JCS Volume 12 Issue 2

Volume 12 Issue 2

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Regulatory Watch: Rare Disease Day Review Phase Assessment for ANDA Submission in US A Regulatory Review FDA Continues to Strengthen Paediatric Study Expectations Lessons Learned from the Clinical Trial Trenches How to Use Patient Engagement Technology Successfully

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Contents

JOURNAL FOR

4

CLINICAL STUDIES U

Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker 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 50 D, City Business Centre London, SE16 2XB Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

FOREWORD

WATCH PAGES 6

Central Risk-based Monitoring Supports Reduced Cost and Higher Levels of Data Quality

Good Clinical Practice (GCP) focuses on data quality and integrity.

Clinical trial sponsors must demonstrate strict oversight of studies to ensure proper conduct, safety of study subjects and accuracy and completeness of clinical data. Sheelagh Aird at PHASTAR explores how traditionally, oversight of a clinical study includes on-site data monitoring, performed by or on behalf of the sponsors, with monitors visiting each study site at defined intervals.

8

Industry Drive to Improve Information Exchange and Speed Study Start-up

As life sciences companies take action to speed up study execution, there is a significant opportunity to make clinical research processes more efficient. Rik van Mol at Veeva Europe demonstrates how standalone applications such as electronic data capture (EDC), electronic trial master files (eTMF), and clinical trial management systems (CTMS) are now utilised by the majority of sponsors, CROs, and research sites to improve clinical trial execution.

10 Building Bridges Towards Patient Clinical Studies: Critical Considerations in the Drug Development Process Early-phase clinical trials, known as human pharmacology studies, start principally with the aim of collecting information on the safety and tolerability of the drug product. Dr. Arash Ghalamkarpour at SGS Life Sciences outlines why scientifically sound bridges should be established to link human pharmacology studies to initial exploratory studies and later confirmatory studies.

12 Getting Your Bad News Early Will Ensure You Don’t Fail Tomorrow It is extremely rare for CROs to move seamlessly through an entire clinical trial without encountering some problems or hurdles. But what you don’t want is a situation where the challenges are becoming systemic risks and the trial ends up in need of rescue. Leslie Jones at WuXi Clinical highlights how common problems include poor patient recruitment and retention and concerns over the integrity of clinical data, which can all lead to trials falling behind schedule, or even failure.

REGULATORY 14 Regulatory Watch: Rare Disease Day

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 2 March 2020 PHARMA PUBLICATIONS

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In February 2020, the thirteenth international Rare Disease Day was held, where hundreds of patient organisations from countries and regions all over the world organised rare disease awareness-raising activities. Aman Khera at Worldwide Clinical Trials delves into how the FDA continued their long-standing dialogue with the rare disease community, by holding their Rare Disease Day 2020 public meeting aimed at “Supporting the Future of Rare Disease Product Development”.

16 FDA Focuses Efforts on Making Patient Perspectives Count During the last eight years, the US Food and Drug Administration (FDA) has been increasingly focused on realising a vision—to incorporate patient input in drug development and regulatory decision-making as standard practice. Deborah Komlos at Clarivate Analytics looks at how both the Patient-Focused Drug Development (PFDD) initiative and the reauthorisation of the Prescription Drug User Fee Act (PDUFA) are more adept at systematically obtaining the patient perspective on specific diseases and their currently available treatments.

Journal for Clinical Studies 1

Contents MARKET REPORT 18 The Rise of Patient-centric Clinical Trials in Today’s Environment There is a growing movement within the industry to focus on patientcentricity in clinical trials. The FDA and EMA have introduced requirements to include patient input into protocol design, as well as providing lay summaries to patients at the end of trials. Rosamund Round at Parexel demonstrates how the COVID-19 crisis has highlighted the importance of preparing and executing trials in a patient-centric way to ensure they have access to clinical trials, even in potentially unpredictable situations.

20 Review Phase Assessment for ANDA Submission in US: A Regulatory Review Today, the vast majority of drugs available for patients in the United States are generics that have gone through a rigorous system of evaluation supervised by the United States Food and Drug Administration (FDA). Pachipulusu Rajesh, Dr. Balamuralidhara V and Dr. Gangadharappa H.V at the JSS College of Pharmacy demonstrate how to submit the ANDA application as per FDA requirements, and the review phase. They also present a discussion of ANDAs and NDAs, looking at their similarities and differences.

26 Establishing Clear Procedures and Improving Start-up Timeline in Malaysia’s Clinical Research Ecosystem As delays in getting clinical trials up and running have financial implications, pharmaceutical companies and contract research organisations (CROs) are looking at ways to accelerate the study startup process. Noorzaihan Mat Radi and Audrey Ooi at Clinical Research Malaysia describe CRM’s timeline in feasibility assessment, budget negotiation and clinical trial agreement review, besides the regulatory and ethics approval timeline in Malaysia.

the industry to highlight how to use patient engagement technology successfully.

36 Technology at the Edge: Emerging Use of Actigraphy as an Outcome Measure Wearable devices incorporating actigraphic technologies are transforming the way researchers aggregate, display and interpret health-related data. These devices, and the mobile software applications built to work with them, enable researchers to monitor and capture data on a wide range of physiological functions. Andrew Kuhlman, Michael Murphy and Melissa L. Vadnais at Worldwide Clinical Trials look at the evolution of wearable technologies and how it influences the emerging use of actigraphy as an outcome measure.

40 The Digital Twin in Clinical Research Digital twins of assets and processes are established by using Internet of Things (IoT) technology to acquire massive amounts of data in real time. On the other hand, clinical research still relies on collecting huge amounts of data from subjects at rather few points in time, with a reliance on data being manually copied from medical records. Jörg Mielebacher at PCQ Pilots summarises how creating and using digital twins in clinical research could boost efficiency and data quality.

TALKING POINT 44 Home Trial Support: An Interview with JCS Patient-centricity has been at the core of MRN since its inception in 2006, so its impact is substantial. However, the term “patientcentricity” can have different meanings depending on how you engage with patients. This interview with Graham Wylie at MRN examines the patient-centric movement as a response to a chronic, long-term reduction in patient recruitment and retention.

THERAPEUTICS 28 Patient-centricity on Trial The pharmaceutical industry has a problem; clinical trials are failing to recruit and retain the required number of patients at an alarming rate. The statistics are damning, with 46% of clinical trials failing due to poor recruitment and 80% of trials being delayed by at least one month. Will Wilson, Kristian Webb and Mark Evans at Havas Lynx Faze and Vernon Bainton at Havas Lynx Group investigate how underperformance in these key areas can be improved through a patient-centric approach to boost the success of clinical trials.

32 FDA Continues to Strengthen Paediatric Study Expectations After a three-year reprieve, a new US paediatric study requirement kicks in on August 18, 2020. The US Food and Drug Administration Reauthorization Act of 2017 (FDARA) will apply to new drug applications (NDAs) and biologics license applications (BLAs). Meg Egan Auderset at Clarivate Analytics shows how sponsors must incorporate molecularly targeted paediatric cancer investigations into development programmes and submit results in applications for approval.

TECHNOLOGY 34 Lessons Learned from the Clinical Trial Trenches: How to Use Patient Engagement Technology Successfully Taken within the context of clinical trials, patient engagement (PE) technology must be treated with the same reverence as giftgiving. Put simply, organisations who don’t consider their audience will upset patients and sites, while potentially harming their trial.

Mindy Gruba at Signant Health shares the best practices within 2 Journal for Clinical Studies

Volume 12 Issue 2

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Foreword The pharmaceutical industry has a problem; clinical trials are failing to recruit and retain the required number of patients at an alarming rate.

The statistics are damning, with 46% of clinical trials failing due to poor recruitment, 50% of sites enrolling one or no study participants and 80% of trials being delayed by at least one month. Underperformance in these key areas is having a significant impact on the commercial achievements of the companies, as well as a detrimental delay in getting new medicines to those who need them. According to Kristian Webb, Mark Evans and Will Wilson at Havas Lynx Faze and Vernon Bainton at Havas Lynx Group these unacceptable delays are a major contributing factor to the escalating costs of drug development.

The answer, it seems, may lie with patient and public involvement in trial design, which has been demonstrated to improve patient enrolment, especially where they have included people directly affected by the disease in question. It seems that a patient-centric approach is not only the right thing to do, but it is also critical to improving recruitment, retention and ultimately the success of clinical trials. For example, the FDA and EMA have introduced requirements to include patient input into protocol design and provide lay summaries to patients at the end of trials. It’s becoming more apparent that reducing the patient’s burden by putting their needs at the centre of clinical trial development can have great rewards for both the patient and the sponsor. More recently, as outlined by Rosamund Round at Parexel, the COVID-19 crisis has demonstrated the importance of preparing and executing trials in a patient-centric way to ensure they have access to clinical trials, even in potentially unpredictable situations.

Taken within the context of clinical trials, patient engagement (PE) technology is a rising trend, but can be a burden if not implemented correctly. Mindy Gruba at Signant Health describes how to use patient technology successfully, by considering the patient, and the site, and what’s right for them. With the digitalization of the patient experience, production processes in the pharmaceutical and medical device industry are driven by a high level of automation, control, and traceability. Jörg Mielebacher at PCQ Pilots explores the value of digital twins in clinical research, and how wearables are a well-proven approach for 24/7 automatic recording of subject-related data.

I hope you all enjoy our second spring issue, and I look forward to featuring more enlightening articles in the next edition coming out in May. Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies 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.

Speaking of clinical trials, Deborah Komlos at Clarivate illustrates the FDA’s recommendations on the importance of making patient perspectives count, while Aman Khera at Worldwide Clinical Trials outlines the initiatives that the FDA and other regulatory authorities are taking to meet the needs of the rare disease population, in our regulatory section. Both authors demonstrate how the FDA strengthens the “patient voice” in medical product development and regulatory decisionmaking, particularly through technology which allows for remote participation.

JCS – Editorial Advisory Board •

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

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

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

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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Catherine Lund, Vice Chairman, OnQ Consulting

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Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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

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

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

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

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Stefan Astrom, Founder and CEO of Astrom Research International HB

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

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Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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Hermann Schulz, MD, Founder, PresseKontext

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T S Jaishankar, Managing Director, QUEST Life Sciences

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Volume 12 Issue 2

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Watch Pages

Central Risk-based Monitoring Supports Reduced Cost and Higher Levels of Data Quality Good Clinical Practice (GCP) focuses on data quality and integrity. Clinical trial sponsors must demonstrate strict oversight of studies to ensure proper conduct, safety of study subjects and accuracy and completeness of clinical data.

Centralised risk-based monitoring (RBM) of clinical trials greatly enhances this process. Traditionally, oversight of a clinical study includes on-site data monitoring, performed by or on behalf of the sponsors, with monitors visiting each study site at defined intervals.

Data monitoring confirms procedures are being carried out according to protocol. Monitors perform source data verification (SDV), validating that the data in the case report form (CRF) accurately reflects the source. This oversight is a labour-intensive, costly and inefficient process.

(i.e. a trend has occurred). QTLs are monitored at the trial level and pre-defined before the trial commences from a review of historical data from similar trials and where possible, using statistical methods and modelling.

A QTL for protocol deviations can be created and tested using simulated data. Unusually high levels of deviations may indicate an

Electronic CRFs and Technology Enhance Trial Oversight Increasing use of electronic CRFs opened the door to alternatives that provide more efficiencies and cost advantages than the SDV approach. The centralised risk-based monitoring alternative improves monitoring cost-effectiveness without compromising quality and integrity. It identifies trial areas at greatest risk and implements targeted measures and controls to manage trial quality. Additionally, risk-based monitoring helps improve clinical trial design, conduct, oversight, recording, and reporting, while ensuring human subject protection and reliability of trial results.

With ongoing RBM, cumulative data can be examined at subject and site levels, flagging potential errors that must be queried or systematic errors/errors in process that may occur at a site (e.g. measurements that look too low or too high compared to other sites).

The data monitoring team can then take remedial action. This could trigger an on-site monitoring visit, or further site training. Review of query rates by site, subject or form can reveal possible data quality issues. Quality tolerance limits (QTL) can be set and monitored to focus resources on vulnerable areas to guide the level of action required. Centralised monitoring as guided by the FDA1 and as per the EMA Reflection Paper2 is encouraged.

Key Risk Indicators Detect Potential Issues Key risk indicators (KRIs) are critical data and other study variables or operational data that can detect potential issues at site, country or trial levels. Operational data can highlight site level concerns but potentially limited direct impact on subject safety and data integrity.

They can be visualised in a dashboard format for ease of monitoring.

An example of a monitored query is duration of open queries.

OPEN QUERIES

Quality Tolerance Limit Can Trigger Investigations A quality tolerance limit is a level, point, or value associated with a trial variable that should trigger an investigation if a deviation is detected in order to determine if there is a possible systematic issue 6 Journal for Clinical Studies

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issue at that site, but unusually low levels of deviations may indicate under-reporting. QTLs should identify both. Investigations made in real time increase the chance of determining root causes.

Easy data visualisation against the QTL is key to successful RBM implementation. The above example may be plotted against calculated limits to identify breaches and may be seen easily in a dashboard format.

Statistical Methods can Help Identify Patterns Centralised monitoring provides access to cumulative data across sites. The use of statistical methods helps find unusual or implausible patterns in the data to indicate potential manipulation or rates of adverse events (AEs): if one site has a low rate of AEs comparatively, this might indicate under-reporting, or difficulty in how to classify AEs based on symptoms, which should flag further investigation.

• •

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Lack of variability: if a site or subject shows much less variability in a measurement than other subjects/sites, this may indicate the data is not real and trigger further investigation.

Digit preference: data that are invented by people tend to show preferences for certain numbers, like rounding up. Data can be examined to see if the rates of any of the digits are higher than expected.

Inliers: clusters of values very close to the mean may indicate fabricated data.

Centralised Risk-based Monitoring – A Successful Clinical Trial In summary, centralised risk-based monitoring helps streamline trials while alleviating labour-intensive and costly SDVs. At the same time, it improves data quality by guiding and prioritising site visits www.jforcs.com

and setting and monitoring quality tolerance limits using statistical methods. All this adds up to the Good Clinical Practice mission of strict oversight and improved and more efficient approaches to clinical trial design, conduct, oversight, recording, and reporting, whilst ensuring participant safety and clinical study data accuracy and completeness.

REFERENCES 1.

2.

Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based approach to monitoring, Draft Guidance. http://www.fda.gov/downloads/ Drugs/Guidances/UCM269919.pdf EMA Reflection paper on Risk-based Quality Management in Clinical Trials. www.ema.europa.eu/docs/en_GB/document_library/.../11/WC50015 5491.pdf

Sheelagh Aird Sheelagh Aird, Head of Clinical Data Operations at PHASTAR. With more than 30 years of experience in clinical data management, Sheelagh has directed and delivered projects in all phases of clinical trials across numerous therapeutic areas. She has led PHASTAR’s Data Management group since 2016. Sheelagh holds a BSC in pharmacology and doctorate in pharmacokinetics from the University of Bath.

Email: sheelagh.aird@phastar.com

Journal for Clinical Studies 7

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Industry Drive to Improve Information Exchange and Speed Study Start-up Last year, the European Medicines Agency recommended 84 medicines for marketing authorisation. Half of these medicines (42) contained a new active substance that had never been authorised in the EU before1. Furthermore, in the last 10 years, the number of registered clinical trials globally has increased five-fold2. Innovation is accelerating, yet the time it takes to run a trial is no faster. As life sciences companies take action to speed up study execution, there is a significant opportunity to make clinical research processes more efficient.

Industry adoption of function-specific technologies is improving clinical trial execution and fuelling progress, according to the Veeva 2019 Unified Clinical Operations Survey. The research shows that standalone applications such as electronic data capture (EDC), electronic trial master files (eTMF), and clinical trial management systems (CTMS) are now utilised by the majority of sponsors, CROs, and research sites. However, fragmented processes and siloed systems are still slowing trials. These fragmented processes cause numerous issues, including making reporting across different applications difficult, according to survey respondents. This reinforces the need to move to unified systems for better visibility and faster execution.

With advances in science revolutionising the clinical industry, there are now even more opportunities for research sites, academics, CROs, and sponsors to automate information exchange, streamline processes, and utilise new technology and data to increase the speed of drug development.

The two key areas that present a tremendous opportunity to drive greater efficiency and speed trials are improving information exchange among study partners and accelerating study start-up.

Improving Information Exchange Boosts Collaboration Developments in personalised medicine, genomics-based research, and immuno-oncology, have revolutionised the clinical industry. However, there is still room for evolution in sharing information between organisations working together across the clinical environment. The industry’s increased interest in a new class of medicines is also leading to new challenges across the drug development process that slow down trial execution. One of the main issues affecting speed is collaboration.

practices. CROs have helped to make trials more efficient but adding partners to the mix has also introduced growing complexity.

Sponsors and CROs use an average of three methods to share trial data and documents, including email, portals, and file share.

Exchanging information with sites becomes even more complex, with 78% of sponsors and 74% of CROs relying on email to share information with sites. And many still rely on paper shipments.

In fact, half of sponsors, and a third of CROs, reported this as a major method to exchange with sites. Not surprisingly, due to manual methods of data exchange, respondents have challenges with tracking, reporting, and misfiled and/or missing documents.

These traditional administrative methods stifle the ability for sites to quickly execute trials.

Streamlining Information Exchange Without connected technology systems, clinical research sites also find it difficult to share data seamlessly with trial partners. Therefore, sponsors must invest more into sophisticated technologies that will help to make sites more efficient.

Sites are forced to learn the systems and adapt to different ways of formatting and submitting information depending on which sponsor they are working with on any given trial. Multiple systems mean multiple, individual logins are required to manage trials, which also slows trial execution.

Adopting a streamlined approach to exchange information can enable sponsors, CROs, and sites to improve collaboration and speed trial execution by reducing administrative burden.

How to Accelerate Study Start-up Study start-up is one of the most critical parts of the study process

Survey respondents identified information exchange during trials as a major challenge. In fact, all respondents highlighted it as an area for improvement. Sponsors, CROs, and research sites still struggle to exchange the most basic of information in a standard, consistent way. They are motivated to improve information exchange by the potential to reduce manual processes, improve collaboration, and increase visibility and oversight, during clinical trials.

Efficient Collaboration is Key to Reducing Trial Times Sponsors are increasingly partnering with CROs to drive greater efficiency, augment available resources, and leverage best trial 8 Journal for Clinical Studies

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Watch Pages forced to wait for signatures on financial disclosures. E-signatures allow stakeholders to sign off documents instantly. Eliminating siloed systems, like manual signatures, in favour of streamlined applications allows for greater agility and stronger collaboration, whilst enhancing compliance and end-to-end control.

and can have a significant impact on the overall speed of a clinical trial. While science has rapidly advanced, the resource-intensive study start-up phase of clinical trials still runs at the same speed as a decade ago3.

Frustration with study start-up is widespread, likely due to the heavy reliance on manual processes. Most still use spreadsheets to manage this area, with 81% of respondents reporting spreadsheets as their primary start-up tool. The use of spreadsheets in the study start-up phase is a challenge because manual methods slow down processes and limit visibility into status.

Utilising digital tools in the study start-up process enables CROs to be more responsive and coordinate actions more efficiently.

A recent global survey carried out by Deloitte and MIT Sloan Management Review4 found only 20% of biopharma companies are expanding their use of digital tools. This highlights the extent to which the life sciences industry still trails other industries in adopting new technological solutions to enable timely delivery of information to stakeholders.

The shift to adopt study start-up applications is also on the rise. In fact, nearly a quarter of respondents reported adoption of newer, purpose-built study start-up applications to speed cycle times. This shift will streamline study start-up, enable trials to run more quickly, and allow for faster enrolment of patients. This was reflected in the majority of respondents citing faster study start-up times as the primary driver to improve the study start-up process.

The use of e-signatures can also facilitate faster trial execution.

Studies are further slowed down when sponsors and CROs are

Digitisation and Developments in Healthcare Technology will Impact Trials The life sciences industry gathers large amounts of data during the development of a treatment or therapy. With advances in personalised medicines, telehealth and medical devices, there is potential for new technologies to change the way we conduct trials.

Using wearables, for instance, could help to extend the scope to enrol patient populations that are smaller and widely dispersed.

Used effectively, data from these types of technologies can help the life sciences industry learn how to best develop trials that maximise the patient’s utility. In addition, wearable tech can help to further understand disease states and how drugs function.

The Journey to Streamlining Study Execution Sponsors and CROs recognise and are committed to the significant opportunity to improve the way trials are run and are committed to improving trial efficiency, visibility, and collaboration. Therefore, we are seeing progress in the adoption of advanced clinical applications. Better alignment amongst stakeholders will make drug development more efficient and accelerate time to market.

The continuous advancements in scientific innovations will mean that advanced cloud-based platforms and data analytics technology can help processes to keep up with speed drug development. Time is crucial; manual processes can affect patients awaiting life-saving therapy. The move to a unified clinical landscape offers a solution.

REFERENCES 1.

2.

3.

4.

European Medicines Agency, Human medicines: highlights of 2018, published 4 Jan 2019. Available at: www.ema.europa.eu U.S. National Library of Medicine. Clinical Trials.gov. Available at: www. clinicaltrials.gov Lamberti, MJ, Chakravarthy, R, Getz, KA. Assessing Practices & Inefficiencies with Site Selection, Study Start-Up, and Site Activation.

Applied Clinical Trials, August 2016 https://www2.deloitte.com/us/en/insights/industry/life-sciences/ digital-transformation-biopharma.html

Rik van Mol Rik is VP responsible for the Veeva Vault R&D suite of applications with a focus on the European market. He has nearly 20 years’ experience in business/IT consulting and regulated content management in the Life Sciences / Pharmaceutical sector. His experience has been built in assisting clients through complex transformational programs across the Life Sciences value chain, including clinical, regulatory and manufacturing/supply chain areas, for some of the world’s largest companies. Prior to joining Veeva, Rik was a leader in IBM’s (PwC) Life Sciences Global Business Services Practice, where he was responsible for managing a consulting team focused on life sciences technology innovation, compliance and regulated content management. Rik holds a master's degree in Commercial Sciences and Information Technology Management from the University of Leuven / EHSAL.

www.jforcs.com

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Building Bridges Towards Patient Clinical Studies: Critical Considerations in the Drug Development Process Early-phase clinical trials, known as human pharmacology studies, start principally with the aim of collecting information on the safety and tolerability of the drug product. However, the ultimate objective of any drug development programme is to deliver a drug product that is safe and shows a positive benefit/ risk balance for treatment of the target patient population.

The International Council of Harmonisation (ICH) E8(R1) draft guideline “General Considerations for Clinical Studies”, outlines that the cardinal logic behind serially conducted studies is that the results of prior studies should inform the plan of subsequent studies.

Scientifically sound bridges should, therefore, be established, linking human pharmacology studies to initial exploratory studies and later confirmatory studies. This advancement through the late-phase life cycle development of the drug product is performed by collecting precise data during the early-phase clinical trials that are performed, in the majority of cases, in healthy volunteers. But what can be done to ensure these bridges are scientifically sound?

Firstly, the investigation of possible biomarkers, or surrogate markers, is one of the measures that could help to better understand the mode of action of a new drug and assist in the prediction of the efficacy in patients in the later stages.

Additionally, modelling and simulation of clinical trials can be very useful in some cases to extrapolate data from healthy volunteers to predict the efficacy and drug behaviour in patients. These models can be disease-based, or use predictive pharmacokinetics (PK)/ pharmacodynamics (PD) data, or be complex mechanistic models.

The most effective strategy in order to provide accurate information on efficacy of the drug product remains to involve patients as soon as possible in clinical studies. Obviously, in some cases this approach is mandatory, such as for genotoxic oncology drugs where administration of the drug product is a serious risk to healthy individuals. In other cases, a combined protocol in order to assess the preliminary efficacy of the drug product can be carried out to follow up an early-phase clinical trial in healthy volunteers, and the drug product can be investigated in patients after a short duration of drug exposure to a limited number of patients with target indication, or sub-population of patients. This approach has also been endorsed in the ICH E8(R1) draft guideline, justifying the involvement of patients early in human pharmacology studies, but depends on the drug’s properties and the objectives of the drug development programme.

The scientific aspects below should be studied carefully and addressed during the development of the study design for various early-phase studies in patients, as well as for later clinical development plans: • To determine the safe dose range that could be used in early clinical studies in patients, ensuring the dose can be tolerated and is high enough to be effective.

• To investigate any foreseeable adverse events in the target population for treatment.

• To establish and understand the pharmacokinetic properties of the drug product (absorption, distribution, metabolism, and excretion; ADME), as early as possible in the target patient population, so that the dosing regimen can be improved.

10 Journal for Clinical Studies

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To collect as much pharmacodynamics and efficacy data as possible in early patient trials to benefit late-phase clinical development.

The proof-of-concept studies in the intended target patient population should collect data to enable the safe and effective dose and regimen to be defined and be used in subsequent confirmatory studies.

Case Study 1 A first-in-human (FIH) study of an intra-articular administered investigational medicinal product for pain caused by osteoarthritis was being planned to assess the maximum tolerated dose. The potential issue was that the maximum tolerated dose could vary in patients with knee pain compared to healthy volunteers, and because of the intended mode of administration, it was considered unethical to conduct the FIH study in healthy volunteers without osteoarthritis.

The FIH study was conducted in 20 patients with osteoarthritic knee pain with a pain score of at least 4 on the visual analogue scale.

The study allowed not only the tolerability of multiple doses of the product in patients to be assessed, but also have a first indication of the analgesic effect of the compound at several doses in the actual target population. The result was that the potential therapeutic benefit could be determined and enabled the easy and rapid bridging to a larger dose-confirmation and proof of efficacy Phase II trial.

Case Study 2 A trial was required to be designed to allow an FIH single ascending dose/multiple ascending dose study in healthy volunteers and a proof-of-concept Phase II study in post-menopausal women with vasomotor symptoms. The objectives of these studies were to evaluate the safety and tolerability of different dosages, as well as collecting PK and PD information defined as effects on sex hormones and luteinising hormone (LH) and follicle stimulating hormone (FSH) levels. These data were considered as the scientific basis for the design of the later proof-of-concept study in patients and justifications for dose selections.

The Phase II study involved approximately 90 post-menopausal women with vasomotor symptoms, and using the PK/PD response data in the healthy volunteer studies, in combination with the available safety data of each dose level, a correct dose selection was decided upon in the Phase II trial. The results from this trial gave a clear first proof-of-efficacy result and led to the appropriate dose selection for the Phase III study.

Arash Ghalamkarpour Arash Ghalamkarpour is an MD and holds a Ph.D. in Biomedical Sciences. He has more than 10 years of experience in clinical research, and for the past 4 years, has held the role of Associate Medical Director at SGS, where his main responsibilities include supporting the medical and scientific needs of clinical development programmes, and feasibility assessment for patient studies.

Email: lss.info@sgs.com

Volume 12 Issue 2

Corporate Profile Ramus Corporate Group

is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in 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.

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• • • • • • • • • • •

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

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 11 11

Watch Pages

Getting Your Bad News Early Will Ensure You Don’t Fail Tomorrow It is extremely rare for CROs to move seamlessly through an entire clinical trial without encountering some problems or hurdles. But what you don’t want is a situation where the challenges are becoming systemic risks and the trial becomes in need of rescue. Even the best and most capable CROs can experience challenges should they fail to undertake additional planning, particularly for trials that are concerned with rare and complex diseases. Common problems include poor patient recruitment and retention, an unmotivated staff and site team, lack/loss of resources and concerns over the integrity of clinical data can all lead to trials falling behind schedule or even failure. In fact, it is estimated that around 70% of clinical studies are at least a month behind schedule, with sponsors losing between $660,000 – $8 million for each day the trial delays product launch1.

But don’t be too perturbed – with a good relationship, contingency planning and proper resource allocation, the CRO and sponsor can work together to overcome the vast majority of problems in a timely fashion. In this article, we will look at those unfortunate times when despite your best efforts, a rescue study and new CRO are needed. We will walk through some practical examples of how to go about planning and undertaking a rescue so that you can continue to advance your product towards clinic. In these situations, you may be looking at full or partial transition to a new CRO, and we will explore how to do this whilst minimizing disruption to the trial.

For example, in one recent case we were required to come-in during a large phase III clinical study on a women’s health target, taking over from a global CRO. The initial study goals were to compare a new drug to a placebo in order to determine its effect in preventing pre-term labor and neonatal mortality and morbidity.

The sponsor decided that the study needed rescuing because they became frustrated with the change orders from the originally selected CRO. In addition to this, they felt that the CRO Project Manager was not proactively communicating with the sponsor when it came to handling and solving issues that arose throughout the study.

The main challenge for the sponsor was how to get the trial properly back on schedule, and the project was beset by a number of complex challenges including the closure of non-enrolling sites and the cancellation of all site and vendor contracts – forcing a time consuming and debilitating process of renegotiation. To overcome this, a rapid response team of experienced professionals were deployed to manage an increasingly intricate and detailed process to facilitate an on-schedule transition – starting with tying vendors, irrespective of the volume discounting they provided to the previous CRO (preferred pricing), to previous pricing. Several Outside of United States sites were also closed at transition, with more to follow after – leaving the challenge of filling the enrollment and placebo-controlled groups.

One of the first courses of action saw the data management team transferring all paper records to Electronic Data Capture 12 Journal for Clinical Studies

(EDC) systems. However, this then required the trial to be in a hybrid data collection state for a portion of the trial, further increasing the logistical challenges. The next stage was to complete five batch locks, while ensuring older clinical data had undergone all data cleaning processes, and had been reviewed by the entire project team in anticipation for the final database lock. In addition to this, the drug received US approval during the course of the study, resulting in an understandable but huge loss in enrollment from US sites (which were the highest enrollers at this point). In response, it was necessary to quickly find new sites globally to make up for this loss; with similar demographics and a good supply of willing participants Eastern Europe was seen as the best chance of progressing the study quickly. After informing the sponsor of the new challenges, the cost of expansion in Eastern Europe was mitigated by the closure of non-enrolling sites in the US. It was a complex trail, which by completion, had seen over 1,700 patients enrolled at over 70 sites in eight different countries – the US, Canada, Czech Republic, Hungary, Italy, Russia, Spain and Ukraine.

In another project, a Phase III Pediatric Cardiothoracic Surgery study, we were contracted to undertake a rescue after the project’s start-up stalled over the course of a year. The sponsor was driven to drastic action by multiple staff changes at the CRO (which naturally presented continuity issues), but more crucially reoccurring errors within key study documents, despite their continued best efforts.

The study’s aim was to evaluate the safety and effectiveness of a drug that may help reduce complications of acute lung injury for pediatric subjects undergoing surgery for congenital heart defects. After so many changes enrollment rates were lagging far behind the sponsor’s timeline, a situation exacerbated by an extremely small patient population and the acute nature of the condition.

The immediate challenges for the rescue was to understand where the study currently stood and what roles and responsibilities were needed. Identifying the most critical aspects of the study to address first, and then devise the necessary short and intermediate term plans. Rather than trying to ‘dive straight in’ so to speak, it was crucial to the study’s long-term success that we started with a two-day intensive planning meeting alongside the sponsor, followed by weekly update meetings before revising and refining the new plan. It’s at this stage that an experienced team must hold firm, ensure the Sponsor it’s not ‘more wasted time’ and build the rapport that will sustain the next stage. It is always better to get the planning right first time, rather than have to redo work as the project progresses. Time ‘sacrificed’ here will deliver vast savings later in the project and could literally be the difference between success and failure.

After the initial planning stage was complete, we actioned the data management team to transition the database and complete all data-related validation and documentation. Another area they had to look at was assisting the sponsor and clinical team with modifications to the clinical database, which had a very Volume 12 Issue 2

Watch Pages

dense casebook and multiple local labs. They also needed to audit sites to identify barriers to recruiting subjects in the ICF (informed consent form) and modify the document accordingly – again a process that will deliver an expedited recruitment once the initial work is complete. Meanwhile, the clinical monitoring team launched a multi-pronged enhancement plan that involved site visits by the medical monitor as well as recruiting tools and dear doctor letters – collectively this lead to an almost immediate impact on enrollment. The time used in the extra planning ultimately delivered a trial that finished ahead of even the sponsor’s corporate stretch goal – by over a week.

So, what are the biggest takeaways you ask from these differing studies? It may sound cliched and an often-repeated mantra for at WuXi Clinical, but the strength of the relationship between CRO and sponsor is critical. It’s the single biggest advice we can pass on to anyone – get the team core right and by that we mean sponsor, site and CRO. Trust is therefore the first priority, followed by the experience of the day-to-day team (make sure the people that wow you in the pitch are the same people you get the week after), and be prepared for a CRO that pushes back early (not one that finds excuses later). You might not always like what you hear, but it is often what you need. It’s www.jforcs.com

much better to have someone that will under promise and overdeliver. In a rescue, you want all your bad news as earlier as possible, and then from here, you can trust things will improve – and often rapidly.

REFERENCES 1.

https://www.atlantclinical.com/rescue-studies

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.

Journal for Clinical Studies 13

Regulatory

Regulatory Watch: Rare Disease Day Approvals of orphan drugs have risen significantly over the past two years. The Alliance for Regenerative Medicine said in a report that, at the end of 2019, there were 647 ongoing clinical trials in rare diseases. Of the total, 252 are Phase I trials; 353 are Phase II trials, and 42 are Phase III trials. These trials focus primarily on gene-modified therapies, cell-based IO therapies, cell therapy and tissue engineering.1 29 February 2020 was the thirteenth international Rare Disease Day coordinated by EURORDIS2. On and around this day, hundreds of patient organisations from countries and regions all over the world hold rare disease awareness-raising activities.

In honour of the day and to continue their long-standing dialogue with the rare disease community, the FDA held their Rare Disease Day 2020 public meeting3 on 24 February, aimed at “Supporting the Future of Rare Disease Product Development.”

The day brought together stakeholders to address challenges and opportunities surrounding rare disease product development, and showcased FDA centres’ updates and current thinking. The FDA wanted to hear from rare disease stakeholders on strategies to optimise registry and natural history data collection. It also wanted to hear about opportunities and challenges when developing medical products for diseases or conditions that only affect one person, or just a few.

Additionally, in February, the FDA announced their ongoing commitment in this space, in addition to announcing three new actions4 to support the development of new treatments and support for those living with rare diseases.

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New request for applications (RFA)5 for the Orphan Products Grants Program6. The FDA funds research in rare diseases through congressionally mandated programmes like the Orphan Products Grants Program that supports natural history studies and clinical trials for rare diseases. This new RFA includes “increased clarity of funding goals, continued emphasis on efficiency in all phases of product development and added focus to including patient input into study designs, building successful infrastructure, and leveraging financial resources.”

Additional information on orphan “exclusivity protected uses.”

This will make information about orphan drug designations and differences between an approved indication and the exclusivity protected indication clearer for patients, providers and drug developers website7.

Enhanced rare disease patient website. An enhanced rare disease patient website improved online presence8 to help patients and their families better navigate the FDA’s organisation and its offices supporting the rare disease space.

14 Journal for Clinical Studies

The morning started with opening remarks from Amy Abernethy, MD, PhD, Principal Deputy Commissioner and Acting Chief Information Officer, FDA and moved swiftly onto the first topic for discussion on “Strategies to Optimise Registry and Natural History Data to Support Rare Disease Product Development”. The first session’s goals were to provide perspectives on regulatory considerations related to natural history and registry data. The session was moderated by Erika Torjusen, MD, MHS, Director of the Rare Pediatric Disease and Humanitarian Use Device Designation Programs and Pediatric Device Consortia Grants Program, OOPD, FDA, and had panellists including: Wilson Bryan, MD, Director, Office of Tissues and Advanced Therapies (OTAT), Center for Biologics Evaluation and Research (CBER), FDA, Daniel Caños, PhD, MPH, Acting Director, Office of Clinical Evidence and Analysis, Office of Product Evaluation and Quality, Center for Devices and Radiological Health (CDRH), FDA, Stein, MD, Director, Office of New Drugs and Acting Director for Rare Disease Group, Office of New Drugs (OND), Center for Drugs Evaluation and Research (CDER), FDA. The second session, Natural History and Registry Data in Rare Diseases, had the goals of outlining the importance of collaboration to support successful registries and natural history studies; identifying common challenges and strategies to address these challenges and to consider the types of data that are being collected, and the intended use of the data. The moderator for this session was Theresa Mullin, PhD, Associate Director for Strategic Initiatives, CDER and panellists included: Kathleen Donohue, MD, Clinical Team Leader, Division of Gastroenterology and Inborn Errors Products (DGIEP), OND, CDER, FDA; Jen Farmer, MS, Chief Executive Officer, Friedreich’s Ataxia Research Alliance; Petra Kaufmann, MD, MSc, Vice President R&D, Translational Medicine, AveXis, a Novartis company; Anne Pariser, MD, Director, Office of Rare Disease Research, National Center for Advancing Translational Sciences, National Institutes of Health and Klaus Romero, MD, MS, Executive Director Clinical Pharmacology and Quantitative Medicine, Critical Path Institute.

In the afternoon, the public meeting continued with the topic titled: Rare Disease Product Development: New Opportunities and Challenges. The first of two sessions in this topic was a discussion with FDA Center Directors providing their perspectives on new challenges and solutions for rare disease product development.

Stephen Hahn, the FDA commissioner, stressed the importance of driving rare disease drug development by unleashing the data from very small populations, that is allowing for the modernisation of FDA’s approach. FDA has had to revisit an initial decision due to the new data being presented. He spoke to the fact that there was a need to integrate more data sources. It was also stressed that the patient had a voice at the table; FDA was more open to hearing what patients want.

Peter Marks, Director of FDA’s Center for Biologics Evaluation and Research, Janet Woodcock, director of FDA’s Center for Drug Volume 12 Issue 2

Regulatory Evaluation and Research, and Jeff Shuren, director of FDA’s Center for Devices and Radiological Health, discussed what their centres are working on with respect to rare diseases.

CDER stressed that the greatest challenge was that not enough was known about rare diseases and not enough patients can be found to enroll for trials. The need to develop more registries and natural history studies was reinforced. It was also noted that FDA has received a number of applications with a single patient in mind and that new policies are coming.

CBER discussed some of the difficulties that companies have in manufacturing cell and gene therapies for such small populations, and how even the not-so-rare diseases become rare when they are split apart into their different genetic mutations. CBER is working on guidance to help companies in cases where a product made with one manufacturing technique can be slightly modified to address a different disease, and whether the drug-maker will be able to just modify that initial application.

On the device side, CDRH discussed the need for new, progressive approvals. It was noted how companies’ return on investments can be difficult in the rare disease space because as soon as a new device is brought to market, other companies can re-engineer around intellectual property, making exclusivity periods “generally meaningless”. He also noted that there have not been a lot of devices developed under the Humanitarian Device Exemption pathway, noting that there had been “very little innovation” in the paediatric device space.

The next session, Perspectives on Individualised Therapies, had the goal of providing various perspectives on individualised therapies, with an emphasis on regulatory considerations. Panellists included Ella Balasa, a patient with cystic fibrosis and recipient of phage therapy, Virginia Commonwealth University; Patroula Smpokou, MD, Clinical Team Leader, DGIEP, OND, CDER, FDA; Julia Vitarello, Founder and CEO, Mila’s Miracle Foundation; Celia Witten, PhD, MD, Deputy Director, CBER, FDA and Timothy Yu, MD, PhD, Attending Physician, Division of Genetics and Genomics, Assistant Professor in Pediatrics, Harvard Medical School.

The session of the Ecosystem of Rare Disease Product Development considered the importance of collaboration to support successful strategies in rare disease product development, discussing factors and considerations in the ecosystem of rare disease product development. The moderator was Susan McCune, MD, Director, Office of Pediatric Therapeutics, FDA. Panellists included Christopher P. Austin, MD, Director, National Center for Advancing Translational Sciences, National Institute of Health; Martha Donoghue, MD, Clinical Lead, Gastrointestinal Cancer Team, Division of Oncology, Office of Oncologic Diseases, FDA; Sheila Mikhail, JD, MBA, CEO, Co-Founder, AskBio; Vasum Peiris, MD, MPH, Chief Medical Officer and Director – Pediatrics and Special Populations CDRH, FDA and Rhiannon Perry, a patient with sickle cell disease and lupus.

At the time of writing this article, the webcast recording can be viewed online9.

The FDA has approved drugs and biologics for more than 800 rare disease indications. In 2019, the agency approved 22 novel drugs and biologics with orphan drug designation. In CDER, 21 of the 48 novel drug approvals were orphan products. In CBER, one of the five novel biologic approvals was an orphan product.

Since 1990, CDRH has approved 77 medical devices for orphan indications under the Humanitarian Device Exemption program. In www.jforcs.com

2019, the FDA approved three devices in the programme. CDRH is also currently working with stakeholders from across the medical device ecosystem to vet and further develop a framework, coined ‘SHIP’ (System of Hospitals for Innovation in Pediatrics), designed to incentivise device development for paediatric and small populations.

Later this year, FDA will begin accepting applications for orphan drug designation through an online portal. The agency said the effort will build on the FDA’s Orphan Drug Modernization Plan from June 2017, and will streamline the orphan drug designation request process.

Through the initiatives and communications in this article, FDA and other regulatory authorities are making progress to meet the needs of the rare disease population.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

https://alliancerm.org/indication-data/rare-disease-2019-pdf https://www.rarediseaseday.org/ https://www.federalregister.gov/documents/2020/01/21/2020-00829/ food-and-drug-administration-rare-disease-day-2020-supporting-thefuture-of-rare-disease-product https://www.fda.gov/news-events/fda-voices-perspectives-fdaleadership-and-experts/rare-disease-day-2020-fda-continuesimportant-work-treatments-rare-diseases https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-21-001.html https://www.fda.gov/industry/developing-products-rare-diseasesconditions/orphan-products-clinical-trials-grants-program https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ https://www.fda.gov/patients/rare-diseases-fda http://fda.yorkcast.com/webcast/Play/465f9f72411b41139af25df30f84b8 d51d

Aman Khera Aman Khera is the 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 commercialization.

Email: aman.khera@worldwide.com

Journal for Clinical Studies 15

Regulatory

FDA Focuses Efforts on Making Patient Perspectives Count During the last eight years, the US Food and Drug Administration (FDA) has been increasingly focused on realising a vision – to incorporate patient input in drug development and regulatory decision making as standard practice.

In 2012, the FDA established the Patient-Focused Drug Development (PFDD) initiative, via the Food and Drug Administration Safety and Innovation Act (FDASIA) and the reauthorisation of the Prescription Drug User Fee Act (PDUFA), to more systematically obtain the patient perspective on specific diseases and their currently available treatments. Under the fifth authorisation of PDUFA (PDUFA V; fiscal years [FYs] 20132017), the FDA conducted 24 disease-specific PFDD meetings.

After PDUFA V (FY 2018 and onward), the agency hosted two additional PFDD meetings. Thus far in 2020, two PFDD meetings were planned (March 10, on stimulant use disorder; March 30, on vitiligo), but both were postponed by the FDA “due to extenuating circumstances.”

In the meeting notice for several of the FDA’s originally scheduled meetings for 2020, the agency has posted the following announcement: “The FDA, like other government agencies, is taking the necessary steps to ensure the agency is prepared to continue our vital public health mission in the event that our day-to-day operations are impacted by the COVID-19 public health emergency. Therefore, we are cancelling or postponing all non-essential meetings through the month of April. We will reassess on an ongoing basis for future months. Where possible the agency will leverage technology to host meetings allowing for remote participation.”

According to the FDA, patients “are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation” because they live with their condition. With this backdrop, the agency has continued its efforts to help strengthen the “patient voice” in medical product development and regulatory decision-making.

of measures. Also, FDA reviewers at times may receive multiple independent COAs to review. In addition, Bent said, the FDA has noticed variability in quality of the tools and the resulting data.

With that in mind, the FDA developed the COA/endpoints grant programme to: • • •

help make incorporating the patient perspective more sustainable; enable the development of publicly available standard core sets of measures of disease burden and treatment burden for a given area; and provide avenues to advance the use of patient input as an important part of drug development.

On September 11, 2019, the FDA made three awards under the COA/endpoints grant programme to advance the use of patient input as an important part of drug development that can foster innovation and the availability of safe and effective drugs. The awards cover the areas of 1) migraine, 2) acute pain in infants and young children, and 3) physical function across a range of chronic conditions.

Pragmatic Data Collection COAs are often endpoints in clinical trials used to support drug approval and labelling claims or other communications regarding clinical benefit. The FDA defines clinical benefit as a positive clinically meaningful effect of an intervention on how an individual feels, functions, or survives. The agency uses COAs primarily to determine whether a drug has been shown to provide clinical benefit to patients. COAs can also measure severity of side effects or treatment burden. A standard core set of COAs can include different types of COAs such as patient-reported outcome (PRO), clinician-reported outcome (ClinRO), observer-reported outcome (ObsRO), and performance outcome (PerfO) instruments and their related endpoints.

Giving the patient perspective at the December meeting was Katie Golden, a patient advocate who is living with chronic migraine disease. Golden is also the director of patient relations at the Coalition for Headache and Migraine Patients (CHAMP).

Golden emphasised the importance of getting the public to

A recent undertaking was initiated last fall, when the FDA launched a pilot grant programme – the Center for Drug Evaluation and Research (CDER) Standard Core Sets: Clinical Outcome Assessments (COAs) and Endpoints Grant Program (COAs/endpoints grant programme). Developed as part of the agency’s PFDD efforts, this programme was discussed at a public workshop in December 2019.

As PFDD efforts began maturing, the FDA noticed little coordination in work to develop COAs, including within a given disease area, said Robyn Bent, RN, MS, director of CDER’s PFDD programme and programme officer for the COAs/endpoints grant programme, at the December meeting. She said there is a considerable amount of duplication of efforts and numerous types 16 Journal for Clinical Studies

Volume 12 Issue 2

Regulatory understand “invisible illnesses” such as migraine, which can completely disable a patient who otherwise may not appear to be disabled.

Migraine covers a wide spectrum and presents differently in different people, Golden said. “I'm sitting here telling you that I have – in eight, almost nine years – I have not had a pain-free moment,” she said. “And you might not believe me because I'm wearing movie star sunglasses and, you know, I've curled my hair and I put my makeup on and I put a dress on… I look decent.”

Golden shared a visual – shaking her heavy medication bag – and said that, in her view, patients “would love to be able to lighten this load.” That could be done, she said, by having clinical outcomes geared toward what patients care about. She added that collecting real-world evidence (e.g., migraine during pregnancy) will be very important.

Golden is one of the members of the Expert Technical Advisory Committee for the migraine grant programme, which was presented at the December meeting by Richard Lipton, MD, Albert Einstein College of Medicine. Lipton noted that although there have been several migraine treatments approved, the field has continued to use the same endpoints over many years (Figure 1).

days, Lipton said. Echoing the concerns regarding acute treatment endpoints, he noted that challenges for preventive treatment endpoints include that they were developed without the patient voice and disability and QOL are neglected (Figure 2).

A public docket was opened for the December meeting, and a total of four comments were received. Among their comments, both Eric Olson, vice president, US product development regulatory, Genentech, Inc, and Danielle Friend, PhD, director, science and regulatory affairs, Biotechnology Innovation Organization (BIO), spoke to the importance of transparency and communication of learnings among stakeholders. They advised that the FDA develop “a centralised mechanism” to permit ongoing communication and interaction between all relevant stakeholders – including grantees, patients, drug developers, clinicians, regulators, and payers – to avoid duplication of efforts under the pilot grant programme.

Docket No. FDA-2019-N-5157 remained open until March 6, 2020.

Figure 1. Acute Treatment for Migraine – Regulatory Endpoints and Challenges Source: Presentation slides, Richard Lipton, MD, December 5, 2019

Lipton elaborated on the endpoints; for example, pain freedom measured at two hours post-treatment (2hPF) is a common acute treatment endpoint used in migraine. A challenge with this endpoint and the others, however, is that it was developed without the patient voice. “I’ve never seen a patient who says, well, what I really care about is what my level of pain is at two hours and I don’t care what happens before that and after that,” Lipton said. Another challenge is that relatively little attention is given to disability and quality of life (QOL).

On the prevention side for migraine, the usual primary endpoint is change from baseline in monthly migraine days or headache

Deborah Komlos Deborah Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis suite of life science intelligence solutions at Clarivate. In this role, her coverage centres on FDA advisory committee meetings, workshops, and product approvals. Her previous positions have included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work.

Figure 2. Preventive Treatment for Migraine — Regulatory Endpoints and Challenges Source: Presentation slides, Richard Lipton, MD, December 5, 2019 www.jforcs.com

Email: deborah.komlos@clarivate.com

Journal for Clinical Studies 17

Market Report

The Rise of Patient-centric Clinical Trials in Today’s Environment There is a growing movement within the industry to focus on patient-centricity in clinical trials. For example, the FDA and EMA have introduced requirements to include patient input into protocol design and provide lay summaries to patients at the end of trials. It’s becoming more apparent that reducing the patient’s burden by putting their needs at the centre of clinical trial development can have great rewards for both the patient and the sponsor. More recently, the COVID-19 crisis has demonstrated the importance of preparing and executing trials in a patient-centric way to ensure they have access to clinical trials, even in potentially unpredictable situations.

Patient-centricity is all about making it as easy as possible for patients to learn about and participate in clinical trials. It’s about identifying the challenges faced by patients (often the most practical things like transportation to visits and, in extreme circumstances like COVID-19, global barriers to healthcare access), and then taking steps to reduce these barriers.

Patient-centricity: Supporting Clinical Operations and Study Adherence When it comes to clinical trial participation, the main barriers faced by patients are geographical, financial, and practical. In terms of geography, sometimes the patient lives too far away from the study site to make it feasible for them to visit as often as is required for the trial. Data from Forte Research shows 70% of potential clinical trial participants live more than two hours away from their nearest study centre. In this case, we look at ways to make it easier for them to travel to the site or, if it is simply too difficult, we take elements of the study to them by using a decentralised trials (DCT) approach. With the COVID-19 health crisis, we have observed how global situations can unexpectedly impact the ability of patients to physically visit a site, which is another impetus for the increased consideration of decentralised trial approaches.

We created a Patient Innovation Centre to put the patient at the centre of the way we operate in terms of clinical trials. This approach considers each person’s life as a whole, rather than just focusing on their time as a patient, and we then take that human aspect into account when we run our trials, which is particularly important as we respond to changing health circumstances that further challenge patient access to new medicines.

Financially, the patient often has trouble covering the cost of getting to the clinical trial site. For instance, it may be too expensive for them to travel to a hospital site as often as they need to, or they can’t cover parking costs for the time they’re required to be there.

We work with them to lift that burden.

And practically, it can be very difficult for a patient to participate in a study with hours-long visit requirements. They must take time off work, arrange childcare, and postpone other tasks and errands necessary for daily living. Here, we can look at those practicalities for the patient and work to reduce the more burdensome elements within 18 Journal for Clinical Studies

the protocol where possible, or support with practical solutions where they are critical to the scientific integrity of the study.

By putting patients at the centre of trial planning and execution, it makes it easier for them to learn about the trial and understand its details so that they can fully grasp what it means for them. It allows them to make a truly informed decision about participation. And once they’re in the study, we’ve already looked at the potential barriers and addressed them so that the trial process is clear and simple, making it a much more positive experience for the patient.

Sponsors Also Reap the Rewards Patient-centricity benefits our sponsors as well. A simpler, more practical clinical trial protocol enhances recruitment and retention and leads to fewer protocol amendments, which, in turn, reduces trial cost. And if recruitment and retention are going well, there’s the potential to get the drug to market faster.

According to “The Innovation Imperative: The Future of Drug Research”, a report undertaken with The Economist Intelligence Unit (The EIU), drugs developed using patient-centric designs are 19% more likely to launch – they have an 87% chance of launch versus 68% for drugs developed without this approach. And when it comes to recruiting the first 100 participants, patient-centric clinical trials took only four months to do so, compared with the average of seven months for all trials.1 Through the Patient Innovation Centre, we proactively seek opportunities to address the needs of commercial stakeholders and build a better value story. In addition, our regulatory experts incorporate guidance to address agency requirements from a patient-centric perspective.

Collaboration with Patients and Caregivers is Key From the outset, our approach to decentralised clinical trials (DCTs) involves collaborating closely with patients, caregivers, clinical research sites, and patient advocacy organisations. Rather than assuming what the patient wants or needs, we ask the patients directly through global patient advisory boards and Patient Insights Methodology.

Our Patient Innovation Centre uses a combination of web listening and input from patients, caregivers, and site staff to get a clear picture of the key patient and caregiver burdens. We study the way patients talk about their disease and treatment options, elicit direct feedback from patients and caregivers through our patient advisory council, and consult with site staff to understand what is important to them and the challenges they face. From this, we design targeted decentralised trial strategies that take the needs and preferences of patients and caregivers into account and reduce the burden of participation. This can accelerate patient enrolment and supports retention.

To reduce the burden on patients when it comes to trial participation, Parexel’s decentralised clinical trials protocol can take parts of the trial to patients in their home. It includes elements Volume 12 Issue 2

Market Report such as online recruitment, home nursing, direct-to-patient drug shipments, patient apps, and sensors to enhance patient experience and compliance.

As a result of the COVID-19 crisis, we have seen a renewed enthusiasm to consider decentralised trials or hybrid approaches.

This is particularly from a regulatory perspective, where new guidance is coming out swiftly with a number of agencies proactively stating their preference for a DCT approach to support patients. The key to success in moving to a decentralised approach is prioritising trial standards and consistency to ensure patient safety.

Many sponsors are becoming more open to DCTs as they work to maintain patient safety and data quality, and we are working closely with sites and members of our patient advisory council to ensure that we’re keeping both the site and patient input top of mind as we shift a number of traditional trials to the home.

Our Patient Sensor Solution service builds and deploys strategies to continuously collect data through the use of sensors that remotely capture, transmit and store data in a secure cloud-based platform.

This way, the patients and their caregivers have the research brought to them without the geographical, financial, and practical burdens inherent in traditional clinical trials procedures.

Decentralised trials involve working in close partnership with clinical trial sites. We communicate with investigative site staff so they can tell us where they see trial participation as being challenging for patients, what types of communication will resonate most, and which trial elements can be deployed effectively in the home. This collaboration helps us make the study experience better for patients, so that participating in a clinical trial fits in with their personal circumstances. Our goal is to fit the trial as closely as possible to their regular routine, with minimal disruption to sites.

Even before the addition of a trial, patients spend so much time and effort managing their disease; the last thing we want to do is add further complications to their lives.

Listening to What Patients Really Want By conversing and collaborating with patients, we sometimes find that they want something that has not been considered in the study design. For example, we recently worked on a decentralised trial strategy for a long study with an intense visit schedule. Our initial assumption was that taking the trial to patients in the home would be beneficial, but we always work to test our assumptions with patients directly. So, we interviewed 1500 prospective patients and found that they overwhelmingly preferred to come into the clinic for the visits. They appreciated the extra care and attention from the staff and the close bonds formed through these long and frequent visits.

On another project with a study that required 17-hour site visits, we discovered that questionnaires for patients and caregivers related to an exploratory endpoint were responsible for five hours of those visits. So, we worked with the sponsor to support the adjustment of the protocol, balancing the burden on participants against the scientific needs of the study.

Paediatrics and rare disease studies are two of the areas where we are most active from a patient-centric perspective, often deploying decentralised trials to improve access to care and help patients and their families manage participation as part of their daily lives. When kids are participating in trials, it’s very difficult for them to take long periods of time away from school. Parents of a sick child often have other children to care for as well, so it can be problematic for them to arrange childcare for the extended periods required to participate in studies. And, in the case of children with autism or other special needs, it can be extremely difficult, if not impossible, to travel over long distances to reach a clinical site. In those cases, having a nurse visit the home versus having to travel is a game-changer. www.jforcs.com

Patients Beyond the Clinical Trial Our work with patient engagement is relentless. We continue to talk with patients through our advocacy group connections, patient advisory council and Patient Insights Methodology projects. Recently, our CEO and Chief Medical and Scientific Officer both joined our patient advisory groups in the US and EU to listen to patient input and understand the patient point of view, helping us to continue to improve the trial experience for patients.

We also continue to look beyond the study. How can the patient continue to access the drug when participation ends? When will it be available on the market? How can we help patients understand study outcomes and ways to transition to a post-study treatment plan? How can we continue to support patients through our managed access programmes to facilitate early access to promising new medicines for patients with unmet needs?

Our responsibility doesn’t end with that last visit. The patient has given us their time and dedication, so we feel it’s important to give them our gratitude and continued attention.

What’s Next for Patient-centric Trials The many benefits to patient-centric decentralised clinical trials are clear. Yet the report found that only about 5% of the Phase II and III trials conducted over a five-year period employed patient-centric approaches. With the advent of COVID-19, companies are quickly rethinking the benefits of considering decentralised or hybrid approaches.

For the most part, our clients agree that patient-centricity is important and that it holds great potential, but they often don’t know where to start. Our Patient Innovation Centre can help sponsors to shorten that learning curve considerably and we continue to provide consultancy, partnership and support to continue the development of this critical area of the R&D process.

REFERENCES 1.

https://druginnovation.eiu.com/

Rosamund Round Rosamund Round is Vice President of Parexel’s Patient Innovation Center and spends her time devoted to simplifying the patient journey in clinical trials. Focused on the reduction of geographical, financial and practical barriers to study participation, Rosamund is excited by the industry shift towards a truly patient centric approach. Her first job in an oncology clinic at Massachusetts General Hospital (USA), sparked her passion for putting patients at the center of clinical research planning and implementation. Subsequent roles in patient recruitment in both the pharma and CRO industries have enabled her to innovate and explore better ways to communicate with patients. This includes addressing literacy and health literacy, exploring technological advancements, and constantly scanning the environment to help generate new ideas to make clinical trial participation more accessible and convenient. Always looking for the next best thing in patient recruitment, Rosamund is delighted to share her learnings around patient centricity and innovation in patient engagement.

Email: rosamund.round@parexel.com

Journal for Clinical Studies 19

Market Report

Review Phase Assessment for ANDA Submission in US: A Regulatory Review Abstract: Today, the vast majority of drugs available for patient in the United States are generics. They have gone through a rigorous system of evaluation, supervised by the United States Food and Drug Administration (FDA), to ensure the drugs are safe and efficacious. USFDA is one of the most regulated agencies, wherein the submission process is critical. Generic medicines are those where patent protection has expired of innovator drugs, and which have been placed on the market at a lesser price but with therapeutic action, safety and efficacy. The accessibility of generics made easier to the public. This study considers how to submit an ANDA application as per FDA requirements and review phase with a discussion of ANDAs, and its similarity and differences with NDAs. Applicants should submit information showing the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent. By law, generics must be shown to be safe and effective before they can be approved by the agency for marketing. After submission, CDER reviews the application by issuing queries within the scheduled timeline: information request (IR), discipline request letter (DRL), and complete response letter (CRL), which accelerate the approval of the ANDA application.

Key words: CDER, ANDA, information request (IR), discipline request letter (DRL), and complete response letter (CRL) Introduction The Food and Drug Administration (FDA) is a regulatory agency of the United States Department of Health and Human Services, a federal executive department1. It is composed of seven centres responsible for ensuring the safety, efficacy, oversight and security of the nation's human and veterinary drugs, tobacco products, biological products, medical devices, food, cosmetics and products that emit radiation2. The mission of FDA's Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective. In the ANDA submission, FDA CDER does not test drugs, although the Center's Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness3. The agency considers a generic drug to be “identical, or bioequivalent, to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use”4. The generic drug comes onto the market once the patent ends or the patent owner waives his rights, and the FDA requirements are met. Once the generic drug becomes available, the market competition is increased, hence the prices of both the generic and the original brand are lowered. Generic drugs are usually sold at a much lower price compared to the original brand drug5. The FDA is also responsible for advancing public health by helping with innovations that make medicines and food more effective, safer and more affordable, and helping the public to get proper, scientific information about food and medicines to improve their health6.

Abbreviated New Drug Application (ANDA) An abbreviated new drug application (ANDA) contains data 20 Journal for Clinical Studies

which is submitted to FDA for the review and potential approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, lower-cost alternative to the brand-name drug it references7. Once the ANDA is approved, the manufacturer can market the safe, effective and less expensive generic version.

Generic drug applications are referred to as “abbreviated” because they are not required to submit any clinical and animal studies to prove their safety and efficacy. The generic drugs are scientifically proven to have the same properties as those of the innovator drug.

To demonstrate that a generic drug is similar to the innovator drug is to measure the bioavailability of the drug in the systemic circulation of healthy volunteers. Bioavailability, the rate of absorption of the generic drug, will be evaluated by conducting a ‘bioequivalence’ study and is compared to the branded drug.

To be approved by the FDA, the amount of active ingredients in the circulatory system of the patient should be same for both the generic and the innovator drug. Enactment of the Drug.

Price Competition and Patent Restoration Act of 1984, better known as “The Hatch-Waxman Act” is the major force for generic market development in the US. It has created opportunities for developing and marketing generics, better called an abbreviated new drug application, with 180 days. Final approval of the ANDA by the FDA takes minimum18 months. Under ANDAs, a pharmaceutical manufacturer can develop and market low-price generic versions of previously approved innovator drugs, thus providing the same product to a patient at a lower price with safety and efficacy. All approved products, both innovator and generic, are listed in FDA’s orange book8.

The USA defines a generic drug product as “a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use”9.

Facts About Generic Drugs 1. The FDA requires generic drugs to have the same active ingredient, strength, dosage form, and route of administration as the brand-name drug.

2. The generic manufacturer must prove its drug is the same (bioequivalent) as the brand-name drug.

3. All manufacturing, packaging, and testing sites must pass the same quality standards as those of brand-name drugs.

4. Many generic drugs are made in the same manufacturing plants as the brand-name drugs10.

Hatch-Waxman Act This is also known as "Drug Price Competition and Patent Term Restoration Act of 1984". It established the approval pathway for generic drug products, under which applicants can submit an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

It takes account of provisions regarding new drug applications regarding patents and exclusivities. The ANDA applicant should demonstrate the generic product is “bioequivalent” with the reference listed drug (innovator drug).

Volume 12 Issue 2

Market Report Types of Certifications Provided under the Hatch-Waxman Act 1. Paragraph I: Patent details have not been filed 2. Paragraph II: Patent(s) expired 3. Paragraph III: Patent(s) remain(s) extant 4. Paragraph IV: Patent is purported to be invalid or generic product is purported to infringe11.

International Council of Harmonisation This is a unique initiative taken to achieve harmonisation of regulatory authorities and pharmaceutical industry. Since its inception in 1990, it has had well-defined objectives as follows: i. To encourage the global registration process ii. To accelerate the new drug development iii. To develop the harmonised guidelines12.

Common Technical Document (CTD) This is a harmonised specification developed and maintained by ICH. It is a globally accepted model to submit one single application to a country or multiple countries at the same time for the registration of a human pharmaceutical product (innovator or generic drug product).

Initially it was developed by the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Ministry of Health Labour and Welfare (Japan).

Figure 1: CTD triangle

The CTD outline is divided into five modules: Module 1. Administrative Information and Prescribing Information This module contains country-specific official papers and it will be detailed by the respective regulatory agency. (Ex: application forms, label text).

1.1 Forms • Form [form-type] 1.2 Cover letters 1.3 Administrative information • 1.3.1 Contact/sponsor/applicant information • 1.3.1.1 Change of address or corporate name • 1.3.1.2 Change in contact/agent • 1.3.1.3 Change in sponsor • 1.3.1.4 Transfer of obligation • 1.3.1.5 Change in ownership of an application or reissuance of license • 1.3.2 Field copy certification • 1.3.3 Debarment certification • 1.3.4 Financial certification and disclosure • 1.3.5 Patent and exclusivity www.jforcs.com

• 1.3.5.1 Patent information • 1.3.5.2 Patent certification • 1.3.5.3 Exclusivity claim • 1.3.6 Tropical disease priority review voucher 1.4 References • 1.4.1 Letter of authorisation • 1.4.2 Statement of right of reference • 1.4.3 List of authorized persons to incorporate by reference • 1.4.4 Cross-reference to previously submitted information 1.5 Application status • 1.5.1 Withdrawal of an IND • 1.5.2 Inactivation request • 1.5.3 Reactivation request • 1.5.4 Reinstatement request • 1.5.5 Withdrawal of an unapproved BLA, NDA, ANDA, or Supplement • 1.5.6 Withdrawal of listed drug • 1.5.7 Withdrawal of approval of an application or revocation of license 1.6 Meetings • 1.6.1 Meeting request • 1.6.2 Meeting background materials • 1.6.3 Correspondence regarding meetings 1.7 Fast track • 1.7.1 Fast track designation request • 1.7.2 Fast track designation withdrawal request • 1.7.3 Rolling review request • 1.7.4 Correspondence regarding fast track/rolling review 1.8 Special protocol assessment request • 1.8.1 Clinical study • 1.8.2 Carcinogenicity study • 1.8.3 Stability study • 1.8.4 Animal efficacy study for approval under the animal rule 1.9 Pediatric administrative information • 1.9.1 Request for waiver of pediatric studies • 1.9.2 Request for deferral of pediatric studies • 1.9.3 Request for pediatric exclusivity determination • 1.9.4 Proposed pediatric study request and amendments • 1.9.5 Proposal for written agreement (no longer applicable) • 1.9.6 Other correspondence regarding pediatric exclusivity or study plans 1.10 Dispute resolution • 1.10.1 Request for dispute resolution • 1.10.2 Correspondence related to dispute resolution 1.11 Information amendment: Information not covered under modules 2 to 5 • 1.11.1 Quality information amendment • 1.11.2 Nonclinical information amendment • 1.11.3 Clinical information amendment • 1.11.4 Multiple module information amendment 1.12 Other correspondence • 1.12.1 Pre IND correspondence • 1.12.2 Request to charge for clinical trial • 1.12.3 Request to charge for expanded access • 1.12.4 Request for comments and advice • 1.12.5 Request for a waiver • 1.12.6 Exception from informed consent for emergency research • 1.12.7 Public disclosure statement for exception from informed consent for emergency research • 1.12.8 Correspondence regarding exception from informed consent for emergency research • 1.12.9 Notification of discontinuation of clinical trial • 1.12.10 Generic drug enforcement act statement • 1.12.11 ANDA basis for submission statement • 1.12.12 Comparison of generic drug and reference listed drug Journal for Clinical Studies 21

Market Report • • • • • 1.13 • • • • • • • • • • • •

1.12.13 Request for waiver for in vivo studies 1.12.14 Environmental analysis 1.12.15 Request for waiver of in vivo bioavailability studies 1.12.16 Field alert reports 1.12.17 Orphan drug designation Annual report 1.13.1 Summary for nonclinical studies 1.13.2 Summary of clinical pharmacology information 1.13.3 Summary of safety information 1.13.4 Summary of labeling changes 1.13.5 Summary of manufacturing changes 1.13.6 Summary of microbiological changes 1.13.7 Summary of other significant new information 1.13.8 Individual study information 1.13.9 General investigational plan 1.13.10 Foreign marketing 1.13.11 Distribution data 1.13.12 Status of postmarketing study commitments and requirements • 1.13.13 Status of other postmarketing studies and requirements • 1.13.14 Log of outstanding regulatory business • 1.13.15 Development safety update report (DSUR) 1.14 Labeling • 1.14.1 Draft labeling • 1.14.1.1 Draft carton and container labels • 1.14.1.2 Annotated draft labeling text • 1.14.1.3 Draft labeling text • 1.14.1.4 Label comprehension studies • 1.14.1.5 Labeling history • 1.14.2 Final labeling • 1.14.2.1 Final carton or container labels • 1.14.2.2 Final package insert (package inserts, patient information, medication guides) • 1.14.2.3 Final labeling text • 1.14.3 Listed drug labeling • 1.14.3.1 Annotated comparison with listed drug • 1.14.3.2 Approved labeling text for listed drug • 1.14.3.3 Labeling text for reference listed drug • 1.14.4 Investigational drug labeling • 1.14.4.1 Investigational brochure • 1.14.4.2 Investigational drug labeling • 1.14.5 Foreign labeling • 1.14.6 Product labeling for 2253 submissions 1.15 Promotional material [promotional-material-audience-type] • 1.15.1 Correspondence relating to promotional materials • 1.15.1.1 Request for advisory comments on launch materials • 1.15.1.2 Request for advisory comments on non-launch materials • 1.15.1.3 Presubmission of launch promotional materials for accelerated approval products • 1.15.1.4 Presubmission of non-launch promotional materials for accelerated approval products • 1.15.1.5 Pre-dissemination review of television ads • 1.15.1.6 Response to untitled letter or warning letter • 1.15.1.7 Response to information request • 1.15.1.8 Correspondence accompanying materials previously missing or rejected • 1.15.1.9 Withdrawal request • 1.15.1.10 Submission of annotated references • 1.15.1.11 General correspondence • 1.15.2 Materials attribute = [promotional-material-doc-type] • 1.15.2.1 Material [promotional-material-type, material-id, issue- date] • 1.15.2.1.1 Clean version • 1.15.2.1.2 Annotated version 22 Journal for Clinical Studies

• 1.15.2.1.3 Annotated labeling version • 1.15.2.1.4 Annotated references 1.16 Risk management plan • 1.16.1 Risk Management (Non-R EMS) • 1.16.2 Risk Evaluation and Mitigation Strategy (REMS) • 1.16.2.1 Final REMS • 1.16.2.2 Draft REMS • 1.16.2.3 REMS Assessment • 1.16.2.4 REMS Assessment Methodology • 1.16.2.5 REMS Correspondence • 1.6.2.6 REMS Modification History 1.17 Postmarketing studies • 1.17.1 Correspondence regarding postmarketing commitments • 1.17.2 Correspondence regarding postmarketing requirements 1.18 Proprietary names 1.19 Pre-EUA and EUA 1.20 General investigational plan for initial IND Module 2. Common Technical Document Summaries This Module comprises of seven sections as specified below: 2.1 Table of contents 2.2 Introduction 2.3 Quality Overall Summary 2.4 Non-clinical Overview 2.5 Clinical Overview 2.6 Non-clinical Written and Tabulated Summaries 2.7 Clinical Summary Module 3. Quality This module comprises the information regarding chemistry manufacturing and control (CMC). It gives an overview regarding drug product composition, formulation development and quality attributes.

3.1 Comprehensive Table of Contents for Module 3 3.2. S Drug Substance 3.2. P Drug Product 3.2. A Appendices 3.2. R Regional Information 3.3 Key Literature References Module 4. Nonclinical Study Reports It comprises the complete pharmacological and toxicological study reports and information equivalent to the quality of the drug to provide the evidence of the safety of the drug product.

4.1 Comprehensive Table of Contents 4.2 Study Reports 4.3 Literature References ANDAs generally do not contain data required for Module 4.

Module 5. Clinical Study Reports These generally comprise the human study reports, bioequivalence and study tagging file studies in the ANDA submission.

5.1 Comprehensive Table of Contents 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports 5.4 Literature References Review Phase Assessment • The ANDA review process commences with submission of the ANDA to the Office of Generic Drugs (OGD) within the Center of Drug Evaluation and Research (CDER).

• An ANDA pre-assigned application number will be assigned within three working days upon request through secure email to cderappnumrequest@fda.hhs.gov14.

• OGD and OPQ simultaneously review ANDA on key elements, like: Volume 12 Issue 2

Market Report i. Pharmaceutical Quality ii. Bioequivalence iii. Labelling FDA Commitment Towards ANDA Review Process • The FDA introduced Generic Drug User Fee Amendments (GDUFA) to enhance the efficiency and effectiveness of the review process.

• GDUFA I was introduced in 2012 as part of the Food and Drug Administration’s Safety and Innovation Act. It was introduced to facilitate the appropriate resources to review ANDA applications, which were received in large numbers.

• GDUFA I has been reauthorized (GDUFA II) on August 18, 2017 and it will remain effective until September 30, 2022.

• GDUFA II set a goal of a standard 10-month review cycle time.

• GDUFA II derived two terms, i.e. standard and priority submissions.

• Standard: The submissions not affirmatively identified as eligible for expedited review pursuant to the CDER (Center for Drug Evaluation and Research) prioritisation MAPP (Manual of Policies & Procedures).

• Priority: The submissions affirmatively identified as eligible for expedited review pursuant to CDER’s MAPP 5240.3, prioritisation of the review of original ANDAs, amendments and supplements15.

• GDUFA II enriches the communication between agency and applicant by issuing of IR(s) and DRL(s) at an appropriate midpoint of the review.

• GDUFA II fiscal fees for years 2018 and 2019 are detailed below in Figure 216:

Figure 2: GDUFA fee comparison of FY 2019 and FY 2018

GDUFA II Role in Review Phase: • Two programme enhancements centred on improving communications during a review cycle: 1. Discipline Review Letters (DRLs).

2. Information Request (IR) Letters.

• ECDs are no longer used.

• Multiple DRLs and IRs can be issued in one GDUFA cycle.

• Impact of GDUFA II: • Reviews of ANDAs will begin earlier in the review cycle • Applicants will receive preliminary thoughts on their application at about the mid-point of the review period • Applicants may have an opportunity to resolve issues during the review cycle • The goal is to improve review efficiency and reduce review cycles (get generics to market faster).

Information Request (IR): • “A letter that is sent to an applicant during a review to request further information or clarification that is needed or would be www.jforcs.com

• • • •

helpful to allow completion of the discipline review.”17 It will be issued for clarification or additional information required to complete a discipline review with a specified response date.

It will be issued early in the review cycle by the discipline or sub-discipline through teleconference, e-mail, facsimile or letter.

In case of no response or partial response by agency, then it may be included in a further issued DRL or CRL. An extension may be requested when unable to respond by the requested response date in an IR.

Discipline Review Letter (DRL) • “A letter used to convey preliminary thoughts on possible deficiencies found by a discipline reviewer and/or review team for its portion of the pending application at the conclusion of the discipline review. FDA does not consider a DRL to be a CRL because it does not represent a complete review of the entire submission (and, therefore, does not complete the review cycle for an ANDA).”

• It will be issued based on possible deficiencies found by a discipline reviewer and/or review team with a specified response date through teleconference, e-mail, facsimile or letter.

• If the review team finds no deficiencies, then the particular discipline will issue a DRL that states no deficiencies are identified at the current time.

• A discipline will reach the conclusion of their review and issue a DRL no later than about the mid-point of the review (i.e., mid-cycle date (MCD), meaning the mid-point of the GDUFA goal date plus 30 days). a. Eight-month GDUFA clock – five-month MCD (fourmonth mid-point + 30 days) b. 10-month GDUFA clock – six-month MCD (five-month mid-point + 30 days) • An extension may be requested when unable to respond by the requested response date in a DRL. • Mid-review cycle meeting via teleconference with the applicant to discuss current concerns with the application and next steps.

CDER will schedule a mid-review cycle meeting after the last key discipline has issued its IR and/or DRL for ANDAs that were the subject of prior product development meetings or presubmission meetings.

Complete Response Letter (CRL) • “A written communication to an applicant from FDA usually describing all of the deficiencies that the Agency has identified in an ANDA that must be satisfactorily addressed before it can be approved. Issuance of a CRL completes the review cycle for an ANDA.” • It was introduced in 2008 to replace the old “approved”, “approvable”, and “not approvable” letters.

• CRLs are important documents to a drug application’s success or failure.

• It must be dealt with in a timely fashion to maximise the chance for an application’s approval.

• Most successful drug applications receive only one CRL. • A CRL may be issued on multiple deficiencies like manufacturing sites, safety, efficacy, bioequivalence, faulty statistics, product quality and stability, and proposed labelling.

Office of Pharmaceutical Quality • This is organised around discipline and expertise. It streamlined the FDA to assess and monitor drug quality.

• It enhances the interactions, communication and consistency among sub-disciplines.

• Office of Pharmaceutical Quality developed a 10-month Journal for Clinical Studies 23

Market Report process timeline for original ANDAs and a review flow described in the figure below.

9.

10.

11.

12.

13.

Figure 3: OPQ GDUFA ll snapshot of OPQ process quality review timeline.

14.

15.

16.

17.

note-0 [Cited on 23-Feb-2019].

United States Food and Drug Administration. Available from: https://www. fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/ GenericDrugs/ucm567297.htm [Cited on 25-Feb-2019] United States Food and Drug Administration. Available from: https:// www.fda.gov/downloads/drugs/resourcesforyou/consumers/ buyingusingmedicinesafely/understandinggenericdrugs/ucm305908.PDF [Cited on 25-Feb-2019] Abbreviated New Drug Application (ANDA): Generics. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDeveloped [Cited on 27-Feb-2019].

International Council for Harmonisation US FDA and Health Canada Regional Public Consultation. Available from: https://www.fda.gov/downloads/Drugs/ NewsEvents/UCM554742.pdf [Cited on 27-Feb-2019].

ICH Harmonised M4 Guideline Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (R4). Available from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/ M4_R4_Organisation/M4_R4__Granularity_Document.pdf [Cited on 27-Feb-2019].

Requesting a Pre-Assigned Application Number. Available from https://www. fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-preassigned-application-number [Cited on 27-Feb-2019].

Prajapati J, Patel D. Generic Drug User Fee Act II: The positive features for generic drug industry. Journal of Generic Medicines. 2017 Dec;13(4):206-13.

Generic Drug User Fee Amendments Available from: https://www.fda.gov/ industry/fda-user-fee-programs/generic-drug-user-fee-amend-ments [Cited on 01-Mar-2019].

Office of Generic Drugs and Office of Pharmaceutical Quality Issuance of Information Requests and/or Discipline Review Letters for Abbreviated New Drug Applications. Available from https://www.google.com/ search?q=OFFICE+OF+GENERIC+DRUGS+AND+OFFICE+OF+PHARMACEUTICAL+QUALITY+Issuance+of+Information+Requests+and%2For+ Discipline+Review+Letters+for+Abbreviated+New+Drug+Applications &oq=OFFICE+OF+GENERIC+DRUGS+AND+OFFICE+OF+PHARMACEUTICAL+QUALITY+Issuance+of+Information+Requests+and%2For+ Discipline+Review+Letters+for+Abbreviated+New+Drug+Applications& aqs=chrome..69i57.867j0j4&sourceid=chrome&ie=UTF-8 [Cited on 01Mar-2019].

Dr. Balamuralidhara V

Figure 4: Review flow of ANDA application

REFERENCE 1.

2.

3.

4.

5.

6.

7.

8.

Definition of the Food and Drug Administration (FDA or US FDA) [Internet].

Wikipedia; 2018 [Cited on 06-Feb-2019] Available from: https://en. wikipedia.org/wiki/Food_and_Drug_Administration FDA Human Drug Review and Approval Basics Module [Cited on 08-Feb2019] Available from: https://www.accessdata.fda.gov/scripts/cderworld/ index.cfm?action=humandrugreview:main&unit=1&lesson=1&topic=2 Role of FDA's Center for Drug Evaluation and Research (CDER) [Internet].

U.S FDA; 2015 [cited on 10-Feb-2019]. Available from: https://www.fda.gov/ Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ Dylst P, Vulto A, Simoens S. Overcoming challenges in market access of generic medicines in the European Union. Journal of Generic Medicines.

2012;9(1):21-8. [Cited on 16-Feb-2019].

Hassali M et al. Physicians’ views on generic medicines: a narrative review.

Journal of Generic Medicines. 2010;7(1):30-9. [Cited on 16-Feb-2019].

Generic Drugs, U.S. Food and Drug Administration. Available from: http://en. wikipedia.org/wiki/U.S._Food_and_Drug_Administration [Cited on 19-Feb-2019].

United States Food and Drug Administration. Available from: https://www.fda. gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/ approvalapplications/abbreviatednewdrugapplicationandagenerics/default.htm [Cited on 23-Feb-2019] Generic drug. Available from: http://en.wikipedia.org/wiki/Generic_drug#cite_

24 Journal for Clinical Studies

Dr. Balamuralidhara V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India.

Email: baligowda@jssuni.edu.in

Dr. Gangadharappa H.V. Dr. Gangadharappa H.V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India.

Email: hvgangadharappa@jssuni.edu.in

Pachipulusu Rajesh M Pharm, Regulatory Affairs Group, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru Email: reddypharmacy7@gmail.com

Volume 12 Issue 2

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 25

LogisticsReport Market & Supply Chain Management

Establishing Clear Procedures and Improving Start-up Timeline in Malaysia’s Clinical Research Ecosystem As delays in getting clinical trials up and running have financial implications, pharmaceutical companies and contract research organisations (CROs) are looking at ways to accelerate the study start-up process. Challenges in processes such as feasibility assessment, site selection, compilation of essential documents, submission to ethics committee, and application for investigational product import license can affect study milestones and timelines.1,2 In Malaysia, the Ministry of Health established a corporate entity, CRM, that functions as a one-stop centre to facilitate industry-sponsored research in the country to ensure an efficient start-up process. The organisation offers services such as feasibility assessment, budget negotiation, clinical trial agreement review and placement of study coordinators. This article describes CRM’s timeline in feasibility assessment, budget negotiation and clinical trial agreement review, besides the regulatory and ethics approval timeline in Malaysia.

Centralised Feasibility and Site Selection Services The company has a centralised feasibility team that handles feasibility queries from CROs, pharmaceutical, medical device, and biotechnology companies. The feasibility team maps the sites according to disease specialities and workload, saving the time it takes to identify the right investigators and sites with interest in a particular clinical trial. It also assists interested potential investigators to address the queries and submits the completed feasibility questionnaire to the CRO or sponsor (Figure 1). Having a centralised service is far more efficient as the individual databases of the CROs and sponsors may not always be updated and sufficiently comprehensive.3 As the single point of contact, the standardised processes lead to streamlined communications which reduce delay and confusion on the ground. As a result, the turnaround time is shorter than if a sponsor or CRO were to approach individually. With CRM’s central database and feedback from the sites and investigators, a completed feasibility questionnaire can be sent back to the enquiring company within 5–10 working days (Table 1).

Prompt Review and Negotiations of Clinical Trial Contracts The top cause of delays in clinical trial start-up time is related to contract and budget negotiations.1,4 Lack of effective communication, unclear processes, bureaucracy, and difficult to understand contracts can lengthen the time it takes to finalise the clinical trial agreements (CTAs).4,5 To address these challenges, an experienced legal and regulatory affairs department reviews and endorses CTAs (on behalf of principal investigators) for all clinical trials conducted at public hospitals in Malaysia within 14 calendar days, from the last feedback received from the party involved in the study budget negotiation (Table 1). In addition to an experienced legal team, CRM has implemented an online system for submission and internal review of CTAs to shorten the timeline for review. Prior to this, the average time to review a CTA was 59 days.

26 Journal for Clinical Studies

Parallel Ethics and Regulatory Approval Processes Clinical trials that are conducted in the Ministry of Health (MOH) facilities will require ethics approval from the MREC (Medical Research and Ethics Committee), which is the sole ethics committee for Malaysia’s MOH facilities. MREC also acts as an independent ethics committee for facilities outside the MOH who do not have their own ethics committees.

Malaysia’s regulatory authority for pharmaceutical trials is the National Pharmaceutical Regulatory Agency (NPRA). The NPRA is responsible for approving applications for clinical trial import licence (CTIL) and clinical trial exemption (CTX). Ethical approval is needed Table 1 before ortimelines CTX isinreleased Clinicalthe studyCTIL start-up Malaysia (Figure 1).

Study start-up processes Feasibility assessment Ethics approval* Regulatory approval* - CTIL/CTX approval - Notification of Exemption from Registration of Medical Devices for Clinical Use and Research Supportive Use Clinical Trial Agreement review

Timelines 5-10 business days 50 business days 30 business days 14 business days 14 business days

*Parallel submission CTIL, clinical trial import license; CTX, clinical trial exemption

Table 1. Clinical study start-up timelines in Malaysia

For medical device trials, the Medical Device Authority (MDA) oversees the issuance of the letter of no restrictions for notification of medical devices for clinical use and research supportive use. This would take 14 working days. On the other hand, notification of medical devices for clinical investigational use will go through a review by the Technical Committee of Medical Device Clinical Evaluation (TCMDCE). The issuance of Figureof 1 no restrictions would take seven working days after a letter Clinical trial start-up in public hospitals in Malaysia: from feasibility to study initiation

CRM receives feasibility request from CRO/sponsor

CRM works with clinical trial site(s) to complete the feasibility questionnaire and forwards the completed questionnaire to the CRO/sponsor

If CRO/sponsor decides to select the site(s), CRM assists CRO/sponsor and the site(s) with the contact agreement and budget negotiation

1 Parallel submissions of clinical trial documents

Institutional review board(s) for ethics approval

Drug Control Authority/Medical Device Authority for regulatory approval

Study initiation.

CRM provides on-site study coordinators to principal investigators

Figure 1. Clinical trial start-up in public hospitals in Malaysia: from feasibility to study initiation Volume 12 Issue 2 1

Market Report

evaluation by the committee. In 2019, an online system was introduced to facilitate the process.

6.

Applications and tracking of progress are done through a local online registration of clinical studies, the National Medical Research Register (NMRR). With the NMRR being linked to the MREC, ethics approval processes are fast and convenient. An NMRR registration is also needed for CTIL/CTX application.

7.

In Malaysia, regulatory and ethical submissions are done in parallel.6 Regulatory approval takes approximately 30 business days while MREC ethics approval takes about 50 business days7,8 (Table 1).

Ethical review and approval can be as short as one month from the time of application if there are no issues/queries.8,9 On average, it takes about four months to obtain regulatory and ethics approval.10

10.

Conclusion Consistent timelines, reliability and efficient processes are important criteria for sponsors and CROs in deciding where to conduct its clinical trials. With CRM’s involvement at the feasibility and startup phase, as well as a standardised process for regulatory and ethics approval, sponsors will have better understanding and assurance on the timeline, processes and reliability of conducting clinical trials in Malaysia.

REFERENCES 1.

2.

3.

4.

5.

Clinical Researcher. Accelerating Study Start-Up: The Key to Avoiding Trial Delays (February 1, 2017). Available at https://acrpnet. org/2017/02/01/accelerating-study-start-up-the-key-to-avoiding-trialdelays/, visited on 1 November 2019.

Lamberti, M.J. Clinical Trials Take A Long Time to Get Started. Here’s How to Speed It Up (March 28, 2018). Available at https://www.statnews. com/2018/03/28/clinical-trials-startup-speed/, visited on 1 November 2019.

Ooi, A.J.A & Khairul, F.K. A Unique Model to Accelerate IndustrySponsored Research in Malaysia. Journal for Clinical Studies. 11(1), 24–27 (2019).

Applied Clinical Trials Editors. Clinical Trial Agreement Negotiations (June 1, 2012). Available at http://www.appliedclinicaltrialsonline.com/ clinical-trial-agreement-negotiations, visited on 1 November 2019.

Abdul Rahman, N.A. & Yusop, N. Evolution of Clinical Trial Agreement Review in Malaysia Through Clinical Research Malaysia. (September 21, 2018). Available at http://www.appliedclinicaltrialsonline.com/evolutionclinical-trial-agreement-review-malaysia-through-clinical-research-

www.jforcs.com

8.

9.

malaysia, visited on 1 November 2019.

Malaysian Investment Development Authority. Guide on Pharmaceutical Industry in Malaysia. June 2017.

Ali, S., Egunsola, O., Din Babar, Z.U. & Hasan, S.S. Challenges of Conducting Clinical Trials in Asia. Int J Clin Trials. 5(4), 194–199 (2018).

Society of Clinical Research Professionals Malaysia. A Guide to Conducting Clinical Trials in Malaysia (1st edition) 2016.

Burton, P. Malaysia: A Clinical Trials Hub For Southeast Asia? (November 20, 2018). Available at https://pharmaboardroom.com/articles/malaysiaa-clinical-trials-hub-for-southeast-asia/, visited on 1 November 2019.

Frost & Sullivan (2016) Asia: preferred destination for clinical trials. https://novotech-cro.com/sites/default/files/170217_FrostSullivan_ Asia%20white%20paper_full.pdf

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

Email: noorzaihan@clinicalresearch.my

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

Email: audrey.ooi@clinicalresearch.my

Journal for Clinical Studies 27

Therapeutics

Patient-centricity on Trial Abstract The pharmaceutical industry has a problem; clinical trials are failing to recruit and retain the required number of patients at an alarming rate. The statistics are damning, with 46% of clinical trials failing due to poor recruitment, 50% of sites enrolling one or no study participants and 80% of trials being delayed by at least one month. Underperformance in these key areas is having a significant impact on the commercial achievements of the companies, as well as a detrimental delay in getting new medicines to those who need them.

The answer, it seems, may lie with patient and public involvement in trial design, which has been demonstrated to improve patient enrolment, especially where they have included people directly affected by the disease in question. It seems that a patient-centric approach is not only the right thing to do, but it is also critical to improving recruitment, retention and ultimately the success of clinical trials.

The recent ubiquity of ‘patient-centricity’ supports this notion, with every company allegedly building patient-centric trials.

However, when you dig a little deeper, it becomes clear that the clinical trial and pharmaceutical industry still has a long way to go, and that in reality patients are still being overlooked.

This article explores the importance of patient-centricity in clinical trials and identifies key lessons that we can learn from some of the world's leading consumer brands such as Apple, Amazon and Uber – brands who truly understand what it means to put customers at the centre of their activities.

choices for patients. The number of trials has skyrocketed, with an astonishing 13,000% more trials registered in 2018 than in 20001 [Figure 1].

To put this astronomical rise in context, the number of trials alone registered on clinicaltrials.gov has grown significantly more than Amazon’s entire sales revenue in the same time period (8,306% between 20005 and 20186). Unlike Amazon, however, the industry has failed to adapt and deal with the challenges this brings.

Most trial recruitment follows the archaic model of hospital database recruitment and healthcare professional referrals, with retention efforts doing little beyond handing patients a cheap branded water bottle in return for their valuable time and priceless health data.

The rules of engagement have changed. Recruitment is more competitive than ever, with many more sites competing for the same pool of patients. Over the same period, the way people interact with consumer brands has changed beyond recognition and this has coincided with a transformation in our expectations.

The average person is thought to see as many as 3000 advertising messages every day across all media7. The competition for share of voice when it comes to clinical trials goes well beyond just competing trials, but has expanded across alternative and holistic therapies, as well as powerful consumer brands such as Apple, Facebook, Amazon and Nike. Trial recruitment now must compete against a ‘wall of communication noise’, where brands win over consumers by engaging, empowering and valuing them with personalised offers, loyalty schemes and retention programmes8.

The Commercial Implications of Failing Clinical Trials Today, there are over 300,000 clinical trials registered worldwide, with over 52,000 of them actively recruiting patients1.

This is one of the industry’s biggest challenges, with clinical trials simply unable to recruit and retain the required number of patients.

The statistics are shocking, with 46% of clinical trials failing due to poor recruitment, 50% of sites enrolling one or no study participants2, and 80% of trials being delayed by at least a month3.

It is these unacceptable delays in drug development that are a major contributing factor to the escalating costs of drug development. Recent estimates suggest that, adjusted for inflation, it now costs 80 times more to develop a new medicine than it did in 19504. Manufacturers are losing more than $1.1BN in ‘time costs’ alone, for every drug programme funded3.

So, what’s going wrong?

For a start, there were fewer trials being run, which means fewer 28 Journal for Clinical Studies

Figure 1: Number of successful drugs authorisations compared to ballooning number of studies and costs1,9

How do we make clinical trials fit for the modern day whilst ensuring highest quality compliant science?

The answer may lie in greater patient and public involvement (PPI).

Evidence suggests that PPI improves patient enrolment, especially when those people affected directly by the disease have been Volume 12 Issue 2

Therapeutics consulted10. It just makes sense that more solutions may be found using a patient-centric methodology.

Of course, patient-centricity is not a new concept; it has been around for as much as a decade in clinical trials, and the number of trials citing patient-centricity is on the rise11 [Figure 2].

An extensive review published in the BMJ last year found that involving people with ‘lived experience of a health condition’ improves clinical trial enrolment. Understanding and improving the patient experience makes as much sense for researchers and the pharmaceutical industry as it does for patients’ wellbeing and satisfaction10.

In the United States, the FDA has been a pioneer in the design and implementation of clinical trials that recognise the importance of patient voices. This emphasis on the significance and increase in patient-reported outcomes in trials is a result of increased awareness of the levels of engagement in patient-centric trials12.

The Patient-Centered Outcomes Research Institute (PCORI) is very much focussed on determining relative effectiveness of medicines using patient-centred outcomes, promotes patient involvement, and funds patient-centred research.

Figure 2: Number of trials citing patient-centricity over time

11

What does patient-centricity mean and how can we improve it?

Patient-centricity in its purest form is the consideration of the patient and their experience throughout every single touch-point in their clinical trial journey.

It’s important to remember that being a patient on a trial is not a job. A trial becomes a part of a patient’s life, and must fit in around their family life, their job and other day-to-day responsibilities they must contend with.

Clinical trial participation can be time-consuming and may require a significant commitment, which is why understanding and addressing the ‘normal everyday practicalities’ is just as important as developing high-tech solutions to improve the trial experience as a whole.

What are the advantages and drawbacks of patient-centric trials?

‘Patient-centric’ trials aren’t just simply a nicer touchy-feely experience for patients, but they may also run more effectively than most traditional trials. A recent analysis by the Economist Intelligence Unit found that studies focused on making participation as easy as possible for patients showed a 10–20% increase in likelihood of reaching market authorisation and launch, compared to drugs developed without a patient-centric methodology11.

Patient-centric trials can also accelerate the recruitment process; on average patient-centric trials took three months less time to recruit 100 participants (four months) than traditional ones (seven months)11. That three-month difference is even more significant when considering not only the additional costs of study development but the lost opportunity costs for commercial developers [Figure 3].

There’s been a significant increase in the number of trials that are using patient-reported outcome (PRO) measures to capture data required for marketing authorisation applications. PROs can, however, be considered to be too patient-centric, because in many cases, clinical trial data is collected away from the trial sites, in the patient’s own time. PROs tend to capture ‘softer’ quality of lifestyle data, often dependent on the patient’s subjective experience.

Nevertheless, PROs are having a positive impact on both the patient experiences and the industry13.

Adapting data capture to become more patient-centric does not stop at PROs. Reducing the amount of data being captured by streamlining supplementary endpoints is one way of improving the patient experience. In theory, fewer data points mean fewer time-consuming tests and procedures for patients.

But clearly this depends on the study design and hypotheses being tested.

The disadvantage of reducing data points may hinder the capture of broader data required to find evidence for efficacy or safety, if a trial fails to meet its primary endpoints, and by reducing the data set being collected for the benefit of the patient experience, sponsors may be putting their marketing authorisation application at risk.

There is often a disconnect or conflict between research topics that patients want and prioritise (quality of life), and those actually investigated, and of focus for academic centres of the pharmaceutical industry (for drug development), exacerbated by economic constraints. In the UK, the traditional paradigm is being inverted using a robust, replicable framework to better engage and involve patients right from the start with patient-led research14.

On balance, it seems clear that clinical trials benefit from patient involvement for both trial design and patient recruitment.

Exploring the current standard of patient-centricity – is it good enough?

Clinical trials are now established as the lifeblood of the pharmaceutical industry. Patients at the centre of these trials have traditionally been viewed through an ethical or regulatory lens, with guidance such as the Nuremberg Code15, the Declaration of Helsinki16 and the International Conference on Harmonisation Good Clinical Practice Guideline ensuring the rights and safety of patients17.

Figure 3: Studies that improve the patient experience have a higher chance of achieving new drug launches 11 www.jforcs.com

The recent ubiquity of the term ‘patient-centricity’ suggests that this has been taken to new levels, with more and more companies Journal for Clinical Studies 29

Therapeutics building in their own take on patient-centricity within their clinical trial processes. Dig a little deeper, however, and it soon becomes apparent that both academia and the industry have a long way to go, with patients often still being overlooked in practical terms.

Consider the way clinical trials traditionally communicate with patients. Recruitment adverts are often couched in impersonal and functional language tailored to the needs of sites and not to the needs of patients. ‘Do you have asthma? Are you 18–35 years old?

You might be eligible for our study.” This is the industry standard for attracting patients to a study, however this lacks the sophistication of the advertising we see from commercial brands and is the equivalent of Nike asking you if you have feet [Figure 4].

As clinical trial recruitment becomes more and more competitive1 we should be adopting and adapting the best practices of the proven experts in recruitment and retention – large consumer brands with a loyal customer-base. Certainly, people with ill health do not engage with medications or healthcare services (including clinical trials) in exactly the same way as choosing a consumer brand, nevertheless similar approaches may be applied constructively and compliantly within the clinical study setting.

Early Adopters are Reaping the Rewards There are already some sponsors who are leading the way, embracing this paradigm shift and seeing exceptional results.

In 2016, Sanofi completed a virtual Phase IV diabetes trial called VERKKO, using a patient-centric online clinical trial platform and a 3G-enabled wireless blood glucose meter, in a completely remote clinical trial setting.

Sixty patients, all recruited through Facebook, participated in the study. The results exceeded expectations, with an 81% conversion rate among patients who showed interest in participating and a less than 10% dropout rate. This valuable proofof-concept trial shows new models of clinical trial recruitment and retention can work19.

Figure 4: Mock advertisement for a consumer product if the brand were to use the principles currently used in clinical trials

Who can we learn from?

The customer-centric model is not new. The clinical trial community can learn a great deal from leading global consumer companies such as Amazon or Uber.

By understanding that to create products or services that consumers really engage with, it’s an absolute imperative to consider their customers’ every need and then include them in the process. Involving the consumer in the development journey, maintaining dialogue, taking their feedback seriously, listening and refining and optimising the experience is fundamental to ongoing success. Moreover, it engenders trust, promotes loyalty and creates brand ambassadors.

Let’s take Apple as an example. The company has taken the time to truly understand its customers and uses this understanding to make conscious business decisions, which ultimately improves the customer experience.

Apple understands that simplicity is key, and that anything that they can do to make the use of their products more convenient has a positive impact on the end user. Examples of this include the connected ecosystem that they have created between their different products, allowing your watch to speak to your phone and your laptop, as well as introducing services such as Apple Pay so consumers pay with a simple tap of their smartphones instead of having to go through wallets or purses and use their bank card.

The retail experience at Apple is both innovative and revolutionary. Instead of picking up items from the shelves and carrying them to a cashier to pay, Apple introduced their ‘Town Square’ model where customers are encouraged to interact with the products as well as sales staff in a more engaging environment. This change was based purely on the customer experience and has led to a shift in the way that many companies approach their in-store sales18.

30 Journal for Clinical Studies

A Silicon Valley tech company, working in partnership with the American Sleep Apnea Association, recruited a staggering 1000 patients for a large-scale web-based sleep study in less than 24 hours20. When further considering announcements such as the joint healthcare venture between Amazon, J.P. Morgan and Berkshire Hathaway – called Haven – there can be little doubt that we will see many more of these sorts of large-scale virtualised real-world studies21.

Conclusion The current model isn’t working, yet there’s a temptation to hold onto the way we’ve always done things. It’s no surprise at all that we are now seeing companies like Google and Amazon expanding their offering into healthcare.

They know that the future is customer-centric and they know their strength in this area will give them the edge over current academic and industry incumbents.

For researchers and commercial drug developers, this isn’t about making ‘brave’ business decisions. It’s about evolving to meet patient expectations, instead of following the tried-and-failed model and slowly losing relevance and money.

We must look at how consumer companies and brands have behaved and see how they can be safely and compliantly applied to improve the clinical trial experience for our most important components – the participants. Let’s take the principles we know work. They have involved customers in every part of their business for years. Not because they think it makes them look good, but because they know it’s both a sound academic and commercial decision, and you can’t create or promote products and services – including clinical trials – to people who you don’t understand.

The real winners will be those organisations who embrace patient-centricity throughout their organisation, those who continuously put the patient firmly at the heart of their thinking and processes. Not simply because it’s the right thing to do, but because it is the only way to fix a broken model.

Volume 12 Issue 2

Therapeutics REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

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15.

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18.

19.

20.

https://clinicaltrials.gov/ct2/resources/trends, visited on 10th February 2020 http://www.pharmafile.com/news/511225/clinical-trials-and-theirpatients-rising-costs-and-how-stem-loss, visited on 10th February 2020 https://www.pharmaceutical-technology.com/features/featurecounting-the-cost-of-failure-in-drug-development-5813046/, visited on 10th February 2020 https://www.nature.com/articles/nrd3681, visited on 10th February 2020 https://ir.aboutamazon.com/static-files/49b9a96d-f5ce-4695-a9a170eb8ffd3b87, visited on 10th February 2020 https://ir.aboutamazon.com/static-files/0f9e36b1-7e1e-4b52-be17145dc9d8b5ec, visited on 10th February 2020 Hunt, J., Visual Communication Design: An Introduction to Design Concepts in Everyday Practice. 2017. p35 https://emtemp.gcom.cloud/ngw/globalassets/en/marketing/ documents/intelligence-loyalty-2018-excerpt.pdf, visited on 10th February 2020 Scannell, J., Blanckley, A., Boldon, H. et al. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11, 191–200 (2012). https://doi.org/10.1038/nrd3681 Crocker, J.C., Ricci-Cabello, I., Parker, A., Hirst, J.A., Chant, A., Petit-Zeman, S. et al. Impact of patient and public involvement on enrolment and retention in clinical trials: systematic review and meta-analysis. BMJ 2018; 363 :k4738 https://druginnovation.eiu.com/patient-centric-trials/, visited on 10th February 2020 https://www.fda.gov/media/113653/download, visited on 10th February 2020 http://www.pharmafile.com/news/516200/pros-and-cons-pushingpatient-centricity, visited on 10th February 2020 https://researchinvolvement.biomedcentral.com/articles/10.1186/ s40900-018-0104-4, visited on 10th February 2020 Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, (1949) World Medical Association. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bulletin of the World Health Organization, 79 (4), 373 – 374 (2001). https://www.ich.org/page/ich-guidelines, visited on 10th February 2020 https://www.forbes.com/sites/christinemoorman/2018/01/12/ why-apple-is-still-a-great-marketer-and-what-you-canlearn/#70b9701315bd, visited on 10th February 2020 https://www.businesswire.com/news/home/20160621005604/en/ eClinicalHealth-Announces-Successful-Results-Remote-OnlineClinical, visited on 10th February 2020 https://evidation.com/news/evidation-health-grants-its-first-

Will Wilson

21.

digital-research-collaboration-award-to-the-american-sleep-apneaassociation/, visited on 10th February 2020 https://www.cnbc.com/2019/03/06/amazon-jp-morgan-berkshirehathaway-health-care-venture-named-haven.html, visited on 10th February 2020

Kristian Webb Entrepreneurial Cardiac Physiologist leading innovative approaches to improving clinical trial patient experiences. During 7 years in the NHS, Kristian became the Chief Physiologist at Frimley Park Hospital in Surrey where he specialised in Pacemakers, ICD’s and supporting complex PCI. An Allied Professional of the Heart Rhythm Congress, he is also the only Cardiac Physiologist in the UK to have created CME accredited courses for Physicians. In 2013 Kristian created a patient support website for those with heart disease that grew to over 1 million hits within 3 years. His success in digital communications lead to him being featured by Havas Lynx in their “Generation Now” White Paper. Since 2018 Kristian has been paving the way in healthcare communications, specialising in clinical trial patient engagement, recruitment and retention as part of the Havas Lynx Faze team.

Email: kristian.webb@havas.com

Mark Evans Bringing expertise in consumer communications to redefine how we design clinical trial experiences for patients. Leading clinical trial recruitment agency Havas Lynx Faze with the mission to help redesign the patient experience around patients. Regular speaker and author on the subject of designing clinical trials around patients. Evans was involved with many industry firsts, including the awardwinning AIIR game, thought to be the first example of using gaming – integrated into ePRO – to motivate young clinical study participants. He was also involved in recruiting patients through Facebook in one of the first ever fully remote clinical studies, VERKKO, in collaboration with eClinicalHealth and Sanofi.

Email: mark.evans@havasfaze.com

Vernon Bainton

Clinical trial specialist improving patient experiences globally by incorporating the patient voice. Having gained on-the-ground experience working on clinical trials recruiting over 12,000 patients at IQVIA and GlaxoSmithKline, Will moved to Havas Lynx Faze where he is responsible for developing the strategy behind global patient recruitment and retention campaigns. Will specialises in speaking to real patients and using the insights gained to improve the clinical trial experience for patients at every possible touchpoint in their journey.

Erstwhile clinician. Scientist with commercial acumen. Technophile. Policy puzzler.

Art-fiend. Insatiably curious questioner.

Applying Creativity to healthcare, he leads the Scientific function of the Havas Lynx Group providing medico-strategic expertise to change outcomes and redefine what’s possible in healthcare communications.

He embodies an eclectic mix including a neuropharmacology degree, qualifying in medicine and began training as a physician and anaesthetist then transitioning to Big Pharma in medical and commercial roles. For the past 13 years he has combined his passions in agency life to deliver world-class healthcare communications and digital innovation.

Email: will.wilson@havasfaze.com

Email: vernon.bainton@havas.com

www.jforcs.com

Journal for Clinical Studies 31

Therapeutics

FDA Continues to Strengthen Paediatric Study Expectations After a three-year reprieve, a new US paediatric study requirement kicks in on August 18, 2020, for sponsors of certain molecularly targeted oncology drugs.

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 (FDARA) introduced the requirement, which applies to new drug applications (NDAs) and biologics license applications (BLAs) for any new, molecularly targeted cancer drug or biologic that is 1) intended to treat an adult cancer and 2) directed at a molecular target that is “substantially relevant to the growth or progression of a paediatric cancer.”1 FDARA gave sponsors three years to adjust to the new provision – but that delay is coming to an end, and sponsors soon must incorporate molecularly targeted paediatric cancer investigations into development programmes and submit results in applications for approval.

The FDARA requirement is meant to ensure there are early paediatric investigations of molecularly targeted cancer drugs that have the potential for anti-tumour efficacy in babies, children, and adolescents, to speed an understanding of both their potential effectiveness and toxicities. The requirement applies even when an adult cancer indication does not appear in paediatric patients – and it ends a provision exempting orphan cancer drugs from paediatric study requirements.

Relevant Regulations The FDA’s authority to require paediatric safety and efficacy studies for certain drugs and biological product applications stems from the Pediatric Research Equity Act (PREA) of 2003.2 PREA applies to applications “for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration”. PREA studies must: • • •

Use age-appropriate formulations, Assess safety and effectiveness “in all relevant paediatric subpopulations”, and Be adequate to support dosing and administration in subpopulations where safety and effectiveness are established.

PREA allows sponsors to extrapolate paediatric efficacy from adequate and well-controlled studies conducted in adults if the disease course and drug effects are “sufficiently similar”. The FDA can waive a product from PREA requirements if studies are “impossible or highly impracticable”; evidence “strongly” suggests the product would be ineffective or unsafe in paediatric patients; or if the product does not offer “meaningful therapeutic benefit” over existing treatments or is unlikely to be used in a “substantial number” of paediatric patients.

Until 2017, PREA also stated an exception to paediatric study requirements: in an attempt to incentivise drug development for orphan diseases, PREA exempted drugs with orphan indications.

FDARA changed that when Title V – also called the Research to Accelerate Cures and Equity (RACE) for Children Act – eliminated 32 Journal for Clinical Studies

the orphan exemption for cancer drugs directed at certain molecular targets.

Historically, requirements for paediatric studies of new cancer drugs were based on a product’s indication: if a product was intended for use in paediatric patients, studies were to be conducted in the relevant paediatric subpopulations. Under FDARA, the requirement for a “molecularly targeted paediatric cancer investigation” is based on the proposed product’s molecular mechanism of action, not its indication. The law directs the FDA (in collaboration with several groups, including the National Cancer Institute) to “establish, publish, and regularly update” a “Relevant Molecular Target List” and a “Non-Relevant Molecular Target Leading to Waiver List”.3 New FDA Draft Guidances Are Intended to Help Sponsors Adjust The FDA recently published two draft guidances intended to help oncology drug sponsors understand and implement the FDARA paediatric study requirement.

FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act, published in December 2019, gives an overview of FDARA requirements and how to fulfill them. It also discusses the relevant and non-relevant molecular target lists and how the FDA updates them; the content of an initial paediatric study plan (iPSP); recommendations for studies; special considerations for rare cancers; and situations in which a waiver or deferral may be granted.

Pediatric Study Plans for Oncology Drugs: Transitional Information Until Full Implementation of FDARA Section 504, published in January 2020, is written in question-and-answer (Q&A) form. In it, the FDA responds to some of the queries received since FDARA was enacted in 2017. Topics addressed include: • • •

How requirements vary before and after August 18, 2020.

When an iPSP is required and when an abbreviated iPSP is acceptable. iPSP and study requirements for drugs in cross-labelled oncology drug combination regimens.

The Orphan Drug “Loophole” The new draft guidance documents follow other FDA actions aimed at strengthening paediatric study requirements. For example, the FDA intended its December 2017 final guidance, Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases, to “close a loophole” in PREA that enabled sponsors to skirt requirements for paediatric studies, according to a September 2017 “FDA Voices” column by then-FDA Commissioner Scott Gottlieb, MD. The loophole became apparent when sponsors sought and obtained orphan designation for paediatric subtypes of “otherwise common and non-orphaned” adult diseases, Gottlieb explained.

Volume 12 Issue 2

Therapeutics

Once a sponsor attained paediatric orphan designation for a drug, the product became exempt from PREA requirements — it never had to be studied in paediatric patients.

“In effect, by letting sponsors designate paediatric subpopulations of drugs intended to treat adult diseases, the drug

makers receive an unintended ‘free pass’ from having to study drugs in these or other paediatric uses,” Gottlieb wrote. “Thus, rather than ensuring more paediatric research, as Congress envisioned, we can end up with fewer paediatric studies.”

In the FDA’s introduction to Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases, the agency states that it “does not expect to grant any additional orphan-drug designation to drugs for paediatric subpopulations of common diseases.”

REFERENCES 1.

2.

3.

Section 504 of FDARA amended section 505B of the Federal Food, Drug, and Cosmetic (FD&C) Act. PREA is codified at section codified at 505B of the FD&C Act. Both lists are available at: https://www.fda.gov/AboutFDA/Centers Offices/OfficeofMedicalProductsandTobacco/OCE/ucm544641.htm

Meg Egan Auderset Meg Egan Auderset, MS, MSW, is a writer and editor of more than 20 years, with experience in a variety of settings in both the US and Western Europe. Currently a Medical & Regulatory Writer and Editor for Clarivate Analytics, her primary assignments include reporting on FDA advisory committee meetings and drug approvals for Cortellis and the AdComm Bulletin, as well as editing several publications.

Email: margaret.egan-auderset@clarivate.com

www.jforcs.com

Journal for Clinical Studies 33

Technology

Lessons Learned from the Clinical Trial Trenches: How to Use Patient Engagement Technology Successfully When Googled, “how to choose the right gift” returns 748 million results with articles written by Forbes, The Huffington Post, and more. This is with good reason.

Whether it’s a family member, a significant other, or a close friend, gift giving is an art that has the potential to take a good relationship to new heights or undercut its foundations. A good gift confirms your understanding of a person, their values, and their interests. A poor gift, on the other hand, can make the recipient question how well they really think you know them.

Taken within the context of clinical trials, patient engagement (PE) technology must be treated with the same reverence as gift giving. Put simply, organisations who don’t consider their audience will upset patients and sites, while potentially harming their trial. Thus we have giftwrapped our findings from an early 2019 webinar in order to share some best practices with the industry.

Be Mindful of the Patient and Site Populations Technology is great, but it can be a burden if not implemented correctly. You must consider the patient, and the site, and what’s right for them. Thus, before choosing PE, organisations must first understand the types of populations their trial will need while also considering their own goals and organisational structure.

force them to use yet another new tablet or phone. However, if they dislike the experience they are currently receiving with their devices, they may welcome a new start.

With all of these considerations at hand, it can be difficult for organisations to come to a solid conclusion about their patient and site populations. Thus, in order to make a well-educated decision, we recommend that organisations…

Create an Organisation-specific Decision Tree While our example tree (pictured to the right) is a fantastic starting point, we recommend companies create a decision tree that follows the logic of their trials.

An honest look at the trial and its goals will reveal how to best start on a decision tree. For instance, is the protocol complex? Would patients benefit from understanding why they are asked to do specific tasks, and how it may impact their health or the study? Do you think patients will need reminders to stay on target? Is patient retention critical? Are diaries involved?

Organisations that have a firm understanding of their needs will find that a tree allows them to easily choose the PE path that’s best for them. And, once they know the solution of best fit, they can begin to…

While these considerations may differ wildly across trials and companies, organisations should at least consider a population’s age, location, country, familiarity level, demographics, language, psychographics, and more before thinking about PE. For instance, does the trial involve older populations? If so, it’s important to note that while mobile uptake among older populations is lower compared to younger users, mobile technology may still be successful in certain trials, but additional care should be taken. People in this group typically prefer to be shown how to use the technology and have time to practise. They may do well with SMS reminders and emails but may be turned away by overengineered solutions that are complex to use.

Countries with very strict technology regulations, or places where technology is not yet prevalent, may require further evaluation.

However, it’s important to remember that PE does NOT need to be 100% deployed by a population in order to see important gains. Thus, if you have several countries where PE is a good fit, consider using it only in these areas.

When it comes to your clinical trial sites, it’s important to try to work within the boundaries that they are already using. If sites are well-versed with existing tablets and phones, a “bring your own device” (BYOD) application of PE will fare much better than trying to 34 Journal for Clinical Studies

Volume 12 Issue 2

Technology Pick the Right Partner Using Data Organisations must find a trusted and experienced partner that: 1.

2.

3.

4.

Understands the trial, has experience with the therapeutic area or patient population, has experience with the countries where the trial will be conducted, and has experience with similar studies.

In order to find the right partner who meets these needs, we recommend that organisations discuss proof points with their vendor, such as the ability to offer satisfaction surveys to patients and sites, reductions in protocol deviations, and increased patient retention rates.

When analysing data, it’s important to make sure that organisations are looking at comparable data that highlights how patients using PE tools did versus patients who did not. In instances where vendors don’t have an exact data match on your type of trial, look for something that’s a close fit. For example, if you have a phase two oncology trial in South Korea, oncology metrics in AsianPacific countries may be a good reference point to evaluate patient engagement fit in that region.

How to Measure Success Once in place, it’s important to start measuring the current success of your trial and PE vendor. This can be accomplished using the feedback mechanisms available to your site and patient populations.

Organisations who are using a low-touch SMS approach may elect to send a survey to patients, while those using full-fledged PE apps may prompt users to indicate their satisfaction within the application itself.

The primary goal of either of these approaches is to ensure that the patient has a “voice,” and that the patient voice impacts the way current and future trials are conducted. Organisations should also use these same tactics to assess the sites’ voice.

In addition to patient and site voice, organisations must ensure that they continually monitor: 1.

2.

3.

4.

5.

6.

Patient retention rates, protocol deviations, improved adherence to medication or procedures, diary completion rates, long-term follow-up, and any other metric that is vital to the success of the study.

Typically, this is achieved through access to the vendor’s system, a review of reports, governance meetings, or any other form of study check in. Regardless of the medium, it’s important to establish a regular cadence for review.

How to Maximise the Number of Patients Using PE Once the study is live and patients are enrolled, it’s important to help steer as many patients as possible towards PE. The best way to do this is by integrating PE early, such as during study consent, and also through site reinforcement. Start early, at the investigator meeting and ensure that each site receives training on PE, how to talk about it, and the benefits it provides to them as well as patients.

From here, find site champions who are using PE well and share their success stories. Leverage the data you do have to show others what they are missing and take time to speak with sites who have a low percentage of enrolled patients. www.jforcs.com

For sites who are reluctant to engage, deploy the features of PE to give them a voice. Ask them how they feel about the trial, PE itself, and what else can help them better run the trial.

Make it a Gift to Remember As stated earlier, technology is great, but it can be a burden if not implemented correctly. Thus, before implementing PE, organisations must consider the lives and experiences of their patients and sites.

That’s because, above all else, PE is like a gift. Good gifts stay with us, shaping the way that we feel and interact with that person for years to come. But then again, so do the bad ones.

Mindy Gruba Mindy Gruba is a Senior Product Manager at Signant Health, responsible for developing the product strategy and roadmap for TrialGuide, the company’s mobile solution for patient engagement in global clinical trials. Mindy has worked with top 20 pharmaceutical companies and CROs to develop gamification, patient education, virtual trial and mobile engagement strategies for vaccine, rare disease, and oncology studies, leveraging her 10+ years of experience in mobile technology, product development, and behaviour change communication. Prior to Signant Health, she worked at J&J’s Human Performance Institute and multiple health information technology start-ups, taking products from concept to market.

Mindy has also spent time advancing her health research and communication strategies at the NIH, Peace Corps, and NASA’s Kennedy Space Center. Mindy holds an MPH from The George Washington University and a BS from the University of Wisconsin-La Crosse.

Email: signant@discovery-pr.com

Journal for Clinical Studies 35

Technology

Technology at the Edge: Emerging Use of Actigraphy as an Outcome Measure Wearable devices incorporating actigraphic technologies are transforming the way researchers aggregate, display and interpret health-related data. These devices and the mobile software applications built to work with them enable researchers to monitor and capture data on a wide range of physiological functions – including cardiovascular parameters and movement, temperature, galvanic skin response, blood and oxygen saturation. The devices can collect data passively or actively, which can be used to collect data at random times, at all times, on a set schedule, or in response to specific prompts.

They can capture data while the patient is at home or at work, awake or asleep, active or at rest. Among wearable devices, the use of accelerometers has gained ascendancy because of the rich portfolio of information that can be derived.

Actigraphy has long been used to measure clinical sleep parameters, but the evolution of wearable technologies suggests a far wider range of applications such as safety monitoring, patient phenotyping and medication adherence monitoring. However, evolving capabilities raise questions about new methods of data acquisition, analysis and interpretation. They prompt discussion regarding data ownership, data sharing and informed consent.

These are questions that are accentuated by geographical differences in regulatory and societal endorsement, adding an element of complexity when it comes to incorporating wearables within the context of international clinical research.1 Nevertheless, both patients and developers are increasingly interested in using technology that facilitates ecologically meaningful assessments, while promoting more participatory activity on the part of patients and families. This interest ripples through almost every element of protocol design and study operations today, partially eclipsing the historical dominance of clinical measures with the capture of remote assessments.

Correspondingly, patients and advocacy groups are increasingly well-informed about emerging technologies in research and development and aware of potential benefits as well as possible liabilities.2 Actigraphy in Observational and Interventional Studies Wearable devices based on actigraphic technologies have proven to be useful for measures of sleep parameters such as total sleep time, wake after sleep onset, number of awakenings and sleep efficiency. There is an abundance of literature on the utility of actigraphy for this application and searching the terms “actigraphy” and “sleep” can retrieve over 3600 publications. More recently published data indicate that actigraphy can provide a moderately accurate way to identify levels of mobility in adults across a range of indications.

For example, a variety of accelerometer-based motion sensor devices with indirect calorimetry have been used successfully to measure physical activity intensity in youth with cerebral palsy.3–5 The data within this indication as well as others suggest that most instrumentation would have comparable performance 36 Journal for Clinical Studies

characteristics in the context of controlled activity movements.

With inter-instrument reliability (ICC=.94–.99) and good concurrent validity, all of these accelerometers discriminated physical activity intensity across most activity trials.6 Numerous studies have examined actigraphy tracking of motion in dementia patients and found that it was possible to acquire objective data on individual motor behaviour of patients using actigraphy and that sensor-derived analyses were consistent with clinical observations and symptoms.7–10 Thus, concordance between clinical measures of activity and those obtained through instrumentation generally are supported within different environments, although exceptions and potential confounders have been reported.

A study by Straiton et al. (2020) on the validity and reliability of consumer-grade activity trackers in older adults found that while wearables accurately measured step count and activity duration, slower walking pace and impaired ambulation reduced the levels of agreement.11 A paper by Verceles and Hager (2015) reviewed several studies that used accelerometry to measure physical activity in the care of mechanically ventilated adult ICU patients. It found that while accelerometry correlated well with direct observation in reporting the frequency and duration of various physical activities (rolling, sitting up, transferring, walking), it could not differentiate intensities of activity or whether movements were voluntary or involuntary.12 Likewise, a case study by Lauritzen et al. (2013) examined activity trackers in walker-dependent elderly with reduced mobility. Their findings indicated that slow walking speed and gait disorders hampered the utility of these devices for physical activity measurement, a finding that is clinically intuitive.13 A 2017 study by Mitchell et al. found that activity patterns vary across lifespan and differ by race, sex, and education – potentially identifying additional sources of variability.14 A 2019 meta-analysis of actigraphy found that daily activity tracking is effective in evaluating mood disorders and treatment effects, but the study also identified confounding factors, including the type of actigraphy device used, patients’ illness severity, hospitalisation versus outpatient status and the influence of medications.15 As studies move to use consumer-grade actigraphy devices for data collection in real-world settings, new parameters influence decisions for the use within protocol, including technical issues such as disconnection and syncing challenges, practical considerations such as loss of the device, and the logistics required to ensure smooth data collection across sites, regions and phases of protocol.16 Controlled Activity Versus Spontaneous Movement Measuring how accelerometers perform in tracking and permitting quantitative analysis of freestanding, spontaneous movements, remains to be established, although promising results have been reported.

A home study using accelerometers to evaluate upper-limb activity in non-disabled adults and adults with chronic stroke produced results that were consistent with findings from patients in the more controlled setting of an inpatient rehabilitation Volume 12 Issue 2

THE CURE FOR THE COMMON CRO It’s hard to put a finger on what, exactly, makes Worldwide different from other CROs — but you 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 www.jforcs.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

Journal for Clinical Studies 37

Oncology and Hematology | Other Therapeutic Expertise

Technology centre.17,18 Another study found that accelerometer-produced data on upper limb daily performance was highly consistent across neurologically intact, community-dwelling adults. Yet another study proved the validity of accelerometry to assess bilateral upper extremity activity during the performance of set, everyday tasks in neurologically intact adults.19,20 These findings indicate that accelerometers can produce clinically meaningful data in both clinical and non-clinical settings when the framework for the movement is defined. However, the small number of data sets as well as device limitations suggests improvements are needed. Wearable devices have been of questionable and inconsistent utility for measurement of movement, unless that movement is within a protocol with choreographed procedures. When manoeuvres have been codified and highly regimented, accelerometers have produced data that correlates well with clinical measures of interest. However, movement that is not orchestrated can also be informative, particularly when coupled with machine learning.21,22 An Emerging Opportunity: Extracting the Signal from the Noise As of February 2020, actigraphy is currently being used as an outcome measure in 762 trials on clinicaltrials.gov in a wide range of disparate indications, including arthritis, Alzheimer’s disease, cancer, multiple sclerosis, pregnancy, chronic pain and heart failure.

hypertension (PH) associated with interstitial lung disease (PHILD), which includes physical activity data captured by wearable actigraphy monitors.24 Ultimately, the granularity of data that might be obtained using an accelerometer offers an exciting prospect for innovative trial design. Actigraphy would provide an exceptionally attractive and clinically intuitive option, demonstrating a larger effect size with possibly fewer patients and a shorter duration of treatment to demonstrate other clinically relevant effects. Correlations with assessments based upon quality-of-life and patient-reported outcomes are also potentially demonstrated25–28, while assessment of key clinical sleep parameters is well established.29–32 For patient activity, structured data acquisition by time of day, day of week, and week of study has ascendancy, including sampling activity from orchestrated as opposed to spontaneous movement as a study end point.

REFERENCES 1.

2.

3.

Although studies suggest that the data collected through actigraphy correlates with functionally important outcomes, there remain open questions about how actigraphy might be used to maximally inform study sensitivity. Specifically, should it measure overall activity, overall activity minus sedentary activity, or moderate to severe activity only? Parameters include the number of days per week during which actigraphy will be used, the number of weeks during which the measurements will be captured, the number of hours within the week that need to be recorded, as well as the methods of aggregating the data and managing missing data for purposes of analyses.

Actigraphy focuses on measurable parameters, such as capturing daily time spent in non-sedentary activity and total daily life physical activity. In some studies, a mean value from the previous week of study treatment is proposed to determine the change from baseline conditions in interventional trials.

Others will simply collect activity data over a period of weeks without limitations in structure. Maximal use of accelerometers enjoys utility in observational studies to help define the range of assessments and sampling times that might be employed in a subsequent interventional study.

Proof of Concept or Potential Registration Study?

Actigraphy has ecological validity in a post-approval setting because it correlates well with quality of life, is easy for patients to use and can potentially monitor the effectiveness of clinical care.

For example, activity monitoring was shown to be an acceptable means of measuring functional status in idiopathic pulmonary fibrosis patients. The mean daily activity level correlated with quality of life (QoL) measures and forced vital capacity (FVC).23 Recent clinical trial announcements also suggest a growing acceptance of accelerometer data as an addition to traditional end points beyond the anticipated acceptability of this methodology within proof of concept or post-approval studies. In one example, the federal drug administration regulatory authorities (FDA) agreed to a Phase II/III study in patients with pulmonary 38 Journal for Clinical Studies

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Izmailova ES, Wagner JA, Perakslis ED. Wearable devices in clinical trials: Hype and hypothesis. Clinical Pharmacology and Therapeutics.

2018;104(1):42-52.

O’Hagan J, Zupancic B, Murphy MF. The Emerging Use of Social Media in Orphan Disease Drug Research: White Paper 2019.

Available from: http://www.samedanltd.com/uploads/pdf/white_ paper/5f082dd20953575838a34b3a8a0fd9ec.pdf.

Keawutan P, Bell KL, Oftedal S, Ware RS, Stevenson RD, Davies PSW et al. Longitudinal physical activity and sedentary behaviour in preschoolaged children with cerebral palsy across all functional levels. Dev Med Child Neurol. 2017;59(8):852-7.

Claridge EA, McPhee PG, Timmons BW, Martin Ginis KA, Macdonald MJ, Gorter JW. Quantification of physical activity and sedentary tme in adults with cerebral palsy. Med Sci Sports Exerc. 2015;47(8):1719-26.

Gorter JW, Noorduyn SG, Obeid J, Timmons BW. Accelerometry: a feasible method to quantify physical activity in ambulatory and nonambulatory adolescents with cerebral palsy. Int J Pediatr.

2012;2012:329284.

O'Neil ME, Fragala-Pinkham M, Lennon N, George A, Forman J, Trost SG. Reliability and validity of objective measures of physical activity in youth with cerebral palsy who are ambulatory. Phys Ther. 2016;96(1):3745.

Fleiner T, Haussermann P, Mellone S, Zijlstra W. Sensor-based assessment of mobility-related behavior in dementia: feasibility and relevance in a hospital context. Int Psychogeriatr. 2016;28(10):1687-94.

Ishimaru D, Tanaka H, Nagata Y, Takabatake S, Nishikawa T. Physical activity in severe dementia is associated with agitation rather than cognitive function. Am J Alzheimers Dis Other Demen.

2020;35:1533317519871397.

Knuff A, Leung RH, Seitz DP, Pallaveshi L, Burhan AM. Use of actigraphy to measure symptoms of agitation in dementia. The American Journal of Geriatric Psychiatry: official journal of the American Association for Geriatric Psychiatry. 2019;27(8):865-9.

Hartman YAW, Karssemeijer EGA, van Diepen LAM, Olde Rikkert MGM, Thijssen DHJ. Dementia patients are more sedentary and less physically active than age- and sex-matched cognitively healthy older adults. Dement Geriatr Cogn Disord. 2018;46(1-2):81-9.

Straiton N, Alharbi M, Bauman A, Neubeck L, Gullick J, Bhindi R et al. The validity and reliability of consumer-grade activity trackers in older, community-dwelling adults: A systematic review. Maturitas.

2018;112:85-93.

Verceles AC, Hager ER. Use of accelerometry to monitor physical activity in critically ill subjects: A systematic review. Respir Care.

2015;60(9):1330-6.

Lauritzen J, Munoz A, Luis Sevillano J, Civit A. The usefulness of activity trackers in elderly with reduced mobility: a case study. Stud Health Technol Inform. 2013;192:759-62.

Mitchell JA, Quante M, Godbole S, James P, Hipp JA, Marinac CR et al.

Variation in actigraphy-estimated rest-activity patterns by demographic factors. Chronobiol Int. 2017;34(8):1042-56.

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Tazawa Y, Wada M, Mitsukura Y, Takamiya A, Kitazawa M, Yoshimura M et al. Actigraphy for evaluation of mood disorders: A systematic review and meta-analysis. Journal of Affective Disorders. 2019;253:257-69.

Duignan C, Slevin P, Sett N, Caulfield B. Consumer wearable deployments in actigraphy research: Evaluation of an observational study. JMIR Mhealth Uhealth. 2019;7(6):e12190.

Bailey RR, Klaesner JW, Lang CE. Quantifying real-world upperlimb activity in nondisabled adults and adults with chronic stroke.

Neurorehabil Neural Repair. 2015;29(10):969-78.

Rand D, Eng JJ. Disparity between functional recovery and daily use of the upper and lower extremities during subacute stroke rehabilitation.

Neurorehabil Neural Repair. 2012;26(1):76-84.

Lang CE, Waddell KJ, Klaesner JW, Bland MD. A method for quantifying upper limb performance in daily life using accelerometers. J Vis Exp. 2017(122).

Bailey RR, Klaesner JW, Lang CE. An accelerometry-based methodology for assessment of real-world bilateral upper extremity activity. PloS one. 2014;9(7):e103135.

Andreu-Perez J, Garcia-Gancedo L, McKinnell J, Van der Drift A, Powell A, Hamy V et al. Developing fine-grained actigraphies for rheumatoid arthritis patients from a single accelerometer using machine learning.

Sensors (Basel). 2017;17(9).

Clevenger K, Moore RW, Suton D, Montoye AH. Accelerometer responsiveness to change between structured and unstructured physical activity in children and adolescents. Measurement in Physical Education and Exercise Science 2018.

Crooks M, Hart S. M265: Daily activity monitoring in idiopathic pulmonary fibrosis. Thorax. 2014;69:A219.

FDA agrees to change study of Bellerophon’s INOpulse for PH-ILD patients [press release]. Pulmonary Hypertension News. 2019.

Evangelista LS, Dracup K, Doering L, Moser DK, Kobashigawa J. Physical activity patterns in heart transplant women. J Cardiovasc Nurs. 2005;20(5):334-9.

Innominato PF, Komarzynski S, Palesh OG, Dallmann R, Bjarnason GA, Giacchetti S et al. Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer. Cancer Med. 2018;7(9):4396-405.

Deenik J, Kruisdijk F, Tenback D, Braakman-Jansen A, Taal E, Hopman-Rock M et al. Physical activity and quality of life in longterm hospitalized patients with severe mental illness: a cross-sectional study. BMC Psychiatry. 2017;17(1):298.

Anokye NK, Trueman P, Green C, Pavey TG, Taylor RS. Physical activity and health related quality of life. BMC public health. 2012;12:624.

Smith MT, McCrae CS, Cheung J, Martin JL, Harrod CG, Heald JL et al.

Use of actigraphy for the evaluation of sleep disorders and circadian rhythm sleep-wake disorders: An American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2018;14(7):1209-30.

Yavuz-Kodat E, Reynaud E, Geoffray MM, Limousin N, Franco P, Bourgin P et al. Validity of actigraphy compared to polysomnography for sleep assessment in children with autism spectrum disorder. Front

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Kawada T. Validation study of accelerometer in measuring some sleep parameters in adults. Sleep Breath. 2018;22(2):537-8.

Marino M, Li Y, Rueschman MN, Winkelman JW, Ellenbogen JM, Solet JM et al. Measuring sleep: accuracy, sensitivity, and specificity of wrist actigraphy compared to polysomnography. Sleep. 2013;36(11):1747-55.

Andrew Kuhlman Andrew Kuhlman, MS, is a Medical Writer at Worldwide Clinical Trials. He has a master of science in microbiology, immunology, and molecular genetics from UCLA. He has previously held a role as a research associate at Harvard Business School, where he has published case studies for MBA students on advanced financial instruments.

Email: andrew.kuhlman@worldwide.com

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

Email: michael.murphy@worldwide.com

Melissa L. Vadnais Melissa L. Vadnais, VMD, PhD, is a Clinical Research Methodology Fellow at Worldwide Clinical Trials. She has a comprehensive understanding of multiple diseases and focuses on the scientific method and treatment development to best optimize patient health outcomes. She holds a cell and molecular biology doctorate from the University of Minnesota.

Email: missy.vadnais@worldwide.com

Journal for Clinical Studies 39

Technology

The Digital Twin in Clinical Research

In industrial applications the concept of digital twins is successfully applied currently to gain insights into complex processes. In clinical research this concept would offer impressive advantages. Its implementation requires major challenges to be met.

Background Clinical research is facing a paradoxical situation: Production processes in the pharmaceutical and medical device industry are driven by a high level of automation, control, and traceability. Digital twins of assets and processes are established by using internet of things (IoT) technology to acquire massive amounts of data in real time. On the other hand, clinical research still relies on collecting huge amounts of data from subjects at rather few points in time. It relies on data being manually entered into CRFs or being manually copied from medical records. Things turn out to be even more paradoxical, when the same subjects are using wearable devices to continuously track sleep, heart rates, or physical activity. They are creating their digital twin as well. Indeed, it is a paradoxical situation. But creating and using digital twins in clinical research could boost efficiency and data quality.

Digital Twins in Industrial Production In industrial production, the concept of digital twins is gaining a lot of attention throughout the past few years; it is thought to be one of the major trends in information technology as well. In industrial production, such digital twins are the key to real-time optimisation and decisions. They are used for simulation, for education, and for virtual prototyping as well. Some of the most interesting applications can be found in the field of predictive analytics, when digital twins are being used to predict future performance and failure of their counterparts.

Being a digital, thus virtual, representation of assets, processes, people, systems, etc., a digital twin needs to be far more than a structural design. They need to include dynamic properties as well. Such properties are derived from sensor data that is being acquired in real time, which is probably one of the most important applications of so-called internet of things (IoT) technology.

Following this concept, the digital twin’s physical counterpart is equipped with a set of connected sensors that collect data continuously. A digital twin therefore basically consists of a huge and growing amount of data that sufficiently reflects all required structural and dynamic properties.

Of course, the massive amount of data, all related hardware and software, as well as the corresponding statistical approaches brought a revolution to industrial production, which requires the convergence of operation technology (OT) and information technology (IT).

Decreased lot sizes, reduced maintenance efforts, and improved quality are promising results of current digital twin approaches.

The Visit Gap At first glance, clinical research and production might look rather disparate. A closer look unveils important similarities: 40 Journal for Clinical Studies

• • •

In both worlds a lot of effort is put into ensuring a high level of quality and traceability.

Processes are usually standardised and documented, which allows for automation and modelling.

Collecting, storing and analysing data is inevitable.

When clinical data is being collected through the course of a study, this aims at providing sufficient evidence for efficacy, tolerability, and safety. Such data therefore serves as the subject’s digital twin. However, the way data is acquired for this digital twin does not fulfill the requirements that we would expect nowadays for a digital twin in production, because clinical data is usually collected at very sparse points in time, usually during the subject’s visits (Figure 1). This visit gap in data acquisition might be appropriate for slowly changing parameters like the subject’s weight. Fast-changing data (e.g. physical activity) cannot be captured adequately. Spontaneous events (e.g. cardiac arrhythmia) might simply be missed, if they do not occur during a visit. The visit gap therefore imposes major limitations to the digital twin, which is why the gap should be narrowed down.

Figure 1. Data acquisition in presence of visit gap

Bridging the Visit Gap Traditionally, the visit gap in data recording can be bridged by using patient-reported outcomes (PRO), either with paper-based diaries or with modern ePRO software. PRO approaches clearly rely on the subject’s compliance in entering the correct values at the intended time or event. Therefore, a lot of effort is put into monitoring the subject’s compliance. On the other hand, using PRO implies parameters that can be recorded by the subject.

The PRO market has already seen several diagnostic or therapeutic devices that have been extended by diary functionality, reminders etc., e.g. for COPD monitoring. Such devices can improve compliance in using the devices and entering data. However, they still require interaction by the user and do not usually record data in a continuous way.

Continuous data recording would ultimately bridge the visit gap, because relevant parameters are recorded 24/7. For such purposes, wearable devices (Figure 2) are spreading in the consumer market, where users try to learn more about their individual level of fitness.

Most of the time those wearables are worn as smartwatches or integrated into textiles. They provide continuous recording of heart rate, ECG, blood pressure, blood glucose levels, physical activity, Volume 12 Issue 2

Technology temperature, sleep, physical stress, and much more. Wearable technology brings in many important advantages for within clinical research: • • •

Wearables can be used at home requiring only few training efforts.

Data acquisition is performed automatically, i.e. the subject is not required to enter data or to trigger recording manually.

Automatic recording reduces effects due to subject noncompliance and potential fraud.

cardiac arrythmia event) be uploaded to the clinical database, while irrelevant data is omitted automatically. This approach is currently being used in medical event recorders as well as in consumeroriented wearables.

Besides those rather strategic questions, there are some rather practical considerations: • • • •

Figure 2. Example of a wearable device worn as chest strap

Rethinking Data Analysis Diaries and CRFs are designed to collect data in a structured and study-specific way. Wearables and other network-enabled diagnostic or therapeutic devices often provide less structured, complex streams of real-time data. Such data streams offer deep insights into the subject’s health status as well as treatment effects or safety events. Unveiling such relevant pieces of information from a vast amount of data requires the use of advanced data analysis techniques.

Traditionally, activity measures and quality of life measures are highly aggregated scores that are provided by the subjects themselves. With 24/7 recordings of physical activity such scores can be derived in a more objective way (Figure 3). The same applies to stress levels, sleep, etc. Safety-related events (e.g. arrythmia, immobility, fever, etc.) could also be detected in the data streams automatically, which already is applied in consumer devices.

Figure 3. Processing of data streams

Technical Challenges Applying analysis techniques to streams of data might sound straightforward; in fact it assumes a single stream of data to be available. Most of the time, multiple sensors are needed; their individual data streams need to be concentrated by gateway systems, which requires common communication protocols to be used for every sensor. Unfortunately, the market for wearables and for other diagnostic and therapeutic devices is still rather heterogenous towards communication protocols.

The massive amount of data requires a rethinking of data storage.

Database technology, especially so-called timeseries databases, is required on the device level. However, there are important strategic decisions needed: Uploading all data to cloud systems could result in data privacy issues and cause high archiving efforts throughout the retention period. Therefore, data could be pre-processed locally and only relevant features (e.g. time and characteristics of a www.jforcs.com

Low power consumption and user-friendly charging options (e.g. wireless charging) are needed for battery-powered devices.

Broadband communication might be unavailable due to the building’s structure or to regional restrictions in service.

Firmware upgrades need to be applied without user interaction.

Technical support needs to be available for a variety of devices.

Data Security and Privacy Data security traditionally focusses on confidentiality, integrity and availability. From the technological point-of-view there are wellproven approaches to ensure security for the digital twin and the devices used to maintain the digital twin. Nevertheless, the scenario involves some threats that are challenging in total. All devices are connected through networks, most of these being wireless networks.

Every device itself could be compromised, which would affect the whole network. Threat modelling and security analysis is inevitable, as are secure programming techniques. The variety and rather large number of devices involved requires automatic monitoring systems to be in place that detect outdated firmware revisions, manipulation attempts or limitations of service.

Privacy tends to be critical for the subject’s digital twin, because it offers deep insights into the subject’s health status. Therefore, common privacy standards, like the GDPR, impose additional requirements for personal health information (PHI). Those include data encryption, access control, the individual’s control, etc. PHI becomes even more critical when 24/7 data streams are stored, because they would allow insights into the health status that exceeds the trial’s focus, which raises ethical questions as well. In any case, the digital twin must include a sponsor view that ensures necessary data and information are hidden.

Regulatory Challenges Decentralised 24/7 recording and storage of data raises the question of source data and audit-trail maintenance. The same applies to raw sensor data versus processed event data. Consumeroriented device manufacturers are struggling with the national certifications, because of the different regulations. Those challenges are accompanied by discussions related to direct data capture (DDC) that we have seen during recent years. All those questions involve a high level of uncertainty, which is also reflected by contrary opinions of auditors and inspectors.

At first glance, validation activities might look much easier to handle than the rather general questions raised above. A lot of experience is available towards device validation. However, there are specific characteristics that need to be considered, e.g. security testing, distributed systems, usability, and most of all, assessment of performance and reliability for powerful data analysis techniques.

From Subjects to Trials Besides the subject’s digital twin, there are other applications where digital twins could improve processes in clinical research. Every clinical trial itself could be digitally represented by a digital twin.

This twin would comprise the trial’s structure, i.e. visits, inclusion/ exclusion criteria etc., as well as dynamic properties. Data needed for this can be acquired from various electronic tools available, Journal for Clinical Studies 41

Technology

e.g. e-CRF, e-TMF, IWRS, CTMS etc. Merging this data into a digital twin appears to be quite similar to current approaches like dashboards. Its intention, however, is different in a way that it is less focused on specific KPIs or rule-based alerts, but rather provides a rich data source for anomaly detection. Where KPIs and rules are used to monitor expected deviations, anomaly detection can unveil unexpected deviations upon statistical measures.

With the traditional set of tools and processes, a trial’s digital twin could suffer from some data being collected only during on-site visits. This can best be seen when looking at the several logs and trackers that the monitors need to check. They also indicate potential for acquiring data automatically. IoT technology, e.g. identification techniques, connected devices, etc., can provide such data. Moreover, integrating all subjects’ digital twins into the trial’s digital twin could massively improve availability and completeness of data. This would change monitoring and oversight processes completely.

Conclusion Digital twins in clinical research offer impressive advantages like 24/7 data recording, automatic assessment of health status, reporting of safety-related events, etc. Appropriate analysis techniques need to unveil relevant pieces of information out of heterogenous streams of real-time data, which could be acquired by using IoT technology. Wearables are a well-proven approach for 24/7 automatic recording of subject-related data. IoT technology as well as the corresponding storage, communication, and analysis 42 Journal for Clinical Studies

processes are spreading outside clinical research. While the technology basically is available, there are major challenges related to data security, data privacy, and regulatory compliance. Those challenges and concerns might remind us of the change from paper CRFs to electronic CRFs. Besides such challenges, there is the everyday challenge of recruiting subjects. Digital twins can lower the burden for subjects to fulfill their duties because of automatic data recording. Of course, if subjects are used to track their personal health status with smartwatches, connected balances, etc., they would expect clinical research to use such technology as well.

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 the founder and CEO of PCQ Pilots in Bremen (Germany), a vendor of various software solutions for clinical research, including e-CRF, e-TMF, risk management, randomization, and training. He is also an honorary professor for computer science.

Email: joerg.mielebacher@pcq-pilots.com

Volume 12 Issue 2

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Journal for Clinical Studies 43

Talking Point

Home Trial Support Q1: We have seen the industry adopt the term “patientcentricity” in an effort to increase patient engagement. What impact do you think the patient-centric movement has had?

A: Patient-centricity has been at the core of MRN since its inception in 2006 so I believe its impact is substantial.

However, the term “patient-centricity” can have different meanings depending on how you engage with patients.

Therefore, it may be difficult to measure the true impact of “patient-centricity”. For MRN, patient-centricity means we put the patient at the centre of what we do – by bringing the trial to the patient, in their own community. The patient-centric movement in the industry is in response to a chronic, long-term reduction in patient recruitment and retention. For many years, access to the study IMP was considered sufficient to attract patients to trials, coupled with a willingness to do whatever their doctor advised them. Over the last two decades we have seen a cultural shift away from blind trust in doctors as well as a broadening of therapeutic areas under research – embracing many more mild and moderate conditions as well as more rare but serious conditions. All of these changes mean we have to be more aware of the patient’s needs in order to enrol them in studies. The patientcentric movement recognises patient need and has introduced patient involvement, from how we assess their condition medically (making it more relevant) to how we manage the logistics of the trial with the patient in mind (reducing the impact on their lives). MRN works in the latter part of this scope. In our hands, recruitment will increase in a site operating Home Trial Support anywhere from 60% to 600% (we have seen all of these) and retention levels hit around 98%.

Q2: Companies today are more open and do not view patients as simply subjects who generate data – but as informed collaborators whose participation is core to the overall success of trials. Can you talk us through the current trends and new, innovative opportunities in the industry that you think of as patient-centric?

A: We know that 85% of clinical trials fail to recruit enough patients and 30% of patients drop out of studies once they enrol. Because of this, CROs and sponsors are focusing on innovating to improve trial design and implementation in collaboration with their patients.

While there are many innovations in clinical trials today, more so than I have seen at any other time in my 30 years in the industry, only some of these are patient-centric; others are focused on sites or sponsors.

Firstly, we’ve seen innovation in community-based trial services.

Each of these can operate separately but the best results will come from a combination in any given trial.

44 Journal for Clinical Studies

•

Home Trial Support. Our own core service, allowing patients two key freedoms – to be seen where they want, and to be seen when they want. This reduces the impact of the trial on a patient’s life and is profound if they don’t have frequent travel to a site. This service has seen exponential growth over the last decade.

•

Telemedicine. This service is much newer, is sweeping through the mainstream health sector and is finally getting traction in trials. It will be a critical way of keeping patients in the community, again reducing the impact of the trial.

•

Concierge services. This has been available for several years now and is best suited for very long travel and overnight stays for patients and families when they still have to go into the site.

We’ve seen an increase in the patient voice.

•

There is a new approach of many specific condition charities to focus on their own investment in trial sponsorship, turning their advocacy into investment – a huge benefit in focusing the patient voice. Organising patients into effective advocates improves the way we listen to and address the needs of patients in trials.

•

Digital endpoints are now more relevant to patient outcomes, more sensitive than traditional assessments and simpler to do.

This is already adding value and will accelerate dramatically in my view in the next few years.

•

FDA requirements for patient-orientated endpoints are now starting to penetrate requirements for endpoints in draft labels and in dossier reviews. Other regulatory authorities are behind but starting to catch up.

Lastly, we’ve seen innovative approaches to data collection.

•

Sensors in the home and in wearable devices are now able to gather data about a patient on a continuous basis. These are likely to be strongly outcome-based at present – measuring activities of daily living, for example.

•

As we see various methods of measuring simple but powerful parameters, we can combine them into complex algorithms to predict changes in illness, leading to earlier diagnosis and awareness of disease progression.

•

Data capture techniques have extended to more patientfriendly devices such as their own phones and watches, and further integration with traditional data collection systems is simplifying the approach and reducing costs, as well as making data easier to report for patients.

Volume 12 Issue 2

Talking Point Q3: Putting the patient first is at the forefront of MRN’s Home Trial Support (HTS), a service that is designed to positively impact the patient experience. Can you tell JCS how MRN seeks to make participation easier for patients in clinical trials?

A: Some of the biggest challenges of delivering a successful clinical trial are identifying, recruiting and retaining patients. A patient-centric approach asks the question “How do we meet the needs of patients to make it easier for them to take part in our trial?”

Although there is limited publication in this area, what does exist, along with expert opinion, is clear. Patients want to travel less, to be at a site visit for less time and to be able to have visits out of hours and any day of the week. They want reduced time costs and incidental costs for them and their partners, carers and families.

Patients want the freedom to be seen where they want. Given the chance to be seen at home, patients will take it. Not offering it to them because they CAN get to the site misses the point. By not having to travel to the site, they can get on with their lives. An hourlong visit takes all afternoon in a clinic, and incurs travel costs (a pain, even if they are reimbursed).

Patients also want the freedom to be seen when they want – not just on the day the clinic is open. They may need to go to school, go to work, look after family and a host of other things they want to fill their lives with. They want to be people first and patients second, but the system rarely allows that.

The convenience that a community trial solution like Home Trial Support (HTS) offers patients makes trials with these services more attractive to patients and keeps them in trials once enrolled.

It’s important to note that we don’t replace the site or the oversight of the principal investigator, we simply relocate a number of visits.

The simple step of seeing a patient at home for perhaps two-thirds of their visits allows for a much better experience for the patient.

We encourage drug developers to offer innovative services allowing patients to participate from their community, not only to retain patients, speeding up the trial, but also to give patients a better opportunity to care for their families and maintain their everyday lives.

Q4: The relationships between sponsors, contract research organisations (CROs) study sites, and vendors can present many challenges in clinical trial planning and execution. How does MRN work to engage with all stakeholders to ensure the success of the trial? How do you forge and maintain strong relationships with the site study team?

A: It’s important that all stakeholders have clear pathways of communication with each other. We know from working with all parties that when open communication is hampered, it leads to silos, creating a lack of transparency of workflows. Ultimately, this type of organisation will lead to unnecessary and costly delays.

Workflow transparency allows service providers to have access to each other’s systems when necessary; this is especially important when implementing in-home and remote solutions. In addition to clear communication, it’s important that we all understand we have shared patient-centric values and goals. www.jforcs.com

Patient-centricity is not something that should exclude any given stakeholder. Sites and sponsors are critical to trial success and their needs also need to be met. What we should aim for is balance. We all benefit from a successful trial and that can only happen when all stakeholders communicate and collaborate. Sites and sponsors are incredibly important to MRN and we work hard to ensure they feel comfortable using our services and confident in the quality of care we are providing their patients.

Q5: What are your thoughts on the growing trend in the use of technology and telemedicine in clinical trials and how is MRN responding? Do support organisations like MRN have the ability to work with technology providers as the digitisation of clinical trials increases?

A: MRN have always valued innovation in clinical trials and we feel that telemedicine is a significant step in the right direction for the industry’s drug developers and for patients. It has clear synergies with Home Trial Support. Some visits need a physician assessment that does not require an examination. In other cases, a nurse may be concerned about a patient and need a medical opinion, which can be accessed on the spot through a telehealth service. We can imagine several other scenarios where nurses and technology work together. We have an R&D function within our business, dedicated to finding new ways to work and new ways to offer our existing services. Telemedicine has been part of this exploration as we strive to continue building a patient-centric service and innovate to keep up with the growing trends in the market. As a result, we have successfully delivered our services alongside telemedicine for several studies. We have also worked with the extended eCOA solutions, BYOD solutions and internet-enabled devices for specific data collection.

Q6: We’ve seen MRN listed as one of the UK’s top 1000 companies on the London Stock Exchange, with MRN having a reported 30% + CAGR year after year. What has made MRN so successful in the clinical trial support organisation sector?

A: MRN was founded by and is currently run by experts with decades of experience running trials in project management, nursing and pharmacy.

Our experienced team focuses on structure, quality, resource management and financial control which has given us the ability to be an ultra-high growth business (defined as over 25% per annum) since 2006. This way of operating has allowed us to scale consistently to meet our customer needs whilst maintaining our quality mantra. Within MRN, we have almost 1000 years combined experience in clinical trials and we partner with other sector-leading services providers when required. We’ve performed over 40,000 visits and continue to evolve our services in response to trends in the market, securing MRN’s growth as a leading provider for the foreseeable future. Our success is not only a result of our experience and quality delivery but it’s also because of our people.

Teamwork, engagement and creativity are our core values that we started the business with and continue to guide us today. We focus heavily on employee engagement within our business. We have unusually high scores using the Gallup 12 engagement scoring system (a de facto corporate gold standard), meaning our people like working at MRN and work hard for everyone’s mutual benefit – not just for MRN, but also for each other, for patients and for customers.

Journal for Clinical Studies 45

Special Feature

Q7: There is a lot changing in the industry and there are a lot of potential solutions to trial challenges. How do all the innovations we’ve spoken about fit together and how do you think these innovations will shape the future of clinical trial design?

A: Clinical trial designs are going to start to change.

Data collection will move out of visit structures and start to be designed into streaming data collection tools. Nursing in the home will be for ‘high touch’ trial designs – blood sampling, drug administration, targeted examinations, complex operator assessments (ECG, spirometry) etc. Technology will focus on automated measurements, questionnaires and self-assessments. Yet all IMP is inherently dangerous, and technology cannot yet replace an experienced professional meeting a patient face to face and assessing their morbidity – face-to-face elements are likely to remain, some in the home and some at the site. Phase IV trials are more likely to be ‘low touch’, requiring less, sometimes zero, face-to-face contact. We will see visit schedules determined only by medical need and patient psychology, rather than simply being the only way to collect data.

Some visits might be suitable for telemedicine, some might be better face to face with a physician, some can be done by a nurse. Each innovation we’ve discussed has a different and complex rationale; improvements in quality, changes in data types, increases in speed of recruitment and improved (endpoint) relevance to the patient.

46 Journal for Clinical Studies

If patient-centricity works, more patients will recruit per month and be retained. That must ultimately decrease recruitment times and probably reduce site numbers. MRN has complex models that show the improvements we see in recruitment lead to costneutral budgets. The optimal solution will depend on the style of trial being designed, the therapeutic area, the development phase, and more. Protocol designers are going to have to get their heads around these changes to unlock the true value of the solutions – as of today, we have barely scratched the surface.

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 Medica l 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 13 years.

Volume 12 Issue 2

THE LEADERS IN DELIVERING IN-HOME CLINICAL VISITS We understand the complexities of today’s clinical trial environment and the burden this places on patients and sites. Our services are designed to ease these burdens, from community nurses through to investigator site professional support, accelerating patient recruitment and retention. We work to maximize the efficiency of clinical trials for drug developers, by improving the patients' experiences, no matter where their community is in the world.

We are constantly innovating based on our industry-leading experience, so we can deliver the complex efficiently, bringing trials to patients.

www.themrn.co.uk UK Tel: +44 (0)1908 261 153 I HTSinfo@themrn.co.uk I US Tel: +1 (847) 779 7857 www.jforcs.com

Journal for Clinical Studies 47

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Worldwide Clinical Trials

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Volume 12 Issue 2

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