JCS Volume 12 Issue 5

Volume 12 Issue 5

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Cerebral Palsy Rescue Study Ensuring Diversity in COVID-19 Vaccine Registration Trials How Using Saliva in Malaria Diagnostics Empowers People in Malaria-endemic Communities to Fight the Disease Automating Adverse Event Data Capture A Missed Opportunity?

www.jforcs.com

THE CURE FOR THE COMMON CRO It’s hard to put a finger on what, exactly, makes start to get it when you experience the passion, expertise, and commitment in every team member.

We put everything into our projects. Our dogged determination to get it right. Our spirit of invention.

Our rigorous processes. Always curious. Always dedicated to delivering quality data. It keeps our customers coming back, choosing Worldwide as their partner time after time. We’re out to change how the world experiences CROs — in the best possible way.

Learn more at worldwide.com

AWARD-WINNING SERVICES Bioanalytical Services | Phase I-IIa | Phase IIb-III Phase IV | Rater Services | Real-World Evidence

THERAPEUTIC FOCUS AND EXPERTISE Central Nervous System | Cardiovascular and Cardiometabolic General Medicine | Rare and Orphan Disease Oncology and Hematology | Other Therapeutic Expertise

Contents

JOURNAL FOR

4

CLINICAL STUDIES U

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

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles.

Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright.

Volume 12 Issue 5 October 2020 PHARMA PUBLICATIONS

www.jforcs.com

FOREWORD

WATCH PAGES 6

US FDA Publishes Draft Guidance for Industry Regarding Cannabis and Cannabis-Derived Compounds

In July 2020, the US Food and Drug Administration (FDA) published the draft guidance entitled Cannabis and Cannabis Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry.

The 12-page draft contains non-binding recommendations and is not for implementation. Instead, Julie Odland at Clarivate shows why the FDA draft guidance is intended for public comment for the agency to consider as it compiles the final version of the guidance.

8

Cerebral Palsy Rescue Study

Patient enrolment is a pivotal aspect of any clinical trial. Without a large enough subject group, trial results may lack statistical significance as not enough data has been collected. Beth Cotton & Leslie Jones at WuXi Clinical explains why it is crucial that CROs enrol the desired number of subjects for trials in the agreed timeframes to ensure that the necessary amount of data is collected to determine the safety and/ or efficacy of the drug being assessed.

10 Changing Rules on Data Transfer from the EU The introduction of the General Data Protection Regulation (Regulation (EU) 2016/679) (“GDPR”) was a painful process for many companies as databases were stripped, new practices introduced and consents to hold data obtained. Some requests were ignored or forgotten, and valuable contact details had to be deleted. However, Patricia Barclay at Bonnacord believes that the changing rules on data transfer from the EU was a welcome reform for clinical trial practice.

REGULATORY 12 Ensuring Diversity in Covid-19 Vaccine Registration Trials While more information needs to be learned about COVID-19, it has become clear that poorer outcomes and the risk of mortality in the US population is alarmingly 2.5 times greater in the black population, and 1.2 times greater in Hispanics, than in whites. Henry J. Riordan, Drew Matheson, Natalia E. Drosopoulou and Aman Khera at Worldwide Clinical Trials explores why ensuring diversity in COVID-19 trials is so important, as to date there is no clear present pathophysiological explanations behind the ethnic/racial/minority mortality differences observed with COVID-19.

16 Risk Based Monitoring Through COVID-19 and Beyond Risk-based monitoring (RBM) may be a relatively recent phenomenon, but it has become a commonly used methodology in clinical trials as evidence of its benefits has grown when compared with the limitations of source data verification. Steven Thys at SGS Life Sciences analyses how RBM is particularly relevant during the COVID-19 pandemic, because it not only uses remote solutions, but it also offers guidance on how to deal with change in ongoing trials.

18 Virtual Or Decentralized Clinical Trials: Defining The New Normal Clinical trials are a cornerstone of drug development, providing scientific evidence on the safety and efficacy of novel pharmaceutical compounds. While traditional trials have effectively served their purpose until now, the ongoing pandemic has forced researchers to think of alternatives. Hence the virtual clinical trial was born.

Subhajit Hazra, a Freelance Medical Writer aims to review this new concept of clinical trials while shedding light upon practical challenges that we face as we navigate our way towards the new normal.

Journal for Clinical Studies 1

Contents MARKET REPORT

38 Modernising TMF Processes to Accelerate Clinical Trials

20 Converting Compliance from a Cost Centre to a Critical Success Factor Maintaining compliance can be a relentless drain on resources.

Alternatively, business can make good use of the data collected for compliance to gain actionable business insight. Denis Gross at ProductLife Group, describes how to derive business value from compliance activities.

Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research, committed to bringing forward the day that all cancers are cured. The charity’s Centre for Drug Development (CDD) sits at the heart of their innovation network of Experimental Cancer Medicine Centres. Rik van Mol at Veeva and Stephen Nabarro at Cancer Research UK shows how the CDD has prioritised TMF modernisation to accelerate trial delivery and ultimately help bring new therapies to market faster.

24 Hybrid Remote Trials –Current Trends and Application

40 Electronic Product Information: Are Companies Ready?

The global crisis caused by the coronavirus has disrupted our personal and professional lives in ways that seemed inconceivable only a few months ago. This is also true for the conduct and operation of ongoing clinical trials. Denis Curtin and Bill Byrom at Signant Health look at how social distancing rules, and reluctance to visit public places have presented significant challenges for the continued operation of studies and the collection of important clinical endpoint data.

Regional health authorities across the world are developing an increased appetite for electronic product information, which could be a much more efficient and patient-friendly way of conveying the latest manufacturing details and safety recommendations. But how ready are life sciences firms to deliver regulated product information in this way?

Agnes Cwienczek at Amplexor assesses the broader potential business case and suggests how companies might determine their readiness for delivering reliable electronic product information – and begin to scope the work ahead.

26 What Does It Take To Have A Good Recruitment In Clinical Research: Malaysia A staggering number of clinical trials fail to meet recruitment goals, leading to delays, early termination, or inability to draw conclusions at trial completion due to loss of statistical power. It is estimated that roughly 80% of clinical trials fail to meet enrolment timelines and approximately 30% of Phase III study terminations are due to enrolment difficulties. Joanne Yeoh and Aina Farhana at Clinical Research Malaysia demonstrates how the impact of failure to enrol patients and meet with timelines can delay product launch that could translate into huge financial losses.

30 Pandemic Patient Support – Navigating the New Norm of Clinical Trials?

Working in the clinical trial space teaches you a lot about resilience, there is a sense of duty to get things done, and this intensifies, especially if you are patient-facing. The whole industry is raising its investment in patient-centric capabilities as it hunts for the perfect contingency plan. Chris Wells at Illingsworth Research explains how to navigate the new norm of clinical trials, highlighting that investment is now being led by what patients will value.

THERAPEUTICS 32 How using Saliva in Malaria Diagnostics Empowers People in Malaria-Endemic Communities to Fight the Disease Malaria acts quickly. Every hour that passes after the onset of symptoms increases the risk of death or permanent disability. Therefore, a diagnostic test is critical as soon as symptoms present. Dr. Benji Pretorius at ERADA Technology Alliance, examines how the use of saliva, rather than blood, in malaria diagnostics could both improve accessibility to malaria tests and help to uphold COVID-19 social distancing and empower people living in malaria endemic communities.

TECHNOLOGY 36 European Group Uses Graph Technology to Reveal Research Data Connections The amount of data in scientific research is growing exponentially.

Big Data and other advances in data science hold huge potential for medical researchers to gain previously unattainable insights that could yield medical and pharmaceutical breakthroughs. But the life sciences sector is failing to maximize the potential. Alicia Frame at Neo4j reports how leading European research group is using graph-based data management techniques to make research inroads – and support efforts to find drugs and vaccines for COVID-19.

2 Journal for Clinical Studies

42 Gaining Efficiency through Interoperability Despite powerful electronic tools in clinical research, we still see data being copied from one system to another every day. With an ever-increasing amount of data, true integration of systems becomes inevitable. Jörg Mielebacher at PCQ Pilots shows how interoperability through standardisation and state-of-the-art technology has the potential to significantly improve efficiency and data integrity in clinical research.

46 Automating Adverse Event Data Capture: A Missed Opportunity?

Life sciences companies are widely failing to maximise opportunities to automate the capture of adverse event data, according to a new study involving pharmaceutical organisations in the UK and US. The research reveals that pharmacovigilance (PV) automation plans are less advanced than they may first appear. Dr. John Price at Arriello, analyses the research findings.

LOGISTICS AND SUPPLY CHAIN MANAGEMENT 48 Managing Collection of Temperature Sensitive Patient Samples during a Clinical Trial Direct-to-patient collection of biological samples is a growing trend that poses complex, but solvable logistics challenges during clinical trials. Providing a convenient and easy method to maintain the patient sample temperature is critical to the success of these clinical trials.

Vince Paolizzi at Pelican BioThermal explains how in order to resolve these challenges, innovative temperature-controlled packaging has been developed to address this growing need.

SPECIAL FEATURE 52 An Interview With MRN On Decentralized Clinical Trials Demographic, epidemiological, social, and cultural trends in European countries are changing the traditional patterns of care and a diseaseorientated approach is no longer appropriate. Dr. Graham Wylie at MRN showcases why home trial support (HTS) and the decentralised clinical trial model mitigates the need for traditional care approaches in this exclusive interview.

Volume 12 Issue 5

Need global life science solutions?

Rely on us. Problem solved.

n Regulatory Affairs n Clinical Research n Medical Devices n Manufacturing n Legal n Medical Research n Medical Publishing n Marketing Communications

er for global life s n t r cie pa e nc l b e ia l so re

Over 55 years’ experience in providing expertise, global translation solutions and language consultancy in the following specialist areas:

ns o ti u l

Y o ur www.dwlanguages.com E-mail: info@dwlanguages.com Tel.: +44 (0)20 7229 4552 @DWLanguages

Foreword It is safe to say that 2020 has been an unpredictable year. The outbreak of COVID-19 created unprecedented circumstances for the conduct of clinical trials across the world.

While the industry has experienced challenging conditions in managing research before, for example, during political unrest or natural disasters, this type of crisis was typically local, short-term, and contingency plans could in many cases utilise lessons learnt from past occurrences.

This is a sentiment echoed by Marcelina Rybiańska and Aman Khera at Worldwide Clinical Trials who explain how COVID-19 has put a huge strain on the healthcare system. The unique situation of patients placed under quarantine plus disruptions in Investigational Medicinal Product (IMP) supply made it difficult to adhere to the approved research plans and forced urgent modifications to secure data validity.

As a result, the clinical trial space has had to adapt, innovate, and explore virtual options, such as wearables, video calls and remote technology to facilitate a better patient experience. According to Tom Ruane at Parexel, remote technology is particularly useful for COVID-19 trials, in which patients are isolated yet there is still a need to frequently report their symptoms to clinicians. This is because the pandemic has exponentially hastened our need for accurate data in real time to help drive sound medical decisions. Remote monitoring not only provides accurate data, but it also cuts down on speed trial timelines, bringing therapies to more patients, as told by Rik Van Mol at Veeva.

The rise of the virtual clinical trial landscape is a growing trend, with sponsors, CROs, investigators, and IRBs modifying clinical trials, by moving visits from clinics to living rooms worldwide. With a sizeable shift in attitude and practice towards innovative remote and virtual techniques that bring trials to patients, the clinical space as we know it is changing. Special considerations must now be put in place for vulnerable age groups, such as children, to govern when and for whom a move to virtual visits is possible.

Joan Busner at Signant Health explains why decisions to move child psychiatric trial visits from face to face in-clinic to virtual and remote require careful deliberation and multiple special considerations. This kind of heart-felt empathy reduces fear and encourages parents to consider clinical trials in the context of helping not only their child, but other children whose parents are experiencing the same gripping fear and uncertainty.

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

Anxiety during clinical trials is certainly not uncommon, but is especially heightened during the pandemic, with Vicenzo Salvatore and Giulia Tengalia at BonelliErede showing that the government’s intrusion into our personal lives has manifested into us feeling distrust and fear. When there is fear, recruiting patients for clinical trials or even new technologies becomes overwhelmingly challenging. As a result, the use of virtual technologies like contact tracing apps needs to be revaluated to maintain regulatory compliance, whilst putting patient-centricity first.

Big data, artificial intelligence and digital platforms might have dramatically transformed the clinical research landscape, but clinical trial diversity is still somewhat lacking. Countries like Africa hold immense potential because of its size, demographic and desire to improve health and life expectancy. However, it only accounts to less than 2% of the number of clinical trials. Carole Wallis and Sofie Vandevyver at Cerba Research believes this is because of limited infrastructure, cultural barriers and unpredictable clinical trial regulatory timelines, which are some of the key issues hindering investments in this area and hence causing a burden to conducting clinical trials within Africa.

Although the low representation of Africa in clinical trials is not unusual, more must be done to ensure that clinical trials are not homogeneous, so that patients from all backgrounds are fairly included. Clinical trial diversity, remote monitoring and regulatory compliance will remain as hot topics throughout 2020.

I hope you all enjoy your summer and I look forward to welcoming you back in Autumn, with more enthralling articles to be included in JCS. You may have noticed that we have changed the theme of the front cover picture of the JCS Journal. We started JCS with the unique goal of highlighting emerging countries and thoroughly analysed these countries as a clinical trial destination. Hence, we featured the national flower of one of the countries highlighted in that issue. Although we remain committed to bringing you a market analysis of emerging clinical trial destinations, JCS will now focus on therapeutic and regulatory aspects throughout 2020. The front cover picture will represent one of the therapeutic focuses that we have in this issue.

Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies

•

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

•

Catherine Lund, Vice Chairman, OnQ Consulting

•

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 of Europe

•

•

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

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

•

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

•

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

•

Stefan Astrom, Founder and CEO of Astrom Research International HB

• • •

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

•

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 12 Issue 5

europital.com

The Science Driven CRO

Medical Affairs

Pharmacovigilance

Clinical Operations

Regulatory Affairs

Biometrics

Medical Writing

www.jforcs.com

Europital is an international Contract Research Organization (CRO) providing a full range of clinical services for the pharmaceutical, biotechnology and medical device industries.

Journal for Clinical Studies 5

Watch Pages

US FDA Publishes Draft Guidance for Industry Regarding Cannabis and Cannabis-derived Compounds In July 2020, the US Food and Drug Administration (FDA) published the draft guidance entitled Cannabis and CannabisDerived Compounds: Quality Considerations for Clinical Research Guidance for Industry.1 The 12-page draft contains non-binding recommendations and is not for implementation.

Rather, FDA draft guidance is intended for public comment for the agency to consider as it compiles the final version of the guidance. The public comment period for this draft guidance ended on 21 September 2020.

This draft guidance outlines the FDA’s current thinking on several topics relevant to the clinical research and development of drugs containing cannabis and cannabis-derived compounds: 1) The source of cannabis and cannabis-derived compounds for clinical research, 2) general quality considerations for developing drugs that contain cannabis and cannabis-derived compounds, and 3) calculation of percent delta-9 tetrahydrocannabinol (THC) in botanical raw materials, extracts, and finished products.

The legality of cannabis in the US has been changing over time at both the state and federal levels. Currently, 33 states, Puerto Rico, and Washington, DC, allow medical use of marijuana under state

6 Journal for Clinical Studies

law, and 14 additional states have state law medical programmes that are limited to cannabidiol (CBD) products. Additionally, 11 states and Washington, DC, have legalised marijuana for recreational use under state law, and 16 other states have decriminalised recreational marijuana possession in some form under state law.

In the US, parts of the Cannabis sativa plant have been controlled under the Controlled Substances Act (CSA) since 1970 under the drug class “Marihuana.” Cannabis contains more than 80 biologically active chemical compounds, including the two bestknown compounds, THC and CBD. The Agriculture Improvement Act of 2018, or the Farm Bill, removed hemp from the CSA’s definition of marijuana. The Farm Bill defined hemp as cannabis or derivatives of cannabis with a very low THC content (below 0.3% by dry weight). As a result, although marijuana remains a Schedule I drug (i.e., the most restrictive), hemp is no longer considered a controlled substance under federal law.

The Farm Bill explicitly preserved the FDA’s authority to regulate products containing cannabis or cannabis-derived compounds under the Public Health Service Act. In doing so, the US Congress recognised the FDA’s public health role with respect to the products it regulates, including products that are or contain cannabis ingredients.

In general, drugs containing cannabis and cannabis-derived

Volume 12 Issue 5

Watch Pages

compounds are subject to the same authorities and requirements as drugs containing any other substance.

that comes from THC – the primary psychoactive component of marijuana.

Drugs intended for human use are evaluated by the FDA’s Center for Drug Evaluation and Research (CDER) to ensure that drugs marketed in the US are safe and effective for their intended uses and will be manufactured in a manner that ensures quality. A CDER subunit called Small Business and Industry Assistance (SBIA) helps small pharmaceutical businesses and industry navigate FDA information about drug development and assists in understanding the regulation of human drug products.

Ahead of the Epidiolex approval, in April 2018, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (PCNSDAC) offered unanimous support for the benefit-risk profile of this CBD oral solution for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged two years and older. The PCNSDAC based its support on data from three Phase III studies in patients with Lennox-Gastaut syndrome or Dravet syndrome, for which the primary endpoint was percentage change from baseline in seizure frequency (drop seizure frequency in two trials, convulsive seizure frequency in the third).

As noted in the Federal Register announcement for the July draft guidance, the FDA encourages drug developers to meet with agency regulators early in their development programmes – ideally, before submitting an investigational new drug application (IND). Pre-IND meetings offer an opportunity to obtain FDA input on research plans and required content for an IND submission, complementing guidances and other information provided by the agency. Early interactions with FDA staff through a pre-IND meeting can answer sponsors’ questions related to a specific drug development programme and provide information that will assist them in preparing complete IND applications. “Efficient use of FDA resources can lead to more efficient drug development.”2 First CBD Product Approved by the FDA to Treat Rare Forms of Epilepsy In June 2018, the FDA approved Epidiolex (cannabidiol), from GW Research Ltd – the first approved drug composed of an active ingredient derived from marijuana – to treat rare, severe forms of epilepsy (Dravet syndrome, Lennox-Gastaut syndrome). The FDA granted several incentives during the development of Epidiolex: priority review designation for the application, fast-track designation for the Dravet syndrome indication, and orphan drug designation for both the Dravet syndrome and Lennox-Gastaut syndrome indications. The FDA Press Release about the Epidiolex approval noted that CBD does not cause intoxication or euphoria (the “high”) www.jforcs.com

REFERENCES 1.

2.

Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research; Draft Guidance for Industry; Availability, Federal Register 85 (141), 22 July 2020, 44305-7. https://www.govinfo.gov/ content/pkg/FR-2020-07-22/pdf/2020-15907.pdf Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry Draft Guidance for Industry, July 2020 https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/cannabis-and-cannabis-derivedcompounds-quality-considerations-clinical-research-guidance-industry

Julie Odland Julie Odland is a writer and editor with more than 25 years of experience in publishing. She joined Clarivate in 2017 and specialises in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin.

Email: julie.odland@clarivate.com

Journal for Clinical Studies 7

Watch Pages

Cerebral Palsy Rescue Study

Patient enrolment is a pivotal aspect of any clinical trial.

Without a large enough subject group (as determined by both the nature and phase of the study), trial results may lack statistical significance as not enough data has been collected1.

Subsequently, the main questions posed by the clinical trial may not be answered to respectable standard, and this could result in sponsors having to redo whole trials, effectively wasting time and resources. It is therefore crucial that CROs enrol the desired number of subjects for trials in the agreed timeframes to ensure that the necessary amount of data is collected to ultimately determine the safety and/or efficacy of the drug being assessed.

There are a number of common barriers that may impede clinical trial enrolment, such as lack of awareness of trials amongst the target patient population, fear of side-effects, or maybe the study protocol appears too complex for the patients2. Generally, a number of patient hesitations can be overcome through more extensive marketing, including both producing better educational material about the study and increasing awareness of the trial through the press and mass media.

However, paediatric trials pose their own unique patient enrolment problems. The most obvious difference between adult and paediatric clinical trials is the age between the subjects. Typically, paediatric study subjects will need consent from their parents/ guardians in order to participate in the trial, but many are in fact reluctant to provide it. This is because participation can place a strain on the whole family, as parents/carers will have to assist children with study drug dosing, completing diary entries, taking them to and from study sites for multiple site visits etc, and this will undoubtedly interfere with their own working lives3. The parents/carers may also not deem the particular study of significant importance – for instance, if the purpose of the study is to assess a treatment for a non-life-threatening and relatively mundane illness/disease – and therefore may not be motivated enough by the long-term medical benefit the study could bring.

8 Journal for Clinical Studies

As mentioned previously, successful patient enrolment is fundamental to the success of any clinical trial and serves as a key milestone. If a CRO cannot enrol the required number of subjects as specified by the sponsor in an agreed timeframe for whatever reason, then the sponsor may seek a new CRO to take over in order to get the study back on track.

In one case, a clinical trial required rescuing primarily due to the aforementioned challenges of paediatric patient enrolment.

This Phase II study was evaluating the efficacy of glycopyrrolate oral solution in treating sialorrhea – uncontrollable drooling – in paediatric cerebral palsy patients. The biggest challenge with this particular indication is that it was non-life-threatening and also the study had a placebo arm, meaning that any patients already on medication would have had to undertake a washout period and potentially receive no treatment during the study. Because of this, many parents did not agree to have their children participate, and subsequently patient enrolment was extremely difficult and slow. This unfortunately meant that the CRO was unable to meet the timeline as agreed with the sponsor.

These patient enrolment delays were also influenced by the fact that the CRO was not fully focused on the project – the study was mainly managed by one of the in-house physicians, who had his working attention divided across a number of projects at the time.

WuXi Clinical was brought in by the sponsor to take over project management, clinical monitoring, and medical writing services, as previously contracted to the initial CRO. Following our team’s introduction into the study, we worked closely with the investigative sites to discuss their perspective on the protocol design limitations and provided this feedback to the sponsor. By efficiently cooperating with the sponsor, we were together able to identify, qualify, and initiate eight additional sites in order to complete patient enrolment in a timelier manner. Our work with the client resulted in three protocol amendments to ease the patient enrolment restrictions without compromising the integrity of the trial. Ultimately the sites were able to enrol the desired number of patients for the study which resulted in an NDA approval.

Volume 12 Issue 5

Watch Pages

Due to the nature of this particular indication, our project manager and CRAs needed to develop a deep understanding of the challenges of the patient cohort. During the transition period they quickly gained a strong understanding of the drug being studied, as well as the typical questions and issues encountered by all of the sites, trainers, caretakers and even subjects themselves. In particular, the study team needs to understand the difficulties and hurdles that can arise when obtaining both consent and assent for the paediatric patient population.

The challenges of patient enrolment should never be underestimated, and it is the CRO’s responsibility to make every effort to ensure that the trial in question enrols enough subjects to yield an adequate amount of trial data. The challenges for paediatric studies compared to conventional studies do differ, and CROs should ensure that they can provide customised and effective communication with the parents/carers of children to best build trust, knowledge, and interest to ultimately gain consent for the subjects’ participation. Being able to educate the subjects and parents/carers on the importance and advantages of clinical research in order to help the parents best deal with and prepare for any inconveniences the study may cause could be crucial when trying to achieve enrolment milestones in a paediatric study.

REFERENCES 1.

2.

3.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933537/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936073/ https://prahs.com/insights/3-steps-to-effective-pediatric-recruitmentand-retention

www.jforcs.com

Leslie Jones Leslie Jones is the Executive Director of Clinical Operations US for WuXi Clinical. She has over 25 years of clinical research experience, ranging from working in a Phase 1 unit, to performing GCP site audits, to managing clinical and data teams on large-scale Phase 2 and Phase 3 trials.

She has a great ability to unify internal and external resources and provides focus to the teams to achieve client goals and outcomes.

She has been with WuXi Clinical for over a decade and is based in Austin, TX.

Beth Cotton Beth Cotton has been with WuXi Clinical for over 10 years and within the field of clinical research for over 25 years. Her hands-on experience includes working in positions ranging from Subject Recruiter to Associate Director, Clinical Management have provided a proven track record of success in areas of management and monitoring of clinical programs across Phase I-III. Her therapeutic area experience includes 40 clinical studies in a variety of therapeutic areas, such as urology, cardiovascular, CNS, ear, nose, and throat, endocrinology, gastroenterology, infectious disease, neurology, OB/GYN, oncology, pain management, pulmonary/respiratory, and rheumatology.

Journal for Clinical Studies 9

Watch Pages

Changing Rules on Data Transfer from the EU

The introduction of the General Data Protection Regulation (Regulation (EU) 2016/679) (“GDPR”) was a painful process for many companies as databases were stripped, new practices introduced and consents to hold data obtained. Some requests were ignored or forgotten and valuable contact details had to be deleted. For clinical trial practice, however, it was a welcome reform. The previous law was a directive that had to be introduced separately in each member country with the inevitable local variations, which led to additional costs and frustrations. A regulation has automatic effect across the EU and should be interpreted in the same way in each Member State.

The GDPR prohibits export of personal data to countries that do not provide individuals with enforceable privacy rights over their data, but transfers to countries with levels of protection for personal data that the Commission deemed adequate are permitted and minimal additional processes are required. Until recently, the US was on the approved list. While some privacy lawyers had some doubts as to whether the US Privacy Shield really did offer sufficient protection, industry was generally pleased and of course in the context of the international pharmaceutical industry and cross-border clinical trials, it was a huge relief. This summer, however, the European Court invalidated the adequacy finding by the European Commission for the US, throwing the whole situation into uncertainty (Case C-311/18 Data Protection Commissioner v Facebook Ireland Limited and Maximillian Schrems).

The case known as Schrems II is highly complex, but fortunately the judgement is quite clear. The lawyer who brought the case, Max Schrems, had previously brought a case that struck down the previous data transfer system between the US and EU, known as the Safe Harbour scheme. This second case focussed on two points; firstly the Privacy Shield which had been introduced in response to the demise of the Safe Harbour scheme and was meant to address its shortcomings. He argued successfully that this new scheme gave primacy to US rules permitting electronic surveillance over the rights of individuals required by the EU rules, and that this meant that the protections offered were not in fact adequate. Secondly, he argued against the alternative form of protection for exported data, the Standard Contractual Clauses. These are a set of contractual terms laid down by the Commission which, if included in a contract, are intended to ensure that the parties handle personal data in a manner that provides adequate protection to the EU citizen whose data has been exported, and in fact predate the GDPR (https://ec.europa.eu/ info/law/law-topic/data-protection/international-dimension-dataprotection/standard-contractual-clauses-scc_en). As an example, in his suit he challenged the use of such clauses by Facebook. In this part of his case, he was not successful. The court found that the clauses were a valid way in which to protect citizens’ rights and that their use could continue; however, there was a sting in the tail. The court ruled that in using the Standard Contractual Clauses, a party had to also consider the context of that use and the legal protections offered by the country to which export was to be made. In particular, consideration had to be given to the extent to which public authorities 10 Journal for Clinical Studies

in the destination country had the right to access the exported personal data. If the data controller in the EU was dissatisfied with the level of protection offered, then the transfer should not take place even where the foreign party had accepted the Standard Contractual Clauses. As the European Court has specifically said that the US laws do not provide adequate protection, then this would seem to automatically prohibit the use of the Standard Contractual Clauses in relation to export of data to the US. Where then does that leave us? The court judgement, unlike a new piece of legislation, does not have a transition period. It takes immediate effect, so companies must consider their current contracts and practices and not just future activities that are being planned.

Clearly any reliance on the Privacy Shield must stop immediately.

Companies must undertake due diligence to consider whether the countries to which they are transferring data do offer appropriate data privacy, even where the Standard Contractual Clauses are used, and ideally not transfer data to such countries. Both the US and the EU have said that they are working on an alternative to the Privacy Shield and the EU has said that it is working on revising and strengthening the Standard Contractual Clauses. Companies should keep an eye out for these changes, but in the meantime should review their consent forms and contracts to ensure that the data subjects are aware of the situation, and give full consent in these changed circumstances. Wherever possible, personal data should be held and processed within the EU and not transferred out of the block.

Additional clauses in contracts could be considered, such as greater use of anonymity, encryption and prohibitions on transfers to other companies, but these will need to be considered on a case by case basis.

A further issue on the horizon for international trials is the potential impact of Brexit. The UK is currently compliant with all the EU rules on data protection and will incorporate such laws automatically into UK law at the end of the year. The UK government has previously indicated that the GDPR regime would continue postBrexit. This should mean that there should not be any immediate impact on the acceptability of the UK as a data transfer destination; however, as a non-EU country, contracts will need to be revised to include the Standard Contractual Clauses and companies may have to appoint a data representative within the EU. Moving forward, the UK will no longer be subject to the European Court and so it is to be Volume 12 Issue 5

Watch Pages

expected that there will be different interpretations over time by UK courts. While new UK laws could again be anticipated over time, it seems that this may be coming sooner than originally thought. The UK government published its National Data Strategy on 9th September (https://www.gov.uk/government/publications/uk-national-datastrategy/national-data-strategy) and this has raised a number of concerns in Brussels, in particular in relation to government access to and use of personal data which may well conflict with the Schrems judgement. It is, of course, early days and the strategy document is only a first step on which comment is now being sought, but it is certainly a complicating factor.

So while many may have thought once they had addressed the GDPR reforms and updated their processes to accommodate those, that they could forget about data protection for a while, it seems that is not to be the case and that we are again looking at substantial upheaval ahead. www.jforcs.com

Patricia Barclay Patricia Barclay studied law at the Universities of Edinburgh and Oxford before embarking on a career in the life science industry. She held a number of senior positions at Pfizer before becoming General Counsel of Vernalis plc. She subsequently served as General Counsel of the Ferring Group and of Solvay Pharmaceuticals before setting up Bonaccord a law firm dedicated to supporting the scientific community. Bonaccord has won many awards including as UK Life Science Law Firm of the Year. In addition to her legal work Patricia is an active business mentor and teaches at both academic and professional levels.

Email: patricia@bonaccord.law

Journal for Clinical Studies 11

Regulatory

Ensuring Diversity in COVID-19 Vaccine Registration Trials While much more information needs to be learned about COVID-19, it has become clear that relatively poorer outcomes and the risk of mortality in the US population is alarmingly 2.5 times greater in the black population, and 1.2 times greater in Hispanics, than in whites. Some of the reasons advanced for this worrisome discrepancy are higher prevalence of comorbid illnesses such as diabetes, obesity and cardiovascular disease, restricted access to healthcare, relatively crowded housing conditions, and riskier essential occupations which often demand violating social distancing guidelines1. Minority healthcare workers are more likely to report using inadequate or reused protective gear, and nearly twice as likely as white counterparts to test positive for the coronavirus. Recognising the role that socioeconomic status plays in COVID-19 outcomes, the income gap may partially explain the increase in deaths seen in lower-income groups but does not explicate the relatively higher death rates of black people and Hispanics in higher income groups. To date there are no obvious pathophysiological explanations behind the ethnic/racial/minority mortality differences observed with COVID-19.

The poorer outcomes seen in underserved communities have all been in response to therapeutic treatments. However, with several COVID-19 vaccine trials beginning to enter Phase III testing in the US, UK and China recently, it is important to understand if comparable inferior outcomes will be evidenced in minority populations’ response to COVID-19 vaccine candidates. To determine this, clinical triallists will need to ensure that the data generated in these vaccine registration trials are statistically robust and generalisable across ethnic populations, particularly blacks and Hispanics, but also Asians and indigenous people.

One might assume that in large vaccine trials enrolling greater than 20-30,000 subjects, ethnically diverse underserved populations of various ages and health concerns would be adequately represented, permitting firm statistical conclusions regarding efficacy and safety.

However, the number of potential variables that may impact these trials is so numerous that important findings may be obscured or misrepresentative, despite such large enrolment numbers.

Additionally, in terms of vaccine adoption, individuals from black and Hispanic US communities are historically less likely to receive yearly influenza vaccinations than their white counterparts irrespective of age2, pointing to the need to ensure adequate representation of all ethnicities in vaccine trials. We know that, for the influenza virus, there are significant variations in genetic factors in vaccine response with one important human gene having 14 different forms that vary greatly between blacks, Asians, and whites. As the different polymorphic forms of the antibody produced bind to different targets on the viral surface, there could be potentially 12 Journal for Clinical Studies

significant variation in vaccine effectiveness3. To the contrary, with the H1N1 influenza virus, the black population had significantly greater antibody titres compared to whites4. Nonetheless there were higher rates of hospitalisation seen in this ethnic group during the 2009 H1N1 influenza season, which the Centers for Disease Control and Prevention (CDC) suggested may be due to greater preponderance of susceptible underlying conditions, such as asthma and diabetes5.

These examples (albeit for a different viral class than COVID-19) serve to illustrate that outcomes for individual minority groups cannot be predicted in advance without collecting important variables from specific populations when testing new vaccine candidates.

Therefore, a proactive enrolment strategy is urgently needed to ensure adequate ethnic representation in COVID-19 vaccine trials that is sufficiently representative of a country or region, so that statistical robustness can be confidently applied to both efficacy and risks of a novel vaccine that are pertinent to specific minority groups.

If risks are potentially related to ethnicity, then calculations will also need to specify the number of subjects per patient group needed to confidently identify less common adverse events according to a predetermined threshold. Given the large subject numbers required for enrolment, it should be relatively easy to identify common adverse events, but rare events which may be related to ethnicity and other independent factors may require increased numbers within each population in order to identify risks which occur at less than a 1% incidence at a high degree of confidence.

A proactive approach to recruitment can best be accomplished by having a wide national and global reach, with the understanding of important cultural and ethnic factors in the various countries included in the trial, as well as the ability to target desired demographic variables by assisting sites with links to social media, community organisations/foundations and clinics such as those specialising in comorbid illness such as diabetes and cardiovascular disease. It will be necessary to continuously track incoming demographic data and efficiently adjust recruitment strategies in order to meet the necessary demographic targets per subject cohort for enrolment.

Regulatory Guidance on Diversity in Clinical Trials Although the number of countries submitting clinical trial data to the FDA has doubled over the past two decades, the proportion of white participants in clinical trials has actually declined, from 92% to 86%. As a result, several measures, acts and guidances have been put in place to ensure more diversity and inclusion in the clinical trial process. One of the most noteworthy of these is the FDA guidance posted in June 2019 concerning “Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs” which serves as a helpful general starting guide to ensure ethnic diversity in clinical trials6. This guidance provides wide-ranging recommendations including broadening eligibility criteria to increase diversity in enrolment, making trial participation less burdensome for participants, and adopting enrolment and Volume 12 Issue 5

Regulatory retention practices that enhance inclusiveness of underrepresented minority communities. Presciently, the FDA recommended that researchers reduce the frequency of study visits to those needed to appropriately monitor safety and efficacy, and to consider flexibility in visit windows, as well as the use of electronic communication devices (e.g., telephone/mobile telephone, secured electronic mail, social media platforms) or mobile technology tools that can be used to replace site visits and provide investigators with real-time data – all of which have become important tools during the COVID-19 pandemic. An obvious criticism is that these electronic platforms and devices may not be as readily available to lower-income subjects and these ostensibly helpful actions may actually result in less inclusion of underrepresented minority subjects overall, unless this equipment and internet infrastructure is being supplied by the sponsor or site; a practice that is increasingly less common in the current BYOD (bring your own device) research environment encouraged by many electronic patient-reported outcome (ePRO) vendors.

Of note, FDA guidance also recommends that during the recruitment process potential subjects should be made aware of financial reimbursements for expenses associated with costs incurred by participation in clinical trials related to travel and lodging expenses. Importantly, the FDA does not consider reimbursement for reasonable travel expenses to and from the clinical trial site and associated costs such as parking and lodging as characterizing undue influence7. Appropriate, simple and rapid reimbursement may be especially beneficial to low-income subjects, and numerous patient support vendors provide such financial services. Specifically, many of these vendors support the use of a “patient reimbursement card” which can be immediately updated with payments from the site once a procedure or site visit is completed.

The FDA guidance also encourages researchers to use enrolment and retention practices to enhance inclusiveness. As such, researchers are encouraged to work directly with communities to address subjects’ needs and endeavour to involve subjects, advocates, and caregivers in the design of study protocols as much as possible as they are more likely to provide valuable insights into challenges and burdens as

www.jforcs.com

well as risks/benefits that may be unknown to site staff. Community engagement and the use of medical advocates/liaisons also known as “patient navigators” has been very successful in specific underserved and minority community recruitment efforts. Explicitly, guidance recommends that sites hold recruitment events often that are easily accessible during evening and weekend hours and having these in trusted community locations as a means of connecting with diverse subject groups.

Although these recommendations are generally quite useful and serve as a good starting-point, this guidance is intended mostly for enrolment in treatment studies and are not specific to vaccine studies, and does not go nearly far enough in addressing specific barriers to enrolment of diverse populations and how these can be successfully overcome in vaccine studies. In regards to vaccine studies there is much more work to be done, and steps to be taken in providing information and educating underserved minority groups about clinical research and the development journey of products may be helpful in increasing awareness. Unfortunately, guidelines from the FDA for COVID-19 vaccines FDA “encourages” enrolment of racial and ethnic minorities but do not require it for approval8.

Specific Barriers to Enrolment in Vaccine Studies There have been several efforts to identify the most important barriers to enrolling diverse populations in clinical trials. Based on literature review and evaluation, as well as vital input from key stakeholders, including minority subjects and referring physicians, Clark et al.9 have suggested the following three broadly-defined categories of critical barriers to minority participation in clinical trials: (1) mistrust, including lack of information about and comfort with the research process; (2) logistical barriers such as time and resource constraints; and (3) limited clinical trial awareness.

Researchers tend to spend much of their efforts focusing on solutions related to logistical considerations, as these are most easily addressed and seem to resonate with subjects, including providing transportation, flexible hours for subjects, appropriate compensation, and mobile technology support such as an app for subjects and

Journal for Clinical Studies 13

Regulatory

mobile phones for those who do not have one. Addressing subjects’ logistical and financial concerns also permits more patient-centricity in trials and may not only increase the likelihood of participation but also may increase satisfaction and improve the overall experience of minority subjects9.

However, although important for recruitment of minority subjects across virtually all clinical trials sites, it may not be fully appreciated that the foremost issue for most minority subjects seems to be “trust” – an issue which appears to be amplified for trials involving vaccines. Despite the fact that specific minority groups stand to benefit enormously from the development of a safe and effective COVID-19 vaccine, some groups from underserved communities remain distinctively distrustful of the medical establishment. This distrust is likely based on current disparities in healthcare access as well as past transgressions, such as the Tuskegee syphilis experiment, which was so profoundly disturbing and predominant that the lack of trust in the research process is often referred to as the “Tuskegee effect”. This effect is echoed in a recent news poll suggesting only 32 per cent of black adults said they would definitely get a vaccine, compared with 45 per cent of whites and Hispanics10. Of note, annual reports from the CDC on vaccination rates for diseases like influenza, pneumococcal pneumonia, HPV and herpes zoster commonly confirm that racial and ethnic vaccination differences persist for all vaccinations, with generally lower coverage for most vaccinations among black, Hispanic, and Asian adults compared with white adults.

Furthermore, notwithstanding the absence of an actual approved vaccine for COVID-19, there is a very robust and organised multinational “antivax” movement which has been extremely vocal in regard to unfounded assertions of disproportionate harm to minority and underserved groups. Confounding this issue, several national public health groups have publicly considered offering some of the first approved vaccine doses of the COVID-19 vaccine to the most 14 Journal for Clinical Studies

vulnerable groups, including the elderly, healthcare workers and those at greatest risk of harm, as well as diverse populations such as blacks, Hispanics and indigenous peoples, as part of a larger public health plan.

However sincere these motives may be (reflecting the desire to provide the vaccine to those most in need), they have been called into question with criticisms of underserved minority populations serving as “guinea pigs” for subsequent majority populations who would be dosed once more information on safety is known.

In order to overcome issues such as these, it will be important to build trust within various minority groups by partnering with multicultural professional associations and by utilizing patient navigators on a local level whenever possible. In a recent survey, Lavinia et al. reported that 44% of the site respondents indicated that the use of patient navigators was one of the most effective methods of improving recruitment of underserved minority participants into clinical trials, and particularly in assisting with clinical trial education11. Communication about clinical trial opportunities through postings on various websites and through written materials translated into numerous languages were also reported to be effective, as was the use of financial incentives including the use of prompt travel reimbursement and monetary incentives. As noted, technology is also helping to drive better research and development of treatments and ensuring that historically excluded minority communities are given the same access to medical advancements and trials12. One unanticipated outcome of the COVID-19 pandemic is that many clinical trials are finally utilising technology to their advantage, whether replacing or supplementing traditional clinic visits with virtual visits which can also aid recruitment efforts given the reluctance of some patient groups to come into site/hospital settings. Furthermore, tablets/devices can be used outside the traditional bounds of a trial to gather important information on symptoms that might be used to more clearly identify patient subgroups that respond to vaccine candidates as well as on outcome measures that can reliably assess the longer-term efficacy and safety of vaccines.

Volume 12 Issue 5

Regulatory Summary Increasing clinical trial participation in COVID-19 vaccine registration studies among minority and underserved populations will require a paradigm shift in researchers’ approaches to and conduct of clinical trials, and importantly, in how researchers engage their communities.

Large-scale registration COVID-19 vaccine trials can only provide meaningful and generalisable data regarding a specific subgroup’s success and safety rates if diverse communities are recruited, and if all important information is fastidiously collected, including at a minimum, age, gender, ethnicity/race, socioeconomic status, residential/occupational status and comorbid medical conditions.

Any significant lack of diversity in the clinical trial process can result in efficacy and safety outcomes that may be flawed and distorted; and when diverse populations are knowingly excluded from vaccine trials there is a real risk of making assumptions about drug safety and effectiveness that may not be accurate at all12. There are also pragmatic reasons for minority recruitment in regard to vaccine trials which demand that subjects eventually be exposed to SARS-CoV-2 in order to determine efficacy as this exposure has been shown to be more pervasive in underserved minority communities. Given the myriad scientific, ethical and practical reasons, it is imperative that researchers attempt to fill the breach in trial participation among minority and underserved minority populations for COVID-19 vaccines by using some of the tools suggested above and frankly, by any and all means possible.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Center for Disease Control and Prevention (CDC) website report, July 24, 2020. Provisional Death Counts for Coronavirus Disease 2019 (COVID-19). Healthcare Disparities: Race and Hispanic Origin. https:// www.cdc.gov/nchs/nvss/vsrr/covid19/health_disparities.htm Egede LE and Zheng D; Racial/Ethnic Differences in Adult Vaccination among Individuals with Diabetes. Am J Public Health 93(2):324-329, 2003 Avnir Y et al.; IGHV1-69 Polymorphism modulates Anti-Influenza Antibody Repertoires, correlates with IGNV Utilization Shifts and varies by Ethnicity. Science Reports 6:20842, 2016.

Kurupati R et al.; Race-Related Differences in Antibody Responses to the Inactivated Influenza Vaccine are linked to Distinct Pre-Vaccination Gene Expression Profiles in Blood. Oncotarget online, oncotarget 11704, 2016.

CDC website report 2009 H1N1 and Seasonal Flu and African American Communities: Questions and Answers. https://www.cdc.gov/h1n1flu/ african_americans_qa.htm Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Design https://www.fda.gov/ media/127712/download Payment and Reimbursement to Research Subjects — Information Sheet (January 2019), available at https://www.fda.gov/ RegulatoryInformation/Guidances/ucm126429.htm Covid-19 Vaccine Trials Have a Problem: Minority Groups Don’t Trust Them available at: https://www-wsj-com.cdn.ampproject.org/c/s/ www.wsj.com/amp/articles/covid-19-vaccine-trials-have-a-problemminority-groups-dont-trust-them-11596619802 Clark LT, Watkins L, Piña IL, Elmer M, Akinboboye O, Gorham M, Jamerson B, McCullough C, Pierre C, Polis AB, Puckrein G and Regnante JM; Increasing Diversity in Clinical Trials: Overcoming Critical Barriers.

Current Problems in Cardiology, 08 Nov 2018, 44(5):148-172.

Goldstein A and Clement S; June 2, 2020. 7 in 10 Americans would be likely to get a coronavirus vaccine, Post-ABC poll finds https://www.washingtonpost.com/health/7-in-10-americanswould-be-likely-to-get-a-coronavirus-vaccine-a-post-abc-pollfinds/2020/06/01/4d1f8f68-a429-11ea-bb20-ebf0921f3bbd_story.html Lavinia D and Gansauer L; Recruiting and Retaining Minorities in Oncology Clinical Trials: A Nurse Navigator Perspective. Journal of Oncology Navigator and Survivorship. Sept 2018 Vol 9, No 9mber . http://www.jons-online.com/issues/2018/september-2018-vol-9no-9/1976-recruiting-and-retaining-minorities-in-oncology-clinical-

www.jforcs.com

12.

trials-a-nurse-navigator-perspective Hebenstreit C; How Technology Is Helping Increase Diversity In Clinical Trials https://www.forbes.com/sites/forbestechcouncil/2020/06/18/ how-technology-is-helping-increase-diversity-in-clinicaltrials/#1bf39ca4bf89

Henry J. Riordan Dr. Riordan is the Chief Development Officer at Worldwide Clinical Trials. He has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years. He has over 120 publications, including co-authoring two books focusing on innovative clinical trials methodology.

Email: henry.riordan@worldwide.com

Drew Matheson Drew Matheson is the Executive Director of the Immune Mediated Inflammatory Disorders Division and is the Pandemic Response Lead for the COVID-19 Task Force at Worldwide Clinical Trials and as such oversees all ongoing COVID-19 trials. Specialising in project management and statistical support in complex project environments, including a focus on device trials, Drew has worked in clinical research for more than 20 years, leveraging invaluable, fundamental knowledge of the ins and outs of clinical research.

Email: drew.matheson@worldwide.com

Natalia E. Drosopoulou Dr. Drosopoulou is the Executive Director and Global Franchise Leader at Worldwide Clinical Trials who leads the International Clinical Project Management Team. She received her PhD in biochemistry specialising in developmental neurobiology from King’s College of London.

With over 18 years in the clinical research industry, her experience spans from small intricate Phase I studies to large global Phase III programmes.

Email: natalia.drosopoulou@worldwide.com

Aman Khera Aman Khera is Global Head of Regulatory Strategy at Worldwide Clinical Trials. Ms Khera has over 23 years’ industry experience in providing global strategic direction in regulatory affairs. She has led a wide variety of regulatory projects providing regulatory strategy and development services for a variety of client sponsor companies in many therapeutic indications. Ms Khera is well versed in developing comprehensive regulatory strategies. Her career is built on helping client sponsor companies achieve their end-to-end regulatory strategies from study submission to commercialisation.

Email: aman.khera@worldwide.com

Journal for Clinical Studies 15

Regulatory

Risk-based Monitoring Through COVID-19 and Beyond Risk-based monitoring (RBM) may be a relatively recent phenomenon, but it has become a commonly-used methodology in clinical trials as evidence of its benefits has grown when compared with the limitations of source data verification (SDV). In 2013, both the FDA and the EMA officially embraced the concept of risk-based quality management,1,2 and paved the way for its practical implementation, and in 2016, the addendum R2 to the ICH-GCP guidelines included explicit expectations around risk-based quality management.3 RBM can range from very light to very detailed monitoring strategies, depending on the overall risk level of the trial. However, the focus should always be on the critical data and processes, which support and underpin data quality and subject safety and wellbeing.

It is a holistic approach to quality control and therefore involves many different stakeholders, including data managers, central monitors, statisticians and others, all supported by technologies and tools allowing for more and better centralised data review, while facilitating interactions between functional groups via user-friendly interfaces.

By definition, RBM is an adaptive and dynamic approach in which activities in one functional area may trigger actions in another.

Risks are reviewed on an ongoing basis and lead to adjustments in

16 Journal for Clinical Studies

the chosen strategy. It is this feature of the methodology that makes it particularly appropriate in these unprecedented times we are witnessing with the COVID-19 pandemic, because it offers guidance on prioritising and how to deal with change in ongoing trials. RBM also uses more remote solutions which can be of great advantage when on-site visits are not possible.

In the current situation, regulators expect trial sponsors to evaluate the potential risks and benefits of their trials, which may result in substantial changes to study protocols, which could lead to changes in the list of critical variables. For example, safety considerations related to COVID-19 could oblige sponsors to adjust withdrawal criteria, or change the inclusion criteria to exclude groups of high-risk patients to minimise the chances of infection by the SARS-CoV-2 virus. Sites that were qualified prior to the pandemic when preventive measures against COVID-19 were not needed may now need to put a process in place to safely allow patients to attend their premises. Other new ways of working could include supplying investigational product direct to patients, switching from central to local laboratories, or from hospital-based measurement to home monitoring and nursing.

All of these new approaches have underlying processes that could potentially make a difference to the quality of the trial, and therefore need to be carefully assessed. The list of trial aspects that are now important will no longer be the same as historic ones, and “new” processes and data should be evaluated.

Volume 12 Issue 5

Regulatory In parallel with the review of critical variables, a new round of risk assessment related to the actual conduct of the trial will have to be initiated. Potential risks include: trial participants and staff being infected with COVID-19; a higher subject drop-out rate due to travel limitations and self-isolation; more protocol deviations resulting from communication difficulties, last-minute changes to protocols, and altered visit schedules; and recruitment being halted or delayed to the extent that the initial sample size will not be achieved and the statistical power could be reduced.

Once a new set of risks has been identified and assessed, the decision must be made as to whether the risk would substantially change the outcome of the trial or affect subject safety, and whether it can be prevented or mitigated, transferred to another party or accepted within certain tolerance limits. One way of managing risk is by adapting trial oversight activities at the programme, study, country, and site level. For new risks, a suitable indicator needs to be determined, while already existing indicators may also need to be adjusted.

The next step is to adjust the monitoring strategy in accordance with the outcome of the risk assessment and to find a good balance between what can be done on-site and what activities can be done remotely. The result should be a new monitoring plan with different emphases, but in which the sum of the different monitoring approaches still offers an effective strategy for ensuring quality oversight with focus on critical aspects.

Obviously, the first priority is to protect the safety, rights and wellbeing of trial participants, which means keeping the focus on critical areas. At the same time, the extent and nature of oversight measures must be weighed against the extra burden for the site under these exceptional circumstances. Depending on restrictions, urgency, and availability of staff, it could make sense to cancel or postpone onsite monitoring activities – at least for a certain period – or to amend the schedule of subsequent visits to reduce risks.

If on-site activities are being reduced, remote monitoring activities can be intensified both in frequency and extent, such as more regular remote electronic case review form (e-CRF) review, and extending the number of electronic data capture reports to be checked by monitors and medical monitors. In some instances, remote SDV may be possible depending on the processes or systems in place at individual sites, so the monitoring plan should be flexible. Centralised monitoring capabilities can also be expanded, including new key risk indicators (KRIs) and more frequent data surveillance. The outcome and trends can be used to prioritise remote and on-site activities.

There are drawbacks to using the centralised method, and these include the need for statistical analysis software, a separate independent central monitoring team and the requirement for large subject numbers, which may rule out some smaller projects from adopting the method. Regional stay-at-home orders may reduce the reliability of site quality assessments, while the lack of on-site staff or staff turnover may cause a delay in data entry, thereby delaying central analysis of KRIs. In these cases, remote visits are essential to maintain subject safety and data integrity, and to ensure study endpoints are protected.

Some items may still need to be undertaken or revisited during an on-site visit.

In these exceptional circumstances, ensuring the team is prepared for an on-site visit becomes a high priority, and a decision tree can be implemented on a case-by-case basis to ensure such a visit is indeed possible. The team should be instructed on how to conduct on-site www.jforcs.com

visits safely, with regard to personal hygiene and social distancing, and the provision of the correct personal protection equipment.

Safety, as ever, is paramount.

Some of the changes being implemented during the current pandemic may become permanent, but others should be considered temporary measures. Follow-up measures need to be planned ready for implementation when the situation is normalised, including increased on-site monitoring; rectifying any problems at the site that could not be resolved during lockdown; re-monitoring of critical data; and proper documentation of deviations.

The current situation can be used as an opportunity to learn and take remote processes to the next level. Certainly it requires more weight to be put on centralised approaches, but not to the exclusion of on-site activities – both are still needed.

REFERENCES 1.

2.

3.

https://www.fda.gov/media/116754/download https://www.ema.europa.eu/en/documents/scientific-guideline/reflectionpaper-risk-based-quality-management-clinical-trials_en.pdf https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6r2-guideline-good-clinical-practice-step-5_en.pdf

Steven Thys Steven Thys has more than 19 years’ experience within the pharmaceutical and drug development industry, and before joining SGS in 2019, held a number of positions in clinical operations at Servier.

These included Director of Global Trial Management where he was responsible for delivering the company’s portfolio of Phase I-IIIb trials in a variety of therapeutic areas. Mr Thys graduated as a pharmacist from the University of Leuven, and holds a master’s degree in medical & pharmaceutical research from the University of Brussels (VUB).

Journal for Clinical Studies 17

Regulatory

Virtual or Decentralised Clinical Trials: Defining The New Normal Clinical trials are a cornerstone of drug development, providing scientific evidence on the safety and efficacy of novel pharmaceutical compounds. While traditional trials have effectively served their purpose until now, the ongoing pandemic has forced researchers to think of alternatives.

Hence the virtual clinical trial was born. This article aims to review this new concept of clinical trials while shedding light upon practical challenges that we face whilst navigating our way towards the new normal.

In March 2020, the USFDA issued its guidance on ways to conduct trials during the ongoing pandemic. In its statement, the FDA encouraged sponsors to start assessing alternative methods for keeping going on track within the existing limitations of COVID-19.1 This paved the way for virtual clinical trials and started defining the ‘new normal’ in the clinical trial arena.

What Exactly Is A Virtual Clinical Trial?

A virtual clinical trial (VCT) is a method of conducting clinical trials whereby a participant can be monitored directly from his/ her place of residence during each stage of the clinical trial.2 In doing so, technology (apps and monitoring devices) and web-based platforms form the cornerstone for these types of clinical trials as they not only improve comfort, convenience, and confidentiality of research participants, but also increase their adherence to trial protocols.2,3

How Are VCTs Different From Their Conventional Counterpart?

A conventional trial starts from a patient recruitment process and goes all the way until the assessment of their health in research centres or is designated for such a purpose. A VCT is no exception to this and is similar to its conventional counterparts. But this leads us to a very important question: Is there any advantage2–6 associated with VCTs? Well, to answer this let us dive deep into some of the key differences [Figure: 1] between a VCT and site-based CT. Thus through the above-mentioned advantages, VCTs help pharma industries to conduct trials having low risk and high returns.2 Some of the providers who offer remote clinical trials include IQVIA, ICON, Covance, PRA Health, Parexel, etc.7 What About The Unprecedented Hurdles?

Despite its advantages, VCTs suffer various challenges owing to their relatively novel nature of conducting clinical trials. These challenges include: •

Data privacy: VCTs require sending large amounts of sensitive health data over the internet. Transferring such large amounts of sensitive data can be a daunting task. However, by making use of proper technology and data protection strategies (storing anonymised data on external web servers secured by ID and password, using secure webmails, and web servers hosted by trusted providers) this risk can be minimised.2,8

•

Data integrity, accuracy, and reliability are the other issues that many fear to have a negative impact on VCTs. To deal with

Figure 1: Key differences between a VCT and its conventional counterpart.

18 Journal for Clinical Studies

Volume 12 Issue 5

Regulatory such a challenge, companies are making use of a two-way digital health technology where they can reach out to study participants to confirm the accuracy of collected data (e.g. data collection from a smartphone app or a mobile device). Here the participant would have the opportunity to review the data collected and ensure error-free data.2 •

Regulatory acceptance: A VCT is as new to the regulatory body as it is to a sponsor. Thus in terms of novelty, it imposes equal challenges to regulatory authorities as it does to a pharma company. In this respect, the USFDA is looking for inputs for the following issues: how to encourage the adoption of technological tools in clinical trials; what are the barriers to a VCT; how a VCT will influence patients, and eventually the regulatory requirements.9

So, Why Are We Exploring VCTs As An Alternative?

The current pandemic has delivered a great blow to our efforts in conducting clinical drug trials. This scenario is made worse by the global (health) initiative to practice social distancing and contactless delivery of care. Though the importance of such initiatives cannot be undermined, it is here where the importance of a virtual clinical trial comes to light. Thus, a VCT is now the new normal and will continue to be so in years to come.

Have Pharma Companies Tried Out A VCT Yet? Pfizer pioneered and holds the title of the first company ever to invest in a virtual clinical trial.

The ‘Research On Electronic Monitoring of Overactive Bladder Treatment Experience’ (REMOTE) trial was the first randomised clinical trial to use web and smartphone to recruit, enrol, and collect study data without requiring patients to visit a trial site. The trial, aimed at determining whether the results of the REMOTE trial could replicate the results of a previously completed Phase IV trial on Detrol LA (Tolterodine Tartrate). However, the trial experienced issues as the target of recruiting 283 participants could not be attained.

Despite the challenges and eventual termination of the trial, Mr Miguel Orri (the director of clinical services) said that “the company could not only demonstrate its ability to distribute blinded investigational drugs directly to the patients in their homes but also use mobile and web-based platforms to capture data from patients.” Therefore, Pfizer’s REMOTE trial was the first of its kind to pave the way for our modern-day learnings on VCTs.6,8 Conclusion To conclude, until now VCTs have been used in Phase II–IV trials.

Results from these trials have shown promising results. Besides, it has also been able to meet the goal of the pharma industry (low risk and high return) when conducting clinical trials.

Take-home Message Virtual clinical trials are now a feasible option for carrying out clinical trials. Furthermore, through VCTs companies can also expect an early launch of their novel pharmaceutical products.

Acknowledgment The author would like to thank Sara Ahmed Zaki (Freelance Medical Writer; Egypt) for helping out with the peer-review of the article.

REFERENCES 1.

Coronavirus (COVID-19) Update: FDA Issues Guidance for Conducting Clinical Trials [Internet]. FDA. 18 March 2020. [Cited: 13 Sept. 2020].

www.jforcs.com

2.

3.

4.

5.

6.

7.

8.

9.

Available at: https://www.fda.gov/news-events/press-announcements/ coronavirus-covid-19-update-fda-issues-guidance-conducting-clinicaltrials Ali Z, Zibert JR, Thomsen SF. Virtual Clinical Trials: Perspectives in Dermatology. Dermatology. 2020;236(4):375-382.

Hanley M. Virtual Clinical Trials Improve Profitability [Internet]. Virtrial.

11 Sept. 2018. [Cited: 10 Sept. 2020]. Available at: https://virtrial.com/ virtual-clinical-trials-improve-profitability/ Grabski I. Virtual Clinical Trials: Testing new drugs from afar [Internet].

Science In The News (Harvard University). 25 Nov. 2019. [Cited: 12 Sept.

2020]. Available at: http://sitn.hms.harvard.edu/flash/2019/virtualclinical-trials-testing-new-drugs-afar/ Virtual trials: welcome to the present [Internet]. Clinical Trials Arena. 9 July 2020. [Cited: 13 Sept. 2020]. Available at: https://www. clinicaltrialsarena.com/analysis/virtual-clinical-trials-covid-19/ Hand S. Virtual Clinical Trials – Can Remote Trials Change The Clinical Trial Landscape? [Internet]. Xtalks. 10 May 2018. [Cited: 13 Sept. 2020].

Available at: https://xtalks.com/virtual-clinical-trials-1/ Katsarova N. List of Virtual / Remote Clinical Trial Providers [Internet].

TrialHub. 7 April 2020. [Cited: 13 Sept. 2020]. Available at: https://trialhub. findmecure.com/blog/virtual-remote-clinical-trial-providers/ Jadhav S. Virtual Clinical Trials: The Future of Patient Engagement?

[Internet]. Applied Clinical Trials. 12 July 2016. [Cited: 14 Sept. 2020].

Available at: https://www.appliedclinicaltrialsonline.com/view/virtualclinical-trials-future-patient-engagement Lucchini C. Industry embraces the virtual trial platforms [Internet].

Pharma World Magazine. 4 June 2018. [Cited: 14 Sept. 2020]. Available at: https://www.pharmaworldmagazine.com/industry-embraces-thevirtual-trial-platforms/

Subhajit Hazra Subhajit Hazra, M.Pharma (Pharmacology), is an experienced medical writer specializing in the creation of medical/scientific content for the medical communication industry in India.

Email: subhajithazra.freelancer@gmail.com

Journal for Clinical Studies 19

Market Report

Converting Compliance from a Cost Centre to a Critical Success Factor Maintaining compliance can be a relentless drain on resources. Alternatively, business can make good use of the data collected for compliance to gain actionable business insight. Denis Gross, Vice President of Delivery at ProductLife Group, describes how to derive business value from compliance activities.

In the pharmaceutical sector, manufacturers have become accustomed to the significant and increasing ‘burden’ of regulatory compliance demanding that they update their processes, systems and skills to accommodate the latest reporting requirements. Of course, life sciences regulators exist to hold companies to account and keep customers safe, by enforcing certain standards and ensuring that

20 Journal for Clinical Studies

manufacturers adhere to them over time (and can demonstrate, on demand, that they have done so).

Each time companies think they have got on top of compliance, one set of specifications is updated or a new wave of change comes along. It can be demoralising, and draining – from a time and resource perspective. A better way to drive value from an investment in compliance is to look for a wider range of wins. Traditionally, companies would have approached regulatory requirements as a necessary evil, something to satisfy the authorities and minimise business risk. Beyond this, organisations have not typically looked for strategic benefits.

In today’s digital new world, there is a chance to treat compliance very differently. That’s as companies move away from processes built

Volume 12 Issue 5

Flexibility.

Adaption to our clients’ needs.

Offering customized solutions is one of our core values that governs our daily work. Being highly flexible we have extended our lab expertise to meet current customer demands in clinical trials.

• Flow Cytometry • PBMC isolation • RT-PCR • Extended single and multiplex assay capacity

MLM Medical Labs is a leading global central laboratory for clinical trials. For over 25 years we have been supporting clinical studies phase I-IV with full laboratory services, kit building and logistics.

For further information please contact Isabel Struik at istruik@mlm-labs.com or visit us at mlm-labs.com.

www.jforcs.com

MLM Medical Labs Dohrweg 63 41066 Mönchengladbach Journal for Clinical Studies 21 Germany

Market Report around manually filling in paper or PDF documents for each unique regulatory reporting requirement, toward building rich, dynamic databases whose contents can be re-purposed many times over. A definitive central resource where all of the required information (and more besides) can be collated, checked, refined and updated – so that anything else that happens thereafter with that information is, by default, correct and compliant.

Beyond Legacy Systems The pharmaceutical sector has tended to be slow to adapt to the benefits of this approach – because of the legacy data, systems and processes companies have had to unravel first. But unless they strive to do things fundamentally differently, they will be increasingly at a disadvantage.

Basing compliance activity on structured, ready-to-go data, in a consistent format, means the latest, correct information can be called up and prepared at speed using the latest digital tools to ensure efficient data exchanges with authorities, with full details/a clear line of sight across all products right along its life-cycle – for reliability, traceability and protected data access.

By harnessing these characteristics, pharma companies can start to think beyond the immediate goal of compliance for its own sake, and toward the wider benefits that come with being able to quickly access great detail about products – including their application, use, and efficacy in the real world.

Traditionally, audits, inspections, complaints handling, and pharmacovigilance have put the spotlight on non-compliance. That is why, in the US, we see lawyers and other professionals with roles dedicated to damage limitation and crisis management.

But what if positive action and pre-emptive compliance were made business differentiators? If they became a signal to the market, and to customers/patients, that a company has an enriched sense of public duty, of ‘wanting to do the right thing’? Amid the continued COVID disruption, and more recently the Black Lives Matter movement, there is an expectation that businesses review their culture, policies, and practices. Markets and customers have heightened sensitivity to whether companies are ‘walking the talk’, or whether everything they do is secondary to making a profit.

Proactive Compliance In life sciences CMC and, more recently, safety disciplines, new concepts have been developed by adopting a proactive rather than a defensive approach to compliance. The ‘quality by design’ initiative in CMC makes it possible to incorporate potential non-compliance risk in the development phase of the manufacturing process, for instance.

The idea is to establish methods to increase robustness, minimising post-market manufacturing inspection impacts. And, by extension, improve the patient experience by bringing better products to market, faster.

The premise of proactive safety planning is similar – eliminating more risk at the outset, simultaneously hitting two targets: a higher/ faster market success rate, and becoming a more trusted brand/ supplier. Here, risk management plans involve anticipating and paying close attention to an initial holistic review of all aspects (both positive and negative) of a product from its earliest development stages, allowed to anticipate and mitigate the safety profile of each drug.

In a world where more and more detail is captured about products, and shared with agencies right across their life-cycle – in some cases even made accessible to the public through digital channels 22 Journal for Clinical Studies

– anticipating non-compliance becomes strategically important for a whole range of reasons. Companies don’t just want to avoid fines; they want to improve their safety records and show the public where their priorities really lie.

Maintaining Active ‘Compliance Intelligence’ Companies can still look for cost-efficiencies in all of this. Rather than lament next waves of regulatory demands, smart companies will look out for them – and be ready.

This means maintaining active ‘compliance intelligence’ – proactively identifying and anticipating trends in emerging rules, laws, or good practices. Regulation rarely comes out of nowhere.

First, positioning papers are composed, shared and developed. Then, guidelines and staged implementations follow, with time allowed for transition. Where once the tendency might have been to ‘wait and see’, in case of delays or changes to requirements, companies are realising increasingly that deferring action can put them on the back foot and render them less able to capitalise on adjacent opportunities for the business, and for customers/patients.

With new waves of regulatory advancement never far away, there will never be a better time to transform compliance measures.

We generally advise the relevant team within the company – or a suitable partner – to conduct a risk assessment within the context of the organisation’s current business model, highlighting points to anticipate as new requirements appear on the horizon.

Companies might also consider spinning off compliance activity.

This could involve appointing a dedicated team (usually associated with a risk management department), or even relying on a service partner to outsource it Once official requirements are published, the next task is to perform a gap analysis identifying all the potential implication arising.

These might range from a simple but time-consuming review of a number of inter-related documents and data that will be involved/ affected, to potential additional technical and scientific work (e.g., to replace a banned ingredient/questionable material by another) – and then gain approval from the authorities for any changes made.

Preparing to Maximise New Regulatory Demands Where a company has adopted a proactive approach to compliance, or better still harnessed compliance as a lever to optimise the way it develops and manages its products, then the really smart thing to do is capture the lessons learned, perform a risk assessment and engage in process changes through a controlled transformation process.

Life science businesses that are proactive in planning to address emerging compliance demands will benefit from compliance as an ongoing contributor to the organisation’s success. When compliance demands are no longer an unwanted imposition but a business driver, then pharma leaders will be well placed for business success – and the best possible patient outcomes.

Denis Gross Denis Gross is Vice President of Delivery at ProductLife Group.

Email: dgross@productlife-group.com

Volume 12 Issue 5

YOUR BRIDGE BETWEEN LIFE-CHANGING THERAPIES AND PATIENTS

THE PCI WAY

OUR INTEGRATED CLINICAL SERVICES INCLUDE:

Delivering unmatched

• Drug Development

expertise and flexibility, allowing a customized

• Manufacturing including Micro-Dosing Technology

approach to your unique trial requirements.

www.pci.com www.jforcs.com

• Primary and Secondary Packaging • Labeling • Global Storage and Distribution

talkfuture@pciservices.com Journal for Clinical Studies 23

Market Report

Hybrid Remote Trials – Current Trends and Application The global crisis caused by the coronavirus has disrupted our personal and professional lives in ways that seemed inconceivable only a few months ago. This is also true for the conduct and operation of ongoing clinical trials. Social distancing rules, and reluctance to visit public places have presented significant challenges for the continued operation of studies, the collection of important clinical endpoint data, and the continued care and oversight of participating patients by study investigators.

Our industry has adapted quickly by leveraging technological solutions that have been available for some time. However, these solutions were suddenly scaled from small use cases to broad general application. The result? Sponsors have been conducting components of studies remotely, adapting studies initiated prior to or during the COVID-19 crisis to become hybrid remote trials (HRTs). HRTs are trials where some but not all study conduct is implemented away from the study site. The necessity to shift to HRTs has expanded industry experience and understanding of how and where these approaches work well and work best, and which will serve clinical researchers well in the design of new studies and programmes during and beyond the pandemic.

Some of the most common technology components of HRTs include enabling electronic informed consent (and re-consent) to be completed by patients from home; video consultation and visits; adapting site-based clinician assessments to be conducted via secure video or telephone; implementing site-based electronic patient-reported outcome measures (ePROMs) from home via web or interviewer administration; dispensing study medication to the patient at home; and enabling more engaging review meetings between site staff and patient using video.

Remote Consent Remote consent is often discussed in the context of a study where patients are recruited through online campaigns and those meeting qualification criteria are provided access to an eConsent solution to learn more about the study and offer their consent to participate.

One major limitation of this model is in our inability to confirm the identity and diagnosis of patients that are not known to the study investigator(s). However, remote eConsent offers a ready, practical and convenient approach to conducting the informed consent process with patients already known or identified by the study site(s). Patients can review study information through a web portal, tablet, or mobile app, using a media-rich presentation to review the terms, confirm understanding, and confer with family and friends.

It’s important that eConsent not be a patient-alone process. Thus, remote consent encourages flagging questions to ask on parts of the study information. This enables the patient and investigator to retain the discussion around trial participation ahead of any consent decision. This way, patients can provide written informed consent to participate while having time to fully review materials and learn more about areas of uncertainty through one-to-one conversations with the study site personnel. While not yet optimised for global use in 24 Journal for Clinical Studies

completely site-less clinical trials, eConsent enables and significantly enhances the consenting process in traditional and HRTs. Clinician Assessments and Ratings Secure, compliant video solutions offer the opportunity to deliver telemedicine as an alternative to on-site appointments. The success of this approach centres around the type of clinical endpoints to be measured at each “virtual visit”, and whether these endpoints can be measured accurately, reliably, and consistently using alternative approaches. Examples include the measurement of vital signs using at-home sensors provided to the patient for use during a supervised video consultation; provision of a scheduled stool sample using a sample collection kit with courier pickup; and the measurement of complex clinician-reported outcomes (ClinROs) through video interviews with the patient. The determination of the acceptability of a clinical endpoint for remote measurement requires scientific and clinical judgement. For example, a psychiatric rating scale that is normally implemented using a structured interview in a face-toface setting may require specific considerations including: •

Does the scale assess non-verbal cues as part of the rating (such as facial expression and tone of voice), and can these be adequately assessed via video or audio?

•

Does the scale include assessments of a physical nature, such as tremor or muscle rigidity? Can these be observed and assessed adequately via video, even over lower bandwidth connections?

•

Is the patient able to use the technology independently, or can this be achieved through the help of a caregiver or home-visit nurse?

With respect to HRT technology capacity of patients, a recent study examining “telemedicine readiness” amongst older US adults (n = 4525; mean age = 79.6 years) identified factors such as possible/ probable dementia, difficulty communicating, and individuals that had not emailed, sent an SMS or “gone online in the last month”, as measures of unreadiness of older adults to use telemedicine as part of routine care assessments1. Assessing the appropriateness of remote assessment technology for the study population is of vital importance, and in some cases it may be important to be able to triage between independent use, caregiver-assisted, and home-visit nurse-assisted implementation on an individual patient basis.

Site-based Patient-reported Outcomes Some PROMs, such as quality of life and work productivity questionnaires, are typically collected infrequently and during site visits. In HRTs, these may be collected at the site where a physical visit is scheduled or collected at home where on-site attendance is not required. When combined with home-based patient diaries (e.g., a daily symptom diary), solutions provided to patients for home diary completion may switch use between “home-instrument” and “site-instrument” completion when patients attend site or when these assessments are scheduled for remote completion. In other cases, for example where PRO data is only collected at study visits, patients can complete instruments using on-site hardware during Volume 12 Issue 5

Market Report site visits (e.g., site tablet), or using alternative approaches for athome completion (e.g., via the web or through a telephone interview with a trained interviewer). As with clinician assessments, where flexibility in the collection approach is designed into the study, it is important to be able to distinguish the data collection approach used for each assessment so that the consistency between approaches can be measured and reported to support the combination of the data in the final statistical analysis.

Direct-to-patient Medication Supply RTSM systems that control the dispensation of study medication and the study’s medication supply chain are adaptable to different models of direct-to-patient medication supply. These include supporting site-to-patient “last mile” delivery logistics of medication provided from the on-site medication inventory; or shipping medication direct to patient directly from local depot or central pharmacy upon the investigator’s instruction. For HRTs, the latter approach has implications on the medication supply chain model and parameters associated with depot and site inventories, thereby adding complexity to the modelling needed to predict required inventories in both locations. Moreover, ensuring investigators retain dispensing authority throughout the study independent of the direct-to-patient supply chain model used is of paramount importance. Ensuring an “Amazon-like” delivery experience for patients, such as integrated shipping tracking, notifications, and delivery day/time rescheduling is an important additional feature that RTSM solutions are beginning to incorporate. Integration with patient engagement and eCOA apps provides the capability to provide traceability all the way to the patient through, for example, medication pack scanning.

Patient Engagement In HRTs, keeping patients engaged and informed in the presence of fewer in-person clinic visits is increasingly important. Engagement apps typically comprise solutions to provide dynamic and scheduled reminders relating to study progress and procedures with the aim of driving greater protocol adherence; and comprehensive study and visit-by-visit guides to keep patients informed of study requirements. While routinely available for traditional studies, their value is seen as higher in studies such as HRTs where in-person meetings are less frequent. Engagement and eCOA solutions also provide the framework through which other technology components can be implemented – such as courier interactions, video meeting components for site-patient interactions, and reimbursement solutions.

Summary While the use of remote study components may have increased as a result of the pandemic, in general these solutions are not new. This trend, however, does increase our experience and understanding of the use of these HRT building blocks which will enable their continued and optimised adoption in the new studies we are designing and implementing now and post-pandemic. Originally considered “trials of the future”, HRTs have the potential to become far more mainstream than ever before – benefiting patients and making trial participation more convenient and attractive. The future starts today, not tomorrow2.

REFERENCES 1.

2.

Lam K, Lu AD, Shi Y, Covinsky KE. Assessing Telemedicine Unreadiness Among Older Adults in the United States During the COVID-19 Pandemic. JAMA Intern Med. Published online August 03, 2020. doi:10.1001/jamainternmed.2020.2671 Pope John-Paul II

www.jforcs.com

Bill Byrom Bill serves as Vice President of product strategy and innovation at Signant Health, where he also leads a team of ePRO scientists.

He has worked in the Pharmaceutical industry for 30 years and is the author of over 70 publications and two industry textbooks on electronic patientreported outcomes (ePRO). His recent scientific work includes the use of wearable technology and bring- your-own-device (BYOD) eCOA in clinical trials. Bill recently served as Vice Director of the C- PATH ePRO Consortium and is an active member of the DIA Study Endpoints Community where he leads a cross-disciplinary group on the use of endpoints derived from wearable devices to support labelling claims and regulatory decision making. Bill provides independent eClinical commentary via LinkedIn and Twitter (@billbyrom).

Denis Curtin Denis Curtin is Principal, eCOA and Patient Engagement, in the Science and Medicine practice at Signant Health. Previously, he co-founded mProve Health, a mobile device-based software solutions company specializing in clinical research and commercial healthcare, which was acquired by Signant Health in 2017. Dr. Curtin’s experience also includes more than twenty years in pharmaceutical industry roles leading drug and vaccine clinical development and commercial brand management; product lifecycle and franchise portfolio strategic planning; and clinical trial design and management. At Signant Health he advises the company’s leadership in scientific matters, and guides the development of company research capabilities, evidence for commercialized research products, and communication of product offerings to scientific and customer communities.

Journal for Clinical Studies 25

Market Report

What does it Take to have a Good Experience of Recruitment in Clinical Research: Malaysia Introduction A staggering number of clinical trials fail to meet recruitment goals, leading to delays, early termination, or inability to draw conclusions at trial completion due to loss of statistical power.

It is estimated that roughly 80% of clinical trials fail to meet enrolment timelines and approximately 30% of Phase III study terminations are due to enrolment difficulties1. In a separate analysis of more than 100 trials, the data showed that less than a third and half were awarded an extension2. The impact of failure to enrol patients and meet with timelines can delay product launch that could translate into huge financial losses for the pharma company.

Patient Recruitment: Asia vs. Europe & USA Traditionally, industry-sponsored research has been conducted in high-income countries in Europe and the US due to their established research infrastructure, and being the birthplace of major pharma companies3. However, globalisation has resulted in shifting this research outside these countries by reaching out to Asian countries.

The key thing that attracts a pharma company to approach the Asian population is the availability of treatment-naïve patients, which has resulted in speedy recruitment. The large treatment-naïve population including Japan, Malaysia, Thailand and China presents a significant opportunity4. One of the barriers to conducting clinical trials in the US and Western Europe is participant recruitment and retention. In the US and Western Europe, racial and ethnic minorities, women and the elderly are often underrepresented in enrolment. One trial for HIV-associated cryptococcal meningitis recognised low US patient enrolment and subsequently added Thailand as a trial site, where it recruited 99 patients in five sites. The trial added an average of four patients per site in Thailand over three months compared with one per site in the United States5. Malaysia has a strong research ecosystem in all its healthcare facilities, provided by the Ministry of Health (MoH), Ministry of Education (MoE) and private hospitals.

In MoH, the responsible unit for conducting clinical research is the clinical research centre (CRC) which is located at every public hospital. To date, there are 35 CRC distributed in the peninsular and East Malaysia. Under MoH, there are also government health clinics or ‘klinik kesihatan’ which support the work of clinical research in Malaysia. Besides the facilities provided by MoH, there are also teaching hospitals under the purview of MoE that are actively conducting clinical research, namely the University Malaya Medical Centre (UMMC), Universiti Kebangsaan Malaysia Medical Centre (UKKMC), Hospital University Sains Malaysia (HUSM) and International Islamic University Malaysia Teaching Hospital (IIUM Teaching Hospital). And last but not least, there are also several private hospitals conducting clinical research and are supported by a private clinic. In 2018 and 2019, there are about 330 trials conducted in Malaysia in all healthcare facilities with 235 of these trials being conducted in MoH facilities, and the remaining trials were conducted at MoE and private facilities.

Clinical Research Malaysia (CRM) CRM is a non-profit company wholly owned by the Ministry of Health. CRM was established in June 2012 to position Malaysia as a 26 Journal for Clinical Studies

preferred global destination for research and to function as an enabler and facilitator to the industry and medical fraternity for the conduct of clinical trials. CRM plays an important role in improving the local ecosystem to support growth in industry-sponsored research, facilitate the needs and requirements of industry players, grow the pool of capable investigators, support staff and trial sites and improve their capabilities and capacities to conduct this research. CRM is committed to work on three important key strategies; quality, speed and reliability, to ensure satisfaction of relevant stakeholders. With the controversial challenges in patient recruitment globally, CRM has set a key performance index (KPI) to support the recruitment performance of the trials supported by CRM. One of the parameters that we are monitoring is on recruitment achievement for all sites that completed recruitment and we are going to discuss this parameter (result from year 2018 and year 2019) in this article.

Methods Trial sites identification In CRM, we have the database to capture the recruitment data on the clinical trials handled by our study coordinators at each trial site across Malaysia which started from the year 2012. The database includes important information regarding the patient recruitment number for each key therapeutic area. Every month, CRM SCs will update the database and the recruitment specialist will then analyse the data according to different parameters. The following criteria were included for the analysis: • •

Recruitment started on the 1st January 2012 onwards (this cut-off was chosen as the database was established in 2012); and Recruitment closed on or before 31st December from 2018 to 2019

Note: Trials which were terminated earlier or withdrawn are not included in the analysis.

Data extraction Data was extracted from four major fields in the database which includes 1) trial details (e.g. title, site, region and therapeutic area); 2) study timelines (e.g. site initiation visit (SIV) date and site activation date); 3) recruitment summary (e.g. recruitment target, number of patients randomised); and 4) description of barriers and the strategy used related to each trial. The data was further categorised into regional sectors across Malaysia i.e. northern (Perak, Kedah, Perlis and Pula Pinang), central (Kuala Lumpur and Selangor), southern (Putrajaya, Negeri Sembilan, Melaka and Johor), east coast (Pahang, Terengganu Kelantan and east Malaysia (Sabah and Sarawak).

Data analysis The data was analysed using Microsoft Excel version 10. Descriptive statistics (frequencies and percentages) were used to present information and patterns of trials in 2018 and 2019. The χ2 test was used to compare the number of trials in 2018 and 2019 with respect to the different characteristics of the trials used.

Results Characteristics of the trial sites From our database, a total of 241 trial sites fulfilled the inclusion Volume 12 Issue 5

Our Vision Be the best patient focused solutions company for clinical trials worldwide.

Our Mission Bring a unique combination of services to facilitate worldwide participation in clinical trials for all.

Patient

Powered by Illingworth Research Group

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

Contact us info@illingworthresearch.com Journal for Clinical Studies 27 www.illingworthresearch.com

Market Report criteria and were included in the analysis. Table 1 summarises the characteristics of the trial sites that completed recruitment in 2018 and 2019. Most of the trial sites were involved in oncology trials (26.6%), followed by nephrology trials (10.4%) and paediatric trials (8.7%). Moreover, most of the trial sites were from central Malaysia (25.7%), with 57.7% of the trial sites having a target recruitment of five subjects and below, while the majority of the recruitment period falls under one year (51.9%).

Comparison of trial sites from the year 2018 and 2019 There were significant differences in the recruitment target and recruitment achievement as shown below for year 2018 in comparison to 2019 (Table 1). In 2019, most of the recruitment targets are made up of more than five subjects and most of the trial sites have achieved the recruitment target of 100% and more (p-value <0.05). In 2018, the percentage of sites that achieved their recruitment target is 41%, and it increased to 62% in 2019 (Figure 1).

analysis, we have found that the recruitment rate was improved from 2018 to 2019. It is believed that the following active initiatives taken by CRM have supported the recruitment performance at the trial sites: 1. Active Monitoring and Constant Communication with Relevant Stakeholders CRM, through the support of study coordinators placed at the hospital and the recruitment specialist who centrally monitors the recruitment data, which has shown improvement to recruitment performance at the trial sites. Active communication to discuss possible new recruitment strategies with the relevant stakeholders (i.e. investigators and sponsors/contract research organisation) kicks in whenever there are recruitment challenges seen at the trial sites. CRM believes this is a shared responsibility for recruitment and our strategy is in line with a study conducted by Rashmi Ashish Kadam7, where he suggested that it is best to build a relationship with the players involved in the specific trials and always keep a regular contact with the site staff. Lou Shapiro8 also reported that in order to ensure success in recruitment, communication with medical doctors and support site staff is important.

Discussion Failure to enrol and retain an appropriate number of participants into clinical trial results in the reduction of statistical power to prove the hypothesis, prolongs study duration time, drains scarce research resources and threatens the validity of research results6. There are 2. Create Awareness of Clinical Trials Among the Public many barriers to patient recruitment in clinical trials as reported in CRM fully supports educating the public on clinical trials and other literature, including the complexity of study protocol, lack of creates awareness of such topics to the nation. A series of clinical awareness about clinical trials in patients, and sociocultural issues trial promotions such as ‘I am Aware’ and a ‘Clinical Trial Day’ were Tablethe 1:barriers Characteristics of trial related to trial participation7. Despite reported from our sites conducted to support this. The activities were done in either hospitals

Cha r a c t e r i s t i c

2 01 8

2 01 9

Tot a l( n) : 1 1 7 n( %)

Tot a l( n) : 1 2 4 n( %)

64( 2 6.

6%) 2 0( 8.

3 %) 3( 1 .

2 %) 1 0( 4 .

1 %) 2 5( 1 0.

4 %) 7( 2 .

9%) 1 6( 6.

6%) 4( 1 .

7 %) 2 1( 8.

7 %) 1 2( 5 .

0%) 3( 1 .

2 %) 7( 2 .

9%) 5 0( 2 0.

7 %)

3 2( 2 7 .

4 %) 1 1( 9 .

4 %) 3( 2 .

6%) 7( 6.

0%) 1 6( 1 3 .

7 %) 4( 3 .

4 %) 1 0( 8.

5 %) 3( 2 .

6%) 6( 5 .

1 %) 4( 3 .

4 %) 3( 2 .

6%) 7( 6.

0%) 1 1( 9 .

4 %)

3 2( 2 5 .

8%) 9( 7 .

3 %) 3( 2 .

4 %) 9( 7 .

3 %) 3( 2 .

4 %) 6( 4 .

8%) 1( 0.

8%) 1 5( 1 2 .

1 %) 8( 6.

5 %) 3 9( 3 1 .

4 %)

62( 2 5 .

7 %) 7 3( 3 0.

3 %) 4 3( 1 7 .

8%) 2 4( 1 0.

0%) 3 9( 1 6.

2 %)

3 2( 2 7 .

4 %) 3 6( 3 0.

8%) 1 5( 1 2 .

8%) 1 4( 1 2 .

0%) 2 0( 1 7 .

1 %)

3 0( 2 4 .

2 %) 3 7( 2 9.

8%) 2 8( 2 2 .

6%) 1 0( 8.

1 %) 1 9( 1 5 .

3 %)

1 3 9( 5 7 .

7 %) 1 02( 4 2 .

3 %)

80( 68.

4 %) 3 7( 3 1 .

6%)

5 9( 4 7 .

6%) 65( 5 2 .

4 %)

Tot a l N=2 41

The r a pe ut i ca r e a Onc o l o g y Ca r di o va s c ul a r Endo c r i no l o g y Rhe uma t o l o g y Ne phr o l o g y Ha e ma t o l o g y Ga s t r o e nt e r o l o g y I nf e c t i o usDi s e a s e Pa e di a t r i c Ne ur o l o g y Ps yc hi a t r y Re s pi r a t o r y Ot he r s Re g i o n No r t he r n Ce nt r a l Ea s tMa l a ys i a Ea s tCo a s t So ut he r n Re c r ui t me ntt a r g e t ≤ 5 > 5

pva l ue -

0.

3 4

< 0.

005 *

Re c r ui t me ntpe r i o d

0.

06

≤1Ye a r 1 2 5( 5 1 .

9 %) > 1Ye a r 1 1 6( 4 8.

1 %) Re c r ui t me nta c hi e ve me nt No ta c hi e ve d 1 1 6( 4 8.

1 %) Ac hi e ve d1 00% 62( 2 5 .

7 %) Ove r a c hi e ve d> 1 00% 63( 2 6.

1 %) * Si g ni f i c a nt l ydi f f e r e nc ewi t hpv al ue<0.

05

68( 5 8.

1 %) 4 9( 4 1 .

9 %)

5 7( 4 6.

0%) 67( 5 4 .

0%)

69( 5 9 %) 2 9( 2 4 .

8%) 1 9( 1 6.

2 %)

4 7( 3 7 .

9%) 3 3( 2 6.

6%) 4 4( 3 5 .

5 %)

< 0.

005 *

Table 1: Characteristics of trial sites 28 Journal for Clinical Studies

Volume 12 Issue 5

Market Report 2.

McDonald, AM, Knight, RC, Campbell, MK, Entwistle, VA, Grant, AM, Cook, JA et al. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies. Trials Journal. [Internet]. 2006 Available from: https://trialsjournal biomedcentral.com articles/10.1186/17456215-7-9 3.

Murthy, S, Mandl, KD & Bourgeois, FT. Industry-sponsored clinical research outside high-income countries: an empirical analysis of registered clinical trials from 2006 to 2013 // Health Research Policy and Figure 1: Comparison of recruitment achievement in the year 2018 and 2019 (cumulative data from previous month) System. [internet]. 2015. doi: 10.1186/ s12961-015-0019-6 4.

ClinicalTrials.gov, Methodology as per: Trends in the globalization of or public or private institutions where clinical trial information was clinical trials, Fabio A. Thiers, Anthony J. Sinskey & Ernst R. Berndt, shared with the public through our knowledgeable staff. Volunteers Nature Reviews Drug Discovery 7, 13-14 (January 2008) who had an interest in participating in clinical trials (healthy 5.

Zimmer, LO. International Collaboration between US and Thailand on a volunteers or patients) may also fill up the consent form for trial Clinical Trial of Treatment for HIV-associated Cryptococcal Meningitis. mapping through our internal database later, i.e. the information Contemporary Clinical Trials. [Internet]. 2010. Available from: http://www. of the volunteers will be forwarded to respective trial sites with ncbi.nlm.nih.gov/pmc/articles/PMC2861565/ active recruitment for possible participation if eligible. In 2019, we 6.

Villarruel, AM, Jemmott, LS, Jemmott, JB & Eakin, BL. Recruitment and conducted eight campaigns at different hospitals, with more than 600 retention of Latino adolescents to a research study: lessons learned from a randomised clinical trial. Journal of Specialists in Pediatric Nursing. volunteers registered, and we have seen positive outcomes where [internet]. 2006. doi: 10.1111/j.1744-6155.2006.00076.x https://www.ncbi.nlm. patients were successfully randomised into trials. nih.gov/pubmed/16999746/ 7.

Kadam, RA, Borde, SU, Madas, SA, Salvi, SS & Limaye, SS. Challenges in In addition to this, CRM has also put up an online platform recruitment and retention of clinical trial subjects. Perspective in Clinical on our website for the public to register if anyone is interested in Research. [Internet]. 2016. Available from: https://www.ncbi.nlm.nih.gov/ participating in a clinical trial. This is called ‘Find a Clinical Trial’ pmc/articles/PMC4936073/ (FACT) and the following are included on the website: 8.

Shapiro, L. Five Tips for Expediting Clinical Trial Recruitment and Enhancing Patient Retention, Pharma Voice.com, https://www. a) The disease of interest in active recruitment stage pharmavoice.com/article/clinical-trial-recruitment-0615/

b)

The location of the trials being conducted

The participants can register themselves through FACT and the relevant information will be shared to the participating sites to further determine their eligibility for participation. In 2019, we have received more than 20 volunteer registrations and we have seen the positive outcome of patient enrolment in the study. With the positive progression observed, CRM has also started to reach out to relevant patient support groups to advertise the FACT website, hoping to attract a more targeted patient population in patient recruitment.

3. Training CRM conducts training in ‘Recruitment and Retention’ for investigators and health professionals who have an interest in hospitals. The training was done through lectures and interactive case scenarios among the participants to discuss the recruitment challenges and new recruitment strategies. In 2019, we conducted seven training sessions at the trial sites across Malaysia with more than 200 participants.

Conclusion The recruitment performance for the studies handled by CRM SCs have improved from 2018 to 2019. Several key initiatives taken by CRM started in 2018 including active engagement with relevant stakeholders, close monitoring and creating awareness of clinical trials among the public, where training has brought positive progression to the recruitment status in Malaysia.

REFERENCES 1.

White paper by Inventive Health, “Forecasting Trial Enrollment: More Data, Better Analytics, Greater Predictability.”

www.jforcs.com

Aina Farhana Binti Zulkipli Aina Farhana graduated from the International Islamic University of Malaysia with a Bachelor of Biomedical Science and later went on to obtain a master’s degree in Medical Science from the University of Malaya. She currently works at Clinical Research Malaysia as a Patient Recruitment Specialist. She has more than 5 years’ experience in recruiting patients. She has been liaising with doctors, pharmaceutical companies, and Clinical Research Organization to strategize in patient recruitment.

Email: aina.farhana@clinicalresearch.my

Joanne Yeoh Joanne Yeoh graduated from University of Melbourne, Australia with a Bachelor of Biomedical Science. She has vast experience in clinical research operation which she has done for 15 years and was supporting the Clinical operations across Malaysia, Singapore, Taiwan and Hong Kong in the CROs prior joining CRM. Joanne is currently the Head of Clinical Operations in CRM. Email: joanne.yeoh@clinicalresearch.my

Journal for Clinical Studies 29

Market Report

Pandemic Patient Support – Navigating the New Norm of Clinical Trials?

Some time ago, a survey was conducted on clinical trial professionals to determine what concerns worried the industry most. Experts were consulted from far and wide within pharmaceutical company sponsors, contract research organisations, site representatives and vendors. Despite all the great work by these collective groups, an overwhelming number of studies fail for the simple reason, that not enough patients stick with them.1 A whopping 85% in fact, according to Forte Research.2 Interesting that once the results were assessed, ranked fourth behind the likes of trial complexity, regulatory frameworks and increasing costs, were patient recruitment and retention.

Then, early this year, in a moment of history we are unlikely to forget, COVID-19 happened. Suddenly hospitals and healthcare facilities the world over were sent into pandemic pandemonium, and as we scrabbled for solutions, many non-essential clinical trials were put on hold and their patients left in limbo.

We were entering the Twilight Zone, and for a moment stood collectively in horror. Principal investigators feared loss of control, sites feared loss of revenue, sponsors feared loss of investment, CROs feared the loss of patients, and patients – well, they feared setting foot outside their front doors. A cycle of fear playing on loop, with no TV remote on hand to change the channel.

A lot has happened since then; things are on the up and the future does not look quite so bleak. We may have the threat and uncertainty of a secondary wave hitting over the winter, but society has adapted; we are better prepared for it.

Working in the clinical trial space teaches you a lot about resilience. There is a sense of duty to get things done, and this intensifies if, like me, you are patient-facing. The whole industry is raising its investment in patient-centric capabilities as it hunts for the perfect contingency plan. What once were considered as ‘nice to have’ services by pharmaceutical companies are now being recognised as competitive drivers. Measuring business value continues to be key, but investment is now being led by what patients will value.

There has been a noticeable shift in mindset, and this resilience means not settling for the tired old ways of doing things pre-COVID. Power suits and executive boardrooms have been replaced by sweaters and living room offices at the click of an MS Teams button, and something quite remarkable and unpredictable has happened.

Self-confinement has actually made us more open, more human. On that next call you dial into, you might hear the sound of builders next door, a washing machine on its last cycle or a child screaming in the face of homework, but it’s real and it’s humbling.

With guards down, everyone now seems to get a say, which means the voice of the patient can finally be heard. Pressures are shared and there is a genuine sense of compassion and togetherness. Building 30 Journal for Clinical Studies

a clear organisational and operational strategy becomes achievable, helping to ensure clinical trials can be structured for success.

Being a patient concierge specialist, I have witnessed the growing weight of expectation put on clinical subjects and their families over the course of this year. Alleviating the logistical, social and financial barriers is more important than ever before, as retention can fail in an instant. At the start of the lockdown period, all eyes were on the changing landscape of air travel and public transportation. How could we protect those part-way through their visit schedule; how could we ensure patients continued to receive their often, life-saving therapies? Could we switch to Zoom or any of the multitude of other platforms that came out of nowhere for vital consultations? Could we be certain compliance is protected?

A disaster recovery scenario delivered to your door faster than even Amazon could.

As we know, rare-disease support can mean helping some of the most vulnerable people in society, so with the threat of a potential exposure to COVID-19, airports and scheduled airlines can prove too much of a risk. The aviation industry is doing a fantastic job of ensuring traveller safety, but there are alternative options available through private charter flights, and the use of long-distance, chauffeur-driven vehicles with partitions and other preventative features to ensure those in need make their visits.

As governments scratch their heads on how to manage restrictions, and we adjust to the new norm, another potential pitfall has emerged.

Where patients and their families were once happy to shoulder some initial expense before the reimbursement, the effects of redundancies and furloughed working within families means that even the smallest deficit can be enough to trigger them pulling out of the study. That is an unacceptable outcome, and totally avoidable if there is the right approach from the start by all parties. Patient concierge support is there to take away the logistical challenges of getting patients from their home to the site; that in turn gives the site team time back to focus on what really matters, and the patient is left without the stress and able to focus on getting well.

Patients must be convinced that a trial has been designed with their needs in mind, and they are likely to have the best experience possible through it. With digital channels playing a dominant role in making patients aware of options, access to HCPs in person, social media platforms or online support can boost the experience and trial performance.

Another positive is the rapid evolution of technology. Patients can engage with nurses and study teams at the touch of a button, and through their own mobile devices. This is an area I have personally been involved in, and the results have been like a foot on the accelerator of patient engagement.

Whilst the innovation around wearables can often grab the headlines, it is the development and integration with technologies behind the scenes that can have the most impact. Who knows the potential to ramp up findings, boost patient outreach, and set the pathway for patient involvement and peer review?

Volume 12 Issue 5

Market Report

So, to summarise, whilst 2020 has been a year like no other, in some ways it has been the shake-up we all needed. We are not naïve; the fear of getting it wrong is still there, but we now have the chance to shed the conservative reputation of clinical research and embrace change, building trials that are faster and more efficient with better patient outcomes in the process.

They say after every storm comes a rainbow, and I have a feeling these colours will enrich us all.

REFERENCES 1.

2.

Burrows A. (2016, November 30). REPORT: The 8 biggest challenges facing clinical trial professionals Information Connect – Clinical & Medical Affairs. Retrieved from https://informaconnect.com report-biggest-challenges-clinical-trials-pt-1 Applied Clinical Trial Stakeholder Survey https://www.appliedclinicaltrialsonline.com/view/barriers-clinical-trial-recruitment-and-possiblesolutions-stakeholder-survey

www.jforcs.com

Chris Wells Chris Wells is an accomplished travel specialist, event planner, creative thinker and patient pioneer. Having spent years building programmes in the healthcare and technology sectors, Chris dedicates every minute of every day to better understand and eradicate the burden of clinical trial participation on patients and their families. As director of patient concierge services at Illingworth Research Group, their PatientGO division works tirelessly to ensure patients receive the optimum home-to-site experience. This helps to reduce study dropout, relieves the pressure on sites and gives the medicines of the future a fighting chance of helping humanity’s most challenging and deadly diseases.

Journal for Clinical Studies 31

Therapeutics

How Using Saliva in Malaria Diagnostics Empowers People in Malaria-endemic Communities to Fight the Disease Malaria acts quickly. Every hour that passes after the onset of symptoms increases the risk of death or permanent disability.

Therefore, a diagnostic test is critical as soon as symptoms present.

But current rapid diagnostic tests for malaria that use blood, and must be administered by a medical professional, are problematic during the COVID-19 pandemic and social distancing recommendations.

Dr. Benji Pretorius, GP and managing director of ERADA Technology Alliance, examines how the use of saliva, rather than blood, in malaria diagnostics could both improve accessibility to malaria tests and help to uphold COVID-19 social distancing and empower people living in malariaendemic communities to have more control over their own healthcare.

Malaria in a Time of Disruption Malaria programmes have been severely affected by the novel COVID-19 virus. In a recent global survey, led by the World Health Organization (WHO), 46% of countries reported disruption to malaria diagnosis and treatment. In addition, many countries have been forced to delay or cancel mosquito net distribution campaigns, leaving people unprotected and vulnerable to malaria.

Health workers are essential for managing malaria in communities, as their tasks can include administering malaria diagnostic tests, raising awareness of malaria and distributing insecticide-treated nets to people’s homes. But these essential workers are also at greater risk of illness during the pandemic. The lack of digital infrastructure and modern technology that the West often takes for granted is sparse in the world’s poorest communities.

Raising awareness and offering health advice must be done the oldfashioned way, face-to-face and door-to-door. Health and medical workers face the risk of contracting COVID-19 or passing the virus on to potentially already-sick patients in clinics or whenever they make a home visit to conduct a malaria test. Sadly, hundreds of health workers in Kenya have tested positive for COVID-19 and, at the time of reporting, ten had died.

The COVID-19 pandemic has introduced even further complications into the fight against malaria. Malaria and COVID-19 share some symptoms, such as a high fever, which may cause confusion. While the advice is to self-isolate on displaying symptoms associated with COVID-19, if a high fever is due to malaria, every hour of delay decreases the patient’s chance of making a full recovery. The deadliest strain of human malaria, Plasmodium falciparum, may be fatal if treatment is delayed beyond 24 hours after the onset of clinical symptoms.

32 Journal for Clinical Studies

Warnings that the disruption and complications caused by the pandemic could reverse more than a decade of hard-won gains and cost millions of lives have continued for months.

It’s clear that innovation and change, particularly in the technology used in malaria diagnostics and how diagnostic tests are delivered, is needed now.

But even before the pandemic, there was a need for change. Too many people in rural malaria-endemic areas rely on visits from health workers to receive a rapid diagnostic test (RDT) for malaria or are forced to travel a long way to the nearest health clinic.

The problem is, in part, that current RDTs are blood-based.

Blood samples involve sharps (needles) and, therefore, can only be administered by a medically-trained professional. Especially now, during the pandemic, the numbers of medical professionals available to administer blood-based tests are lacking. Between lockdowns, social distancing restrictions, shielding and self-isolation, COVID-19 is taking its toll on the numbers of staff available to administer these critical diagnostic tests.

Could Saliva be the Solution?

Saliva is a clinically informative biological fluid (biofluid) and presents an attractive alternative to using a blood sample. The general advantages of using saliva, rather than blood, include its inherently lower infection risk (absence of sharps during collection; lower risk of cross-contamination or additional contraction of infection/ complications caused by poor hygiene) and that saliva-based RDTs could be inclusive to cultures with blood-based taboos.

Most importantly, that saliva-based RDTs do not require use of sharps means that they could be administered by non-medically trained workers, and even parents and teachers, opening up a world of possibilities and holding the potential to dramatically improve access to testing.

Children under five remain the most vulnerable to malaria and, according to the WHO World Malaria Report 2019, accounted for 67% of malaria deaths in 2018. Making RDTs for malaria more accessible to children, and the parents of young children, will be crucial in accelerating progress against the disease.

Our non-invasive saliva-based RDT for malaria, SALVA!, was designed to be easy to use for anyone. The person displaying symptoms spits into a tube and the technology detects subclinical carriage of Plasmodium falciparum parasites from a 5ml saliva sample. Results are delivered from the kit within 5-20 minutes and there is no need to send samples back to a lab for testing. Saliva is easy to collect and, although a challenge to stabilise and store, our technology has met these specific challenges. In the future, as technology continues to evolve, we expect stabilising and storing saliva to be less of a challenge.

Volume 12 Issue 5

Therapeutics

We envision use of our SALVA! kit in schools, community centres and people’s homes, lessening the reliance on health worker visits or securing an appointment at a clinic for those who live in malariaendemic communities and rural areas, and taking the burden off medically trained professionals and allowing them to focus on treatment for malaria and COVID-19. Most importantly, we want to give parents the power to save their children’s lives.

The Importance of Early and Regular Testing One of the main factors enabling the continued transmission of malaria is ‘carriers’ of the parasite. These individuals are free from symptoms but carry the malaria parasite in their blood. However, the parasite numbers in the blood are so low that they cannot be detected by current blood-based diagnostic tests.

There is a risk that these individuals who carry the parasite could be bitten by a mosquito and infect it; this, in turn, may lead to the infected mosquito biting another person and transmitting the malaria parasite to them.

As my colleague, Dr. Richard Schmidt, said: “Early detection of malaria is crucial to malaria eradication because individuals who carry the parasite without exhibiting symptoms, known as carriers, are the reservoir which leads to infection of mosquitoes and transmission of the disease. A parasite needs a host to survive.

If you eliminate the source, you can eradicate it.”

The true size of this parasite reservoir in the human population is unknown. This is why SALVA! was designed to spot malaria carriers before they start to exhibit symptoms or fall ill.

Some aspects of the damage that malaria can wreak on people’s lives are often forgotten. While reports highlight the number of cases and deaths, malaria can have long-lasting effects on survivors, including permanent disabilities, loss of education and loss of income.

Provision of easy-to-use RDTs for malaria holds the potential to make regular testing possible – in schools, for example. While having a medical professional administer invasive blood-based tests to each school child at the beginning of each day seems unrealistic, the option of non-invasive saliva-based tests that could be administered by teachers to their class of pupils is far more achievable.

Regular testing, including for those who are not displaying symptoms, will be the key to identifying ‘carriers’ of the parasite and ensuring that they receive treatment before they fall ill. Not only is www.jforcs.com

early treatment critical in the context of offering the patient the best chance of survival, but it could help to limit the effects of the disease on education and income.

We believe that the potential utility of non-invasive biofluid sampling approaches for rapid malaria diagnosis has not been fully explored and, furthermore, that non-invasive RDTs that use saliva could be used to diagnose other parasitic diseases and could even lead the way in improving diagnostics in healthcare.

Empowering Communities The WHO African Region carries 93% of the global malaria burden, while African health systems remain under strain and operate at near capacity outside of a pandemic. The risk of infection with either malaria or COVID-19 is worst for the poorest and most vulnerable of the world’s population, who are further disadvantaged by a lack of access to quality healthcare.

Therefore, we believe that solutions to combatting malaria (and any other disease that disproportionately affects the world’s poorest regions) should be focused on improving access and inclusivity, removing barriers to critical healthcare, such as reliance on clinics and health worker visits and, ultimately, empowering malaria-endemic communities and the people that live within them to have more agency in acquiring the crucial diagnostic tools they need, when they need them.

Saliva-based RDTs that can be used outside of clinical settings could also help to promote awareness of malaria in rural communities.

Awareness of a disease, how it spreads and how people can protect themselves is where the fight against any disease, including malaria, begins.

Taking diagnostic tools out of clinics and into the wider community has the potential to promote conversations and learnings about malaria and other mosquito-borne diseases. As an example, a child who has received a saliva-based malaria test in school could then pass on awareness of malaria to parents, grandparents and neighbours. If saliva-based tests were conducted in places and through organisations that promote gathering of members of the community, such as places of worship, this again equips members of the community with knowledge to pass on to their social circles.

Increased awareness could lead to more people in communities at risk taking preventative measures.

Our fight isn’t just against malaria, but against poverty, which goes hand-in-hand with malaria due to the strain on health services and government spending to manage the disease, as well as its severe impacts on low-income families.

Journal for Clinical Studies 33

Therapeutics Paying for medicine to treat malaria (less than $10 USD) can push struggling families into debt and, overall, households in Africa lose an estimated 25% of their income to the disease. Malaria can also affect African businesses by causing staff sickness and having negative impacts on business reliability. A survey in sub-Saharan Africa found that 72% of companies reported a negative malaria impact, with 39% perceiving malaria to have a serious impact. The disease can negatively affect children’s education, careers of working adults and entrepreneurial endeavours. All of these factors can keep generations of families trapped in a cycle of poverty and illness.

It’s estimated that malaria costs Africa approximately $US 12 billion in lost gross domestic product (GDP) every year. Additionally, leading economists estimate that the disease has slowed Africa’s economic growth by 1.3% per year as a result of lower productivity and loss of life.

A great deal of anti-malaria funds rely on foreign aid, and many not-for-profit organisations work tirelessly to help combat malaria in some of the world’s poorest regions. While it is absolutely necessary that these contributions and efforts continue, what is also needed is investment in elevating malaria-endemic regions, and the people, out of the vicious cycle of continued poverty.

Investment in infrastructure and transport could help to improve distribution channels and delivery of malaria nets, medicines and diagnostic tools. Investment in and strengthening public health systems could provide greater access to critical care for the poorest, which should help to save lives and should free the people from the terrible choice between survival or crippling financial debt – truthfully, this is not really a choice at all.

Focus on these areas is desperately needed in combination with innovation in malaria diagnostics. It’s possible to manufacture saliva-

based diagnostics for a price that people living in poverty could afford without facing further financial hardship, but the channels to distribute life-saving tools to rural and impoverished communities must be built and maintained as well.

There are many battles to be won in the fight against malaria – one such battle emerging is the climate crisis, as research shows that warmer temperatures and excess rain and flooding may increase the spread and cases of malaria. Widespread access to easy-to-use and non-invasive RDTs in the world’s poorest communities is just one step in winning the war against one of the world’s oldest and deadliest diseases, but an important one.

Further information about ERADA and SALVA! is available at: http://www.eradatechnology.com/.

Dr. Benjamin Pretorius Dr. Benjamin (Benji) Pretorius is the founder and managing director of ERADA Technology Alliance and a senior partner in a general medical practice in Musina, SA. Like many medical practitioners in Africa, Benji has faced the challenges of dealing with malaria throughout his career.

His own experience of contracting malaria led to him founding ERADA and committing to the aim of eradicating malaria.

34 Journal for Clinical Studies

Volume 12 Issue 5

Corporate Profile Ramus Corporate Group

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

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

•

• • • • • • • • • • •

Medical Centre Ramus with Phase I Unit

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

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

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

Safe

• • • •

Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

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

Others: • • • • •

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

Medical Diagnostic Laboratory Ramus Ltd

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

Ramus Medical Ltd Tu

to Cito

www.jforcs.com www.jforcs.com

V

e re

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 35 35

Technology

European Group Uses Graph Technology to Reveal Research Data Connections A leading European research group is using graph-based data management techniques to make research inroads – and support efforts to find drugs and vaccines for COVID-19.

Neo4j’s Alicia Frame reports.

techniques such as Artificial Intelligence (AI) to make connections that no-one else can. This innovative approach to working with large, complex datasets could play a vital role in helping in the prevention, discovery of new subtypes, early diagnosis and treatment of major illnesses.

The amount of data in scientific research is growing exponentially.

Big Data and other advances in data science hold huge potential for medical researchers to gain previously unattainable insights that could yield medical and pharmaceutical breakthroughs. But the life sciences sector is failing to maximise the potential.

DZD Head of Data and Knowledge Management, Dr Alexander Jarasch, and his team are using Neo4j’s graph software to find connections across all its data, speeding up data analysis dramatically.

DZD has built a ‘master database’ to consolidate data and provide its 500-strong team of scientist peers with a holistic view of available information.

The interdisciplinary nature of life sciences research and the highly heterogeneous nature of medical data present a real challenge when it comes to modelling scenarios and making connections.

Classic analysis tools of the past 30 years – spreadsheets and relational databases – have reached their limits. They cannot cope with the huge heterogeneity associated with the vast amounts of data, let alone the complexity of the multiple sources data scientists need to explore. The problem is intensified by the fact that a significant part of today's data is highly unstructured and highly connected.

Researchers need a dynamic way to leverage and connect big data to provide new, valuable insights. Database software called graph technology has appeared as a viable and powerful alternative. One prominent convert to the graph technology approach is the German Centre for Diabetes Research, DZD. DZD brings together experts from across Germany to develop effective prevention and treatment measures for diabetes across multiple disciplines. DZD’s research network accumulates a huge amount of data from clinical trials and patient information covering a host of disciplines, distributed across various locations.

To answer challenging biomedical questions about diabetes, DZD must connect data from many different studies, reports and surveys.

The organisation needs to incorporate research projects from multiple locations in Germany, including 500 researchers and 10 university hospitals.

The data covers various disciplines, from studies on a molecular level to pathway analyses and animal models. This encompasses data from clinical trials, multi-omics experiments and patient information.

Clearly, it is increasingly necessary to integrate and link more and more data. Doing that will be the next step in biomedicine. In addition, the healthcare sector, which is increasingly turning away from general blockbuster drugs and moving to individualised, precision medicine or treatment, needs better visibility of data.

DZD decided it needed a better and more complete way of seeing all this data. Now, DZD uses graph technology in combination with 36 Journal for Clinical Studies

Cross-disciplinary Integration DZD’s research focusses on diabetes, a metabolic disease. It is not enough for researchers to only look at metabolic data. They must take into account data from disciplines such as genomics or proteomics, through to environmental influences. In the human body, everything is connected to metabolic pathways. A gene encodes a protein that is active in a metabolic pathway and metabolises a metabolite, which in turn is able to regulate another gene.

Human metabolism is a network of thousands of components that are connected with each other, similar to a graph data model.

That’s why it’s so important to be able to uncover these connections and to create a new layer of analysis on top of this data using graph technology.

DZD is using graph database software to mine deeper into its diabetes ‘map’ to seek out hidden connections and relationships, allowing its researchers to examine new avenues of research. It is also looking to build new data models and better compare animal and human data. In a graph representation, abnormalities, patterns or connections can be easily identified and interrogated.

DZD plans to roll out graph technology further, to target discoveries in other clinical studies. In future, data from diabetes research could be integrated with that of cancer and Alzheimer’s research, for example, to discover possible connections. DZD is also looking to exploit the combination of machine learning with graph technology to identify new subtypes of diabetes.

Knowledge Graph to Fight COVID-19 Neo4j graph software is also at the heart of a new Knowledge Graph to help fight COVID-19. This open-source initiative of DZD data scientists, developers and data people from academia and industry connects data from a range of well-established public sources and links them in a searchable database. This is helping researchers and scientists throughout the world to navigate through the 128,000-plus publications on the disease and related disease areas such as SARS, plus over 32,000 relevant patents and 1700 clinical trials.

Volume 12 Issue 5

Technology

The Knowledge Graph allows researchers and scientists to create new hypotheses by querying not only clinical information but also data on a gene or protein, clinical trial, drug and drug targets. This is a critical capability in the absence of long-term clinical trials and with the minimal peer-reviewed research available in the current pandemic.

Researchers tend to have only a passing awareness of research outside their field. Yet life sciences companies face the challenge of distilling the findings of many papers across multiple disciplines and assimilating all that information, to create effective COVID regimes and develop a vaccine as quickly as possible.

Normally, it would be necessary to carry out searches on the patent database, the publication database and the gene database, and then make the connections manually. Researchers create Excel sheets, a list of identifiers, and then they go to the database and type in these identifiers to get further information. This yields limited results because of the lack of connections. It is very manual work, error-prone, extremely inefficient and slow. Indirect connections may be missed.

In contrast, the COVIDgraph.org is a graph database that allows researchers to structure this data and to connect it to fundamental things from biology, including genes, the proteins and their functions.

A clinical trials database allows researchers to understand what kind of COVID-19 clinical trials are out there. The dataset specifies typical inclusion criteria, such as people under a certain age, or a specific risk group, like diabetic patients. This is valuable information that is usually scattered across different databases.

ACE2 Breakthrough An early breakthrough has been around ACE2, the host cell receptor www.jforcs.com

that mediates infection by SARS-CoV-2, the coronavirus responsible for COVID-19. The assumption might be made that the receptor ACE2 is just active in lung tissue, because one of the most vulnerable groups to the virus is patients with lung disease. In fact, of 55 human tissues in DZD’s database, the receptor is active in 53 of them. This means the ACE2 receptor can attack almost every tissue of the body. As a result, scientists quickly realised that any potential vaccine will need to be able to fight the virus in all of these different tissue areas.

Graph technology is playing a key role in surfacing details like these to support the race to find a COVID-19 vaccine – as well as take the life sciences sector to the next level in precision medicine, prevention and treatment of diabetes. Graph technology’s ability to discover relationships between data is taking life sciences research to the next level and supporting researchers as they make discoveries that will have a major clinical impact.

Alicia Frame Alicia Frame is currently the Lead Product Manager and Data Scientist at Neo4j, where she works on the company’s product management team to set the roadmap and strategy for developing graph-based machine learning tools. She earned her PhD in computational biology from the University of North Carolina at Chapel Hill and a BS in biology and mathematics from the College of William and Mary in Virginia, and has over eight years of experience in enterprise data science at BenevolentAI, Dow AgroSciences, and the EPA. Email: alicia.frame@neo4j.com

Journal for Clinical Studies 37

Technology

Modernising TMF Processes to Accelerate Clinical Trials Abstract Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research, committed to bringing forward the day that all cancers are cured. The charity’s Centre for Drug Development (CDD) sits at the heart of their innovation network of Experimental Cancer Medicine Centres and serves as a pivotal enabler for the transition of novel therapeutic concepts from bench to bedside. The CDD manages the design and delivery of a portfolio of 20 innovative early phase clinical trials. The CDD has prioritised TMF modernisation to accelerate trial delivery and ultimately help bring new therapies to market faster.

The global spotlight is on the need to quickly develop and license anti-virals and vaccines for the treatment of COVID-19. However, the reality is that conducting a clinical trial today is no faster than it was a decade ago, averaging six to eight years to develop a new product.

Paper-based and manual processes are holding trials back. There is an industry-wide urgency to modernise clinical systems and processes in major clinical areas such as electronic trial master file (eTMF) applications to run faster studies.

More organisations are adopting advanced eTMF applications.

The number of companies using purpose-built eTMF applications has tripled since 2014. Clinical operations teams are moving away from file repositories towards eTMF systems that can manage study documents and activities in real time as the TMF is generated, or active TMF management.

“As a charity working to beat cancer sooner through early-phase drug development, it’s important that we operate as efficiently as possible,” said Stephen Nabarro, head of clinical operations and data management. “We moved away from maintaining our TMF manually to a modern, cloud-based system for active TMF management and faster execution.”

The charity’s transition to an eTMF provides valuable lessons for life science companies transitioning from paper-based systems to active TMF management.

Active File Management and a Paperless TMF A critical drawback of paper TMFs is that they fail to keep pace with a dynamic clinical trial. It is a process that slows down teams, with offline files that are often out of date and information that is difficult to access and share. Significant work is also necessary both during the trial to ensure that files are inspection-ready, and at the end of the trial when preparing for archive.

This is because TMF management is traditionally a passive process, where documents are uploaded into the system only after they are finalised. Even if systems have been updated to an electronic format, they are still based on legacy paper processes. Work is still conducted outside the application, documents are stored in multiple locations, and content is not tracked in progress.

38 Journal for Clinical Studies

With active TMF management, the charity can now ensure that all documents, related information, and processes are managed in the same system, at the same time, as they are executed.

With up to 25 projects in its portfolio at any one time, the CDD’s paper-based TMF was labour-intensive and slow. Documents had to be created, printed, signed, and scanned. Filing took 15 hours of staff time every week and significant costs in storage facilities. It became clear that preparation for routine inspections and archiving information to meet ICH E6(R2) guidelines consumed too many resources.

With all documentation now created and stored in the cloud, the organisation has cut annual storage costs in half. Productivity has also increased, freeing research teams to focus on critical trial work.

The charity estimates that an advanced eTMF saves around 240 hours of administration per clinical trial.

Complete Visibility and Continuous Collaboration Today, the charity has access from anywhere to manage study documents in one system, in real time, as they are executed. Research teams are able to tailor dashboards and run reports to continually assess the status of each TMF. The charity has complete visibility of progress at every stage, ensuring that the TMF is inspection-ready.

Integration of our eTMF with Microsoft Office 365 makes collaboration easier, with multiple users in different locations now able to access the same files at the same time.

This enhanced collaboration also extends to industry partnerships.

The eTMF allows the charity to easily share documentation with their pharma and biotech partners to take a new drug to market. All documentation is complete, accurate, and validated.

The consistency and quality of documents in the TMF is now greatly improved. Research teams can easily see what changes have been made — when, where, and by whom. With the ability to build in its own defined, objective, and automated quality control processes, the charity has seen average document quality control pass rate jump from 70% to 95%.

Dr Nabarro commented, “With clear rules around the quality of documents acceptable within the TMF, users now understand what is expected before a document is file-ready. We now have a system where the document creator is the ultimate owner. It brings individual accountability and a focus on the value of content.” eTMF has also allowed the charity’s CDD to continue working on trials during the COVID-19 lockdown. With all charity staff working from home, teams can still create, check, approve, file, and maintain documents in real time remotely. This was particularly valuable in the early stages of lockdown, with remote teams able to create risk assessments that could be shared, reviewed, and implemented.

Constant Inspection-readiness With an active TMF, files are in a constant state of inspectionreadiness. As a result, compliance is continuous, not an end state.

Volume 12 Issue 5

Technology

The eTMF also supports regulatory audit, building confidence in the charity’s trial process. As an example, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) favours the unsupervised audit of files. The cloud-based application enables this approach with remote access and easy navigation. A userfriendly dashboard ensures that data collection is rapid, simple, and accurate.

“Our eTMF gives us confidence that we are ready for the next scheduled inspection,” said Dr. Nabarro.

Accelerate Clinical Trials A modern eTMF has transformed the charity’s clinical processes.

Removing paper files has reduced administrative burdens and significantly reduced costs. Researchers now focus on their clinical trials work and are able to collaborate more effectively with colleagues wherever they are based. File quality has improved and every TMF is in a state of constant inspection-readiness.

Dr. Nabarro believes that the modern eTMF delivers strategic benefits. “Reducing the burden of manual processes and paperwork through an active eTMF enables our limited team to take on a larger portfolio of trials,” he said. “This ultimately means we can say ‘yes’ to more trials for vital new treatments that might otherwise not happen.

Veeva Vault eTMF accelerates our clinical trials process and speeds the delivery of innovative medicines to patients.”

A modern eTMF has clearly exceeded initial goals and progresses the charity’s strategic mission to “beat cancer sooner.” It is a powerful illustration of the transformational nature of an advanced, purposebuilt eTMF and the effectiveness of active file management. www.jforcs.com

REFERENCES 1.

https://www.veeva.com/resources/new-survey-findsfragmented-processes-and-system-silos-slowing-clinical-trials/

Rik van Mol Rik van Mol is a senior executive with 20+ years of experience in both management consulting and cloud software in the life sciences/pharmaceutical sector. His experience has been built in assisting clients through complex transformation programmes across the life sciences value chain for most of the world’s largest companies. Rik is a recognised thought leader in the life sciences industry with deep expertise in architecting, launching, and implementing innovative and industry-leading strategies and solutions.

Stephen Nabarro Stephen Nabarro is a clinical research professional with more than 20 years’ experience in oncology research and drug development. His scientific background includes a PhD in paediatric oncology at University College London and a Postdoctoral Fellowship at the Medical Research Council Laboratory of Molecular Biology in Cambridge. Stephen is a specialist in clinical trial operations within the Cancer Research UK Centre for Drug Development.

Journal for Clinical Studies 39

Technology

Electronic Product Information: Are Companies Ready?

Regional health authorities across the world are developing an increased appetite for electronic product information, which could be a much more efficient and patient-friendly way of conveying the latest manufacturing details and safety recommendations. But how ready are life sciences firms to deliver regulated product information in this way, and what could it mean to companies themselves?

Amplexor’s Agnes Cwienczek assesses the broader potential business case, and suggests how companies might determine their readiness for delivering reliable electronic product information – and begin to scope the work ahead.

Continued reliance on paper-based instruction leaflets to inform patients and healthcare professionals when and how to use medicinal products or medical devices, and to advise them about required safety considerations, makes increasingly less sense in the digital world.

Although they may remain an important option for mature generations or populations without ready access to the internet, paper leaflets are far from the most effective or efficient means of disseminating critical information. The documents may be mislaid, for instance. The small print may be very hard to read, and there may be several pages to plough through because of the detail that companies are required to cover – not to mention the multiple languages that may need to be included.

All of this is likely to be off-putting to the patient. There is a risk that the leaflets may not be read, or that it may be difficult to distil key information relevant to a patient’s particular circumstances. Too often the content is not user-friendly, nor well pitched for the target reader.

More critically, paper-based product information/instructionsfor-use can soon become out-of-date, either because new safety signals have been identified since the current batch of products went into distribution, or because key medicines have been sitting in a patient’s medicine cabinet for months or even years. Obtaining updated safety guidance out with products can take quite a bit of time, depending on companies’ cycle times and how much stock is already out in markets.

At the same time, an over-reliance on non-structured product information – which is typically the case when preparing paper patient leaflets – can make it difficult for companies to accurately assess the likely impact of any changes to content, to ensure compliant documentation while keeping pace with market demands.

‘Digital First’ Makes Practical Sense For all of the reasons cited above, health/regulatory agencies across the world are showing increasing interest in introducing standardised requirements for electronic product information (ePI) – including the package leaflet for patients and the summary of product characteristics (SmPC) for healthcare professionals. Issuing product information electronically, and managing the contents in a structured way, will promote more confident decision-making among 40 Journal for Clinical Studies

healthcare professionals, for instance, making it easier for them to search for the latest safety advice. In addition, patients will be able to more readily find the information that matters to them – correct dosage information for their needs, any contra-indications or adverse reactions to look out for, and so on.

The idea is to make all of the latest details and advice about a product readily accessible online / via a mobile phone – via a web link, or by scanning a barcode/QR code on a product label, with the ability to display the information as required by a specific context.

For human pharmaceuticals and medicinal products, providing structured electronic product information is already mandatory in the US, while countries/regions including Canada, the EU and Asia are piloting or looking at programmes too, defining guiding principles and polling the market for feedback.

For life sciences manufacturers and distributors, a gradual shift towards digital product information delivery would be a positive development for a whole host of reasons. An obvious benefit is speed-to-market with the latest safety advice, boosting the patient experience and overall outcomes, not to mention public trust. Another substantial advantage is cost efficiency. As long as organisations have streamlined and reliable means of managing and approving changes to content, being able to publish this online/digitally will in due course relieve the pressure on paper-based information publishing – and all of the logistics involved, not to mention the potential for label/ leaflet waste each time information or viable messages changes. And of course, shorter change management, review and publishing cycles contribute to accelerated regulatory processes, resulting in improved speed-to-market with products, and strengthened continuity of supply.

Even if paper leaflets persist for some time, the ability to publish updates or additional details online/digitally and easily provide access when and as required paves the way to scale back some of the busy text that is currently included in paper-based product information and IFUs. That might be different language versions, legal small print, or tailored advice for specific patient categories.

Making it Happen: Enabling Labelling Transformation With so much to gain as product information goes digital, it follows that life sciences companies should embrace the potential at their earliest opportunity. But how ready are they? How conducive are their information/content management processes to deploying accurate, structured information and updating it at frequent intervals, as needs dictate – and across global markets?

The answer, unfortunately, is that most life sciences companies are not ready for this at all – certainly not pharmaceutical companies. Their capabilities for managing regulated content in a structured manner are so constrained that many companies – especially those with low volumes of changes over time – outsource their labelling management requirements if those go beyond paper.

It seems easier to send data and get structured print-ready files back two to three times a year, than to contemplate transforming their regulatory content management backbones to better support process innovation.

Volume 12 Issue 5

Technology This, in turn, is potentially limiting their operational progress in all sorts of ways. For starters, teams have limited sight of which markets are still supplying products with outdated product information and IFUs. That’s before they can even envisage distributing this content in new and more dynamic ways.

Delivering electronic/digital product information is actually a robust use case for structured content management, where companies can confidently assemble the latest, correct information (which has been approved for use), for the current purpose. If companies had a facilitating content management backbone extending from one end of the organisation to the other globally, and were able to work with approved core data assets which had been captured in a structured way to enable easy re-use, they would have the potential to transform the way they manage labelling – and publish changes online.

A Three-pronged Attack So how might life sciences companies move forward, so that they can start capitalising on new efficiencies and lay the groundwork for electronic product information delivery?

Successful transformation of label content lifecycle management will rely on improvements to content, technology, and processes – in concert. That is, any investment in technology to support digital transformation must be matched by measures to assess, connect, clean up and restructure current data sources; and new thinking about how information and content processes could be managed in future to drive innovative, more effective and efficient labelling strategies.

Certainly, at a regional level companies should start to unify as much of their information and content preparation as possible, in accordance with regional or local regulatory requirements. Using the controlled vocabularies set out by electronic submission standards (currently xEVMPD in the EU, to be succeeded by the more detailed ISO IDMP-based requirements; and Structured Product Labelling (SPL) in the US; regulatory agencies and health authorities (HAs) provide or have begun to provide recommended schema), they can start to impose improved consistency in a way regulated product information is constructed. This will help them create solid content components or building blocks for all labelling.

Establishing a definitive repository for correct, current, approved content assets is essential as well – along with details of current product registration and marketing status and submission activities globally, including information about which labels are in circulation where. So, an end-to-end regulatory information management (RIM) platform will play an important part, forming the backbone across which all active and historic content, along with associated status information, can be viewed and managed.

With a vision for positive change in place, companies can begin thinking through the details. Considerations may include: How well aligned is our labelling content within the regulatory boundaries? How easy is it to conduct an impact assessment and introduce changes? How well do we manage oversight and control? How well connected is the end-to-end process across the organisation? Do we understand who owns which content? Do we have the technology and mindset in place to deal with structured content? To what extent are we utilising vocabularies and master data in our content? Will we need a conversion tool to analyse, compare and transform existing labelling information? How can we transition to structured content, and how will we stay aligned with evolving IDMP data parameters? Also, if we run a pilot, how will this work? www.jforcs.com

Crucially, life sciences companies must look for the added value they can deliver from all of this, for their own operations and for their market partners and for patients. Returning to the business case for electronic product information, new value is likely to include greater information accuracy; easier content creation and validation; accelerated regulatory processes; rapid safety updates; and the phasing out of frequent print updates and the potential for wastage each time information changes.

Waiting for regulators to mandate change to (structured) electronic product information delivery will be to leave all of this too late. The path to digitisation may be a gradual one, but there is no doubt that global markets are converging towards the same goal. That’s because agencies understand that continuing with current labelling practices and product information delivery is unsustainable from every angle – something companies already know deep down too.

Agnes Cwienczek Agnes Cwienczek is Head of Product Management and Consulting at Amplexor with a remit that includes the provision of business process and data management expertise in the areas of regulatory information management, document management, and submission management. Prior to joining Amplexor, Agnes worked at Merck in its Global Regulatory and Quality Assurance department. She received her Master’s degree in information management from the University of Koblenz-Landau.

Email: agnes.cwienczek@amplexor.com

Journal for Clinical Studies 41

Technology

Gaining Efficiency through Interoperability

Despite powerful electronic tools in clinical research, we still see data being copied from one system to another every day.

With an ever-increasing amount of data, true integration of systems becomes inevitable. Interoperability through standardisation and state-of-the-art technology has the potential to significantly improve efficiency and data integrity in clinical research.

Background Data is essential for clinical research and thus ensuring data integrity is a fundamental requirement. Most of the time data integrity is addressed by focusing on the ALCOA attributes – attributable, legible, contemporaneous, original, and accurate.

ALCOA+ adds four attributes – complete, consistent, enduring, and available, which makes ALCOA more appropriate for the various electronic systems that are being used in clinical research.

There are powerful tools for eCRFs, ePRO, IWRS, and much more. On the other hand, most of the data entered in those tools resides in electronic health records (EHR) and must be transferred manually (Fig. 1). This so-called swivel chair integration is prone to errors and obviously inefficient. This will become even more challenging when wearable technology produces a huge amount of data 24/7. The increasing amount of data makes it inevitable to use automatic data acquisition. This shift from manual data entry to automatic data acquisition involves integrating a multitude of systems, of communication protocols, of data formats, and of different semantics. Without reliable interoperability data integrity cannot be ensured in such scenarios.

even more challenging, because the tools are using different technologies, data models, and user interfaces, while vendors are following different strategies, and interfaces are often poorly documented or insufficient. Therefore, we still see users performing swivel chair integration.

The Four Tiers of Interoperability Interoperability is an important prerequisite for integrating systems and the data processed by those systems. Interoperability refers to the degree to which two (or more) different systems can seamlessly exchange data in order to cooperatively achieve a common purpose.

Therefore, interoperability can be seen as an approach to turn heterogenous systems into a coherent entity.

Figure 2: The four tiers of interoperability

Figure 1: Example of swivel chair integration between EHR and eCRF

The Challenge of Integrating Software Tools Interoperability is an important concept in many fields of application. Flexible systems are needed to cope with the highly dynamic environments, while sluggish, monolithic systems are disappearing. The gain in flexibility is achieved by combining smaller systems into complex systems.

In clinical research we see more and more specialised tools entering the market, but for every project we need to tie those tools together that will best meet our requirements. Of course, users expect this to be done without logging into each module separately and without entering the same data multiple times. This becomes 42 Journal for Clinical Studies

Current definitions of interoperability are based on a four-tier model, with each tier building on one another (Fig. 2). The bottom tier is called technical interoperability or connectivity. This tier ensures that the systems are connected and can communicate with each other. At first glance this can be fulfilled quite easily, because almost every current system requires a network connection. In most feature lists we will find that the system includes a so-called “API”, an application programming interface, that is promoted as making it easy to integrate with other systems. APIs are the key to interoperability because they allow access to a system without using its graphical user interface, which makes it very suitable for automatic access by other systems. With network connections and Volume 12 Issue 5

Technology APIs available, we would expect that integrating systems is rather plug-and-play. In real life, things turn out to be more complicated: Sometimes APIs do not provide the data or functions needed, or they are poorly documented. An eCRF tool’s API, for example, could have various importing functions, but without sufficient exporting options, we cannot push data into a CTMS for status reporting.

Besides that, technical interoperability can suffer from limitations of connectivity because of security reasons, or in order to promote the vendor’s own software tools.

When looking at the four tiers of interoperability, one can easily see that interoperability is based on agreements for every tier. Those agreements need to be followed by each system. While we still see vendors sticking to proprietary interfaces that restrict interoperability to this vendor’s systems, there is an increasing trend in using open standards, which improves interoperability through APIs. Much of this is driven by the world outside clinical research, where integrating many services into large, powerful cloud applications is state-of-theart and has enabled successful business models.

Relying on technical interoperability, syntactic interoperability serves as the second tier of interoperability. Syntactic interoperability is very important from the data point of view, because it requires us to use the same data formats, the same encoding, the same date and time formats, etc. Especially in an international context this becomes crucial. For example, sending a date value of 10/12/2019 could result in one system interpreting this as a date in December, while the other would interpret it as a date in October. The same applies to decimal marks or encoding of special characters. Syntactic interoperability can be achieved by agreeing on common standards for data formatting. However, it is always good advice that the systems’ APIs enforce and check those data formats.

Example 1: Electronic Health Record Electronic health records (EHRs) are a vast source of data for clinical research. Usually, they include the patient’s medical history, diagnoses, treatments, radiology images, medication, etc. Much of this data is available as structured data, often with coded terms, because this data is also needed for accounting purposes.

While syntactic interoperability focusses on data formatting, the third tier of interoperability requires a common understanding of data. Semantic interoperability focusses on the meaning of data exchanged between systems; it ensures that both systems extract the same information out of the data. In other words, semantic interoperability reduces ambiguity. Ambiguity can result from different units being used for measurements, which can be standardised in a rather straightforward way. Handling free texts, on the other hand, tends to be challenging, because we have to cope with synonyms, abbreviations, different language skills, spelling errors, and much more. Ensuring a common understanding of free texts in medical applications has ever since been addressed by the field of medical documentation. Classifications and nomenclatures like ICD-10, SNOMED etc. have reduced ambiguity in health records massively. By using them, various terms can be mapped to a unique code that ensures a common and clear understanding of information. While medical documentation first aimed at ensuring “human interoperability” through health records, those approaches can be applied to interoperability of software systems very well.

Analysing well-structured codes is more efficient and effective, than trying to normalise and match free text in a fuzzy way. Medical coding can therefore be seen as the key to semantic interoperability in clinical research.

Earlier definitions of interoperability were only using the threetier model of technical, syntactic, and semantic interoperability.

Nowadays, we are using a fourth tier on top of semantic interoperability. Organisational interoperability focusses on the processes being used. To understand the need for organisational interoperability we need to remember that interoperability is always related to cooperatively achieving a common purpose. This relies on the fact that the systems are being used in a similar context with data being recorded, processed, and interpreted in the same way. When integrating systems within a single organisation, this assumption usually holds true, at least, if the systems have been selected to match the organisation’s requirements. When integrating systems and data of multiple organisations, organisational interoperability needs to be considered thoroughly. In clinical research this tends to be easier, because organisations are working according to standardised processes, and agreeing on such processes (e.g. through SOPs) is a routine task in every project. www.jforcs.com

Surprisingly enough, even today we are still entering data into an EHR and again into an eCRF (Fig. 1). Its obvious inefficiency increases the costs and the time needed for data acquisition. Time-consuming data entry is a common complaint by the sites, while delayed eCRF completion is a common source of sponsor complaints. Besides that, we need to identify and resolve data inconsistencies by edit checks, by monitoring activities, queries etc., which is also time-consuming.

In an ideal world, each EHR would provide a level of interoperability that would allow the eCRF to extract required data automatically.

Instead of checking manually copied data, validation of this interface would provide evidence that all extracted data matches its EHR counterpart. Unfortunately, we are not living in this ideal world yet. In 2018, FDA’s guidance “Use of Electronic Health Record Data in Clinical Investigations” addressed the lack of interoperability and included further recommendations, e.g. data structure, EHR certification, validation activities, record-keeping, etc.

Example 2: Wearable Technology Wearable technology lets clinical research acquire data 24/7. It allows for continuous tracking of physical activity, cardiac events, blood pressure, etc., which provides deeper insights and more reliable data than when using patient diaries or on-site visits. An increasing number of subjects is using such devices for tracking their individual health status and their sports activities. The question of interoperability is gaining a lot of attention, because those devices and their related cloud infrastructures provide access to a huge amount of chronological data. Swivel chair integration would be useless in this scenario. Most vendors of such devices already provide APIs or semi-automatic export interfaces. But the world behind those interfaces tends to be a black box. For EHRs, FDA stated that no 21CRF11 compliance is required, however audit trails etc. must be available, which would also apply to wearable technology. Of course, wearable technology designed for clinical research is available and usually fulfils the expected requirements, while this usually does not hold true for consumer-oriented devices. The same applies to the certification of measurement processes. The higher compliance with applicable regulations usually involves higher costs, and the subjects might need to wear their own device as well as the projectspecific devices. We see, however, that important manufactures try to achieve FDA certifications for their consumer-oriented devices, because this enables interesting business models based on diagnostic services. Following this strategy, we might also see interoperability with EHRs in the future, which could be used for the purposes of clinical research.

The Dark Side of Interoperability In clinical research we see a multitude of systems for various purposes. Trying to integrate the best systems on a per-project Journal for Clinical Studies 43

Technology

basis will be too expensive at least for small and medium projects.

We expect to see “best practice integrations” that can be applied to several projects, which leverages the setup and maintenance costs.

But still the cost for swivel chair integration might be lower than programming an automatic interface by IT specialists. In that case it is worth taking into account the higher level of data quality, reduced monitoring efforts, less frustration by the sites, better compliance, etc.

Security considerations are inevitable when talking about integration and interoperability. APIs have often been targeted by attackers, because they provide an automatic access to large amounts of data. Therefore, security testing of APIs is crucial. Besides that, the connectivity tier must rely on encrypted transmission of data and strong authentication. Some APIs also allow for white-listing of systems that access the API, which provides additional security.

With every system integrated, the complexity of the overall system increases drastically. Despite this complexity, validation activities need to show that data is exchanged accurately, consistently, and completely. As this might be needed for every change to one of the systems, automatic test tools are needed for this. There are many test tools available that focus on automatic testing of APIs and integration of systems. However, we might run into situations where sufficient testing cannot be performed within the project’s budget, because of too many EHR systems being involved. Certification of system interoperability might help in reducing this testing effort.

Many of the systems to be integrated are located in data centres spread all over the world, which also involves various country-specific regulations; for example, privacy regulations, regional service restrictions, security requirements, medical coding standards, etc. Among these, privacy regulations tend to be very critical, because medical data is being processed and potentially combined with other data. Thorough analysis and adaptation of privacy policies and informed consents is needed to prevent compliance issues. Additionally, most vendors offer regional data centres to avoid such situations.

44 Journal for Clinical Studies

Conclusion Interoperability is the key to integrating systems. This will become more important than ever for clinical research, when data needs to be acquired automatically from EHRs, wearable technology, and other network-enabled devices. APIs can serve as the key to interoperability, but standardising data formats, data interpretation, and the organisational context need to be considered thoroughly.

Currently, there is no plug-and-play approach that lets us integrate systems easily. Adequate vendor-independent standards should be established soon to push interoperability further and to provide a basis for interoperability certification. We can learn a lot from the world outside clinical research, where integrating services through APIs is an everyday task.

Getting rid of swivel chair integration will change and improve many processes in clinical research. Error-prone and inefficient data entry can be reduced significantly, which should increase data integrity and data availability; monitoring efforts can be reduced. With a rapidly increasing amount of data, automising data acquisition through interoperability becomes inevitable.

Jörg Mielebacher Jörg Mielebacher (PhD) has studied medical informatics and has worked in this field for more than 15 years. He is an experienced IT consultant and software specialist, with a specific focus on automated analysis of processes in clinical research. He is founder and CEO of PCQ Pilots in Bremen (Germany), a vendor of various software solutions for clinical research, including eCRF, e-TMF, risk management, randomisation, and training. He is also honorary professor for computer science.

Email: joerg.mielebacher@pcq-pilots.com

Volume 12 Issue 5

Volume 9 Issue 1 - Spring - 2017

Volume 9 Issue 1

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

IPI – International Pharmaceutical Industry

INSIGHT / KNOWLEDGE / FORESIGHT

MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding

Three Ways to Mitigate the Risk of

Late-Stage Failure in CNS Drug Development

Data

The Foundation of Clinical Trials www.ipimediaworld.com

Temperature Management Keep Your Cool

www.ipimediaworld.com

SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS

IPI

Peer Reviewed, IPI looks into the best practice in outsourcing management for the Pharmaceutical and Bio Pharmaceutical industry.

www.ipimediaworld.com

JCS

Peer Reviewed, JCS provides you with the best practice guidelines for conducting global Clinical Trials. JCS is the specialist journal providing you with relevant articles which will help you to navigate emerging markets.

www.jforcs.com

Volume 4 Issue 1 Volume 4 - Issue 1 Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

PEER REVIEWED

Applying Game Theory to One Health Modelling Veterinary Healthcare Delivery International Animal Health Journal - Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

Mastitis due to Mycoplasma bovis Insights Pet Obesity Prevention is Better than Cure Leadership Skills of Extraordinarily Successful Executives

www.animalhealthmedia.com

Official Supporting Associations -

Sponsor Companies -

www.animalhealthmedia.com 11_IAHJ_February2017.indd 1

25/02/2017 13:37:17

IAHJ

Peer Reviewed, IAHJ looks into the entire outsourcing management of the Veterinary Drug, Veterinary Devices & Animal Food Development Industry.

www.animalhealthmedia.com www.jforcs.com

IBI

Peer reviewed, IBI provides the biopharmaceutical industry with practical advice on managing bioprocessing and technology, upstream and downstream processing, manufacturing, regulations, formulation, scale-up/technology transfer, drug delivery, analytical testing and more.

www.biopharmaceuticalmedia.com

Journal for Clinical Studies 45

Technology

Automating Adverse Event Data Capture: A Missed Opportunity?

Life sciences companies are widely failing to maximise opportunities to automate the capture of adverse event data, according to a new study involving pharmaceutical organisations in the UK and US. The research reveals that pharmacovigilance (PV) automation plans are less advanced than they may first appear. Dr John Price, life sciences regulatory and safety consultant and advisor to Arriello, analyses the research findings.

Upholding the highest levels of patient safety demands that life sciences organisations track and report on adverse reactions to drugs as these are reported in the real world – information which could come in via frontline healthcare professionals, manufacturers/ supply-chain partners, directly from patients, or indirectly via patient forums online. It is incumbent on pharmaceutical brands to capture this information, assess its significance, and report it in a timely manner to the authorities so that safety information can be updated and, if appropriate, additional action can be taken.

Given the diverse ways this information is submitted, and the huge volumes of data there is to go through and analyse, it might be assumed that pharma companies would harness the latest technology to capture and process the workloads. Today, the range of technology options to help with all of this is considerable; they are proven in their reliability and are highly cost-efficient.

Transatlantic PV Survey To determine whether or not life sciences companies are capitalising on these tools, we recently commissioned a transatlantic survey into life sciences companies’ attitudes towards and plans for PV automation, particularly for case intake and reporting. The online Censuswide survey with companies in the UK and US took place in late June 2020, polling 200 respondents in senior roles across the pharmacovigilance (PV), drug safety and product safety departments of life sciences companies of different scale and focus.

Surprisingly, a high proportion of respondents claimed their use of advanced technology in PV was already strong, or imminent. This is at odds with general observations of pharmaceutical companies, certainly when it comes to managing adverse event data capture which tends to be predominantly manual. Just under half of all respondents said their organisations were using some form of robotic process automation today, and a further third said they had plans to adopt such capabilities over the coming year. Companies in the UK appear to be ahead with this – for now.

Almost two-thirds of respondents at large pharma companies claimed to use some form of standalone PV automation solution today, and almost half of SMEs said the same. Conversely, the proportion of respondents who said they had no imminent plans to implement PV automation was negligible. Yet these findings aren’t as conclusive as they might seem.

When asked whether they thought their organisations were already using automated case intake solutions, or planned to do so 46 Journal for Clinical Studies

over the year ahead, only a fifth of respondents said they already had such a capability, while almost half said any plans were at least 6–9 months off – if in place at all. UK companies appeared to be significantly more ambitious here. Only 10 per cent of US respondents said they already had automated AE reporting, and just a fifth had imminent plans to adopt an IT solution for this.

Uncovering Immaturity Comparing these findings with the earlier claims made about high levels of existing PV automation suggests that respondents are making blanket references to solutions used across the whole spectrum of PV operations. These could include basic electronic data capture (EDC) in clinical development; autonarrative generation (dropping data into pre-defined templates); programmed summary tabulations; and listings for aggregate reports and so on, which are often included in the applications/ services provided by safety vendors. While all of these productivity aids are useful, they do not add new value to the PV function.

So the findings could mask relative immaturity in AE case intake automation.

To determine how far along organisations are with PV automation generally, and the specific areas they have advanced the most, the research asked what else companies had automated or planned to automate within the PV function.

Clinical and medical information compilation (both mentioned by almost two-thirds of respondents, rising to up to 80 per cent among respondents in product safety roles) emerged as the most advanced areas for process automation, with almost two-thirds of all respondents saying facilities for this were already in place.

Use of automation in standard document compilation and product quality compliance information was also common, cited as being in place at over half of companies. Automated solutions for managing regulatory intelligence information, literature screening, and auto-narrative generation were prevalent for more than four in 10 organisations.

Barriers and Benefits While most respondents claimed their organisations were planning an automated solution for AE case intake within the next year, the survey indicated a number of practical barriers likely to inhibit progress – the top three being IT-related challenges. Respondents revealed that an inability to validate new systems (cited by 41 per cent), a lack of familiarity with AE case intake technology options (indicated again by 41 per cent), and inadequate IT infrastructure (cited by 38 per cent across all sizes of organisation) stood in the way of automating these vast and largely manual workloads.

There is a strong perception, especially among PV professionals, that PV automation equates to a rise in AE reporting volumes.

A follow-up question confirmed that respondents see this as a benefit of automation. The greater an organisation’s capability for capturing reliable information quickly, efficiently and effectively, the higher the volumes of data that teams will be able to process – and the greater the likelihood of important cases being identified and analysed.

Volume 12 Issue 5

Technology

Across all company sizes, the top three benefits of PV automation (jointly) were seen as improved compliance; higher reporting volumes; and speed.

There were differences in perception between small and large pharmaceutical organisations, however. Over half of respondents from SMEs rated improved efficiency as the primary benefit, followed by speed of turnaround. For large companies, keeping pace with peers and meeting compliance targets were deemed the main advantages.

Surprisingly only just over a third (35 per cent) of all respondents cited the potential for resource redeployment as a target benefit.

Adding Value with PV Automation It is clear that many businesses are missing an opportunity to manage PV workloads more effectively and cost-efficiently, while optimising use of skilled resources. Yet most respondents did not see an absence of PV automation as a disadvantage. In fact, only six per cent of all respondents felt their organisation would be ‘very disadvantaged’ by a lack of PV automation.

It appears to be very much the case that PV functions are widely viewed as a cost centre rather than a function that could add value to the business. The research reveals that the benefits of letting www.jforcs.com

advanced technology take the strain of AE data capture and PV information processing and reporting aren’t fully on the radar of senior management and business stakeholders. PV professional and solution providers may need to work together to communicate the numerous tangible benefits linked to capturing the high throughput of case data in an automated way.

The full report, Pharmacovigilance Automation Adoption Survey – UK & US – Key findings and discussion, is here https://www.arriello. com/automation/

John Price John Price, owner and MD of John Price PharmaSolutions LLC, is a life sciences regulatory and safety veteran and consultant, and an advisor to PV managed service provider Arriello.

Email: drjsprice@pharmacovigilantes.com

Journal for Clinical Studies 47

Logistics and Supply Chain Management

Managing Collection of Temperature-sensitive Patient Samples during a Clinical Trial Direct-to-patient collection of biological samples is a growing trend that poses complex, but solvable logistics challenges during clinical trials. Providing a convenient and easy method to maintain the patient sample temperature is critical to the success of these clinical trials. In particular, temperature-sensitive samples collected directly from patients pose logistical risks associated with controlling payload temperature, such as the 2 to 8°C range. To resolve these challenges, innovative temperature-controlled packaging has been developed to address this growing need.

There are two areas showing growth trends – direct-to-patient (DTP) collection kits, drug and shipping supplies and direct-frompatient (DFP) biological samples for testing. There are several factors driving the growth trends including convenience for patients and biopharma benefits to engage and retain more patients for the duration of clinical trial studies.

The convenience factors involve making it easier for patients to receive healthcare attention at home versus driving to the physician or clinic office. Some patients are simply too ill to travel for treatment, or live in rural areas. Administering home healthcare increases clinical trial protocol compliance and improves patient recruitment through greater willingness of patients to participate in the trial.

48 Journal for Clinical Studies

The other consideration is that these clinical trial studies are increasingly conducted on a global scale. The collection centres where samples are collated are more likely to be situated in locations which are not close to the participating patients.

This patient-centric collection of biological samples is a trend with growing popularity in recent years. Certain types of packaging products lend themselves to these applications because they are easier to use and there is no need for conditioning. As a result, we are seeing a rise in demand within the sector for specific packaging systems which address these needs by providing improved payload protection performance and ease of use.

Logistical Challenges There are current complex challenges when it comes to the logistics involved during these clinical trials, with the sector constantly developing options to address their particular needs. As stated, some patients involved in DTP clinical trial applications live in rural areas, which creates challenges in sample collection and transport.

Thankfully, biopharma can contract with nurses and phlebotomists to go directly to the patient homes to administer drug, monitor patients and collect and transport samples.

Logistically, it is important that these healthcare teams understand the temperature requirements for collected samples and the packaging that is supplied to ship the samples. For example, if dry

Volume 12 Issue 5

Logistics and Supply Chain Management

ice is needed to ship a frozen sample, accommodations must be made to source and supply dry ice for the packaging system on a local basis.

This means biopharma logistics personnel must coordinate these specialised needs for DTP and DFP activities. The industry cannot rely on patients to draw their own blood and that is why biopharma is addressing this with additional personnel like phlebotomists to go to patient homes and manage the complex steps of collection and shipping compliance for clinical trial protocols.

Temperature-sensitive Samples There is a rise in the number of samples within clinical trials which tend to be temperature-sensitive and this comprises approximately 50% of collected samples. Some of the samples must be stored and transported at controlled room temperature. It is vitally important to ensure compliant collection of temperature-sensitive patient samples throughout the clinical trial process. Laboratory testing of the samples provides important clinical trial study data indicating how the participating patients are reacting to the drug throughout the duration of the study.

While those samples don’t have a monetary value, they are, in many circumstances, considered irreplaceable. When sample data cannot be gathered due to a compromised sample, that’s one less data point where the trial sponsor can’t prove or disprove the effectiveness of the drug. Any loss of such data will have repercussions within the study. It is critical that the samples be kept at the proper temperature range in order to provide accurate patient monitoring data to demonstrate the safety and effectiveness of the drug. www.jforcs.com

Compromised patient samples can lead to insufficient results in clinical trial testing which can require retesting due to samples falling out of compliance with required temperature transport parameters.

How is the sector responding to rising requirements regarding the need for innovative temperature-controlled packaging and what are the latest developments?

For DTP collection and DFP sample transport, the sector has responded with temperature- controlled packaging that is easier to use at remote sites since no conditioning of gel packs or wet ice is required to activate these cooling systems. Just one touch of an activation button on such systems starts the cooling process for refrigerated samples. Some dry ice shippers are easier to pack-out for users making these solutions more user-friendly. Some of the latest systems also comprise a smaller footprint, making them lighter and more cost-effective for sample transport.

We are seeing an increase in the collection of tissue samples from tumours and other diseased tissues that are being treated by different cancer drugs. Specialised temperature-controlled packaging is being deployed for such collection opportunities, which is designed to keep those tissues cold and protected during shipment.

We are also seeing a trend developing for smaller and lighter sample transport packaging for clinical trial participants. Simple innovations include putting handles or straps on the back of the containers so they are easier for patients and healthcare personnel to carry between home and clinic or post office.

Journal for Clinical Studies 49

Logistics and Supply Chain Management my opinion, once the vaccines come to be then testing will be less and less prevalent.

Within the sector, we are not currently seeing patient sample collection for COVID-19 vaccine development. My theory is that it is so important that they are actually bringing the people participating into places where they can get all the information quickly and control it. Therefore, they are not leaving it to shipping from home and with that kind of caution it is likely such samples will be handcarried.

Future Trends Biopharma companies will need to be flexible in terms of including DTP and DFP activities to take advantage of this market space to encourage higher patient participation and retention.

To this extent, service providers will be called on by biopharma companies to be active in contracting services in these areas.

Biopharma and their associated logistics providers of home healthcare service, in combination with DTP and DFP services, can benefit from driving down overall development cycles and project costs.

Sometimes, depending on how large a sample is and the types of requirements, they can weigh up to 20 to 40lb depending on what kind of cooling system is being used, whether they use phase change materials (PCM), geo packs or on-demand packaging system. The performance of the packaging product is important along with ease of use.

Impact of COVID-19 We are seeing a majority of clinical trials that have been either suspended or adjusted to delayed milestones due to the concern of the patient for being involved in the study or the sponsor’s caution on the potential interaction of Covid-19 with the patients’ health and the impact of that on their clinical trial study results.

If healthcare specialists were deployed to a patient’s home to conduct the collection and transport of samples, there might be concerns about the ability to adhere to social distancing measures, which have been implemented in many countries in a bid to try and prevent the spread of COVID-19. As a result, participation may decrease in the trials due to either patients’ or caregivers’ reluctance to risk being in close contact and becoming infected with the coronavirus that causes COVID-19.

We may also see more focus on COVID-19 testing as people start going back to work. A lot of companies are looking to have an antibody test available for their employees when they return to the workplace on some kind of regular basis. This type of testing will require blood draw and then a way to ship the temperature-sensitive blood sample.

A lot of these office environments don’t have refrigerators, freezers or areas where they have ice, so they may need a simple and easy way to send those samples to the testing laboratory.

This is likely to be a key area of growth. In the US, some testing companies are starting to market these tests to businesses.

If they are not contracting one of these testing companies, large organisations are trying to organise testing processes themselves so it is definitely a big opportunity, but how it will progress is not yet certain. It could be a six-month blip or it could go on for a while. In 50 Journal for Clinical Studies

Such a global network of select providers can expand skilled and flexible services required under clinical protocols. These procedures include: • Study drug administration, including subcutaneous and intravenous infusion • Blood draws and other biologic sampling • EKG/ECG • Clinical assessment of vital signs and other mobile-based data collection • Patient and caregiver training and education • Reduced exposure of patient personal health information by booking DTP requests and home visits at the same time • GDPR and HIPAA compliance to ensure data protection and privacy • Electronic completion and submission of visit documentation for streamlined administration in accordance with 21 CFR Part 11 It is worth noting that these patient-specific services may not just be limited to clinical trials. There are other tests requiring the need to get the product directly from the participant. Therefore, making the collection process as convenient as possible whereby the patient doesn’t have to leave home will increase participation, mitigate risks and ultimately improve results that can be achieved.

Vince Paolizzi Vince Paolizzi, Director of NanoCool Sales, Pelican BioThermal has over 15 years of experience in various sales leadership roles within the Pharmaceutical packaging industry. He is responsible for the global sales growth of the NanoCool line of products. Paolizzi’s experience includes key account management to maintain strong relationships with customers as well managing multidisciplined project teams to secure new accounts. Prior to joining Pelican BioThermal, Paolizzi held various sales positions within the packaging, tooling and food industries. He received his degree in Business Management from West Chester University of Pennsylvania.

Email: vince.paolizzi@pelican.com

Volume 12 Issue 5

Corporate Profile

Multi award winning Bonaccord is a law firm dedicated to supporting the scientific community across the UK and beyond Our services are friendly, flexible and cost effective. We are proud to have long term relationships with clients, working with them to bring great new ideas to the market improving patient lives. We are very happy to work with start ups and spin outs as well as more established businesses and can be accommodating in our billing.

We work right across the life science sector with both product and service businesses: pharmaceuticals, medical devices, genetics, biotechnology, AI, diagnostics, animal health.

We try to take the administrative burden off our clients so that they can carry on doing brilliant science with a standardised board pack and board management services. We can also provide company secretarial services so ensuring that your records are always compliant and that key documents reach your directors in good time and in a convenient format.

Our simple to complete standard templates for regular contracts help manage client’s legal costs.

Some contracts by their nature are complex, in particular multi party R&D collaborations or licensing arrangements which are key areas

Our understanding of the complex service issues and developing concepts of intellectual property in cutting edge fields such as AI and genetics allows us to craft contracts specific to the situation that recognise the interests of all the stakeholders.

We will support you across your legal needs as you build your business:

of our expertise but we believe in using plain English to ensure clients understand the terms and can mange the contract themselves going forward without constantly having to refer a clause back for explanation.

Corporate set up Board management Sourcing investment IP strategy R&D collaborations Clinical trial contracts Licensing contracts Manufacturing contracts Employment and consultancy issues International distribution arrangements M&A More than just a law firm we engage with an international network of specialists across all areas of life science from patenting to recruitment and business strategy, to regulatory, manufacturing and sales. If you have a gap in your network we aim to help you fill it. We will also work with you to source investment.

Let us be part of your team.

For a no obligation chat about how we might work with you contact enquiries@ bonaccord.law or 0131 202 6527 www.bonaccord.law

www.jforcs.com

Journal for Clinical Studies 51

Special Feature

Decentralized Clinical Trials

JCS Speaks with Dr. Graham Wylie at MRN on Home Trial Support and Decentralized Clinical Trials 1. Demographic, epidemiological, social, and cultural trends in European countries are changing the traditional patterns of care and a disease-orientated approach is no longer appropriate. Can you tell JCS why home trial support (HTS) and the decentralised clinical trial model mitigates the need for traditional care approaches?

The DCT model, more specifically, HTS, is focused on delivering clinical trials efficiency by helping patients participate while remaining in their communities, wherever they live around the world.

The aim is to reduce the inconvenience and disruption of patient’s lives caused by trial visits to investigator sites as much as feasible, by running those visits in their own home. By building DCT models into protocols, the industry is able to respond to the change in cultural trends, which most certainly will continue to be shaped by the global pandemic. We continue to see patients who are more willing and more able to adapt to these “new” models and to new technology being brought into their homes. This is of course not limited to European countries or clinical trials. We have seen the release of technology from providers like Apple collecting health information from consumers via the Apple watch with new technology built in to measure blood oxygen levels and take ECGs at any time. As we continue to see the development of technology, not just in the clinical trial arena, become more sophisticated and better adopted by consumers, we will continue to see changes in what was the traditional patterns of healthcare. Adopting a decentralised approach will be advantageous to drug developers. We have seen this for over 14 years – by reducing the burden of the trial on patients and their families we can directly increase patient recruitment by 60% or more and typically maintain retention at over 95%. There is a very clear speed-to-value relationship for pharma companies running decentralised clinical trials. There are also cost implications for sites.

When we remove specific visits from sites and increase recruitment rates, we increase the frequency of the higher revenue visits into the sites. Of course, this will be dependent on the type of trial and disease.

2. Improvements in public health and changes in the landscape of disease have contributed towards changing epidemiology.

Why do you think a rise in non-communicable diseases such as Alzheimer’s influences the demand for decentralised clinical trials?

Long-term chronic illness is endemic in the western world today because we are getting older, driven by our ability to treat the acute life-threatening diseases more effectively. Such patients need to be cared for in their own homes for their benefit 52 Journal for Clinical Studies

and for the benefit of their families, as well as to limit the drain on centralised healthcare systems. Trials need to be run the same way. Decentralised trial design works well for Alzheimer’s disease because of the comorbidities, the patient population, and social aspect that surrounds this disease. Decentralised services should be built around the patient type, not necessarily the therapeutic area. For example, for a patient with Alzheimer’s disease, they will probably be relying on a caregiver either for their healthcare and/ or for transportation to and from site visits. By bringing the visit to the patient, we reduce the travel burden on the patient and on their caregivers, often their adult children. Travel burden can be thought of as not only the time it takes to travel but also logistical complications when travelling with someone who may have low mobility or may require complicated overnight stays. Giving patients a flexible visit schedule ensures fewer missed visits and a greater chance of fewer drop-outs, resulting in more complete data.

The demand for decentralised services will continue as we see a rise in disease prevalence and as we continue to see the rise in costs of running trials. Drug developers will continue to offer trials to dependent patient populations, so it is important that cost-effective solutions are employed.

3. Technological innovation together with new and modern forms of service delivery organisation can represent a viable solution to developing decentralised clinical trials (DCT).

What needs to be considered to improve the responsiveness, continuity, efficiency, of clinical trials moving forward?

The past 12 months has dramatically changed the healthcare landscape globally. Only time will really show the long-term effects of the COVID-19 pandemic on clinical trials, but there have certainly been some significant learnings about the importance of real-time data capture and analysis, as well as integration of data systems between organisations and patients themselves.

Ensuring patients are safe, cared for and comfortable during treatment isn’t simple; making sure data is collected on schedule and accurately, so that the study either proves the efficacy of a treatment or disproves it quickly isn’t simple; coordinating medical professionals, patients, investigational medicinal product to a single point in time and location isn’t simple; managing sample collection, on-site processing and shipping to central laboratories from multiple, domestic, locations isn’t simple. Pulling this all together across multiple patients, locations and visits is very complex and we have defined best practice in the delivery of community-focused clinical trials, expanding the type of visits achievable in the community. We’re always working to continually drive our innovation so we remain adaptable and agile and can respond to changing trial requirements Volume 12 Issue 5

Special Feature

and patient needs. Sponsors likewise will have to learn how to design protocols to take advantage of these new capabilities and services.

4. Changes in social attitudes, values and behaviours are contributing to the demand for decentralised clinical trials (DCT). Can you talk us through your predictions for DCT and how it will evolve during COVID-19?

While the industry in recent years has discussed various patient-centric strategies, COVID-19 has brought their implementation to the very forefront of clinical trial development. In reaction to the global pandemic, sites have closed, studies are losing their trial patients and hundreds of millions of research dollars are at risk.

As part of these patient-centric strategies we have seen a growing response for patient empowerment in clinical trials. As a result, drug developers have been bringing the patient voice to the protocol design table and working to integrate the patient perspective through their trial experience. This change in behaviour has been bolstered by the current clinical trial environment with COVID-19. I think we will continue to see the patient voice invited to the table but my hope would be that their influence will be greater. Now that patients have had the opportunity to participate from their homes, I think we will continue to see a demand for the use of decentralised solutions such as home trials support (HTS) and telemedicine. Sponsors traditionally see the site as the critical stakeholder, but the patient is the actual final consumer of their product; therefore, as sites become less critical to the delivery of care and to finding patients for trials, so the sponsors will have to increase the sophistication of their approach direct to patients, who can consume their product through multiple healthcare provision channels.

5. The COVID-19 pandemic has been an unprecedented change agent and has acted as an accelerant for the acceptance of telemedicine and decentralised clinical trials. What steps has MRN taken to modify their home trial support service for the conduct of clinical trial visits in the patient’s home?

In response to the global pandemic, both existing and new clients are turning to MRN to help rescue their trials from imminent failure; since March, we have received over 500 requests for proposals from clients, more than 2.5X the expected rate. Already we are seeing actual monthly patient visit numbers more than double (about 2.4X). We have increased our direct operational headcount by over 80% to ensure we have the personnel to support the increasing demand. We have built in efficiencies into our processes from proposal and protocol evaluation process through to visit delivery.

We have introduced additional processes, PPE and training to HTS nurses. Our response to the pandemic allows our clients to continue to recruit and retain their patients, keeping their at-risk studies and www.jforcs.com

their patients’ wellbeing on track. We are also introducing backup plans to cover the now inevitable second peak. We have also dramatically increased our nursing network to provide much higher nurse coverage in key geographies in the US and Europe, to allow us to attempt to meet the increased demand as fully as possible.

6. You collaborate with telemedicine providers to further your remote patient monitoring, patient care, and clinical assessments capabilities. How has this maintained the importance of clinical trial continuity during a pandemic?

So far we have seen a growth in interest in telemedicine within sponsors, but consistent with the take-up of technology being much earlier in the adoption cycle than HTS, the number of new projects we are participating in is around XX, whereas we have seen an increase in the number of trials incorporating HTAS has gone up around X times more than that. The future holds both solutions working in concert to give the most convenient and safest experience to the patient and their sites.

MRN has built alliances with technology companies to enhance our ability to deliver patient care and support drug developers as they have been required to redesign and reimagine how trials visits will be conducted. By integrating telemedicine with HTS we are able to further diversify what HTS nurses can do in the home, and enhance our service offering. This type of alliance is important as patients not only require communication with their physicians or nurses through telemedicine technology, but, sites also need the confidence that a specialised research nurse is having face-to-face contact with patients and performing protocol required activities as if they were at site. Alliances with telemedicine companies mean that we have created streamlined processes to work together, allowing fast and efficient start-up, as well as pre-identified risk with mitigation planning for our pharma clients.

Graham Wylie Dr. Graham Wylie, CEO of MRN, has worked in the pharmaceutical industry for over 30 years and has been an agent of change throughout. His career started at Pfizer, spanning clinical trial management, development of global technology platforms and global change management and continued at PAREXEL as a Medical Director and then Vice President of Account Management. He formed MRN as CEO in 2006, which has since become the leader of the community based Clinical Trials Support Organisation sector and has been one of the fastest growing companies in the UK throughout the last 14 years.

Journal for Clinical Studies 53

News Bristol Myers Squibb's Zeposia Boosts Remission Rates over Placebo in Ulcerative Colitis Patients Bristol Myers Squibb has big hopes for a next-gen entry in Zeposia, and it is angling for a foothold in ulcerative colitis to get the ball rolling. Zeposia helped 18.4% of ulcerative colitis patients reach clinical remission at the 10-week mark of treatment compared with 6.8% of patients on placebo and maintained those results after one year, according to data from the phase 3 True North study, presented Saturday at the United European Gastroenterology virtual meeting. Zeposia, a sphingosine-1-phosphate (S1P) receptor modulator, helped 37% of patients maintain remission at the 52week mark of treatment compared with 18.5% of those who received placebo, Bristol said.

Source: Fierce Pharma Use Virtual Visits to Enhance the Patient Centricity of Clinical Trials After a concerted effort by our industry over the last several years, sponsors, clinical research organizations (CROs) and clinical trial suppliers have added “patient centricity” to our vocabulary and study planning. The shift to not just think about the patient but think as the patient is a critical effort to advance clinical research for and with patients. Patient-focused strategies such as protocol design insights, focus groups, satisfaction surveys, indicationspecific content and study results sharing continue to evolve as potential standard approaches in research studies.

Source: MedCityNews Scientists Develop New Type of Precise Therapeutic Vaccine against Leukaemia Exploration of new leukaemia antigens and construction of appropriate delivery systems using FDA-approved material are important strategies for developing leukaemia vaccines for clinic use. Researchers from the Institute of Process Engineering (IPE) of Chinese Academy of Sciences and Zhujiang Hospital of Southern Medical University have developed a new type of precise therapeutic vaccine against leukemia. It utilizes self-healing polylactic acid microcapsules for co-encapsulating a new epitope peptide and PD-1 antibody.

Source: News Medical Life Sciences SARS-CoV-2 Neutralizing Antibody Structures Inform Therapeutic Strategies The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptorbinding domain (RBD) of the SARS-CoV-2 spike show therapeutic promise and are being evaluated clinically. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories.

Source: Nature Seagen, Astellas Eye Earlier Padcev use in BLadder Cancer with Long-Lasting Phase 2 Results Right now, Seagen and Astellas’ Padcev is cleared only for metastatic bladder cancer patients who have already received chemo and a checkpoint inhibitor from the PD-1/PD-L1 class. But thanks to new findings, the drug may be headed for an OK earlier in treatment.

Monday, the pair revealed that their antibody-drug conjugate produced long-lasting responses in patients who had received immunotherapy but were ineligible for cisplatin chemo. The drug 54 Journal for Clinical Studies

spurred a response in 52% of patients, with patients experiencing benefits for a median 10.9 months.

Source: Fierce Pharma Johnson & Johnson COVID-19 Vaccine Study Paused Due to Unexplained Illness in Participant The study of Johnson & Johnson’s Covid-19 vaccine has been paused due to an unexplained illness in a study participant. A document sent to outside researchers running the 60,000-patient clinical trial states that a “pausing rule” has been met, that the online system used to enrol patients in the study has been closed, and that the data and safety monitoring board – an independent committee that watches over the safety of patients in the clinical trial – would be convened. The document was obtained by STAT. J&J confirmed the study pause, saying it was due to “an unexplained illness.

Source: Stat News UK leads Europe in Phase I and Phase II trials, ABPI Findings Show The ABPI has found that the UK is leading the rest of Europe in early-stage clinical trials and makes suggestions on how the country can maintain this position. he Association of the British Pharmaceutical Industry (ABPI) has announced that the UK is leading the rest of Europe in early-stage clinical research. The findings are part of the second annual report on the state of clinical trials in the UK. European Pharmaceutical Review Building the Supply Chain for Large-Scale Covid-19 Testing Widespread Covid-19 testing will be a fact of life for years to come.

Scaling up the supply chain requires governments to answer five key questions. Scaling up access to Covid-19 testing is one of the most serious challenges that the global healthcare supply chain has ever faced. And it is not going away anytime soon. Testing shortages in many countries were a major contributing factor to the botched early response to the pandemic. Without an effective vaccine, proactive and robust testing is the one of the most effective measures for stamping out burgeoning clusters before infection becomes widespread.

Source: Insead Knowledge RPS Calls for Prevention of Counterfeit Medicines in UK’s Supply Chain The Royal Pharmaceutical Society of Great Britain (RPS) has called on the UK government to take immediate action to fight counterfeit medicines from entering the country following the UK’s exit from the European Union. The RPS, in a letter addressed to Health Secretary Matt Hancock, emphasised the need for rigorous plans to be put in place to maintain formal links with the EU. This will help to authenticate the legitimacy of medicines that move between the EU and the UK. Under current plans, the UK will cease to benefit from the FMD. Source: Pharma Times Personalised Dementia Care in Care Homes Receives £1.2m Funding Support NIHR and UK Research and Innovation (UKRI) have awarded £1.2m to support the development of an innovative online programme designed to improve and personalise care for people with dementia in care homes. With many of the 400,000 people living in care homes around the UK having dementia, mental Volume 12 Issue 5

News health, or neuropsychiatric symptoms, alongside several physical illnesses, ensuring effective, high quality care is essential.

to support clinical trials of potentially life-changing treatments for patients with rare diseases”.

Source: National Health Executive

Source: My ChesCo

£210M World-Class Life Science Campus Set for the West Midlands Birmingham is set to lead the delivery of medical innovation in the Midlands through the development of Birmingham Health Innovation Campus; attracting significant inward investment, creating high value jobs in the region, and accelerating the development and deployment of new drugs, diagnostics and healthcare technologies to patients. The Campus will be the only science park in the Midlands dedicated to translational health and life sciences research.

Dynacure Announces New Program, DYN201, for Hereditary Spastic Paraplegia (HSP), a Rare Neurodegenerative Disease Dynacure, a clinical-stage drug development company focused on improving the lives of patients with rare and orphan disorders, announced today that they have entered into a license agreement with the Paris Brain Institute to acquire intellectual property rights related to the development of the Company's second pipeline program, DYN201 for the treatment of Hereditary Spastic Paraplegia.

HSP is a group of neurodegenerative diseases, characterised by motor dysfunction and spasticity.

Source: University of Birmingham Can Wearable Technology Help Care Homes Save Lives?

Wearable digital devices are to be trialled in care homes to establish whether the technology can help reduce covid-19 infections and prevent deaths. Similar in size to a wristwatch, the devices register when wearers come into contact with each other. Residents, staff, and visitors in 32 care homes will wear them. The data is automatically fed to researchers at the University of Leeds, who can analyse it quickly and feed results back to care home leaders.

Source: University of Leeds Sanofi’s Dupixent Reduces Severe Asthma Attacks in Children Sanofi’s biologic therapy Dupixent (dupilumab) hit the mark in recently published data from a pivotal phase III trial.The study evaluated Dupixent in children aged six to 11 with uncontrolled moderate-to-severe asthma, with Sanofi’s drug hitting the primary and all key secondary endpoints.In a broad type 2 inflammatory asthma patient population – defined as having elevated eosinophils (EOS) or elevated fractional exhaled nitric oxide (FeNO) – Dupixent significantly reduced asthma attacks and improved lung function.

Source: Pharma Times NORD Highlights New Era of Innovation and Public Health Awareness in Virtual 2020 Rare Diseases and Orphan Products Breakthrough Summit On October 8 and 9, the National Organization for Rare Disorders (NORD®) virtually hosted the 2020 Rare Diseases and Orphan Products Breakthrough Summit, the first time the organization representing over 25 million Americans impacted by rare diseases has presented the conference exclusively online. Nearly 900 registrants from more than 20 countries around the world gathered online for the annual event, the most impactful rare disease conference in the United States. Each year the NORD Summit brings together participants spanning the rare community, including rare disease experts and leaders from patient advocacy groups, government, industry and academia.

Source: Cision PR Newswire FDA Awards Six Grants to Fund New Clinical Trials for the Treatment of Rare Diseases The U.S. Food and Drug Administration recently announced that it has awarded six new clinical trial research grants to principal investigators from academia and industry totalling over $16 million over the next four years. These trial research grants, enhance the development of medical products for patients with rare diseases.

“Now, more than ever, we see the important role of these FDA grants www.jforcs.com

Source: BioSpace Cancer Treatments Fall as Referrals are Slow to Recover, Show Figures The number of cancer patients starting treatment between April and July 2020 in the UK has reduced by 26% (31 000) compared with the same period in 2019, according to figures analysed by Cancer Research UK.The charity said the drop is from a reduction in the number of people being referred to or attending secondary care, as well as the pause of screening programmes and some diagnostic tests because of the pandemic.

Source: The Bmj Alkermes is Expected to Expand its Presence in the Schizophrenia Market with its Candidate ALKS-3831, says GlobalData Following the announcement of positive voting outcomes from the joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, appointed by the FDA in support of Alkermes’ ALKS3831 for the treatment of Schizophrenia and Bipolar I Disorder; Alessio Brunello, Managing Pharma Analyst at GlobalData, a leading data and analytics company, offers his view.“The development of drugs with enhanced safety profiles has been consistently an unmet need for schizophrenia.

Source: Global Data Movember to Launch World’s First Cancer Registry ‘Super Network’ Movember is launching the world’s largest network of prostate cancer patient registries which will have the power to transform treatment and care of the disease by harnessing the ‘real world’ experiences of over 130,000 men. The global ‘super network’ – believed to be the first of its kind – will contain detailed clinical information on the diagnosis, treatment and survivorship of prostate cancer patients from over 15 countries.

Source: Movember Formedix Announces Expansion to Meet Demands for Clinical Trial Automation Formedix, a software organization that provides a clinical trial automation platform to help companies conducting clinical trials to submit studies rapidly, announces expansion of its development and test teams. By expanding the workforce, Formedix can stay abreast of technological breakthroughs and meet greater client demands for the enhancement and advancement of its platform.

Source: Formedix Journal for Clinical Studies 55

Ad Index

BC Bioquell

Page 51

Bonaccord

Page 3

Dora Wirth Languages

Page 5

Europital

Page 27

Illingworth Research Group

Page 21

MLM Medical Labs

Page 23

PCI Pharma Services

Page 45

Pharma Publications Group

Page 35

Ramus Medical Limited

IBC

SGS

IFC Worldwide Clinical Trials

I hope this journal guides you progressively, through the maze of activities and changes taking place in the pharmaceutical industry

JCS is also now active on social media.

Follow us on:

Subscribe today at

www.jforcs.com or email info@pharmapubs.com

56 Journal for Clinical Studies

www.twitter.com/jforcsjournal www.facebook.com/Journal-for-Clinical-Studies www.plus.google.com/+Jforcsjournal www.jforcs.tumblr.com

Volume 12 Issue 5

LIFE SCIENCE LIFE INSPIRED, QUALITY DRIVEN

CLINICAL RESEARCH SOLUTIONS

RELIABILITY

NETWORK

© SGS Group Management SA – 2020 – All rights reserved – SGS is a registered trademark of SGS Group Management SA

QUALITY

SGS provides clinical research and bioanalytical testing, with a focus on early stage development and biometrics.

Delivering solutions in Europe and North America, SGS offers clinical trial services. SGS has its own clinical unit in Belgium including a viral challenge testing facility and two phase I patient units based in Belgium and Hungary.

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

CONTACT US clinicalresearch@sgs.com

• PK/PD Modeling and Simulation

www.sgs.com/CRO

• Regulatory and Pharmacovigilance

www.sgs.com/Linkedin-life

SGS IS THE WORLD’S LEADING INSPECTION, VERIFICATION, TESTING AND CERTIFICATION COMPANY

B IO - DECO NTA M INAT IO N PHA R M AC EU T ICA L

ENSURE PEACE OF MIND

ENSURE BUSINESS CONTINUITY WITH BIOQUELL RAPID BIO DECONTAMINATION SERVICE (RBDS) Bioquell has data from over 50 peer-reviewed publications related to bacteria, viruses, spores and more.

Scalable from a single room to an entire facility, Bioquell RBDS offers a proactive approach to limit the impact of a contamination event and minimise the extent of any downtime when included in business continuity plans.

There are two business continuity options with Bioquell: PRIORITY RESPONSE PLAN

CRITICAL RESPONSE PLAN

ensuring a rapid response

providing a pre-agreed response time of 24, 36 or 48 hours

Both plans ensure a rapid return to production minimising lost manufacturing time.

To find the right plan for you and learn more, visit:

bioquell.com/StayOpen

© 2020 Ecolab USA Inc. All rights reserved. 27AUG20/EU

10456.2

USE BIOQUELL PRODUCTS SAFELY. ALWAYS READ THE LABEL AND PRODUCT INFORMATION BEFORE USE.