JCS V13 I2

Volume 13 Issue 2

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Perspectives of Clinical Trials in Inflammatory Bowel Disease Recent FDA Approvals Target Zaire Ebolavirus Bayesian Methods: Transforming the Future of Clinical Research FDA UDI vs. EU MDR Regulations: Consideration of the Regulations and Implications for EU Labelling

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Contents

JOURNAL FOR

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

4

FOREWORD

WATCH PAGES 6

Recent FDA Approvals Target Zaire ebolavirus

Two drugs recently approved by the US Food and Drug Administration (FDA) treat disease caused by the Zaire ebolavirus, one of the three viral species responsible for the largest EVD outbreaks. Bundibugyo ebolavirus and Sudan ebolavirus are the other two species. Zaire ebolavirus is the most fatal, according to the US Centers for Disease Control and Prevention (CDC). Meg Egan Auderset at Clarivate explains the recent FDA approvals to target Zaire ebolavirus.

8

Could COVID-19 be the Catalyst for Change in Future Rare Disease Research?

Around 300 million people suffer from a rare disease. Figures published in Tufts CSDD Impact Reports (2019) highlight the passion within the rare disease population to be involved in research, with dropout rates lower than in any other indication. Amy Bumford at Illingworth shows how clinical research can better support individuals and their families in the future.

10 Challenges to Clinical Trials During a Pandemic There has been a difficulty with patient recruitment if patients are homebound or reluctant to go to clinics, or if clinics allow only essential or critical visits or refuse to take part in trials. Obtaining informed consent for trial participation has typically taken place faceto-face, but with this not being possible due to COVID restrictions, the industry should attempt to move to electronic consent methods. James Klingelhoefer and Ben Singleton at Peli BioThermal demonstrate some of the challenges to clinical trials during a pandemic.

12 Digital Health and a New Drug Discovery We are currently facing an industrial revolution in the era of big data and artificial intelligence (AI) which affects all fields, including biomedicine.

This industrial revolution started first in society and the relationship between people, driven by commonly used social media, and has finally reached medicine, where it is changing our approach to understanding and fighting diseases. Caterina AM La Porta at ComplexData analyses how digital health is related to new drug discovery.

REGULATORY 14 Bayesian Methods: Transforming the Future of Clinical Research

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 13 Issue 2 April 2021 PHARMA PUBLICATIONS

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Today, a range of Bayesian methods or techniques are being used to drive some of the most important scientific advancements of our age, from novel oncology drugs and pandemic vaccines to medical device innovation. Bayesian methods offer powerful predictive capabilities and evidence-based hypothesis adjustment, leading to de-risked and expedited clinical trials. Ofir Harari, Pantelis Vlachos and Yannis Jemiai at Cytel analyse how Bayesian methods are transforming the future of clinical research.

18 FDA UDI vs. EU MDR Regulations: Consideration of the Regulations and Implications for EU Labelling In the EU, the new EU MDR regulation came into force in May 2017 (2017/745) and will replace the current Medical Device Directive Journal for Clinical Studies 1

Contents (MDD) for all medical devices distributed in the EU. Similar to the US UDI regulation, it will require a code for tracking and a mark on the device itself. Debi Schimpf at Navitas Life Sciences explores the current FDA UDI regulation for medical devices and compares it to the upcoming EU MDR/IVDR regulation that will come into effect on 26 May 2021.

22 How to Develop a Statistical Analysis Plan for Clinical Trials A statistical analysis plan (SAP) is a defined outline of the planned statistical analyses for a clinical trial, including basic and advanced methods. An SAP is crucial, as it is one of the key regulatory confidential documents in the development of a clinical trial. It provides explicit guidance on statistical programming, as well as the presentation of results for a clinical trial. Depending on the organisation, statistical analysis plans might also be known as reporting and analysis plans or data analysis plans. Rudra Patel at Kolabtree explains how to develop a statistical analysis plan for clinical trials.

TECHNOLOGY 36 How CDMSs Are Driving the Switch from Clinical Data Management to Clinical Data Science Over the last ten years, the clinical research industry has evolved in many aspects. For instance, the industry is shifting from simple trials to global and more patient-centric trials. As the access to new data sources like wearables and electronic patient diaries (e-diaries) increases, data volume continues to grow. Therefore, integrating and analysing the data to extract its maximum value is becoming more complex. Rohit Jain, Sukhwinder Kaur, and Rebecca Lorenzo at Axtria explore the benefits for life science companies to use CDS to stay ahead of the curve as clinical trials continue shifting digitally.

MARKET REPORT 26 Paving the Way for a Robust Research Ethics Review Structure in Malaysia The foundation of good research is built on sound ethical principles, which require a good rationale, a solid methodology and proper consideration of the important ethical issues that may arise from the research. The main task of research ethics committees is to ensure the above principles, so all research involving human subjects will have adequate protection of their dignity, rights and safety. Asha Thanabalan, Hans Van Rostenberghe et al. at Clinical Research Malaysia aim to lay out the current challenges faced by various research ethics committees in the region, detailing the current Malaysian ethical and review landscape and present NERCIM as a proposed way forward to address these issues.

29 Decentralised Clinical Trials in Europe: Lessons from a Pandemic Many elements of decentralised clinical trials (DCTs) have long been available – including mobile devices, remote monitoring, telemedicine, and home health providers – but the decision to run these types of trials was simply a matter of preference. Since the onset of the COVID-19 pandemic, travel bans and site closures have forced a rapid transition from physical clinical investigative sites to virtual environments. Graham Belgrave at Advanced Clinical focuses on learnings from the pandemic in Europe, including case studies of the successful use of virtual approaches to run more agile and adaptive trials. The author explores how these advances may shape the future of drug development in this region.

THERAPEUTICS 32 Perspectives of Clinical Trials in Inflammatory Bowel Disease Inflammatory bowel disease (IBD), an umbrella term for chronic intestinal disorders with two subtypes: Ulcerative colitis (UC) and Crohn’s disease (CD), the result of an unrelenting, severe inflammatory response against an environmental trigger in a genetically susceptible host, with a lifelong and remitting course. Maxim Kosov and John Riefler at PSI CRO AG show some perspectives of clinical trials in inflammatory bowel disease.

2 Journal for Clinical Studies

Volume 13 Issue 2

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Foreword Last year has shown, more than ever, the value of a strong strategy, the ability to take risks, and the need to act courageously. Right across the pharmaceutical industry, people have risen to the challenges of bringing expertise and discovery in epidemiology, diagnostics, therapies, clinical practices, policies and economic impact to address the pandemic. New partners have emerged, new levels of courage have been mustered.

The traditional face-to-face patient–medical care model has had to be re-examined in many countries, with digital technology and new models of care being rapidly deployed to meet the various challenges of the pandemic.

Many elements of decentralised clinical trials (DCTs) have long been available, including mobile devices, remote monitoring, telemedicine, and home health providers, but the decision to run these types of trials was simply a matter of preference. Since the onset of the pandemic, travel bans, and site closures have forced a rapid transition from physical clinical investigative sites to virtual environments. Graham Belgrave at Advanced Clinical focuses on learnings from the pandemic in Europe, including case studies of the successful use of virtual approaches to run more agile and adaptive trials. The author explores how these advances may shape the future of drug development in this region.

Even before the pandemic hit health systems worldwide, hopes were high that the widespread development and deployment of artificial intelligence (AI) within healthcare could help overstretched care providers through the development of new drugs, the optimisation of data and information flows and the personalised and timely delivery of care. With the pandemic in full swing, it is timely to reflect on how AI can help (or has helped) health systems to manage the crisis and to consider the role of AI as countries prepare for a potential second wave of infections linked to coronavirus.

and the relationship between people, driven by commonly used social media, and has finally reached medicine, where it is changing our approach to understand and fight diseases. Caterina AM La Porta at ComplexData analyses how digital health is related to new drug discovery.

The COVID-19 pandemic should not make us lose sight of the major impact of environmental and lifestyle risk factors in the current burden of other diseases, which also bear an increasing toll on mortality. Two drugs recently approved by the US Food and Drug Administration (FDA), treat disease caused by the Zaire ebolavirus, one of the three viral species responsible for the largest EVD outbreaks. Bundibugyo ebolavirus and Sudan ebolavirus are the other two species. Zaire ebolavirus is the most fatal, according to the US Centers for Disease Control and Prevention (CDC). Meg Egan Auderset at Clarivate explains the recent FDA approvals to target Zaire ebolavirus.

In this journal, we will also look into inflammatory bowel disease (IBD), an umbrella term for chronic intestinal disorders with two subtypes: Ulcerative Colitis (UC) and Crohn’s Disease (CD). The result of an unrelenting, severe inflammatory response against an environmental trigger in a genetically susceptible host -with a lifelong and remitting course. Maxim Kosov and John Riefler at PSI CRO AG show some perspectives of clinical trials in inflammatory bowel disease.

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. I hope that you enjoy reading this edition of the journal and keep well.

Beatriz Romao, Editorial Co-Ordinator Journal for Clinical Studies

We are currently facing an industrial revolution in the era of Big Data and artificial intelligence which affects all fields, including biomedicine. This industrial revolution started first in the society JCS – Editorial Advisory Board • Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA • Bakhyt Sarymsakova – Head of Department of International

Cooperation, National Research Center of MCH, Astana, Kazakhstan

• Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

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

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

of Europe

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

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

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

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

Recruitment & Retention

• Francis Crawley, Executive Director of the Good Clinical Practice

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

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

• Georg Mathis, Founder and Managing Director, Appletree AG

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

• Hermann Schulz, MD, Founder, PresseKontext

• T S Jaishankar, Managing Director, QUEST Life Sciences

4 Journal for Clinical Studies

Volume 13 Issue 2

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SGS has a wealth of expertise in FIH studies, viral challenge testing, biosimilars and complex PK/PD studies with a high therapeutic focus in Infectious Diseases, Vaccines, and Respiratory. We offer a variety of tests that are bespoke, client-specific and support the full clinical development, from Phase I First-in-Human trials in our Clinical Pharmacology Units, to Phase II and Phase III studies in patients: • Drug Development Consultancy • Clinical Pharmacology Unit • Clinical Trial Management In Europe and Americas • Biometrics – Data Management, Statistics, PK/PD and Medical Writing

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Journal for Clinical Studies 5

Watch Pages

Recent FDA Approvals Target Zaire ebolavirus While the ongoing COVID-19 global pandemic continues to dominate both news cycles and the priority lists of pharmaceutical companies large and small, other viral diseases persist, sometimes catching the world off guard with devastating outbreaks that ravage communities in impoverished countries. The Ebola virus disease (EVD) is one.

Two drugs recently approved by the US Food and Drug Administration (FDA) treat disease caused by the Zaire ebolavirus, one of the three viral species responsible for the largest EVD outbreaks; Bundibugyo ebolavirus and Sudan ebolavirus are the other two species, but Zaire ebolavirus is the most fatal, according to the US Centers for Disease Control and Prevention (CDC). Zaire ebolavirus was linked to the largest EVD outbreak to date, in West Africa in 2014–2016. It infected more than 28,600 people and killed 11,310, most of them in Guinea, Sierra Leone and Liberia.

An ongoing outbreak in the Democratic Republic of Congo is also associated with Zaire ebolavirus.

6 Journal for Clinical Studies

The recently approved medications share the same indication: for the treatment of Zaire ebolavirus infection in adults and children, including neonates born to mothers who had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for Zaire ebolavirus.

• Inmazeb (atoltivimab; maftivimab; odesivimab-ebgn), by Regeneron Pharmaceuticals Inc, is a fixed-dose combination of three glycoprotein-directed human monoclonal antibodies (mAbs). It received FDA approval on October 14, 2020.

• Ebanga (ansuvimab-zykl), a glycoprotein-directed human mAb, was developed by Ridgeback Biotherapeutics LP under licence from the National Institute of Allergy and Infectious Diseases (NIAID). It received FDA approval on December 21, 2020.

EVD incubation ranges from two to 21 days, according to the World Health Organization (WHO), but symptoms can develop suddenly.

Initially, symptoms can include fever, fatigue, muscle, pain, headache and sore throat, the WHO says; subsequent symptoms can be very severe, including vomiting, diarrhoea, rash, impaired kidney and liver function, and internal and external bleeding. EVD is often fatal.

Volume 13 Issue 2

Watch Pages Initial ebolavirus infection in humans likely occurs via contact with wild animals, such as fruit bats or non-human primates, according to the CDC. The virus then spreads quickly from person to person, through direct contact with infected blood or bodily fluids, or via objects contaminated by infected blood or bodily fluids. Even after a person has recovered from EVD, certain bodily fluids can remain infectious, including semen.

Ebanga and Inmazeb Approvals Supported by the PALM Trial Data from the PALM trial (NCT03719586) formed the basis for both approvals. The open-label, randomised controlled Phase II/III trial evaluated four investigational drugs: Inmazeb, Ebanga, remdesivir, and the control, ZMapp (porgaviximab; larcaviximab; cosfroviximab).1 The primary endpoint was death at 28 days. PALM took place in the Democratic Republic of Congo, whose Ebola outbreak began in August 2018.

PALM opened in November 2018. The trial ultimately enrolled 681 subjects, including neonates and pregnant women. To qualify, patients had a positive RT-PCR for the nucleoprotein gene of Zaire ebolavirus and had not received other investigational treatments (excepting experimental vaccines) during the previous 30 days.

In August 2019, the PALM data safety and monitoring board recommended that patients be assigned only to the Inmazeb and Ebanga arms, after an interim analysis pointed to the superiority of those drugs over ZMapp and remdesivir.

According to the FDA-approved product labels for Ebanga and Inmazeb: •

•

174 subjects received Ebanga (ansuvimab-zykl 50 mg/kg) as a single intravenous (IV) infusion. At 28 days, 35% (61) of Ebanga patients had died versus 49% (83) of patients in the control arm (p-value = 0.008).

154 subjects received Inmazeb (atoltivimab 50 mg/kg; maftivimab 50 mg/kg; odesivimab 50 mg/kg) IV as a single infusion. At 28 days, 34% (52) of Inmazeb patients had died versus 51% (78) of patients in the control arm (p-value = 0.0024).2

Both the Inmazeb and the Ebanga sponsors received a Material Threat Medical Countermeasure (MCM) Priority Review Voucher from the FDA, which can secure priority review for a future drug application. Section 565A of the Federal Food, Drug, and Cosmetic (FD&C) Act established the priority review voucher programme for material threat MCMs, defined as “medical products intended to diagnose, prevent, or treat diseases or conditions associated with chemical, biological, radiological, and nuclear (CBRN) threats and emerging infectious diseases,” as the FDA’s Material Threat Medical Countermeasure Priority Review Vouchers guidance document explains.

Vaccines Approved to Prevent Zaire ebolavirus Infections The Inmazeb and Ebanga approvals followed the FDA’s approval of the first vaccine to prevent Zaire ebolavirus: Ervebo, by Merck Sharp & Dohme Corp (Merck), on December 19, 2019. The European Medicines Agency (EMA) had approved Ervebo a few weeks earlier, on November 11, 2019. Both agencies authorised the vaccine’s use in adults aged 18 years and older. Multiple other countries have since licensed Ervebo, including Burundi, Central African Republic, the Democratic Republic of the Congo, Ghana, Guinea, Rwanda, Uganda, and Zambia, according to the WHO. Ervebo remains the only FDA-approved vaccine for any species of ebolavirus. The EMA also approved the Zabdeno vaccine, by Janssen Pharmaceutica NV, on July 1, 2020, authorising its use to prevent www.jforcs.com

Zaire ebolavirus infection in adults and in children aged one year and older.

The FDA’s review of Ervebo safety and effectiveness took less than six months, a reflection of the “public health importance” of a vaccine to prevent Ebola virus disease, according to the agency. Approval came with a Tropical Disease Priority Review Voucher for Merck.3 Like the FDA’s priority review voucher programme for material threat MCMs, the tropical disease programme is intended to encourage sponsors to develop treatments in less-lucrative disease areas. Ebola rarely occurs in the US, the FDA has acknowledged; when US cases have arisen, they have involved healthcare workers who had treated EVD patients or people who were infected in other countries and then travelled to the US. REFERENCES 1.

2.

3.

Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019 Dec 12;381(24):22932303.

The Inmazeb arm was added later in the trial, so PALM compared Inmazeb patients to patients in the control arm who were enrolled at the same time during the trial.

The FDA’s Tropical Disease Priority Review Vouchers industry guidance, from October 2016, outlines requirements.

Meg Egan Auderset Meg Egan Auderset, MS, MSW, is a writer and editor of more than 25 years, with experience in a variety of settings in both the US and Western Europe. Currently a Medical & Regulatory Writer & Editor at Clarivate, her primary assignments include reporting on FDA advisory committee meetings, drug approvals, and the AdComm Bulletin, as well as editing several publications.

Journal for Clinical Studies 7

Watch Pages

Could COVID-19 be the Catalyst for Change in Future Rare Disease Research?

As we have just passed another Rare Disease Day, I wanted to concentrate on how clinical research can better support individuals and their families in the future. 300 million people suffer from a rare disease1. A tiny percentage of the whole population, but a significant figure, nonetheless.

Figures published in Tufts CSDD Impact Reports (2019)2, highlight the passion within the rare disease population to be involved in research, with dropout rates lower than in any other indication.

Recruitment rates were higher across all indications than in previous years but with an average dropout rate of 19.1% across all indications it demonstrates how incredibly low rare disease dropout is, at just 6.5%.

You would expect these dropout rates would mean clinical trial design was perfect for these populations, but I worry this is not the case.

Patients and families are so committed to trying to find treatments or support with their condition, it seems no length is too great. The most shocking example of this was an Icelandic family who were travelling to Canada for their trial visits. This usually involved at least a three-day round trip and all the family attending to manage the journey. In this example a specialist mobile research nurse was placed with the family who were considering dropping out as they simply could not cope with the travel any longer.

Fast forward a year and COVID-19 starts to take hold. Site visits halted, families left in limbo, managing rare diseases with little to no support and frightened of how COVID-19 might affect them. Suddenly, the clinical research landscape was forced into reform. If studies were to continue, alternative solutions would be required. That was where mobile research nursing came in, a service already growing in popularity within rare disease studies, but now brought to the front of sponsors’ wish lists.

Mobile research nursing enables patients to complete some of their clinical trial visits in a location to suit them, generally in the home.

Procedures such as bloods, vital signs, ECGs and abbreviated physical exams can be completed by a specialist skilled research nurse – a solution which offered a lifeline in keeping research going throughout the pandemic. Initially in some cases considered a short-term solution, but COVID-19 thought otherwise.

This service has been particularly successful within rare disease populations, as the distance to site becomes less of a factor when deciding to enrol. In one case study in Duchenne Muscular Dystrophy (DMD) all UK patients had to visit Great Ormond Street Hospital every week; challenging for a DMD patient, even if they live locally.

An example of this was a family who before mobile research nursing support had a journey which involved over 12 hours of travel, including a ferry trip, none of which were reimbursed. The introduction of the service meant this challenging and tiring journey was reduced from weekly to monthly visits for the family, enabling them to continue in the study.

We still want to develop the service further to truly understand how patients with certain needs due to their conditions can best be supported. For example, in an indication like Epidermolysis Bullosa, how can we best minimise pain for these patients when they need to travel? When COVID-19 restrictions allow, we hope to be able to discuss solutions with advocacy groups and families to develop a truly patientfocused solution for their issues.

8 Journal for Clinical Studies

In the meantime, patient travel within COVID-19 studies is an area we have been supporting by offering vehicles with a dual ventilation system, keeping both the patient and driver safe when site visits are required. This is offered as a part of our patient concierge service, PatientGO®, which delivers patient travel, hotels and reimbursements.

Again, an option which, alongside research nursing, sponsors will view as an option which improves the patient experience. Within the rare disease space, we see this as very beneficial in reducing the burden on families where travel and finances can become incredibly difficult, when a patient may have a debilitating condition specifically.

It's not all doom and gloom. We spoke with our Proposals Manager, Jessica, last year about her daughter’s rare condition and how they had coped during COVID-19. Jessica’s daughter, Amelia, received a diagnosis for her rare autoimmune condition in 2019. Jessica commented, “although COVID-19 has produced new obstacles for Amelia we are fortunate that she has been safely thriving at home. She has been able to continue checking in with specialists through mainly telehealth appointments.” Interestingly, Jessica also spoke about how virtual learning had actually benefitted Amelia and helped her engage with her classmates on a more level playing field.

Jessica and Amelia’s telemedicine experiences highlight another option for rare disease research. It's well documented that patients are often vast distances away from their sites, due to the nature of rare populations. During COVID-19, telemedicine has offered a lifeline to medicine, but why should it stop there? Telemedicine could be used alongside a mobile research nurse – this would allow the site to “see” their patient whilst a research nurse could perform any procedures required by the study, reducing the burden on the patients but also keeping them safe.

In conclusion, rare disease patients and their families are some of the most committed and wonderful people within the clinical trial community. It seems to me that it is time research was catered to them and their needs; after all, without their commitment, no study in these smaller populations would get started. I am hopeful the pandemic has taught us the importance of patient-centricity within research and demonstrated how technology and clinicians can start to deliver new solutions within the rare community.

REFERENCES 1.

2.

rarediseaseday.org, “meet the community”. https://www.centerwatch.com/articles/24543-recruitment-rates-rising-butretention-rates-fall-according-to-new-study

Amy Bumford Amy Bumford is a marketing specialist and Member of the Chartered Institute of Marketing. Amy has worked with Illingworth for 5 years and has focused on highlighting the growing number of patient-centric services within the clinical trial space. As Marketing Manager at Illingworth Research, Amy oversees the companies external profile and development of future marketing and patient facing materials.

Email: amy.bumford@illingworthresearch.com

Volume 13 Issue 2

Corporate Profile

Need to Keep a Safe Sterilizing Transit Path For laboratories wanting to maintain a secure, sterile path for media and waste as it passes in and out of a sealed laboratory specialist British autoclave manufacturer Priorclave can supply a choice of double-door (pass-through) autoclaves in various capacities.

Pass-through or Double door autoclaves are used in relatively small numbers and require often complicated building work as part of the installation process. Speak with a specialist, as they are considered a bespoke design and build – a unique build-program is required, introducing special bulkhead mounts to facilitate a strong structural fix into a dividing wall between the sterile lab and non-sterile areas. Once installed, the double-door autoclave is the perfect partner for creating that all important sterile transit path.

When Brunel University required a double-door/pass-through steam sterilizers as part of a new CAT III containment laboratory suite it was sourced direct from Priorclave. A 350L double-door autoclave was supplied and installed within the Heinz Wolf building, a Centre for Infection, Immunity and Disease Mechanisms, and a School of Health Sciences with a CAT II and CAT III Research Facility for secure decontamination of hazardous waste.

The autoclave is used for de-contamination of hazardous material prior to its release from the containment suite, therefore it was imperative that the double-door design had both ends of the autoclave isolated. Sealed at the point of passing through the wall by means of a specially designed bulkhead, the actual autoclave incorporates interlocks that prevent the door at the unloading end from being opened until the sterilization cycle has been successfully completed and the load is safe to pass into the unloading end.

Following installation Priorclave engineers returned to Brunel University to test the autoclave with actual loads and adjust the autoclave

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small-footprint, free-standing, vertical chamber autoclaves

Watch Pages

Challenges to Clinical Trials During a Pandemic Challenges There has been difficulty with patient recruitment if patients are homebound or reluctant to go to clinics, or clinics allowing only essential or critical visits or refusing to take part in trials.

Also, obtaining informed consent for trial participation has typically taken place face-to-face, but with this not being possible due to COVID restrictions, the industry should attempt to move to electronic consent methods.

Vendors and contractors have sometimes been unable to meet certain obligations, such as delivering drugs to certain sites due to limited flight availability/delivery options in-country being subject to local restriction, or limited availability of thermal packaging caused by the global increase in demand. All CT stakeholders need to ensure there are robust end-to-end supply chain processes in place to mitigate any risks in supplying CT material to patients.

Preparation and training – preparation of standard operating practices (SOPs) and training/guidance documents for staff not familiar with decentralised methods for trial conduct will help facilitate a smoother transition in the face of potential further disruption. Creating formalised, structured methods of conducting telemedicine will help in gathering consistent reliable data. If direct-to-patient supply of the investigational medicinal product (IMP) is appropriate, sponsors should consider any training or information the research staff and trial participant will need to allow selfadministration of the IMP at home. If self-administration is not feasible, the sponsor should consider the logistics of home visits and how to capture data from remote patient monitoring visits. In preparation for moving to a decentralised model of trial conduct, sponsors should begin to set up vendors and conduct due diligence on providers, including home care providers.

Hybrid Clinical Trials The pandemic required the rapid adaption to decentralised clinical trial models. What’s more is that the regulators (FDA and other agencies) worked closely with pharmaceutical sponsors to provide guidance on how to continue to clinical studies within the realm of the new COVID world. Although decentralised clinical trials and patient-centricity were already trending themes pre-pandemic, the trajectory of frequency has been significantly accelerated. Therefore, we expect to see future clinical trials build decentralised trials into their clinical study protocols.

These clinical supply chains will require careful planning to ensure that proper resources, such as conditioned temperature-controlled packaging, is provided to several distribution locations utilised in these hybrid clinical trial models. These distribution locations will include facilities like clinical sites (for site to patient distribution) or central pharmacies, that do not typically have significant resource to support conditioning of temperature-controlled packaging with freezers and refrigerators. As a result, we anticipate that pharma sponsors/CROs will seek cold chain support from their thermal packaging partners.

Technology The pandemic also spurred the increased utilisation of technology 10 Journal for Clinical Studies

in clinical trials. Virtual clinical trials which include telemedicine visits, remote monitoring, and wearable devices, have become part of the norm. As the pharma industry seeks to leverage additional data from technology, we also anticipate that technology will also be further leveraged in pharma supply chains. The pandemic cast a spotlight on the need for end-to-end supply chain visibility, and we believe the industry expectation will be that crucial investigational and commercialised therapies will be tracked with real-time tracking devices and integrated into holistic supply chain platforms.

Frozen Temperatures The race towards a rapidly authorised COVID-19 vaccine brought about interesting new challenges related to frozen temperature control. As these vaccine candidates were developed at “WARP Speed”, condensing what normally takes upwards of 10 years of research into one year, it necessitated transport of research and ultimately emergency authorised vaccine at temperatures colder than most distribution facilities can accommodate. In working with our customers, we supported “exotic” frozen temperature ranges that included: -30°C to -40°C, -40°C to -50°C, -60°C and colder.

With the deep-frozen temperature demand, it also created surging demand for dry ice. With a dual concern of sufficient dry ice supply and dry ice offload potential for air freight, pharma companies turned to phase-change refrigerants as an alternative to dry ice. These phasechange materials do not require dry ice to support frozen product temperature requirements, and they help avoid the risks associated with dry ice supply and air transport.

Ben Singleton Ben Singleton is Senior Business Development Manager at Peli BioThermal. Ben has worked for Peli BioThermal for over 12 years and is responsible for a number of key accounts in the Pharmaceutical, Clinical, and Specialist Courier industries. Prior to joining Peli BioThermal, he held a variety of Customer Service, Operational, Sales and Commercial Management roles during 10 years at a worldwide logistics company.

Email: ben.singleton@peli.com

James Klingelhoefer James Klingelhoefer Director of Sales Americas, has over 12 years experience in various leadership, sales and customer support roles having worked closely with pharmaceutical sponsors, CRO’s, CMO’s, packaging/labeling providers, and other life science organizations to leverage supply chain efficiencies and identify risk mitigation opportunities. As the former North America Sales Director at World Courier he was responsible for sales operations and clinical operations teams.

Email: james.klingelhoefer@pelican.com

Volume 13 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

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

Medical Diagnostic Laboratory Ramus Ltd

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Ramus Medical Ltd Tu

to Cito

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V

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Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 11 11

Watch Pages

Digital Health and a New Drug Discovery

We are facing an industrial revolution in the era of Big Data and artificial intelligence (AI) which affects all fields, including biomedicine. This was possible thanks to the capability to store a great amount of data and to the growing speed of computers which are able to perform more operations in a shorter time. This industrial revolution started first in society and in the relationship between people, driven by commonly used social media, and has finally reached medicine, where it is changing our approach to understanding and fighting diseases. Data sets grow rapidly in part because they are increasingly gathered by cheap and numerous informationsensing internet devices such as mobile phones. These technologies are entering in medicine too, speeding up the collection and increasing the amount of data. For instance, epidemic surveillance can now rely on large but low-quality data from social media to complement traditional public health approaches. Algorithms for automatic image analysis are rapidly outperforming trained humans in the classification of certain types of cancers or cognitive disorders including Alzheimer’s, schizophrenia, etc.

I started to work on these topics (AI and Big Data) about 15 years ago when very few people in biomedical research were trying to explore quantitative biology or quantitative imaging and apply machine or deep learning to biological data. Publishing these results, which were highly interdisciplinary, was not easy and it was also difficult to find the right journals that could appreciate a multidisciplinary point of view.

Like every revolution, in the beginning it is often ignored by most, but then suddenly becomes popular, contributing to a disruptive change. In fact, innovation does not happen gradually, and this is also true for learning and for other important steps in human life.

The main achievement of digitalisation in biomedicine is the possibility to extract useful information from all these data. It is well known that AI works very well on image recognition and indeed this has been its first application in biology. However, nowadays the mainstream is the possibility to connect genomic data to transcriptomes, proteomes and images in a multiplex network (Figure 1). This allows the identification of key aspects of a specific subject and the proposal of a personalised treatment. In this connection, the most pressing issue is to develop computational tools that are able to integrate and analyse data coming from different sources and, at the same time and more importantly, to ask the right questions to the data. In Figure 2 is shown a typical workflow where the data that are usually unstructured should become structured and then integrated, eliminating possible batch effects. Thus, they can be analysed using machine learning, through a complex network analysis or unsupervised learning to cluster the data and identify subcategories. The system is circular since the results and their meaning can help improve the analysis of other data. Combining data into large sets allowed us to better explore hidden but relevant information that would not appear when analysing small data sets because of the inevitable background noise. Big data analysis in biology is, however, still difficult and one of the main sources of difficulty is related to the fact that data shared within the scientific community are not uniform in their format. The potential of using these approaches, not only in the discovery of new drugs but also

Figure 1. An illustration of a multilayer network (CC BY-SA 4.0 Manlio de Domenico).

12 Journal for Clinical Studies

Volume 13 Issue 2

Watch Pages

Figure 2. The cycle of data. Image by Francesc Font-Clos.

during the treatment of a patient, would be very powerful. I provide here a simple example: if we had a platform that was able to segment the patients between responding and non-responding to a specific drug during treatment, it would be possible to perform a personalised medicine and the physician could modify the treatment accordingly.

Pharmaceutical companies are also changing their approach and start to appreciate the potentially interesting information hidden in already available data. Real-world data (RWD), in fact, include all the data going beyond what is usually collected in Phase III clinical trials and also any outcome that is not purely interventional.

Healthcare decision-makers are now starting to devise policies based on integrated evidence coming from a multitude of sources. This is important because it can provide information that goes beyond what has been obtained in the trial, such as the way a particular drug works in populations not covered by the trial. Finally, RWD includes information about the actual treatment patients received, also including co-morbidity, so that RWD can be used to study the effect of multiple interventions. www.jforcs.com

Caterina AM La Porta Caterina AM La Porta is an expert of Digital Health, Professor of General Pathology at the University of Milan, co-founder of the Center for Complexity & Biosystems of the University of Milan (www.complexitybiosystems.it), group leader of the OncoLab (www.oncolab.unimi.it) and CEO of ComplexData (www.complexdata.it), an Innovative startup of University of Milan. She developed and brought to the market ARIADNE (www.ariadneweb.it) an innovative platform that use AI to calculate the score of aggressiveness of triple negative breast cancer. ARIADNE has filed an international patent and got the CE mark form April 2021.

Email: caterina.laporta@unimi.it

Journal for Clinical Studies 13

Regulatory

Bayesian Methods: Transforming the Future of Clinical Research Today, a range of Bayesian methods or techniques are being used to drive some of the most important scientific advancements of our age, from novel oncology drugs and pandemic vaccines to medical device innovation. Bayesian methods offer powerful predictive capabilities and evidencebased hypothesis adjustment, leading to de-risked and expedited clinical trials. Yet these techniques are sometimes avoided owing to the computational complexity required for their successful implementation, as well as the need to elicit prior distributions, which can be a point of contention. This paper discusses the benefit of Bayesian methods in earlyand late-phase clinical trial design and explores their oftenoverlooked role in augmenting and optimising frequentist trials.

From Prior to Posterior – the Method that Updates the Evidence The essence of the Bayesian technique is to develop an informed or non-informed prior for a specific trial outcome and then apply Bayes’ rule to update the prior to a posterior as more data are gathered.

Crucially, every piece of available data can be applied to create both the prior and subsequent posteriors, allowing for evolving clinical trials that take account of new in-trial insights. As a result, trials become flexible, allowing for near real-time learnings and accelerated decision-making.

Given enough time and data-gathering, evidence will inevitably lead to increasingly accurate inferences – whatever the prior distribution.1 Crucially, knowledge gathering from interim analyses becomes simpler, enabling trial managers to discern optimal dosing levels, and also stop and refocus trials where efficacy or safety issues emerge.

Where big data meets the need for fast-paced and flexible trials, Bayesian techniques, such as Bayesian dynamic borrowing and Bayesian hierarchical methods, provide the statistical basis to use all available information to drive fast and accurate decisions about the most successful direction for the trial. Bayesian methods are transforming clinical research in every therapeutic area, from oncology and rare diseases, where they protect patients by efficient modelling, to medical device trials where the gains in effectiveness can be quickly calculated using Bayes’ rule.

To Choose Bayesian or Frequentist Methods – Is That the Question?

It can be tempting to set Bayesian and frequentist methods against each other in a fight for statistical supremacy. But, in truth, no one method is better than the other. That said, there is usually a clear choice to make for each trial, and it will depend on myriad factors. Fundamentally, the design should demonstrate a thorough understanding of the research question, be aligned with the programme-level strategy, and be positioned to drive rigorous conclusions under resource and time constraints. With a good 14 Journal for Clinical Studies

understanding of both frequentist and Bayesian methodologies, knowledgeable statisticians can choose the method that best meets the objectives of the trial while considering all parameters.

It is important to note that the two methods are not mutually exclusive and that Bayesian methods can often be used to strengthen frequentist trials, not least through the use of historical data. Bayesian predictive probabilities can be used independently, whether the final primary analysis is planned in a Bayesian or frequentist framework.

For example, a Direct Monte Carlo (DMC) approach can use Bayesian predictive probabilities of success to help inform decisions for a frequentist trial. In fact, most existing examples of Bayesian methods utilised in late-stage adaptive clinical trials are frequentist trials that have been calibrated to meet classical frequentist type I error rate and power requirements, using Bayesian decision criteria. That being said, early-phase designs have more routinely been designed using a purely Bayesian approach.

The Bayesian approach is certainly the oldest of the two methods, established in the 18th century, yet it was largely unused in clinical trial design until the 1980s. Frequentist methods were by far the preferred method for drug development in the 1960s and 1970s because of the computational complexity required for the implementation of Bayesian methods. Today, the availability of modern computational power allows the wide implementation of Bayesian methods.

However, the deep expertise needed to design Bayesian trials is still a hurdle to their adoption.

With the widespread use of frequentist methods, the p-value and the type 1 error rate (significance level) are widely referenced, indicating the probability of false positives. The main differences between the two methods are that, while frequentist approaches calculate the likelihood of the results being seen if the null hypothesis were true, Bayesian approaches define the probability of the treatment effect exceeding a set threshold based on all available data, including in-trial results.

Importantly, frequentist methods are less intuitive. They can rely on data not observed, such as the sampling distribution under the null hypothesis, and can violate the likelihood principle through a dependence on the clinical trial design. (Conversely, Bayesian methods do not always take into account all the features of clinical trial design, which perhaps they should.) The p-value can also be misinterpreted as the probability that the null hypothesis is true, and in many situations, frequentist methods can be less flexible or efficient. However, both techniques have their strengths and weaknesses, depending on the situation.

Boosting Safety and Efficacy in Early-phase Trials Bayesian methods are commonly applied to early-phase clinical trial designs. Where little is known about the toxicity of a drug and its effect on the human body, Bayesian methods can be invaluable for Volume 13 Issue 2

Regulatory interim analyses, using trial data to adjust doses or stop and refocus trials where efficacy is limited, or where there are safety concerns.

Allocating patients to safe and efficacious doses and establishing the maximum tolerated dose (MTD) are important goals in Phase I trials. Bayesian dose-finding techniques such as the continual reassessment method (CRM), the Bayesian logistic regression method (BLRM) and the modified toxicity probability interval (mTPI) are popular methods to increase the probability of finding the MTD. Bayesian techniques are also frequently used for Phase Ib expansion cohort trials, where further exploration of the MTD and more accurate assessment of the drug activity takes place, including multiple cohort expansion (MUCE) designs in oncology drug development2.

Multi-arm Phase II trials, with their more adaptive structure, also benefit from the in-trial posterior adjustments that can compare the success probability for each arm. This has led scientists to use Bayesian hierarchical models to assess efficacy in basket trials where therapeutics are being tested against multiple disease indications3.

Continuous monitoring in single-arm Phase II trials and dose-ranging designs for non-oncology drug development also benefit from the adaptability of Bayesian techniques3,5. In fact, the range of Bayesian techniques now driving precision oncology trial design is testament to the power and accuracy of this method6.

Solving the Predictive Predicament to Accelerate Drug Development By using Bayesian approaches, external data can be incorporated to augment the trial design. Relevant data are identified from previous or ongoing studies and assessed for exchangeability with data at the aggregated trial level. Bayesian techniques such as commensurate priors, power priors and meta-analytic predictive (MAP) priors are all powerful tools for incorporating historical information.

The MAP approach uses Markov Chain Monte Carlo (MCMC) algorithms to perform random-effect meta-analysis of historical data to derive a prior distribution. This prior distribution is represented by a parametric mixture, determined by using an expectation-maximisation algorithm. A weakly-informative prior component, derived from the previous steps, can further enhance the robustness of the MAP prior, which can then be assessed along with its effective sample size.

In both Bayesian-only and frequentist-Bayesian combined trials, Bayesian model-based meta-analyses can help to select promising candidates for the next stage of clinical development, as well as anticipate the data requirements for latter-stage design. Particularly in oncology, where drug developers are evaluating seamless and adaptive studies, analysis that evolves with the trial is an essential component.

In any drug development programme, the benefit of the therapy must be shown to outweigh the risks, and every piece of data that may influence the benefit-risk balance should be included in the calculation. Bayesian techniques are particularly well suited to this task, as they can integrate myriad sources of data, including historical trial data, into a single benefit-risk calculation to aid better-informed decision-making.

Frequentist methods for borrowing information from historical studies are also widely used, such as propensity score matching and weighting for individual-level patient data, and matching-adjusted indirect comparison (MAIC) for summary-level data. However, the Bayesian interpretation of the process as a probability has its strengths here.

Bayesian techniques are just as valuable to late-phase and postmarket trials as they are to early-phase trials, showing their power in

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Regulatory shortening trial durations and reducing the cohorts needed to confirm hypotheses. In a case study redesigning the Phase III OSCAR trial for the use of high-frequency oscillation in acute respiratory distress syndrome (ARDS), Bayesian sequential design showed that the trial duration could have been reduced by 15 to 40 weeks and required 231 to 336 fewer patients7. Similarly, another trial showed that adrenaline could have been declared as a superior treatment with 30-day survival rates, with 1500 fewer patients using Bayesian trial design8.

Post-hoc Bayesian analysis also shows considerable benefits. In both of the recent high-profile EOLIA and ANDROMEDA-SHOCK trials, a large clinically important mortality difference was observed, but a p-value less than or equal to 0.5 was not reached9. Post-hoc Bayesian analysis helped inform the interpretation of the study beyond the frequentist’s binary (positive or negative) delineation9,10,11.

In the race to get drugs approved and made available to those who need them, shortened trials and smaller cohorts can accelerate patients’ access to new therapies, addressing their unmet medical needs and also saving valuable time and money. Interim analysis is critical for optimising late-stage trials, where patient numbers are larger and the stakes are higher.

Futility is inherently a prediction problem that can be resolved using predictive probabilities or p-values. Yet, seeing as only the former takes into account both observed and yet-to-be-observed data, futility (and early stopping more generally) is better addressed by predictive probability than by p-value. Even partial data can be used to drive decisions, and, although not relevant for regulatory submission, it can provide vital context to help de-risk a trial where there are questions around futility or efficacy, especially for trials with long follow-up periods12.

Using Bayesian Methods to Expedite and De-risk Trials Driven in no small part by the computing power and technology available to statisticians today, the first tentative calculations of the 18th century have exploded into a range of powerful Bayesian techniques and methods that are changing the way clinical trials are designed and analysed. From early-phase design to late-phase development, Bayesian techniques are expediting and de-risking trials and even augmenting frequentist designs. They deliver the predictive power to enable scientists to draw robust conclusions and adapt trials.

Frequentist techniques will always have a place in trial design, but the case for wider adoption of Bayesian methods is strong. With the increasing demands for targeted therapies and the very urgent medical needs caused by rapidly evolving infectious diseases, such as COVID-19, fast learning and flexible trial designs will become ever more important in bringing therapies to market faster and more efficiently.

REFERENCES 1.

Hawthorne J. "On the Nature of Bayesian Convergence." PSA: Proceedings of the Biennial Meeting of the Philosophy of Science Association 1994 (1994): 241-49. Accessed March 4, 2021. http://www.jstor.org/stable/193029.

2. Lyu J, Zhou T, Yuan S, Guo W, Ji Y. MUCE: Bayesian Hierarchical Modeling for the Design and Analysis of Phase 1b Multiple Expansion Cohort Trials. arXiv.org. https://arxiv.org/abs/2006.07785. Published 2020. Accessed October 21, 2020.

3. Simon R. “Critical Review of Umbrella, Basket, and Platform Designs for Oncology Clinical Trials.” Clinical Pharmacology & Therapeutics 102, no. 6 (2017): 934–41. https://doi.org/10.1002/cpt.814.

4. Lee J, Liu D. A predictive probability design for phase II cancer clinical trials. Clinical Trials: Journal of the Society for Clinical Trials. 2008;5(2):93106. doi:10.1177/1740774508089279 5. Dragalin V, Bornkamp B, Bretz F, Miller F, Padmanabhan SK, Patel N, Perevozskaya I, Pinheiro J, Smith JR. “A Simulation Study to Compare New Adaptive Dose–Ranging Designs.” Statistics in Biopharmaceutical Research 2, no. 4 (2010): 487–512. https://doi.org/10.1198/sbr.2010.09045.

6. Ji Y, Tsimberidou A, Müller P. Innovative trial design in precision oncology [published online October 3, 2020]. Semin Cancer Biol.

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7.

8.

9.

10.

11.

12.

Ryan E, Bruce J, Metcalfe A et al. Using Bayesian adaptive designs to improve phase III trials: a respiratory care example. BMC Med Res Methodol. 2019;19(1). doi:10.1186/s12874-019-0739-3 Ryan E, Brock K, Gates S, Slade D. Do we need to adjust for interim analyses in a Bayesian adaptive trial design? BMC Med Res Methodol.

2020;20(1). doi:10.1186/s12874-020-01042-7 Harhay M, Casey J, Clement M et al. Contemporary strategies to improve clinical trial design for critical care research: insights from the First Critical Care Clinical Trialists Workshop. Intensive Care Med. 2020;46(5):930-942. doi:10.1007/s00134-020-05934-6 Goligher E, Tomlinson G, Hajage D et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial. JAMA. 2018;320(21):2251. doi:10.1001/ jama.2018.14276 Zampieri F, Damiani L, Bakker J et al. Effects of a Resuscitation Strategy Targeting Peripheral Perfusion Status versus Serum Lactate Levels among Patients with Septic Shock. A Bayesian Reanalysis of the ANDROMEDASHOCK Trial. Am J Respir Crit Care Med. 2020;201(4):423-429. doi:10.1164/ rccm.201905-0968oc Saville B, Connor J, Ayers G, Alvarez J. The utility of Bayesian predictive probabilities for interim monitoring of clinical trials. Clinical Trials: Journal of the Society for Clinical Trials. 2014;11(4):485-493. doi:10.1177/1740774514531352

Dr. Ofir Harari Harari has worked in statistics and data analysis since 2007. His experience includes design and analysis of randomized and cluster-randomized clinical trials, Bayesian data analysis, adaptive designs, statistical emulation, and more. As Principal Statistician at Cytel, Harari leads projects in real-world evidence and develops statistical software for Bayesian trial design and analysis as well as for adaptive strategies.

Previously, Harari was a postdoctoral fellow at the University of Toronto and Simon Fraser University.

Dr. Pantelis Vlachos Prior to joining Cytel in 2013, where he is currently Principal Statistician and Strategic Consultant, Vlachos was a statistician at Merck Serono and a Professor at Carnegie Mellon University for over twelve years. His research interests lie in adaptive designs, mainly from a Bayesian perspective, as well as hierarchical model testing and checking. However, his secret passion is Text Mining. He has served as Managing Editor of the journal “Bayesian Analysis” as well as on the editorial boards of several other journals and online statistical data and software archives.

Dr. Yannis Jemiai As Chief Scientific Officer at Cytel, Jemiai has oversight of the corporate-level scientific agenda, which includes research portfolios in Bayesian, small sample, and other flexible designs, as well as complex innovative designs, including adaptive trials, master protocols and multi-arm multi-stage (MAMS) trials. Jemiai also has an extensive portfolio of research in adaptive trial design, financial and pharmaceutical strategy, decision theory, and regulatory affairs.

Volume 13 Issue 2

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info@Astell.com +44 (0)20 8309 2031 Journal for Clinical Studies 17

Regulatory

FDA UDI vs. EU MDR Regulations Consideration of the Regulations and Implications for EU Labelling This paper explores the current FDA UDI regulation for medical devices and compares it to the upcoming EU MDR/ IVDR regulation that will come into effect on 26 May 2021.

We examine the similarities and differences between the two regulations and the impact that the EU MDR regulation will have on regulatory labelling, outlining proactive steps for a smoother transition.

Background In the US, the FDA published its final rule on the Unique Device Identification (UDI) System for medical devices on September 24, 2013, which became effective December 23, 2013 (78 FR 58786).

NOTE: On June 30, 2020 the FDA issued an immediate-in-effect guidance on its policy regarding compliance dates for class I and unclassified devices that are not implantable, life-supporting, or life-sustaining. The FDA does not intend to enforce UDI labelling (21 CFR 801.20 and 801.50), Direct Mark (21 CFR 801.45), GUDID Data Submission (21 CFR 830.300), and Standard Date Format (21 CFR 801.18) requirements before September 24, 2022.

The objective of the regulation is to be able to easily track a medical device and facilitate more accurate reporting of adverse reactions and corrective actions enabled through the following requirements: • All medical devices in the US must contain a UDI on the label and on the device itself unless an exemption has been granted for approved reasons

18 Journal for Clinical Studies

•

UDI information must be entered into the FDA’s Global Unique Device Identification Database (GUDID) for tracking purposes.

In the EU, the new EU MDR regulation came into force in May 2017 (2017/745) and will replace the current Medical Device Directive (MDD) for all medical devices distributed in the EU. Similar to the US UDI regulation, it will require a code for tracking and a mark on the device itself. The MDD will remain applicable during the transition period to the EU MDR regulation and is set to expire 27 May 2025.

Whilst there are similarities between the two sets of regulations, there are also some fundamental differences, and these are laid out in Figure 1.

Having identified the additional requirements for the EU, let’s take a deeper dive into what this looks like: Responsible Person Designation The role of a PRRC (person responsible for regulatory compliance) requires that a medical device manufacturer assign a designated appropriately qualified employee to ensure that compliance is met for the EU MDR. This person is responsible for the following: • • • •

The device is inspected and verified that it conforms to required specifications before it can be released Ensures that the technical documentation and the EU declaration of conformity are prepared and kept up to date All post-market surveillance activities are performed All reporting requirements are satisfied.

Volume 13 Issue 2

Regulatory US UDI

Regulation

EU MDR

Direct Marking Except Class I devices that bear a UPC on their label and device packaging

All Classes Impacted

4 Classes Class I Class IIa

3 Classes Class 1

Device Classifications

Class 2

Class IIb

Class 3

Class III

UDI Database Responsible Person Designation Notified Bodies

Technical Documentation Updated Clinical Evidence CE Mark Post-Market Surveillance

Figure 1: High-Level Comparison between US FDA and EU MDR Regulations

The qualifications of that individual versus required compliance tasks must be documented.

Notified Bodies As part of the new EU MDR regulation, each country’s notified body must be re-certified to assess and approve that a company’s medical device product conforms to the new regulations; this is known as a conformity assessment. The certification is performed by the EU Notified Bodies Operations Group (NBOG).

The European Commission maintains a list of the notified bodies that have currently been certified for the EU MDR conformity assessment and can be found on the NANDO (New Approach Notified and Designated Organizations) website1.

It’s important for a company/manufacturer to be aware if their current notified body is applying for re-certification, if their notified body has received designation, or if they need to establish a relationship with a new notified body.

The status of re-certified notified bodies is shown in Figure 22.

Applications Designated

Withdrawn

Pending

MDR

19

1

6

IVDR

4

1

4

Figure 2: Status of re-certified notified bodies

Common Specifications The EU MDR regulation requires that medical devices must meet certain general requirements. It can be determined during an audit or assessment of the technical documentation if these general requirements have been met. The EU MDR regulation allows manufacturers to utilise harmonised standards for evidence of meeting the requirements. If harmonised standards don’t exist or are not sufficient, then common specifications can be used to meet this requirement. If these requirements are not met, then a manufacturer is not allowed to place the device on the market.

The EU Commission will implement common technical specifications if no harmonised standards exist or if they are www.jforcs.com

Technical Documentation Manufacturers are responsible for preparing technical documentation regarding the medical device product. The exact requirements for that documentation are listed in the EU MDR regulation under Annexes II and III. This documentation (organised in seven chapters) can be maintained either electronically or on paper (although electronically is strongly recommended).

In essence, the documentation must establish that the device performs as claimed, is safe and effective for patients, provides the lowest risk possible, and demonstrates the claimed medical benefits.

The documentation must be updated if any changes are made to the device, hence the need to maintain this documentation in a readily accessible format.

Common Specifications

Type of Application

not sufficient. These specifications will be created/issued by the Medical Device Coordination Group (MDCG). The definition for a common specification is a set of technical and/or clinical requirements for which no harmonised standard is available, or the harmonised standard insufficiently covers the requirements.

If there are changes to the device, it may require re-approval from the notified body.

Updated Clinical Evidence All devices are required to complete the clinical requirements of Article 61 and Part A of Annex XIV. This means that a device will either require clinical data on an equivalent device already available in published literature, or a clinical investigation will need to be performed to meet the required clinical data.

CE Marks In order to commercialise a medical device in the EU, a CE mark certificate is needed. This certification verifies that a device meets all regulatory requirements for medical devices.

Medical devices in the EU have to undergo a conformity assessment to demonstrate that they meet legal requirements to ensure they are safe and perform as intended. EU Member States can designate accredited notified bodies to conduct conformity assessments.

The conformity assessment usually involves an audit of the manufacturer’s quality system and, depending on the type of device, a review of technical documentation from the manufacturer on the safety and performance of the device.

Manufacturers can place a CE (Conformité Européenne) mark on a medical device once it has passed a conformity assessment.

Post-market Surveillance Manufacturers are responsible for implementing a proactive and systematic process to take corrective and preventative actions (CAPA) on their medical devices and their performance. The surveillance and reporting of incidents allow identification of issues with the design, manufacture or use of medical devices, and patient safety.

In addition, manufacturers of Class I medical devices are required to prepare a post-market surveillance report to summarise the results and conclusions of the data gathered as defined in the PMS plan. A periodic safety update report (PSUR) is required from manufacturers for all other classes of devices.

So, How do you Prepare for these Upcoming Changes?

With so many changes regarding the new EU MDR regulation, it can Journal for Clinical Studies 19

Regulatory

be daunting to figure out where to start to be ready to implement the new rules. Below is a step-by-step guideline to ensure that you’re ready for approvals and implementation with minimal disruption to your supply chain.

1. Establish Governance Due to the size and importance of the EU MDR project, it’s critical to properly set up governance for this project at the outset. Some key factors to keep in mind while setting this up include insuring that the project framework is clearly established, that the roles and responsibilities for the group are completely defined (and that the right people are selected for the group), and that the stakeholder engagement and communication plan is developed to guarantee that information is provided to stakeholders in a timely manner.

G. Post-market surveillance process H. Responsible person 4. Create a Roadmap Once you’ve identified the activities that must be completed, you’ll then need to prioritise and create a roadmap for implementing each item, keeping in mind that the EU deadlines must be met. The roadmap must be realistic in terms of timing, resources, and budget.

A good project manager will ensure that these deliverables will be met in a timely manner, so it’s essential to choose your PM wisely.

5. Address Issues Quickly Due to the magnitude of this project, it will be vital to address any issues as soon as they are identified. It may be necessary to escalate issues to the steering committee to resolve items quickly.

2. Determine Resources and Budget It’s important to determine at the outset of this project what resources are available to you and how much time they will be able to devote to this project. Some questions you may want to ask yourself:

In closing, it's important to get organized quickly and work through each activity to get a better understanding of the work required to meet the deadlines for the new regulation.

a. Will you be using internal or external resources? If internal, do they have the bandwidth and expertise for the project? Will they be pulled away for any other projects? b. If external, do you have an established relationship with a company that knows your needs up front? Do you have the budget for external resources? Do you know what the costs would be for external resources? Whose budget will be responsible for the project?

1.

2.

3. Perform Gap Analysis and Risk Assessment First and foremost, a gap analysis and risk assessment will need to be performed to determine what activities will need to be done and the risks associated with these activities. Some areas that should be focused on are: A. B. C. D. E. F.

Current device classifications Design and manufacturing processes Risk management programme Clinical evaluation process Development and maintenance of technical documentation Quality management system

20 Journal for Clinical Studies

REFERENCES https://ec.europa.eu/growth/tools-databases/nando Status as of 01 March 2021

Debi Schimpf Debi Schimpf has over 32 years of pharmaceutical and medical device experience in Regulatory Labelling, Packaging and Artwork. She has focused on evaluating processes, compliance, technology, and change management. Debi is keen on establishing and implementing best practices for governance, re-organizations, and streamlining business processes. She has demonstrated her ability to implement consistent methods and technology across global business units.

She possesses strong leadership, communication, presentation, and managerial experience. Debi has been the Past Chairperson for the Pharmaceutical and Medical Device Labelling Committee (PMDLC), a technical committee of the Institute of Packaging Professionals (IoPP).

Volume 13 Issue 2

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Journal for Clinical Studies 21

Regulatory

How to Develop a Statistical Analysis Plan for Clinical Trials A statistical analysis plan (SAP) is a defined outline of the planned statistical analyses for a clinical trial, including basic and advanced methods. An SAP is crucial — it is one of the key regulatory confidential documents in the development of a clinical trial. It provides explicit guidance on statistical programming, as well as the presentation of results for a clinical trial. Depending on the organisation, statistical analysis plans might also be known as reporting and analysis plans or data analysis plans (DAP).

The most important thing to ensure while conducting a clinical trial is that it is executed with minimum bias. Therefore, each clinical trial needs to have a clear and detailed SAP to support reproducibility.

In clinical studies, the SAP is a critically important document.

It ensures that the analyses used to evaluate all pre-planned study hypotheses are conducted in a scientifically valid manner and that all decisions are well documented. For best practice of clinical trials, reproducibility of research, and to avoid concerns of misuse of clinical research, a clear, detailed and very transparent SAP is crucial. In addition, the more comprehensive it is, the easier it will be for an SAS programmer to present in their analysis report later on.

However, producing a good quality SAP is a challenging task in clinical trial protocol development, which requires a strong command of statistical methodology, medical terminology and visualisation power.

There are four important types of SAP used in a clinical trial: • • • •

Data monitoring committee SAPs Interim SAPs Integrated statistical SAPs SAPs for clinical studies

• •

Communication: Clear communication with everyone involved in the study on how to proceed Replication: Facilitates replication so that a future research team can follow the same steps to confirm the results on the same or a new sample

As per standard guidelines and best practice, it is important that the clinical trial project statistician/biostatistician prepares the study’s SAP before the clinical trial starts, detailing all the planned analyses and study parameters, including analysis of set definitions and basic/advanced statistical methodology. The techniques must be chosen and defined in advance, to avoid the possibility of a particular method being selected because it results in the most positive results.

For example, if applying transformations, the thinking behind this should be explained clearly. The SAP can also specify what will be reported, using which unit of measurement, and whether this will include confidence intervals and p-values. Similarly, if multiple methods are being used to analyse the primary outcome, the SAP should specify which is the primary analysis method.

It is important to note the SAP is a working document, as the statistical analysis may depend on unpredictable factors or new statistical protocols may be established during the trial.

Who is Involved?

The clinical trial SAP should be started with an in-depth discussion between the study’s principal investigators and a statistician. A medical statistician/biostatistician should then take charge of developing the SAP in coordination with the principal investigator of the study.

The statistician’s roles and responsibilities include: •

Writing a research statement or hypothesis for the clinical trial study Determining the primary endpoints and secondary endpoint Establishing and developing a strategy to reduce bias Selecting a sample size for the clinical trial Defining all appropriate statistical methods for clinical trial data analysis

What Does an SAP Cover?

SAPs are mostly written as separate documents, but they can be included in the clinical study protocol as a standard operating procedure for dealing with the statistical part of the clinical study.

The SAP must properly explain: the aims and primary objectives, secondary objective, exploratory objectives, primary/secondary/ exploratory endpoints, trial population, design of the trial, sample size calculations with justifications/assumptions and the randomisation methods. Additionally, an SAP must describe in detail the statistical methodology, such as efficacy analysis, safety data analysis and reporting conventions. For example, the SAP must assure that the sample size is adequate for the nature of the tests used and the comparisons made.

• • • •

There are three essential factors an SAP needs to maintain in a clinical trial:

As well as developing the SAP, another big contribution of the medical statistician/biostatistician is the designing, monitoring and analysing of clinical trial data.

•

Transparency: Transparency concerning how the analysis will proceed, by specifying methodology that will be applied in advance

22 Journal for Clinical Studies

The document should be reviewed with special attention by a senior blinded biostatistician and finalised before it is submitted to the review board and regulatory authorities. If any protocol amendments are required, then the SAP will need to be amended as well. The importance of reviewing a statistical analysis plan is well documented, such as in the conference paper Ahrweiler et al. published in 2011.

For many clinical trials, developing a SAP requires the support of a freelance clinical statistician. This can either be for the Volume 13 Issue 2

Regulatory statistician producing the SAP, or as an impartial reviewer who was not involved in its development. With the help of an experienced freelance biostatistician, you can develop a thorough and error-free SAP, that will improve the quality of your clinical trials.

How Should the SAP be Developed?

When developing an SAP, the statistician will consider the details of the planned statistical analysis, the principal features of the technical analysis, the trial objectives, the data sources, the population studied, the study endpoints, the statistical methodology and sensitivity analysis and missing data.

Additionally, some other important considerations relating to the SAP in a clinical trial include: 1.

2.

3.

Blinding the biostatistician to minimise bias Documenting the SAP in such a way that all the data manipulations and analyses performed can be replicated Maintaining a trial master file with all the relevant documentation

The SAP should guide the statistician to all necessary resources, such as The CONSORT Statement (and any extensions), the ICH E9 Statistical Principles for Clinical Trials PDF, the EQUATOR Network (a resource centre for good reporting of health research studies) and the National Institute for Health Research Trial Planning and Design Station.

In 2017, Gamble et al. published guidelines that recommend a minimum of 55 important items to be considered during the SAP, including title and registration (11), introduction (2), study methods (9), statistical principles (8), trial population (8) and analysis (17).

Because there are so many factors to consider when designing an SAP, it can help to use a checklist.

Additional Guidelines to Follow The most important guidelines include the FDA’s Guidance for Industry: Statistical Principles for Clinical Trials. Additionally, to improve reproducibility, transparency and validity in clinical trials, the National Institutes of Health (NIH) published its “Rules for clinical trial studies registration and results information submission”, which mandates trial registration, posting of clinical trial ongoing recruitment or results within ClinicalTrials.gov, and submission of the separate original document SAP along with the clinical trial research study protocol.

Additional important guidelines used in SAP development are the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E9) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). Importantly, though these guidelines give us an idea of the body content of individual sections of the SAP, E3 and E9 do not specify specific statistical techniques. This is up to the statistician.

Because statistical methodology directly affects clinical trial decision-making, well-documented, confidential and transparent statistical conduct is essential. ICH E9 guidelines state that “the principal features of the eventual SAP of the data should be described in the statistical section of the protocol”. However, SPIRIT guidelines refer to a separate SAP. Because the SAP is such an essential document, it needs to be reported to regulatory authorities like the Food and Drug Administration (FDA) or European Medicines Agency (EMA). www.jforcs.com

Standard guidelines suggest that the SAP needs to be stored confidentially in the clinical trial master file — it can then be used during regulatory authority audits to check if statistical documents have followed standard guidelines exactly.

Further points to remember include: • • •

The SAP is not a standalone document. It should be read in conjunction with the clinical trial protocol The clinical trial protocol should be consistent with the principles of the SPIRIT 2013 Statement The SAP is to be applied to a clean or validated data set for analysis

Detailed guidelines are also available from funders, regulatory authorities, journals, industry representatives and UK Clinical Research Collaboration registered Clinical Trial Units (UKCRC CTUs). Additionally, the Guidelines for the Content of Statistical Analysis Plans in Clinical Trials in-depth details are described in JAMA. An elaboration document is also available to provide a more in-depth detailed explanation of each checklist item. Finally, you can view the SAP statement in the EQUATOR Network and the MRC-NIHR Trials methodology research partnership.

REFERENCES 1.

2.

3.

4.

5.

6.

https://www.ct-toolkit.ac.uk/routemap/trial-planning-and-design/ https://jamanetwork.com/journals/jama/fullarticle/2666509 https://lctc.org.uk/Content/SAP%20Statement_%20Elaboration%20 Document%20v1.0.pdf https://www.bristol.ac.uk/media-library/sites/social-communitymedicine/documents/conduct2/Gamble.pdf MRC-NIHR Trials Methodology Research Partnership (TMRP) UK Clinical Research Collaboration registered Clinical Trial Units

Rudra Patel Rudra Patel is a freelance medical writer and biostatistician at Kolabtree, providing scientific and regulatory writing services as well as end-to-end statistical services. He is a clinical operations manager at SymGet Technologies, a contract research organisation (CRO) that focuses on advanced project management, clinical operations, medical writing, statistical analysis, staffing and training.

He has over 15 years of clinical research experience working with pharmaceutical companies, CROs and the medical device and healthcare industry.

Journal for Clinical Studies 23

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Market Report

Paving the Way for a Robust Research Ethics Review Structure in Malaysia Introduction The foundation of good research is built on sound ethical principles, which require a good rationale, a solid methodology and proper consideration of the important ethical issues that may arise from the research. The main task of research ethics committees is to ensure the above principles, so all research involving human subjects will have an adequate protection of their dignity, rights and safety.

With over 30 years’ experience in clinical research, Malaysia has a well-established and experienced ethics and regulatory infrastructure.

There are 13 recognised research ethics committees/institutional review boards (RECs/IRBs) in Malaysia, each responsible for the ethical review of research proposals involving human participants conducted at their respective institutions. The Medical Research Ethics Committee (MREC) within the National Institutes of Health (NIH), which is part of the Ministry of Health (MOH) Malaysia, reviews all clinical research protocols involving any of MOH facility.

The majority of public universities and a few private institutions have their own REC/IRB and for institutions that do not have their own REC/IRB, the ethics application is sent to any of the recognised RECs/IRBs. In the case of multicentre research proposals, making use of facilities of different institutions, ethical approval is obtained from each of the institutions involved in the research.

In an attempt to increase the capacity and quality of ethical review of research proposals involving humans, and to streamline and harmonise the processes of the various IRBs/IECs in Malaysia, the Network of Ethical Review Committees in Malaysia (NERCIM) was established in 2015. This article aims to lay out the current challenges faced by various research ethics committees in the region, detailing the current Malaysian ethical and review landscape, and present NERCIM as a proposed way forward to address these issues.

Challenges Faced with Research Ethics Committees in the AsiaPacific Region While ethics review and all processes involved in it seem to be quite uniformed and harmonised for many of the high-income countries, it is just not feasible to adopt all of their processes especially, when factoring in the protection of populations in many low- and middleincome countries in our region. Basic differences in accessibility to healthcare facilities and drugs are quite notable between countries, and even between provinces within many countries. There are also significant gaps in the education, let alone health awareness and commitment to a healthy lifestyle.

On top of the difference in needs between the low- and middleincome countries versus the high-income countries, many of the countries in the region still experience a certain lack of capacity to conduct high-quality ethical review of complex research proposals, 26 Journal for Clinical Studies

often causing unnecessary delays in the start of international projects and sometimes depriving their institutions of good research opportunities.

Studies of existing research ethics committees (RECs) within different countries across the region pointed out some pertinent issues which are listed in Table 1.1–5 A selection of these issues will be discussed for the Malaysian REC landscape in the next section.

Challenges within research ethics committee frameworks from various countries in the Asia-Pacific region1-5 • Inappropriate composition of committee o Primarily consisting of medical and scientific reviewers o Experts that may not cover all necessary specialties o Under representation from the public (lay persons), legal profession, younger members and/or female population o Inclusion of administrators in institutional and private hospital committees and, directors/heads of related departments • Lack or insufficient expertise on ethical issues • Lack of importance placed in capacity building exercises • Insufficient resources to operate the RECs • Inactive/inconsistent participation of members • Not completely independent especially private and institutional RECs that are funded by their own institution • Lack of standardised standard of operating procedures (SOPs) among the different RECs within a country that leads to variations in practice between institutions • Infrequent meetings leading to delays in the overall timelines of clinical trials Table 1: Various challenges faced by countries within the Asia Pacific involving the structure and the Table 1: Various challenges faced by countries within theregion Asia-Pacific region involving operations of researchstructure ethics committees. and operations of research ethics committees.

The Current Malaysian REC Landscape Malaysia developed its first Good Clinical Practice (GCP) guidelines in 19996 based on the ICH-GCP, as the country prepared to launch itself into the international clinical trial environment. Since then, the country has continuously built up its capabilities, resources and experiences, ensuring that Malaysia has a firm footing in the international clinical trial sphere.5,7,8 In 2007, MOH issued a directive that requires all RECs/IRBs approving drug-related clinical trials to be registered with the National Pharmaceutical Regulatory Agency (NPRA), which is the secretariat of the local drug control authority (DCA).1 The aim was to allow the NPRA to audit and monitor these RECs, ensuring that it complied with the Malaysian GCP, regulatory requirements and other established guidelines. The NPRA practices a three-yearly visit to all recognised RECs/IRBs, including those who applied for first-time recognition. They give feedback and demand proper actions before recognition is given and, as such, they contribute in a major way to the capacity and quality of the ethical review processes in Malaysia.

While most RECs/IRBs in Malaysia tend to have quite a balanced composition in terms of representation of the speciality, gender representation as well as medical, scientific and layperson reviewers, the variety of research projects presented to individual committees is large and not all committees may have enough experts to cover some of the specialised areas and research methods.

Volume 13 Issue 2

Market Report While it is not bad to have a decentralised structure of different committees making important decisions for their own institutions and subsequently ensure the post-approval processes for their own researchers, harmonisation of the review process among the different committees is a desirable aim. A study by See in 2018 showed that even though all recognised RECs/IRBs in Malaysia were compliant to the Malaysian GCP, there was a large variation in referral to other documents in operational procedures, especially with regard to the review process.

Network of Ethical Review Committees in Malaysia (NERCIM): The Way Forward In 2013 and 2014, respectively, two Malaysian RECs/IRBs, MREC and the REC of University of Science Malaysia (JEPeM) obtained recognition from FERCAP (Forum for the Ethical Review Committees in the Asian and Western Pacific Region), a voluntary, paid membership organisation that was established in 2000.

FERCAP is a regional forum within the SIDCER (Strategic Initiative for Developing Capacity in Ethical Review) programme and aims to assist and assess the regional RECs’ compliance to international ethics guidelines and local regulatory requirements. In the process, they build up the capacity of their member RECs to deliver goodquality ethical reviews.

Existing (2010–2020) strategic objectives of FERCAP include creating a network between different RECs at national, regional and international levels to promote and facilitate training, sharing of common values and goals and, to offer accreditation to RECs by continuous monitoring and evaluation processes.9

www.jforcs.com

In 2015, MREC and JEPeM decided to initiate the formation of a Malaysian national network of ethics committees, named NERCIM (Network of Ethics Review Committees in Malaysia), following the examples set by established national networks from the Philippines (Philippine Health Research Ethics Board) and India (Forum for Ethics Review Committees in India ), which had achieved successes in harmonisation and organisation of their own local RECs/IRBs. It was the aim of NERCIM to share the beneficial experiences of getting FERCAP recognition with other committees and to harmonise the review processes (including the post-approval processes) among all RECs/IRBs in Malaysia.

As an informal network, NERCIM operated with biannual meetings jointly organised by MREC and JEPeM. The meetings consisted of an educational event regarding ethics review of various topics, followed by closed-door meetings where common issues and the opportunities for joint educational events and the potential to come up with common guidelines were discussed. Clinical Research Malaysia (CRM), a government body created with the objective of supporting the creation of a robust clinical trial ecosystem in Malaysia, has supported the efforts of NERCIM and has contributed to NERCIM in the planning of the content of the educational meetings and logistics arrangement.

NERCIM’s main objective still focuses on capacity-building exercises such as providing training and sharing of experiences with an aim for individual local RECs to evolve in their processes to harmonise processes amongst them. While individual RECs can maintain some form of autonomy in their review processes,

Journal for Clinical Studies 27

Market Report SOPs according to the format and guidelines of FERCAP have been recommended and the newer RECs have been encouraged to attend training sessions for FERCAP recognition. One of the achievements of the discussion was an informal agreement to expedite reviews of proposals that already got approval from other committees.

NERCIM offers a platform for local FERCAP members to share their experiences and knowledge gained being part of the organisation, as not all RECs in the country have the available resources to become members of the FERCAP. Following the establishment of NERCIM, two additional RECs in Malaysia were recognised by FERCAP, joining the likes of MREC and JEPeM. In the beginning of 2019, the process to formalise NERCIM as an association was undertaken. The concept in forming a registered association comprising RECs across the country, through voluntary application, is to provide an official platform for Malaysian RECs to increase capabilities and facilitate opportunities to overcome current shortcomings. Other than providing training and experience sharing among more established RECs, the platform could guide newer RECs, as more hospitals and universities with medical schools begin to participate in clinical research.

NERCIM members are also discussing the possibility of enhancing collaboration between RECs/IRBs. A first step, a work in progress at the time of writing this article, is a collaboration between MREC and a university-based IRB. A very good thing would be the establishment of a joint review board with representation of most stakeholders involved for protocols of studies being conducted in MOH and this university’s facilities. This would effectively cut short unnecessary time and resources as experienced with current practice.

All drug-related trials conducted in Malaysia require ethics approval from each investigation site involved before a Clinical Trial Import Licence (CTIL) and Clinical Trial Exemption (CTX) is released by the NPRA. If a joint review board could be established, that meets at least once per month, most of the large industrysponsored trials that make use of the facilities of several institutions may be granted approval within a period of 30 to 45 working days, without the need to get approvals from each and every individual REC/IRB. This may make the review process of higher quality, more efficient and more timely.

4.

5.

6.

7.

8.

9.

future. Perspect Clin Res. 2017;8(1):22-30.

Gao C-Q, Wang M-M, Liu Y-B. Rapid response to: Researcher who edited babies’ genome retreats from view as criticism mounts. BMJ 2018;363:k5113. DOI: 10.1136/bmj.k5113.

Maisarah AS, Nurul Ajilah MK, Siti Amalina MR, Norazuroh MN. Short review: implementation of biomedical ethics in Malaysia. Health and the Environment Journal 2016;7(2):54-76.

Ministry of Health Malaysia. Malaysian Guideline for Good Clinical Practice. 4th edition, 2018.

Ooi AJA, Khalid KF. A unique model to accelerate industry sponsored research in Malaysia. Journal for Clinical Studies 2018;11(1):24-27.

Ooi AJA, Khalid KF. Malaysia’s clinical research ecosystem. Applied Clinical Trials 2017. Available at http://www.appliedclinicaltrialsonline. com/malaysia-s-clinical-research-ecosystem. Accessed June 2020.

Torres CE. Reflections on the FERCAP Experience: Moving forawar with partnerships and networks. In: FERCAP@10: In commemoration of a decade of capacity building in ethical health research in the Asia-Pacific Region. 2011. Available at http://www.fercap-sidcer.org/publications.php.

Accessed June 2020.

Conclusion Through the initial steps initiated by RECs across Malaysia with the formalisation of NERCIM, Malaysia takes another step in its effort to firmly entrench its standing within the international clinical trials environment. Continued efforts to streamline and ensure the adherence to international standards will facilitate and speed up the ethical approval process by all IRBs/RECs of the research active institutions. Setting up of a national committee for industry-sponsored RCTs seems to be achievable in the long run.

It will require a lot of discussion and flexibility on the part of all institutions involved.

Asha Thanabalan

REFERENCES

Head of Psychiatric and Mental Health Department, Hospital Kuala Lumpur & Chairman of Medical Research & Ethics Committee, Ministry of Health Malaysia

1.

2.

3.

See HY, Mohamed MS, Mohd Noor SN, Low WY. Addressing procedural challenges of ethical review system: Towards a better ethical quality of clinical trials review in Malaysia. Accountability in Research.

2019;26(1):49-64.

Panichkul S, Mahaisavariya P, Morakote N, Condo S, Caengow S, Ketunpanya A. Current status of the research ethics committees in Thailand. J Med Assoc Thai. 2011;94(8):1013-1018.

Thatte UM, Marathe PA. Ethics Committees in India: Past, present and

28 Journal for Clinical Studies

Business Development Manager, Clinical Research Malaysia

Professor Hans Van Rostenberghe Department of Paediatrics, Hospital Universiti Sains Malaysia & Chairman of Human Research Ethics Committee of USM, Universiti Sains Malaysia

Dr. Salina Aziz

Dr. Lee Keng Yee Secretary of Medical Research & Ethics Committee, Ministry of Health Malaysia

Volume 13 Issue 2

Market Report

Decentralised Clinical Trials in Europe: Lessons from a Pandemic Introduction Many elements of decentralised clinical trials (DCTs) have long been available – including mobile devices, remote monitoring, telemedicine, and home health providers – but the decision to run these types of trials was simply a matter of preference.

Since the onset of the COVID-19 pandemic, travel bans and site closures have forced a rapid transition from physical clinical investigative sites to virtual environments. DCTs have been implemented out of sheer necessity and have been critical to advancing clinical research by minimising in-person interactions.

Benefits include the potential to improve recruitment, facilitate data collection, and reduce the need for travel by patients and CRAs alike, resulting in efficiencies and continued profitability.

DCTs demand new roles and partnerships which will likely continue long after the pandemic comes under control.

This article focuses on learnings from the pandemic in Europe, including case studies of successful use of virtual approaches to run more agile and adaptive trials. The author explores how these advances may shape the future of drug development in this region.

Steep Learning Curve After the emergence of COVID-19, sites and sponsors had to quickly overcome a steep learning curve to adopt telemedicine, remote monitoring, and other virtual elements in real time.

Sponsors and sites that adapted rapidly were often able to maintain efficiency and profitability despite the events created by the pandemic. However, many smaller and mid-sized pharma companies were slower to adopt remote monitoring, in part due to the need for significant investment in technology, training, and changes to standard operating procedures (SOPs). These companies are now increasingly making this shift, even if rather unwillingly.

Remote monitoring in particular offers an adaptive and flexible environment, allowing monitors to dedicate more of their time to data review and risk mitigation, and less time to travelling and compiling manual documents (Figure 1).

CHANGE IN MONITORING NOTION 100% SDV - early phase studies

Remote/On-site Combination Visits

Remote Monitoring COVID-19

Risk-Based Monitoring Figure 1: Changes in the concept of monitoring

Managing the Transition to DCTs A five-part approach can be used by contract research organisations (CROs) to transition trials to a more virtual setting, comprising: www.jforcs.com

1.

Adaptation of internal procedures to support the continuation of trials, taking into account the need for: planned noncompliance, risk mitigation plans, a remote monitoring standard operating procedure (SOP), site surveys to continue gathering relevant information, and development of a COVID-19 impact form for data management

2.

Close communication with sponsors, based on a clear plan for continuing trials, review of this plan by project managers and teams, and executive-level calls with clients

3.

Internal communications with the CRO’s staff to clarify new expectations, including the need to work from home and comply with travel restrictions, which have been especially significant for clinical research associates (CRAs)

4.

Tracking and compliance with COVID-related and other regulatory guidance, including attending educational initiatives such as webinars

5.

Devising an ‘exit strategy’ to recover from emergency mode and move to a ‘new normal’, including setting up a working group and initiating proactive planning

On the regulatory front, guidance on clinical trials during the COVID-19 pandemic from the European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) broadly encourages the use of virtual elements (Sidebar 1).

Sidebar 1: European regulatory guidance European Medicines Agency (EMA) on the Management of Clinical Trials during the COVID-19 (coronavirus) Pandemic Under current EMA guidance, remote monitoring is possible during the pandemic. Off-site monitoring activities might include phone calls, video visits, and e-mails or other online tools. “Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be re-assessed and temporarily, alternative proportionate mechanisms of oversight may be required. The first priority when considering any change is to protect the rights, safety and well-being of trial participants.”1 UK Medicines and Healthcare products Regulatory Agency (MHRA) Guidance on Managing Clinical Trials during Coronavirus (COVID-19) MHRA guidance states, “We support remote monitoring where appropriate… The MHRA will be as flexible and pragmatic as possible with regard to regulatory requirements for clinical trials during this time.”2 In many cases, local data privacy regulations have complicated the transition to virtual trial technology, including the European Union General Data Protection Regulation (GDPR, Sidebar 2).

Journal for Clinical Studies 29

Market Report Sidebar 2: The EU General Data Protection Regulation The EU adopted the General Data Protection Regulation (GDPR)3 to protect citizens’ personal data on May 25, 2018. The GDPR allows for two encryption methods to secure personal data: standard encryption (unintelligible to those not authorised to access it, even in case of data breaches); and pseudonymisation (which encodes personal data with artificial identifiers such as a random alias or code).

Pseudonymisation is considered to be partial encryption, while encryption is viewed as the safest and most straightforward technique to secure data. Seamless encryption ensures the security of data during transfer as well as the security of static data.

Scenarios for DCT Adoption As sponsors and sites adopted remote monitoring during the COVID-19 pandemic, four main scenarios have been seen, depending on the existing level of adoption and extent of digital data collection: 1.

Prompt adoption at sites in countries where remote monitoring is allowed, and that already had technology and SOPs in place. For sites that were already mid-way through a trial, transitioning to remote interim monitoring visits (IMV) could be achieved rapidly if a policy was already in place to allow access to the electronic medical record (EMR). Use of electronic regulatory and pharmacy software solutions can also enable full virtual regulatory and investigational product accountability.

2.

Innovative approaches were applied at sites in countries that do not allow remote monitoring, and/or that lack electronic regulatory solutions and EMR access. It is important to minimise delays to data review and accelerate adoption by establishing an SOP for direct EMR access, and to devise a remote IMV workflow, so that remote monitoring can begin.

3.

4.

Customised solutions were used at sites that are mainly paper-based, involving significant scanning of documents, implementation of new data platforms, and changes to SOPs. This approach aims to maintain monitoring momentum throughout the pandemic.

Tailored approaches were most appropriate for sites that choose to limit their EMR access due to institutional policies or EMR capabilities. Here a hybrid approach can be helpful, using a secure solution for uploading documents ahead of a scheduled IMV. This gives the site time to prepare and redact agreed-upon sources based on critical data points affecting subject safety, eligibility, and protocol endpoints.

Technology Platforms as a Key to Future Success To be successful as the ‘new normal’ evolves, virtual approaches will remain essential, including technology platforms that can support eSource, eDiaries, eConsent and EMR; high-speed networks and connectivity to support technology solutions; telemedicine tools; and wearable devices for remote monitoring with minimal or no onsite visits (Figure 2).

Continued efforts are needed to make clinical trial participants comfortable in a remote environment, including offering home 30 Journal for Clinical Studies

VIRTUAL TRIAL TECHNOLOGY: ENABLING CHANGE IN CLINICAL RESEARCH eSource, eDiaries, eConsent, EMR

High speed networks

Ability to support remote monitoring

Wearable devices

Telemedicine tools 12

Figure 2: Types of virtual trial technology

visits by nurses and phlebotomists, and use of local healthcare services, drug delivery services (to provide investigational product), and concierge services (to help handle travel logistics when patient site visits are essential).

In this new environment, certain skill sets are becoming more prominent, with a need for a shift in mindset and use of differing strategies, and all involved stakeholders must be open to this.

Strategic thinking and flexibility will continue to be vital, along with strong communication, adaptability to new and changing technology, and the ability to manage an increased volume and speed of data collection (Figure 3).

Figure 3: Changing skill sets

UK Case Study: Innovative Workarounds In the case study described in Sidebar 3, innovative workarounds were used for data verification in a situation in the UK where GDPR rules did not allow remote monitoring.

Sidebar 3: UK Case Study: GDPR rules prevented remote monitoring, requiring innovative workarounds Situation: A small UK site uses paperwork and electronic source options to monitor patients. During the pandemic, CRAs were unable to access the site. Due to GDPR, sites could not upload unredacted patient files.

Solution: To meet monitoring requirements, the site coordinator read the data virtually to the CRA. When inconsistencies in data occurred, the verification stopped and issues were addressed. Pharmacy contact occurred via intermittent calls for updates. The PI found this challenging, because they were working from home.

Results: Data verification took longer but was eventually completed over more visits. Advanced Clinical is currently exploring other avenues to have the sign-offs completed more efficiently within timelines.

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Market Report

Conclusion: Embracing lessons learned during the pandemic Experience during the pandemic has on balance shown that stakeholders – individuals, institutions, ethics committees (ECs), institutional review boards (IRBs), and competent authorities – have supported the continuation of clinical research while protecting patient safety. Rapid development and implementation of COVID-19 risk mitigation plans have played an important role.

Study awareness was successfully increased through sponsorCRO-site communications, and sites have been receptive to a collaborative approach to advance trials in challenging times.

Training, culture change, and stakeholder support have been repeatedly shown to be key to success. Virtual trial elements deliver many time, cost, quality and diversity benefits for sites and sponsors, including easing time and travel burdens for patients, reducing CRA travel burden, expanding patient populations available for trials, enabling investigators to oversee more patients in less time, and improved data quality.

More challenging situations have occurred based on certain local conditions; for example, where the clinical trial staff were seconded to emergency room tasks, the IRB/EC were not able to meet (even remotely), and the competent authorities were focused on other COVID-related tasks. Other challenges have included some sponsors being less receptive to change than others; some sites being unwilling to use remote monitoring; issues with site communication; an overall increase in protocol deviations directly attributable to missed in-patient trial participant visits; and barriers due to country-level regulations.

Lessons learned during the pandemic include the need to: 1.

2.

Have risk mitigation plans within every trial plan – including those with virtual elements.

Consult all stakeholders, gain their approval, and document this step.

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3.

4.

Consider using a hybrid approach with specific virtual elements that bring value to sites and patients, and retaining other traditional approaches. A 100% virtual approach is not required to benefit from these models.

Closely monitor regulatory opinions and guidance on virtual trials to ensure continued compliance.

Applying these learnings will help ensure that the benefits of DCTs can continue to be reaped in future.

REFERENCES 1.

2.

3.

European Medicines Agency Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic. April 28, 2020.

Version 3. https://ec.europa.eu/health/sites/health/files/files/eudralex/ vol-10/guidanceclinicaltrials_covid19_en.pdf UK Medicines and Healthcare products Regulatory Agency guidance: Managing clinical trials during Coronavirus (COVID-19). March 19, 2020; updated May 21, 2020. https://www.gov.uk/guidance/managing-clinicaltrials-during-coronavirus-covid-19 EU data protection legislation text, April 27, 2016 https://eur-lex.europa. eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0679

Graham Belgrave Graham Belgrave, SVP and Head of European Operations at Advanced Clinical, has 36+ years’ experience successfully leading drug development across clinical operations (Phases I–IV), outsourcing and contract management, and project, programme and vendor management.

Before joining Advanced Clinical in 2017, he was most recently COO at a speciality mid-sized UK CRO. He is a graduate of Warwick University, UK.

Journal for Clinical Studies 31

Therapeutics

Perspectives of Clinical Trials in Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is an umbrella term for chronic intestinal disorders with two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD) – the result of an unrelenting, severe inflammatory response against an environmental trigger in a genetically susceptible host, with a lifelong and remitting course. While we have learned a great deal about predisposing factors, clinical symptoms, pathways, pathology, and genetics, the exact cause remains unknown. Even though there is a rich armamentarium, including untargeted therapies, as well as targeted biologic therapies, up to 30% of patients receiving biologic therapies do not have a response to initial treatment, and in up to 50% of patients, the response is lost over time. These highly debilitating diseases are consistently associated with a reduced quality of life and substantial economic impact. Even though clinical trials aimed at discovery of novel therapeutic options increase annually, they are becoming more complex and challenging. This review gives our perspectives on IBD clinical trials, including limitations and new therapies.

Epidemiology and Risk Factors Epidemiology of both UC and CD share common features – they almost equally affect males and females, occur in all ages, and more commonly occur in industrialised countries. The highest reported prevalence rates were in Europe (UC 505 per 100,000 in Norway; CD 322 per 100,000 in Germany) and North America (UC 286 per 100,000 in the USA; CD 319 per 100,000 in Canada). Cohort studies described the rising incidence of IBD in countries outside the western world1.

The overall trends in IBD incidence shows a steady increase and “a helicopter view” covering a 16-year period from 1999 to 2015, shows an astonishing picture: in the US there were 1.8m patients with IBD in 19992 and 3.1m in 20153. A forecast of the global burden of IBD between 2015 and 2025 predicted exponential growth of the number of patients, due to increased rates of diagnosis and low mortality.

Increasing incidence of IBD results in a significant financial burden both personally and nationwide. During 1999–2017, the overall hospitalisation rate for CD and UC decreased among older adults, with a sharper decline in the hospitalisation rate for UC4. At the same time, rising costs of medications contributed to the annual mean healthcare costs for patients with IBD >threefold higher than patients without IBD (approximately $23,000 vs $7000)5. The major cost drivers for IBD patients include: treatment with specific therapeutics (biologics, opioids, or steroids), admissions to emergency department, and healthcare services associated with relapsing disease and complications from treatment and adverse events from medications.

The four main components of IBD pathogenesis include: 1) genetic predisposition, 2) disruption of the intestinal mucosa barriers, 3) a dysregulated immune response, and 4) an altered response to gut microorganisms. Numerous genetic variants (e.g., NOD and PTPN22) have been identified for CD and UC6,7, but it is important to note that 32 Journal for Clinical Studies

these genetic risk factors are permissive (or have a potential of IBD development), but none of them are causative (or the presence of even the strongest genetic risk factor does not mean that the disease will inevitably develop). The current concept of IBD development attributes the main role to the intestinal microbiota, which is necessary for intestinal homeostasis and function, and colonisation with specific detrimental microbes, leading to disease. Alterations of the intestinal barrier defence mechanism most commonly occur due to a broad spectrum of enteric infections, with Salmonella and Campylobacter the most frequent triggers8. Various medications associated with the risk of IBD development include: antibiotics, oral contraceptives, nonsteroidal anti-inflammatory drugs, and hormone replacement therapy. There are several additional environmental risk factors that might contribute to IBD development, however the data are controversial. For example, tobacco use is generally considered protective in UC, but may increase the risk of CD9. There are numerous publications on dietary influence on IBD development, but mainly inconclusive, failing to identify strong and statistically significant dietary risk factors. On a different note, a high-fibre diet rich in fruits and vegetables reportedly provides protection against IBD development10.

So, there is a paradox. We know a lot about genetics, pathogenic mechanisms and the role of enteric microbiota and have identified numerous risk factors, which with different levels of certainty may reflect a potential for development of IBD, but at the same time, no mechanism has been suggested as the leading or primary one.

This leads to a lack of specific and adequate diagnostic tests and procedures to establish the diagnosis of IBD. Diagnosis The diagnosis of IBD involves clinical symptoms that generally depend on which part of the intestinal tract is involved. The guideline of the World Gastroenterology Organization (WGO) describes these symptoms: diarrhoea, constipation, bowel movement abnormalities that may manifest as pain, rectal bleeding, bowel movement urgency, and tenesmus, nausea and vomiting11. At the same time, IBD, a systemic inflammatory disease, can affect other organs. Up to 47% of patients with IBD have at least one extra-intestinal manifestation, that may include dermatological (e.g. pyoderma gangrenosum, erythema nodosum), ocular (e.g. uveitis, conjunctivitis), rheumatological (e.g. spondyloarthropathy, arthralgia) or hepatic disorders (e.g. primary sclerosing cholangitis)12. These clinical symptoms are not specific, require a broad differential diagnosis, and years ago, when computerised tomography (CT) was not a routine examination, the diagnosis of CD frequently occurred at the time of laparotomy for presumed appendicitis. Now, to establish the correct diagnosis requires confirmation by endoscopic and radiological findings.

Endoscopic evaluation, the current standard of IBD diagnosis has significant limitations: cost, complexity, invasiveness, and risk of complications – for example, a risk of perforation is evaluated as 4.59.7 cases per 10,000 patients13.

Volume 13 Issue 2

Therapeutics Non-invasive biomarkers with the potential to avoid invasive diagnostic tests and potential complications are needed. There are a number of biomarkers currently used in clinical practice, but none helps make an accurate diagnosis of IBD. Biomarkers could be used for diagnosis and monitoring (e.g., C-reactive protein, erythrocyte sedimentation rate, various stool-based biomarkers), and to subclassifiy IBD to UC and CD (blood-based biomarkers, (e.g., antineutrophil cytoplasmic antibodies (ANCAs), anti–outer membrane protein C (Anti-OmpC), pancreatic antibodies))14. Despite a long list of tests, there is no universally accepted biomarker for an ultimate diagnosis of IBD, limiting their use to addition to clinical data and endoscopic examination. Another limitation of biomarkers is the inability to predict response to therapy in patients with IBD. Inflammatory biomarkers are not only non-specific, but paradoxically, can be normal during the disease flare. In addition, they do not provide diagnostic or predictive value in IBD. With the frequent primary lack of response, or, currently seen with biologics therapy, a loss of response, predictive biomarkers are vital to “catch” the earliest possible moment for starting treatment, and secondly, to understand when the therapy stops working and thus reduce exposure to ineffective treatment and eliminate adverse events.

Current Treatment The twofold treatment goal includes achieving remission, and once achieved, maintaining it for the maximum duration. Historically, IBD management utilised a step-up approach with new drugs added when a patient fails the initial treatment or needs addon therapy. Such a symptomatic approach was not aimed at the deeper pathophysiological mechanisms of the disease and thus was suboptimal in long-term disease outcomes. The current treatment paradigm, based on the concept of combining risk stratification that identifies patients who may have an aggressive disease and an early intervention assumes the shorter the disease duration, more patients will enter remission with fewer complications. Now, the prevalent strategy is to “treat deeper”, achieving deep mucosal healing, particularly in CD and to “treat to target” focusing on achievement of disease remission. Commonly used, so-called conventional therapy, including 5-aminosalicylates, corticosteroids, thiopurines, antiTNFs and others, is effective in controlling symptoms and to some extent, pathological changes, but it will not work if disease progresses.

Such adverse side-effects as immunosuppression, systemic fungal infections and potential for cancer development may have a negative impact on disease outcome. For instance, all anti-TNF-α drugs in the

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US carry a boxed warning due to the increased risk of infections.

Anti-TNF-α drug therapy treatment failure occurs in 25–30% of patients with limited treatment options afterwards. A promising drug that was thought to close this gap was etrolizumab, but according to Genentech updates as of 09 Aug 2020, Etrolizumab met its primary endpoint of inducing remission versus placebo for patients with UC in only two of three studies, and failed to meet its primary endpoint versus placebo as maintenance therapy. Further analyses of the data, including secondary endpoints continue, but this preliminary release was disappointing. Four well-recognised international guidelines on IBD treatment include: 1) World Gastroenterology Organization Global Guidelines on the IBD11, 2) Consensus Guidelines on the Management of Inflammatory Bowel Disease from the British Society of Gastroenterology15, 3) Guidelines on the Medical and Surgical Management of Crohn Disease from the European Crohn's and Colitis Organization (ECCO)16, and 4) the Clinical Practice Guidance on the Medical Management of Adult Patients with Moderate to Severe Ulcerative Colitis (UC) from the American Gastroenterological Association (AGA)17.

Clinical Trial Perspectives With a steady increase of IBD prevalence worldwide and discovery of new disease pathways, pharmaceutical companies have growing interest in IBD drug development. A survey of Trialtrove Informa database (Pharma Intelligence) in April 2019 revealed 47 companies conducting studies with 70 investigational or approved drugs in the IBD therapeutic area, composed of 43 compounds for UC, 29 for CD, and six for both indications18. During the 10-year period from 2010 to 2020, the number of clinical trials in the IBD therapeutic area almost doubled, not only because of a continuous development of biologics, but also due to discovery of new pathways and consequently new classes of medications. Currently, the drugs under investigation belong to four therapeutic classes with several mechanisms of action: 1) monoclonal antibodies (α2β1 integrin antagonists, Interleukin-6/12/21/23 antagonists, CD40 and CD134 antagonists), 2) protein kinase inhibitors (JAK 1/3 inhibitors), 3) immunosuppressants (S1P receptor modulators), and 4) antisense therapy (ICAM1 antagonists, TLR9 agonists). In such a competitive landscape with the large and growing number of compounds utilising different mechanisms of action, it is critical to understand how a potential drug may fit the unmet needs in IBD management. Based on literature analysis and feedback from clinical trial investigators (and indirectly from patients), patients prefer an oral formulation

Journal for Clinical Studies 33

Therapeutics

over subcutaneous or intravenous administration. We conclude lack of oral drug formulations constitutes the primary unmet need in management of moderate to severe IBD. The first oral drug for UC Pfizer’s XELJANZ® (tofacitinib), a small molecule directed against the JAK/STAT pathway, blocking the inflammatory cascade received FDA approval for this indication in 2018. The efficacy of XELJANZ® for the treatment of moderately to severely active UC was demonstrated in three placebo-controlled clinical trials. Initially, it was considered that the incidence of tofacitinib-related adverse events (AEs) in UC does not differ from that of patients with rheumatoid arthritis (the primary indication for this drug) and there were no particular safety concerns. However, after one year of use in UC patients, FDA issued a black box warning for the 10-mg, twice-daily dosage of tofacitinib in patients with UC due to a potential for increased blood clots and death risks seen in a rheumatoid arthritis trial19.

Recently, Bristol Myers Squibb announced results from True North, a pivotal, placebo-controlled Phase III trial evaluating oral ZEPOSIA®(ozanimod), an oral, sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5, as an induction and maintenance therapy in adult patients with moderate to severe ulcerative colitis (UC) who did not adequately respond to prior treatment20. The study demonstrated 34 Journal for Clinical Studies

statistically significant and clinically meaningful results for clinical remission compared to placebo at induction and in maintenance.

The overall safety observed was consistent with the known safety profile for ZEPOSIA® and patients with moderate to severe UC, however, more safety data is needed, and particularly long-term prior to recommending ZEPOSIA® for extensive use. The first drug in this class, GILENYA® (fingolimod), has been used in treatment of multiple sclerosis, and recently raised some concerns due to first-dose bradycardia and atrioventricular block. However, it will not be correct to extrapolate fingolimod safety data to ozanimod, as the adverse effects’ profile depends on the particular receptors targeted by the drug, with S1P2 and S1P3 receptors associated with cardiovascular, pulmonary, and theoretical cancer-related risks, and targeting S1P1 receptors proved beneficial for inflammatory conditions. Fingolimod is a non-selective S1P modulator targeting S1P1, S1P3, S1P4, and S1P5 receptors, leading to a wide range of adverse events. The current focus of drug development is on selective S1P modulators that targets predominantly or exclusively S1P1 receptors.

Until recently, in addition to ozanimod, two S1P modulators with differing selectivity for S1P receptors were in clinical development for IBD: etrasimod and amiselimod. Recently published results of a Phase II placebo-controlled study of amiselimod in moderately to severe CD did not show a significant effect on clinical disease activity, but no Volume 13 Issue 2

Therapeutics clinically significant reports of bradycardia, ventricular tachycardia, or atrioventricular block, as well as no deaths, opportunistic infections, clinically significant negative laboratory or abnormal ECG findings21.

Phase II study data on etrasimod, a selective S1P1, S1P4, and S1P5 receptor modulator concluded the 2 mg dose was more effective than placebo for improving the modified Mayo Clinical Score at week 12 in patients with moderately to severely active UC. However, the study has limitations – namely, an induction study with only 12 weeks’ duration and 156 patients randomised, and the safety and efficacy during longerterm maintenance therapy were not investigated22. The safety and efficacy will be further evaluated in Phase III clinical studies.

9.

We speculate that the increasing number of new drugs is positive, but there is another issue: the number of clinical trials in IBD does not parallel the number of patients enrolled in the studies, and moreover, enrolment rate moves in the opposite direction show a significant decline. For example, during a 20-year period from 1998 to 2018, the average recruitment rate in moderate to severe UC decreased from 0.32 to 0.13 patients per site per month, while the average recruitment rate in moderate to severe CD decreased from 0.65 to 0 to 0.10 patients per site per month18. Paradoxically, enrolment decreased due to success in drug development, particularly by FDA approvals of vedolizumab in 2014, ustekinumab in 2016, and tofacitinib in 2018.

With new therapies available, the interest in conducting placebocontrolled trials (a frequent clinical trial design in the IBD setting) has decreased. No easy and universal solution of this problem exists, however general recommendations may include: optimisation of study outcomes, including endoscopic weighted inclusion and outcome criteria, and what we consider critically important – to make long-term extensions available to patients.

14.

Conclusion New therapeutic options evolve in IBD therapy, including early diagnosis and intervention, treat to target strategy and control of biomarkers. Novel potentially effective therapies appear almost every year, but in a highly competitive field not all achieve the study endpoints. The current trend in IBD drug development shifts to effective oral therapy, which still has pros and cons and subsequently, makes conducting clinical trials more challenging than 10 years ago.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

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Ng, S.C., Shi, H.Y., Hamidi, N. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. www.thelancet.com Published online October 16, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32448-0 Nguyen, G., Chong, C. and Chong, R. National estimates of the burden of inflammatory bowel disease among racial and ethnic groups in the United States. Journal of Crohn’s and Colitis. 8, 288-295 (2014) Dahlhamer, J., Zammitti, E., Ward, B., Wheaton, A. and Croft, J. Prevalence of inflammatory bowel disease among adults aged ≥18 years—United States, 2015. MMWR Morb Mortal Wkly Rep. 65, 1166–1169 (2016) Xu, F., Wheaton, A., Liu, Y., Lu, H. and Greenlund, K. Hospitalizations for Inflammatory Bowel Disease Among Medicare Fee-for-Service Beneficiaries — United States, 1999–2017. MMWR Morb Mortal Wkly Rep. 68, 1134–1138 (2019) Park, K., Ehrlich, O., Allen, J. et al. The cost of inflammatory bowel disease: an initiative from the Crohn’s and Colitis foundation. Inflamm Bowel Dis. 26 , 1 (2020) Peters, L., Perrigoue, J., Mortha, A. et al. A functional genomics predictive network model identifies regulators of inflammatory bowel disease. Nature Genetics, 49. 1437-1449 (2017) Chang, J.T. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med. 383, 2653-64 (2020) Gradel, K., Nielsen, H., Schnheyder, H. et al. Increased short- and longterm risk of inflammatory bowel disease after Salmonella or Campylobacter gastroenteritis. Gastroenterology. 137, 495-501 (2009)

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Mahid, S., Minor, K., Solo, R. et al. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. 81, 1462-71 (2006) Ananthakrishnan, A., Khalili, H., Konijeti, G. et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 145, 970-977 (2013) World Gastroenterology Organisation Global Guideline. Inflammatory bowel disease: a global perspective. Clin Gastroenterol. 50, 803-818 (2016) Ott, C., Scholmerich, J. Extraintestinal manifestations and complications in IBD. Nat Rev Gastroenterol Hepatol. 10, 585–595 (2013) Blotière, P., Weill, A., Ricordeau, P. et al. Perforations and haemorrhages after colonoscopy in 2010: a study based on comprehensive French health insurance data (SNIIRAM). Clin Res Hepatol Gastroenterol. 38, 112–117 (2014) Soubieres, A., Poullis, A. Emerging biomarkers for the diagnosis and monitoring of inflammatory bowel disease. Inflamm Bowel Dis. 22, 2016– 2022 (2016) Lamb, C., Kennedy, N., Raine, T. et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 68 (Suppl 3), s1-s106 (2019) Torres, J., Bonovas, S., Doherty, G. et al. ECCO guidelines on therapeutics in Crohn's disease: medical treatment. J Crohns Colitis. 14, 4-22 (2020) Feuerstein, J., Isaacs, K., Schneider, Y. et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis.

Gastroenterology. 158, 1450-61 (2020) Harris, S., Wichary, J., Zasnik, M., Reinish, W. Competition in clinical trials in inflammatory bowel disease. Gastroenterology. 157, 1457-1461 (2019) https://www.fda.gov/drugs/drug-safety-and-availability/fda-approvesboxed-warning-about-increased-risk-blood-clots-and-death-higher-dosearthritis-and, visited on 01 Mar 2021 https://news.bms.com/news/corporate-financial/2020/Bristol-MyersSquibb-Announces-Positive-Topline-Results-from-Pivotal-Phase-3-TrueNorth-Trial-Evaluating-Zeposia-ozanimod-in-Patients-with-Moderate-toSevere-Ulcerative-Colitis/default.aspx, visited on 01 Mar 2021 D’Haens, G., Slatkin, N., Israel, R. and Heimanson, Z. P097 favorable safety profile for amiselimod, a selective S1P receptor modulator, in Crohn’s disease. Inflammatory Bowel Diseases. 26 (Suppl 1), S1–S2 (2020) Sandborn, W., Peyrin-Biroulet, L., Zhang, J. et al. Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis.

Gastroenterology. 158, 550-561 (2020)

Maxim Kosov Maxim Kosov, MD, PhD, is Senior Medical Advisor at PSI CRO AG (USA). He is a board-certified physician in paediatrics and intensive care. Maxim has more than 25 years of experience in both the medical and clinical research industry. He conducted medical monitoring in more than 60 clinical trials across a broad range of indications. He is also the author/co-author of more than 50 publications.

Email: maxim.kosov@psi-cro.com

John Riefler John Riefler, MD, MS, is Director, Medical Monitoring & Consulting at PSI CRO AG (USA). He has an MS is in microbiology (SC State Traineeship, full scholarship) and his clinical training is in internal medicine and infectious diseases. He is a Fellow, Infectious Disease Society of America (FIDSA) and Fellow, American Heart Association (FAHA).

He has 33 years’ experience in clinical development in big pharma and CROs. He is also the author/co-author of 35 publications.

Email: john.riefler@psi-cro.com

Journal for Clinical Studies 35

Technology

How CDMSs are Driving the Switch from Clinical Data Management to Clinical Data Science Over the last ten years, the clinical research industry has evolved in many aspects. For instance, the industry is shifting from simple trials to global and more patient-centric trials. As the access to new data sources like wearables and electronic patient diaries (e-diaries) increases, data volume continues to grow. Therefore, integrating and analysing the data to extract its maximum value is becoming more complex.

This evolution has marked the shift of clinical data management (CDM) towards clinical data sciences (CDS) and more advanced clinical data management systems (CDMSs). These systems enable real-time data integration, data standardisation at different layers, risk-based monitoring, real-time data reviews, and advanced analytics.

Within the life sciences industry, future-forward companies are reaping the benefits of this new technology, such as time- and costefficiency, clinical trials globalisation, and faster time-to-market on new drugs. However, not all companies have shifted to CDMS or digital data capture. This article will explore the benefits for life science companies to use CDS to stay ahead-of-the-curve as clinical trials continue shifting digitally.

Defining CDM and CDS CDM (clinical data management) is a process to collect, manage, and validate clinical data during clinical trials. In this process, clinical data managers ensure proper coding, validation, and data review, then they prepare it for generating analysis datasets.

Over the last ten years, clinical research methodologies have evolved significantly. Clinical trial globalisation, complex trial designs, and the shift to patient-centric trials have led to the use of advanced technology over conventional data management. Through new technology, conventional CDM activities evolved.

CDS (clinical data sciences) is an evolution of the CDM process that involves managing data collection from various sources at different frequencies, identifying different data sources, using algorithms to ingest and integrate data, and advanced analytics to analyse data on an ongoing basis. CDS supports these tasks in addition to conventional data management activities like query management, coding, and clinical data validation.

were not just costly – they also risked data error and limited the scope of more data sources or clinical sites across the globe.

As technology advanced, the life sciences industry adopted electronic data capture (EDC) systems, enabling clinical sites to feed the clinical data into clinical databases directly. EDC also opened a gateway of diversified data sources and helped globalise clinical trials. By deploying EDC systems, clinical trials could collect data from different sites and locations. Digital channels became much more cost- and time-efficient than manual methods. Thus, the industry began shifting from CDM to CDS and from traditional clinical databases to advanced CDMSs accordingly.

The industry is also transitioning from paper-based trials to different digital data sources and simple trials to more complex, remote trials. As per the Food and Drug Administration (FDA), data can enter the electronic CRF from many different sources, such as investigators, study staff, clinical labs, patient reports, imaging facilities, barcode readers, electronic health record (EHR) systems, etc. This data should be saved in a way that the investigator has control of the record, and outside parties cannot interfere with it.1 Respectively, CDMSs now support direct data entry from investigator sites and data ingestion from various digital data source systems. The data is integrated and standardised as per industry standards before being available for review, validation, and analytics.

The Growing Need for CDMS As the clinical research industry shifts from simple trials to complex, global trials, the generated data begins qualifying as big data. IBM classifies big data as datasets whose size or type is beyond the ability of traditional relational databases to capture, manage, and process the data with low latency.2 Big data has one or more of the following characteristics: high volume, high velocity, high veracity, or high variety. When the data presents these four Vs, CDMSs have the right capabilities to handle

The Shift from Paper-based Trials to Electronic Data Sources The shift from paper trials to electronic data capture initiated the evolution of CDM to CDS. Traditionally, paper-based trials used paper case report forms (CRFs) to collect data from the clinical sites. Data entry operators entered data from paper CRFs to clinical databases. These methods 36 Journal for Clinical Studies

Sources: Axtria Inc.; IBM; Grand View Research

Figure 1: The Growth of Clinical Trials as Per the Four Vs of Big Data Volume 13 Issue 2

Technology it, whereas relational databases cannot. In respect to the four Vs, clinical trial data is expanding (see Figure 1).

Robust CDMSs – including platforms, workbenches, reporting framework, etc. – are vital to interact with an end-to-end ecosystem of technologies supporting all emerging clinical data needs. The following explains how clinical trial data has become big data: 1. The clinical trials' market growth is rising. Awareness of disease prevalence, stringent regulatory guidelines, and developing countries’ growing demand for clinical trials are accelerating this growth. In 2019, the value of the global clinical trials' market was USD 46.8 billion. Between 2020 and 2027, researchers expect the market size to grow at a 5.1% compound annual growth rate (CAGR).³ 2. Personalised medicines and orphan drugs are rising in demand.

Personalised medicine aims to provide specific patient subgroups with tailored treatments. For these individuals and subgroups, treatment design is dependent on their specific genetic makeup and medical data. Today, researchers can better determine which patients such trial drugs will benefit the most.

According to the Precision Medicine Initiative, personalised medicine is "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person."4 Orphan products – drugs, biologics, medical devices, and medical foods to treat rare diseases or conditions – are also in high demand.

3. Clinical trials have gone global. Such factors supporting this globalisation include emerging contract research organisations (CROs) covering trials worldwide, opportunities for pharma companies or CROs to reach their patient recruitment goals faster, and harmonising clinical research regulatory guidelines (Figure 2).

2. Quality control and data integrity retainment: As data volume and sources increase, it is imperative to generate generating more value from the data while ensuring data quality. Robust CDMS allow users to create, configure, and reuse the algorithms that identify discrepancies as soon as data flows in, thus ensuring quality control. Advanced CDMS tools offer access controls and efficient data governance capabilities to ensure data integrity.

3. Regulatory compliance: CDMSs provide a validated environment to ensure clinical data meets all regulatory compliance requirements. As the FDA defines in the Code of Federal Regulations Title 21 (21 CFR Part 11), any CDMS design must conform to the regulatory requirements for electronic records and security requirements for a closed system.6 All electronic records and electronic signatures submitted must comply with 21 CFR Part 11, which defines the data's compliance and submission requirements.6 A robust CDMS is validated to ensure the audit trail of the creation, modification, and deletion of any data inclusive of user access and rights. In compliance with 21 CFR Part 11, some of the critical needs that CDMSs fulfil are: a. Electronic records control: Systems accurately and fully reproduce the electronic records with a complete audit trail of the dates and metadata.6 b. Proper sequencing of steps or transactions: This means having a defined security hierarchy to control the object life cycle, data access, and system functionality.6 4. Assist with regulatory submission: To streamline and speed up the review process, it is crucial that regulatory agencies receive clinical submissions that are complete, high-quality, and meet the aforementioned standards. CDMSs enable the generation of submission packages needed for completeness, including, but not limited to: •

• •

Source: U.S. National Library of Medicine5

Figure 2: The Percentage of Registered Studies by Location (as of Jan. 2021)

4. Virtual trials and complex trials now incorporate various data sources. Handling this data requires improved data collection, processing, analysis, and archiving.

CDMS: Enabling the Shift A CDMS provides a validated, controlled repository capable of handling the needs of big data, thus yielding the following benefits: 1. Time- and cost-efficiency: Cloud-based CDMSs and big data architecture offer real-time data flow and sufficient space for data and algorithms. These features enable ingestion and integration of real-time data from various sources like wearables and e-diaries, enabling data managers to perform risk-based monitoring rather than validate the collected data. This approach also reduces the need for frequent site monitoring, which saves time and money. www.jforcs.com

• • • •

The study database, which contains the raw data collected from various trial sites. This data includes SAS datasets, manually or electronically-created CRFs, demographic data, adverse events, etc. Within CDMSs are defined metadata, which stores study data and is thoroughly validated and secured.

Study data with controlled terminology and coded as per standard dictionaries.

Database analysis, which includes all statistical analyses performed on the raw datasets to support the clinical trial study analysis.

Supporting programs like SAS and R. Defined .xml, which contains the metadata of the submitted data.

The data reviewer's guide.

Data validation reports and quality reports generated by comparing the datasets with the Clinical Data Interchange Standards Consortium (CDISC) standards like the Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM).

Source: Axtria Inc.

Figure 3: Data Exchange Models Journal for Clinical Studies 37

Technology

A CDMS has different layers of data standards that it can use to generate analysis datasets that comply with regulations (Figure 3).

These features help regulatory authorities receive data submissions faster and speed up review.

What's Next – Virtual Clinical Trials?

Before the 2020 COVID-19 pandemic, experts already speculated that virtual clinical trials would eliminate clinical site trials. Leonard Sacks, Associate Director for Clinical Methodology in the FDA Office of Medical Policy, predicted that clinical trials will be completely different a decade from now. "Trials might take place in patient homes or at their private doctors, patients might wear sensor devices, flash pictures of their lesions from their cell phones, submit patientreported outcomes on their tablet computers, perhaps even receive their study drugs by drone.”1 As lockdown mandates and stay-at-home orders shut doors, the pandemic forced healthcare operations – including clinical trials – to virtualise. In March 2020, the FDA encouraged virtual trials and issued extensive guidance in their document, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards.”

As stated in the document, the “FDA recognizes that monitors may not be able to access the trial sites for on-site visits in a 38 Journal for Clinical Studies

timely manner during the COVID-19 public health emergency.

Sponsors should work to find alternative approaches to maintain trial participant safety and trial data quality and integrity, such as enhanced central monitoring, telephone contact with the sites to review study procedures, trial participant status and study progress, or remote monitoring of individual enrolled trial participants, where appropriate and feasible.”7 The Bottom Line: CDMS Enables All Aspects of Data Science Advanced CDMSs have boosted the CDM evolution to CDS in all aspects – from data collection through the generation of analysis datasets. By using advanced analytics on the trial data, CROs and sponsors can extract the data's greatest value.

Furthermore, the upward trend in clinical trials means regulated authorities are ramping up regulations. For such reasons, CDMSs are necessary to ensure that the submitted data complies with the latest standards. Providing data correctly also fast-tracks the go-to-market completion time for a drug.

Overall, CDMSs enable CROs and sponsors to collect data from various sources in real time. These systems ensure quality data submission, which streamlines faster drug discovery and accelerated time-to-market. As clinical trials become digitised and virtualised, the industry will eventually adopt CDS with the help of advanced technology like CDMS. Therefore, organisations should thoroughly Volume 13 Issue 2

implement and execute CDS practices to meet advancing business needs while complying with standards-based clinical entities.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

Sacks L. Electronic technology in clinical trials [Internet]. Cited Jan. 7, 2021. FDA Available at: https://www.fda.gov/media/91920/download What is big data analytics? IBM [Internet]. Cited Jan. 7, 2021. Available at: https://www.ibm.com/analytics/hadoop/big-data-analytics Clinical trials market size, share & trends analysis report, 2020– 2027 [Internet]. Grand View Research. May 2020 [Cited Jan. 7, 2021].

Available at: https://www.grandviewresearch.com/industry-analysis/ global-clinical-trials-market What is precision medicine? [Internet]. Medline Plus. [Internet].

Updated Sept. 22, 2020 [Cited Jan. 7, 2021]. Available at: https:// medlineplus.gov/genetics/understanding/precisionmedicine/ definition/ Trends, charts, and maps. U.S. National Library of Medicine [Internet].

Updated Jan. 6, 2021 [Cited Jan. 7, 2021]. Available at: https:// clinicaltrials. gov/ct2/resources/trends CFR – Code of Federal Regulations Title 21. U.S. Food and Drug Administration [Internet]. Updated April 1, 2020 [Cited Jan. 7, 2021].

Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=11.10 A guidance on the conduct of clinical trials of medical products during the Covid-19 public health emergency [Internet]. Mar. 2020 [Cited Feb. 1, 2021]. Available at: https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/fda-guidance-conduct-clinical-trialsmedical-products-during-covid-19-public-health-emergency

Rohit Jain Rohit Jain has over 15 years of experience in data management consulting and implementation. His expertise includes CDM, master data management (MDM), and data governance within the pharma industry.

Rohit has successfully led global CDM and MDM delivery programmes. Currently, Rohit is a director at Axtria, Inc., with a Master’s degree in computer applications and a postgraduate diploma in business administration.

Sukhwinder Kaur Sukhwinder Kaur has over 12 years of experience as a subject matter expert (SME) in the clinical domain. She has experience in clinical data management, clinical warehouse development, robotic process automation, advanced analytics, and risk-based monitoring.

Currently, she is a business SME at Axtria, Inc. She has a Bachelor’s degree in physiotherapy and a postgraduate diploma in clinical data management.

Rebecca Lorenzo Rebecca Lorenzo has over seven years of digital marketing, PR/communications, and content creation experience. She creates insightful content with life sciences experts.

Currently, Rebecca is a marketing associate at Axtria, Inc. She is a director for a music publication in her free time and a highly acclaimed, multi-industry writer. She holds a Bachelor’s degree in communications and a Minor in literature.

www.jforcs.com

Journal for Clinical Studies 39

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