JCS Volume 14 Issue 2 by Senglobal

Volume 14 Issue 2

Journal for Clinical Studies PEER REVIEWED

Personalised Medicine and Clinical Studies The Attempt to Untie a Gordian Knot A Long but Worthwhile Wait for Vitiligo Treatments Six Ways the Shift to Digital Will Redefine Product Development in 2022 Growing the Pool of Clinical Research Investigators in Malaysia

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Contents 4 FOREWORD WATCH PAGES 6

Journal for Clinical Studies MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT info@senglobalcoms.com EDITORIAL MANAGER Beatriz Romao beatriz@senglobalcoms.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Jessica Chapman jessica@senglobalcoms.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Senglobal Ltd. Unite 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.journalforclinicalstudies.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by Senglobal Ltd.

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 14 Issue 2 March 2022 Senglobal Ltd.

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Achieving Diversity and Inclusion in COVID-19 Vaccination Trials

Moderna’s COVID-19 mRNA vaccine trial was one of the most diverse clinical trials in history. LaQuinta Jernigan, Executive Vice President for the Americas at mdgroup and Jameka Hill, Director of Patient Engagement and Advocacy and Clinical Trial Diversity at Moderna, discuss why diversity in vaccine trials matters, the ways Moderna achieved diversity and inclusion, and the lasting legacy of this commitment to diversity within the clinical research industry. 8

A Long but Worthwhile Wait for Vitiligo Treatments

The drug development landscape for vitiligo is sparse despite its social impact on individuals irrespective of race, ethnicity, or gender. Sometimes dubbed a “cosmetic condition,” years of research suggest vitiligo is an autoimmune disorder that could be triggered by an event (e.g., sunburn, illness, stress) or linked to specific genes. Jaime Polychrones at Clarivate, explores more about the lack of treatments that are approved by the US Food and Drug Administration (FDA) for repigmentation of vitiligo lesions. REGULATORY 10 Accelerating the Transformation of Healthcare through Open-Source Algorithms Wearables have the potential to transform healthcare. They can help to inform timely, data-driven interventions. But validating each new digital measure is time-consuming, intensive, and complex. Using open-source algorithms can dramatically streamline this process. Geoffrey Gill at OWEAR, describes examples of how wearables can improve healthcare; the challenge of adopting wearables in medical applications; and the benefits of and barriers to using open-source algorithms in wearables. 14 Six Ways the Shift to Digital Will Redefine Product Development in 2022 This past year has seen life sciences companies settle into new operating models and digital ways of working, many of whom have come to realise that a return to the pre-COVID-19 days is no longer a necessity. The innovations and advancements achieved over the last year have paved a path toward long-term change across research and development. Rik Van Mol at Veeva Vault R&D shows six ways the shift to digital will redefine product development in 2022. 16 Overcoming the Challenges of Obtaining Informed Consent During the Pandemic The COVID-19 pandemic created a public health emergency that has had a profound impact on all aspects of the clinical trial industry. Quarantine requirements, and limited access to hospitals and clinics made it very difficult for investigators and site staff to conduct inperson informed consent discussions with potential clinical trial participants. It was also hard to identify and contact participants’ legally authorised representatives (LARs), when they were unable to provide consent themselves. Heather Kim at WCG IRB, discusses that industry transition and address some of the questions and issues it provoked. Journal for Clinical Studies 1

Contents 20 Why Risk-Based Quality Management Represents the Future of Clinical Research By empowering researchers to detect data quality issues in realtime, Risk-Based Quality Management (RBQM) and Risk-Based Monitoring (RBM) have proven their value during the race for a COVID-19 vaccine in which trials required the processing of huge volumes of data from dozens of global sites. RBQM is now driving significant changes throughout clinical research, helping to speed up the drug development pathway without compromising data quality while ensuring early risk detection remains a priority. Patrick Hughes at CluePoints, outlines why RBQM is the future-proofed solution to managing risk for the entire clinical trial life cycle – and how the benefits for clinical research can be fully unlocked. MARKET REPORT 22 Growing the Pool of Clinical Research Investigators in Malaysia The Malaysian government has continuously strived to improve and expand its clinical research ecosystem for the past ten years. The primary goal is to provide a competitive landscape with internationally recognised clinical trial hubs as more pharmaceutical companies continue shifting their clinical trial bases to Asia. Nur Ain Amir, Cheng Shu Hui and Audrey Ooi at Clinical Research Malaysia focus on the current status of Malaysian investigators and the future perspectives for CRM and the MoH in growing the country’s clinical investigators pool. THERAPEUTICS 26 Personalised Medicine and Clinical Studies – The Attempt to Untie a Gordian Knot Classical drug development is undoubtedly indication- and productdriven. Simply put, a preclinically developed substance is optimised for clinical application in an appropriate galenic preparation and, in the best case, brought to market maturity in various phases of clinical development. Sven Engel at SynapCon GmbH talks more about personalised medicine. 30 Psychedelics on Trial: Blinding and Therapeutic Setting Key to Success Steffanie Wilson at The Emmes Company affirms that both public and medical opinion is changing quickly and substances that were once regarded as ‘party drugs’, psychedelics such as MDMA, LSD and psilocybin (the active ingredient found in magic mushrooms) are now being studied increasingly as potential treatments for a number of different neuropsychiatric disorders including PTSD, intractable depression and alcohol addiction. TECHNOLOGY 34 Artificial Intelligence in Clinical & Medical Research While clinical trials have become lengthy and very costly with low success rates, the application of innovative artificial intelligence (AI)based approaches has been recognised for its potential to transform the slow and expensive current approach to clinical trials into a more cost-effective process with higher success rates. Dana Jasek and Luis Olmos will describe novel AI-based approaches that are currently being developed and implemented in clinical trials, provide regulatory considerations, and make some final remarks on the near future of AI-driven clinical trials. 2 Journal for Clinical Studies

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Foreword Personalised medicine can be defined as the adaptation of medical treatments to the specific characteristics of patients. This approach allows health providers to develop therapies and interventions by taking into account the heterogeneity of illnesses and external factors such as the environment, patients’ needs, and lifestyles. In recent years, the field of personalized medicine has greatly expanded and has attracted great interest not only among professionals but also from the general public. Classical drug development is undoubtedly indication- and product-driven. Simply put, a preclinically developed substance is optimised for clinical application in an appropriate galenic preparation and, in the best case, brought to market maturity in various phases of clinical development. Sven Engel at SynapCon GmbH talks more about personalised medicine. Vitiligo is characterised by the selective loss of melanocytes which results in typical nonscaly, chalky-white macules. In recent years, considerable progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Vitiligo is often dismissed as a cosmetic problem, although its effects can be psychologically devastating, often with a considerable burden on daily life.

speed up the drug development pathway without compromising data quality while ensuring early risk detection remains a priority. Patrick Hughes at CluePoints outlines why RBQM is the futureproofed solution to managing risk for the entire clinical trial life cycle – and how the benefits for clinical research can be fully unlocked. The Malaysian government has continuously strived to improve and expand its clinical research ecosystem for the past ten years. The primary goal is to provide a competitive landscape with internationally recognised clinical trial hubs as more pharmaceutical companies continue shifting their clinical trial bases to Asia. Nur Ain Amir, Cheng Shu Hui and Audrey Ooi at Clinical Research Malaysia focus on the current status of Malaysian investigators and the future perspectives for CRM and the MoH in growing the country’s clinical investigators pool. I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals. Beatriz Romao, Editorial Manager Journal for Clinical Studies

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Hermann Schulz, MD, Founder, PresseKontext

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Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA

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

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Bakhyt Sarymsakova – Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Catherine Lund, Vice Chairman, OnQ Consulting

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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Deborah A. Komlos, Principal Content Writer, Clarivate

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

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

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

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

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Stefan Astrom, Founder and CEO of Astrom Research International HB

Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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4 Journal for Clinical Studies

Volume 14 Issue 2

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Achieving Diversity and Inclusion in COVID-19 Vaccination Trials Moderna’s COVID-19 mRNA vaccine trial was one of the most diverse clinical trials in history. LaQuinta Jernigan, Executive Vice President for the Americas at mdgroup and Jameka Hill, Director of Patient Engagement and Advocacy and Clinical Trial Diversity at Moderna, discuss why diversity in vaccine trials matters, the ways Moderna achieved diversity and inclusion, and the lasting legacy of this commitment to diversity within the clinical research industry. COVID-19 has had a disproportionate impact on people of color. In the US, Black people have been infected at nearly three times the rate of White Americans and were twice as likely to die from the virus, according to a report by the National Urban League.1 As well as a lack of health infrastructure and vaccine hesitancy in some states,2 vaccine accessibility disproportionately affects lowincome people of color. This heavy toll on people of color means it was more important than ever for COVID-19 vaccine trials to increase inclusion. There needed to be a step change in thinking and a prioritisation of diversity. Over the past 18 months we have seen greater use of community outreach, a recognition of the need to prioritise public education and increased awareness of the need to build community demographic knowledge and goals at a site level. Now, we need to extend these diversity-first approaches throughout the clinical trial space and empower patients from every demographic to take part in research. A Diversity-First Approach COVID-19 was the catalyst for taking a diversity-first approach for Moderna. From the beginning of Moderna COVID-19 mRNA vaccine trials, the research team wanted to make sure people from all backgrounds were aware of the opportunity to enroll and began forward planning how the team would navigate barriers to participation. Diversity is about more than just race. True diversity takes into account age and gender, job role, economic status, physical and mental health. Historically, most clinical trials are comprised of middle-aged white men living in coastal regions. To address this imbalance, benchmarks must be set from the outset of trial design to make sure, for example, there are representative female to male ratios. We also need to look at how people with underlying conditions and of a range of ages can be represented. A strategic approach, adopted at the core of clinical trials and led by empathy and understanding, is key to success and greater health 6 Journal for Clinical Studies

equity. Equitable access to treatments and improved outcomes must begin with clinical research. Pausing Enrolment to Ensure Diversity Enrolling participants onto a study and ensuring a diverse patient population have often been seen as mutually exclusive. However, working closely with trial sites can ensure diversity is equally prioritised alongside enrolment. In September 2020, Moderna decided to slow enrolment to its COVID-19 mRNA vaccine trials when it appeared sites were failing to recruit enough Black, LatinX and Native American participants. Sites had begun enrolling patients so quickly they were no longer hitting diversity goals. Moderna paused enrolment and reassessed the patient recruitment strategy. Enrolment was then able to restart at pace while ensuring diverse populations were represented. This demonstrates the importance of setting goals for sites upfront. They should have access to information about the demographics of their community and a clear understanding of what they need to contribute, along with other sites, to ensure research involves a mosaic of our diverse society. Working with Communities To ensure full and fair representation of diverse communities, local community leaders should be involved in clinical trial development from the outset. Historically, there has not been much awareness or understanding of clinical trials among the general public, particularly in diverse populations. We need to understand the questions people may have around participation, as well as individual and collective fears if we are to increase diversity. The significant efforts of local advocacy and community organisations have boosted recruitment efforts by engendering trust within communities and helping people raise their hand. However, increased public awareness of clinical research has also highlighted huge gaps in knowledge and understanding and raised the importance of widespread healthcare education. The onus is now on the clinical industry and governments to make clinical research awareness a public health initiative. This has been particularly important for the Moderna vaccine which uses technology typically misunderstood by the general public. Misunderstanding can lead to mistrust but there are simple solutions. For example, accessible information and videos on the basic mechanism of how mRNA works in the body and how it differs from traditional vaccines is available on the Moderna website. Volume 14 Issue 2

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Site Experience Pharmaceutical companies need to work closely with sites to ensure all participants feel comfortable and accepted. When we think about COVID-19 and what is polarising people, news topics are at the heart of that. Simple fixes, like turning on a cooking show or something that is non-political in site waiting areas, can have a huge impact. People want to be sensitive but historically sites lack confidence to work with and engage different groups. Enabling them to work with organisations which are already amplifying the patient voice can help build this confidence. People Over Profit The Moderna COVID-19 trials have communicated a key message to the industry and world at large – healthcare is for everyone. The learnings around diversity, accessibility and inclusion can be used to make considerable contributions to the future of medicine. There is still much to be done. Of the 57% of Americans who have had at least one dose of the COVID-19 vaccine,3 where ethnicity data is available, only about 15% are Hispanic and 9% are Black – both lower rates than their proportion of the US population. To address these challenges and, as we move through the pandemic, we need to see the continuation of patient-first approaches to clinical trial design, and the commitment of research institutions to www.journalforclinicalstudies.com

create diverse and inclusive strategies that result in true healthcare equity. REFERENCES 1. 2. 3.

https://soba.iamempowered.com/2020-report https://www.theguardian.com/world/2021/jun/12/black-latino-leftbehind-covid-19-vaccines https://covid.cdc.gov/covid-data-tracker/#vaccination-demographic

LaQuinta Jernigan As the head of North America, LaQuinta brings a wealth of healthcare knowledge and expertise in building sustainable, strong commercial relationships. By listening carefully to each client’s challenges, concerns and goals, LaQuinta works with them to find effective solutions. With a life sciences career spanning operations and sales, she has a balanced perspective: she knows what it takes to bring a product to market on time, retain patients and do so within budget, while putting the patient at the heart of what we do. Enthusiastic and energetic, LaQuinta is motivated by a desire to improve the patient experience by removing any challenge that could impact their quality of life during a clinical trial. For her, being part of mdgroup is about more than selling a service: it’s about focusing on lasting and productive partnerships that always put the patient first.

Journal for Clinical Studies 7

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A Long but Worthwhile Wait for Vitiligo Treatments The drug development landscape for vitiligo is sparse despite its social impact on individuals irrespective of race, ethnicity, or gender. Sometimes dubbed a “cosmetic condition,” years of research suggest vitiligo is an autoimmune disorder that could be triggered by an event (e.g., sunburn, illness, stress) or linked to specific genes. Approximately 25–50% of people diagnosed with vitiligo have a relative with the condition.1 Individuals with this disorder may be more predisposed to having other autoimmune disorders as well, such as Addison’s disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, thyroid disease, and type 1 diabetes. The cause for vitiligo is unknown. Vitiligo is a chronic disorder in which the skin loses its pigment cells (melanocytes), resulting in a “milky-white color,” according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH).2 These cells produce melanin; when they die or no longer make melanin, patches of white slowly grow on the skin in irregular shapes. Vitiligo is classified into two types: 1.

Nonsegmental (or generalised), the most common type of vitiligo. This type is characterised by white patches that appear symmetrically on both sides of the body (i.e., on both hands, on both knees). Nonsegmental vitiligo can develop rapidly, resulting in loss of pigment over a large area. Segmental vitiligo. This form of vitiligo is less common and occurs when white patches appear only on one segment or side of the body. Segmental vitiligo usually begins at an early age, progressing for approximately 1–2 years and typically stopping.

Worldwide, 70 million people are diagnosed with vitiligo, according to the Global Vitiligo Foundation.3 In 2020, vitiligo prevalence (diagnosed and undiagnosed) in the US was estimated at approximately 0.76% (1.9 million) to 1.11% (2.8 million individuals), and approximately 40% of vitiligo cases in adults may be undiagnosed.4 There are no available treatments that are approved by the US Food and Drug Administration (FDA) for repigmentation of vitiligo lesions. Monobenzone, an FDA-approved therapy for patients with vitiligo, is no longer on the market and was indicated for final depigmentation. Patients seek treatment for vitiligo to slow or stop disease progression, encourage melanocyte regrowth, and restore colour to the affected skin area. Treatments include corticosteroids, calcineurin inhibitors, vitamin D analogs, phototherapy, and surgical procedures, such as skin or blister grafting. Bringing Vitiligo to Light A year has passed since the FDA engaged patients in a full-day discussion about their perspectives on vitiligo – its effects on their overall health and well-being, their experiences using treatments, and challenges to accessing medical treatments. In March 2021, the agency held a public workshop as part of its patient-focused drug development (PFDD) initiative to ask patients about living with vitiligo. 8 Journal for Clinical Studies

In December 2021, the FDA published The Voice of the Patient, a publication resulting from the March 2021 workshop that summarised the discussions at the meeting.5 Some patients noted experiencing “severe emotional distress,” social isolation and stigma, and impacts on relationships and identity due to their vitiligo. They also highlighted a need for further research into the causes of vitiligo and treating the “underlying pathology.” Meeting participants and individuals who submitted comments to the FDA docket agreed that the “ideal treatment effect” would be permanently regaining pigment and stopping the spread of additional depigmentation. Drug Development for Vitiligo In the US, a few products are nearing the end stages of research into treating vitiligo. Three Janus kinase (JAK) inhibitors have reached phases 2 or 3 of clinical development, and one monoclonal antibody is in phase 2. The end goal with these treatments is to stop depigmentation and provide repigmentation that is lasting. Ruxolitinib Incyte Corporation has developed ruxolitinib, a JAK1 inhibitor approved by the FDA in September 2021 under the trade name Opzelura for an atopic dermatitis indication. In December 2021, the FDA accepted a supplemental new drug application (sNDA) for ruxolitinib cream for the treatment of individuals aged ≥12 years with vitiligo and granted it priority review with a Prescription Drug User Fee Act (PDUFA) target action date of April 18, 2022.6 If the FDA approves the sNDA, ruxolitinib could be the first US-marketed treatment for vitiligo that helps to restore pigmentation. Incyte is evaluating the safety and efficacy of ruxolitinib cream in a phase 3 clinical program (TRuE-V) in >600 subjects aged ≥12 years with nonsegmental vitiligo. In 2 studies, the primary endpoint is the proportion of patients achieving ≥75% improvement from baseline in the facial Vitiligo Area Scoring Index (F-VASI75) at week 24. Results announced at the 30th European Academy of Dermatology and Venereology (EADV) Congress noted that 29.9% of patients who used ruxolitinib cream achieved 75% improvement from baseline in the F-VASI75. INCB054707 Incyte is also evaluating the safety and efficacy of INCB054707, another JAK1 inhibitor in the company’s pipeline, in a randomised, double-blind, placebo-controlled, dose-ranging phase 2 study followed by an extension period in >160 subjects with vitiligo. The primary endpoint is the percentage change in total VASI (T-VASI) at week 24. The estimated study completion date is January 2023. Upadacitinib Marketed in the US as Rinvoq, upadacitinib is a JAK1 inhibitor from AbbVie Inc indicated to treat rheumatoid arthritis, active psoriatic arthritis, and atopic dermatitis. The agent is under evaluation for the treatment of nonsegmental vitiligo in a multicenter, randomised, double-blind, placebo-controlled dose-ranging phase 2 study in >150 subjects with vitiligo. Participants will be placed in two of five treatment arms, and the primary endpoint is the percent change from baseline in F-VASI at 24 weeks. The estimated study completion date is December 2023. Volume 14 Issue 2

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AMG-714 The NIH’s National Institute of Allergy and Infectious Diseases (NIAID), along with collaborators, including Amgen Inc, is evaluating AMG-714, a human IgG1-kappa anti-interleukin-15 (IL-15) monoclonal antibody, for the treatment of vitiligo in a double-blind, placebo-controlled, multicenter, proof-of-concept phase 2a study (REVEAL). The primary endpoint is the proportion of participants achieving facial VASI ≥35 (F-VASI35) at week 24. The study is estimated to complete in March 2023. Filling an Unmet Need For many people, white patches begin to appear before the age of 20, but vitiligo can develop early in childhood. While it is not life threatening and does not affect general functioning, it can have psychological effects. The skin discoloration can contribute to low self-esteem or poor quality of life and can increase the risk for sunburn. Almost half (46%) of respondents in the Vitiligo and Life Impact Among International Communities (VALIANT) study considered daily administration of their vitiligo burdensome to their lives.7 The next few years could address this treatment void and lead to future breakthroughs in understanding the origin of vitiligo. REFERENCES 1. 2. 3.

Vitiligo. Genetic and Rare Diseases Information Center (GARD) Website. https://rarediseases.info.nih.gov/diseases/10751/vitiligo Vitiligo. National Institute of Arthritis and Musculoskeletal and Skin Diseases Website. https://www.niams.nih.gov/health-topics/vitiligo Vitiligo Facts. Global Vitiligo Foundation Website. https://globalvitiligo

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5. 6.

foundation.org/vitiligo-facts/ Gandhi K, Ezzedine K, Anastassopoulos KP, et al. Prevalence of vitiligo among adults in the United States. JAMA Dermatol. 2022;158(1):43-50. http://doi.org/10.1001/jamadermatol.2021.4724 The Voice of the Patient. (2021). US Food and Drug Administration. https:// www.fda.gov/media/155068/download Incyte Announces Acceptance and Priority Review of sNDA for Ruxolitinib Cream (Opzelura) as a Treatment for Patients with Vitiligo. (2021). Incyte. https://investor.incyte.com/press-releases/press-releases/2021/IncyteAnnounces-Acceptance-and-Priority-Review-of-sNDA-for-RuxolitinibCream-Opzelura-as-a-Treatment-for-Patients-with-Vitiligo/default.aspx Vitiligo impacts mental health, quality of life. (2022). MyStress. https:// ohmystress.com/2022/01/26/vitiligo-impacts-mental-health-quality-oflife/

Jaime Polychrones Jaime Polychrones is a Senior Content 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, government proposals, 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

Journal for Clinical Studies 9

Regulatory

Accelerating the Transformation of Healthcare through Open-Source Algorithms Abstract: Wearables have the potential to transform healthcare. They can help to inform timely, data-driven interventions. But validating each new digital measure is time-consuming, expensive, and complex. Using open-source algorithms can dramatically streamline this process. This approach creates a plug-and-play dynamic where, with reference to the V3 framework, a wearable need only be verified, if the relevant algorithm has already satisfied analytical and clinical validation. GGIR and Sleep.Py are two examples of open-source algorithms. Barriers to this approach must be overcome; adjacent opportunities pursued, so that open-source algorithms can pave a way to widespread endpoint development in a reasonable time frame and at a reasonable cost. Today’s wearable sensors can collect continuous and objective medical quality data. This data has the potential to transform healthcare from reactively treating sickness to proactively preventing it. If the technology exists, why is it not in widespread use? The short answer is that this technology must be applied very carefully and each use must be validated. For example, one study by the Mayo Clinic found that 85% of the people diagnosed with Afib by the Apple Watch did not have it.1 Widespread use of such a tool could create much unnecessary concern among patients and significant overuse of expensive medical resources. Adoption of open-source algorithms has the potential to dramatically streamline the validation process. The benefits of doing so accrue to both patients and healthcare companies because this approach complements – and enhances – the proprietary development of medicines and devices. To expound on this logic, we describe examples of how wearables can improve healthcare; the challenge of adopting wearables in medical applications; and the benefits of and barriers to using open-source algorithms in wearables. Proactive Prevention Through Wearables Wearable sensors take a variety of measurements that can potentially inform proactive intervention before the onset of more debilitating symptoms. For example, Chronic Heart Failure (CHF) is a growing problem costing $30–50 billion annually in the U.S. A wearable device can monitor a patient’s activity, posture, electrocardiogram (ECG), thoracic impedance – that is, respiration and, potentially, fluid in the lungs.2 This data can potentially identify the need for intervention before hospital readmission becomes necessary. If so, the patient’s quality of life improves and their economic burden is reduced. Another even more costly example is falls: the second leading cause of global unintentional injury deaths, according to the United Nations.3 Annually, falls cost $50 billion or more in the US alone. Yet wearables have the potential to identify people at risk for falls and appropriate exercise interventions can reduce the rate of serious falls by approximately 50%.4 10 Journal for Clinical Studies

Diabetes illustrates what can be done and the need to accelerate the process of developing these solutions. Diabetes can potentially be managed with what is effectively an artificial pancreas: a closed loop system comprising continuous glucose monitoring and an insulin pump. Steps in this direction have already improved patient outcomes and quality of life – taking us further down the path of development and real-world application than other wearable technologies. It has taken too long however. The glucose test was developed in 1908; in 1965, the glucose test strip. In 1999, the continuous glucose monitor was developed; in 2016, the semiautomatic artificial pancreas.5 We still await a truly automated artificial pancreas. It is clear that these technologies have the potential to improve both patient health AND healthcare costs. Why, then, does it take so long? The Process of Adopting Wearables Broadly speaking, the process of adopting wearables for treating disease may be broken down into 4 steps. First, you must measure something of interest (taking 2 months–2 years). Second, you must validate that this measure appropriately tracks the progression of a disease in a target population (3–4 years). Third, you must determine a clinical protocol, demonstrating what the intervention should be, when it should be triggered, what outcomes are to be expected—all optimised for patient health and healthcare economics (3–4 years). Fourth, this must be integrated into a jurisdiction’s healthcare system, each one different from the next (1–2 years). In theory, this process could take as little as 8–12 years; in practice, it is much longer. It requires a lot of work. But could big data and artificial intelligence (AI) automate large swathes of this process, just as they have done in other areas? In reality, these techniques address only the first step. Machine learning techniques can rapidly identify unlikely connections within the data to discover measures of interest. A good data scientist can construct such models in as little as a couple of months. But collecting the data is more time-consuming and issues such as insufficient data and incomplete data also plague big data and AI techniques. Readily available data such as that from consumer wearables typically provides only processed outcomes (like step counts). Much of the information in the signal is removed and it does not have any independently verifiable data, dramatically limiting its potential benefit. Even then, AI and big data techniques do not address steps 2–4 of the process outlined opposite. Rather than trying to build more complete, closed-loop, treatment systems like an artificial pancreas, we believe early adoption of wearables will be in clinical trials. To be valuable for use in clinical trials, the wearable needs only assess whether the treatment being tested is working. In other words, Volume 14 Issue 2

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to get to the second step – validation that the algorithm is tracking the disease progression. The use of wearables within clinical trials potentially confers many benefits, such as providing more accurate endpoints, enabling faster trials, potentially with fewer participants, and improved safety. They could also be employed in virtual or decentralised trials. Furthermore, using open-source algorithms in those wearables could dramatically streamline the progression to step 2.

produces accurate sample-level data. The second component is analytical validation: ensuring that the algorithms convert the sensor data into physical phenomena, such as steps. The third component is clinical validation: evaluating whether the physical phenomenon meaningfully tracks a relevant aspect of the patient’s health.7

The Challenges of Validation Validating that a measure appropriately tracks the progression of a disease is, itself, a long and complex procedure. This process has been articulated using various frameworks in part or in whole. For instance, the Clinical Trials Transformation Initiative (CTTI) has helpfully set out a 13-step novel endpoint development guide.6 Each step is accompanied by detailed guidance.

And herein lies the challenge: every combination of wearable, its proprietary algorithm, and resulting endpoint (or endpoints) must be qualified for each disease symptom AND each population of interest. There are hundreds of wearables, each with their own proprietary algorithms. Even a different version of an algorithm generates a different endpoint. Try conducting a simple experiment by placing two different versions of the same smartphone in your pocket. The steps measured by each device will likely be different. The possible combinations of wearables, their proprietary algorithms, and resulting endpoints, for different diseases, are in the millions. The work of validating them all is tremendous.

Another approach is the V3 framework championed by the Digital Medicine Society (DiMe), which is considered here. Its first component is verification: demonstrating that the wearable sensor

An Illustrative Example Suppose the disease in question is atopic dermatitis, which involves a chronic inflammation of the skin. A wearable may produce a

www.journalforclinicalstudies.com

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measure that tracks the progression of this disease. When evaluating the first component in the V3 framework, verification, you may demonstrate that the wearable produces accurate accelerometer data. Next, analytical validation: you then prove that its algorithm applied to the data accurately derives, say, nocturnal scratching (as opposed to a light brush, or typing on a smartphone, or some other physical phenomena). Finally, clinical validation: you evaluate the specific, algorithmically derived measure of nocturnal scratching (i.e., endpoint) for its meaningful relevance to a patient with atopic dermatitis. Only then, will you have qualified the sensor to measure this symptom of atopic dermatitis. In addition, regulatory approval must be sought. All in all, validation is an intensive undertaking. How, then, might we simplify and accelerate the adoption of wearables? Streamlining the Validation Stage Taking an open-source approach to algorithms for wearables can streamline the validation step without losing any of its rigor. When an algorithm is made publicly available, the inputs it requires are known. Wearable manufacturers can engineer or configure devices to produce these inputs. This establishes a plug-and-play dynamic, where the adoption of a new wearable may not necessarily entail plodding along the same analytical and clinical validation paths. If a relevant algorithm has already satisfied the analytical and clinical validation criteria, all that’s left for the validation of a new digital measure is 12 Journal for Clinical Studies

verification, by manufacturers, to confirm that the wearable produces the right sample-level data. Transparency is key: black box algorithms diminish interoperability and hinder this dynamic. An open-source repository of algorithms used in wearables gives healthcare companies a powerful box of tools to compare and choose from. They may also plug and play different wearables, depending on the changing needs of their study or wearable-enabled therapeutic. Existing algorithms and endpoints may be adapted to other diseases that share similar symptoms, rather than starting from a blank slate. Contributors benefit from their peers confirming the validity of their algorithms. Eventually, performant algorithms emerge. Furthermore, greater transparency and standardisation will assuage concerns of skeptical regulators down the line. The use of open-source algorithms offers a path to widespread endpoint development in a reasonable time frame and at a reasonable cost. The Open-Source Reality Open-source algorithms exist and are becoming more mainstream. Pfizer has been working on a nocturnal scratching algorithm, Sleep. Py, which has been made publicly available.8 Sleep duration, sleep efficiency, activity levels and a host of other endpoints may be calculated using an algorithm within the R-package called GGIR, which was developed by Dr. Vincent van Hees. GGIR is an opensource library of algorithms for wrist-based accelerometer data. It has Volume 14 Issue 2

Regulatory been used widely in academic and other research. More than 300 peer-reviewed articles have it listed in their references. That research base is growing at more than 100 studies per year.9 Hundreds of thousands of participants have been studied, across a wide variety of therapeutic areas and patient cohorts: cardiovascular conditions, obesity, ageing, mental health, diabetes, etc.10 GGIR is, arguably, the most studied package of wearable algorithms available today. Building on those advances, the Open Wearables Initiative or OWEAR was formed to facilitate the adoption of open-source algorithms used in wearables. Its website facilitates the listing of and access to algorithms and datasets.11 Many leading pharmaceutical companies, clinical research organisations, healthcare non-profits, and research consultants are participating in OWEAR and share this vision. As with any initiative, there are barriers to implementing an open-source approach and benefits from pursuing adjacent opportunities. Barriers to Open-Source Open-source initiatives often provoke the concern that developers may not be sufficiently incentivised to contribute. Scientists and academics are generally rewarded for discoveries and inventions. Doing the detailed documentation and collation to make the algorithm useful to a general population requires significant time and effort and is generally not rewarded in academia. Although we have found many academics willing to share their work, they cannot afford the time and effort to make it useful. In addition, a lack of standardisation may slow down the adoption of open-source algorithms. There is a tendency to invent new and better ways to perform the same tasks. Consequently, redundant algorithms may proliferate. But GGIR serves as an example of the tremendous benefits of having de facto standards for validation and acceptance. Despite these barriers, a significant volume of software has been moved to open source by individuals and leading organisations like Pfizer, Mobilise-D, and Novartis. Opportunities Beyond Open-Source Beyond open-source algorithms, there are several opportunities that, if pursued, would make fertile ground for the adoption of wearables. First, share data that already exists, and the task of developing and validating algorithms becomes easier. Tens of thousands of clinical trials and studies are being run. This generates vast volumes of high-quality data: detailed demographics, wearable sensor data, and outcomes data. Data sharing may, however, be met with a degree of hesitancy or hindered by competition, intellectual property, privacy and patient concerns. Second, collect raw data because this reaps many benefits. Raw data can feed into various open-source algorithms and endpoints, is device-independent, provides a measurement of noise, enables investigation of anomalies, facilitates comparisons between studies, and leaves open the possibility of updating algorithms. Third, the patient benefits of wearables can only be appreciated with a paradigm shift from population thresholds and averages to self-benchmarking. At Shimmer, we have conducted numerous studies using participants’ galvanic skin response (GSR), or changes in sweat gland activity, to measure their emotional response to different stimuli. These studies were conducted in laboratory conditions – so the data was as clean as one can get. Yet participants’ baselines may vary by a factor of 40 or more in the same study. Different people also www.journalforclinicalstudies.com

have different response levels. And despite the excellent conditions, there was still quite a bit of noise in the data. These observations are commonly found in other wearable sensor data. A standard approach of setting ranges and thresholds based on population norms and averages may not work. However, we can make sense of the data by benchmarking individuals against themselves and determining whether they are responding. Then we can calculate the percentage of participants responding at any given moment, perhaps, in response to stimuli or treatment. Summary We live in a world of wearables. In healthcare, wearables and other digital technologies have the potential to inform proactive, more timely interventions, improving patient quality of life and reducing costs. But the process of adopting wearables takes time. Validating measures produced by wearables for medical applications is particularly rigorous and complex. An open-source approach to algorithms used in wearables streamlines the validation stage. It establishes a plug-and-play dynamic—such that wearables need only be verified, if the relevant algorithm has already satisfied analytical and clinical validation, to produce a validated digital measure. Initiatives, such as OWEAR, already exist to foster such collaboration around endpoints and algorithms. The GGIR library is a foretaste of what can be done. Barriers to the adoption of an open-source approach need to be overcome, so that wearables in healthcare can become an everyday reality. REFERENCES 1.

2. 3. 4.

6. 7. 8.

9. 10.

11.

https://www.mobihealthnews.com/news/apple-watchs-abnormal-pulsefeature-driving-many-unnecessary-healthcare-visits-mayo-clinic, visited 31 Jan 2022. Shimmer internal analysis https://www.who.int/news-room/fact-sheets/detail/falls, visited 31 Jan 2022 El-Khoury, F., et al. The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults: systematic review and meta-analysis of randomised controlled trials. BMj, 347 (2013). Hirsch IB. Introduction: History of Glucose Monitoring. Role of Continuous Glucose Monitoring in Diabetes Treatment. Arlington (VA): American Diabetes Association, 2018 Aug. https://ctti-clinicaltrials.org/wp-content/uploads/2021/06/CTTI_Novel_ Endpoints_Detailed_Steps.pdf, visited 31 Jan 2022 https://www.dimesociety.org/tours-of-duty/v3/, visited 31 Jan 2022 Mahadevan, N et al. Development of digital measures for nighttime scratch and sleep using wrist-worn wearable devices. NPJ digital medicine, 4(1), 1-10 (2021). https://www.owear.org/ggir-airtabl, visited 31 Jan 2022 Migueles JH, Rowlands AV, et al. GGIR: A Research Community-Driven Open Source R Package for Generating Physical Activity and Sleep Outcomes From Multi-Day Raw Accelerometer Data. Journal for the Measurement of Physical Behaviour. 2(3) (2019). https://www.owear.org/open-algorithms, visited 31 Jan 2022

Geoffrey Gill Geoffrey Gill, MS, is President of Shimmer Americas, leading the U.S. operations and the commercial efforts for North and South America for Shimmer Research, a designer and manufacturer of medical-grade wearables. Geoffrey is also a Co-founder of the Open Wearables Initiative (OWEAR), an industry collaboration designed to promote the effective use of high-quality, sensor-generated measures of health in clinical research through the open sharing of algorithms and datasets.

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Six Ways the Shift to Digital Will Redefine Product Development in 2022 This past year has seen life sciences companies settle into new operating models and digital ways of working, many of whom have come to realise that a return to the pre-COVID-19 days is no longer a necessity. The innovations and advancements achieved over the last year have paved a path toward longterm change across research and development. Fueled with insights from having stronger and more reliable data, the industry will reach new levels of efficiency and speed to enable patient-centric care. Here’s how we see this becoming a reality in 2022 and beyond. Patient and Site Centricity Will Define the Future of Clinical Trials During COVID-19, the industry accelerated the adoption of decentralised trial capabilities to bring more study activities directly to patients. However, predictions that pharma would adopt an entirely virtual model that diminished research sites’ role has already been proven wrong. The industry is now moving toward a hybrid clinical trial model with some decentralised elements. Sites (and the investigator) will continue to play a central role as touchpoints for patient engagement and retention. As more clinical data is captured electronically, we’ll see faster, better-managed trials that accelerate the delivery of new therapies. In addition to more effective data management, greater patient and site centricity will drive further change in studies. Some of the decentralised clinical trials that ran in 2020 and 2021 weighed patients down by requiring the use of multiple digital applications, while research sites felt constrained with a multitude of point solutions that made it more challenging to manage trials. Now, as they work to reduce the technology burden on patients, more sponsors will minimise the digital applications and portals that they require sites to use. This will allow sites to spend less time on administrative tasks and more on patient safety and care. Drug Development Will Increasingly Depend on One Consistent Source of Information As research and development teams work to reduce the number of solutions they use, many realise the importance of maintaining high-quality data. In studies, as an example, patient information must be aggregated and cleaned if data from new sources, such as smartwatches and sensors, is to connect to clinical and clinical operations data. Companies that can’t do this will have to hurdle big challenges to learn from past events to improve operations. In the coming year, we expect to see more companies adopt data management applications that will automate and speed up this work by ingesting, aggregating, and cleaning data so that it’s easier to analyse, report on, and share. GSK1 and Novartis2 are among the companies focusing on data quality and moving toward real-time interactive dashboards, using a platform approach that simplifies the sharing of information. Instead 14 Journal for Clinical Studies

of just storing info in a data lake and then analysing it, this approach deals with the disparity of data and their sources, whether entered manually or sent from wearable devices. The result will be a single source of data that will deliver better cross-functional collaboration by enabling information to flow across different functions within drug development quickly. Artificial Intelligence Will Deliver Greater Efficiency Gains Across the Clinical Ecosystem The adoption of advanced electronic trial master file (eTMF) applications has quadrupled since 2014,3 shifting the industry from manual tasks to digital operations. This has fueled positive change in the industry and enabled organisations to manage their TMF more actively and optimise their processes. In 2022, artificial intelligence (AI) in TMF will help life sciences drive more efficiencies and strategic process improvements for long-term success. One leading clinical-stage biotechnology company applied AI within its eTMF to accelerate document processing. In doing so, they found that site management documents were frequently duplicated during the handoff between the site start-up team and the monitor’s first on-site visit after site activation. With AI to auto-classify documents, they could speed the processing of documents and deliver greater visibility across teams – lowering the risk of having duplicate records. AI offers tangible ways to improve day-to-day operations and replace transactional processes, like document classification, with strategic activities that support continuous improvement. We expect to see more stories around the effective application of AI in clinical research to enable flexibility and speed. Pharmacovigilance Transformation Accelerates Research and development may have been one of the last areas in the industry to modernise operations. However, the use of new processes, business models, and technology has had a major impact on clinical and regulatory management. Pharmacovigilance is now catching up as more companies reinvent case intake and processing while also meeting their document management needs. Safety departments are also taking a more proactive approach earlier in drug development and investigating new technologies for signal detection, analysis, and management. Automation and finding new ways to process data will be vital to improving patient safety and maintaining compliance in 2022. So will simplifying data management systems, their validation, and ongoing maintenance. We’ve seen a rapid increase in life sciences companies, from small visionaries to large enterprises, modernise pharmacovigilance data management4 to simplify safety operations. As tech modernisation continues, safety teams will focus on managing their end-to-end pharmacovigilance processes and data more holistically, in a more efficient and compliant way. Diagnostics and Pharma Form Stronger Partnerships for Personalised Treatment The genomics revolution is picking up as costs drop and disease Volume 14 Issue 2

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states expand, driving increased collaboration between genomics organisations and pharma companies. These partnerships will redefine precision medicine with innovative companion products (CDx) personalised for patients and therapeutic areas. As a result, companies will be able to identify risk of adverse events or opportunities to adjust treatments for higher efficacy much faster. With a collaborative, patient-centric model, the gathering and exchange of outcomes will be key for future advancements. This will lead to a shift toward more connected, digital landscapes that enable seamless and automated data exchange across stakeholders. European Regulatory Requirements Drive Significant Advancements in Operations The industry has been preparing for EU MDR and IVDR for almost five years, and still, additional work remains to ensure compliance once these regulations take effect. This is critically important as companies adapt to changing market conditions and growing global demand. As an example, an area in need of modernisation is claims management. Claims are continuing to get narrower and more specific. Companies should connect their regulatory and marketing content operations to adequately manage claims under these new requirements. Regulatory teams that benefit from running end-to-end claims management processes can drive quicker content reviews and approvals, better compliance, and increase insights into actionable data like claim usage and campaign performance. As the second’s tick closer towards the full implementation of EU MDR and IVDR, the industry will continue to strengthen their operations and establish a robust data foundation, improve connections across teams, and drive transparency into data and content. If companies can do this, they will be ready come implementation time. The Shift to Digital Speeds Innovation in Life Sciences With more change expected, an increasing number of life sciences companies are taking drastic steps to modernise their operations. www.journalforclinicalstudies.com

The industry is accelerating toward digital and connected systems5 to drive efficiency and speed across product development. The good news is that positive change is happening across R&D, supported by advanced technologies. This will help EU companies keep up with ever-changing market dynamics – from new regulatory changes like IDMP to increasing patient expectations – and fast-track the development and delivery of potentially life-changing products to the patients that need them. REFERENCES: 1. 2. 3. 4. 5.

https://www.veeva.com/gsk-puts-data-first-in-new-clinicalagility-benchmarks/ https://d4-pharma.com/digital-transformation-a-novartismini-review/ https://www.veeva.com/resources/clinical-operations-surveyreport-2020/ https://www.veeva.com/eu/resources/more-than-50companies-modernizing-pharmacovigilance-with-veeva-vaultsafety-suite/ https://journalforclinicalstudies.com/modernising-studymanagement-for-greater-visibility-and-speed-in-trials/

Rik Van Mol Rik Van Mol is the vice president of R&D strategy for Veeva Europe, responsible for the Veeva Vault R&D suite of applications with a focus on the European market. He has nearly 20 years' experience in business/ IT consulting and regulated content management in the Life Sciences/Pharmaceutical sector. His experience has been built in assisting clients through complex transformational programs across the Life Sciences value chain, including clinical, regulatory and manufacturing/supply chain areas, for some of the world's largest companies.

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Regulatory

Overcoming the Challenges of Obtaining Informed Consent During the Pandemic Synopsis The COVID-19 pandemic created a public health emergency that has had a profound impact on all aspects of the clinical trial industry. Quarantine requirements, and limited access to hospitals and clinics made it very difficult for investigators and site staff to conduct in-person informed consent discussions with potential clinical trial participants. It was also hard to identify and contact participants’ legally authorised representatives (LARs), when they were unable to provide consent themselves. The United States Food and Drug Administration (FDA) responded rapidly, supplementing its existing regulations covering informed consent with additional guidance to address the new realities facing sponsors, clinical research organisations, and sites. It also promptly published responses to frequently asked questions (FAQs) from the industry. This healthcare crisis hastened the clinical trial industry’s adoption of remote and e-consent approaches, creating challenges and benefits in the process. This article will discuss that industry transition and address some of the questions and issues it provoked. COVID-19’s impact started being felt in the clinical trial field in March 2020, when businesses and local governments began to shut down, and our Institutional Review Board (IRB) received an avalanche of questions about how to proceed not only with clinical trial conduct, but also interpreting the regulations in the context

16 Journal for Clinical Studies

of the pandemic. Fortunately, there were several existing and new resources that we could draw upon for reference. FDA’s Code of Federal Regulations (CFR) Title 21 Section 50.20 states that before investigators can involve a human being as a participant in research covered by those regulations, they must obtain “the legally effective informed consent of the subject or the subject’s [LAR]. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimise the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in a language understandable to the subject or the representative.” Furthermore, 21 CFR 50.27 (a) states that a written consent form approved by the IRB, should be signed, and dated by the participant or their LAR at the time of consent, and a copy given to the person signing the form. The regulations do not specify that informed consent requires a wet ink signature. They are quite flexible in that regard. Neither do the regulations stipulate how informed consent should be obtained, they just define the elements it should contain. There was also existing Department of Health and Human Services (HHS) and FDA e-consent guidance upon which to draw, including the “Use of Electronic Informed Consent: Questions and Answers,” which was published in December 2016. In response to the pandemic, the FDA issued new guidance for sponsors and investigators on the “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency” in March 2020. The Agency also issued updates as either new information became available, or it received additional questions. The most recent update was issued in August 2021.

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Regulatory Another resource that we relied upon was FDA’s email address ClinicalTrialConduct-COVID19@FDA.HHS.gov, which allowed the Agency to provide very quick responses. We also posted answers rapidly on our IRB website to the large volume of questions we were receiving. Many university IRBs and hospital IRBs also posted guidance for their investigators, which provided local context. Obtaining Remote Consent For this article, remote consent refers to instances in which informed consent was obtained at a distance and then the handwritten, signed consent form was sent back to the site or investigator. FDA’s guidance outlined many different scenarios in which consent could be obtained remotely in an FAQ document. The methods most frequently employed were as follows: The consent form was sent to a prospective participant via email, US mail or a courier, such as UPS or FedEx. The potential participant reviewed the consent form remotely, and then asked questions of the site staff or investigators either by telephone or video conference call before deciding whether to give consent. If the potential participant agreed to join the study, they signed the consent form and returned it. The guidance described several ways in which the form could be returned. For example, the participant could print the form, sign it, then photograph their signature on the document and return that image via email. Alternatively, they could print, sign, scan and email the consent form back, or return the signed hard copy via courier or US mail. Many sites started providing a stamped return envelope so that participants could sign the consent form and send it back easily. If a participant could not print the consent form, the FDA guidance allowed documentation of verbal consent, but recommended that a witness be present. Alternatively, the participant could send an email stating that they consented to join the study and would sign the consent form during their next on-site visit. Another option was to record the phone call or video call, to provide verbal or visual documentation of consent. Documentation is key for successful implementation of the remote consent process. Sites should implement a Standard Operating Procedure (SOP) describing their remote consent process to ensure their staff know the organisation’s expectations and that consent is approached in a consistent manner. When sites or sponsors contacted our IRB and asked about remote consent, we recommended that they create checklists or forms so that their documentation was standardised and consistent and could be more easily compiled for future audits. That way, they would not have some remote consents with a witness and others without or some that had the investigator sign the remote consent process and others that just noted their name. We also recommended that any recordings, emails, signed consent forms, and other communications be filed in the appropriate participant’s folder for audit purposes. Obtaining E-consent There are two types of e-consent. There are digital storyboards, which usually involve animation or interactive sections where a potential participant can click and get answers to their questions and then sign their consent to join the study electronically. Then, there is simply an electronic version of the consent form. This article focuses on the second type of e-consent because during the pandemic, especially at the beginning when companies started shutting down, there was an urgent need to obtain consent in a safe way due to the risks of exposure. The easiest, most accessible approach was to create an electronic version of the paper consent form. www.journalforclinicalstudies.com

From a regulatory standpoint, the FDA guidance states: “Systems used to generate electronic signatures…including informed consent documents, during the COVID-19 public health emergency, must comply with the requirements outlined in FDA regulations at 21 CFR part 11.” The pandemic does not exempt sites or sponsors from complying with the part 11 requirements for obtaining e-signatures. Before establishing or certifying a participant’s or LAR’s electronic signature, site staff must verify the individual’s identity using an official document such as a driver’s license or passport, answers to security questions, or their username and password combination. During the e-consent process, the organisation must still give potential participants suitable opportunity to ask questions and provide them with a record of the e-consent. Electronic records must also be available for inspection. The e-signature tools that our IRB has seen employed most often include FDA’s COVID MyStudies app, Adobe Sign, DocuSign, and REDCap. Adobe Sign and DocuSign scan documents as PDFs and then send them out for e-signature. REDCap allows some customisation, enabling investigators to add checkboxes or buttons, for example. But even though those technologies are available, sites and sponsors are still responsible for ensuring that they are part 11 compliant. Some versions of Adobe Sign and DocuSign, generally the free versions, have non-part 11 compliant components. There are separate, paid part 11 compliant versions of the systems. In addition to determining that the e-signature tool it plans to implement is part 11 compliant, the site also must define how the sponsor, monitors, and inspectors will have access to review the e-consent documents. That information should be outlined either in training procedures or SOPs. Part 11 also requires documented staff training on those systems prior to implementation. Identifying LARs An LAR is defined under 21 CFR 50.3(1) as “an individual, or judicial, or other body authorised under applicable law to consent on behalf of a prospective research subject to the subject’s participation in the procedure(s) involved in the research.” Some state laws differ on who can act as an LAR or give surrogate consent. When HHS revised the Common Rule in 2018 (45 CFR 46.102 (i), it clarified that “in jurisdictions where there is no applicable law for allowing an LAR to provide consent on behalf of a prospective research subject, LAR means an individual recognised by institutional policy as acceptable for providing consent in the non-research context on behalf of the prospective research subject to the subject’s participation in the procedure(s) involved in the research.” Therefore, if there is no applicable law for allowing an LAR, then the institutional policy determining who is allowed to consent for a patient who is incapacitated in a hospital setting also applies in the research setting. For example, as COVID-19 had such a severe impact on an individual’s respiratory function, there was heightened concern about having to consent patients who were intubated and on ventilators and who did not have the capacity to consent. There was also the challenge of identifying the patient’s LAR because many hospitals were at capacity and limiting who was allowed to be with the patient or even enter the hospital. Furthermore, some LARs were in quarantine because they were suspected of having been in contact with an infected person. That said, it was rare for a patient to arrive at the hospital and need to be intubated immediately. There was usually a window of time after the patient was admitted to the hospital before their condition was serious enough to warrant intubation and being put on a ventilator. It is also important to remember that obtaining LAR consent for a participant who is incapacitated is not new. That type of situation occurs with research into stroke drugs, or studies on epilepsy. There Journal for Clinical Studies 17

Regulatory are existing regulations and guidances on conducting research in an emergency setting (21 CFR 50.24).

to approve and disapprove all research activities. That includes the responsibility to ensure an adequate, informed consent process.

Included below are some of the questions that our IRB frequently received at the start of the pandemic.

The move to e-consent or remote consent during the pandemic could be made prior to IRB approval because it fit the category of removing immediate risk of harm, but it still needed to be submitted to the IRB.

Can the IRB Waive Documentation of Consent During the Pandemic? No, the FDA did not grant any special exemptions from obtaining informed consent or signatures for informed consent during the pandemic. However, it did issue guidance on all the different ways consent could be documented. The FDA and HHS have specific criteria that must be met for a waiver of documentation of informed consent to be allowed: the study must be no more than minimal risk; the waiver or alteration would not adversely affect the rights and welfare of participants; and the clinical investigation could not practicably be carried out without the waiver or alteration. Even if a signature is not required, verbal consent should still be obtained. Whenever appropriate, the participants should be provided with additional pertinent information afterwards. If Government Mandates Require all Non-Essential Companies to Shut Down, and Participants Cannot Come in for Visits or to Sign New Consent Documents for Changes, What Should We Do? FDA regulations (21 CFR 56.108(a)(4)) allow changes to be made to research without prior IRB approval to eliminate immediate hazards to human participants. Changes to the protocol to reduce visits or changes to the consent form to allow for remote consent or e-consent to reduce potential exposure to COVID-19, could be seen as actions to eliminate possible immediate hazards to participants. Therefore, IRBs were very flexible in allowing that and communicating that to sponsors and investigators. However, although the regulations allowed those actions to be implemented prior to IRB approval, sponsors and investigators still had to report them to the IRB. Documenting the deviations and rationale were critically important. Do We Have to Revise our Consent Form to Allow for Remote Consent and Remote Monitoring? The regulations do not require informed consent forms to be changed. Our IRB allowed “Dear Participant” letters or informed consent form addendums to be sent to participants. We recognised that making informed consent revisions can be quite a lengthy process and permitting those options would eliminate some of the burden of having to obtain reconsent signatures. At that time, many people were struggling to obtain signatures at all. Of course, the absence of a reconsenting signature on the consent form does not mean participants cannot withdraw from the study. It is simply a way of communicating new information. If a participant learns about new procedures and decides to withdraw, they certainly can, and quite a few did. In terms of remote monitoring, if the informed consent form states that the sponsor, its representatives, the IRB, and regulatory team will have access to personal health information, then the consent form does not need to be updated to allow for remote monitoring, since it already adequately discloses that they will have access. However, if the consent form specifically limits access to personal health information to on-site monitoring, then informed consent form revisions are required. Do We Have to Obtain IRB Approval for Moving to Remote or E-Consents? Yes, the regulations require that the IRB reviews and has authority 18 Journal for Clinical Studies

Benefits and Challenges The pandemic spurred the adoption of remote and e-consent processes, producing both expected and unexpected benefits. E-consent tools helped to ensure that the most up-to-date version of the consent form was used, and flagged missed fields such as checkboxes, dates, and signatures. While e-consent provided a lot of flexibility, it also placed a cost and implementation burden on sites because they had to obtain an e-consent technology, train staff, and implement SOPs quickly. Many sites and e-consent companies were overwhelmed with purchase and implementation requests. Introducing these remote processes also highlighted the difficulty of working with underserved populations, which often had difficulty accessing technology, limited access to internet, or experienced trouble with technical literacy. In addition, it underscored the challenge for potential participants of interfacing with long, complex consent documents, which might require scrolling through 30 pages of information. It emphasised the importance of communicating key information – per HHS’ Revised Common Rule in 2018 – which can help a potential participant decide whether to participate in a study. Perhaps surprisingly, some sites and participants reported increased interactions during the informed consent process when videoconferencing and teleconferencing were employed. Those participants had a greater opportunity to ask questions than previously when they were just given the consent form, told to read it, and come back if they had questions. Also on the positive side, we have seen increased diversity and growing enrolment of non-english speaking participants in clinical trials. Requests to our IRB for informed consent form translations jumped from 2,300 in 2019 to 3,700 in 2020. Conclusion The COVID-19 pandemic presented significant challenges to obtaining informed consent from clinical trial participants. Fortunately, the FDA and IRBs provided prompt, clear guidance, which built upon existing regulations, and provided a framework within which clinical research could continue, enabling breakthroughs to be made with COVID-19 vaccines and therapies.

Heather Kim Heather Kim, MS, RAC, CIP, is Manager, Quality Assurance at WCG IRB, the industry’s first and largest central IRB. She earned a BS in biology at the University of North Carolina at Chapel Hill and an MS in regulatory affairs at Northeastern University. She has worked in IRB compliance for almost 10 years and supported multiple FDA inspections and client audits. Ms. Kim is also a site visitor for AAHRPP.

Volume 14 Issue 2

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 the Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of ISO 9001:2015.

Ramus Medical is full service CRO, working CTs in a variety of therapeutic areas and medical device.

• •

• • • • • •

Medical Centre Ramus with Phase I Unit

Medical writing for drugs and devices Scientific review of documentation Clinical trial management Monitoring Data management Regulatory advising and services during clinical trial

• • • •

Total laboratory automation with Abbott GLP-System Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

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

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

• • •

• •

30 clinical laboratories in Bulgaria and North Macedonia 325 affiliates for sampling in Bulgaria and North Macedonia More than 20 years’ experience in the CT field as central and safety laboratory; Largest PCR laboratory in Bulgaria Laboratory System integrates cluster generation, sequencing, and data analysis

, fast, correc t! Safe

Readability user testing Bridging report Carriage and storage of dangerous goods in compliance with ADR principles

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

to Cito

www.journalforclinicalstudies.com www.journalforclinicalstudies.com

e re

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 for Clinical Studies 19 19

Regulatory

Why Risk-Based Quality Management Represents the Future of Clinical Research After proving its worth in the pandemic, and with its values enshrined in the latest guidelines for good clinical practice, the industry is embracing the benefits of Risk-Based Quality Management (RBQM), writes Patrick Hughes. The emphasis on quality by design (QbD) in the updated version of the ICH E6 principles makes a clear case for a new way of working, which boosts participant safety and the likelihood of trial success. By empowering researchers to detect data quality issues in realtime, Risk-Based Quality Management (RBQM) and Risk-Based Monitoring (RBM) have proven their value during the race for a COVID-19 vaccine in which trials required the processing of huge volumes of data from dozens of global sites. RBQM is now driving significant changes throughout clinical research, helping to speed up the drug development pathway without compromising data quality while ensuring early risk detection remains a priority. The prominence given to quality in the ICH E6 (R3) Guidelines for Good Clinical Practice underscores the value of this method to encourage the more effective use of remote monitoring practices, reduced site visits, and eradicating 100% source data verification (SDV). This article outlines why RBQM is the future-proofed solution to managing risk for the entire clinical trial life cycle – and how the benefits for clinical research can be fully unlocked. Why RBQM is Needed Now By helping researchers to identify and focus on data that matters, EMA- and FDA-backed RBQM methods ensure studies can reliably assess the safety and efficacy of experimental treatments. It makes on-site monitoring of clinical centers – via sourcedata verification (SDV) or comparing data collected in case report forms to those in patients’ medical records – a thing of the past, a dynamic shift that has proved particularly valuable during the pandemic. Instead, robust RBQM solutions allow teams to access information centrally, collaborate on investigations, and document any mitigations or remedial actions. The greater adoption of high-tech Central Monitoring (CM) will enable sponsors to interrogate clinical and operational data in real-time, increasing efficiency, improving patient safety, and reducing costs.1 This means a clean dataset and a much-needed reliable audit trail for regulatory scrutiny. Overcoming Barriers to Adoption Lack of clarity around good clinical practice has hampered the adoption of RBQM in the past, with sponsors and CROs unclear on how to adopt this new way of working. 20 Journal for Clinical Studies

The previous edition of the ICH E6 (R2) guidelines, released in 2016, suppressed advances in the take-up of technology as researchers struggled to understand how to proceed. Some even overcomplicated processes by collecting and monitoring all forms of data rather than solely relevant information, defeating the whole purpose of Risk-Based Monitoring. Unlocking RBQM’s Potential The publication of ICH E6 (R3) draft guidelines in April 2021 represents a seismic shift for the industry. A new emphasis on achieving quality by design (QbD) is outlined in principle 7, which requires: “Quality should be built into the scientific and operational design and conduct of clinical trials.” The focus on QbD and risk-based approaches, and a vow to facilitate innovation while protecting trial participants, now offers researchers much-needed clarity around the use of RBQM. The document outlines how “clinical trial designs and processes should be proportionate to the risks inherent in the trial and the importance of the data being collected.” It also specifies: “Factors critical to the quality of the trial should be identified to ensure the protection of participants, the reliability and interpretability of the trial results, and the decisions made based on those trial results.” For the first time, the revised guidelines also ensure innovations in technology and design are facilitated and encouraged, smoothing the path for more widespread adoption of modern research practices. In addition, this future-facing approach includes adequate flexibility to allow the industry to embrace further advances as they occur. Deployment in Vaccine Development An agile, real-time, risk-based monitoring approach proved successful in helping study teams involved in the pivotal trials to create the COVID-19 vaccine to make decisions based on data rather than perceptions and to monitor safety closely. By focusing on an evolving set of study-specific key risk indicators (KRIs), data quality assessments, and quality tolerance limits (QTLs), with daily analysis to allow quality issues to be identified and rectified in real-time, drug applications were submitted in record time, with very high levels of quality. The trial included more than 40,000 participants recruited at a rate of 5,000 a week from a broad range of demographics across 150 global sites. The challenges were not inconsiderable: to accelerate development, the study encompassed Phases I, II, and III, while infection-control measures presented a logistical challenge for site visits. To support the supervision process and protect the integrity of the vast volumes of data being generated, Pfizer worked with CluePoints to deploy a centrally monitored RBM approach. In addition, two CluePoints databases were created to boost the efficiency of the CM and make it possible to run the respective analyses in real-time. Additional resources were also employed centrally and at the site Volume 14 Issue 2

Regulatory

level to ensure signals were both generated and investigated: this resulted in action being taken on between 50% and 55% of all signals, compared to the non-COVID portfolio average of 15%. This allowed sites to analyse the root cause before issues could affect data quality, while weekly data surveillance meetings took place at the study level to assess all risk signals; the results were uploaded to the Risk Assessment Categorization Tool to keep KRIs up to date. In addition, the development of a range of new reports and visualisations to report findings included a signal and action tracker, which has now become standard across Pfizer’s CM programs. Learning from a Historic Study By employing an agile, RBQM-based approach, Pfizer was able to increase efficiencies to such an extent that drug applications were submitted in record time, with very high levels of quality, despite many challenges. As a result, Pfizer and BioNTech’s mRNA product received regulatory approval just 266 days after the World Health Organization’s pandemic declaration – and hundreds of millions of doses have since been administered around the globe. It represented a historic moment in time, forever altering the landscape on how clinical trials are conducted. So, what did we learn from this? When on-site visits could not take place, CM analytics were extremely valuable in alerting the team to sites with high risk. It showed flexibility with KRIs is crucial, ideally to adjust them throughout the life of the study to correspond with risk signal findings. In this case, reviewing a fortnight’s data allowed the team to ensure KRIs always focused on the most essential subset. In addition, study-specific QTLs shaped trends at the study level and within regions and sites. Rapid Development Without Compromising Quality The acceleration of medical science, compounded by the impact of www.journalforclinicalstudies.com

COVID-19, is driving the innovation of new technology to promote safety and boost success rates. Not before time, the evolution of R3 is paving the way for a shorter drug development timeline without compromising data integrity and bringing long-lasting change for the industry. RBQM now offers the opportunity to embrace new ways of working, with the ability to spot issues earlier and act faster – avoiding the expensive and unnecessary obstacles to approval and market, which had become the norm. REFERENCES 1.

Looking to the Future with RBQM Controlling Risk Across the Entire Study Lifecycle. (2020). https://globalforum.diaglobal.org/issue/september-2020/ looking-to-the-future-with-rbqm/

Patrick Hughes Patrick holds a Marketing degree from the University of Newcastle-upon-Tyne, UK, and a post-graduate Marketing diploma in Business-to-Business Marketing Strategy from Northwestern University – Kellogg School of Management, Chicago, Illinois. Responsible for leading global sales, product, marketing, operational and technical teams throughout his career, Patrick is a Senior Executive with over eighteen years international commercial experience within life sciences, healthcare and telecommunications. In the past, Patrick consulted on corporate and commercial strategy for various life sciences companies and was responsible for successfully positioning ClinPhone as the leading Clinical Technology Organization during his 10-year tenure with the company.

Journal for Clinical Studies 21

Market Report

Growing the Pool of Clinical Research Investigators in Malaysia Introduction The Malaysian government has continuously strived to improve and expand its clinical research ecosystem for the past ten years. The primary goal is to provide a competitive landscape with internationally recognised clinical trial hubs as more pharmaceutical companies continue shifting their clinical trial bases to Asia. One of the strategies implemented with success by the Malaysian Ministry of Health (MoH) is the establishment of Clinical Research Malaysia (CRM). CRM is a non-profit company acting as a “one-stop” centre to facilitate the growth of industrysponsored research (ISR). Since the launch of CRM in 2012, it has successfully closed the various gaps within the clinical research ecosystem and continues to address and improve existing unmet needs. Since early 2000’s, Asia-Pacific has seen the benefits of increasing interest by pharmaceutical industries in conducting clinical trials in the region. The cumulative volume of clinical trial densities of selected countries in the South East Asian (SEA) region has almost tripled from 2016 to 2020.1,2 The clinical trial density in Malaysia doubled from 2016 to 2020, i.e. from 8 to 17, and this is reflected in the increasing numbers of ISRs conducted in the country.1–4 The number of sponsored research conducted in Malaysia is growing steadily from 162 studies in 2019, 191 studies in 2020 and 215 studies in 2021 despite the COVID-19 pandemic.3,4 A crucial aspect in conducting high quality clinical trials is the availability of qualified and experienced investigators. Hence, Malaysia will need to increase the pool of available clinical investigators to match the demand and interest of sponsors and contract research organisations in conducting trials here. This article focuses on the current status of Malaysian investigators and the future perspectives for CRM and the MoH in growing the country’s clinical investigators pool. Global Perspectives on Principal Investigators (PI) Although the day-to-day tasks of a clinical trial are performed by various study team members, PI is pivotal in ensuring the proper conduct of the clinical research and patient safety.5 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E6) Good Clinical Practices (GCP) details the roles and responsibilities of clinical research investigators, including that of the PI.6 All investigators must be GCP certified and have experience in conducting quality trials. Investigators need to demonstrate the ability to recruit the targeted subjects, supervise and complete the trial within the study timelines, as well as to train the support staff. The investigator and institution (clinical trial site) must ensure there 22 Journal for Clinical Studies

are adequate medical facilities to support the clinical trial, especially when adverse events caused by the investigational product occur. The number of PIs worldwide varies widely depending on the source of information.7 Separate databases set up by different clinical research organisations (CROs) and clinical trial organisations estimate between 40,000 to 500,000 PIs globally. Some of these databases reveal that the largest proportions of PIs are in Europe (40%) and North America (32%). Asia-Pacific has the third-highest proportion at 18%. Based on the ClinicalTrial.gov and the DrugDev network databases, an investigator engages with one to three trials per year on average.7 The IMS Health database, however, shows that 32% of investigators undertook only one trial in five years.7 Clinical Studies in Malaysia The Malaysian healthcare system encompasses healthcare facilities under three large categories, i.e. the MoH, the Ministry of Higher Education (MoHE; that includes teaching hospitals) and the private sector. Clinical trials can be conducted in any healthcare facility within the three categories provided they fulfil the regulatory and ethical criteria set by the Malaysian GCP, as well as local regulations and guidelines. From 2017 until 2021, the majority of sponsored research studies were conducted in the MoH public hospitals and health clinics, followed by the MoHE teaching hospitals (Figure 1).4 61% 52%

25% 23%

2017

52%

46%

31% 20% 19%

20%

17%

2018

2019

MoH

MoHE

42%

45%

34%

13%

2020

2021

Private

Figure 1. The percentage of approved sponsored research conducted in the three healthcare systems in Malaysia.4 Note: For multi-centre studies, the same trial could involve multiple sites from different sectors. However, only a single value will be captured under the site sector, irrespective on the number of site(s) within the sector.

The extensive utilisation of the MoH and MoHE hospitals as clinical trial sites is not surprising. Though there are 45% more private hospitals than public hospitals in Malaysia,8 the official bed capacity is 260% more in public hospitals. The vast difference in the patient population can also be seen in the number of admissions and outpatient attendance between the two healthcare sectors. The public sector has approximately twice the number of admissions (2.3 million vs 1 million) and seven times more outpatient attendances (21.4 million vs 3 million).8 The major reason for such high patient volumes in the public sector hospitals is that patient management is heavily subsidised by the government. At a nominal fee, patients Volume 14 Issue 2

Market Report receive consultation, investigations and treatments for all minor and most major conditions/disease. Hence, the patient capacity and potential subject recruitment are significantly higher within the public hospital setting.

their experience in clinical research with the objective to motivate up and coming investigators to embark on clinical research. These initiatives carried out indirectly supported the growth of new investigators involved in ISR in the country (Figure 3). 2090

The Need for More Clinical Investigators In 2018, there were 11,686 registered specialists in Malaysia from both the public and private sectors and across various specialities.9 The public hospitals held more total specialists (58.4%) than the private sector (41.6%). The majority, if not all, of the PIs conducting clinical research are specialists, and the top five number of new ISRs by therapeutic areas between 2015–2021 were oncology, cardiology, infectious disease, endocrinology and haematology (Figure 2).4 In 2020, there were a total of 300 cardiologists and 133 oncologists, of which only 10% and 26% were working in the MoH hospitals, respectively.10 Not all specialists have received Good Clinical Practice (GCP) training and are experienced in conducting or leading clinical trials. Therefore, the discordance created between the number of available specialists and principal investigators as well as the growing number of clinical trials in the top 5 therapeutic areas indicate the pressing need to grow the pool of investigators, especially in those mentioned therapeutic areas. These gaps have led to current investigators being saturated with conducting clinical trials and thus a limitation with accepting more ISRs, and the opportunities to explore new treatment for the population. 66.1%

58.3%

1978 1932 1868

2017

2018

2019

2020

2021

Figure 3 The cumulative growth of new investigators involved in ISR from 2017 to 2021.4

Additionally, to bolster the attractiveness of participating in clinical research as investigators, the Malaysian government continuously strives to improve existing policies that support clinicians. Teaching hospitals within the MoHE allocate sabbatical leave and/or research leave for clinicians to conduct research, participate in clinical research fellowships at global centres of excellence and training attachments at international research institutions. Other than inculcating interest in clinical research, these policies encourage formation of international networking collaborations in clinical research through exposure to high quality research programs and encouraging interactions with other likeminded clinicians.

58.0% 48.7%

42.0%

41.7%

51.3%

50.7%

49.3%

33.9%

2017

2029

2018

2019 Top 5 ISR

2020

2021

All others

Figure 2. Proportion of the top five ISRs based on speciality (oncology, cardiology, infectious disease, endocrinology and haematology) over a 5-year duration compared to the proportion of ISRs conducted in all other therapeutic areas (22 other therapeutic areas such as Immunology, Gastroenterology, Neurology, Paediatric/Neonatology and more). Source: Clinical Research Malaysia.

Addressing the Gaps – Plans and Perspectives In recognising the need to increase the pool of investigators across the public and private sectors in Malaysia, CRM together with the MoH have embarked on several initiatives to create awareness among investigators on the value and importance of clinical research. Since 2017, the CRM Sponsored Research Award is given annually to recognise top investigators who achieved excellent recruitment of study subjects, as well as those who have successfully published research articles in high impact peer reviewed journals. To date, a total of 26 awards have been given to top investigators, trial sites, sponsors and CROs in recognition of the contribution to the clinical research industry in Malaysia. Another initiative is through the conduct of a series of seminars and webinars to attract potential and interested specialists to be involved in clinical research. This complimentary programme which started in 2017, includes multiple roadshows in different regions of the country and online webinars that are open to all Malaysian healthcare professionals. To date, over 20 of such roadshows and webinars have been conducted. CRM also publishes biannual bulletins featuring investigators, sharing www.journalforclinicalstudies.com

Meanwhile, the MOH in 2017, had allocated one day a week for clinicians within their facilities to conduct ISR in line with its efforts in increasing the number of clinician researchers in the public sector. CRM also continuously enables and encourages investigators in the MOH to take up clinical research on top of their daily clinical service. CRM supports these clinicians by managing the clinical trial budget and reviewing clinical trial agreements on behalf of the investigators.11 Additionally, CRM also recruits and trains Study Coordinators to be GCP certified, proficient in trial site related duties and comply to CRM’s standard operating procedures, before placing them at trial sites throughout Malaysia to support the investigators. These financial, legal and human resource support provided by CRM is vital as it allows the investigators to solely focus on the conduct and delivery of clinical trials, and manage their time between clinical service and clinical research activities. The growth of the Malaysian clinical trial ecosystem should also consider planning for the future. Hence, as the country gears up for an increase in the number of clinical trials, strategies for career development in clinical research will be needed. This includes creating new career pathways for the physician-scientist for those interested in focussing on research, and to develop and train support staff with accredited courses for research nurses, clinical trial coordinators and data managers. The rationale is to create pools of qualified and quality members of a clinical research team within established and upcoming clinical trials sites to enable and support the principal investigators. With a well-trained team, the potential for investigators to take on more research activities will increase. Conclusion With the establishment of CRM and its collaborative efforts with the MoH and other government entities, Malaysia has made great strides in enhancing its presence in the global clinical research scene. The gaps in the quantity of qualified clinical investigators, mainly PIs, are being addressed to ensure a sustainable pool of investigators. These steps include programs and policies to improve the clinical Journal for Clinical Studies 23

Regulatory

investigators’ time resources, training and mentoring more specialists, and creating an attractive clinical research pathway. REFERENCES 1.

4. 5. 6.

7. 8.

10.

11.

Frost & Sullivan. Asia: Preferred destination for clinical trials. 2017. Available at: https://frost-apac.com/BDS/whitepaper/Asia-Pacific%20Clinical%20 Trials%20-%20White%20Paper%20-%20Frost%20&%20Sullivan.pdf. Accessed February 2022. Frost & Sullivan. Asia: Preferred desitination for clinical trials. 2020. Available at: https://frost-apac.com/BDS/whitepaper/Asia-Pacific%20Clinical%20 Trials%20-%20White%20Paper%20-%20Frost%20&%20Sullivan.pdf. Accessed February 2022. Clinical Research Malaysia. Annual report. 2020. Available at : https:// clinicalresearch.my/wp-content/uploads/2021/04/210427_CRM_AR2021_ FA4- Digital-low-res.pdf. Clinical Research Malaysia. Annual report. 2021. Available at: https:// clinicalresearch.my/annual-report/ Feehan AK, Garcia-Diaz J. Investigator Responsibilities in Clinical Research. Ochsner J. 2020;20(1):44-49. European Medicines Agency. Guidelines for good clinical practice E6(R2). 2016. Available at: https://www.ema.europa.eu/en/ich-e6-r2-good-clinicalpractice#current- version---revision-2-section. Accessed February 2022. CentreWatch. Number of global clinical PIs remains a mystery. 2015. Available at: https://www.centerwatch.com/articles/15859. Accessed October 2021. Ministry of Health Malaysia. Health facts 2019. Planning Division, Health Informatics Centre 2019; MOH/S/RAN/152.19(PT)-e. Available at: https:// www.moh.gov.my/moh/resources/Penerbitan/Penerbitan%20Utama/ HEALTH%20FACTS/Health%20Facts%202019_Booklet.pdf. Accessed February 2022. Ministry of Health Malaysia. Human resources for health- Country profile 20152018. Available at: https://www.moh.gov.my/index.php/pages/view/1919? mid=626. Accessed February 2022. CodeBlue. Minister: 10% of cardiologists, quarter of oncologists serve MOH hospitals. Avaialble at: https://codeblue.galencentre.org/2020/10/22/minister10-of- cardiologists-quarter-of-oncologists-serve-moh-hospitals/. Accessed February 2022. Clinical Research Malaysia. A unique model to accelerate industrysponsored research in Malaysia. Available at: https://clinicalresearch.my/aunique-model-to- accelerate-industry-sponsored-research-in-malaysiajournal-for-clinical-studies/. Accessed February 2022.

24 Journal for Clinical Studies

Nur Ain binti Amir Nur Ain currently works at Clinical Research Malaysia as a Feasibility Specialist. She has been liaising with doctors, pharmaceutical companies, and Clinical Research Organization to conduct feasibility study for clinical trial. She has experienced with IIR study. She is a graduate of Universiti Putra Malaysia. Email: nur.ain@clinicalresearch.my

Cheng Shu Hui Shu Hui is currently a Feasibility Specialist at Clinical Research Malaysia. She has the experience in diagnostic as well as research and development field. She has her degree with honors in Medical Biotechnology from Sunway University Malaysia. Email: shuhui@clinicalresearch.my

Audrey Ooi Audrey Ooi is the Head of Business Development at Clinical Research Malaysia. She has over 8 years of experience in the clinical research field, with cross-functional roles in marketing, project management, stakeholder engagement and medical writing. She is a graduate of Monash University and holding master degree. Email: audrey.ooi@clinicalresearch.my

Volume 14 Issue 2

From design to manufacturing, we partner in your device strategy

NEMERA: YOUR COMBINATION PRODUCT PARTNER www.journalforclinicalstudies.com

Patients first. Always.

Partnering in drug delivery devices. Holistically.

Going the extra-mile. Together. Journal for Clinical Studies 25

Therapeutics

Personalised Medicine and Clinical Studies – The Attempt to Untie a Gordian Knot – Introduction Classical drug development is undoubtedly indication- and product-driven. Simply put, a preclinically developed substance is optimised for clinical application in an appropriate galenic preparation and, in the best case, brought to market maturity in various phases of clinical development.

This development is driven by two strong trends, almost medical megatrends, molecular genetics-assisted diagnostics, and treatment + (Figure 2), and data analytics.1

The classical medicines of the western type, tried and tested and established, have recognisable disadvantages. With exceptions, these products usually only promise relief, acute illnesses turn into chronic diseases with sometimes lifelong necessary treatment. Moreover, clinical development is a lengthy process and often still fails in late phase III. New therapeutic approaches promise targeted preclinical development, lower failure rates in the subsequent development steps and fewer adverse effects due to the target orientation. Technical Approach The trend towards personalised medicine or precision medicine towards targeted therapies is revolutionising drug development as we move from a blockbuster to a niche mentality. (Figure 1)

Figure 226

Only evolutionary development into a holistic approach will unleash the full efficacy of personalised treatment strategies.2 1.

Over the last two decades, the amount of data in the field of oncology has increased rapidly. For each individual patient, more and more data are being generated and stored. For example, in the European Innovative Medicines Initiative project OncoTrack, close to 1 terabyte (1,000 gigabytes) of data are produced per patient, which is equivalent to 250,000 photos or 6.5 million document pages. This increase in stored information was sparked and promoted by the digitalisation of medicine and technological advances, such as genome sequencing.

The most promising scientific breakthroughsin medical research are only as good as the quality of the clinical operations that accompany them into the clinical setting.

Personalised medicine (PM) aims to harness a wave of ‘omics’ discoveries to tailor drug choices, dosages, and interventions to the biology of individual patients.25

Figure 1 26 Journal for Clinical Studies

Study Design The population-determined protocols can generally pinpoint suitable treatments/interventions for individuals, but the emergence of artificial intelligence (AI) and digital medicine offers the potential to truly optimise patient outcomes.3 Strategies for vetting personalised medicines have been developed, in cancer contexts, and include ‘basket,’ ‘umbrella’ and adaptive – platform trials,4,5,6,7 but the assumptions and measures described should be applicable to other medical specialties as well. Volume 14 Issue 2

Therapeutics The complexity of clinical trial designs increases with the degree of product individualisation + + and the number of questions addressed8 (Figure 3), which directly affects the trial design.

patient-in. The timing of the last-patient-out must become the criterion for success.12 Extend follow-up periods to learn more about e.g., vaccination, if needed. NOTE: Follow-up periods may add scientific value, but the benefit for an individual patient is uncertain.13 Keep the number of involved sites and countries low, this will give you a better handling of the key indicators (see below). This is usually feasible because patient numbers are smaller, a large Phase III trial is rarely necessary, and the usual concerns of statistical error due to low or over-recruitment at a centre have less impact, but the skills needed to implement these complex protocols are critical to success.

Figure 3

++ This means that the highest complexity is reached at N = 1. The extent to which a single patient in a clinical study allows statistically significant statements to be made about treatment due to the enormous amount of data is a matter of controversial debate but will not be dealt with further in this paper. This shift in the conduct of clinical trials has its origins not only in the technologies described but also in the resulting different questions. The classic "intervention focused" clinical trials only ask the question "can this intervention offer benefit over current standards of care or placebo?", while the more "disease focused" platform trials look for the best intervention for a given disease.9 (Figure 4)

Involve trained clinical researchers and back-ups. Contact and inform the medical doctors and staff regularly about forthcoming activities and keep them well trained in common clinical research issues also without direct study relationship. This will make starting the next trial faster and easier. Pay attention to and use the key-success indicators performance, risk, safety and financial. Due to the protocol complexity and flexibility (adaptive), it is essential to establish a Data Monitoring and Safety Committee.14 Trial Management with Adaptive Protocols Although the conduct of the study on the part of the sponsor as well as its representatives and trial sites are undoubtedly extremely important, there are hardly any practical guides or literature to be found on this.15 This is surprising because the operational conduct of a clinical trial is the most complex, also because many people are involved and need to be coordinated to achieve the common goal. The prioritisation is sometimes very different from traditional protocols and almost similar to those used in rare disease trials.16 Table 1 shows an example of the increasing responsibility of the people involved in such projects.

Figure 4

This study design offers many advantages but requires a differentiated approach to implementation. Currently, the FDA has published the Guidance for Industry "Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics" in March 202210 and offers consultation support. It is clear from the personalised target-oriented therapeutic approach that placebo-controlled studies are unlikely to occur for ethical reasons (although there may be justified exceptions).11 It seems that with this study concept, better and more precise planning can be made. With a larger product pipeline, resources can be better planned, and the allocation of funds optimised with a structured clinical development plan. How to Decrease Costs and Increase Quality and Meaningfulness? To gain the most benefit, they should discard the belief in the firstwww.journalforclinicalstudies.com

Table 2: Prioritisation at project level

It is therefore necessary to relieve the operational staff of routine tasks in order to allow more time for the important areas. It may sound absurd, given the increasing responsibility in socalled clinical monitoring, to cut back on several sectors, especially with regard to the time-consuming on-site visits, but this is exactly what I strongly advise. Firstly, more GCP-relevant responsibilities are being fulfilled by the trial centers, secondly, more and more data are being automatically transferred to study databases in anonymised form Journal for Clinical Studies 27

Therapeutics for analysis (Figure 5), and thirdly, with these data volumes, classical clinical monitoring is simply no longer economically feasible.

Finally, a small contribution to a possible development: With the introduction of new technologies, e.g., in the prediction of the 3-dimensional protein structure from the one-dimensional amino acid sequence,27 diseases and their causes can be better understood at the molecular level and therapy approaches can be optimised. The question arises: "At what threshold of precision are clinical studies still useful? In the not-too-distant future, will it only be necessary to validate the manufacturing processes or technologies as medical products? Exciting times! REFERENCES 1.

4. Figure 5

In any case, the new digital technologies will finally help the approach of centralised monitoring to make a breakthrough.17,18,19 This means that scientifically and medically well-trained staff will have enough time for safety-related topics and the management of the projects. This should have a significant qualitative added value. The Health Care Industry – Ready for Digitisation? The healthcare industry offers many opportunities to use the latest technologies. From pre-clinical research to solving complex problems at the molecular level using quantum computers,20 the decentralised management of patient data in hospitals through cloud-based solutions and distributed-ledger-technologies that replace insecure warehousing solutions21), identification solutions in distribution management to drug tracking using blockchain,22 as well as AI driven technologies in research projects are often based on learning algorithms (machine learning).23 Not to forget the technologies we discussed earlier in this paper. Admittedly, the pharmaceutical industry is only at the beginning of its digital development, but this is progressing rapidly and those who want to place competitive products in the future should escalate the organisational development.24 Conclusion As translational medicine has evolved from a unilateral model to a bilateral model (Figure 6) with subsequent involvement of society,28 the digital world is also changing. This has a great impact on the "translation speed" from research to clinical reality and thus on the way clinical trials are conducted.

8. 9.

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Lehmann, J., Cofala, T., Tschuggnall, M. et al. Machine learning in oncology— Perspectives in patient-reported outcome research. Onkologe 27, 150–155 (2021). https://doi.org/10.1007/s0761-021-00916-9 Sven Engel Clinical Trials – Somewhere between tradition and digital modernity – a wakeup call, Journal for Clinical Studies Volume 13 Issue 6, 22-24 (2021) You K, Wang P and Ho D (2022) N-of-1 Healthcare: Challenges and Prospects for the Future of Personalized Medicine. Front. Digit. Health 4:830656. doi: 10.3389/fdgth.2022.830656 Schork, Nicholas J. "Randomized clinical trials and personalized medicine." Social science & medicine (1982) 210 (2018): 71. Amanda J. Redig, Pasi A, Jänne, Basket Trials and the Evolution of Clinical Trial Design In an Era of Genomic Medicine. DOI: 10.1200/ JCO.2014.59.8433 Journal of Clinical Oncology 33, no. 9 (March 20, 2015) 975-977. Published online February 09, 2015. Park, J.J.H., Siden, E., Zoratti, M.J. et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials 20, 572 (2019). https://doi.org/10.1186/s13063-019-3664-1 Mahajan R, Gupta K. Adaptive design clinical trials: Methodology, challenges and prospect. Indian J Pharmacol. 2010;42(4):201-207. doi:10.4103/0253-7613.68417 Getz, K., Campo, R. Trends in clinical trial design complexity. Nat Rev Drug Discov 16, 307 (2017). https://doi.org/10.1038/nrd.2017.65 Jay J.H. Parka, Ofir Harari et al. “An overview of platform trials with a checklist for clinical readers” open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Federal Register/Vol. 87, No. 41/Wednesday, March 2, 2022/Notices Christopher K. Daugherty , Mark J. Ratain et. al. Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials DOI: 10.1200/JCO.2007.13.5335 Journal of Clinical Oncology 26, no. 8 (March 10, 2008) 1371-1378. John Carlos Diaz, G, GeoSera Consulting “Does The First-Patient-In Milestone Really Matter?” https://www.clinicalleader.com/doc/does-thefirst-patient-in-milestone-really-matter-0001 Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev. 2019;9(9):CD002200. Published 2019 Sep 4. doi:10.1002/14651858. CD002200.pub4 FDA – Guidance for Clinical Trial Sponsors “Establishment and Operation of Clinical Trail Data Monitoring Committees Schiavone, F., Bathia, R., Letchemanan, K. et al. This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols. Trials 20, 264 (2019). https:// doi.org/10.1186/s13063-019-3216-8 Sven Engel, Thomas Ogorka Orphan Drugs – Focus on clinical trials – Effective planning and conduct of clinical trials in rare diseases, GoingPublic „Biotechnologie 2013“, page 68 – 69 (available on request from the first author) Ashok Ghone, Centralized Monitoring--A Smart, Reliable Approach, Applied Clinical Trials, October 2015 Guideline for good clinical practice E6 (R2) December 2016 EMA/CHMP/ ICH/135/1995 Committee for Human Medicinal Products FDA Guidance for Industry Oversight of Clinical Investigations — A RiskBased Approach to Monitoring Emani, P.S., Warrell, J., Anticevic, A. et al. Quantum computing at the Volume 14 Issue 2

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frontiers of biological sciences. Nat Methods 18, 701–709 (2021). https:// doi.org/10.1038/s41592-020-01004-3 Erik Westphal, Hermann Seitz, Digital and Decentralized Management of Patient Data in Healthcare Using Blockchain Implementations Front. Blockchain, 26 August 2021 | https://doi.org/10.3389/fbloc.2021.732112 Mueen Uddin, Khaled Salah et.al. Bockchain for drug traceability: Architectures and open challenges Apr-Jun 2021;27(2):14604582211011228. doi: 10.1177/14604582211011228. Weissler, E.H., Naumann, T., Andersson, T. et al. The role of machine learning in clinical research: transforming the future of evidence generation. Trials 22, 537 (2021). https://doi.org/10.1186/s13063-02105489-x Pasi Kemppainen, Sammeli Liikkanen, Pharma Digitalisation: Challenges and opportunities in transforming the pharma industry https://www. europeanpharmaceuticalreview.com/article/51733/pharma-digitalisationchallenges/ Knowles L, Luth W, Bubela T. Paving the road to personalized medicine: recommendations on regulatory, intellectual property and reimbursement challenges. J Law Biosci. 2017;4(3):453-506. Published 2017 Nov 1. doi:10.1093/jlb/lsx030 Nikolaos Perakakis, Konstantinos Stefanakis, The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver

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disease, Metabolism Clinical and Experimental 111 (2020) 154320 Aisha Al-Janabi, Has DeepMind's AlphaFold solved the protein folding problem? Future Science Ltd., BioTechniques Volume 72, Issue 3, January 2022 https://doi.org/10.2144/btn-2022-0007 Randall J. Cohrs, Tyler Martin, et. al., Translational Medicine definition by the European Society for Translational Medicine, Article in New Horizons in Translational Medicine · December 2014 DOI: 10.1016/j.nhtm.2014.12.002

Sven Engel Sven Engel is the founder and managing director of the SynapCon GmbH, a company focused on the digitalisation of the medical product development. He held a number of C-level positions in the CRO and IT industry as well as management positions in the pharmaceutical and biotech industry. He is a biotechnologist and molecular biologist by training with comprehensive global clinical research experience.

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Therapeutics

Blinding and Therapeutic Setting Key to Success Pharma Starts its Psychedelic Journey Both public and medical opinion is changing quickly and substances that were once regarded as ‘party drugs’, psychedelics such as MDMA, LSD and psilocybin (the active ingredient found in magic mushrooms) are now being studied increasingly as potential treatments for a number of different neurospsychiatric disorders including PTSD, intractable depression and alcohol addiction. This renewed interest is carried out by the fact that more trials (40) have been conducted involving MDMA, LSD and psilocybin over the last three years than in the previous nine years combined.1 Yet, despite this current perception, go back a little further and many of these substances – mescalin, LSD and psilocybin – had their origins as therapeutic agents, especially during the 1950s and 1960s. These early trials had as many as 40,000 patients and were showing some encouraging results. But as a result of wider recreational use (in the late 60s) and ultimately the banning in the USA of 81 substances, inducing psilocybin, many decades of research have been lost. Even as recently as just ten years ago (2009) Prof. David Nutt was dismissed from his UK Government role as chief drug adviser as a result of his findings – that ‘ecstasy was less dangerous to public health than alcohol and tobacco’2 – in the country’s largest ever drugs review, emphasising that public and Government opinion globally was perhaps not yet ready to embrace mass clinical research. Fast forward to today, however and Prof. Nutt is a lead on an Imperial University trial benchmarking two doses of psilocybin verses a six-week course of a leading SSRI (Escitalopram).3 This anecdote however is just the tip of an ever-expanding research iceberg, as many institutes from all around the world and pharma companies are pushing ahead in ever greater numbers exploring psychedelic substances as therapeutic agents. Yet, while there is rightly much excitement, undertaking this research comes with some significant technical and regulatory challenges. Designing clinical trials to evaluate the short and long-term therapeutic benefits of psychoactive drugs requires a lot of careful thought if the results are going to be meaningful and accepted by regulatory bodies. However, that should not be a barrier to research, as the FDA's recent approval (March, 2019) of ketamine for treatmentresistant depression shows. Since then, we have also seen a phase 3 study come out from the Multidisciplinary Association of Psychedelic Studies (MAPS). They were evaluating MDMA for PTSD and have just released impressive results showing greater effect sizes than recent pivotal trials of other PTSD pharmacotherapiesi.4 Additionally, Compass Pathways just announced results of their Phase 2b study, the largest randomised controlled trial of psilocybin to date, showing significant reduction in depressive symptoms among those with treatment-resistant depression.5 Apart from the fact that these substances are classified as Schedule 1 of the UN Convention on Psychotrophic Substances – which are deemed to lack therapeutic effects and have a high potential for abuse coupled with serious side effects – meaning there is strict control on the sourcing and use, it can also be very difficult to successfully blind trials involving their use. For these reasons, to date, there has been 30 Journal for Clinical Studies

until recently a dearth of large-scale research into the true therapeutic potential these substances may have. Innovators and CROs must carefully consider blinding, choice of comparator arm, choice of dose, number and timing of doses, and the set and setting of the dosing session when designing these trials, as they will present key touch points from a regulatory perspective. It remains extremely difficult to come up with an effective blind so that the patient doesn't know if they have been given a powerful hallucinogenic or a placebo. For example, some studies have used active comparators in their control group, such as niacin, which usually creates a flushing sensation in the skin, but even this is purported to be easily distinguished from the drug under trial. Other studies have considered a low dose of the active drug; this aids in obscuring the participant’s perception of the treatment assignment but can also make it more difficult to achieve signal detection with the active drug. Another approach to blind maintenance is to separate the clinical site staff who are involved in the dosing of the patient and those who are involved in assessing its efficacy. This means the latter are blinded to what the patient has been given and even which study visit for which they are administering an assessment (e.g., baseline vs. postdosing), and this firewalling should be an advantage from a regulatory submission perspective. Patients being able to assess so easily whether they have been given a drug or a comparator can also make retention in these trials problematic. Those receiving the placebo may be more likely to withdraw as they may perceive they are not going to receive any therapeutic benefit, and this differential dropout can bias trial results. Several study designs can be considered to mitigate this issue, including crossover designs or an open-label extension in which patients in a placebo-controlled trial receive the drug once they have completed the trial. Key benefits of an open label extension are that it allows for the collection of additional longer-term safety data and can provide data on additional doses if the active drug is given to both the drug and placebo groups during the extension. Expectancy effects, where participants or observers have an expectation of a result which unconsciously affects the outcome, can be a real problem in these situations where maintaining the blind is difficult. Participants and/or therapists knowing which treatment they have been given can induce positive effects in the active group and negative effects in the placebo group, leading to a potential overestimation of the treatment effect. Another key challenge when designing these trials is endpoint selection – and particularly the timing of when the primary outcome will be assessed. Unlike standard care treatments for conditions such as depression, which do not really kick in, or start working, for weeks to months, the psychedelics currently under investigation tend to have very immediate, rapid onset effects which can be seen within days. However, questions remain regarding the durability of the effect. Are outcomes going to be measured the next day, next week or six months after the primary or secondary dosing session, or a Volume 14 Issue 2

Therapeutics combination of all three? In fact, with conditions like depression this is going to be an area of ongoing review to establish over what period of time and with what intervals between sessions offer the greatest therapeutic effect. In addition to some of the study design challenges these trials face, several unique and important components of psychedelic drug trials are the role of the facilitator and the setting of the dosing session, both of which contribute significantly to the entire patient experience. Facilitators, usually a trained psychotherapist, establish a rapport and relationship with the study participants ahead of the dosing sessions. It is their role to ensure that the patients feel comfortable and prepared for the experience. Then, during the dosing session itself, the facilitators stay with the participants for the entire time, possibly up to eight hours, and lead them through their experience. They can help guide them through difficult conversations or potential visual perceptual effects they may be experiencing. Over the following couple of days, these facilitators will need to support patients during drug-free integration sessions, covering aspects such as further processing of what happened during the dosing sessions and making sure that the participants are clear of any hallucinogenic effects that they may have experienced during dosing. Facilitators need to be well trained to correctly fill a role that is mission critical. Part of this should be hearing from leading experts in the field about what a patient actually goes through during these dosing sessions, the kind of imagery that may be evoked and how they can walk someone through these potentially frightening experiences. In addition to the critical role of the facilitator, referring back to the environment around the trial, it is important that the dosing room is appropriately furnished and does not look like a typical doctor's office! What's needed is a comforting space, more like a living room, bedroom or up market hotel. This idea of set and setting is an integral component of the psychedelic experience.

Another aspect that the CRO can advise on is patient selection and target sample sizes. CRO experience with similar trials will provide better insights into how many patients are likely fail initial screening or dropout of the trial before its conclusion. With psychedelics, it is vital that patients with certain disorders, such as schizophrenia, are screened out and, for example, as MDMA is a derivative of amphetamine, patient predisposition to potential addiction needs to be factored into the selection criteria. In rare cases, psychedelics may also cause a lasting psychotic reaction so anyone with a family history of psychosis needs to be carefully assessed. During the trial, two key aspects that need to have been carefully thought through are inspection readiness and risk management. Both need to be addressed in all clinical trials but those involving psychedelics are more at risk of regulatory audit of either the sponsor, sites, or the CRO itself. So having a robust risk management plan in place is particularly important and should be complemented by constantly evaluating trends that are being seen. Adopting this approach of continuous and centralised evaluation ensures that issues can be identified both within and across sites and mitigated during the trial rather than uncovered after the fact. Ideally, this kind of evaluation should be undertaken from a number of different perspectives. One of these should be from the clinical research associate staff who are working with the sites, as they are on the frontlines of any trial. They are ideally placed to report on any issues, trends or deviations they see on site visits and ensure that reporting is consistent across all the sites. Data management and statistical staff can centrally evaluate trends in data integrity, timeliness of data entries, and site performance, for example, to complement the boots-on-the-ground monitoring done by the CRAs. Finally, synthesising the trends, informing the sponsor of red flags, and suggesting and implementing follow-up actions is a critical CRO responsibility in implementing a successful risk management strategy.

Given the design and operational complexities of trials in this field as well as the emergence of myriad small pharmaceutical companies with limited experience in executing multisite RCTs, the importance of selecting a CRO with strong qualifications and experience in the field becomes paramount. Trials involving psychedelics are so different than those in other drug classes, and it is vital that companies partner with a CRO that can help them navigate successfully through all the special requirements these entail and allow them to hit the ground running. The Emmes Company has been supporting multisite randomized clinical trials in psychedelics for over 5 years and is uniquely positioned to partner with companies interested in breaking into this exciting space.

And finally, the CRO’s relationship with site networks and a datadriven site identification and feasibility process will be invaluable in meeting Sponsor timelines for study start-up and enrollment. For example, in order to get a trial up and running the site may require a DEA license and that’s a process that can take months of time to be put into place. So it is knowledge of this type of information that forms a critical path, identifying sites who have navigated the process already or working with the site and the investigators to meet these regulatory requirements is key to ensure that start-up can be successful. Additionally, having established links with key academic institutions and commercial sites with infrastructure in place and experienced facilitators and other staff can be critical to a CRO’s ability to get a trial off the ground. Unfortunately, experienced clinical sites with bandwidth to support the huge surge in trials in this field is currently in short supply, but with the growing interest there seems to be an increase in investigators at both academic and commercial institutions eager to get involved.

The value a strong CRO can add to ensuring the success of these trials starts early on in the drug development lifecycle. We are at a unique time right now where companies and regulatory agencies are being faced with many complex questions about how to run rigorous trials in this space and the kind of data that need to be generated to support regulatory approval. CROs can help determine regulatory strategy and facilitate early conversations with regulatory bodies, which can guide the number and nature of trials that are planned. A collaboration between the Sponsor and CRO established from the protocol concept phase onward will enable the CRO to provide expertise in issues related to design, operations, and analysis. CROs can help develop the research questions targeting the key issues Sponsors and regulators care about and translate these into testable statistical hypotheses.

Conclusion The most impressive and important thing we can say is that in the trials we have seen undertaken, while difficult to blind, dose and navigate regulatory issues, we have seen some surprising rapid onset treatment effects with the potential for durability over time. Of course, there are many outstanding questions, and we see the need for innovative designs and strategies to overcome some of these thorny issues. We are excited to serve as a leader in the field to support investigators as they wrestle with these challenges as we have for the past 5 years in supporting multisite psychedelic drug development work. Over the next 5 years, I think we may see psychedelics approved for a number of therapeutic indications related to mental well-being and even other neuroscience indications. For Emmes as a business, undoubtedly with our history in this area and our close relationships with these trial sites we will see

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and, are already seeing, a rapid increase in companies coming to us to explore trial design, development and execution. The challenge, if we are to deliver on the promise already seen, is empowering enough innovators, both large and small, with experienced teams and clinical resources so that therapeutic options can be approved and brought to patients quickly. Yet the rate of growth is only expanding, and we are only at the beginning, with the full research opportunities now being revaluated from so many different angles and for many different indications. CROs and research institutions that have helped bring forward these initial successes are therefore going to be high demand, and if we can help innovators ensure they follow best practice and if the science bears it out we could be heading into a future where a whole raft of psychological disorders with limited or unsatisfactory treatments have a new option for fast and hopefully lasting relief. All on the back of drugs still perceived by society as purely for recreational purposes – what will be fascinating is to see, as perception changes, is all the new research opportunities that begin to abound, and we plan be guiding our partners every step of the way. REFERENCES 1. 2. 3. 4. 5.

https://www.nature.com/articles/d41586-021-00187-9 https://www.theguardian.com/science/david-nutt https://www.bbc.co.uk/iplayer/episode/m000w7bq/the-psychedelic-drugtrial https://www.nature.com/articles/s41591-021-01336-3 https://ir.compasspathways.com/news-releases/news-release-details/ compass-pathways-announces-positive-topline-results

32 Journal for Clinical Studies

Dr. Steffanie Wilson Steffanie Wilson has a PhD in Biostatistics from the University of Pennsylvania and has been working for The Emmes Company since 2011. Over the last ten years, Steffanie has supported studies within the company's neurology portfolio and currently serves as the Director of its Neuroscience Therapeutic Research Unit. In this role, she oversees all of the Neurology and Mental Health clinical research projects run by Emmes in both biopharma and the public sector. This includes work in both common disease indications such as epilepsy, migraine, TBI, PTSD, depression, substance and alcohol abuse and schizophrenia and rare indications including Giant Axonal Neuropathy, Limb Girdle Muscular Dystrophy, NeimannPick Disease, and others. Her portfolio includes Phase 1 through 3 clinical trials as well as long-standing observational studies and a common data element initiative project with the National Institute of Neurological Disorders and Stroke and a tissue consortium project with the National Institute of Mental Health. Steffanie also serves as a Principal Investigator for a number of data coordinating center projects within and outside the company's Neuroscience Unit including the several psilocybin clinical trial programs, the NINDS-sponsored Center for Clinical Research Resources project, and the National Heart, Lung, and Blood Institute sponsored National Myelodysplastic Syndromes Natural History Study.

Volume 14 Issue 2

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Journal for Clinical Studies 33

Technology

Artificial Intelligence in Clinical & Medical Research Abstract While clinical trials have become lengthy and very costly with low success rates, the application of innovative artificial intelligence (AI)-based approaches has been recognised for its potential to transform the slow and expensive current approach to clinical trials into a more cost-effective process with higher success rates. Over the past few years, the number of AI-based approaches are being increasingly applied across different stages of drug development such as drug discovery, manufacturing, clinical trial data management, and pharmacovigilance, which have already increased the biopharmaceutical industry’s ability to improve the drug development process. The adoption of these AI-based approaches is steadily increasing within biopharmaceutical companies, are also now often partnering with a variety of companies developing AI-based approaches. This positive trend in adopting this technology is partially due to a new regulatory frameworks established by regulatory agencies combined with a growing culture of data sharing and data digitisation, which are incentivising biopharmaceutical companies to reshape critical steps of the drug development process and and using AI-based approaches. In the next few years, remarkable advancements and stunning efficiencies in drug development as well as significant patient-centric applications could be gained by implementing novel AI-based approaches. Introduction Rapidly increasing amounts of clinical data available to the biopharmaceutical industry has enhanced the allocation of resources by many established and start-up companies to develop and use novel AI-based approaches. The biopharmaceutical industry is gaining understanding of the power of large-scale data management and analysis by leveraging these AI-based approaches. It is becoming increasingly evident that AI-based approaches can add value across the spectrum of clinical trials, including protocol development, drug regimen selection, clinical site selection, and participant management. Biopharmaceutical companies can now better understand their own data repositories and how they can leverage insights more effectively for future clinical trials using AIbased approaches, which translates into a better use of data, and a higher return on investment (ROI) over time. These AI-based approaches have the potential to improve clinical trials success rates, and therefore bring new treatments to patients sooner. In addition, there is an unparalleled opportunity to adopt a wide range of patient-centered AI-based approaches to reduce the burden on participants in clinical trials. In this editorial, we will describe novel AI-based approaches that are currently being developed and implemented in clinical trials, provide regulatory considerations, and make some final remarks on the near future of AI-driven clinical trials. 34 Journal for Clinical Studies

Novel AI-based Approaches to Clinical Trials Participant selection, recruiting, and retention constitutes the number one cause for clinical trial delays and are key factors causing a clinical trial to be unsuccessful; 86% of all clinical trials do not meet enrolment timelines and close to one third of all Phase 3 clinical trials fail due to enrollment issues.1 Improving participant selection is critical in a clinical trial design because it may decrease the number of participants required to observe a treatment effect – by increasing the likelihood of a participant to respond to the study drug – which has important ramifications, including reducing clinical trial costs and time burden for biopharmaceutical companies and clinical research organisations (CROs). The other side of the coin is that it may decrease the number of participants exposed to treatments from which they are not likely to obtain benefit. This is not trivial, as it has been reported that the ten-highest grossing drugs in the United States (US) fail to improve the conditions of many individuals,2 i.e., there are effective treatments for a few and ineffective treatments for many. While improving participant selection does not guarantee success of a clinical trial, enrolling unsuitable participants increases the likelihood of its failure. There are multiple AI-based approaches that can facilitate more efficient participant identification for a clinical trial. Some AI-based approaches have the ability to correlate large and diverse datasets such as electronic health records (EHRs), medical literature, and clinical trial databases to improve participant-trial matching. Another AI-based approach is changing the traditional approach to drug development; instead of aiming to find the proper treatment for a given disease, it finds the suitable participant for a given treatment by predicting a participant's clinical progression across a specific disease. Improving participant retention during a clinical trial may be critical to demonstrate the efficacy of a study drug. A large number of participants who drop out during a clinical trial may lead to an underpowered clinical trial, which negatively impacts the clinical trial data and the integrity of the clinical trial. Novel AI-based approaches can reduce the clinical trial burden for participants in a variety of ways, and therefore improve participant retention. There are some AI-based approaches that enable capturing participant data outside of the context of a clinical trial, which reduces the burden of data collection for participants. Another AI-based approach is to directly target the participant’s sentiment using semantic tagging and linguistic parsing; this technology can identify participants who are at risk of dropping out and recognise what factors lead participants to consider leaving the clinical trial. Other AI-based approaches have developed ways to analyse conversations between participants and Principal Investigators (PIs)/site staff to improve the participant engagement process; methods have also been developed to capture remote data through sensor-equipped wearable devices and other remote data-capture technologies that enhance the understanding of participants’ behaviour during a clinical trial. In addition, there are AI-based approaches that can enable participant monitoring Volume 14 Issue 2

Technology and gathering of real-time insights by automating data collection, digitalising common clinical assessments, and sharing data across systems, thereby predicting the risk of participants likely to drop out. An AI-based mobile application using facial recognition aimed to measure study drug adherence during a clinical trial has shown to increase compliance by 25% in a Phase 2 clinical trial.3 Proper clinical site identification is one major step in setting up a clinical trial to successfully recruit the required number of participants without incurring costly recruitment delays. The process of selecting clinical sites for a clinical trial typically includes factors such as participant population availability, resources, and data collection procedures at the clinical site. However, the lack of transparency in clinical site quality combined with personal relationships and level of confidence with PIs may create bias in the selection process within biopharmaceutical companies/CROs. AI-based approaches can help to resolve these issues. For example, applying the inclusion and exclusion criteria of a particular clinical trial through an AI-based algorithm to the clinical site database can enable biopharmaceutical companies/CROs to determine a more precise and realistic number of participants available for recruitment at a clinical site for a specific clinical trial. Another unbiased AI-based approach expedites clinical trial start-up and successfully predicts recruitment, identifying highperforming clinical sites and qualified PIs by leveraging mathematical modelling based on past clinical site performance. Poor selection of clinical sites is closely associated with the particularities of each clinical trial protocol. Specific modifications in inclusion and exclusion criteria, endpoints, and particular requirements for each clinical trial may lead to higher levels of screen failures at a given clinical site than anticipated. This is just one reason, among others such as protocol design inconsistencies, regulatory requests, and participant recruitment difficulties, that typically leads to protocol amendments. Protocol amendments can lead to months of delays and adds hundreds of thousands of dollars to the cost of a clinical trial. According to the Tufts Center for the Study of Drug Development (Tufts CSDD), almost 60% of clinical trial protocols are subject to amendments.4 AI-based approaches can de-risk protocol amendments due to the capability to mine large amounts of clinical trial-related documents needed to develop a protocol and attain it faster and on a larger scale. For example, an AI-based platform enables faster and more efficient protocols by recommending the optimal primary and secondary endpoints to ensure they are acceptable to regulators, payers, and participants. The platform can also determine how the eligibility criteria impacts outcomes such as cost, study duration, or participant retention. As the biopharmaceutical industry keeps developing and implementing new AI-based approaches, we can also learn from other industries that excel at adopting novel technologies. For example, adopting novel AI-based approaches such as digital twins – a digital representation that allows modelling the state of a realworld person or process; this technology has been applied to aircraft engineering and spacecraft simulators and is considered to have impressive potential in revolutionising the field of health.5 In the healthcare space, we find start-ups aiming to shorten the time-tomarket for medical devices by creating digital twins of bone and muscle groups to simulate how medical devices or implants might degrade within a patient’s body over time, or creating digital twins focused on metabolism, which individuals and their providers use to plan out lifestyle changes that could help prevent or reverse metabolic disease. Digital twins are the latest technology that biopharmaceutical companies are exploring to transform drug development. Digital twins can be used, for example, to test new drugs to ascertain drug safety and effectiveness. Also, predicted clinical outcomes from www.journalforclinicalstudies.com

digital twins generated from participants’ baseline data in randomised clinical trials (RCTs) can enable clinical trial designs with fewer required number of participants or higher power without introducing bias and generating reliable evidence similar to traditional RCTs. Regulatory Considerations Regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) play a critical role in endorsing the use of AI-based approaches in clinical trials and importantly, accepting these approaches as part of a new drug marketing application package. Regulatory agencies have at least two important roles in this context.1 Serving as active reviewers of AI-based evidence to gain internal confidence in the outcomes. As data sharing becomes recognised as increasingly valuable among regulatory agencies and biopharmaceutical companies, it incentivises the development and implementation of AI-based approaches in clinical trials. This trend should facilitate reproducibility and data validity, which will gradually “move the needle” of the regulatory agencies’ confidence in the safety and effectiveness of this technology in clinical trials.2 Serving as a catalyst of change, working closely with the biopharmaceutical industry to continue expanding regulatory frameworks for assessing AI-based approaches. Currently, the FDA largely regulates AI-based approaches as Software as a Medical Device (SaMD). Approved SaMD includes software that helps to detect and diagnose a stroke by analysing magnetic resonance imaging (MRI) images, or computer-aided detection software that processes images to aid in detecting breast cancer. In addition, the FDA has recently expanded its established qualification programs for drug development tools (DDTs) – biomarkers, clinical outcomes assessments, and animal models – to include the Innovative Science and Technology Approaches for New Drugs (ISTAND). ISTAND is a pilot program to encourage the development of DDTs that are out of scope for the existing DDT program such as AI-based approaches. On the other hand, EMA has well-defined regulatory pathways to qualify novel technologies such as AI-based approaches - the qualification of novel methodologies for medicine development. Recently, the International Coalition of Medicines Regulatory Authorities (ICMRA), a strategic coordinating, advocacy, and leadership entity of regulatory authorities that work collaboratively, has made recommendations to help regulators address the challenges that the use of AI poses for global medicines regulations.6 Some of these recommendations include the need to apply a risk-based approach to assessing and regulating AI, or establishing strengthened governance structures within biopharmaceutical companies and developers of AI-based approaches to oversee algorithms and AI deployments that are closely linked to the benefit/risk of a medicinal product. In addition, there are legal frameworks such as the US Health Insurance Portability and Accountability Act (HIPAA) and the European Union General Data Protection Regulation (GDPR); these statutes and regulations continue to evolve as governing and protecting sensitive health data becomes increasingly complex. AI and Future Clinical Trials In future years, clinical trials are expected to become increasingly decentralised, customised, and built on precise predictions of clinical trial outcomes, which will lessen the financial and time burden on participants. Connected AI-enhanced digital technologies will substantially transform clinical trials by making them safer, more efficient and effective, and above all, truly patient-centric, i.e., making decisions based on participants’ needs and perspectives. While it is evident that there is huge potential for AI-based approaches to transform clinical trials, we cannot avoid the ethical and legal challenges that these AI-based approaches pose. Challenges such Journal for Clinical Studies 35

Technology as including the appropriate description of this technology into the informed consent, safety and transparency, algorithmic fairness and biases, data protection and privacy, or safety and effectiveness need to be carefully considered as we incorporate these technologies. In addition, widespread implementation of AI-based approaches within the biopharmaceutical industry will not happen overnight, as this industry has a long-standing tradition of risk-aversion. Barriers such as the reluctance to incorporate new technologies in an industry with an already high risk of failure, the difficulty in definitively quantifying benefits like patient-centricity and the overall probability of success will need to be overcome. Years from now, when we look back at today’s breadth of AI-based approaches, we will likely determine that we were only seeing the tip of the iceberg for the potential uses of AI-based approaches in drug development. The AI space is experiencing huge momentum

in drug development and adoption of these technologies seems to be within a matter of time despite predictable resistance. A recent market forecast for the global AI use in drug discovery and development is estimating a Compound Annual Growth Rate (CAGR) of 31.6% from 2020 to 2027, with a market valued at $520 million in 2019, and projected to reach $4,815 million by 2027.7 These AI-based approaches will continue to bring greater precision and efficiency to each stage of the process by, for example, leveraging more data from each participant, developing novel participant-centric endpoints, and collecting and analysing real-world data. Importantly, evaluation of successful implementation of AI-based approaches over time will be warranted and key performance indicators such as clinical trial success rates, average time to conduct a clinical trial, participant safety, and reduced participant burden should be taken into account. It is our collective responsibility to embrace the opportunity that AIbased approaches present to make clinical trials significantly more efficient and more patient-centric. To quote the former CEO of the Walt Disney Company Bob Iger, “the riskiest thing we can do is just maintain the status quo.” REFERENCES 1.

2. 3.

6. 7.

Huang, GD, Bull J, Johnston, K et al., 2018. Clinical trials recruitment planning: A proposed framework from the Clinical Trials Transformative Initiative. Contemporary Clinical Trials; 66 (74-79) Schork, NJ. 2015. Personalized medicine: Time for one-person trials. Nature; 520 (609-611) Bain, EE, Shafner, L, Walling DP, et al., 2017. Use of a novel artificial intelligence platform on mobile devices to assess dosing compliance in a Phase 2 clinical trial in subjects with schizophrenia. JMIR Mhealth Uhealth; 5(2): e18 Getz, KA, Stergiopoulos, S, Short, M et al., 2016. The impact of protocol amendments on clinical trial performance and cost. Therapeutic Innovation & Regulatory Science: 50 (436-441) Erol, T, Mendi AF, Dogan, D. 2020. The Digital twin Revolution in Healthcare. 4th International Symposium on Multidisciplinary Studies and Innovative Technologies (ISMSIT). https://www.ema.europa.eu/en/news/artificial-intelligence-medicineregulation Allied Market Research. Artificial Intelligence for Drug Development and Discovery Market By Type, Indication, and End User: Opportunity Analysis and Industry Forecast, 2020-2027

Dana Jasek Dana is a clinical marketing professional whose passions are communication and transforming healthcare with technology. Dana has over 10 years of experience in healthcare, including work in the fields of speech-language pathology, genetics, precision medicine, and clinical research. Dana holds an M.S in communicative Disorders from University of Redlands and a B.A. in Communicative Disorders from University of Wisconsin – Madison.

Luis Olmos Luis is a scientist at heart with interest in business and innovation. Luis has over 15 years of professional experience in neuroscience research at academic institutions combined with work within the pharmaceutical industry. Luis holds a PhD from University of Malaga (Spain), and an MBA from IE Business School (Spain).

36 Journal for Clinical Studies

Volume 14 Issue 2

14 & 15 September 2022 | Geneva, Switzerland

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Journal for Clinical Studies 37

Events Review

ATMP Hybrid Conference – An Irish Perspective The Parenteral Drug Association (PDA) is the leading global provider of science, technology and regulatory information and education for the pharmaceutical and biopharmaceutical community. Founded in 1946 as a non-profit organisation, PDA is committed to developing scientifically sound, practical technical information and resources to advance science and regulation through the expertise of its near 10,000 members worldwide. Conferences, meetings, and courses bring together pharmaceutical manufacturers, suppliers, users, academics, and regulatory officials to discuss and boost issues of mutual interest. These exchanges of technical knowledge, expertise, and best practices assist the advancement of pharmaceutical science and technology in the interest of public health. Recently, the design and development of a modern health policy in the field of regenerative medicine leads to the formation of a new and integrated cognitive field, which requires systematic research and study to produce innovative answers and best practices. Advanced therapy medicinal products (ATMPs) are a new product category, which is at the heart of concern since it has to deal with diseases in which traditional medicine has proven to be ineffective so far. The ATMPs consist of three basic categories of products: 1) gene therapy (gene therapy medicinal products (GTMPs)); 2) somatic cell therapies; and 3) tissue engineering products, as well as any combination of the above. These are products that use human cells and tissues which have undergone gene or other treatment or modification in the laboratory. The donor and the recipient of the cells/tissues may be the same individual (autologous use) or different (allogeneic use). Cell therapy and gene therapy are overlapping fields of biomedical research and treatment. Both therapies aim to treat, prevent, or potentially cure diseases, and both approaches have the potential to alleviate the underlying cause of genetic diseases and acquired diseases. PDA’s Ireland Chapter organised the ATMP Hybrid Conference on the 26th of November 2021 in Dublin. An attendance of more than 250 people both in-person & remotely, gathered to discuss the importance of ATMP as the next wave of therapeutics and enhance the contribution that the biopharma sector makes to the Irish economy as well as deliver solutions to unmet and existing medical needs. “I believe Ireland is very well positioned and with a very strong pharmaceutical and biopharmaceutical industry worth around over €140B in exports. Most of the main companies in the world manufacture here (Ireland). I think we do have all the components of what a very successful sector in the future should be”, affirms Matt Moran, Director at BioPharmaChem Ireland. Moran adds: “The Covid-19 pandemic has had a huge impact and we now have an mRNA vaccine, which is a new technology. And it is proven to be very successful in the treatment or prevention of Covid-19 through vaccination. And what I think is very encouraging about this new technology is that it has got huge potential to be used in other therapeutic areas as well as dealing with new variants of the Covid-19.” The main aim of the event sponsored by renowned organisations like IPS, Bioquell, Koerber, Pharmalex, Steris & SteriTech was an ideal 38 Journal for Clinical Studies

meeting ground to provide comprehensive information on ATMPs, which could be applied in various regenerative medicine and tissue engineering applications. Moreover, ATMPs could be a valuable tool for the physicians for the proper administration of life-threatening diseases, thus could be applied in personalized regenerative medicine. The event gave us a sense of returning to normality after two years of disruption. Although the pharmaceutical industry has never stopped, social gatherings and face-to-face events which have been vital to knowledge sharing & key partnerships had come to an abrupt halt. This conference was vital to regenerate a sense of purpose in the drug discovery and development world. It was also vital to highlight the role which Ireland can play in a global setting. “Bioquell Ecolab solutions are just delighted to be back here, to see people face-to-face again is just so important and we are so happy to support this industry. PDA Ireland events have always been brilliant events and always well attended. It’s just brilliant for us to get in front of these people again and to reconnect.” Says Kristen McKeown at Bioquell, one of the main sponsors of the event. True to PDA’s mission to promote the exchange of rapidly evolving information on the latest technology and regulations, the ATMP Hybrid Conference hosted topics like A Fully Integrated Ecosystem for Manufacturing Gene Therapies from Clinical through Commercialisation, mRNA Vaccines – An Overview of the Manufacturing Challenges & Bottlenecks, New Momentum for Advanced Therapies: How Regulators can help. The event, moderated by Valerie Mulholland, started with a welcome speech from Ann McGee, PDA Ireland President, and Matt Moran, Director BioPharmaChem Ireland. Between face-to-face and online presentations, some important names of the industry gave their insights into some topics, like Bertie Daly at Takeda who talked more about the contamination control strategy for cell therapy manufacturing facility and Dr. Christian Schneider, who spoke about how regulators can help in advanced therapies, between others. The event enabled attendees to • • • •

Discuss business-related questions with regulators, industry, and academic organisations Ignite conversation, collaboration, and change in how we improve access to innovative treatments by accelerating their way to the market and ultimately to patients Gain practical knowledge on how to best navigate the complex access landscape of advanced therapies Create solutions in various formats with plenary sessions and interactive sessions

By the end the event the feedback from all the attendees was excellent. “It’s a delight to be sponsoring the PDA event. There was a sense of joy from people, from seeing the familiar faces and some unfamiliar ones also. It was just great to be back “mentions Bernard Flynn at Elis Cleanroom. Brian O’Connor from MeiraGtx, exclaimed “It is Immediately clear from the interaction you get from before and after the presentation. People will come and chat with you. Something you can’t necessarily do online. You can’t be in person and get that face-to-face interaction” Please find more at: www.pda.org/chapters/europe/Ireland Volume 14 Issue 2

Events Review

PDA Ireland Chapter, Event Committee

Guest Speakers

Valerie Mulholland, GMP Services Ltd, MC

Guest Speakers

Name: Brian O’Connor, Director of Quality Assurance Company: MeiraGTx Ireland Feedback: “Thank you Kevin, and all the PDA Ireland team, for the privilege to speak among such an esteemed panel of speakers. It is clear that the development of ATMP manufacturing in Ireland has great momentum and it was inspiring to hear first-hand the details on the projects happening across academia and industry.”

Name: Matt Moran – Director BioPharmaChem Ireland Company: BioPharmaChem Ireland Feedback: “Great presentation Bertie and Aidan – fascinating to see the challenges that you have overcome to deliver this product – a whole new ball game!”

Name: Niall Barron, Principal Investigator, Cell Engineering Lab Company: NIBRT Feedback: “Thank you Kevin and co at PDA Ireland. Great event and really looking forward to seeing Ireland go from strength to strength in the production and delivery of ATMPs!”

Name: Christian K. Schneider, M.D., Head of Biopharma Excellence/Chief Medical Officer (Biopharma) Company: Biopharma Excellence Feedback: “Also from my side thank you so much for having me in the conference. Brilliant speakers, and the conference highlighted what power the Irish ATMP life sciences community has. I really hope to learn more in the future!”

Name: Bertie Daly, Manufacturing Head Cell Therapy Company: Takeda Feedback: “It was my pleasure to present with Aidan at the prestigious PDA event. Great meeting with the SME’s on the panel sharing their knowledge and expertise on the various presentations. Special mention to the organizers, Aidan Harrington for providing the opportunity to present and of course Valerie Mulholland our moderator for making the event such a success.”

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Name: Kevin Smyth, IPS Company: IPS-Integrated Project Services GmbH Feedback: “IPS were delighted to be the main sponsor of the fantastic event. The PDA Ireland committee successfully managed to provide us with top class international ATMP expert speakers from Ireland, the UK and mainland Europe. In addition to the excellent speakers and presentations, the open floor Q&A sessions were very informative and highly interactive. Everybody who attended this conference established new contacts and learned more about the fascinating and rapidly developing ATMP Biopharma Industry . Well done to all the organisers, presenters and delegates.”

Name: Trevor Brett, Director, Business Development Company: PharmaLex UK Feedback: “Thank you for PDA arranging such an insightful and enjoyable ATMP event: Scores 11 out of 10! The talks by Takeda and Meira were totally awesome.”

Name: Catherine Jomary, PhD., Technology Lead ATMPs Company: IPS-Integrated Project Services GmbH Feedback: “Thank you very much for your kind invitation to the meeting, for introducing me to the Dublin IPS Team and to Ireland experts in ATMPs. I really enjoyed the meeting, and congratulations for the organisation!”

Journal for Clinical Studies 39

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Volume 14 Issue 2

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