatric-cluster European Medicines Agency. 10-year Report to the European Commission. 15 August 2017. EMA/231225/2015. Available at https://ec.europa.eu/ health/sites/health/files/files/paediatrics/docs/paediatrics_10_years_ ema_technical_report.pdf Kweder, S. (2017). Better together: Harmonizing pediatric drug development. Paediatric Conference, European Commission and TOPRA Available at https://www.topra.org/topra/topra_member/pdfs/10_ Sandra_Kweder.pdf. Annual Enpr-EMA workshop 16 May 2017, Irmgard Eichler, Enpr-EMA & Suan McCune, FDA Written communication from EMA dated 15 June 2020. Reaman, G., Herold, R., Norga, K. et al. (2016). Impact of the Food and Drug Administration (FDA)-European Medicines Agency (EMA) Common Commentary (CC) on Paediatric Cancer Drug Development. Ped.Blood Cancer, 63, S212. Poster for the 48th Congress of the International Society of Paediatric Oncology, October 19-22, 2016 in Dublin, Ireland, G. Reaman et al. US Food & Drug Administration, European Medicines Agency. FDA / EMA Common Commentary on Submitting an initial Pediatric Study Plan (iPSP) and Paediatric Investigation Plan (PIP) for the Prevention and Treatment of COVID-19. 2 June 2020. https://www.ema.europa.eu/en/ documents/other/fda/ema-common-commentary-submitting-initialpediatric-study-plan-ipsp-paediatric-investigation-plan-pip_en.pdf Candidate Pediatric Molecular Target List – available at https://www.fda. gov/media/120331/download Karres J., Pratt V., Guettier J.M. et al. (2014). Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes. Diabetes Care, 37:2665–2667.

Dr. Harris Dalrymple Dr. Dalrymple has nearly 40 years’ experience in the pharmaceutical and CRO industries, and over 20 years’ pediatric trial involvement. Originally a pharmacologist, he holds a master’s in medical law & ethics and PhDs in medicine & law. Dr. Dalrymple worked for Pfizer for almost 25 years. His interests include assent/consent/dissent, clinical trials in pregnancy, and ethical issues in clinical trials. He lectures on medical law and ethics for the British Association of Pharmaceutical Physicians.

Dr. Mark Sorrentino Dr. Sorrentino has 20 years of experience in the pharmaceutical and biotech industries. Prior to joining PRA, he spent 5 years as the global chair and founder of the pediatric practice area at a leading CRO. In addition to working at CROs, Dr. Sorrentino has served as the global chief medical officer at ADMA Biologics and as director of medical science at MedImmune.

Dr. Martine Dehlinger-Kremer Dr. Dehlinger-Kremer’s expertise spans 30+ years in the research industry, including 29 years of experience in global regulatory affairs, medical affairs, and pediatric leadership. Prior to joining PRA, she served in several executive leadership roles at global CROs and has experience in global drug development in more than 40 countries.

Journal for Clinical Studies 19

Market Report

Regenerative Medicine: Hype and Hope or Safety and Efficacy? Regenerative medicine, and the underlying stem cell technology on which it is based, offers considerable hope to patients suffering from trauma and acute or chronic disease. Despite this, regenerative medicine can be highly controversial in terms of claims and weaknesses relating to safety and efficacy, the regulatory aspects, the ethical and social aspects, the commercialisation of stem cell technology and – most importantly – the scientific and medical basis of the proposed technology. Regenerative medicine is in its infancy and we must all be very aware that at present, hype and hope are the backbone of the technology. When safety and efficacy are the backbone, then we will truly be in a new trusted area of clinical practice which patients can access with confidence. The issue of patient safety and treatment efficacy in regenerative medicine is arguably the most important factor in the future of the technology and at present we are in a position of extremes. This is because technology such as bone marrow stem cell transplantation, peripheral blood stem cell technology (using mobilised bone marrow stem cells) and cord blood stem cell transplantation are practised globally with a high level of safety and efficacy. There are many centres of excellence around the world where experts carry out these transplants with extensive regulatory guidance. Patients enjoy optimised safety and efficacy when they are treated by these experienced teams in a perfect setting. In stark contrast, there are a rapidly increasing number of stem cell-based ‘treatments’ for which there is little or no safety and efficacy data. These are often provided by stem cell ‘clinics’ and prey on vulnerable patients who are often looking for a ‘cure’ when traditional medicine has been unable to help. This is the dark side of regenerative medicine. The safety and efficacy of treatments offered using stem cellbased regenerative medicine is defined and controlled by the relevant regulatory authorities. Once again, as with safety and efficacy, the regulation of regenerative medicine technology falls into two extremes. The first extreme is in countries such as the UK and USA, where regulation is well developed and therefore patients are protected and can undergo regenerative medicine treatments with confidence. In the UK, for example, there is the Human Tissue Authority (HTA), the Human Fertilisation and Embryology Authority (HFEA) and the Medicines and Healthcare Products Regulatory Agency (MHRA). These organisations come together to regulate every aspect of stem cell technology, making the UK one of the safest places in the world to be treated using regenerative medicine technology. The second extreme is in other countries of the world such as India and China where regulation, if it exists, is poor – and the result is that many patients in such countries receive untested and potentially unsafe ‘treatments’. This means that in these countries, ‘treatments’ can be offered which place patients in potential danger and this has been illustrated only too well by reports of 20 Journal for Clinical Studies

patients suffering life-changing damage following poorly regulated ‘treatments’. There has also been a considerable rise in ‘medical tourism’ where patients travel to a country and as part of their visit receive ‘treatment’ using stem cells. This is a dangerous practice which all patients are well advised to avoid, but the problem is that false information and false promises lure vulnerable patients to have treatment. One of the ways in which we can try to reduce this problem is by patient education, so that patients know what to expect, to ask the right questions and to turn away when things look questionable or even dangerous. We must try to address the problem of patient education by providing clear, understandable advice written with no jargon for the general reader. This will be extremely helpful for anyone considering undergoing a regenerative medicine treatment. There is, unfortunately, another extreme when considering the regulation of regenerative medicine and this is sadly in places in the world such as South America and many small islands, where there is no regulation of regenerative medicine at all. This total lack of regulation means that anyone can set up a ‘clinic’ and offer ‘treatments’ and when doing this, they need not pay any attention at all to the safety and efficacy of the ‘treatments’ being offered. This is an extremely dangerous situation for patients and we must all try to discourage patients from attending any form of unregulated regenerative medicine ‘clinic’. Regenerative medicine is no different from other medical specialities in that it can raise ethical and social concerns. Ethical issues in regenerative medicine come in many forms; for example, if it is proposed to use human embryonic stem cells as a treatment, then this raises issues about the use of a human embryo to create stem cells. This example not only raises ethical concerns but also, for many people, religious concerns. Embryonic stem cell technology has in fact developed extremely slowly since it was first proposed, and this is largely because of technical problems, but the underlying ethical and religious objections have also contributed to the slow uptake of the technology. There is also the fact that there are not many human embryos available to use to create embryonic stem cells and the technology could therefore never be available on a mass scale. The ethical aspects of regenerative medicine technology also arise in the use of donor stem cells of all types (to ensure the wellbeing of donors) and also in the use of gene insertion technology to produce induced pluripotent stem cells from somatic cells. We all must keep ethical implications in mind when either carrying out or recommending regenerative medicine in the same way as we do in all clinical practice. The social implications of regenerative medicine are more complex. There is, first, the very obvious fact that most regenerative medicine procedures in most countries can only be obtained by payment and are therefore largely limited to the rich. Paymentonly regenerative medicine procedures immediately exclude many people, which may be seen as social injustice, but this is in fact no different to the existing global social injustice in healthcare which we all seem happy to accept. This does not mean that this social injustice is either fair or correct, it just means that regenerative medicine seems to follow the same path as the rest of clinical Volume 12 Issue 6

Market Report way to make very big profits in countries where there is little or no regulation. They prey on vulnerable patients who are willing to pay large amounts for untested and unproven ‘treatments’. This activity threatens the viability of regenerative medicine as a safe and trusted procedure, but at present there is little which can be done to reduce this unethical and unsafe practice. Our only hope at the moment is to provide clear advice about regenerative medicine to potential patients and to increase the amount of stem cell education provided in schools and colleges. Finally, we must all be aware of, and guided by, the stem cell science which underpins regenerative medicine. It is absolutely essential that any stem cell-based therapy must have a very clear evidence base composed of peer-reviewed publications and completed clinical trials. Such treatments can then be offered to patients with optimised safety and efficacy. Patients who wish to explore possible regenerative medicine procedures which have yet to go through clinical trials are well advised to enrol as volunteers in clinical trials. This will not ensure their absolute safety because all clinical trials carry risk, but those risks are mitigated to minimise any potential harm to volunteers. This is much better than paying profit-motivated businesspeople to receive untested and unsafe ‘treatments’ which could result in life-changing damage. Regenerative medicine holds considerable hope for the future but there are many hurdles to be cleared before the technology becomes commonplace in clinics and hospitals. These are scientific, medical, business and ethical hurdles and they cannot be rushed if we are going to provide a safe, effective and trusted regenerative medicine service in the future.

Peter Hollands

medicine. Whether this is a good or bad thing needs further debate. This social injustice may also increase the health status of the wealthy, making the difference between the wealthy and the poor even more extreme than it is today. This is clearly a bad state of affairs, but once again this is a generic problem and not one specifically related to regenerative medicine. It will require a global effort to correct these inequalities. There are other more subtle social implications associated with specific areas of regenerative medicine and arguably the most important of these is ‘anti-ageing’. Ageing is a natural process, based around the ageing of stem cells, which is essential for the ongoing survival of the human race. If we do not have ageing and death, or make significant reductions using regenerative medicine, then planet earth would very quickly become totally overloaded and we would all die. The use of regenerative medicine technology in ‘antiageing’ procedures needs careful consideration and, in my opinion, should not be used. If ‘anti-ageing’ was successful it could be the beginning of the end for the human race. The unregulated commercialisation of the stem cell technology used in regenerative medicine is a considerable and increasing problem to us all. There is an analogy within the pharmaceutical industry which is heavily commercialised but equally heavily regulated. This is not the case for Regenerative Medicine which is becoming increasingly commercialised but has little or no regulation on a global scale. The problem is accentuated by business workers who see stem cell technology and regenerative medicine as an easy www.jforcs.com

Peter trained at Cambridge University under the supervision of the co-inventor of IVF and Nobel Laureate Professor Sir Bob Edwards FRS. His PhD was in stem cell technology with a focus on the transplantation of stem cells from the developing fetus. His post-doctoral position was as a Senior Embryologist at Bourn Hall Clinic which was the first IVF clinic in the world. Peter has been the Scientific Director of Cells for Life in Toronto and Smart Cells in the UK and was HTA Designated Individual for Smart Cells. He has carried out research in stem cell technology and has written numerous papers and book chapters on stem cell technology. He has been an invited speaker to many international conferences including personal invitations to speak twice at the Vatican, the UK House of Lords and The Canadian Parliament. Peter also has experience in creating new stem cell technology laboratories and the related accreditation and regulatory aspects of stem cell laboratories. Peter has been the Group Chief Scientific Officer of the worldwide stem cell services company WideCells Group PLC and a Quality Manager for the Fertility and Gynaecology Academy in London. He now works as a freelance Consultant Clinical Scientist. Peter has written a book on stem cell technology for the general public called ‘The Regeneration Promise’ which will be published in November 2020. This is the first of a series of books on medical science. Peter was awarded a Visiting Chair in Regenerative Medicine from Kolkata School of Tropical Medicine in November 2017. This was in recognition of his collaborative work in stem cell technology in Kolkata, India. Email: peterh63@hotmail.com

Journal for Clinical Studies 21

Market Report

The Role of eConsent in Remote Trials

The needs of today’s clinical trials demand flexible approaches and solutions. The drive to make trial participation more convenient and more inclusive for patients living greater distances from sites, has led sponsors to design trials requiring fewer site visits and increasing what can be accomplished by the patient while at home. In addition, the ability to provide study information and consent documents ahead of the first at-site meeting better equips patients to make decisions about study participation, and to identify early those that may not wish to participate. Challenges of Remote Informed Consent There is a clear industry shift from traditional, in-clinic paper-based consent to more flexible electronic solutions that can obtain consent both in-clinic or at home. While there is much discussion about eConsent in fully remote trials, challenges remain where patients are recruited externally to in-clinic pools in terms of the ability to provide robust solutions to identity and diagnosis verification. Recently, one of the more common uses of remote eConsent (and the scope of this article) is in the provision of remote access to patients pre-identified through individual site health records. eConsent Design for Remote Trials Typically, all eConsent systems offer similar workflows through three main components:

an on-site consenting visit, to conduct of the entire process including time to have questions answered by the investigator during a phone or video consultation ahead of online completion of the documents. eConsent systems usually offer the below features to support remote consent: • Access at site or at home using any web-connected computer or mobile device • Automated email of logon credentials to patients following account creation by site • Easy identification of patients ready for study discussion and Q&A completion • Sites can monitor patients’ progress through the investigator interface • Patient and investigator can sign completed consent forms using their electronic signatures • Incorporate gatekeeper step to ensure remote discussion and Q&A between patient and site is conducted ahead of final consent signatures, where required • Access and review consent to optional study components such as biosample usage throughout the study • Sign completed consent forms using electronic signatures • Full online access and download of completed consent for both patients and sites • Real-time updates for sites, CRAs and study teams to remotely monitor the trial’s consenting process and progress of each patient • Date and timestamps as auditable evidence of the consenting process

The three components work together to provide the flexibility to review forms, obtain remote consent and signatures, and monitor progress remotely. Perhaps the biggest benefit of eConsent in 2020 is this ability to offer remote informed consent. Remote eConsent Features Set Remote eConsent features allow patients to review, consent and reconsent at home and at their own pace. This can range from simply providing patients with access to materials for pre-reading ahead of 22 Journal for Clinical Studies

Volume 12 Issue 6

Market Report Remote eConsent: Example Workflow

In this example, the site can set up remote access and accounts for its patients. The account credentials can be automatically emailed to a patient’s verified email. The patient would then access the eConsent form from home on any web-connected computer or mobile device. The patient can flag any section of the consent form as “needs review” with the site. Prior to providing consent, a phone or video consultation can take place where the site addresses the patient’s flagged sections and any questions and concerns raised by the patient. When the patient’s concerns are satisfied, both the site and patient can complete the electronic signature process.

as time of logging in, flagged sections, and date and time stamps of signatures.

eConsent can enhance and result in more focused directto-patient interaction by sites and allows this interaction to be maintained as a core feature of the remote consent process. eConsent systems do allow the site and patient Q&A to be disabled, if needed. We recommend maintaining this functionality. However, in a fully remote trial this may need to be disabled.

Summary eConsent offers sponsors a flexible experience that not only can be deployed remotely, but better informs and educates patients. Scenarios like COVID-19, siteless trials, and expanded patient demographics will likely increase the importance of eConsent as clinical trials shift closer towards the patient’s home.

eConsent Analytics and Reports for Remote Monitoring As mentioned, eConsent offers real-time reporting tools that enable sponsors, monitors and sites to remotely track the progress of the trial and of each trial participant during the consent process.

In March 2020, FDA’s Guidance on Conduct of Clinical Trials during COVID-191 recommended the use of eConsent, when possible, for COVID-19 trials. While not explicitly stated, this recommendation

In fact, most eConsent systems provide detailed reporting as well as high-level dashboards that can offer actionable insights on improving the consent process. An example of such reports includes a colourcoded, holistic real-time study report (Figure 1) on the total number of patients, and the number of patients that consented, are awaiting consent, need to reconsent, or declined to participate. Another example (Figure 2) is a consolidated report of the sections that were difficult for patients to comprehend and hence flagged frequently. This can be further filtered down to various levels for comparison and analysis such as site or language or country-level views. There are also several patient reports (Figure 3) through which sponsors, monitors and sites can view audit logs on patients, or the list of documents the patient has consented to and when, or whether they provided consent for any biosample collection. All activities on patients’ remote consenting journey are also captured, such www.jforcs.com

Reports like these can identify opportunities in several areas; for example, they can result in improving and simplifying consent forms, to creating more effective training materials for patients and sites, to sites getting better prepared to support patient discussions. These reports could also support making trial participation more attractive by highlighting the need for protocol amendments to minimise the perceived risk and uncertainty around the trial.

Figure 1: Example of study level reports Journal for Clinical Studies 23

Market Report

Figure 2: Example of analysis reports

Figure 3: Example of patient-level reports

can be attributed to the tool’s rich feature set and its ability to be conveniently deployed at the patient’s home. Based on current industry trends, sponsors and study teams will continue to consider flexible, at-home data collection solutions that can positively impact patient engagement and even deploy the use of multiple patient-facing technologies on the same device, such as electronic clinical outcome assessments together with eConsent to better support remote clinical trial scenarios. REFERENCE 1.

FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards

24 Journal for Clinical Studies

Neetu Pundir Neetu Pundir is an experienced product and brand manager with prior professional experiences across the globe in the healthcare and life sciences industry, working for companies such as Johnson & Johnson, BIOTRONIK Medical Devices, Henry Schein, and eResearch Technology. Neetu is currently employed as Director at Go To Market Strategy and is part of the Product Management Team at Signant Health. Neetu has a Master’s in Business Administration with degrees from Northwestern University, USA and the University of New South Wales, Australia.

Volume 12 Issue 6

Corporate Profile Ramus Corporate Group

is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of the International Standard for Quality Management System ISO 9001:2015.

Ramus Medical is working CTs in a variety of therapeutic areas and medical device.

•

• • • • • • • • • • •

Medical Centre Ramus with Phase I Unit

Full service CRO Medical writing for drugs and devices Scientific review of documentation GxP trainings Ramus Phase I unit Ramus Analytical laboratory Clinical trial management Monitoring Data management Biostatistics Regulatory advising and services during clinical trial

Medical Diagnostic Laboratory Ramus (SMDL-Ramus) • • •

20 clinical laboratories in Bulgaria and North Macedonia 300 affiliates for sampling in Bulgaria and North Macedonia 20 years experience in the CT flied as central and safety laboratory; , fast, correc t! Safe

• • • •

Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

PK/PD studies Medical devices investigations Phase I–IV Non-interventional studies

Others: • • • • •

Readability user testing Bridging report Archiving services DDD activities Transportation and storage of dangerous goods

Medical Diagnostic Laboratory Ramus Ltd

26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel/Fax: +359 2 944 82 06 www.ramuslab.com email: info@ramuslab.com

Ramus Medical Ltd Tu

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 25 25

Therapeutics

Clinical Development in Inflammatory Diseases: Rheumatoid Arthritis Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by an inflammatory polyarthritis that preferentially affects the small joints. RA is a "multicausal" disease that most likely results from a combination of genetic predisposition and various environmental and lifestyle factors. Articular and systemic manifestations in RA can lead to poor long-term outcomes such as disability and death. The article aims to give a summary on RA and its treatment with emphasis on the new treatments currently under development. RA is estimated to affect approximately 0.24 to 1 per cent of the population based upon the Global Burden of Disease 2010 Study1. Estimates of RA prevalence in the United States and northern European countries are typically higher, usually between 0.5 and 1 per cent2,3. The annual incidence of RA in the United States and Northern European countries is estimated to be approximately 40 per 100,000 persons2,4. RA has a predilection to affect women, with a 3.6 per cent lifetime risk of developing RA in women and 1.7 per cent in men4. Background A series of genetic, demographic, lifestyle, environmental, and physiologic risk factors for rheumatoid arthritis (RA) have been identified in epidemiologic and related studies. A large, Swedish nested case-control study estimated RA hereditability to be 40 per cent5. Familial risk was higher for seropositive and early-onset RA. Over 100 risk loci for RA have been identified, primarily in studies of Caucasian populations6. The strongest genetic predisposition for RA is within the human leukocyte antigen (HLA)-DRB1 region. Within the HLA-DRB1 region, a shared sequence of amino acids at positions 70 to 74 termed the "shared epitope" has been consistently identified as a risk factor for RA7. Demographic factors associated with a higher risk of RA include older age, female sex, North American and Western European ethnicities and selected smaller ethnic groups, and lower socioeconomic status2. Cigarette smoking, poor diet quality, obesity, and physical inactivity are lifestyle factors that may increase RA risk.

related injury. Recommendations of both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) support the early use of DMARDs, usually methotrexate (MTX), for most patients with active disease. DMARDs can be divided into two major groups: • •

conventional synthetic DMARDs (csDMARDs): e.g. methotrexate (MTX) – most commonly used, leflunomide, sulfasalazine, hydroxychloroquine biological DMARDs (bDMARDs): e.g. rituximab, etanercept, adalimumab

In Figure 1, the most recent treatment guideline of EULAR for RA is shown issued in 2019. If there is no contraindication for MTX then it becomes the first line of treatment, otherwise another type of csDMARD is used instead. In case of no clinical improvement, either a csDAMRD is added/changed or a bDAMRD is introduced as well. Treatment decisions are based on disease activity, safety issues, response to previous treatment and other patient factors, such as comorbidities and progression of structural damage.

Current Clinical Management The treatment of RA is directed toward the control of synovitis and the prevention of joint injury, and, increasingly, the reduction of accompanying comorbidities with the overall aim of maintaining function and quality of life. Support for an early aggressive approach to treatment is based upon the observations that joint damage, which may ultimately result in disability, begins early in the course of disease and that the longer active disease persists, the less likely the patient is to respond to therapy8. Therapy is based upon the widely accepted view that all patients diagnosed with active RA should receive disease-modifying antirheumatic drugs (DMARDs) to prevent, arrest, or retard disease26 Journal for Clinical Studies

Figure 1 Volume 12 Issue 6

Therapeutics Clinical Development in RA Although there is no known cure for RA, over the last few decades substantial improvement was achieved in terms of disease progression and quality of life, while drug companies strive to introduce new and better treatments. As of May 2019, according to clinicaltrials. gov there are 99 active interventional studies testing either an active compound or a medical device running all over the world, funded by the pharmaceutical industry. The majority of the investigational products tested fall under the category of biological therapies and small molecules and 73% of the currently running studies feature either one or both of them in combination with each other. Therefore, our main focus will be on these types of investigational products in advanced stages of development for RA, which will be reviewed here.

treatment regimens had significantly better responses for all primary and secondary endpoints than placebo-treated patients. At Week 12, 91% of patients treated with olokizumab every two weeks and 100% of patients treated with olokizumab every four weeks achieved an ACR20 response. Meanwhile, only 37% of placebo-treated patients achieved an ACR20 response. Also at Week 12, DAS28-CRP<3.2 responses were 48%, 55% and 5%, respectively13. Clazakizumab, a humanised rabbit anti-IL-6 monoclonal antibody has shown benefit in patients with RA and an inadequate response to MTX when used either alone or in combination with MTX in a Phase II randomised dose-ranging trial14. Adverse effects in the trial were similar to those seen with other anti-IL-6 and antiIL-6R agents. Further studies are ongoing with novel IL-6 inhibitor antibodies. GM-CSF Receptor Inhibitors The granulocyte-macrophage colony-stimulating factor (GMCSF) is a proinflammatory cytokine involved in pathogenesis of RA through its capacity to promote the activation, differentiation, and survival of macrophages, dendritic cells, and neutrophils. It is upregulated in synovial tissue and circulating cells from patients with RA, and there is interest in the therapeutic utility of targeting the GM-CSF receptor and other colony-stimulating factors in patients with RA.

Table 1: Overview of the most promising therapies under development

Interleukin-6 Antagonists IL-6 is expressed in RA synovial tissues and is implicated in the upregulation of endothelial adhesion molecule expression, in osteoclast maturation, and in bone erosion. IL-6 also mediates systemic features of disease, including fatigue, cognitive dysfunction, and metabolic shift. Several marketed therapies for RA target the interleukin (IL)6 pathway, including antibodies directed against the IL-6 receptor (IL-6R) such as tocilizumab and sarilumab. Another investigational antibody that showed efficacy in clinical trials was sirukumab, which targeted IL-6 directly. IL-6 is a proinflammatory cytokine which mediates pleiotropic functions in immunologic responses during host infection, inflammatory disease, hematopoiesis, and oncogenesis. Sirukumab, a human anti-IL-6 monoclonal antibody, was effective in two Phase III trials involving a total of over 2500 patients, including in patients with inadequate responses to methotrexate (MTX) and in patients resistant to tumour necrosis factor (TNF) inhibitor therapy9,10; however, based upon safety concerns, the US Food and Drug Administration (FDA) Arthritis Advisory Committee did not recommend drug approval, noting evidence of imbalances in death, serious adverse events, major adverse cardiovascular events, serious infection, and malignancy in the sirukumab development programme, although the results were imprecise11,12. The FDA therefore indicated that additional clinical data were needed to further evaluate safety, and the manufacturer subsequently withdrew its application and is no longer developing this agent for the treatment of RA. Olokizumab, a humanised anti-IL-6 monoclonal antibody was superior to placebo in a Phase III trial. Patients in both olokizumab www.jforcs.com

Mavrilimumab, a human monoclonal antibody targeting GMCSF receptor-alpha has shown benefit in randomised both Phase I and II trials in patients with active RA15–18. In Phase II clinical trials in RA, mavrilimumab demonstrated benefits over placebo in patients with an inadequate response to csDMARDs and in patients with inadequate responses to tumour necrosis factor (TNF) inhibitor therapy16–18. Additional trials with better optimised dosing are required to adequately compare the efficacy and safety of mavrilimumab with other biologic agents. Other agents are under trial that are targeting the cytokine itself. Janus Kinase Inhibitors While traditional biologic therapies act outside cells to suppress inflammation and are given by injections or infusions, JAK inhibitors work inside cells and are taken orally. The Janus kinases (JAK) are cytoplasmic protein tyrosine kinases that are critical for signal transduction to the nucleus from the plasma membrane receptors for IL-2, -4, -7, -9, -15, and -21. Some of these agents have become already available for clinical use in many or a few countries, including tofacitinib, baricitinib, upadacitinib, and peficitinib. Filgotinib, a small-molecule, orally active investigational drug that selectively inhibits JAK-1 in vitro. The efficacy and safety of filgotinib have been examined in several trials, where it has shown efficacy generally similar to the marketed JAK inhibitors, including the JAK-1 selective inhibitor, upadacitinib, and was well tolerated. The efficacy and relative safety of filgotinib was evaluated in a randomised trial involving 449 patients with moderate to severely active RA who had an inadequate response or intolerance to prior therapy with one or bDMARDs19. At week 12, patients treated with filgotinib (200 or 100 mg once daily by mouth) were more likely to achieve an ACR 20 per cent improvement (ACR20) response, compared with patients receiving placebo (66 and 58 versus 31 per cent, respectively). ACR20 responses were also more likely among patients with prior exposure to three or more bDMARDs (70 and 59 versus 8 per cent), and responses were sustained at week 24. By week 12, low disease activity (disease activity score in 28 joints using the C-reactive protein [DAS28-CRP] ≤3.2) was more common Journal for Clinical Studies 27

Therapeutics

with filgotinib (41 and 37 versus 16 per cent, respectively). Physical function and fatigue also improved. The incidence of SAEs and early discontinuation were comparable in all three arms.

this agent20. Use of filgotinib was associated with improvements in haemoglobin levels. Greater experience with the JAK inhibitors is needed to determine whether differences in the in vitro selectivity of different JAK inhibitors will translate into meaningful differences in their adverse event profiles in clinical practice.

In Phase II trials in patients with an inadequate response to MTX, filgotinib has shown benefit (in several doses), compared with placebo, both when combined with continued MTX therapy20,21 and as monotherapy19. Patient-reported outcomes also improved with

Conclusion As demonstrated, the clinical management of RA is highly complex and multifactorial. Patients now have an expanded life expectancy and elevated quality of life as a result of the achievements in

28 Journal for Clinical Studies

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Therapeutics therapy over the last few decades, but this also brings a growing challenge of more and more patients becoming DMARD-resistant during the course of their lifetime, thus creating a strong need for new treatment options with compounds affecting new and different pathways of mechanism. The above listed current drugs under development target this goal as well, and in the near future they could possibly improve and widen the options for treatments.

16.

REFERENCE

18.

10.

11.

12.

13.

14.

15.

Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T et al. - The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1316. Epub 2014 Feb 18. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE – Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007 Arthritis Rheum. 2010 Jun;62(6):1576-82 Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol Int. 2017;37(9):1551. Epub 2017 Apr 28. Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ et al. – The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011 Mar;63(3):633-9 Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Askling J Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013;65(11):2773. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al. - Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506(7488):376. Epub 2013 Dec 25. Gregersen PK, Silver J, Winchester RJ - The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205. Anderson JJ, Wells G, Verhoeven AC, Felson DT - Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000;43(1):22. Takeuchi T, Thorne C, Karpouzas G, Sheng S, Xu W, Rao R, Fei K, Hsu B, Tak PP – Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001. Epub 2017 Aug 30. Aletaha D, Bingham CO 3rd, Tanaka Y, Agarwal P, Kurrasch R, Tak PP, Popik S - Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet. 2017;389(10075):1206. Epub 2017 Feb 16. Food and Drug Administration Center for Drug Evaluation and Research. Summary Minutes of the Arthritis Advisory Committee Meeting. August 2, 2017 https://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ UCM575678.pdf (Accessed on 17 May 2020). FDA Briefing Document. Arthritis Advisory Committee Meeting August 2, 2017 https://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ UCM569150.pdf (Accessed on 17 May 2020). Nasonov E, Fatenejad S, Korneva E, Krechikova D, Maslyansky A, Plaksina T et al. - Safety and Efficacy of Olokizumab in a Phase III Trial of Patients with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate – CREDO1 Study Arthritis Rheumatol. 2019; 71 (suppl 10). Weinblatt ME, Mease P, Mysler E, Takeuchi T, Drescher E, Berman A et al. – The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, doubleblind, placebo/active-controlled, dose-ranging study. Arthritis Rheumatol. 2015;67(10):2591. Burmester GR, Feist E, Sleeman MA, Wang B, White B, Magrini F Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, doubleblind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis. 2011;70(9):1542. Epub 2011 May 25.

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17.

19.

20.

21.

Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J et al. - A randomised phase IIb study of mavrilimumab, a novel GMCSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1020. Epub 2017 Feb 17. Burmester GR, McInnes IB, Kremer JM, Miranda P, Vencovský J, Godwood A et al. - Mavrilimumab, a Fully Human Granulocyte-Macrophage ColonyStimulating Factor Receptor-Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70(5):679. Epub 2018 Mar 31. Weinblatt ME, McInnes IB, Kremer JM, Miranda P, Vencovsky J, Guo X et al. - A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70(1):49. Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F et al. - Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA. 2019;322(4):315 Westhovens R, Taylor PC, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M et al. - Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. 2017;76(6):998. Epub 2016 Dec 19. Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F et al. - Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials. Arthritis Rheumatol. 2017;69(10):1949. Epub 2017 Aug 31.

Dr. Peter Benedek, MD An Experienced Physician and Clinical Research Professional with more than 8 years of experience in Clinical Operations and Clinical Monitoring in both Pharma and CRO including Interaction and liaising with KOLs and Investigators in multiple therapeutic areas in addition to a wide range of operational activities from study start-up till Close-out and full site management. Email: info@europital.com

Dr. Vijayanand Rajendran, MD A qualified physician with over ten years of clinical and research experience. Hands-on experience in safety monitoring of Phase I-IV trials in a variety of therapeutic areas including oncology, haematology, respiratory, gastroenterology and the musculoskeletal system. Email: info@europital.com

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

Journal for Clinical Studies 29

Therapeutics

For Paediatric Participants, Patient-centric Trials Must Be Family-centric I was talking about my grandmothers the other day, explaining how I had one grandmother that would always ask if my mother had any mending that needed to be done or laundry to be folded – we called her the “Sewing Grandma”. My other grandmother would invariably have candy for me and my sister so, not surprisingly, we called her the “Candy Grandma”. She would ensure that she acknowledged our birthdays with whichever present we had asked for, and she always brought a smaller gift for the other sister so that child “wouldn’t feel left out”. Telling that story got me thinking about how I had often struggled with the term “patient-centricity” when talking about the design and execution of clinical trials because no clinical trial participant exists in a vacuum; they are part of some larger social unit. In the case of children, that larger social unit is usually a family. But we never really talk about “family-centricity” in clinical research. “Patient-centricity” is a term that has gathered a lot of attention over the past number of years, serving as the subject of a whole raft of conferences or meeting themes dedicated to the topic over the past decade. Patient-centricity has been defined as “integrated measures for listening to and partnering with patients and placing patient well-being at the core of all initiatives”.1 In essence, it represents a holistic approach to disease management. With regard to clinical research, patient-centricity is often interpreted to mean listening to and partnering with the patient, and understanding the patient perspective, rather than simply inserting patient views into the established clinical trial processes. Many articles in industry publications have addressed the impact of adjustments and accommodations to how clinical trials have been conducted during the SARS-CoV-2 pandemic, which have resulted in the acceleration of strategies that have been discussed as patient-centric but which had been implemented only sporadically. Key among the patient-centric changes we have seen being implemented as a result of the SARS-CoV-2 pandemic is the more frequent inclusion of the option for assessments in clinical trials to be performed away from the site, including off-site mobile research nursing or other forms of off-site or remote data collection through telemedicine visits, or the use of “connected” wearable devices that capture data about the user and send it back to the clinical research site or central reader for analysis and inclusion in the study database. These are clearly welcome changes to the standard “go to the site every X weeks and have a set of assessments performed” approach to the design and conduct of clinical trials, but patient-centricity can and should mean so much more, especially when the patients who are participating in the studies are children. Clinical research in paediatric patients has long been the subject of ethical debate, focusing on topics as varied as a minor’s ability to make an autonomous decision to participate in a clinical trial, the difference between informed consent and informed assent, at what age can a child provide true assent to participate in a clinical trial, and the influence of parents or caregivers on the child’s opportunity to exercise self-determination – an issue that is made more complex when patient or caregiver stipends to mitigate 30 Journal for Clinical Studies

the costs of participation are included in the trial. These topics continue to be explored by bioethicists as they should be; however, as these debates continue, what is clear is that children and even adolescents are not just small adults. Their physiology and even their psychology is quite different from those of an adult, and their medical status and participation in a clinical trial impacts all those who are part of their larger social unit, yet while we hear the terms “patient-centricity” or “patient engagement” more frequently now, we don’t really see much discussion about “family-centricity”. So while we are happy to see legislation introduced such as the RACE Act in the United States, which eliminates the orphan exemption for new cancer drugs directed at molecular targets relevant to children’s cancers and which will hopefully lead to more therapies being developed for and studied in children to provide clinicians with treatment options for paediatric patients that are supported by data gathered in children, one still has to ask – are those trials being designed and executed in a “family-centric” manner? Family-centricity, simply put, is the application of patientcentric strategies in the setting of the family rather than limiting the scope of those activities and initiatives to the patient as an individual participant in a clinical trial. Expanding patient-centric concepts to the family or larger social unit means going one step beyond what the industry has come to accept as patient-centricity in a clinical trial. Many pharmaceutical companies and clinical research organisations (CROs) extol the value of engaging with patients to assist with providing input on selected endpoints, assessing the impact of the schedule of assessments on the patient’s daily routines, and even testing out new ways to collect data, such as the development and validation of condition-specific rating scales or functional assessments. Expanding patient engagement to family engagement takes this interaction to the next level, going beyond querying parents about which endpoints would be the most impactful for their child to discussing the impact of the child in question’s condition on the remainder of the family. Are there other children in the family who would be affected by the clinical trial? How would they be affected? What can be done in terms of trial Volume 12 Issue 6

Therapeutics design or execution to acknowledge those impacts and potentially mitigate them? Siblings of children with chronic conditions are known to deal with a number of sequelae related to that chronic illness. At a minimum, there are disruptions in daily life that are related to the care of the chronically ill child, including healthcare appointments limiting options for activities in which the family can participate, or limited access to a parent or caregiver who is the primary caregiver for the child who is ill.2 Siblings of chronically ill children may experience jealousy about the attention the ill child receives, and even guilt that they are healthy while their sibling is not.3 Rarely do these considerations factor into discussions regarding the design and execution of clinical research studies. So how can those of us in industry, particularly those who work in the design and execution of paediatric clinical trials, move from being patient-centric to being family-centric? In the first instance we can expand the roadmap that many companies are now using to be more patient-centric in the first place. •

When sponsor companies and CROs start thinking about patient-centric considerations when designing a trial, they can expand that conversation not just to contemplate the impact of the schedule of events on the patient, but also to ask questions about other family members and how the visit or assessment schedule could impact them. Consider the well-intentioned discussion about selecting sites that agree to see children in the late afternoon or on weekends so as not to disrupt school schedules. Certainly, this is a step in the right direction and should be applauded, but how often does that conversation extend past the child being considered for participation in the trial? For example, are there siblings who won’t be able to attend after-school activities because one of their parents has to transport their brother or sister to the site for a required study visit? Does the family have to seek the assistance of a member of their extended family or community to ensure that the sibling not participating in the trial has transportation to their own activities? Do the parents of the child participating in the trial have to pay for that extra assistance? Could that hidden cost impact their ability to continue in the trial? Even if the site is willing to see the child after school hours, how does that impact the work schedule for the caregiver who has to transport the child to the site? Are there lost wages and does that reduction in income impact the rest of the family? It is in these situations that any opportunity to reduce the need for the participating child to be seen at the site can not just benefit

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the participating child, but indeed could have a beneficial impact on the larger family. Something as straightforward as expanding visit windows to permit a parent to have the flexibility to attend one of the other children’s sporting events or music recitals can have a positive impact on the dynamic of the family and their perception of the burden of participation in the trial. •

Many sponsor companies and CROs are giving more thought to recommendations to support the patient and their caregiver during clinical study visits, such as providing tokens such as colouring books or movie downloads, as permitted by local regulations, but what about the sibling that has to travel with the patient and the caregiver to the visit? Since they are not an actual participant in the trial, what is the sponsor or CRO doing to acknowledge their contribution to their sibling’s participation in the trial? If permitted by local regulations and the relevant ethics committee or institutional review board, can siblings be provided with activities or tokens to pass the time as well or a certificate to acknowledge their support of their sibling’s participation? Are sponsor companies and CROs thinking about these options?

•

It is well established that interactions with patient advocacy organisations (PAOs) can provide significant insight into the challenges of living with a certain diagnosis within a family but again, most of the consultations that occur focus on the affected child and, in some cases, the parent or caregiver in terms of study design, desired outcomes, and the perceived burden of participation for the patient and possibly their caregiver. Sponsors and CROs might gain significant insight into potential recruitment and retention hurdles for their study if they were to expand the conversations with PAOs to ask about the impact of the condition under study on other family members. Indeed, they may generate insights that lead to assessing the perceptions of other family members on the impact of the therapy under investigation too as part of the value statement for the therapeutic.

•

Even in situations where the most well-intentioned sponsor companies or CROs elect to implement burden reduction strategies such as flexible visit scheduling, telemedicine or off-site mobile research nursing, there are still family-centric considerations that should be taken into account when planning out the practicalities of their implementation. Is there a private place where assessments can be performed without siblings being present? How does a parent handle that Journal for Clinical Studies 31

Therapeutics

situation if the sibling is younger and can’t be left alone while still needing to be present during the assessment or having to complete their own assessment? How will other children in the home react to seeing their sibling undergo assessments or procedures such as receiving an injection or an infusion? How will they react if they hear their sibling react in pain to a procedure? Will it scare them? How does a parent console the child that has to have the painful procedure and the sibling who may be frightened by what they are seeing? How are sponsor companies and CROs anticipating these challenges and developing strategies to mitigate them? Would it make sense to work with a family or a PAO to develop a list of questions and answers that can be made available to parents or caregivers to talk about with their children who are not participating in the study, so that those children also know what to expect if their sibling has a home-based research or telemedicine visit? Most of the suggestions listed herein are not new or earthshattering. They form the basis of what sponsors and CROs are already doing in terms of patient-centric study design and execution strategies. They are welcome changes to the way that clinical trials are conducted in general and particularly meaningful in the setting of paediatric clinical research. I am glad to see the progress that has been made in terms of patient-centricity being considered a common and expected component of clinical trial design and execution – I just wonder how we consider the needs and impact on the rest of the family of a paediatric clinical trial participant, especially the other children. Is family-centricity the next step in the evolution of patientcentricity? I think my Candy Grandma would say it has to be. 32 Journal for Clinical Studies

REFERENCE 1.

du Plessis, D., Sake, J., Halling, K. et al. Patient Centricity and Pharmaceutical Companies: Is It Feasible? Ther Innov Regul Sci 51, 460– 467 (2017). https://doi.org/10.1177/2168479017696268 Knecht, C., Hellmers, C., Metzing, S. The perspective of siblings of children with chronic illness: a literature review. J Pediatr Nurs. 2015 Jan-Feb;30(1):102-16. doi: 10.1016/j.pedn.2014.10.010. Epub 2014 Oct 24. PMID: 25458108. Risi, A. “How to Help Children Cope with a Sibling’s Chronic Illness”. Good Therapy Blog. 31 Jul 2014, https://www.goodtherapy.org/blog/how-tohelp-children-cope-with-a-siblings-chronic-illness-0731144.

Juliet “Jules” Moritz Jules is a highly experienced pharmaceutical professional with over 30 years of clinical research experience. Jules completed her undergraduate work in biology and nursing at the University of Pennsylvania. She earned her Master of Public Health degree with honors from the Drexel University Dornsife School of Public Health. She has worked for both sponsor companies and for CROs across a number of therapeutic areas, overseeing trials that range from a 10,000-patient cardiovascular program to a four patient ultra-rare gene therapy trial. She has worked for both sponsor companies and for CROs across a number of therapeutic areas, overseeing trials that range from a 10,000-patient cardiovascular program to a four patient ultra-rare gene therapy trial.

Volume 12 Issue 6

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Therapeutics

Precision Medicine: Targeted Therapy in Paediatric Oncology Patients For several decades, cancer has been one most of the devastating diseases affecting paediatric patients. A huge number of clinical trials and research papers are aimed at solving the puzzle of cancer; however, most scientists and healthcare providers are often shocked by the unpredictable attitude and response of this disease. Nevertheless, huge progress has been made in this field as about 50 years ago, the 10-year survival rate didn’t exceed 20% (patients < 20 years old); but nowadays, it has reached 83%. This has been made possible by the efforts of the cooperative group protocols and multidisciplinary treatment.1 However, the toxicities and adverse effects exhibited by chemotherapeutic agents remain a barrier while treating paediatric oncology patients. In such circumstances, precision medicine can help us deal with the above issues.2 In 2015, Mr Barack Obama, the president of the United States, launched the “Precision Medicine Initiative”.3 Furthermore, he described it as being equivalent to the first moon landing as it aimed at providing individualised care to cancer patients.1 What is Targeted Therapy? And What are its Advantages? Targeted therapy depends on targeting unique receptors or proteins in the malignant cells, thus leading to fewer chemotherapy-induced adverse effects. In this regard, a study published in the Oncology Times aimed at evaluating the efficacy of targeted therapy in paediatric oncology patients with poor prognosis.4 The trial included 149 children with relapsed, refractory, and progressive high-risk malignancies (survival rate: less than 20%; median survival: 9.5 months). By using a particular algorithm, the paediatric oncologists could identify twenty patients with very high priority targets who could benefit from targeted therapy. After receiving the appropriate targeted therapies, these children showed longer progression-free survival than other children (204.5 days versus 114 days). Thus, to achieve the highest benefit from the targeted therapy, we would have to focus on developing the diagnostic tools to facilitate identifying the highest priority targets in each patient. But although targeted therapy can achieve better results, there are only a few approved targeted therapies available for paediatric oncology patients. Thus, the American Society of Clinical Oncology (ASCO) urges the scientific community to undertake precision medicine research and treatment approaches as a critical research priority. But even as it does so, we must be aware of the various challenges faced while developing and using targeted therapy in the paediatric population.5 Challenges of Including Paediatric Population in Clinical Trials To include paediatric patients in clinical trials is not an easy task. According to the European Society for Medical Oncology (ESMO), the legal age in Europe for participation in clinical trials is above 18 years. However, it’s lowered to 12 years in the USA.6 34 Journal for Clinical Studies

Moreover, cancer in paediatric patients has a different histology3 with a few numbers of mutations and genetic alterations in contrast to adults, and this hinders the development of new targeted therapies.1 However, the MATCH-style trials (paediatric cancer clinical trials) are extending its purview to include participants from various countries as Europe (ESMART), Canada (PROFYLE), and United States (NCI Pediatric MATCH).2 And now, let us focus on particular types of targeted therapies for paediatric oncology patients. I. Anti-angiogenic Therapy For nutrient supply to cancerous tissue, new blood vessels originate from the pre-existing ones. This process is known as angiogenesis and is crucial for the growth of the malignant cells. The VEGF (vascular endothelial growth factor) pathway is pivotal for the process of angiogenesis, so most anti-angiogenic drugs, like Bevacizumzb, Sunitinib, and Cediranib, target the VEGF pathway and receptors.5 These drugs decrease the tumour’s interstitial pressure and increase the oxygen delivery to the tumour while decreasing vascular oedema and enhancing the delivery of chemotherapy at the target site.7 In alveolar soft part sarcoma, a rare type of cancer with a prominent capillary vascular pattern, the tumour cells have a poor response to chemotherapeutic agents. But by adding Cediranib and Sunitinib, the tumour cells have shown a good response. Cilengitide, Pazopanib, and Sorafenib are examples of the other anti-angiogenic agents, which are being examined for various malignancies in paediatrics. II. Immunotherapy Although the immune system can defend our bodies from viruses and bacteria, its protective mechanism is weak against cancer cells. Immunotherapy aims at boosting the immune system to target the malignant cells. It is now considered the fifth pillar in cancer treatment, and over 40 ongoing clinical trials are examining the effect of different immunotherapies to treat paediatric cancer patients.1 Vaccination In various paediatric solid tumours (neuroblastoma, hepatoblastoma, high and low-grade glioma, atypical teratoid rhabdoid tumour), the result of vaccination was promising as it increased the survival rates even with high-risk sarcoma. Monoclonal Antibodies In 1997, the FDA approved the first monoclonal antibody Rituximab (targets the CD20 antibody) to treat malignant lymphoma. Nowadays, Blinatumomab (targets CD19 and CD3) is approved to treat B-cell acute lymphoblastic leukaemia (ALL) in adults and is used off-label in relapsed B-cell ALL in paediatric oncology patients. Chimeric Antigen Receptor Transgenic T-cells (CAR T-cells) The T-cells are extracted from the patient’s blood; then, it undergoes Volume 12 Issue 6

Therapeutics genetic engineering to add the chimeric antigen receptors on its surface (CARs). In this way, T-cells can target particular antigens on the tumour cells’ surface once it is injected back into the patient. The CAR T-cell therapies targeting CD19 in B-cell ALL were commonly used in several clinical trials, and they showed encouraging results. An early clinical trial included 30 patients with ALL (children and young adults), and twenty-seven patients showed complete remission without recurrence signs. Then, largescale clinical trials were conducted to ensure the efficacy and safety of CAR T-cells. In August 2017, the FDA approved the release of Tisagenlecleucel for children and adolescents with ALL. However, as some leukaemic cells may become CD19 negative due to antigen loss, several clinical trials were directed to investigate the results of CAR T-cells when targeting CD22. The outcomes of these trials showed promising results as there were complete remissions with no signs of relapse.8 III. Tyrosine Kinase Inhibitors A hallmark event in cancer is the uncontrolled proliferation of cells during suppression of differentiation and cell death. Such an event is facilitated by dysregulated activation of tyrosine kinases (responsible for transmitting signals). Thus identification of dysregulated kinase can form a potential therapeutic target for the treatment of cancer. In this, the identification of tyrosine kinase inhibitors (TKIs) in adults has paved the way for its use in paediatric oncology patients.9 The various TKIs available today include Imatinib, Lestaurtinib (FLT3 TK family), Neratinib, and Brigatinib.10,11 However, most of these drugs are effective only for a short time (except in CML) when used as monotherapy.9,12 IV. BRAF and MEK Inhibitors Genetic mutation is the basis for the pathogenesis of cancer. BRAFV600E is one such genetic mutation that induces activation of the mitogen-activated protein kinase (MAPK) signalling pathway that affects cell proliferation, differentiation, and survival.13 Trials with BRAF-mutant xenograft models have shown that suppression of MAPK signalling by BRAF inhibitors results in tumour regression and may prove to be an effective therapeutic option in patients with BRAFV600-mutant cancer types. Therefore the USFDA and EMA had recently approved Vemurafenib and Dabrafenib for the treatment of unresectable or metastatic melanoma with mutant BRAFV600.13 BRAF mutations are also known to be responsible for paediatric cancer; these genetic aberrations have been identified in the paediatric population with malignant melanoma (50%), gangliogliomas (50%–60%), and highgrade astrocytomas (10%-20%).14,17 Thus, BRAF inhibitors form the cornerstone for BRAF mutated malignancies. However, one must also take into account the incidences of drug resistance (BRAF inhibitors), which result in reactivation of the MAPK 18,19 pathway. Here, the use of combined therapy (BRAF and MEK inhibitors) has demonstrated its ability to overcome resistance in a metastatic melanoma cell.13 V. Proton Beam Therapy Precision radiotherapy has been known to deliver the dose on the tumour. It includes intensity-modulated photon radiotherapy (IMRT) and proton beam therapy (PBT). Both of these treatment modalities developed in the late 1990s; however, as time passed, it was proved that PBT had the upper hand over IMRT in terms of dose distribution and dosimetric control. Initially, the use of PBT www.jforcs.com

was limited to tumours near the critical structure, or those that responded poorly to IMRT. Nevertheless, in recent years, PBT has been applied to treat other neoplasms as well.18 Furthermore, due to the improved sparing characteristic of normal tissue, PBT nowadays is also being used in the paediatric population.19 Yet, there are at least three limitations18 in published data that hinder the large-scale use of PBT. These include: • • •

Studies are retrospective in nature The small sample size of prospective studies The lack of head-to-head comparison between the PBT and conventional radiotherapy

Targeted Therapy: The Other Side of the Story While targeted therapy is traditionally believed to have lesser sideeffects than its non-specific counterparts, it has some side-effects: • • •

•

TKIs as Imatinib lead to significant growth retardation in children receiving them on a chronic basis for the treatment of CML20 Second- and third-generation BCR/ABL TKIs are linked to vascular adverse events, like pulmonary hypertension and occlusive events21 CD19 CAR T-cell therapy has been evidenced to result in disruption of the blood-brain barrier, leading to neurotoxicity and an increase in the risk of infection (due to depletion of B cells)22,23 Almost 85% of melanoma patients treated with Ipilimumab suffer from autoimmune adverse effects24

Moreover, targeted therapies also pose a financial burden on the patient. As of 2018, the costs for Dinutuximab beta was around 173,000€ in the treatment of a paediatric neuroblastoma patient. 1 Similarly, treatment with Tisagenlecleucel (CD19 CAR T-cell therapy) would almost add 330,000$ more to a patient's medical expenditure as compared to traditional chemotherapy for B cell acute leukaemia.25 Conclusion In recent years, the field of precision medicine has experienced some of the most spectacular breakthroughs. However, an increase in the number of prospective trials would facilitate the large-scale use of PBT in paediatric oncology patients. Finally, a continued venture for newer drug development and improved sequencing technique is sure to further expand the scope of precision medicine in paediatric oncology. REFERENCES 1. 2.

4. 5.

Burdach SEG, Westhoff MA, Steinhauser MF, Debatin KM. Precision medicine in pediatric oncology. Molecular and Cellular Pediatrics. 2018; 5:6. Evans WE, Pui CH, Yang JJ. The promise and the reality of genomics to guide precision medicine in pediatric oncology: The decade ahead. Clinical Pharmacology and Therapeutics. 2019. Precision medicine initiative [Internet]: Privacy and trust principles. Obama White House. 9 November 2015. [Cited: 17 October 2020]. Available at: https://obamawhitehouse.archives.gov/sites/default/files/ microsites/finalpmiprivacyandtrustprinciples.pdf Mark LF. Matching high risk pediatric cancer patients to targeted therapies. Oncology Times. 2020;14. Pediatric match trial finds more frequent targetable genetic alterations in pediatric cancers than predicted [Internet]. ASCO. 15 May 2019. [Cited: 17 October 2020]. Available at: https://www.asco.org/about-asco/presscenter/news-releases/pediatric-match-trial-finds-more-frequentargetable-genetic Journal for Clinical Studies 35

Therapeutics

7. 8.

9. 10. 11. 12.

13.

14.

15.

16. 17.

18. 19. 20.

Barrier to early clinical trial access for adolescents and young adults still exist, study shows [Internet]. ESMO. 21 October 20. [Cited: 17 October 2020]. Available at: https://www.esmo.org/newsroom/press-office/ adolescents-paediatric-cancer-clinical-trials-vozy Bernstein ML. Targeted therapy in pediatric and adolescent oncology. Cancer. 2011;117. CAR T cells: Engineering patients’ immune cells to treat their cancers [Internet]. Cancer. 30 July 2019. [Cited: 17 October 2020]. Available at: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells Forrest SJ, Geoerger B, and Janeway KA. Precision medicine in pediatric oncology. Curr Opin Pediatr. 2018;30(1):17-24. Skolnik JM and Adamson PC. Tyrosine kinase inhibitors in pediatric malignancies. Cancer Invest. 2007;25(7):606-612. Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer. 2018;17(1):36. Batson S, Mitchell SA, Windisch R, et al. Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis. Onco Targets Ther. 2017;10:2473-2482. Rizzo D, Ruggiero A, Amato M, et al. BRAF, and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities. Expert Opin Drug Metab Toxicol. 2016;12(12):1397-1405. Daniotti M, Ferrari A, Frigerio S, et al. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. J Invest Dermatol. 2009;129(7):1759–1768. Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010;12(7):621–630. MacConaill LE, Campbell CD, Kehoe SM, et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009;4(11):e7887. Dasgupta T, Olow AK, Yang X, et al. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. J Neurooncol. 2016;126(3):385–393. Hu M, Jiang L, Cui X, Zhang J, Yu J. Proton beam therapy for cancer in the era of precision medicine. J Hematol Oncol. 2018;11(1):136. Thomas H, Timmermann B. Paediatric proton therapy. Br J Radiol. 2020;93(1107):3-9. Bansal D, Shava U, Varma N, Trehan A, Marwaha RK. Imatinib has adverse effect on growth in children with chronic myeloid leukemia. Pediatr Blood Cancer. 2012;59(3):481-484.

36 Journal for Clinical Studies

21.

22.

23.

24.

25.

Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125(6):901-906. Mackall CL, Miklos DB. CNS Endothelial Cell Activation Emerges as a Driver of CAR T Cell-Associated Neurotoxicity. Cancer Discov. 2017;7(12):1371-1373. Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131(1):121-130. Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33(28):3193-3198. Silverman E. Kymriah: A Sign of More Difficult Decisions To Come. Manag Care. 2018;27(5):17.

Subhajit Hazra Subhajit Hazra, M.Pharma (Pharmacology), is an experienced medical writer specializing in the creation of medical/scientific content for the medical communication industry in India. Email: subhajithazra.freelancer@gmail.com LinkedIn: www.linkedin.com/in/subhajithazra93

Sara Ahmed Zaki Sara Ahmed Zaki is a Freelance Medical Writer with a previous history of working as a Clinical Oncology Pharmacist in an Oncology Center in Egypt. Email: sarazaki091@gmail.com LinkedIn: www.linkedin.com/in/sara-ahmed-zaki-313a7816b

Volume 12 Issue 6

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info@Astell.com Journal for Clinical Studies 37 +44 (0)20 8309 2031

Technology

Artificial Intelligence and Machine Learning Combine to Streamline Data Management in Clinical Trials Technology advances are becoming more and more sophisticated, particularly in data management for clinical trials. But despite how advanced these technologies become, clinical trials depend on quality, accuracy, and comprehensive clinical trial data. Without this quality information, companies cannot ensure the safety and efficacy standards that will meet the rigorous requirements necessary to pass strict regulatory reviews.

trial. It provides the basis for analysis, submission, approval, labelling and marketing of a compound. A key process in the collection and management of data is data cleaning to ensure the data is consistent and accurate. Errors do occur in data entry with the most common being spelling errors, transcription errors, range errors and text errors affecting coding. Automated edit checks exist, and these prevent the entry of inaccurate information, however they do not detect all data entry issues.

Today, in spite of technology enhancements, challenges still exist in making sure that all data collected meets these standards. Clinical teams often spend hundreds (or more) hours managing the data cleaning process, leaving less time to focus on insightful analysis of the data. While manual efforts to assure quality requirements are not a time-wasting endeavour, they can be costly and could possibly lead to significant delays in meeting set milestones on the clinical trial timeline.

With data quality at the heart of all clinical trial successes, clinical data management teams also need to employ a manual approach to data cleaning. This manual approach raises queries to the clinical trial site to solve any potential issues or inconsistencies. On some studies there can be high levels of manually generated queries. Understanding the context of these may help improve the automated edit checks or put additional checks and processes in place to help identify potential data issues earlier.

With data and data sources, i.e. wearables, expanding at warp speed, it is critical for CROs and sponsors to investigate better ways of managing data. This is where artificial intelligence (AI) augmented by machine learning (ML) can make a difference, not only in time savings and the ability for teams to collaborate across trial sites, but also to ensure accuracy and quality, which can lead to timely and successful regulatory approvals.

When the application of machine learning is applied to historic manual queries across different studies, it can also create an understanding of the common issues across and within studies, thus enabling a targeted approach to process optimisation for clinical data cleaning.

The increasing adoption of AI and ML is on the upswing in the efforts to streamline clinical trials to create more accurate data management. These technologies can also be helpful for patient recruitment and to meet complex regulatory requirements. Embracing AI and ML offers significant learning curves, but deployment can make a real difference in the ability for companies to streamline drug development and get the right treatment to the right patient – faster – and at a reasonable cost. Trials generate an immense amount of critical data but often functional data silos, disparate systems and human error can be impediments to a successful trial by blocking a comprehensive overview of activities occurring, for example, at multiple global sites. However, by utilising artificial intelligence and machine learning, this data can be cleaned, managed and shared to provide efficiencies, promote collaboration, and to deliver critical insights and metrics to all users. As digital technologies become more ubiquitous and the volume of usable data increases, AI and ML will become more commonplace and critical in providing clear evidence-based decision-making to ensure successful trial outcomes. New Data Management Approaches for Quality Outcomes High-quality clinical data is essential for the success of any clinical 38 Journal for Clinical Studies

As we explore whether AI techniques could be applied to support data management in the generation of high-quality clinical trials, we look at what approaches could be applied to save time and increase efficiency gains in the current process, and identify erroneous data or problematic aspects of data collection and even clinical sites. By the elimination of manual queries, efficiencies can be increased and costs better managed. In fact, it is estimated that the cost of each manual query can be close to $200 (U.S.) from start to finish, which if eliminated altogether or even greatly reduced, can potentially save many thousands of dollars in hard costs, allow more time for keen analysis and reduce the time to reach a successful trial conclusion. And as clinical studies continue to become more complex, for example, by more complex study designs or through the use of remote monitoring technology, it is important that the data generated is used in the optimal way during the trial. Powerful ML technologies have the potential to monitor data as it is generated – identifying issues and inconsistencies as trials are ongoing. With remote monitoring, the potential is to continuously monitor many different measurements from a patient as they go about their everyday lives. This in turn will generate larger volumes of data that would be nearly impossible for a clinician to monitor and analyse across a number of patients on a regular basis. ML technologies could be used, in this case, to flag to a medical team certain changes, potential issues or anomalies for a Volume 12 Issue 6

Technology particular patient, directing the medical team to take further action if they find it necessary after review of the data. Most trials now include data re-use in their consent process, which in turn will expand the volume of data surrounding different treatments and the effects on humans. As the volume of high-quality data continues to increase, and become more accessible, AI and ML will play a vital role in evidence-based decision-making as the trial progresses. Adoption of the AI/ML Approach Across the industry, it is generally agreed that AI and ML adoption creates a big learning curve. For all consumers of AI technology, whether that be a sponsor, medical teams at a site, or patients, it is important that each group understands the limitations of the technology and the context in which it can be used. Specifically, AI is only as good as the data from which it was built, and it may not always have all, or even the right, answers. For decision-makers, those that may use the output of AI technologies, they have the challenge of acting on results. AI, after all, is a machine, not a human. It has no emotions or empathy and would not consider the ethical implications of a decision. Thus, decision-

makers must learn to use these technologies in the right context, in the way they were intended but always applying their own reasoning and intelligence to augment and critically evaluate the output of the AI. In order to maximise the value of data from the clinical trial process and provide essential quality insights, all data generated during the study should be considered, from the clinical data through to the associated metrics and audit trail. Furthermore, data from multiple studies can enhance analyses and/or determine baseline metrics that may inform current studies. To support effective integration into current processes, it is important that the results of these approaches are disseminated to the right people in the most effective way. The development and utilisation of intuitive visualisations can provide such a mechanism, bringing together these powerful analyses into a single source. The application of AI to the manual data queries generated during the data cleaning process is likely to be a human-machine approach for the foreseeable future. While the technology can be highly supportive, the output is determined by the quality of the data input into the system. Unlike a human, a machine can take large volumes of data and sift through it at an alarming rate and without the inherent bias of a human, therefore giving a view of the world based on the data it has seen quickly and efficiently. This is critical for fast decision-making and ultimately saving money and possibly even patients’ lives. AI/ML has the potential to identify data, site, and form issues earlier. These technologies can also create new opportunities to extract more from the data available now and that which will be generated in the future. Rather than replace humans, AI/ML can be used to empower experts, enhance the information available to them to support evidence-based decision-making for diagnosis, treatment decisions, and enhance operational aspects of care. Perhaps the new world might see a real team approach with clinical data managers working alongside their virtual partners. Certainly, the application of AI/ML technologies heightens at a level of reasoning and expertise not available at simply the human level, but the combination may elicit better predictions than either group of humans or machines could generate alone. While the learning curve to embrace AI and ML may seem daunting, even seemingly insignificant data issues could be catastrophic and cost a trial millions of dollars in investment. The assurance that data quality is complete is certainly worth the time and investment to explore, test and finally deploy these new and advanced technologies.

Jennifer Bradford Jennifer Bradford, PhD is Head of Data Science for the CRO PHASTAR. She previously worked for the Advanced Analytics Group at AstraZeneca, leading the development of the REACT clinical trial monitoring tool, which she later customized and delivered to other sponsors as part of Cancer Research UK (CRUK). Within CRUK and in close collaboration with the Christie hospital she worked on EDC, app development and wearables data analytics in the context of clinical trials. She has a degree in Biomedical Sciences from Keele University and a bioinformatics Masters and PhD from Leeds University.

www.jforcs.com

Journal for Clinical Studies 39

Technology

Dealing with the Data Flood in Clinical Studies Managing clinical trials requires the coordination of many processes and mastering of large amounts of information under huge time pressure. In addition, increasingly complex regulatory requirements must be met, and the team must be ready for audits or inspections at any time. Since pharmaceutical, biotech and medical device companies cannot provide every know-how or resource, they usually rely on external partners to conduct the studies. This further complicates the situation as sponsors, clinical research organisations (CROs), laboratory service providers and logistics companies have individual IT structures and specific software systems. This creates data silos, which prevent a consistent and current overview over the project. The solution is a clinical trial management system (CTMS), which supports the project management with key information on the study, while at the same time creating network structures and ensuring data security. Necessary Standardisation of Clinical Applications According to a survey by the software company Veeva Systems, 99% of companies involved in clinical projects state that standardisation of clinical applications is important. While those companies regard improvements in IT and process structures as an important prerequisite for a better overview of the study and faster project implementation, 81% report to still use spreadsheet programs in the particularly challenging initial phase of the study1. It is therefore not surprising that all respondents consider it necessary to improve processes between study centres (sites), clients (sponsors) and the CRO. Outdated and Very Detailed Information The management of large amounts of information from different sources is the fundamental challenge for the project manager (PM) of a clinical trial, especially in studies relevant to approval. Interdepartmental meetings or telephone conferences are a limited tool to achieve an overview of the most important processes and situations that need to be responded to. The overview would involve consolidated information of individual sub-disciplines, such as: – Drug product logistics – Management of study centres – Regulatory submissions – Required training of study staff – Payment of the centres – Contracts – Templates However, in reality the PM receives a multitude of reports from different contractors, which are not all equally up to date. Also, very special details in those reports further complicate the situation. E.g. the information on the storage and temperature of a batch is only relevant in case of a critical temperature alert. Too detailed and inconsistent information poses a problem for the PM and his report 40 Journal for Clinical Studies

to his or her supervisor. Some information must be generated directly by the PM, such as the project risk assessment, reports on the team, the budget plan or resource management. If specific software is used for these tasks this can lead to redundant entries and a higher susceptibility to errors. Security and Protection of Data Moreover, clinical trials have huge requirements of data security, data protection and Good Clinical Practice (GCP). This is especially problematic if using many different IT systems. As for data protection, project participants should only receive the information that is intended for them. In clinical studies with many participants from different disciplines and different company affiliations, this implies a complex authorisation structure. However, these structures can only be mapped using database-based programs. With these, the structures and requirements can be defined and implemented as required. External access to all data is also possible in the case of databases. The use of secure protocols and interfaces supports safe access to data from any authorised client. High demands are also placed on a clinical trial management system in terms of GCP, an internationally recognised ethical and scientific standard for the planning, conduct, documentation and reporting of clinical trials, which focuses on the safety of the participants and the quality of the results. In order to meet this, a CTMS must undergo detailed testing and be validated in accordance with Good Automated Manufacturing Practice (GAMP) categories. Data security is another important GCP-relevant aspect. The utilised electronic data capture (EDC) systems must be a secure data source for the CTMS and should be backed up at least once a day to prevent too much data loss after unforeseen events. Frequently used spreadsheet programs cannot guarantee the requirements for validation, data security and data protection. With CMTS Data Floods are Manageable In recent years, the amount of data has increased for reasons of internationalisation, digitalisation and growing regulatory requirements in clinical research and so has the responsibility of the project team to keep track of it and to intervene in critical developments. IT structures and processes should reflect this growing complexity and allow filtering through it. Otherwise, informationbased decisions are at risk. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) focused on this issue in its revised GCP guideline (ICH E6 (R2) Integrated Addendum) from 2016. It states that the flood of information should never obscure essential information, making important decisions impossible, as the patient health has highest priority throughout the study. Therefore, the guideline obliges the sponsor to adopt a riskbased approach in all phases of a study to ensure the required data quality. Risk-based quality management is a documented, structured and systematic procedure that precedes the actual clinical trial2. Hence, data and processes responsible for the protection of study participants Volume 12 Issue 6

Technology and the reliability of the information need to be identified from the outset. According to the current ICH guideline, the methods used to ensure and control trial quality should be proportionate to the risks involved and the importance of the information collected. In other words, the risk-based approach needs to avoid unnecessary data collection and complexity. Apart from risks for patients and quality assurance, budget and time risks are critical for sponsors as well. For these reasons, clinical studies should be carried out with IT systems that filter the data and sustain the PM with structure and transparency. CTM systems are designed to support the PM and the study team throughout all phases of clinical trials. This includes the scope of study design, preparation, organisation and evaluation. Some typical functions of a CTMS (Fig. 1) are therefore: – Budget planning – Project management – Subject management – Patient recruitment – Document management – Reporting system – Management of investigational medicinal products (IMPs) – Risk management – Project status – Adverse event reporting – Support in complying with official regulations or legal guidelines

Customised solutions are necessary in most cases, depending on e.g. sponsor demands or special trial requirements. To some extent, such adaptations can be realised with purchased complete CTMS. Though special needs of a customer can be considered by the software producer in upcoming releases, IT manufacturers usually react only if a critical mass of customers has the same demand. The only way out then is to commission individual adaptations. But even in this case, the company is bound to the provider’s reaction time and readiness to react, which rarely makes individual changes accessible within a current study. An alternative for flexible and quick adaptations of sponsor requests or study-specific requirements is the development of an in-house CTMS. Due to so-called low-code development platforms, this demanding approach has become even feasible for many small and medium-sized companies. In the following, different CTMS implementations will be examined and compared. Different Ways of Implementation When switching to a CTMS, a company should be aware of several aspects in order to pick the appropriate strategy. Important framework parameters are: – Size of the company – Budget – Cast – Areas of competence of the company's IT department – Existing IT infrastructure in the company – Heterogeneity of projects – Level of requirements for specific reports and views – Required functional range The more diversified the project and the higher the need for specialisation, the sooner commercial off-the-shelf systems (COTS: standard software) reach their limits. In-house solutions require IT development competence and resources in the company. For small and medium-sized companies, this usually is a major hurdle. External developers are hard to find due to the lack of skilled workers. But even if identified, for validation of the CTMS the developer needs to be sensitised to regulatory requirements and to understand the processes involved in conducting clinical trials. There are three ways to implement a CTMS: – Use of an existing software system (COTS) – Completely new development – Development based on a low-code platform

(source: SSS International Clinical Research GmbH)

Figure 1: Possible functions of a CTMS in clinical trials.

The Limitations of Commercial CTMS Commercial CTMS create a dependency of the end user on the respective provider, which contradicts their one-fits-all concept. Firstly, the software usually does not include all functions that are necessary to carry out the study, e.g. the remuneration of doctors or pharmacies or the training and monitoring of the suitability of study personnel that often needs to be mapped by special software. Secondly, standard software often does not depict the specific course of studies and the individual processes of a company. www.jforcs.com

COTS: Low Risk, Low Flexibility Most companies purchase a CMTS already available on the market and customise it. This has certain advantages: Purchased systems often include a so-called support contract, which ensures assistance if there are technical problems during the clinical trial and can help reducing the downtime of the system. Furthermore, important is the validation of this software systems in a GxP-regulated environment. Configurable off-the-shelf software is usually classified in GAMP category 3, which puts the user at low risk. Therefore, no or only a flat validation with user acceptance tests would be necessary. One disadvantage of COTS is that there is no direct access to the program code. This severely limits the flexibility of this approach to mere configurations. So, responding to specific sponsor requirements or special features in the study is complicated. Finally, COTS also tend to be associated with very high acquisition and running costs for updates, system maintenance and the familiarisation and training of employees. Journal for Clinical Studies 41

Technology make it possible to conform the IT structure to changing internal company processes. With low-code systems, even medium-sized companies can develop comprehensive and powerful software solutions that manage complex database structures and interfaces. Decision-relevant triggers can be extracted from the wealth of data, optimising project and company management. This is also an advantage for the sales department: Customers appreciate the quick adaptability of the CTMS to project-specific needs.

Setting Up a Completely New Development The creation of an entirely new CTMS implies a high development effort and leads to a very limited range of functions for the majority of small and medium-sized CROs. All functions, including the graphical user interface, need to be redesigned and implemented from scratch and an entire team is needed to achieve results in a manageable timeframe. The advantage of this solution is the unlimited flexibility of development and design. However, for the mentioned CROs, the disadvantage of high development costs outweighs it. Low-code Platforms: Customising with Low Programming Effort Implementing a CTMS by using a low-code development platform is finally another approach. This allows in-house designing via a largely graphical user interface (GUI)-based construction kit. The graphical user interface makes application software operable by means of graphical symbols and control elements. The systems are usually based on a relational database such as MS SQL Server or MySQL3 for data management. This enables the developer to quickly visualise the processes and applications he has implemented. The manipulation of the elements with program codes stays possible using common programming languages such as Java, C# or JavaScript. Despite the simplified implementation, software development should be carried out with a standardised process model such as Scrum, XP or V-Modell XT4. Their adaptability and comparatively short development time of a usable product are clear advantages of low-code platforms. This allows quick adjustment to special sponsor requirements like reports and individualised functions. One example might be a web-based information dashboard, on which all important key figures of the study – such as the status of patient recruitment or the participating centres – can be presented in precise and understandable diagrams. A further advantage, compared to completely newly-developed CTMS solutions, are the low acquisition costs. However, any development costs incurred must be considered. What also has to be observed: When making far-reaching changes to a lowcode system, the developer has to understand the automatic code generation affected. Changes of graphic elements, for example, imply considering the programming paradigms used in the platform in order to ensure the systems’ consistency. Conclusion Small and medium-sized companies face the challenge of managing enormous amounts of data in clinical research. In addition, IT structures must be very flexible due to the heterogeneity of clinical studies (specifics in the countries, different clinical phases, etc.) and need to be adapted on a regular basis. Against the background of these complex requirements, the decision to purchase software should not be taken without reflection. Third-party software does not offer quick adaptability to changing conditions and often cannot cover all process aspects individually, which forces the user to adjust the processes to the IT environment. In-house developments 42 Journal for Clinical Studies

However, the introduction of an in-house CTMS requires absolute willingness on the part of all people involved, especially the management, to develop the system further on an ongoing basis. Expenses for system maintenance by the in-house IT department quickly add up to a six-digit sum. Nevertheless, the individual solution quickly pays for itself if all company processes are covered and homogeneity of the own IT system is achieved. This creates synergy and efficiency effects and a noticeably better data quality, which is of highest importance in the field of clinical research. REFERENCES 1.

2. 3. 4.

see Veeva Systems (2019): “Veeva 2019 Unified Clinical Operations Survey Report. The state of unifying clinical systems, processes and stakeholder collaboration.” see Eberhardt, Reinhild (2018): Management und Monitoring klinischer Prüfungen. 7. Aufl. Aulendorf: Editio Cantor Verlag. see MySQL Documentation: https://dev.mysql.com/doc/, 05.11.2019. see Heinrich et al. (2014): Informationsmanagement. 11. Auflage. Oldenburg: De Gruyter. S. 438 ff.

Dr. Lars Behrend Lars Behrend, Phd, is Chief Operating Officer at SSS International Clinical Research with responsibility for business development and strategic positioning. After studying biology and obtaining his doctorate, he worked for seven years in cancer research. He previously spent 15 years as founder and managing director of three companies, among others in the biotech industry.

Sebastian Weis Sebastian Weis is IT Process Specialist at SSS International Clinical Research and responsible for the analysis, optimisation and implementation of IT processes. During and after his successfully completed master's degree in business informatics, he worked as a freelancer in database development for several years before joining SSS International Clinical Research.

Dr. Michael Sigmund Michael Sigmund, DVM, is Chief Executive Officer of SSS International Clinical Research, which provides CRO services to the pharmaceutical and biotech industry. After studying veterinary medicine, he completed a doctorate in virus research. Michael then joined the pharmaceutical industry and held several positions within biotech and contract research companies before starting SSS. The company founder has more than 30 years of experience in clinical research and related fields.

Volume 12 Issue 6

Our Vision Be the best patient focused solutions company for clinical trials worldwide. Our Mission Bring a unique combination of services to facilitate worldwide participation in clinical trials for all.

Patient

PatientGO®, A patient travel, expense reimbursement and accommodation booking service which goes hand-in-hand with the world’s longest-established international mobile research nursing provider, facilitated by research nurses and supported www.jforcs.com by innovative technology.

Technology

Advancing Clinical Trials through Artificial Intelligence: A Legal Perspective The current health crisis and the pharmaceutical industry’s subsequent efforts to develop new treatments and vaccines for COVID-19 have brought the complexities of clinical research and development to the forefront of public attention. Regulators and the industry alike are seeking new paths and solutions to speed up the demanding process of developing a new pharmaceutical treatment and ascertaining its effectiveness and safety for human use. The endeavour to innovate and improve the process of clinical development is, however, by no means a new one, namely due to steeply rising research and development costs, lengthening timelines and high likelihood of failures. As widely known, it takes an average of 12 years and entails costs between USD 1.5 to USD 2.0 billion to bring a new medicine onto the market. Digital Innovation and AI in Healthcare Digital technologies are key factors in the pursuit of innovation in healthcare. These technologies include several interconnected domains such as wearable devices, health-monitoring apps, virtual reality and other computer simulations, telemedicine platforms and electronic health registers, all of which generate enormous volumes of health-related data. These data, in turn, contribute to the ever more sophisticated realm of artificial intelligence (AI). Recently defined as “a system (…) that displays intelligent behaviour by, inter alia, collecting, processing, analysing, and interpreting its environment, and by taking action, with some degree of autonomy, to achieve specific goals”1, AI has at its core the ability to perform tasks and improve independently from human input and control, for example by discovering new insights and patterns in data without being explicitly requested to do so. AI in Clinical Trials In the specific context of clinical trials, both the increasing availability of data and the ability to gain insights from that data using AI have the potential to act as game-changers. Examples of how these instruments are being leveraged include: •

•

In silico clinical trials: by creating a computer model of the treatment, as well as a virtual model of the patient, computer simulations of the molecule’s performance and effects may be carried out, refining the results of pre-clinical testing and thus leading to better trial design and reducing the size and duration of clinical trials2. Patient recruitment: data mining from different sources (electronic health registers, clinical trial registers, as well as information available online) can help improve patient recruitment by matching trials with eligible patients, whereas AI can analyse patients’ clinical history and specific biomarkers to identify other relevant insights such as the likelihood that the patient will respond to the treatment. Furthermore, in silico techniques and real-world evidence may also be used to reduce the need for control arms (i.e. patients being assigned a placebo), lightening the composition of the patient cohort3. Patient monitoring: throughout the clinical trial, AI coupled with “smart” systems such as smartphone apps or wearable

44 Journal for Clinical Studies

devices can improve patients’ adherence to the trial protocol and remote monitoring of their conditions, while generating accurate data related to each patient’s reaction to the treatment. Law at the Intersection between Clinical Trials and AI While AI’s “intelligent” and autonomous nature is a key driver of innovation, it is also at the root of many ethical, social and legal challenges. These issues have been high on the EU agenda in recent years, leading to the EU Parliament’s resolution1 of 20 October 2020 on a “Framework of ethical aspects of artificial intelligence, robotics and related technologies”, which includes a legislative proposal for a Regulation “on ethical principles for the development, deployment and use of artificial intelligence, robotics and related technologies”. One of the main questions is that of the reliability of AI and the extent to which decisions may be made based on the outcome of analysis carried out by an AI system. In the specific context of clinical trials, this question encounters a process which already contains multiple decision-making “checkpoints” on the regulatory side, namely the regulatory authority and ethics committee decision to authorise a clinical trial and, further down the road, the decision on marketing authorisation. This means that regulatory authorities will need to be equipped with appropriate knowledge and frameworks in order to assess the robustness and reliability of data provided by applicants who have made use of AI-based techniques during trial design or during the trial conduct. The EU Parliament’s Regulation proposal sets forth a number of obligations aimed at ensuring transparency and accountability of AI technologies in “high-risk sectors” (including healthcare). These include the obligations to develop, deploy and use AI-based technologies: •

• •

in a manner that ensures that the performance of their aims and activities is accurate or, if occasional inaccuracies cannot be avoided, the obligation to indicate the likeliness of errors and inaccuracies (9.1 d); in an easily explainable manner so as to ensure that there can be a review of their technical processes (9.1 e); in a “transparent and traceable manner so that their elements, processes and phases are documented to the highest possible and applicable standards, and that it is possible for the national supervisory authorities referred to in Article 18 [i.e. an ad hoc national authority responsible for the monitoring of the application of the Regulation”] to assess the compliance of such technologies with the obligations laid down” in the Regulation (9.2).

The need for transparency surrounding the inner mechanisms of AI algorithms and the criteria and values embedded in them has already been highlighted in other sectors where regulatory intervention is necessary, such as personal data protection2, and is normally referred to using the concept of “explainable AI”. Healthcare Data, Sharing Initiatives and Regulatory Frameworks The availability of high quality and reliable data is crucial to the development of any AI system. Given the high threshold of data reliability and robustness needed in the context of clinical trials, obtaining quality data which is relevant to a specific trial requires Volume 12 Issue 6

Technology

relevant investments. Big data and data processing technologies have the potential to address this scarcity issue and transform it radically, by aggregating data from different sources, classifying it, “tagging” it to enable searches, and “crunching” large volumes of information which would be unmanageable by human teams. In this context, a “silos” model in which each clinical trial sponsor maintains secrecy over data generated in clinical trials – with the sole exception of data which must necessarily be presented for regulatory purposes – appears to be unsustainable for the industry at large. Multiple initiatives on the side of the industry and of regulators in the past years have acknowledged the need for collaborative approaches to “promote increased information sharing on clinical trial design, conduct, results and best practices”6. Private initiative uses many different models of data sharing, with licensing agreements and consortium-based models among the most frequently adopted paths. On the legal and regulatory side, data sharing may be fostered and encouraged: •

•

by harmonising legislation related to electronic health registers (“EHRs”). In February 2019, the European Commission adopted a Recommendation on a “European Electronic Health Record exchange format”, highlighting the value of interoperability with regard to EHRs and the value of sharing health data to support new scientific discoveries; with regard to data protection, by further clarifying the requirements related to so-called “secondary uses” of clinical trial data (i.e., use outside the clinical trial protocol in connection to which the data were originally collected). It is debated whether secondary use of clinical trial data containing personal data would be “covered” by the same legal basis which justified personal data processing in the original trial7. The European Data Protection Board examined this issue in Opinion no. 3/20198 and held that secondary use of clinical trial data might fall within the specific provisions and derogations set forth by art. 89 GDPR for, inter alia, scientific research purposes (in which case, the secondary processing would be considered covered by the original legal basis). The EDPB, however, also indicated that further attention and guidance on its side would be necessary, mainly with reference to the safeguards to be implemented by the data controller.

REFERENCES 1.

European Parliament resolution of 20 October 2020 with recommendations to the Commission on a framework of ethical aspects of artificial intelligence, robotics and related technologies (2020/2012(INL)). See art. 4 (a) of the Regulation proposal. Viceconti M, Henney A, Morley-Fletcher E. in silico Clinical Trials: How Computer Simulation will Transform the Biomedical Industry. Research and Technological Development Roadmap, Avicenna Consortium,

www.jforcs.com

3. 4. 5.

6. 7.

Brussels Jan 2016. DOI: 10.13140/RG.2.1.2756.6164. Intelligent clinical trials: Transforming through AI-enabled engagement – Deloitte Centre for Health Solutions European Parliament resolution of 20 October 2020, cit. See, for example, the EU General Data Protection Regulation (“GDPR”, Regulation no. 2016/679), art. 14.2 g), which requires the data controller to provide the data subject with “meaningful information about the logic involved”, where automated decision-making is carried out. European Medicines Agency, EMA Regulatory Science to 2025 – Strategic Reflection, p. 20. Alternatively and according to the specific situation, (i) the data subject’s express consent, (ii) reasons of public interest or (iii) the legitimate interest of the data controller. Opinion 3/2019 concerning the Questions and Answers on the interplay between the Clinical Trials Regulation (CTR) and the General Data Protection regulation (GDPR) (art. 70.1.b)). adopted on 23 January 2019.

Vincenzo Salvatore Vincenzo Salvatore is counsel and leader of the Healthcare and Life Sciences Focus Team at BonelliErede. Full Professor of European Union Law, he joined BonelliErede in 2015, bringing his specific regulatory and compliance skills in terms of clinical trials, marketing authorisation procedures, pharmacovigilance, personal data protection, promotion and marketing of medical devices, inspections and enforcement. Vincenzo has gained significant experience in complex litigation representing public and private entities before the European Court of Justice based in Luxembourg, in EU law disputes. In addition, he was Head of the Legal Service at the European Medicines Agency from 2004 to 2012. Email: vincenzo.salvatore@belex.com

Vivian Grace Chammah Vivian Grace Chammah, has been an associate at the leading Italian law firm BonelliErede since 2015 and is a member of the firm’s Digital Innovation Focus Team. Qualified as a lawyer at the Paris Bar and practicing as an established lawyer in Milan, Grace specializes in intellectual property and information technology law. Her work involves providing assistance on a wide range of tech-related matters, such as software and data-driven projects, cybersecurity and data protection, activities in the e-commerce field and assistance to startups. Email: vivian.chammah@belex.com

Journal for Clinical Studies 45

Logistics and Supply Chain Management

Minimising Risk and Maximising Efficiency by taking a Strategic Approach to Comparative Trial Supply Widely acknowledged to be a prerequisite for formulary listing and even successful licensure, comparator drugs and co-therapies are used within an estimated two-thirds of clinical trials1 and provide sponsors with the ability to demonstrate a study drug’s enhanced efficacy and tolerability over the best performing, commercially available alternative. A core driver for the growing popularity of comparative trials is the increasingly competitive global drug development marketplace, which in recent years has seen a surge in new drug launches and a marked decrease in the average time to market2. Factors contributing to this growth are the rise of co-therapies for diseases like HIV, which have previously responded poorly to single therapies, and the increasing complexity of protocols for sophisticated therapies that allow several experimental drugs to be tested at once. While comparative trials offer unquestionable benefit, they bring with them the burden of additional risk. So, what can sponsors do to effectively minimise these added risks, while maximising efficiency so that patients receive the right drug, at the right time, with the right expiry, in the right place and under the correct conditions? Examining the Supply-based Risks Synonymous with Comparative Trials Before methods can be assessed to optimise comparative trial supply, it’s important to apply appropriate scrutiny to the added risks present in comparator product supply chains. It’s vital that this activity doesn’t become an afterthought once other aspects of the clinical trial operation are already in place. Instead, strategic risk assessment and forward planning should take place at the earliest opportunity. This way, hot spots can be appropriately identified, and sponsors empowered to adapt with speed, agility and precision to implement effective mitigations that safeguard supply and support bigger-picture programme success.

scenarios, and closely monitoring patient enrolment data even more vital. Placebo matching is another core challenge sponsors of comparative trials commonly encounter. Given the commercial sensitivity around conducting comparative trials, securing an appropriate placebo, which encompasses identical components to ‘match’ the comparator drug can be almost impossible, especially if the presentation of the drug varies across markets. With an estimated 10% of all medicines sold worldwide classed as counterfeit3, with ‘higher prevalence in regions where drug regulatory and enforcement systems are weakest’4, comparative trial sponsors have a leading role to play in tackling the wider problem, while protecting their own interests. To mitigate the risk of propagating substandard and falsified drugs in comparative studies, supply sources need to be trusted and regularly audited, and drug supply traceability known. The ability to authenticate comparator products and provide corresponding documentation is necessary to prevent counterfeit products entering the supply chain and posing a risk to patients. Several other risk hot spots need to be appropriately assessed before comparative studies commence. These include, but are not limited to, the enhanced difficulty of upholding blinding protocols, managing country-specific regulation, nuances surrounding import/ export activity, maintaining safety and efficacy of biologics-based comparator products, and managing potentially lengthy bulk supply lead times. Developing a Strategic Comparator Sourcing Approach The added complexity and risk that comes with managing comparative trial supply places greater emphasis on the importance of adopting a ‘strategic’ approach to managing the sourcing, procurement and supply of commercialised products for use within comparative studies.

Some of the more obvious risks associated with conducting comparative trials include the increased difficulty of accurately forecasting demand, given the global scale and complexity typical of many comparative trials. Inaccurate forecasts can have a detrimental impact on comparator sourcing activity, risking stockouts or wastage depending on which way the balance tips. This risk is amplified against the context of global comparator drug shortages and makes calculating clinical supply/demand over time, simulating a range of supply/demand 46 Journal for Clinical Studies

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Logistics and Supply Chain Management right questions during the planning stages of a clinical trial, risks can be identified early and effective strategies implemented. Defining the Best-fit Sourcing Strategy Once risk hot spots have been assessed, regulatory requirements understood and core questions thoroughly considered, an appropriate sourcing strategy will begin to take shape. At this point, sponsors may have to weigh up the pros and cons of a central, local or hybrid sourcing strategy. Selecting a best-fit approach will be dependent upon a myriad of factors but access to the required commercial drug product is ultimately what will determine the route sponsors take. Forward planning is essential in order to avoid a domino effect that threatens overall programme performance.

To successfully minimise risk and maximise supply efficiency, comparator product sourcing should not be treated as a bolt-on exercise but as a vital component of the overall clinical supply chain operation. When it comes to comparator sourcing, the ethos must be ‘plan early and revisit often’. To design a fit-for-purpose source & supply strategy, a thorough comprehension of key regulatory requirements and appropriate analysis of core aspects of comparator sourcing are required. Both must be informed by a comprehensive understanding of the technical side of supply chain management and complemented by trial-specific knowledge. For instance, recent updates to the EU Falsified Medicines Directive (FMD) have increased compliance pressure on sponsors / CROs & CMOs operating comparative studies involving sites and patients located in the European Union. Designed to bolster existing legislation and ensure medicines supplied in the EU are safe, the new ‘safety features’ aspect of the FMD requires use of unique identifiers (UI) and anti-tampering devices (ATD) on drug packs. UI data must be uploaded by the marketing authorisation holder onto the central European Medicines Verification System (EMVS). However, once packs are removed from the marketed product supply chain and enter into the clinical supply chain, responsibility for decommissioning packs from the relevant EMVS must be appropriately assigned. Likewise, in the US, the Drug Supply Chain Security Act (DSCSA) places similar pressure on comparator trial sponsors to play an active role in protecting consumers and patients ‘from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful’5. Failure to meet these key regulatory requirements can not only result in penalties and reputation damage, but also have a negative impact on study timelines and outcomes. Regulation aside, there are several other core aspects of developing effective comparator sourcing strategies that warrant close attention. Again, at the earliest opportunity, sponsors should consider some important questions such as the types of drug and ancillaries needed, whether centralising sourcing is feasible, what documentation may be required for drug import or export and the likelihood of encountering availability constraints. The answers to these questions will help sponsors and CMOs create and develop strategic source & supply solutions, as required, to challenges that arise throughout the lifecycle of the project and facilitate smart decision-making. By taking a bigger-picture approach to comparator sourcing, through awareness of key regulatory requirements, and by asking the www.jforcs.com

While drug availability will ultimately determine the sourcing route sponsors take, it’s important to understand the nuances associated with the different sourcing models available. For example, a central sourcing approach refers to the procurement of a comparator product from a single country for subsequent packaging / labelling and distribution within all countries participating in the clinical trial. Although central sourcing is typically used for larger studies and is often best suited to trials involving countries with straightforward import processes, limited access to comparator products can mean central models are not always feasible. When supply is plentiful in a single country, central sourcing can reduce the risk of overstocking local depots; minimising the risk of wasted supplies. Central sourcing is also typically less complex to plan, and requires lower set-up, storage and management fees, in comparison to a local model. However, a central approach may increase freight costs and courier fees. Weighing up the pros and cons of a central model at the earliest opportunity will help to keep timelines and budgets on track. If comparator products are more difficult to procure, or desired quantities aren’t available in a central supply model, a local sourcing approach may offer an ideal solution. Local sourcing model refers to the procurement of comparator drug product in an individual country for use within the same country. This approach can also be used when import processes are long or cumbersome, as it removes the need to ship drugs across borders and is therefore a lower-risk option, especially for temperature-controlled supplies. Returns can be sent to local depots, which also eliminates equally drawn-out, resource-intensive export activity. While a local sourcing approach may deliver lower freight costs and courier fees, higher set-up, storage and management fees are likely. Understanding drug availability constraints early in the process will therefore help sponsors to select a model tailored to the specific criteria of their comparative studies. Central and local sourcing models offer a number of benefits to sponsors, depending on their exact needs and the availability of the comparator product in question. Yet, many sponsors prefer to ‘pick ‘n’ mix’ from both the central and local approach to create a hybrid sourcing strategy that has the potential to offer the best of both worlds. This model combines specific aspects of both a central and local sourcing approach to provide a bespoke solution able to meet a global study’s unique requirements. A hybrid sourcing approach can be particularly beneficial for more complex studies, particularly when recruitment outperforms projections and gaps in supply need to be urgently filled. Weighing Up the Business Case for Strategic Comparator Sourcing It’s all too easy to approach comparator sourcing as an afterthought and to take a cost vs value approach to procurement and management. Journal for Clinical Studies 47

Logistics and Supply Chain Management

Procuring comparator drugs from wholesalers may initially seem like a value-for-money proposition. Yet, while wholesalers may reliably supply comparator products, they rarely offer the guidance and support most sponsors need in order to effectively balance overall study risk and cost, manage expiry dating issues and ensure all necessary documentation is available.

In a fiercely competitive market, where drug availability issues have been compounded by disruptions caused by the global Coronavirus pandemic, it has never been more important to plan early and adopt a strategic comparator sourcing approach that minimises risk, safeguards supply, and promotes timely, costeffective trial completion.

Taking a best-practice approach to comparator sourcing requires timely planning and in-depth research to capture a study’s unique requirements, identify potential challenges and design appropriate sourcing strategies and processing protocols. It requires cultivating relationships with manufacturers, suppliers and wholesalers within a vast, global marketplace to define and deliver best-fit supply strategies. It also requires in-depth expertise to identify suitable comparator materials, the optimal source to procure them, available options, market limitations, and supply lead times.

REFERENCES

For most sponsors, maintaining this niche specialism in-house is commercially unviable. It is, however, still possible to achieve comparator sourcing best practice through partnerships with clinical supply chain specialists. Through these partnerships, sponsors can obtain visibility over what is available in each market, based on the different formulations, presentations, strengths, and brands, and create enhanced insight over access and availability, including expiration, lead times and licensing.

3. 4.

Tracking Trial Cost Drivers: The Impact of Comparator Drugs and CoTherapies. PharmExec.com. http://www.pharmexec.com/print/203238? page=full&id=&sk=&date=&=&pageID=3 The Changing Landscape of Research and Development: Innovation, Drivers of Change and Evolution of Clinical Trial Productivity. The IQVIA Institute for Human Data Science. April 2019. Fighting fake drugs: the role of WHO and pharma. Lancet. 2011 May 14; 377(9778):1626. World Health Organization. Medicines: spurious/falsely-labelled/ falsified/counterfeit (SFFC) medicines 2012. http://www.who.int/ mediacentre/factsheets/fs275/en/ https://www.fda.gov/drugs/drug-supply-chain-integrity/drug-supplychain-security-act-dscsa#:~:text=The%20Drug%20Quality%20and%20 Security,distributed%20in%20the%20United%20States

Nicholas Griffin Nicholas has more than 30 years’ experience in global procurement and supply with over 25 years’ experience dedicated to the pharmaceutical industry. During this time, Nicholas has built up a wealth of knowledge of pharmaceutical procurement within the clinical supply environment. Over the past 5 years Nicholas has been responsible for developing and growing the Global Commercial Product Procurement department within Almac, managing global teams in Europe, America and APAC. Nicholas and the team ensure that every element of comparator and commercial drug supply, under contract to Almac, is executed in a highly efficient manner, ensuring that strict time lines are achieved, quality is maintained and cost is managed. Nicholas holds a BSC in Politics & Procurement from the University of Ulster and is MCips accredited. Email: nicholas.griffin@almacgroup.com

48 Journal for Clinical Studies

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Disease knows no borders A fast-moving pandemic requires a global perspective and new ways of monitoring the patient journey and treatment outcomes, live, across geographies.

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Journal for Clinical Studies 49

Cardiovascular Safety

A New Twist in the Brief History of the Cardiac Safety Regulations

An Update of the ICH- E14 and S7B 2000 Q&A Revision In the last 30 years, cardiac toxicity of pharmaceuticals, primarily drug-induced proarrhythmia and the risk of sudden cardiac death, emerged as a primary public and regulatory drug safety concern. This has led to the development of new guidance designed to establish an infallible scientific and regulatory process to ensure the cardiac safety of new drugs in development. In May 2005, the ICH steering committee adopted two new guidance documents addressing the clinical and the non-clinical aspects of cardiac safety assessment of new drugs in development – the ICH-E141 (“The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”) and the ICH-S7B2 [“Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals”]. The hallmark of the E14 guidance was a new dedicated Thorough QT (TQT) study, while the S7B presented a process comprised of in vitro ion channel assays (primarily the hERG/Ikr potassium channel assay), tissue assays (using Purkinje fibres’ action potential duration) and in vivo animal QT assays. However, while the new guidance proved most successful in preventing drugs with cardiac proarrhythmia risk from entering the market, the logistical and financial burden of the TQT study prompted the US Food and Drug Administration (FDA) to launch a new regulatory scientific initiative in 2013. The initiative, titled ‘Comprehensive in vitro Proarrhythmia Assay’ (CiPA), was designed to shift the cardiac safety assessments to a predominantly nonclinical paradigm through a multi-component process comprised of: (1) drug effects on multiple ion channels, (2) in silico reconstruction of human cellular ventricular electrophysiology, (3) in vitro effects on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and (4) clinical evaluation of drug-induced QT prolongation in early clinical development studies. Yet, despite the immense work and significant progress, the new cell-based models are still evolving and have not yet been fully validated for a regulatory decision process. While CiPA is being developed, the ICH-E14 was updated regularly through questions & answers (Q&A) regulatory documents. The most critical revision, introduced in the 2015 Q&A (R3)3, promoted a concentration-response modelling analysis of the QT data as an alternative to the E14 by timepoint analysis, or intersection-union test (IUT), as the primary basis for decisions to classify the cardiac risk of a drug. This revision, combined with the CiPA clinical component, allowed pharmaceutical sponsors to apply for a waiver from conducting a TQT study based on concentration-response analysis of the QT data and other ECG parameters (primarily PR and QRS duration) from early development clinical trials. 50 Journal for Clinical Studies

Yet, a new revision of the ICH E14 and S7B guidance released on August 27th 20204, presented for the first time a working model for a fully integrated clinical and non-clinical evaluation drug-induced QT/QTc interval prolongation and proarrhythmic potential. This revision also updated Q&As related to the use of concentrationresponse modelling (CRM) of the QTc data (Q&A 5.1 in the 2015 ICH-E14 Q&A R3) and ‘special cases’ discussing alternative study designs when a conventional TQT study might not be feasible, e.g., in oncology products (Q&A 6.1). A Two-stage Approach In a recent webinar (October 15–16, 2020)5 the ICH E14/S7B Implementation Working Group (IWG) reviewed the new concepts introduced in the August 2020 Q&A revision. The IWG defined two stages. In stage 1 the Q&As were updated as follows: • •

S7B Q&As provided more details on the integrated risk assessment, best practice considerations for in vitro and in vivo assays, and principles of proarrhythmia models. E14 Q&As expanded on how to use the non-clinical data to decrease the need for TQT studies (e.g., CRM) and improve regulatory decision-making and labelling when a TQT study or equivalent cannot be performed (e.g., in oncology indications).

Currently, the E14 and S7B Q&As are open for public comments until November 30th, 2020. Following this, the working group will proceed to stage 2 where it will discuss the use of proarrhythmia models and ECG biomarker data to inform decision-making and labelling for QT prolonging drugs, and how to define low-risk drugs that might not require detailed clinical QT assessment. Large proteins and monoclonal antibodies are already exempted from a detailed clinical QT evaluation (and TQT studies) due to their low likelihood of ion channel interactions (2015 Q&A 6.3). This approach can be expanded to additional areas including other therapeutic proteins (e.g., intermediate size proteins and oligonucleotides), to drugs with low systemic bioavailability such as dermal and ocular products, and possibly to other compounds, although each may require different considerations. New Scenarios for Decision-making The IWG introduced two new scenarios for non-clinical data to inform clinical decision-making: 1) 2)

Double negative scenario: When the in vitro hERG assay and in vivo QT assay are negative. Non-double negative scenario: When the in vitro hERG assay and/or in vivo QT assay are positive. Volume 12 Issue 6

Cardiovascular Safety

In the revised Q&A 5.1 (CRM) the double negative non-clinical assessment is used to support lower clinical exposures needed to waive the positive control, whereas in the revised Q&A 6.1 (‘special cases’) the double negative scenario is used to support alternative clinical study designs to exclude drug-induced QTc prolongation risk. Q&A 5.1 also defines two pathways to waive the need for a positive control in clinical QT studies: (a) if there are data characterising the response at a sufficiently high multiple of the clinically relevant exposure, or, (b) if the high clinical exposure scenario has been fully covered in the clinical ECG assessment and non-clinical integrated assessment is double negative, i.e., no hERG block and no QT prolongation. The revised Q&A 5.1 may therefore further reduce the need for TQT studies, by use of double negative non-clinical data to allow for additional TQT study ‘substitutes’ when the drug exposure in concentration-QTc analysis is not high enough to meet current requirements. The principles on how to define a double negative non-clinical assessment are described in the revised Q&A 1.1 (the use of nonclinical information to inform the design of clinical investigations and their interpretation) and 1.2 (how to compute the hERG safety margin). The alternative scenario of non-double negative, defined as either a drug-induced hERG block or QT prolongation, may require followup studies to further evaluate proarrhythmia risk. The integrated risk assessment, including the results from followup studies and other relevant clinical and non-clinical information, can contribute to the design of subsequent clinical investigations and interpretation of their results. Further Requirements for ‘Alternative’ Clinical QT Studies The revised Q&A 6.1 (for ‘alternative’ QT studies) requires that the study has ‘sufficient power’ to detect a QTc prolongation effect of a magnitude similar to a dedicated clinical TQT study. To support a www.jforcs.com

drug as having low likelihood of proarrhythmic effects due to delayed repolarisation, the assessment should demonstrate three criteria: 1)

Double negative non-clinical assessment: This requires that the hERG safety margins for parent compound and major metabolites under best practice are higher than certain thresholds calculated based on reference drugs with known proarrhythmia risk using the same assay (S7B Q&A 1.1–1.2). It also requires that no QTc prolongation in an in vivo study of sufficient power to detect a QTc prolongation effect of a magnitude similar to a dedicated clinical TQT study (S7B Q&A 3.4) and exposures greater than the high clinical exposure scenario.

Alternative clinical study: The high-quality ECG data collected do not suggest QT prolongation, generally defined as ΔQTc less than 10 msec, as computed by the concentration-response analysis or the intersection-union test. The strength of the clinical ECG data depends on the upper bound of the two-sided 90% confidence interval around the mean ΔQTc estimate. Also, no notable imbalances between treatment/dose arms in the proportion of subjects exceeding outlier thresholds.

Cardiac safety database across studies: Does not suggest increased rate of adverse events that signal potential for proarrhythmic effects.

Redefining Best Practice Principles The above approach is contingent on achieving good-quality ECG data and adherence to ‘best practice’ principles. Best practice considerations for some follow-up studies are described in the S7B Q&As, including additional ion channels assays (Q&A 2.1), human derived cardiomyocytes (Q&A’s 2.2–2.4), and proarrhythmia risk prediction models (which can be in vitro, in silico, in vivo, ex vivo) to quantify arrhythmia risk level (Q&A’s 4.1–4.3). Principles to Define a Negative hERG Assay A negative hERG assay requires that the hERG safety margin (IC50/ Cmax) of a new drug is higher than a ‘certain’ threshold calculated Journal for Clinical Studies 51

Cardiovascular Safety based on reference drugs with known proarrhythmia risk using the same assay.

and is appropriately powered to detect QTc prolongation similar to the TQT study.

Negative in vivo QT study is defined as no significant QT prolongation in animal studies where the investigational drug’s exposure (parent and metabolites) covers high clinical exposure. The level of study sensitivity is different for E14 Q&As 5.1 vs. 6.1.

The new integrated risk assessment Q&As provide additional recommendations for the use of non-clinical data to support clinical development and suggests optional follow-up studies that can be used to further evaluate QT prolongation and proarrhythmia risk when non-clinical core assays are not negative.

The hERG IC50 should be determined following Q&A 2.1 “best practice” considerations. The same experimental protocol should be applied to the new drug and the reference drugs. Cmax is defined as the mean steady-state maximum plasma concentration when the maximum recommended therapeutic dose is given with intrinsic or extrinsic factors (high clinical exposure scenario). The high clinical exposure will be estimated early in development and will subsequently be updated based on additional data. Principles to Define a Negative In Vivo QT Assay A negative in vivo QT assay requires that no QT prolongation is found in animal studies when a new drug’s exposure includes and exceeds the anticipated clinical exposure. This includes both the parent and any major human metabolites. Experiments should follow general in vivo best practice considerations, e.g., species selection, heart rate correction, reporting format, etc. To support Q&As 5.1 and 6.1, exposures should cover the anticipated high clinical exposure scenario. The adequacy of exposure to any major human specific metabolites should be determined (see ICH S7A and S7B). To support Q&A 6.1, the in vivo study should have the power to detect a QTc prolongation of a magnitude similar to dedicated clinical QT studies. Summary of Revised ICH E14 and S7B Q&A Document The current revision of the ICH-E14 Q&A document (August 2020) is focusing on two of the 2015 revision (R3) key Q&A’s, namely 5.1 and 6.1, providing a more detailed approach with the aim of further reducing the number of required TQT studies through the TQT waiver application. The document introduces a new criterion for regulatory decisionmaking – the double negative non-clinical assessment. In Q&A 5.1 (concentration-response modelling) it is used to support lower clinical exposure needed to waive the positive control, whereas in Q&A 6.1 (‘special cases’, e.g., oncology) it can support an alternative clinical study design to demonstrate low QTc prolongation risk. The double negative non-clinical assessment is using best practice and requires an hERG safety margin greater than that of reference drugs with the same assay, and in vivo QT study testing doses covering the high clinical exposure scenario. The document also reinforces the need for following best practice principles, obtaining and covering the high clinical exposure scenario. It requires that clinical QT studies follow quality standards established for TQT studies, including high-quality ECGs and as many elements of the TQT study to control and reduce data variability. The Revised S7B Q&A’s require that double negative nonclinical assessment are based on best practice, including hERG safety margin for the parent compound and major metabolites greater than that of reference drugs with the same assay, although it stops short of defining the threshold of an acceptable safety margin (defined as >30 by Redfern et al5). It also requires that the in vivo QT study should cover a high clinical exposure scenario 52 Journal for Clinical Studies

Nonetheless, while the new ICH-E14/S7B Q&A are a welcome update, there remains the question of the future shape of the cardiac safety guidance as the future and role of the CiPA guidance is still unclear. There is also some uncertainty surrounding the role of the TQT study in the future cardiac safety paradigm, as it continues to be the gold standard for clinical QT assessment and sponsors are still required to apply for a waiver in order to avoid this study. REFERENCES 1. 2. 3. 4. 5. 6.

https://database.ich.org/sites/default/files/E14_Guideline.pdf https://database.ich.org/sites/default/files/S7B_Guideline.pdf https://admin.ich.org/sites/default/files/inline-files/E14_Q_As_R3__ Step4.pdf https://database.ich.org/sites/default/files/ICH_E14-S7B_QAs_ Step2_2020_0827_0.pdf https://www.fda.gov/media/142132/download Redfern WS et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58(1):32-45.

Boaz Mendzelevski, MD Dr. Boaz Mendzelevski is a consultant cardiologist and founder of Cardiac Safety Constants, a London based consulting group supporting pharmaceutical and biotechnology sponsors on cardiovascular safety and efficacy issues. Dr. Mendzelevski received his MD degree from the Ben-Gurion University in Beer-Sheva, Israel. He is a Board Certified expert in both Internal Medicine and Cardiology. He completed further training in Interventional Cardiology and Electrophysiology at the Royal Brompton Hospital in London, UK. Dr. Mendzelevski founded the first CardioPulmonary monitoring centre in London, which was acquired by Quintiles Transnational (now IQVIA) as its core ECG laboratory. Dr. Mendzelevski served as VP of Cardiology for Quintiles, Covance and Bioclinica and is now an independent industry consultant. Dr. Mendzelevski provides expert input regarding cardiovascular safety and efficacy in drug development, including clinical and regulatory strategies, study design, protocol development, data analysis and expert reports. He worked directly with regulatory agencies in USA, EU, Asia and other regions and supported many NDAs and MAAs. He also served on many Advisory Boards, Data Safety Monitoring Boards, Endpoint Adjudication and Clinical Endpoint Committees. Dr. Mendzelevski chaired 20 international cardiovascular conferences in USA, Europe and Asia and is a regular speaker at scientific, regulatory and industry meetings. He is also an active member of the Cardiac Safety Research Consortium and its Scientific Oversight Committee, Planning and Database Committees. He authored multiple scientific publications. Email: boaz.mendzelevski@cardiacsafetyconsultants.com

Volume 12 Issue 6

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Cardiovascular Safety

Assessing Cardiac Safety in Oncological Drug Development Advances in the development of anti-cancer drugs, including immuno- and targeted therapies, have decreased mortality rates for many cancers and increased patient survival. However, despite these improvements, concerns have been raised about possible medium- and long-term adverse effects of these new anti-cancer agents, including, specifically, the risk of cardiovascular toxicity. Cardiovascular diseases are increasingly being recognised as an adverse effect of anticancer therapies. Attention has mostly focused on heart failure, but other types of cardiotoxicity, including cardiac rhythm disorders, can occur in patients with no underlying cardiomyopathy. This article reviews the main mechanisms of cardiotoxicity for older and more recently developed drugs in cancer patients, focusing particularly on atrial fibrillation (AF), ventricular tachycardia (VT), and QTc prolongation, and their characteristics. We also advocate for the establishment of advanced cardiovascular safety assessments during the development of new drugs, to mitigate these risks. Cardiac Toxicity of Anti-cancer Drugs There is no universal definition of cardiotoxicity. The definitions used in clinical trials differ, but all define cardiotoxicity on the basis of various criteria relating to coronary artery disease, cardiac arrhythmias, conduction abnormalities or heart failure (HF). Cardiac arrhythmia in cancer patients can be worsened by a combination of multiple concomitant factors, such as underlying heart disease, direct effects of the tumour on the cardiovascular system, and the cardiotoxicity of the anti-cancer treatment. Myriad mechanisms may contribute to this process, including immune system modulation, systemic inflammation, electrolyte or endocrine abnormalities, impaired oxygenation, and direct cardiac metabolic

alterations, potentially leading to death. Arrhythmias appear to be an underappreciated adverse effect of anti-cancer agents, and their incidence, significance and underlying mechanisms are currently under investigation. In the context of anti-cancer treatment, arrhythmias seem to result from a combination of effects leading to direct and acute modifications of specific molecular pathways critically linked to arrhythmogenesis (such as IKr inhibition prolonging the QTc interval) or indirect mechanisms with effects in the medium-to-long term, due to the creation of a substrate for structural arrhythmia (such as myocardial damage/modification through inflammation, fibrosis, apoptosis or ischemia). Many drugs have been shown to produce a small, but reproducible effect on prolonging QTc interval. In particular circumstances, this marked prolongation of the QTc interval may trigger the form of polymorphic ventricular tachycardia known as ‘torsades de pointes’ (TdP) (generally through direct hERG-channel inhibition and/or by phosphoinositide-3-kinase pathway inhibition for anti-cancer drugs), which may cause syncope or sudden cardiac death. Cancer patients seem to be particularly at risk of having multiple factors precipitating TdP (e.g. prolonged baseline QTc duration, hypokalemia, bradycardia, and the co-administration of drugs blocking IKr). This is because both the cancer itself, and the drugs used to treat it can induce hypokalemia (by causing vomiting and diarrhoea) and cancer patients often present comorbid conditions that can increase the risk of QTc prolongation (e.g. hypocalcemia or hypomagnesemia). Most, but not all, ventricular arrhythmias induced by anti-cancer agents are, therefore, related to QTc prolongation. As summarised in Table 1, the major anti-cancer drugs responsible for QTc prolongation in this context are kinase inhibitors, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, antiandrogens and selective oestrogen receptor modulators.

Pharmacological class

Known risk

Main anticancer drugs

Specific comments

Anthracyclines

Acute: any form of arrhythmia, QTc prolongation, TdP, sudden death Delayed: AF (with or without heart failure)

Doxorubicin Epirubicin

Dose-independent effects are presumed No FDA statement

Other cytotoxic agents

Acute: QTc prolongation, TdP, Sudden death, AF, VT Delayed: AF

Gemcitabine Cisplatin Melphalan, cyclophosphamide Arsenic trioxide

Intra-class variability concerning risk of arrhythmic side effects Dose-dependent effects regarding QTc prolongation induced by arsenic trioxide FDA boxed warning: QTc prolongation (arsenic trioxide)

Kinase inhibitors

Acute: QTc prolongation, TdP, Sudden death Delayed: AF, VT without any QTc prolongation

Anti ALK: ceritinib, crizotinib Anti BCR-ABL: bosutinib, imatinib, nilotinib, ponatinib (+ antiVEGFR) Anti BTK: acalabrutinib, ibrutinib Anti CDK: ribociclib Anti EGFR/HER2: afatinib, lapatinib Anti RAF/MEK: dabrafenib, regorafenib (+anti-VEGFR), sorafenib (+ anti-VEGFR), trametinib, vemurafenib Anti VEGFR: cabozantinib, lenvatinib, nintedanib, Pazopanib, sunitinib, vandetanib

Intra-class variability concerning risk of arrhythmic side effects Dose-dependent effects regarding QTc prolongation FDA boxed warning: QTc prolongation for vandetanib and nilotinib FDA warning and cautions: AF for ibrutinib, QTc prolongation for several KIs (sunitinib, lapatinib, crizotinib, vemurafenib, sorafenib, ceritinib, pazopanib, ribociclib, dasatinib, bosutinib and lenvatinib)

Histone deacetylase inhibitors

Acute: QTc prolongation, TdP, sudden death

Depsipeptide, panobinostat, romidepsin, vorinostat

Dose-dependent effects regarding QTc prolongation FDA boxed warning: QTc prolongation

Selective estrogen modulators Acute: QTc prolongation, TdP, sudden death

Tamoxifen, toremifene

FDA boxed warning: QTc prolongation for Toremifene

Androgen deprivation therapy (anti-androgenics)

Acute: QTc prolongation, AF, TdP, sudden death

Anti-CYP17: abiraterone GnRH agonists: leuprolide, goserelin GnRH antagonists: degarelix

Intra-class variability concerning risk of arrhythmic side effects FDA warning and cautions: QTc prolongation (leuprolide, goserelin, degarelix)

Immune Checkpoint inhibitors (anti-CTLA4, anti PD-1/PDL-1)

Acute: any form of arrhythmia

Other immunotherapies

Acute: AF, sudden death

Anti-PD-1: nivolumab Anti-PDL-1: atezolizumab, avelumab, durvalumab Cytokine: interleukin-2 Anti-CD20: rituximab Anti-EGFR: cetuximab, necitumumab

Dose-independent effects No FDA statement Intra-class variability concerning risk of arrhythmic side effects FDA boxed warning: sudden death with cetuximab and necitumumab

Source: Courtes of Joe-Elie Salem, MD, PhD and J. Alexandre et al. / Pharmacolo & Thera eutics 1892018 89–103 gy p y ( )

Table 1 Cancer therapies and associated arrhythmia profiles 54 Journal for Clinical Studies

Volume 12 Issue 6

Cardiovascular Safety Recent studies focusing on anti-cancer drugs leading to QT prolongation have revealed new pathways of drug-induced QT prolongation, in addition to the well-known effects involving direct IKr blockade. The identification of non-IKr-dependent pathways leading to QT prolongation will be important for risk assessment, not only for anti-cancer therapies, but also for other QT-prolonging drugs. The identification of these new pathways, most of which are mediated by phosphoinositide-3-kinase pathway inhibition, will shed light on the importance of new signalling pathways modulating QT duration and the associated risk of arrhythmia. Many cancer therapies, especially kinase inhibitors, require QT monitoring, and warnings are clearly printed on the FDA label (see Table 1). For example, ribociclib (Kisqali, Novartis) is a recently approved kinase inhibitor (CDK4/6 inhibitor) for breast cancer. The FDA label recommends monitoring QT at baseline and during the first two cycles of treatment. Anti-androgenic therapy, used in prostate cancer, has also been associated with a QT prolongation of 10 to 20 milliseconds. QT prolongation has also been observed in early clinical trials for luteinising hormone agonists (leuprolide, goserelin) and antagonists (degarelix), prompting the FDA to issue warnings for these therapies. In addition to QT prolongation, cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs), such as ibrutinib, can also drive supraventricular tachycardia, mostly involving atrial fibrillation. Heart failure on anthracyclines, trastuzumab and other agents is also of particular importance in adjuvant therapy for breast cancer patients, in whom life expectancy may be more severely affected by serious cardiovascular events than by cancer prognosis. Is Cardiotoxicity Adequately Assessed in Current Trials? Despite growing concern about the cardiotoxic side-effects of new anti-cancer agents, a surprisingly small number of ongoing trials include cardiac end points in their design. According to the clinicaltrials.gov website, current cancer-related trial designs are heterogeneous and non-standardised in terms of the methods used to assess cardiotoxicity. Few of these studies include cardiac safety among their primary or secondary endpoints. Cardiovascular risk factors are often considered in the inclusion criteria for these trials, but population-based impacts (e.g. age, comorbid conditions) should also be taken into consideration during the management of patients receiving these new therapies, to prevent the creation of arrhythmogenic substrates. Establishing a causal relationship between anti-cancer agents and cardiac arrhythmia remains challenging, due to interference from the following factors: •

Comorbid conditions in the patients: cancer patients often have concomitant common diseases, such as hypertension, diabetes or heart failure, which may increase their susceptibility to arrhythmia,

•

Complex treatment regimens: anti-cancer drugs are usually used in combinations, making the establishment of causality more challenging.

Risk stratification is therefore important in these studies, and requires greater collaboration between cardiologists and oncologists. Along with greater standardisation in the use of traditional endpoints, such as the monitoring of left ventricular function (LVEF), there is a need for the prospective validation and integration www.jforcs.com

of novel endpoints and means of diagnosis, such as diastolic dysfunction and serum biomarkers. New initiatives are advocating new definitions of cardiac toxicity and proposing standard designs and strategies, to increase the efficiency of cardiotoxicity evaluation for novel anti-cancer agents. QT Interval Assessment The QT interval of the electrocardiogram corrected for heart rate (QTc) remains the gold standard (despite its well-recognised limitations) method for measuring the duration of ventricular repolarisation in human studies. It is still widely used as a surrogate marker of ventricular arrhythmia risk. Bazett's correction (QTcB = QT/RR^0.5) has been widely used, but Fridericia's correction (QTcF = QT/RR^0.33) is currently preferred, in accordance with the E14 ICH Guideline adopted by the FDA and EMA in 2005, as this correction is generally more accurate. Standard guidelines provide a classification and severity grading system for drugs considered to have a clinically significant QTc interval-prolonging effect: a QTc >500 ms and, to a greater extent, a QTc >550 ms, are associated with at least a two- to three-fold increase in the risk of TdP (Priori et al., 2003; Sauer et al., 2007). QT interval varies between individuals and is influenced by diverse physiological and pathophysiological factors, including sex, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases, such as diabetes. Evaluation of Cardiac Function in Patients on Anti-cancer Drugs There is also controversy regarding the best method and mode of LVEF monitoring during cancer treatment. It is important to note that the various modes of LVEF monitoring generally used to assess cardiac function have different normal reference values. MUGA scan is one mode of LVEF monitoring. Its inter- and intra-observer variabilities are low (<5%), and the values obtained are strongly correlated with the findings of cardiac magnetic resonance imaging (cMRI) and 3D echocardiography. The principal disadvantage of this method is the need for repeated exposure to radiation at each time point. However, the use of MUGA in trials does not reflect the current preference for cardiac ultrasound, which has increased in popularity at many centres. 3D echocardiography is more accurate and reproducible than 2D echocardiography for the measurement of LVEF, and has the best temporal reproducibility during cancer therapy. Echocardiography with estimation of diastolic dysfunction is also being investigated as a more sensitive method for measuring early cardiac damage. Cardiac ultrasound and scintigraphy remain the most frequently used techniques for estimating LVEF, but they lack consistency in the degree of reduction from baseline or absolute values considered to indicate cardiotoxicity. The recent position paper from the European Society of Cardiology defined cancer therapeutics-related cardiac dysfunction (CTRCD) as a decrease in LVEF of > 10 percentage points, to a value < 50%. This position paper considers transthoracic echocardiography (TTE) to be the method of choice for the detection of CTRCD, before, during and after cancer therapy. Other types of imaging can also be used to follow LVEF, but radiation exposure during radionuclide angiography and the low Journal for Clinical Studies 55

Cardiovascular Safety

availability and high cost of cardiac magnetic resonance imaging have limited the use of these techniques.

Whatever the approach used, the bottom line is that the mode of diagnosis used must be accurate and reproducible enough to identify a real change in cardiac function reliability. The same technique should be used for baseline assessment and follow-up studies, during and after cancer treatment.

Biological Markers In addition to clinical and echocardiographic variables, biological markers of myocardial necrosis (troponin I and T) and natriuretic peptides have emerged as possible prognostic factors identifying subclinical myocardial stress and potentially predicting major cardiovascular events, including heart failure.

Several studies have demonstrated the prognostic value of the serum troponin assay performed immediately before or after anthracycline exposure. Some studies have suggested that 30–35% of patients treated with anthracyclines display significant increases in troponin levels. These increases precede LVEF deterioration by three to four months, and the troponin peak seems to be correlated with the severity of left ventricular systolic dysfunction (LVSD). Conclusion Recent advances in cancer treatment, including many targeted therapies, have greatly improved the prognosis of cancer patients. Arrhythmia is a common side-effect of several major classes of antineoplastic agents, but the true incidence and significance of this condition has not been adequately characterised. In the future, oncological clinical trials should monitor cardiovascular endpoints with a standardised approach, to characterise possible ECG alterations and the development of cardiac rhythm disorders. REFERENCES 1. 2.

A current understanding of drug-induced QT prolongation and its implications for anticancer therapy by Dan M Roden. Cancer treatment–induced arrhythmias: focus on chemotherapy and

56 Journal for Clinical Studies

targeted therapies by Vitaly Buza, Bharath Rajagopalan, Anne Curtis. Cardiac arrhythmias: An emerging issue with anticancer drugs by JoeElie Salem, MD, PhD; and Javid J. Moslehi, MD. Cardio-oncology: Clinical and imaging perspectives for optimal cardiodetection and cardioprotection in patients with cancer by Franck Thuny, Olivier Huttin, Stéphane Ederhy Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms by Joachim Alexandre, Javid J. Molsehi, Kevin R. Bersell, Christian Funck-Brentano, Dan M. Roden, Joe-Elie Salem Is cardiotoxicity being adequately assessed in current trials of cytotoxic and targeted agents in breast cancer? by S. Verma M.S. Ewer

Dr. Joe-Elie Salem Dr. Joe-Elie Salem is currently the associate professor of medicine and leading PitieSalpétrière APHP. Sorbonne CardioOncology Program and Paris Est Clinical Investigation Center. His research focus is on cardiovascular pharmacology, cardio-immunology, heart failure and drug-induced arrhythmias applied to cardio-oncology. He has an active collaboration with Vanderbilt University Medical Center Cardio-oncology and Pharmacology programs where he still has an adjunct associate professor position.

Alexandre Durand-Salmon Alexandre Durand-Salmon, MBA joined Banook Group in 2010 and brings over 15 years of experience in the eClinical arena as the Co-founder and Director of Operations for KIKA Medical, an EDC company created in 1997 and acquired by Merge Healthcare in 2010. Mr. DurandSalmon successfully blends the technologically advanced medical imaging programming and software with the medical and scientific needs of the clinical trial world. He is currently the CEO of Banook Group.

Volume 12 Issue 6

People service Science, Science serving People

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Journal for Clinical Studies 57

Cardiovascular Safety

Commentary: On the Revised ICH E14 and S7B Q&As The International Council on Harmonisation (ICH) released a new set of questions and answers (Q&As) for ECH E14 and ICH S7B in August 2020 (available at: https://www.ich.org/ news/ich-e14s7b-draft-qas-available-now-ich-website). This represents Step 2 of the ICH process; these Q&A documents are now currently open for public review and comment. On October 15 and 16, FDA hosted a webinar on the Q&A document and we would like to share some thoughts and considerations in terms of what this may mean for drug developers. Since the release of the S7B and E14 guidances in 2005, all new drugs with systemic exposure have been required to undergo assessment of their risk of producing Torsades de Pointes (TdP), a ventricular arrhythmia that is often lethal. Torsades is very rare, even for most of the drugs removed from the market due to an excess of deaths due to this arrhythmia. As a result, it is not feasible to directly detect an increased risk of TdP in the clinical trials performed during the drug development process. Instead, the E14 guidance described use of a surrogate endpoint, drug-induced QT prolongation, and for the most part, since 2005 all new drugs have undergone an assessment of the drug’s effect on the QT interval as measured on the 12-lead ECGs that are collected during clinical trials. The assessment of risk for TdP has almost entirely been based on a review of the ECG data (and more recently on the relationship between drug exposure and QT prolongation), whereas the nonclinical assays described in the S7B guidance mostly have been used to ensure that a drug is safe to take into first-in-human (FIH) studies, and have played a minor role for the subsequent clinical development. However, since 2005, we have learned a great deal about how drugs affect the QT interval and how they may produce TdP, and our scientific understanding of the biological mechanisms responsible for drug-induced ventricular arrhythmias has grown tremendously. The ICH E14 document has been clarified through several Q&A documents, which have been attached to the guidance, most recently in December 2015. The latest Q&A document (R3 from December 2015) allowed concentration-QTc (C-QTc) analysis to be applied to data from healthy subjects to definitively demonstrate that a drug did not cause clinically relevant QTc prolongation, defined as exclusion of an effect on the placebo-corrected, changefrom-baseline QTc larger than 10 ms1. An important point was then that a separate positive control would not be necessary if the following condition is met: There are data characterizing the response at a sufficiently high multiple of the clinically relevant exposure (see ICH E14 Section 2.2.2). This allows C-QTc analysis to be applied to serial ECG and PK data from first-in-human (FIH) studies and if sufficiently high concentrations are achieved, waive the request for a later, dedicated thorough QT (TQT) study, and thereby allowed a more efficient method for ECG evaluation of new drugs2,3. Current FDA practice, not necessarily followed by all other regulators, has been to request a TQT study with a positive control in cases where very high concentrations (supratherapeutic concentrations in the graph below) cannot be, or have not been, achieved in e.g., FIH study, as shown in Figure 1: 58 Journal for Clinical Studies

Source: Slide 4 in Dr. Garnett’s presentation at the public webinar on S7B/E14 Q&A, October 15–16, 2020: Revised E14 Q&As and Presentation of Examples to Highlight the Impact of Nonclinical Data on Clinical Development and Interpretation.

Figure 1

Q&A 5.1 Q&A 5.1 has now been revised to also state: “If the maximum therapeutic exposure has been fully covered in the clinical ECG assessment (e.g., concentrations representative of the maximum recommended dose at steady-state in situations of intrinsic and/or extrinsic factors that increase bioavailability), but sufficiently high multiples cannot be obtained (e.g., for reasons of safety, tolerability, saturating absorption), then a nonclinical integrated risk assessment that includes the hERG assay, an in vivo QT assay, and any follow up studies can be used as supplementary evidence. See ICH S7B Q&A 1.1 for details; in summary, the nonclinical studies should include1 a hERG safety margin higher than the safety margins computed under the same experimental protocol for a series of drugs known to cause torsade de pointes (TdP) and2 no QTc prolongation in an in vivo assay of sufficient sensitivity conducted at exposures of parent compound and humanspecific major metabolites that exceed clinical exposures.” The proposed change will therefore, to some extent, further decrease the number of TQT studies, and enable acceptance of robust high-quality ECG data, using C-QTc analysis, supplemented by non-clinical data, to demonstrate that the drug does not cause clinically relevant QT prolongation. It should then be emphasised that as the text is written, this applies only to drugs for which sufficiently high concentrations cannot be obtained (e.g., for reasons of safety, tolerability, saturating absorption). If the assumption that ‘the maximum therapeutic exposure has been fully covered’ is shown to be correct, higher concentrations will not be seen in patients, including those with impaired clearance of the drug and those at risk for proarrhythmic events, and the revised text then gives a path forward without performing a stand-alone TQT study. In this context, it is important to point out the role of high concentrations in terms of detecting the QT effect of a drug4. We know that high concentrations are key for the ability of C-QTc analysis to detect small QTc effects, and thereby to increase our confidence in the data. We have made this observation in several projects, including one recently published example, based on a multiple ascending dose (MAD) study5. It therefore seems prudent to restrict 5.1 to those cases where sufficiently high concentrations cannot be obtained, rather than broadly applying these criteria. Volume 12 Issue 6

Cardiovascular Safety At the webinar, Dr Garnett from FDA showed the following graph (Figure 2):

Source: Slide 9 in Dr. Garnett’s presentation at the public webinar on S7B/E14 Q&A, October 15–16, 2020: Revised E14 Q&As and Presentation of Examples to Highlight the Impact of Nonclinical Data on Clinical Development and Interpretation.

Figure 2

The key point, which is not acknowledged in this slide, is that 5.1 applies to drugs for which supratherapeutic concentrations cannot be obtained. Furthermore, the chart does not provide insight as to why ‘supratherapeutic concentrations’ were not obtained, which in some cases is simply because doses in FIH studies were not being pushed high enough, and not necessarily due to reasons of safety, tolerability, or saturated absorption. It is therefore not clear to what extent the proposed 5.1 pathway will further reduce the proportion of TQT studies, but we can certainly expect a continued debate between sponsors and regulators on this point. It may be appropriate and clarifying to specifically point this out in the text by, e.g., adding a statement along the following lines: If sufficiently high multiples of maximum therapeutic exposure were not obtained in the clinical ECG assessment, it should be clarified why sufficiently high exposures cannot be achieved. Q&A 6.1 In the answer to Q&A 6.1 in the proposed E14 Q&A revision, it is stated that: In situations where it is not possible to evaluate the QT/ QTc effects at higher exposures than are anticipated with the recommended therapeutic dose, it is particularly important that the nonclinical in vivo studies are conducted at exposures exceeding the clinical therapeutic exposures. Under Decision-Making, point 2., the following is said (our bolded text): A totality of evidence argument based on the results of an integrated nonclinical and clinical QT/QTc assessment could be made at the time of marketing application. To support a drug as having low likelihood of proarrhythmic effects due to delayed repolarization, the assessment should demonstrate the following: Further down, under 2): 2. The high-quality ECG data (see ICH E14 and E14 Q&A 1) collected in the alternative QT clinical assessment do not suggest QT prolongation, generally defined as ΔQTc greater than 10 ms, as computed by the concentration-response analysis (see E14 Q&A 5.1 for details) or the intersection-union test. The strength of the clinical ECG data depends on the upper bound of the two-sided 90% confidence interval around the mean ΔQTc estimate… ‘Low Likelihood of Proarrhythmic Effects’: Since this refers to a claim that a sponsor can make at the time of marketing application, it should be noted that the risk/ benefit assessment and labelling are performed separately by www.jforcs.com

each regulatory authority (see E14 5.2), and may therefore vary across regions, especially when an effect on ΔQTc > 10 ms cannot be excluded. It may well be that regulators will see this in a similar way for a drug with a small effect, e.g., 4 ms with an upper bound (UB) of the 90% CI of 12 ms, as in the example shared by Dr. Garnett at the webinar (slide 18 and 19; available at: https://www.fda.gov/drugs/news-events-human-drugs/newapproaches-integrated-nonclinical-clinical-qtproarrhythmic-riskassessment-10152020-10162020). It is, however, not evident, in our view, that the same is true for a drug with a larger effect, still within the 6.1 definition, e.g., mean ΔQTc of 9 ms, UB of the 90% CI 17 ms. If a harmonised regulatory approach is desired, it seems better to retain the threshold that most parties can agree on, i.e., exclusion of a 10 ms effect (UB of the 90% CI less than 10 ms). The issue we see with Q&A 6.1 is that the consequences for patient studies of ‘low likelihood of proarrhythmic effects’ are not described. The stated purpose of the ICH E14 guidance is to inform the level of ECG monitoring that will be required for Phase III studies, even though the data from a TQT will also be used in an integrated nonclinical and clinical assessment of proarrhythmia risk. Even though it is clearly stated that the claim about ‘low proarrhythmic effect’ can be made at the time of marketing application, the clinical QT evaluation will in many cases be performed before pivotal studies are initiated, e.g., by applying C-QTc analysis on data from the FIH study in cancer patients. It can then be argued that a drug that can be categorised as having low likelihood of proarrhythmic effects based on 6.1 criteria, can be given safely to patients in Phase III trials, without exclusion criteria or cautionary statements in regard to concomitant medications with drugs that are known to cause QT prolongation, or to patients at risk based on, e.g., family history of LQTS, cardiovascular disease or hypokalemia. As defined under 6.1, a drug that causes a mean ΔQTcF of 9 ms with a UB of 17 ms could be regarded as ‘safe’ from this perspective. We disagree that such a drug can be taken into large patient trials without specified exclusion criteria and precautions and without ECG monitoring, but much more importantly – there is consensus across regulators on this point. This conflict between the proposed 6.1 pathway and the current regulatory consensus means that sponsors will not know what to expect and that the desired harmonisation across regulators will not be achieved. It is important to describe the consequences for subsequent patient studies by referring to the E14 section 2.3 if a new term is introduced into the guidance. We suggest that it would be better Journal for Clinical Studies 59

Cardiovascular Safety to keep the threshold on which there is consensus (exclusion of a 10 ms effect, as defined above) and then allow regulators to make case-by-case decisions, depending on the severity of the indication and the unmet medical need. Alternatively, the text under 2) in Q&A 6.1 can be revised along the following lines (added text in bold): ….generally defined as ΔQTc greater than 10 ms, as computed by the concentration-response analysis (see E14 Q&A 5.1 for details) or the intersection-union test. The strength of the clinical ECG data depends on the upper bound of the two-sided 90% confidence interval around the mean ΔQTc estimate. In case QT evaluation as described here is completed before patient studies are initiated, the level of the mean QTc effect and the 90% confidence interval will be used to determine the need for precautions, exclusion criteria and the level of ECG monitoring in subsequent patient trials (see E14 2.3). Drugs with a Pronounced Heart Rate (HR) Effect In Q&A 6.1, it is also stated that: An integrated QT/QTc risk assessment can also be particularly valuable for drugs with confounding heart rate effects (i.e., >20 bpm) that could impact accurate determination of the QTc. Advanced methodologies for controlling or correcting for heart rate changes in the nonclinical in vivo studies and/or conducting QTc assessments in patients with the disease might be informative in this situation. If tolerance to the chronotropic effect develops with repeat dosing, upward titration regimens can sometimes be employed to avoid or minimize the confounding effects of drug-induced heart rate changes on the QTc assessment. We agree on the point that QT evaluation conducted in patients may be informative in case the drug has a pronounced HR effect and that dose titration can be useful, but it also seems important to emphasise that in most cases there will be a need for ECG monitoring in Phase III trials based on this level of HR effect. As pointed out by the E14/S7B IWG group on several occasions, the role of the QT assessment in healthy subjects is to define which drugs would need ECG monitoring in patients, with the objective to further characterise this effect in the targeted patient population. An HR effect of this magnitude will in most cases be detected during Phase I studies, which further underscores the need of defining the consequences it has for subsequent patient studies. Under Decision-Making, it is stated that a drug with this level of HR effect can be categorized as having ‘low likelihood of proarrhythmic effects due to delayed repolarization’, if 6.1 requirements #1 and #3 are also met. This seems correct if the drug causes a HR increase of this magnitude, since TdP is closely associated with bradycardia. Such drug may however trigger coronary ischemia or worsen congestive heart failure, and thereby cause life-threatening arrhythmias on this basis. A drug that causes a reduction of HR of this size, i.e., is having a strong negative chronotropic effect, is likely to cause clinically significant bradycardia and may trigger sinus pauses and AV blocks. Moreover, if the mean effect on ΔQTc is only somewhat below 10 ms, as an example, 9 ms with an upper bound of the 90% CI of 17 ms, it is probably incorrect, or at least not convincingly shown, that the drug can be categorised as having a ‘low likelihood of proarrhythmic effects due to delayed repolarization’. An important question is then whether data have been shared within the IWG to support this latter point? The HR example is too TdP-centric, and ignores other potential cardiac adverse effects due to large HR effects that clearly would warrant ECG monitoring in patients. As we see it, the example therefore leads in the wrong direction, and should be dropped from the document. 60 Journal for Clinical Studies

Q&As for ICH S7B This is the first set of Q&As for the S7B guidance, “The Non-Clinical Evaluation Of The Potential For Delayed Ventricular Repolarization (QT Interval Prolongation) By Human Pharmaceuticals” since its release in 20056. The Q&As address the current ‘best practices’ for the design and conduct of non-clinical cardiac safety studies and discuss the role of non-clinical cardiac safety data in an integrated risk assessment of the risk of TdP by a new drug. There has been renewed interest in using non-clinical tests to replace, or at least to supplement, clinical ECG data during the drug development process. The current Q&A documents are intended to address this issue, and provide recommendations about when and how a drug development programme might use the nonclinical cardiac safety data as part of an in tegrated risk assessment, particularly when the clinical ECG data collected in healthy volunteer trials cannot be tested at adequately high exposures, or when data on a drug’s QT effects must be collected in patient trials with larger variability and lower precision.

TheThe newnew S7BS7B Q&A document consists of four setssets of questions and answers rela Q&A document consists of four of questions level topics (Table 1) to and begins with a discussion about the begins general principles b and answers related four high-level topics (Table 1) and non-clinical data asabout part of integrated assessment of the of drug-induced with a discussion theangeneral principles behind userisk of nonclinical data as part of an integrated assessment of the risk of druginducedTable TdP.1: Four Topics Discussed in ICH S7B Draft Document Que s t i o n1 : I nt e g r a t e dRi s kAs s e s s me nt Que s t i o n2 : Be s tPr a c t i c eCo ns i de r a t i o nsf o rI nVi t r oSt udi e s Que s t i o n3 : Be s tPr a c t i c eCo ns i de r a t i o nsf o rI nVi v oQTSt udi e s Que s t i o n4 : Pr i nc i pl e so fPr o a r r hyt hmi aMo de l s Table 1: Four Topics Discussed in ICH S7B Draft Document

Q&A discusses, a high the exposures drug exposures that be evaluated TheThe Q&A discusses, at a at high level,level, the drug that should should be evaluated in non-clinical tests (generally at least as high tests (generally at least as high as the expected high clinical exposure, if not a m as the high clinical if not a multiple of this), and theexpected use of safety marginsexposure, to evaluate patch clamp data aboutand drug-induced b the use of safety margins to evaluate patch clamp data about drughERG encoded IKr cardiac channel (‘hERG safety margin’). The Q&A describe inducedfor block of thenegative” hERG encoded IKr cardiac channel (‘hERG criteria a “double non-clinical assessment: safety margin’). The Q&A describes some of the criteria for a “double negative” non-clinical assessment: 1. Ion channel studies that demonstrate that the hERG “safety margin” for and metabolites is higher than the safety margins for a series of drugs k 1. Ion Torsades channel studies that demonstrate that the hERG “safety de Pointes. margin” for the new drug and metabolites is higher than the safety forstudy a series drugsno known to cause Torsades 2. An margins in vivo QT thatofshows evidence of drug induced QT prolon de Pointes. adequately high exposures of the new drug and its metabolites.

The to the question also mention otheroffactors, such as block of oth 2. answers An in vivo QT first study that shows no evidence drug induced QTonprolongation adequatelyand high exposures of the new drug effects ion channelat trafficking, non-ion channel mediated effects that ma QT. and its metabolites.

TheThe second question thequestion S7B Q&A addresses, at a high level,such the ‘best practic answers to theinfirst also mention other factors, cardiac channel and in vivo studies, and including discus as blockion of other ionstudies channel, effects oncardiomyocytes ion channel trafficking, study design and conduct, conditions non-ion channel mediatedstudy effects that mayand alsoverification prolong QT.of the drug concentr verification of the quality of the collected data, and the integrity of the test syste The second questionthat in the the ‘best S7B Q&A addresses, at a high level, specifically comments practices’ discussed are only intended to ap the ‘best in vitro cardiac studies and in who wishpractices’ to use thefor non-clinical data forion an channel integrated risk assessment, complem vivo cardiomyocytes proper study clinical ECG data. In studies, contrast,including sponsors discussions intending toofuse the non-clinical cardiac design andactivities conduct,orstudy conditions and of verification of trials the drug screening to inform the design FIH clinical are not required concentration used, verification of the quality of the collected data, ‘best practices’. The first part of this section discusses ‘best practices’ for ion ch and the integrity of the test systems. The Q&A specifically comments including the topics described in Table 2. The second portion discusses ‘best pra that the ‘best practices’ discussed are only intended to apply to cardiomyocytes studies, including discussiondata of the listed in Table 3. sponsors who wish to use the non-clinical fortopics an integrated

risk assessment, complementing theStudies clinicalDiscussed ECG data.inIn contrast, Table 2: Best Practices for Ion Channel Question 2

sponsors intending to use the non-clinical cardiac data for routine screening activities or for to inform the studies design(IC50 of FIH trialsvalues) are Primary endpoints patch clamp and clinical Hill Coefficient not required to follow these ‘best practices’. The first part of this Volume 12 Issue 6

Cardiovascular Safety section discusses ‘best practices’ for ion channel studies, including the topics described in Table 2. The second portion discusses ‘best practices’ for cardiomyocytes studies, including discussion of the topics listed in Table 3.pat Pr i ma r ye nd po i nt sf o r c hc l a mps t udi e s

P r i m a r y e n d p o i n t s o r p a t c h c l a m ps t udi e s ( I C 5 0 a nd H i l l C o e f f i c i e n t v a l u e s ) P r i m a r y e n d p o i n t s f o r p a t c h c l a m p s t udi e s ( I C 5 0 a n d H i l l C e f f i c i e n t v a l u e s ) T e s t i n g a t p h y s i o l o g t e m p e r a t u r e s ( I C 5 0 a n d H i l l C o e f f i c i e n t v a l u e s ) T e s t i n g a t p h y s i o l o g i c t e m p e r a t u r e s Mo ni t o r i ngo fe a l r e s i s t a nc e , c e l l he a l t h, r e c o r di ngq ua l i t y Te s t i n g a t p h y s i o l o g i c t e m p e r a t u r e s Mo n i t o r i n g o f s e a l r e s i s t a n c e , c e l l h e a l t h , r e c o r di ngq ua l i t y A s s e s s m e n t o f i o n c h a n n e l r e c o r d i n g q u a l i t y Mo n i t o r i n g o f s e a l r e s i s t a n c e , c e l l h e a l t h , r e c o r di ngq ua l i t y A s s e s s m e n t o f i o n c h a n n e l r e c o r d i n g q u a l i t y Co n c e n t r a t i o n v e r i f i c t i o n A s s e s s m e n t o f i o n c h a n n e l r e c o r d i n g q u a l i t y C o n c e n t r a t i o n v e r i f i c a t i o n Us eo fpo s i t i vea ndne g a t i vec o nt r o l s C nc e n t r a t i o n e r i f i c a t i o n Uo s e o f p o s i t i v ev a n d n e g a t i vec o nt r o l s Us eo fpo s i t i vea ndne g a t i vec o nt r o l s Table 3:Table Best2:Practices for for Cardiomyocyte Studies Discussed in Question 2 Best Practices Ion Channel Studies Discussed in Question 2 Table 3: Best Practices for Cardiomyocyte Studies Discussed in Question 2 Table 3: Best Practices for Cardiomyocyte Studies Discussed in Question 2 Me t h o d s( MA Pr e c o r d i ng s , c o nt r a c t i l ea c t i vi t y, EA Ds ) Me t h o d s( MA P r e c o r d i n g s , c o n t r a c t i l e a c t i v i t y , E A D s ) R e q u i r e m e nt s f o r d e s c r i p t i o n o f b i o l o g i c a l p r e p a r a t i o n s Me t h o d s ( MA P r e c o r d i n g s , c o n t r a c t i l e a c t i v i t y , E A D s ) R e q u i r e m e n t s f o r d e s c r i p t i o n o f b i o l o g i c a l p r e p a r a t i o n s ( s o u r c e o f c e l l s , m a t u r i t y , v i a b i l i t y ) R e q u i r e m e n t s f o r d e s c r i p t i o n o f b i o l o g i c a l p r e p a r a t i o n s ( s o u r c e o f c e l l s , m a t u r i t y , v i a b i l i t y ) D e t a i l s o f t e c h n o l o g y p l a t f o r m ( t r a n s m e m b r a n e p o t e n t i a l r e c o r di ng s , ( s o u r c e o f c e l l s , m a t u r i t y , v i a b i l i t y ) D e t a i l s o f t e c h n o l o g y p l a t f o r m ( t r a n s m e m b r a n e p o t e n t i a l r e c o r di ng s , f i e l dpo t e nt i a l s , c o nt r a c t i o nmo ni t o r i ng , c a l c i um s e ns i n g d y e s ) D e t a i l s o f t e c h n o l o g y p l a t f o r m ( t r a n s m e m b r a nm ep o t e n t i a l r e c o r di ng s , f i e l d p o t e n t i a l s , c o n t r a c t i o n m o n i t o r i ng , c a l c i u s e n s i n g d y e s ) D e s c r i p i o n o f a n a l y s i s p a c k a g e u s e d f i e l d p o t e n t i a l s , c o n t r a c t i o n m o n i t o r i ng , c a l c i um s e ns i ngdye s ) D e s c r i p i o n f n a l y s i s p a c k a g e u s e d D e s c r i pt t i o no o fa p l a t e s o r c h a m b e r s u s e da ndt e s tc o ndi t i o ns D s c r i p t i o n o f a n a l y s i s p a c k a g e u s e d De e s c r i p t i o n o f p l a t e s o r c h a m b e r s u s e da ndt e s tc o ndi t i o ns Mo n i t o r i n go f c e l l c o n t r a c t i o n s De s c r i p t i o n o f p l a t e s o r c h a m b e r sus e da ndt e s tc o ndi t i o ns Mo n i t o r i n g o f c e l l c o n t r a c t i o n s Mo ni t o r i ngo fdr ugc o nc e nt r a t i o ni nt e s tc ha mb e r s Mo ni i t o r i n g o f c e l l c o n t r a c t i o n s Mo n t o r i n g o f d r u g c o n c e n t r a t i o n i n t e s t c h a m b e r s t i vea ndne g a t i ve De f i ni ngs e ns i t i vi t yo fc a r di o myo c yt ea s s a ys–poi Mo n i t o r i n g o f d r u g c o n c e n t r a t i o n i n t e s t c h a m b e r s – p o s i t i vea ndne g a t i ve D e f i n i n g s e n s i t i v i t y o f c a r d i o m y o c y t e a s s a y s c o n t r o l s f o r h E R G – p o s i t i ve a n d n e g a t i ve D e f i n i n g s e n s i t i v i t y o f c a r d i o m y o c y t e a s s a y s c o n t r o l s f o r h E R G A s s e s s m e n t o f i n w a r d c u r r e n t s ; p o s i t i v e a n d n e g a t i v e c o n t r o l s c o n t r o l sf o r h E R G A s s e s s m e n t o f i n w a r d c u r r e n t s ; p o s i t i v e a n d n e g a t i v e c o n t r o l s Pr e s e nt a t i o no fr e pr e s e nt a t i ver e c o r di ng s A s s e s s m e n to f i n w a r d c u r r e n t s ; p o s i t i v e a ndne g a t i vec o nt r o l s Pr e s e n t a t i o o f r e p r e s e n t a t i v e r e c o r d i n g s Table 3:n Best Practices for Cardiomyocyte Studies Discussed in Question 2 Pr e s e nt a t i o no fr e pr e s e nt a t i ver e c o r di ng s

Q&A 6.1 allows sponsors to argue at the time of marketing application that a drug ‘has low likelihood of proarrhythmic effect’, if requirements under 6.1 are met. It should then be noted that the risk/benefit assessment and labelling are performed separately by each regulatory authority (see E14 5.2), and may therefore vary across regions, especially when an effect on ΔQTc > 10 ms cannot be excluded. In our view, the main issue in Q&A 6.1 is, however, that the consequences for patient studies of ‘low likelihood of proarrhythmic effects’ are not described. Many times, the clinical ECG assessment is performed before Phase III studies. It can then be argued that in case 6.1 requirements are met, the drug can be safely given in subsequent patient studies with medications known to prolong the QTc interval and to patients at risk for proarrhythmias and with limited ECG monitoring (see E14 2.3). Within the 6.1 definitions, a drug that causes a mean ΔQTcF of 9 ms with an upper bound of the confidence interval of 17 ms, will then be regarded as ‘safe’ from this perspective. As we see it, it seems important to describe the consequences in terms of exclusion criteria and level of ECG monitoring in subsequent patient trials, in case 6.1 requirements are met before pivotal trials are performed.

This first set of Q&As for the S7B guidance is a welcome first step in increasing the use of non-clinical cardiac safety data to complement clinical ECG data for an integrated assessment of the proarrhythmia risk of a new drug. Many of the answers in the draft document, however, contain discussions at a high level TheThe thirdthird question in the Q&A discusses practice’ considerations in vivo studies, of prescriptive detail. Additional details only, withQT a minimum question in the Q&A ‘best discusses ‘best practice’ for The third question thevivo Q&A ‘best practice’ considerations for inmethods vivo studies, about the QT ‘best practices’ for ion channel studies (such as what including discussion of appropriate drug exposures todiscussion test heart rate, for use in considerations forinin QTdiscusses studies, including of correct The third question in of theappropriate Q&A discusses ‘best practice’ considerations for inmethods vivo QTfor studies, including discussion drug exposures to test heart rate, correct useand in hERG safety margin, or the stimulation constitutes an adequate appropriate drug exposures to test heart rate, correct methods for animal ECG studies, assessment of assay sensitivity and the precision of the measurements, including discussion of appropriate drugof exposures toand testthe heart rate, correct methods in animal ECG studies, assessment of assay sensitivity precision ofprotocols the discusses measurements, and thatfor areuse required) would be very instrumental towards use presentation in animal ECG studies, assessment assay sensitivity thequestion the of the data in reports (Table 4). Finally, the and fourth principles animal ECG studies, assessment of assay sensitivity and the precision of the measurements, and standardising the design and conduct of ion channel studies precision of the measurements, and the presentation of the data in the presentation of the data in reports (Table 4). Finally, the fourth question discusses principles of proarrhythmia models, and how proarrhythmia risk assessment models might be used in the the presentation ofmodels, the dataand in reports (Table 4).discusses Finally, the fourthmodels question discusses principles across sponsors and commercial laboratories. Additional details reports (Table 4). Finally, the fourth question principles of proarrhythmia how proarrhythmia risk assessment might be used in the context of an integrated assessment of proarrhythmia risk. of proarrhythmia models, and risk assessment models might used the about inbe vivo QTinstudies, including specifics about sample size, proarrhythmia models, andhow howproarrhythmia proarrhythmia risk assessment context of an integrated assessment of proarrhythmia risk. drug exposure requirements, ECG collection and measurement models might be used in the context of an integrated assessment of context of an integrated assessment of proarrhythmia risk. Table 4: Best Practices for in vivo QT Studies discussed in Question 3 methods, requirements for demonstration of assay sensitivity, and proarrhythmia risk. for in vivo QT Studies discussed in Question 3 Table 4: Best Practices Table 4: Best guidelines as to what constitutes a ‘negative’ in vivo QT study, Appr o p r i a t ePractices s pe c i e s for in vivo QT Studies discussed in Question 3 A p p r o p r i a t e s p e c i e s would also be welcome. Specific details would help standardise Te l e me t e r e da ni ma l s , a ne s t he t i z e da ni ma l s , pa c i ng A p p r o p r i a t e s p e c i e s T e l e m e t e r e d a n i m a l s , a n e s t h e t i z e d a n i m a l s , p a c i n g the design and performance of such trials and would be extremely Re q ui r e ddr uga ndme t a b o l i t ee x po s ur e s T e l e m e t e r e d a n i m a l s , a n e s t h e t i z e d a n i m a l s , pa c i ng R e q u i r e d d r u g a n d m e t a b o l i t e e x p o s u r e s helpful for sponsors who wish to understand if the non-clinical Me t ho dst oc o r r e c tQTf o rhe a r tr a t e R e q u i r e d d r u g a n d m e t a b o l i t e e x p o s ur e s data that they have collected are of adequate standard to be Me t h o d s t o c o r r e c t Q T o r h e a r t r a t e Es t a b l i s h m e n t o f a s s a yf s e n s i t i v i t y Me t h o d st o c o r r e c t Q T f o r h e a r t r a t e used to support an integrated assessment of proarrhythmia E s t a b l i s h e n t o f a s s a y e n s i t i v i t y St a n d a r dm sf o r p r e s e n t i ns g d a t a E s t a b l i s h m e n t o f a s s a y s e n s i t i v i t y risk. In its current state, the S7B Q&A contains enough specific St a nda r dsf o rpr e s e nt i ngda t a St a nda r d s f o r p r e s e n t i n g d a t a details to allow sponsors to identify some of their non-clinical Table 4: Best Practices for in vivo QT Studies discussed in Question 3 cardiac data as inadequate to support an integrated assessment Discussion of proarrhythmia risk. However, it does not contain the level of Current FDA practice has been to request a TQT study with detail that is required for a sponsor to be confident that their nona positive control in cases where very high concentrations clinical cardiac safety data are adequate. cannot be, or have not been, achieved in e.g., the FIH study. The proposed change in Q&A 5.1 will therefore, to some extent, Hopefully, this first Q&A for ICH S7B will lead to further lower this requirement, i.e., decrease the number of TQT detailed recommendations about ‘best practices’, similar to the studies, and enable acceptance of robust high-quality ECG data, example of the ICH E14 2015 Q&A document. This Q&A was using C-QTc analysis, supplemented by non-clinical data, to released in December 2015 and contained a high-level discussion demonstrate that the drug does not cause clinically relevant QT of how concentration response modelling of QTc data might prolongation. As the text is written, this applies only to drugs for be used as an alternative to the standard by timepoint analysis which sufficiently high concentrations cannot be obtained and utilising the Intersection Union Test as a primary endpoint for a QT the revised text then gives a path forward without performing a study. While this was enthusiastically received, the level of detail stand-alone TQT study. In this context, it should be emphasised was not sufficient to completely inform the design and analysis of that when C-QTc analysis is applied to data, high concentrations QT studies. In 2017, members of the FDA and industry published are key for the ability of C-QTc analysis to detect small QTc a ‘Scientific white paper on concentration-QTc modeling’ that effects, and thereby increase confidence in the data. It therefore described many of the elements required for a successful earlyseems important to restrict 5.1 to those cases where sufficiently phase QT study7. Hopefully, more details about the new ICH high concentrations cannot be obtained, rather than broadly revisions will follow quickly, enabling drug developers to take advantage of the new pathways described by the E14 5.1 and 6.1 applying these criteria. www.jforcs.com

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pathways. A step towards this will be the planned training material on the S7B Q&As, which the ICH Implementation Working group will release over the next year. REFERENCES 1. 2. 3.

6. 7.

ICH E14 Questions & Answers (R3) December 10. 2015. Darpo B, and Garnett C. Early QT assessment--how can our confidence in the data be improved? Br J Clin Pharmacol. 2013;76(5):642-8. Darpo B, Garnett C, Keirns J, and Stockbridge N. Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14. Drug Saf. 2015;38(9):773-80. Darpo B, Sarapa N, Garnett C, Benson C, Dota C, Ferber G, Jarugula V, Johannesen L, Keirns J, Krudys K, et al. The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?". Ann Noninvasive Electrocardiol. 2014;19(1):70-81. Timmers M, Sinha V, Darpo B, Smith B, Brown R, Xue H, Ferber G, Streffer J, Russu A, Tritsmans L, et al. Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration-QTc Analysis. J Clin Pharmacol. 2018;58(7):952-64. S7B IHTG. 2005. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, Mehrotra D, Riley S, Sager P, Tornoe C, et al. Scientific white paper on concentrationQTc modeling. Journal of pharmacokinetics and pharmacodynamics. 2018;45(3):383-97.

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Dr. Robert Kleiman Dr. Robert Kleiman is a board-certified cardiologist and cardiac electrophysiologist who has performed research in both basic cellular electrophysiology as well as clinical electrophysiology. Dr. Kleiman completed his training at the University of Pennsylvania and was a member of a cardiology practice for 12 years before joining ERT in 2003. Dr. Kleiman is currently ERT’s Chief Medical Officer and Vice President, Global Cardiology. His responsibilities include oversight of ERT’s cardiology services, consulting with external clients and managing overall satisfaction of ERT’s global customers, including all aspects of ERT’s solutions.

Borje Darpo As ERT’s Chief Scientific Officer, Borje Darpo, MD, PhD oversees ERT’s cardiology services and consults with external customers to ensure the cardiac safety of their compounds in development. He is board-certified in cardiology and internal medicine and has 20 years of experience overseeing projects across all phases of clinical development.

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