JCS Volume 13 Issue 3

Volume 13 Issue 3

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

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The Use of Psychedelics in Neuropsychiatry A New Era in Research Prevention is Key: Shifting the Mindset to RBQM From Little Acorns: A Scandinavian Study’s Implications for Paediatric Development The Central Role of Interactive Response Technology in Today’s Clinical Trials

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Contents

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker BUSINESS DEVELOPMENT Jerome D'Souza info@pharmapubs.com EDITORIAL MANAGER Beatriz Romao beatriz@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Virginia Toteva virginia@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications J101 Tower Bridge Business Complex London, SE16 4DG Tel: +44 02045417569 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

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FOREWORD

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Assessing Study Design and Matching to Systems Based on Efficiency and Cost Outline

Prior to the pandemic, a survey was conducted asking clinical professionals from pharma, clinical research organisations, clinical sites, and clinical vendors alike what they perceived to be their biggest challenges. Ethan Nichols at Illingworth Research investigates how companies have created their systems based on efficiency and cost outline.

8

Interim Report Shows FDA Meeting Goals for Efficient, Transparent Review of Biosimilars Applications

The Program for Enhanced Review Transparency and Communication for 351(k) biologics license applications (BLAs) of the US Food and Drug Administration (FDA), provided for in the Biosimilar User Fee Act (BsUFA), has been “successful” and has provided enhanced review transparency and communication to industry. Molly Fellin Spence at Clarivate evaluates the interim report that shows FDA meeting goals for efficient, transparent review of biosimilars applications.

10 Pandemic Industry Impact – One Year On The pandemic has taken its toll, transforming many markets and sectors irrevocably. Organisations operating within the clinical trial space alongside cold chain collaborators have had to revaluate prepandemic processes. However, there are signs providing hope of lasting change within the industry, which will benefit patients and companies alike. Dave Williams at Peli BioThermal summarises the impact of the pandemic in the industry, one year after the start of the COVID-19 pandemic.

12 A Novel Approach to Clinical Supply Chain Systems Integration In an era of rapid transformation in clinical trials, research sponsors are presented with new logistical and clinical supply management challenges that can be addressed by employing a new approach to clinical supply chain efficiency. Bart Nicholson at Signant Health analyses the novel approach to clinical supply chain systems integration.

REGULATORY 14 Prevention is Key: Shifting the Mindset to RBQM

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

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

Volume 13 Issue 3 June 2021 PHARMA PUBLICATIONS

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Far more than a series of linear quality checkpoints along the way, RBQM spans the clinical trial continuum, scanning data as it accrues and assessing it holistically to detect issues or trends that require further evaluation. Amy Kissam-Sands at Parexel explores why companies must be committed to adopting this mindset for RBQM to be successfully applied across all clinical trials.

16 Preparing – at Last – for IDMP Adoption: How Life Sciences Should Ensure Readiness The objective of IDMP, to save patient lives, bears repeating, especially given the years that have elapsed since its conception: IDMP will make it easier to mine product data to safeguard patients.

With that goal, and a looming compliance deadline, in mind, it Journal for Clinical Studies 1

Contents is time for life sciences companies to resume their preparations accordingly. Karen Harry and Amy Williams at Calyx analyse how IDPM standards will be a significant undertaking requiring careful planning and coordination across many internal functions and external partners.

disorder (SUD), and post-traumatic stress disorder (PTSD). Beatrice Setnik at AltaSciences explains more about the use of psychedelics in neuropsychiatry.

MARKET REPORT

40 The Central Role of Interactive Response Technology in Today’s Clinical Trials

18 Communicating with Patients – Who and How? Even though patient-friendly versions of many regulatory documents are now mandated by the regulations, the most frequently encountered reaction to communicating patient information is apathy, and there are many possible reasons for this. The most usual is that patient information is seen as ‘nothing special’, and something that ‘anyone can write’. Lisa James at Trilogy Writing clarifies who should, and how to, communicate with patients.

22 Clinical Trials in Medical Devices: Life Cycle Risk Management Risk refers to the chance of suffering loss or injury, or anyone proposing a hazard. The process of risk management identifies, evaluates and prioritises potential hazards, then applies initiatives and resources to minimise, coordinate and manage the possibility of hazards occurring, and to lessen the effect of any concerns.

Balamuralidhara. V, Prasannakumar P Bhat et al. at JSS College of Pharmacy describe the fundamental principles of project risk management, and how clinical information can be used to manage risk in medical device projects.

TECHNOLOGY

The clinical trial process has been undergoing substantial change in recent years – even more particularly in the past 12 months. The first signs of the evolution began in the 2000s when protocol complexity significantly increased. Michelle Lynskey at ICON plc. examines the critical delivery elements required from interactive response technology (IRT) providers to support this evolution, with particular focus on the needs of COVID trials.

42 Flexible Virtual Trials for Patient-centricity, Efficiency, and Better Data Before the pandemic, virtual and hybrid trials were a novelty. Although enabling technologies such as bring your own device (BYOD), electronic patient-reported outcomes (ePRO), and direct data capture (DDC) have been in place for several years, the implementation of these hybrid approaches stagnated. Now, remote trials are a proven and valuable necessity. Jonathan Andrus at Clinical Ink discusses practical considerations in virtual and hybrid trials and how these trials can help reduce cost, deliver cleaner data, and improve patient acceptance and engagement.

26 Nursing Report Sheet: An Essential Tool for the Clinical Research Nurse In the past, the research nurse had little time to read the entire protocol and, to manage scheduled visits, they developed nursing summaries of clinical trials. Discussing nursing summaries can help assess research workload, allowing for better planning and resource allocation. Documenting care is not only a legal obligation but, above all, a mature, responsible, and ethical way of acting professionally.

Properly documenting is the best way to protect the two components of healthcare: the citizen, on the one hand, and the professional, on the other. Michela Melissa Stuccillo and Diana Sufragiu at VitaSalute San Raffaele University clarify the experience of creating the nursing records as an essential tool for collecting good quality data in clinical trials.

THERAPEUTICS 30 From Little Acorns: A Scandinavian Study’s Implications for Paediatric Development In December 2020, a paper was published in the journal BMJ Paediatrics Open, a respected journal with a relatively modest impact factor of 2.496, regarding paediatric medicinal product availability in Scandinavia (Norway, Sweden, Finland and Denmark). Harris Dalrymple and Mark Sorrentino at Center for Pediatric Clinical Development analyse the Scandinavian study’s implications for the development of the paediatric department.

34 The Use of Psychedelics in Neuropsychiatry – A New Era in Research Psychedelic drugs are currently under research in several neuropsychiatric disorders, including major depression, substance use 2 Journal for Clinical Studies

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Foreword Effective doctor-patient communication is an essential clinical function in building a therapeutic doctor-patient relationship, which is the heart and art of medicine. This is important in the delivery of high-quality healthcare. Much patient discontent and many criticisms occur due to breakdown in the doctor-patient relationship. However, many doctors tend to misjudge their ability to communicate. Over the years, much literature has been published on this important topic.

Even though patient-friendly versions of many regulatory documents are now mandated by the regulations, the most frequently encountered reaction to communicating patient information is apathy, and there are many possible reasons for this. The most usual is that patient information is seen as ‘nothing special’, and something that ‘anyone can write’. Lisa James at Trilogy Writing clarifies who should communicate with patients, and how to do it.

With an ever-increasing demand for healthcare and financially constrained budgets, it has never been more significant to have the right staff who are educated and competent, delivering the best possible care at the right time for patients. Leadership and innovation are the keys to developing and delivering the right services and care and improving health and wellbeing outcomes for people. Registered nurses are increasingly extending and expanding their scope of practice beyond initial registration in all healthcare settings, developing their skills, competence, and confidence.

In the past, the research nurse had little time to read the entire protocol and, to manage scheduled visits, they developed nursing summaries of clinical trials. Discussing nursing summaries can help assess research workload, allowing for better planning and resource allocation. Documenting care is not only a legal obligation but, above all, a mature, responsible, and ethical way of acting professionally. Properly documenting is the best way to protect the two components of healthcare: the citizen, on the one hand, and the professional, on the other. Michela Melissa Stuccillo and Diana Sufragiu at Vita-Salute San Raffaele University clarify

the experience of creating nursing records as an essential tool for collecting good quality data in clinical trials.

For years, the field of mental health has been largely barren of meaningful treatment advances. But now, scientists have a new hope in the least likely of places: psychedelic drugs. Recent research suggests that certain psychedelic substances can help relieve anxiety, depression, PTSD, addiction, and the fear surrounding a terminal diagnosis.

Psychedelic drugs are currently under research in several neuropsychiatric disorders, including major depression, substance use disorder (SUD), and post-traumatic stress disorder (PTSD).

Beatrice Setnik at AltaSciences explains more about the use of psychedelics in neuropsychiatry.

In this journal, we will also explore more about the paediatric aspects that are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain paediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework.

In December 2020, a paper was published in the journal BMJ Paediatrics Open, a respected journal with a relatively modest impact factor of 2.496, regarding paediatric medicinal product availability in Scandinavia (Norway, Sweden, Finland and Denmark). Harris Dalrymple and Mark Sorrentino at the Center for Pediatric Clinical Development analyse the Scandinavian study’s implications for the development of the paediatric department.

I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals. I hope that you enjoy reading this edition of the journal and keep well.

Beatriz Romao, Editorial Co-Ordinator Journal for Clinical Studies

JCS – Editorial Advisory Board

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Hermann Schulz, MD, Founder, PresseKontext

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

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

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

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Catherine Lund, Vice Chairman, OnQ Consulting

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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Deborah A. Komlos, 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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Steve Heath, Head of EMEA – Medidata Solutions, Inc

• •

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

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Francis Crawley, Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

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Georg Mathis, Founder and Managing Director, Appletree AG

4 Journal for Clinical Studies

Volume 13 Issue 3

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

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

Patient

Powered by Illingworth Research Group

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

Contact us info@illingworthresearch.com Journal for Clinical Studies 5 www.illingworthresearch.com

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Assessing Study Design and Matching to Systems based on Efficiency and Cost Outline We live in a complex world. We are constantly being thrown new problems and trying to find the best and most efficient solutions to those problems. As business competition grows, companies are being forced to think outside of the box more than ever before to provide solutions to their daily challenges.

The clinical health services industry is no different.

Prior to the pandemic, a survey was conducted asking clinical professionals from pharma, clinical research organisations, clinical sites, and clinical vendors alike what they perceived to be their biggest challenges1. Of those surveyed, the four most significant issues industry stakeholders faced were increasing trial complexity (21% of respondents), meeting regulations (15% of respondents), costs being at an all-time high (15% of respondents), and patients being more difficult to access and retain (12%).

Once the pandemic hit, it was estimated in March of 2020 that over 1000 clinical trials were disrupted by COVID-19 and that number has certainly increased in the last year2. In light of this, the need for clinical research continues to grow. However, the execution of clinical research is becoming more difficult than ever before.

For many, it came as a shock when first hearing of major clinical research organisations closing their doors due to the pandemic.

Many companies across the world had to determine how best to move forward considering this unforeseen circumstance. This past year, clinical research has had a spotlight on it and pressure has mounted as we have tried to recover. No one is exempt from this increasingly difficult state. All of us are having to rethink study design from a patient safety perspective. The traditional and longheld model was for patients to travel to a clinical trial site or hospital for treatment. Now, the traditional model is being forced to adapt and develop to a new way of operating.

Fast-forward to the present, a year after the beginning of the COVID-19 lockdown and the pandemic is still the biggest stressor in our industry and one of the biggest stressors of our lifetime. Billions of people across the globe have had their lives disrupted. Clinical professionals are pushed to their limits every day to stay ahead and need to rethink the way clinical trials are conducted. We are being forced to make exceedingly difficult decisions and to answer new questions, such as: • How do we safely get patients to and from clinical sites?

• How do we ensure patients are safe and healthy on-site?

• How do we keep patients enrolled in studies?

• All the while, clinical sites are trying to keep their own team members safe, sane, and healthy.

For many, this pandemic has been far from restful and has brought new layers of intricacies to the clinical industry. As soon as 6 Journal for Clinical Studies

we resolve one concern, we are barraged with three more. For many of us, we are doing all we can to just keep our heads above water. If the survey mentioned earlier was conducted today, I am sure results would indicate that trial complexity and patient retention are the most significant challenges being faced. For many, that can come at a costly price.

On the other side of the coin, patients are wondering if it is even worth it to enroll or stay enrolled in a clinical study. Many patients who badly need treatment are dropping out of studies because of unforeseen risk. Not to mention, if these are patients with rare diseases, then the stakes are even higher when travelling and spending nights at hotels and/or clinical sites. When considering patient health and trial complexity, there is simply too much at risk for one company to provide all the necessary solutions.

As a team member for a company that specialises in mobile research nursing and patient concierge services, I am bombarded with difficult clinical trial designs from clients who need sustainable, cost-effective, clinical trial mitigation strategies. To provide these solutions, our efforts must focus on and assess clinical trial study design first and foremost.

But this time, we are assessing study design not just from a client’s perspective but also through the eyes of the patient.

Many might think that patient and client needs do not always align, as if they are two pieces from completely different jigsaw puzzles. However, we believe these needs can both be mutually satisfied in a study design. A study developed with each patient in mind will not only satisfy patient safety needs but will in turn prove to benefit the client. One of the best examples of how this occurs is through assessing patient retention strategies.

Since the dawn of COVID-19, individual health and safety has been reprioritised as our highest concern. We have even adopted taglines such as “stay safe” or “stay home”. Patient and individual safety alike are at risk and public fear has peaked. Many have been encouraged to stay home and some countries have even enacted stay-at-home orders. Thus, retaining patients has been a growing headache for clinical sites in every country.

Not only is there a risk to those involved in clinical research, but there is also a risk of sabotaging quality patient data. For many patients with rare diseases, the stress of leaving home is high and can interfere with normal bodily rhythms, cause patient anxiety, and increase vital sign variability. Not only do clinical sites need to think about patient retention, but they also must think about how accurate that patient data will be. It is a lose-lose situation for both the clinical company and the patient alike. So, how do we right this ship and get clinical research back on track?

Our tried method to eliminate these risks is through mobile research nursing services that are designed to meet the patient Volume 13 Issue 3

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exactly where they are in their lifestyle, whether that is at work, home, or another convenient location (COVID-19 restrictions allowing). These services allow patients flexibility and help them establish routines to achieve what all people desire; to live a normal life. For many patients, especially if they are plagued by rare diseases, our services have shown promise in delivering patient satisfaction, retaining patients throughout study timelines, and delivering high-quality data with cost savings.

While patient-centricity is excelling, it has come with its fair share of preconceived notions. Many think that a patient-centric model must have major drawbacks. One of the biggest concerns future clients have is how much our services will cost. Rather, the question should be how much value can a patient-centric model bring to the study? From our experience, our services have provided clients with excellent value by reducing clinical site costs and improving patient retention.

Other misconceptions we have received are that clinical sites and hospitals tend to perceive mobile research nursing services as more work for them and less revenue earned. But, in reality, clinical sites and hospitals generally still have access to an agreed-upon percentage of the fee. Also, mobile research nursing will allow site staff to focus on visits and procedures required at the site, which will increase their study capability. This helps distribute the on-site visit workload to the clinical site and the off-site visit workload to mobile research nursing services.

Lastly, many pharmaceutical and clinical service companies continue to perceive mobile research nursing services as a ‘nice to have’ commodity to offer patients which is far too difficult to realistically implement. We receive many questions and concerns about how our services can fit into elaborate study designs. These are the exact questions that we love to answer. We are willing to think outside the box with our clients to assess patient visits that can feasibly be conducted away from the clinical site. We have found that mobile research nursing can provide efficiencies such as reducing trial timelines, keeping patients on study, taking pressure off clinical sites, and producing high-quality data all at the patient’s convenience. Most preconceived notions we have come across are simply misplaced and do not align with our true service offerings.

In addition to our mobile research nursing services, we also offer patient concierge services for patients to safely travel to and from clinical sites. For these visit types, it is a tall order to transport patients to and from a site in a safe and risk-free manner.

Our services include booking travel and managing transportation logistics and overnight accommodation to help eliminate patient www.jforcs.com

stress and unforeseen circumstances faced when travelling. These services help take the burden off the clinical site and patient.

In certain countries, we even offer a unique travel solution to better protect patients, with specialist vehicles fitted with fully sealed and secure passenger compartments, electronic door controls, and independent ventilation systems between patient and chauffeur. All our chauffeurs are tested for COVID-19 prior to pickup. Patient pick-up and drop-off are no-contact, to eliminate risk for the patient. We also meticulously clean the cabin and provide readily available hand sanitiser to patients. This is a patient-centric service offering that works well for clients who simply cannot adjust their trial study designs due to complexities.

In reflecting on this season, if I have learned any one thing, it is that patient safety is of the utmost importance in moving clinical research forward. Having our backs against the wall, we have learned to be more efficient by developing new patient retention strategies, reducing trial timelines, and increasing data quality.

However, the most noteworthy efficiency is the ability to start once again and move research forward. Who knew a virus of all things could close healthcare research facilities? Forward progress is something that we have all taken for granted at one time or another.

May we never again take progress nor our patients for granted.

REFERENCES 1.

2.

Burrows A. (2016, November 30). REPORT: The 8 biggest challenges facing clinical trial professionals Information Connect – Clinical & Medical Affairs. Retrieved from https://informaconnect.com reportbiggest-challenges-clinical-trials-pt-1 GlobalData Healthcare (2020, May 7). U.S. Clinical Trial Sites are Most Affected Due to the Covid-19 Pandemic. Retrieved from https://www. clinicaltrialsarena.com/comment/us-clinical-trials-covid-19/

Ethan Nichols Ethan Nichols is an accomplished proposal manager in clinical research, supporting mobile research nursing services and patient concierge services in both non-rare & rare disease trials. Using a patient-centric research model, he supports the business development and operations team at Illingworth Research Group – A Syneos Health company. Ethan serves both patients & clinical service companies to better develop patient-centric clinical models that create value for clients.

Journal for Clinical Studies 7

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Interim Report Shows FDA Meeting Goals for Efficient, Transparent Review of Biosimilars Applications Overall, the Program for Enhanced Review Transparency and Communication for 351(k) biologics licence applications (BLAs) of the US Food and Drug Administration (FDA), provided for in the Biosimilar User Fee Act (BsUFA), has been “successful” and has provided enhanced review transparency and communication to industry. This is according to Valerie Overton, vice president, Eastern Research Group, Inc. (ERG), who presented the independent contractor’s interim assessment of the programme at an FDA public meeting in late January 2021. The FDA and industry provided similar perspectives on the programme’s successes and challenges during the meeting.

ERG’s interim report on the programme was released on December 2, 2020. Data collection for the report involved FDA databases, direct observations, primary documentation, and post-action interviews with programme applicants and FDA review teams through September 30, 2020. The data encompass original 351(k) BLAs that were submitted and received a first-cycle action — approval (AP), complete response (CR), or withdrawal after filing (WD) during this time.

The goals of BsUFA II, reauthorised in 2017 to cover fiscal years (FYs) 2018 through 2022, are outlined in the FDA’s BsUFA II commitment letter. Promoting the efficiency and effectiveness of the first-cycle review process and minimising the number of review cycles necessary for approval are the main aims of the programme, the FDA has said.

That patients have timely access to safe, effective, and high-quality biosimilar and interchangeable biological products is the ultimate goal for the programme.

In order to enhance review transparency and improve communication between FDA review teams and applicants, the FDA has implemented a new review model for all 351(k) applications. This allows for additional communication between agency review teams and the applicants of biosimilar biological products in the form of a biological product development (BPD) Type 4 meeting.

Both mid-cycle communications (MCCs) and late-cycle meetings (LCMs) were cited during the January meeting as having enhanced the predictability of reviews by serving as “anchor points” for review work and planning, according to Overton. MCCs and LCMs provide a forum for multi-disciplinary discussion of application status and paths forward to resolve approvability issues promptly, if possible.

with the FDA, the report found. ERG recommended that the FDA consider soliciting discussion topics from the applicant and allocating time in the LCM agenda for applicant-identified discussion topics. FDA target dates for information request (IR) responses were sometimes impractical for applicants with a global presence, Overton said. In some cases, time zone differences prevented one- or two-day response times.

ERG recommended that, when feasible, the FDA should propose IR response times of >two days or issue IRs earlier to allow for extended response times.

FDA Perspective Sarah Yim, MD, director, Office of Therapeutic Biologics and Biosimilars, Center for Drug Evaluation and Research (CDER), FDA, presented the FDA’s perspective on the interim assessment of BsUFA II. Among specific recommendations for changes in BsUFA II are minor iterative operational improvements based on best practices, Yim said.

Process and documentation improvements for key review areas is a major objective of the New Drugs Regulatory Program modernisation effort, and the FDA plans to consider how to more consistently implement the best practice recommendations across the therapeutic speciality areas.

As of January 2021, Yim said, the FDA had approved 29 biosimilar products, and a total of 20 biosimilars were launched and are being marketed in the US (see Table 1). The gap between approval and marketing exists due to challenges in biosimilar development such as finding a global comparator for Phase III confirmatory clinical studies and issues with patent abuses, Yim said. There are also challenges to a viable and competitive biosimilars market due to exclusionary contracting practices and stakeholder misinformation (either explicit Table 1. Currently Marketed FDA-Approved Biosimilars Reference Biosimilar Biosimilar name Launch date product Sponsor Neupogen Zarxio (filgrastim-sndz) Sandoz Inc September 2015 Nivestym (filgrastim-aafi) Hospira, Inc October 2018 Remicade

Overton also stated that LCMs have generally been most valuable to applicants when they were able to discuss additional topics of interest 8 Journal for Clinical Studies

Celltrion, Inc

November 2016

Renflexis (infliximab-abda)

July 2017

Avsola (infliximab-axxq)

Samsung Bioepis Co, Ltd Amgen Inc

Neulasta

Fulphila (pegfilgrastim-jmdb)

Mylan GmbH

July 2018

Coherus BioSciences, Inc Sandoz Inc

January 2019

Avastin

Mvasi (bevacizumab-awwb)

Hospira, Inc, a Pfizer Company Hospira, Inc, a Pfizer Company Amgen Inc

June 2020

Epogen/Procrit

Udenyca (pegfilgrastimcbqv) Ziextenzo (pegfilgrastimbmez) Nyvepria (pegfilgrastimapgf) Retacrit (epoetin alfa-epbx)

Zirabev (bevacizumab-bvzr)

Pfizer Inc

December 2019

Kanjinti (trastuzumab-anns)

Amgen Inc

July 2019

Ogivri (trastuzumab-dkst)

Mylan GmbH

December 2019

Trazimera (trastuzumabqyyp) Herzuma (trastuzumab-pkrb) Ontruzant (trastuzumabdttb)

Pfizer Inc

February 2020

Celltrion, Inc Biologics Consulting Group, Inc, authorized US representative for Samsung Bioepsis Co, Ltd Celltrion, Inc Pfizer Ireland Pharmaceuticals Amgen Inc

March 2020 April 2020

Herceptin

The ERG assessment found that in the BPD Type 4 meeting process, providing pre-submission advice and templates for application content and organisation helps sponsors prepare applications that meet FDA expectations, Overton said. By requiring application completeness, the programme has enhanced the FDA’s ability to conduct first-cycle reviews more efficiently and effectively. Thus, ERG recommended that the FDA establish this as good practice in the BPD Type 4 meeting process.

Inflectra (infliximab-dyyb)

Rituxan

Truxima (rituximab-abbs) Ruxience (rituximab-pvvr) Riabni (rituximab-arrx)

July 2020

November 2019

November 2018 July 2019

November 2019 January 2020 December 2020

Table 1. Currently Marketed FDA-approved Biosimilars Volume 13 Issue 3

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or implicit), as well as issues with reimbursement and formulary placement, according to the FDA. Industry Perspectives Several industry organisations delivered prepared remarks on the interim assessment during the January 2021 public meeting. They included Hillel P. Cohen, PhD, executive director, scientific affairs, Sandoz Biopharmaceuticals (a Novartis Company), who spoke on behalf of the Biosimilars Council, a division of the Association for Accessible Medicines. Cohen noted that the percentage of BLA approvals increased after the FDA moved to a 12-month review cycle, compared to 10 months, and called that “a win for all”, including the FDA, manufacturers, and patients. Cohen encouraged further development of transparent communication to assess whether improvements in the BsUFA III programme will continue to enhance the system.

Juliana Reed, MS, vice president, Pfizer Biosimilars, and president of the Biosimilars Forum, spoke on behalf of forum members.

Reed acknowledged the “extremely challenging conditions” in which the FDA had to work in 2020, due to the COVID-19 public health emergency. Despite these challenges, staff across all FDA departments worked tirelessly, Reed said, and she thanked the agency for “remarkable performance during trying times”. Overall, the ERG findings reflect experiences of the forum’s member companies, Reed said. According to the Biosimilars Forum, however, the FDA has met its commitments under the programme.

Presenting on behalf of the Biotechnology Innovation Organization (BIO) was Camelia Thompson, PhD, senior director of BIO’s Science and Regulatory Affairs. According to BIO, the interim findings are encouraging and BsUFA II has been successful in enhancing transparency and communications — the latter are www.jforcs.com

excellent, constructive, and cooperative. Thompson said BSUFA III can build on the successes of BsUFA I and BsUFA II, in seeking ways to improve efficiency to enhance biosimilar development programmes. In BSUFA III, BIO recommends that the FDA develop a more efficient and effective review process.

Jessica Tyson, PhD, MPH, director, Science and Regulatory Advocacy, Pharmaceutical Research and Manufacturers of America (PhRMA), said that group is “encouraged” by ERG’s conclusions in the interim assessment. Specifically, PhRMA agrees with the recommendations proposing IR response times of >two days or issuing IRs earlier to allow for extended response times. Providing more timely feedback to sponsors and more complete guidance, establishing review timelines for safety labelling updates, and hiring recruitment and retention of staff are all items to consider for further improvement, Tyson said.

ERG will continue to collect and analyse data and will analyse regulatory outcomes across first and second cycles of review if data are sufficient. The final assessment will be completed by June 30, 2022.

Molly Fellin Spence Molly Fellin Spence is a writer and editor with more than two decades of experience in publishing. She specialises in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin with Clarivate.

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Pandemic Industry Impact – One Year On

As the COVID-19 crisis continues to have an impact globally and the world works towards a post-pandemic future, much has changed within the past year.

The pandemic has taken its toll, transforming many markets and sectors irrevocably. Organisations operating within the clinical trial space alongside cold chain collaborators have had to revaluate pre-pandemic processes. However, there are signs providing hope of lasting change within the industry, which will benefit patients and companies alike.

COVID-19 clinical trials and vaccine development dominated the sector in 2020, leading to delays or the postponement of numerous non-COVID clinical trials; however, the sector’s seeing a resurgence of non-pandemicrelated trials.

COVID Response Initial COVID-related trials were centred on speed-to-market, getting trials actioned in a bid to develop and produce the first approved vaccines to help fight the virus. In the initial pandemic response, cold chain challenges included needing to meet the varying temperature requirements of various vaccines being developed, approved, and transported globally.

Ensuring cold chain protection throughout the pharma process is critical. From the outset, there was an initial requirement for colder temperature conditions, determined by the requirement of the vaccine or therapeutic that was being developed and approved. Whereas there was a requirement to provide deep-frozen temperature protection for the first vaccines and therapeutics, we are now seeing that shift, whereby the sector is increasingly focused on making moves from deep-frozen to more refrigerated storage temperatures for pandemic payloads.

The initial requirement for -50°C and -60°C alongside storage at the end user point was a challenge, and packaging providers had to adapt quickly to support the requirement, which is more difficult and costly for supply chains. Consequently, everyone is trying to move towards more regular distribution temperatures, whether that is +2°C to +8°C or controlled room temperature, that’s the goal – and I predict we will see more progression towards those temperature ranges.

COVID-19 vaccine development will need to continue. There was speculation at one stage that there would be a vaccine wave, which would ebb and everything would return to normal; however, I don’t see that being the case in the foreseeable future. We’ll continue to see waves of vaccines being developed for the next two to three years at least. It’s proving more challenging than had been anticipated to get the world vaccinated; it’s likely to take several years alongside administering required boosters.

Currently there is a lot of monitoring taking place within trials focusing on levels of anti-bodies once someone’s vaccinated and how long the vaccine has efficacy for.

10 Journal for Clinical Studies

With the number of variants emerging worldwide, going forward there will be the need for boosters and ongoing vaccine development in response, like what is in place for influenza with annual shots supplied.

Business Pressures Measures implemented initially, including temperature testing and contact tracing, have all advanced in the past 12 months, as companies and their suppliers had to learn to deal with COVID-19 challenges. The pandemic has had a huge impact on freight movement in the last year. With worldwide reductions in air travel, air freight was restricted and became very difficult to acquire and we have also seen reduced availability of ocean freight.

There were widespread disruptions including the impact on business travel, where sales teams had to learn to work remotely without being able to visit clients. Consequently, there were repercussions for international trade shows, further impacting an industry which revolved around these key global trade events. It’s anticipated there will be fewer trade shows staged this year and the learning and networking associated with live shows will return, albeit slowly.

Businesses have had to re-evaluate their supply chain, ensuring they have multiple suppliers for all critical components and had to increase inventory levels that are carried in case of interruptions to the supply chain.

Pharma companies also realised their supply chains were linear for some of the base supplies they utilise to create the drugs. As a result, it’s expected that’s going to lead to some reallocation of where APIs get manufactured, so they are located closer or there are multiple sources utilised. Whereas previously a lot was being sourced from China, it’s envisaged there will be a reshuffle to source from Korea, India, or other global locations.

The difficulties presented by the pandemic, however, have led to improvements. Most companies are now better prepared and have a much more robust supply chain in place.

From a logistical standpoint, a closed loop supply chain is so critical to the sector and there will now be more contingencies that need to be in place, especially as direct-to-patient rapidly increases.

Having a supply chain that’s agile and reliable is paramount.

The shift has been to ensure there is not a reliance on one single transportation mode when it comes to services: utilising all air, ocean, rail, and road options is key.

Direct-to-Patient Another significant change in the last year was the increase in direct-to-patient solutions because people were reluctant to go to clinics or hospitals to participate in any trials due to fear of catching COVID-19.

Increasingly, companies continue to see real advantages to going to the patient direct; although it’s more costly, it accelerates their results, which in turn brings its own financial benefits. Organisations Volume 13 Issue 3

Watch Pages had to find innovative ways to keep patients in trials, and alongside achieving faster results by going to the patient’s home, the number of patients participating has increased.

The shift to direct-to-patient was always the way the industry planned to progress; however, the pandemic accelerated this throughout 2020 because of participants’ reluctance to go into hospitals and doctors’ offices. Home-based trials are also offering opportunities for other therapies that are being researched, which the sector will need trials for going forward.

Developments within the temperature-controlled packaging space to supply solutions supporting these home-based trials effectively has included products which are easy to use to collect patient samples, without the need to condition phase change materials.

The rapid response by packaging vendors will see the continued emergence of new, more innovative products and adaptations of existing products, leading to different methods and approaches for future sample collection and drug delivery.

To support the growth in the direct-to-patient space we provide the industry’s most convenient patient sample solution patented technology. Alongside existing products we’re developing others to support more robust, worldwide, direct-to-patient clinical trials.

These include packaging products that are simple to use, convenient, incorporating a simple push-button system whereby a nurse practitioner or doctor pushes a button, and the cooling process starts immediately. Such innovative technology continues to attract interest from cell and gene companies.

From a logistical standpoint we’re increasingly seeing speciality couriers and pharma companies collaborating on how best to serve these growing direct-to-patient based trials. This patient-centric approach will be a major change continuing for the foreseeable future.

Conclusion While COVID-19 will continue to dominate the market there are still many clinical trials currently taking place centred on therapies and treatments for people who become ill from the virus.

It’s a growing market due to an aging patient population alongside the move towards large molecule biologic drug developments, and COVID-19 has accelerated that growth further. The resurgence in non-COVID trials will continue to gather pace and increasingly we will see more drugs entering the clinical trial chain that require temperature-control protection.

The sector’s response to the pandemic was rapid with everyone operating at such unprecedented speed, from the pharma companies through to the supply chain. Innovation saw new products brought to market at an incredibly fast rate to support the new demands.

Temperature-controlled packaging vendors will continue to adapt existing products to utilise dry ice as coolants. Although these products might not be as necessary now for ongoing vaccine distribution, we are seeing other emerging industries in cell and gene therapy that those pioneering products can be utilised for. It’s a further example of how the pandemic has spurred on industry innovation to generate different temperature-controlled packaging products for cell and gene therapy requirements. www.jforcs.com

At present a lot of cell and gene therapy is shipped in liquid nitrogen temperatures (-150°C /-200°C) which is difficult and costly for the pharma base, so they’re collectively looking to see how they can move to warmer temperatures, therefore dry ice is an alternative option.

Within the regenerative medicine space, the worldwide cell and gene therapy market is one of the fastest-growing segments with predictions of accelerated growth globally continuing over the coming years.

As the FDA, EMA and China continue to approve gene therapy products, the increase in delivering pharma products direct to patients’ homes helps grow patient population numbers and increase retention rates.

On reflection, the pandemic has led to the industry changing or revaluating the way they operate, introducing more efficient processes and products to ensure they remain resilient, whatever the future brings.

Dave Williams Dave Williams is the President of Peli BioThermal, a division of Pelican Products, Inc. In this role, he is responsible for the strategic growth of product and service offerings to serve Peli BioThermal’s worldwide clients and partners. Throughout his 30 year career, Williams has held many management and engineering positions. Prior to being appointed President of Peli BioThermal, he held the position of Vice President of Strategic Initiatives at Pelican Products, where he was responsible for the oversight and coordination of evaluating and enhancing the company's systemic strengths and minimising weaknesses for maximum efficiency and profitability, as well as executing approved growth strategies. Williams attended Harvard University in Boston, Massachusetts. He was a 2007 graduate of the Harvard Business School's Executive Strategy Leadership Program and the Thomson Executive Leadership Program.

Email: david.williams@pelican.com

Journal for Clinical Studies 11

Watch Pages

A Novel Approach to Clinical Supply Chain Systems Integration In an era of rapid transformation in clinical trials, research sponsors are presented with new logistical and clinical supply management challenges that can be addressed by employing a new approach to clinical supply chain efficiency.

As clinical trials continue to grow in complexity and scale, clinical supply management strategies should adapt to accommodate new logistical challenges inherent in modern medical research. Sponsors are collecting more data on more endpoints, often requiring multiple trials to run simultaneously in multiple countries. In addition, costs for investigational products, especially for advanced oncology therapies, continue to rise. From forecasting to distribution, an innovative new approach to Randomization and Trial Supply Management (RTSM) system design – enabling free picking instead of traditional RTSMbased ordering – can simplify supply chain processes, maximise product efficiency across studies, and reduce risks and costs over an entire clinical programme or compound.

Limitations to Traditional RTSM Implementations In a traditional RTSM implementation, study supply managers have two primary challenges. First, they must pre-allocate protocolspecific stock, estimating quantities needed for an individual trial while building in a supply buffer to account for unexpected spikes. The buffer usually results in overages that necessitate the destruction of the unused supply – a lost investment in the product as well as the additional costs incurred for their manufacturing, labelling, and storage.

Second, study supply teams are also responsible for coordinating supplies between primary depots and sub-depots, sites, and RTSM systems, which usually requires navigating between two or more software interfaces. This creates duplication of effort and opens the door to potential errors.

Supply Systems Integration and Free Picking Instead of this imprecise forecasting method and inefficient coordination process, an integrated “free picking” interface between the RTSM system and clinical supply management system creates continuity and flexibility by enabling drug pooling across protocols.

The new process has minimal impact on familiar workflows: the RTSM system's free picking interface informs the clinical supply management system how much of what drug is required at each site, much like a traditional ordering integration. However, rather than requesting supplies by specific kit numbers, the free picking RTSM system requests supplies by quantity. The warehouse then picks any kits associated with the dosage or type that are available and meet the needs of the requested shipment. The warehouse then records the data into the clinical supply management system, which in turn informs RTSM of the specific kits/lots/expiry to be sent to the clinical site. All downstream activities in RTSM then follow the traditional process of shipment tracking, receipt, allocation, etc.

This free picking approach maximises the usage of investigational compounds across programmes, as kits do not need to be pre-allocated for a particular study. Additionally, the seamless 12 Journal for Clinical Studies

integration between the RTSM and clinical supply management system simplifies the supply management process by reducing duplication of effort and manual data entry. For example, clinical supplies managers no longer need to release the drug into each RTSM. These advances contribute to operational efficiency and reduced costs – less stock is required since the free picking model enables flexibility with medications across studies. However, there are key design considerations to be cognisant of when designing the RTSM solution.

Design Considerations RTSM systems typically take into consideration a ‘do not ship’ (DNS) value to prevent the shipment of a drug that may expire before it can be received and allocated to a patient. In the new free picking model, this concept is still applicable but is handled slightly differently. The DNS date will be passed from RTSM based on the specifics of the order, and the clinical supply management system will enforce kit selection based on this input. In an advanced application, a dynamic DNS can be passed based on the specifics of the patient for which it is ordered. For example, a patient in a phase of the trial with extended visit windows could have an order placed with an extended DNS, whereas a patient in the phase with more frequent visits could have a shorter DNS passed. This flexibility helps optimise lot utilisation, especially for investigational products with a short stability profile.

Another major shift to traditional RTSM design is how and where a master kit list is stored. In the new free picking model, the RTSM system does not need to host it, as depot inventory lives exclusively at the clinical supply management level. What this means in practice is that once a lot has been released within the clinical supply management system, it is ready for ordering

by RTSM. No releases within RTSM are required. Additionally, common items such as depot transfers, relabelling, or updates to inventory that traditionally had to be replicated in RTSM no longer need to undergo this extra step. This simplifies the design of the RTSM solution, reduces setup effort, minimises user-accepted testing (UAT) effort, and most importantly, simplifies business process in production use. eClinical Integration While efficiency and accuracy in study supplies management is a critical factor in the success of clinical trials, sponsors can fully unlock potential time and cost savings across a clinical programme by bringing RTSM into their supplies systems within the larger eClinical ecosystem. At Signant Health, the patient journey begins with electronic informed consent (eConsent), which generates a patient record that then becomes available directly in the RTSM and electronic clinical outcome assessment (eCOA) systems. Critical touchpoints such as patient eligibility or outcomes data, which can directly impact statistical integrity in the randomisation algorithm, can be programmatically shared to avoid the risk of data entry error. This, combined with a free picking interface, helps ensure an accurate and efficient flow for the patient.

In clinical research, time is of the essence. Bringing together a consolidated, integrated platform, simplified through advanced Volume 13 Issue 3

integrations, will ensure that these technologies do not become the rate-limited factor, either at startup or during amendments. A more continuous, digitised approach to study launch and administration processes can reduce time, costs, and risks associated with navigating a complex landscape of disparate technologies.

Greater Flexibility Today, Future Ready for Tomorrow Sponsors rely on RTSM for effective and efficient allocation of supplies to patients. As trial complexity grows and use cases expand for RTSM to house more than just investigational products (e.g., ancillary supplies), the advantages of pooling are ever increasing.

While the drug pooling concept is not new, a free picking model within an integrated clinical supplies management provides study teams with greater flexibility and more accurate supply management over an entire programme or compound. Additionally, free picking is the first step towards future capabilities associated with just-intime labelling or manufacturing. The end result is a more efficient, simpler, and more powerful approach to RTSM.

Bart Nicholson Bart Nicholson leads the RTSM Product Management team at Signant Health. Since joining Signant in 2011, Bart has supported a diverse set of research projects and is passionate about advancing RTSM into the broader clinical technology platform, all while providing thought leadership as the industry moves towards direct-to-patient supply models. Bart has an undergraduate degree in computer engineering from the University of Delaware along with a Master of Business Administration from Drexel’s Lebow College of Business.

www.jforcs.com

Journal for Clinical Studies 13

Regulatory

Prevention is Key: Shifting the Mindset to RBQM One need only look back at the year behind us to recognise the power of prevention: reducing the risk of coronavirus infection is a far more effective strategy than battling acute symptoms of COVID-19 in the ICU. Similarly, preventive measures could save billions of dollars a year in healthcare spending and millions of lives, with research indicating that nearly half of all health burden in the US is attributable to 84 modifiable risk factors.1 Using the same underlying principle of prevention, the clinical research industry is increasingly adopting a risk-based quality management (RBQM) approach to identify subtle signals or anomalies that are harbingers of potential risks to patient safety or data integrity. The goal is to detect, evaluate signals and take action at the earliest stages of emergence before potential risks escalate into liabilities.

It is a necessary outgrowth of the exponential increase in data volume driven by the influx of real-world data from electronic medical records, patient claims data, sensors and wearables, patientreported outcomes, and much more. Assimilating this massive data repository necessitates a robust, unified and simplified approach to risk management.

What is RBQM? Far more than a series of linear quality checkpoints along the way, RBQM spans the clinical trial continuum, scanning data as it accrues and assessing it holistically to detect issues or trends that require further evaluation. The RBQM platform reviews risks to critical data regardless of source or format and ranks it by order of importance and relevance. Key principles of successful RBQM include:

Transparency: RBQM creates transparency between CROs, sponsors, and sites with team access to a real-time data dashboard that encourages group ownership and accountability to rapidly review indicators of risk and course correct at any and every point along the way.

Communication: Frequent, open dialogue encourages collaborative problem-solving. Expectations are set by the group, with each respective party as equal partners that collectively weigh in on decisions to pivot as data indicate the need. Together, the team establishes a triage process for addressing risks and assigning corrective actions.

Critical Thinking from End to End RBQM requires a cultural shift to flip the paradigm from a reactive, delayed response to a proactive, real-time analysis of critical data to drive key decisions about patient safety and data integrity. All parties are invested in identifying risks up front rather than putting out fires after an issue has been discovered downstream.

Because the data are being surfaced more quickly, they can drive key decisions early on in the study to enhance efficiencies and protect data integrity. For example, a site that shows the same blood pressure values for every patient with no deviations is an immediate indicator of an issue that sophisticated technology platforms can readily identify using statistical programs to aggregate and compare data from other sites. In the past, this error would have been discovered much later in the trial, at which point the CRO or sponsor would have had to question the integrity of all the site’s data. By viewing the data in totality, the RBQM framework embeds quality into culture of the organisation and views all elements as interrelated rather than siloed functions or disparate data elements.

Data Hierarchy: All data are not equal. RBQM establishes risk hierarchies to focus on critical data up front – primary, secondary, and safety endpoints – followed by performance and other data to provide a holistic review. In other words, RBQM is about the right data overseen by the right people at the right time.

Overcoming RBQM Stigmas The industry at large has viewed elements of RBQM with some scepticism – namely, its reduced reliance on conducting onsite monitoring with 100 per cent source data verification (SDV).

Typically, SDV is conducted at prescribed intervals throughout the study, serving as the primary mechanism to verify the integrity and reliability of the clinical trial data and subject safety.

Technology: RBQM leverages technologies with strong statistical power to determine absolute and relative values as well as abnormalities in data, with built-in pressure testing of models to validate their accuracy and strength.

But studies evaluating the error rates of SDV show that less than two per cent of data are inadvertently altered when entered into electronic data capture (EDC) platforms. Thus, the massive expenditure of time and resources yield minimal returns.

Integration: RBQM harmonises central, remote and on-site monitoring into integrated platforms, replacing siloed functions and spreadsheets with a holistic, cross-functional approach that aligns processes, people and technology. Attempting to retrofit RBQM into existing framework precludes the kind of culture shift required to truly embed RBQM into an organisation.

Of much greater value is evaluating critical elements of the data such as how endpoints are being captured and the safety factors related to the patient. This source data review process is much more robust and exhaustive than simply checking for transcription errors to ensure information was properly migrated from the source to electronic data capture systems.

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Volume 13 Issue 3

Regulatory interactive response technology (IRT) and clinical trial management system (CTMS) data all on one platform to catch indicators of risk early and often.

Decentralised Clinical Trials RBQM serves as the foundation for successful decentralised clinical trials, which generate large amounts of remote data from a multitude of sources. Performing a formal risk analysis at the protocol stage helps determine whether the trial will be fully remote or a hybrid model; selecting the most appropriate monitoring strategies; and providing critical insights regarding subject safety and data integrity.

While DCT adds innovative new mechanisms and technologies for study conduct, the core principles, processes, and technologies of RBQM still apply. Sponsors and CROs must predetermine key risk indicators (KRIs) and quality tolerance limits (QTLs) at the outset of a trial, then apply robust statistical analyses across the body of data to flag inconsistencies or deviations that could represent mistakes, non-compliance, equipment failures, performance issues or other concerns. In other words, identifying and surveilling critical data and critical processes are at the core in both DCT and traditional trials.

Known and unknown risks can be rapidly detected on both critical and non-critical data, reducing ‘noise’ by filtering out less relevant data. As such, RBQM does not reduce oversight — it simply allocates resources in a smarter, more efficient manner to identify barriers to operationalising a protocol at the site and patient level. The end result is fewer protocol amendments, fewer database changes, and faster completion of trials because the data are being assessed in a smarter way.

Scores of well-established benefits related to RBQM management adoption include: • • • •

4x lower error rate in critical data in a head-to-head comparison of RBQM to traditional 100% SDV approach2 Up to 40% faster database lock timelines compared to nonRBQM trials2 20% reduction in SDV2 45% reduction in the number of missing pages in RBQM trials vs non-RBQM trials2

Interoperability of Technology The sheer array of technology platforms with robust capabilities complicates the vetting and selection process. But choosing the right technology platforms – those that are compatible with your sponsors’ technology – will drive efficiencies across the trial. Among the many considerations, technology choices must be considered with the end user in mind, as layering on additional systems may discourage adoption and create inefficiencies that complicate the technology’s utility. The platform should also enable bidirectional data flow across multiple workstreams and use and reuse across various systems to increase transparency and efficiency.

Artificial intelligence and machine learning underlie the ability of RBQM to manage large amounts of data from multiple sources.

Using these platforms, RBQM leverages historical data across hundreds of trials to model predictive scenarios and categorise risk by severity of impact. They integrate electronic data capture (EDC), www.jforcs.com

RBQM is the Future In the simplest terms, RBQM is a mindset: a consultative approach in which the organisation builds into trials the potential for likely risks, continually monitors for risk signals, and mitigates risk potential before it undermines data integrity or patient safety.

As part of this consultative approach, CROs must leverage their historical knowledge from previous trials to inform future trials: what worked, what didn’t, how the therapeutic area, patient population, geographic region, and trial design impact risk up front and at every step along the trial continuum. RBQM requires good data stewardship and a cross-functional understanding of critical elements in the end-to-end process of clinical development.

While technology underpins the ability to effectively execute RBQM, companies must be committed to adopting this mindset in order for RBQM to be successfully applied across all clinical trials. RBQM should be seen as a business intelligence solution that utilises data exploration tools and personalised visualisation dashboards to allow groups to explore options, test hypotheses, and drive critical decisions throughout the lifecycle of the trial.

Attempting to retrofit RBQM into existing framework precludes the kind of culture shift required to truly embed RBQM into an organisation.

REFERENCES 1.

2.

https://www.thelancet.com/journals/lanpub/article/PIIS24682667(20)30203-6/fulltext Association of Clinical Research Organizations. https://www.acrohealth. org/wp-content/uploads/2019/10/EDL_ACRO_Graphics_CO3.pdf

Amy Kissam-Sands Amy Kissam-Sands achieved more than 20 years of senior level management experience, working in global Clinical Research Organizations (CROs), particularly in clinical operations, customer alliances, quality control, clinical process integration and technology platform development.

Journal for Clinical Studies 15

Regulatory

Preparing – at Last – for IDMP Adoption: How Life Sciences Should Ensure Readiness Above and Beyond XEVMPD IDMP represents a substantial evolution of existing pharmacovigilance reporting requirements in the EU. In addition to the data points required by the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), the following will be required: • Manufacturing functions, processes, and registered sites for the active ingredient(s), intermediates, and finished product • Details on the administrable dose forms and strengths for each medicinal product • The manufactured item describing the authorised pharmaceutical form of the product and, where applicable, before transformation into the administrable pharmaceutical form • Packaging details including the packaged item container, quantity, and material for the inner and outer packs • Marketing status at the pack level, identifying which products/packs are on the market across the EU • Legal status of supply (Rx or OTC) at the product level where the same status applies across all packs; at the pack level where the status differs

The fact that the EU will soon be implementing global product identification standards created by the Organization for Standardization (ISO) is hardly breaking news. The life sciences industry has known about the impending adoption of Identification of Medicinal Products (IDMP) for nearly a decade. However, the implementation timeline has been a moving target and for many companies this has meant that preparations for IDMP, originally begun in earnest, have understandably been deprioritised.

Publication of version 2 of the IDMP implementation guide by the EMA earlier this year makes it highly likely that in 2022 companies will be able to begin their IDMP iteration 1 submissions, with this becoming mandatory for centrally approved products the following year.

Providing and maintaining standardised IDMP data will have a farreaching impact across life science companies and is one of the most challenging changes that companies with products approved in the EU must address.

With the deadline finally on the horizon, life sciences companies need to regroup and ensure their data is ready for submission. Amidst numerous delays which have occurred over the last decade, extensive data quality assessments and revisions, and project scoping and budget requests, it is easy to forget what the original intention and purpose of IDMP was.

A Worthwhile Initiative, a Long Time in Coming The suite of five standards that compose IDMP have been developed in response to pharmacovigilance legislation enacted in the EU in 2012 (EU No 520/2012, articles 25 and 26). The legislation represented the biggest change to the legal framework for human medicines in a generation. The pharmaceutical industry and regulatory authorities went into the implementation planning fully aware that this would take years to deliver.

Under the legislation, all life sciences companies are required to submit detailed product data for all medicinal products approved in the EU so that descriptors are common across jurisdictions. The standardised identifiers will eventually provide a complete picture of every aspect of every product on the market – the indications approved, the marketing statuses, all product ingredients and manufacturers involved, down to the batch IDs. The standards are designed to support the exchange of unambiguous and accurate product information across global regulatory and healthcare communities. The overarching goal and driving force behind IDMP is to improve patient safety through stronger pharmacovigilance and risk management. Adverse event reports will be based on “a harmonised set of product definitions, improving the quality of data used for signal management and Full implementation of the PV legislation was estimated to save save up to 5910 lives per year and savings to society between 237 million and 2.4 billion Euros per year.2

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speeding up communication, decision-making and regulatory action.”1 The whole system will be built on a data-centric approach using structured content so that trends in safety issues will be easier to spot and sources traced more rapidly. Safety alerts will be easier to disseminate.

Once fully implemented, IDMP will enable products to be tracked from regulatory approval through to every market. The ability to mine and understand this data will allow organisations to flag potential challenges and, ideally, circumvent issues.

Key Aspects of Compliance Full coverage of the compliance requirements is beyond the scope of this piece, although the EMA has published several guidance documents explaining what will be required. The fundamentals are that: •

•

•

The EMA will create and maintain a product management service (PMS), and information already residing in XEVMPD for marketed products will be migrated into the PMS. The product information will need to be enriched to comply with IDMP requirements prior to any submission.

When an application for marketing approval and subsequent lifecycle variations are submitted to regulators via the EU Centralized procedure, the IDMP data elements must be submitted as a fast healthcare interoperability resources (FHIR) message in the working documents folder of the electronic common technical document (eCTD). This means that submitting the IDMP information is on a product’s critical path to regulatory approval.

Having to provide the structured data at the time of submission is a significant shift from submitting XEVMPD data following receipt of approval as we do today. What this means in practice is that the regulatory authorities will have additional structured data to support their review of dossiers. Thus, marketing authorisation holders (MAHs) need to ensure their regulatory information management (RIM) system is up to date at all times and reflects data pending approval in addition to approved details. Aligning dossiers and data will be critical to companies moving forward.

Volume 13 Issue 3

Regulatory A Thought on IDMP and COVID-19 The last 12 months in the COVID-19 pandemic have highlighted the criticality of structured data. With shortages in the drug supply and a dire need for global information sharing as the world has struggled to beat the virus, we can start to appreciate the value that IDMP will bring. Imagine the power of a common data repository on adverse drug reactions related to virus treatments and vaccines... or the benefit of being able to analyse the data you are collecting for EMA to better manage the drug supply and avoid the kind of shortages experienced during the pandemic. IDMP is just one of the structured data initiatives driven by EU Telematics, but the size of the data set and the cross-functional sources spanning regulatory, pharmacovigilance, manufacturing, and drug supply positions it for optimum impact. COVID-19 has proven the catalyst for change. Utilising IDMP to drive structured data governance across the industry will have far reaching benefits, the most important of which is patient safety.

The Time to Prepare Is Upon Us In February 2021, EMA published the second version of the IDMP implementation guide, which makes it highly likely that compliance for centrally approved products (CAPs) will be mandatory in 2023 (the option to start transitioning will begin no earlier than February 22, 2022). The first step of the targeted operating model (TOM) 'currently being finalised and will cover CAPS only. The second step of the TOM will encompass non-centrally approved products.

Life sciences companies that have grown jaded over the subject of IDMP or that have put off preparations should dust off their plans and recommit to readying their organisation. Developing a comprehensive readiness plan will entail (Figure 1):

•

•

•

be addressed first?

In advance of updating RIM systems, MAHs can identify complex CAPs and map these to the IDMP requirements. This will be a valuable exercise to help ensure data owners across the organisation are identified.

Developing and implementing an organisational change management programme with cross-functional representation, to encompass: • Agreeing on data ownership and responsibilities • Assessing significant changes to business processes • Assessing the impact on outsourced work and external partners • Delivering focused stakeholder education (to include third parties as needed) Investing in the RIM team’s skillsets so that team members are equipped to serve as the company’s lynchpins in complying with the regulation. They will need to work across the organisation to ensure that all stakeholders are aware of their responsibilities.

The RIM team must also be capable of coordinating an effective quality control process, engaging with those planning submissions and preparing dossiers, and providing input into the evolving support model.

Conclusion Picking up the adoption of IDMP standards will be a significant undertaking requiring careful planning and coordination across many internal functions and external partners. The objective of IDMP – to save patient lives – bears repeating, especially given the years that have elapsed since its conception: IDMP will make it easier to mine product data to safeguard patients. With that goal – and a looming compliance deadline – in mind, it is time for life sciences companies to resume their preparations accordingly.

REFERENCES 1.

2.

EMA website accessed at: (https://www.ema.europa.eu/en/humanregulatory/overview/data-medicines-iso-idmp-standards-overview) http://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=SEC:2008:2671:FIN:en:PDF

Karen Harry

Figure 1: A comprehensive IDMP readiness plan involves multiple components

•

•

Engaging with the company’s RIM system vendor to ensure that the system will be capable of accommodating IDMP requirements over a product’s lifecycle. Specifically, the RIM system will need to be upgraded to: • Capture all the required Iteration 1 IDMP information, in logically presented fields • Integrate automatically with source systems, according to their application programming interface (API) needs • Cross-reference data points so that information can be entered once and populated elsewhere as needed • Create the IDMP data elements as an FHIR message and include them in the working document folder in the eCTD for submission to the agency and where appropriate, support direct submission to PMS. Determining the company’s priorities for enriching the data that already exists in XEVMPD on products in their portfolio (there will be at least a one-year transition period for centrally approved products). Which products and data elements should

www.jforcs.com

Karen Harry has extensive industry experience in Regulatory Operations and Regulatory Information Management particularly in the implementation of regulatory processes and compliance with regulations. In her current role at Calyx she leads a team of Regulatory Consultants who provide strategic regulatory input into the RIM software development lifecycle and supports clients with their subject matter expertise to effectively manage complex regulatory processes, in alignment with the changing regulatory landscape.

Amy Williams Amy Williams has 15 years of experience working within Regulatory Affairs across various roles. As the Product Marketing Director for RIM at Calyx, she works closely with RIM delivery and client enablement, while supporting the product, marketing, and commercial organizations.

Her passion is understanding the current challenges and needs of the regulatory industry and how Calyx can alleviate these.

Journal for Clinical Studies 17

Market Report

Communicating with Patients – Who and How? I am very fortunate in my role as a strategic medical writer – clients who recognise that I’ve been doing this for longer than it would be polite to admit often ask for my opinion, rather than just give me a set of instructions and tell me to churn out a document. However, what never ceases to amaze me is that whilst discussions of regulatory strategy can certainly become heated, this is nothing compared with the extremes of reaction seen in discussions about patient information, and particularly about who should produce it, and when and how to involve patients in these documents.

Despite the fact that patient-friendly versions of many regulatory documents are now mandated by the regulations, the most frequently encountered reaction to communicating patient information is apathy, and there are many possible reasons for this. The most usual is that patient information is seen as ‘nothing special’, and something that ‘anyone can write’. Therefore, anyone who has the time or vague inclination is given the task of writing the information for patients. Therefore, when a medical writer is finally approached for help with the situation, explaining to clients why their leaflet has failed its readability test or their summary of clinical trial results documents are not getting the desired results is met with a mixture of irritation and bemusement.

This is all understandable, of course, and one of the skills required of a medical writer is to manage such reactions and minimise any conflict until a happy client, and hopefully a beautiful and effective document, result. However, it is worth examining the reasons why a lot of patient information is so poorly communicated, as this has far deeper implications.

The quality of patient information is particularly important in the clinical trial setting, when new drugs or procedures are being investigated, and patient understanding of the potential benefits and risks of their involvement is paramount. Poor patient information can lead to both reluctance to join a trial and poor compliance during it. Once patients have been involved in a trial, they really want to know what the outcome was, and to understand how this has impacted clinical development and the next steps.

Therefore, the communication with patients should not stop when the trial ends.

Additionally, the increasing influence of patient groups should not be underestimated. The European Patients’ Forum has called for patient group involvement in healthcare policy decisions, and Patient View was formed in 2000 to gather together worldwide health non-governmental organisations (including disability groups, carers' groups, gender-based groups), work with, and study, these organisations, and is growing continually in numbers and scale of influence. Recently, Patient View conducted a survey that ranked 18 Journal for Clinical Studies

the top 30 pharma companies on nine indicators, all related to the perspective of patient groups1, and so this issue is under scrutiny by patients themselves.

Failure to take medicines properly is a growing problem, and is very common – 50% of people don't take their medications as prescribed, and this is responsible for 10% of all hospitalisations and over 125,000 deaths annually in the cardiovascular area alone2,3.

Shockingly, approximately 10% of adverse drug reactions can be attributed to a communication failure between provider and patient 4.

Low health literacy is associated with poorer health outcomes and poorer use of healthcare services. It is significantly associated with higher all-cause mortality5, and in the US it is estimated to cost $300 billion per year in avoidable healthcare costs3. Health literacy can be defined as the ability to obtain, process, and understand the basic health information and services needed to make appropriate health decisions and follow instructions for treatment6. There is certainly no doubt that health literacy and numeracy have huge impacts on patient engagement, compliance and health outcomes.

But this is not affected only by an individual’s general ability to read, write, and understand text and numbers, and certainly not just by their overall ‘intelligence’. An individual’s experience of the healthcare system, the complexity of the information being presented, how the material is being presented or explained, and cultural factors (that may influence how decisions are made) all affect the level of ‘health literacy’ or ‘numeracy’ of any individual at any given time.

So how severe is the problem of poor health literacy? In a recent study of adults presenting to an average city emergency department in the US, 15.5% had limited health literacy, which was associated with increasing age, male sex, non-English first language, non-white ethnicity, limited education, and unstable housing7. There is limited information on levels of health literacy in England, however the Skills for Life Survey showed that 1.1 million people in England were functionally illiterate, and approximately 16% of adults have lower literacy skills than those of an average 11-year-old8. The figures are even worse for numeracy, with almost 50% of the population (aged 16–65 years) having lower numeracy skills than an average 11-yearold8, and it is known that people with a lower numeracy level make larger errors in interpreting medicines’ side-effect risk information.

It is therefore very likely that for many people, low health literacy acts as a significant barrier to achieving and maintaining good health.

The regulatory agencies have recognised the increased need for better and more effective patient information. The European Medicines Agency have responded with the introduction of a requirement for a patient-friendly part of the Risk Management Plan9, which was followed by Regulation (EU) 536/2014, which mandates the production of a Lay Summary of Clinical Trial Volume 13 Issue 3

Market Report Results10, not currently mandated by the FDA, but patient-friendly summaries of clinical trial results are recommended). Both of these documents aim to explain complex clinical concepts and results to the general public, to help patients and their carers to make more informed decisions about their healthcare, to increase transparency in the clinical development process, and to put patients at the centre of drug development. In this way, patients are put at the heart of the clinical development process. These aims are vital in the evolving healthcare setting, but all rely on the information produced being clear, understandable, and fit for purpose.

The need for effective communication is especially important in vulnerable groups such as the elderly or paediatric populations.

The elderly population is increasing (there will be around 72 million individuals aged at least 65 in the US in 203011, compared with 38.6 million in 201012) and there are increasing numbers of individuals with dementia. Poor reading skills are particularly problematic in the elderly because of the high prevalence of chronic disease and poor eyesight or cognitive decline – often their diseases have complex treatment regimens, and require multiple consultations with different clinicians. Adherence to medicines by children and young people is even worse than that of adults, despite the oversight of parents13,14.

Tackling the problem of poor patient information has its own challenges. We live in an increasingly information-rich environment, and patients are one of the most information-hungry sub-sections. In a survey of adult internet users, over 50% of internet users looked for health information online15 and 60% said that it had an impact on their decisions or actions16. This trend has increased over the last 10 years in Europe15. Unfortunately, patients do not always understand the information they receive. Studies have consistently shown that patient education leaflets are written at an excessively high reading level. One survey showed that almost a third of patients did not understand their medicine label instructions17 and in a UK outpatients study of COPD patients, 15% were not able to use the written information they had been given18.

It is well known that patients recall less than 50% of what they are told during their consultations19,20, and so it is perhaps understandable that patients would turn to the internet for further information or explanation. Unfortunately, not only are there myriad uncontrolled and unreviewed sites available, but the internet does not necessarily offer more easily understandable healthcare information – even on reputable sites. As examples, information on breast cancer prevention obtained from the National Cancer Institute's website has been assessed as being written at far too high a level21, and there is marked variation in the quality of available patient information on websites about the treatment options for Crohn's disease and ulcerative colitis; few of which provide highquality information22.

So what can be done to improve patient information? The documents need to be written for the right audience. This means taking into account what the reader wants to know, what they need to know, and what they might know already. Patients prioritise four key points of information when they are reading about medicines: the side-effects they might get from the medicine; what to do and what not to do; what the medicine does; and how they should take it.

The medical writer’s job therefore is to provide this information in a format the patient can understand and access as easily as possible. Whilst this might sound very straightforward, it is often far from simple, particularly considering that English might not www.jforcs.com

be the first language of the reader, or that they might be affected by mental or visual impairment, or might not be able to read at all (necessitating the careful use of visuals). It takes experience and skill to identify potential hurdles to understanding, let alone to counter them, but there are some general guidelines that can help along the way.

To be effective, patient information should focus on eliciting key behaviours from the patient, e.g. taking a tablet at the right time, in the right way — not lengthy and unnecessary detail about biochemistry and pathology. Yet many patient leaflets begin with a lengthy discussion of the disease area or physiology, instead of explaining to the patient what they need to do and why they need to do it.

There are a number of tools and techniques which can be employed to make documents more ‘patient-friendly’ such as style and formatting changes, sentence structure, and grammar and vocabulary considerations. The average reading ability of the general public means that text should be written at or below the level of a 12-year-old, and short paragraphs and the active voice should be used. Humans have a cognitive preference for picturebased information, and research has shown that using pictures, including cartoons or pictographs with verbal explanations and use of models, can greatly increase patient understanding and retention of information. Readers will very rarely put effort into trying to decipher what a sentence or paragraph means – they just skim-read it and move on. If the message can’t be gleaned from a quick skim of the text, they will miss the point and the information leaflet is wasted.

Using tools like these can lead to more effective communication with patients and thus higher rates of recruitment, retention and compliance in clinical trials, and lower incidence of side-effects, and more effective use of medicines. However, there is also a certain amount of knowledge and expertise needed to refine the documents even further, and therefore to maximise the effectiveness of the document for its intended audience. It is extremely useful to have patient materials reviewed by people as close to the target audience as possible — ideally patients themselves — to ensure that the information, in the format in which it has been written, can be understood and interpreted correctly. This concept is not new; in 2005, the European Commission introduced a requirement for pharmaceutical companies to undertake ‘consultations with target patient groups’ to ensure that patient information leaflets were usable and understandable for patients23, and the guidance accompanying Regulation (EU) 536/2014 also recommends user testing24.

An extraordinary amount of time, effort, and money is put into creating and marketing medicines – doesn’t it make sense to have the patient information written by specialists who can maximise the chance of the medicine being used in the way it was meant to – or even used at all? If we are truly wishing to increase transparency and put patients at the heart of clinical development, surely we should also be involving them in the production of the documents aimed at helping them to understand the process and the results of the studies they may have taken part in?

Most people believe that writing for patients is ‘common sense’ and that, just like driving well, anyone can write well for patients.

Far be it from me to criticise anyone else’s driving, but the road traffic statistics indicate that not everyone is able to drive as well as they might believe … is it really unreasonable to suggest that not everyone can write as well for patients as they might wish?

Journal for Clinical Studies 19

Market Report

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

https://www.patient-view.com/corporate-reputation/ Accessed April 2021 Deshmukh PR and Wasankar SW. Medical Expert System. Advances in Medical Informatics, (2012) ISSN: 2249-9466 & E-ISSN: 2249-9474, Volume 2, Issue 1, pp.-10-13. https://www.pillsy.com/articles/medication-adherence-stats. Accessed April 2021 Institute of medicine. To err is human: building a safer health system (executive summary). Committee of Quality of Healthcare in America;2000. http://www.nap.edu/catalog.php?record_id=9728 Accessed April 2021 Peterson PN, Shetterly SM, Clarke CL, Bekelman DB, Chan PS, Allen LA, Matlock DD, Magid DJ, Masoudi FA. Health literacy and outcomes among patients with heart failure. JAMA. 2011;305(16):1695-701.

Committee on Health Literacy, Institute of Medicine, Nielsen-Bohlman LN, Panzer AM, Kindig DA, eds. Health Literacy: A Prescription to End Confusion. Washington DC: The National Academies Press;2004 Olives T, Patel R, Patel S, Hottinger J, Miner JR. Health literacy of adults presenting to an urban ED. Am J Emerg Med. 2011;29(8):875-82 Skills for Life Survey 2011. Accessed April 2021 https://www.ema.europa.eu/en/documents/regulatory-proceduralguideline/guidance-format-risk-management-plan-european-unionpart-vi-summary-activities-risk-management-plan_en.pdf. Accessed April 2021 https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ reg_2014_536/reg_2014_536_en.pdf Accessed April 2021 www.nia.nih.gov/Alzheimers Accessed April 2021 http://www.census.gov/compendia/statab/2012/tables/12s0034.pdf Accessed April 2021 Staples B, Bravender T. Drug compliance in adolescents: assessing and managing modifiable risk factors. Paediatric Drugs 2002;4:503–13 Taddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. Paediatr Child Health. 2008;13(1):19-24. doi:10.1093/pch/13.1.19 https://ec.europa.eu/eurostat/web/products-eurostat-news/-/DDN20200327-1. Accessed April 2021 Do patients search for online health information? [cited 16th May 2019].

Available from: https://trialfacts.com/do-patients-search-for-onlinehealth-information/. Accessed April 2021 Davis TC, Wolf MS, Bass PF 3rd, Thompson JA, Tilson HH, Neuberger M, Parker RM. Literacy and misunderstanding prescription drug labels. Ann Intern Med. 2006 Dec 19;145(12):887-94 Taylor SJ, Candy B, Bryar RM, Ramsay J, Vrijhoef HJ, Esmond G, Wedzicha JA, Griffiths CJ. Effectiveness of innovations in nurse led chronic disease

20 Journal for Clinical Studies

19.

20.

21.

22.

23.

24.

management for patients with chronic obstructive pulmonary disease: systematic review of evidence. BMJ. 2005;331(7515):485 Falvo D, Tippy P. Communicating information to patients. Patient satisfaction and adherence as associated with resident skill. J Fam Pract 1998;26:643–7 Schillinger D, Piette J, Grumbach K, Wang F, Wilson C, Daher C, Leong-Grotz K, Castro C, Bindman AB. Closing the Loop: Physician Communication With Diabetic Patients Who Have Low Health Literacy.

Arch Intern Med. 2003;163(1):83-90 Hoppe IC. Readability of patient information regarding breast cancer prevention from the Web site of the National Cancer Institute. J Cancer Educ. 2010;25(4):490-2 Langille M, Bernard A, Rodgers C, Hughes S, Leddin D, van Zanten SV. Systematic review of the quality of patient information on the internet regarding inflammatory bowel disease treatments. Clin Gastroenterol Hepatol. 2010;8(4):322-8 European Commission. The Medicines (Marketing Authorisations Etc.) Amendment Regulations 2005 (SI 2005/2759) https://ec.europa.eu/health//sites/health/files/files/clinicaltrials/ 2016_06_pc_guidelines/gl_3_consult.pdf. Accessed April 2021

Dr. Lisa Chamberlain James After receiving her PhD in Pathology, Lisa started her career as a medical writer in the pharmaceutical industry at Napp Pharmaceuticals in 2000. In 2011, she joined Trilogy Writing & Consulting, a company specialised in providing medical writing. In addition to company management activities as Senior Partner and CEO, she continues to undertake client projects, writing a wide array of clinical documents and with a special interest in drug safety and patient information. She has experience of both communications and regulatory medical writing, and is also an experienced trainer of medical writers, regularly running and assessing workshops for the European Medical Writers Association (EMWA). Lisa is a member of EMWA’s Educational Committee, a member of TOPRA, PIPA, and a Fellow of the Royal Society of Medicine.

Email: lisa@trilogywriting.com

Volume 13 Issue 3

Corporate Profile

Ramus Corporate Group is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in the Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of ISO 9001:2015.

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

• •

• • • • • •

Medical Centre Ramus with Phase I Unit

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

• • • •

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

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

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

• • •

• • •

• •

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

, fast, correc t!

Safe

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

Medical Diagnostic Laboratory Ramus Ltd

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

Ramus Medical Ltd Tu

to Cito

www.jforcs.com www.jforcs.com

V

e re

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 21 21

Market Report

Clinical Trials in Medical Devices: Life Cycle Risk Management Abstract: Risk planning is a crucial aspect for clinical trials, yet is often omitted because clinical teams are hurried or in demand, but they must meet as needed with staff and other stakeholders to be together in the plan. Device designers can take precautions to make items safer through their innovative designs.

Evaluating a control after its introduction has to be analysed and addressed accordingly, with risk analysis. This device can be recommended if it has been demonstrated to have benefits that outweigh its residual risks. This leads to the surveillance of post-market aspects of a product for a number of years.

Survey results indicate that risk management’s (RM's) impact or effectiveness on a medical device is mainly affected by the type of device and its life cycle stage (i.e., pre-market versus post-market). Risk management is necessary for meeting the goals of medical devices projects.

Keywords: Risk Management, Clinical trials, Life Cycle stage Introduction Risk refers to the chance of suffering loss or injury, or anyone proposing a hazard. The process of risk management identifies, evaluates and prioritises potential hazards, then applies initiatives and resources to minimise, coordinate and manage the possibility of hazards occurring, and to lessen the effect of any concerns.

This paper describes the fundamental principles of project risk management, and how clinical information can be used to manage risks of medical device projects.

The clinical study drug development programme is a vital operation that can help the regulators to believe the quality data of the drug. Clinical trials are the most important drivers of research and development costs, as compared to the past. Drug manufacturers are searching to improve the efficiency of clinical trials due to economic and efficiency considerations.

Risk Management Procedure Risk management conceptions can be taken from the “ISO 14971: Risk Management for Medical Devices and ICH Q9: Quality Risk Management”. The initial phase is based on describing the method for leading this action. The simple phases of risk management include: recognise and evaluate risks, lessen risks, and evaluate risks. Supplementary phases that are necessary during the process contain statements of threats, and records of actions.

General Risk Management Process • Step 1 – Plan – plan risk management effort.

• Step 2 – Identify – Identify potential hazards and sources.

• Step 3 – Estimate and Analyse – Estimate / analyse risks for likelihood of occurrence and potential effect.

• Step 4 – Respond and verify – Develop responses / actions to reduce likelihood of negative risks occurring and verifying implemented controls have reduced or eliminated risks, and not introduced new risks.

22 Journal for Clinical Studies

• •

Step 5 – Monitor and control – Monitor and control identified risks and any changes, adding new risks or information.

Step 6 – Report – Summarise risk management effort and outcome.

Risk management is an important fragment of the lifecycle of a medical device invention or project, and is stranded in the context as above.

Lifecycle Risk Management for Projects and Medical Device Products Project Life Cycle: Initiating to Closing Risks Risks to project objectives (scope, quality, resources, budget, schedule) can be either: • Negative (threats or harms) • Positive (benefits or opportunities) Product Life Cycle: Conception to obsolescence (total product life cycle) or TPLC. Risks • Unlike project risks, product risks are negative only; that is, have the potential for harm to the health of people or the environment.

• Risks must be managed to ensure the device operates within its safety or risk profile throughout its TPLC. Project Risk Management Process Besides, the certified Project Management Institute (PMI) provides guidelines for project control. The life cycle process includes five subprocesses: • • • • • •

Initiating Planning Executing Monitoring Controlling & Closing

The project risk management procedure and actions are detailed in the project's life cycle. “Monitoring & controlling” can be equated to the “monitor & control” in the risk management.

The Following Provide Additional Strategic Factors for Managing Risk to Clinical Trial Project Goals • • • • •

Therefore, both project manager and safety should understand and talk with other to achieve project objectives together.

Risk management groups a solid basis for the trial, but is never started or completely finished due to external schedule requirements. Plan to organise a team session to discuss the topic.

Understand both in-scope and out-of-scope to manage both types of risk, for compliance and facilitation.

Provide correct details of requested changes.

Allow everyone to obtain knowledge of relevant information, following issuance of escalation.

Volume 13 Issue 3

Market Report Project life cycle process Corresponding risk management process Initiating

Monitoring & Controlling

Activities

Authorisation

Risk management effort and kick off project, and assign project manager

Plan risk management

Define how project risks will be managed and change control pathway process

Identify risks and sources

To define either negative and positive causes

Perform risk analysis

To determine potential impact either positive or negative, to categorize, evaluate and prioritize risks. Estimate likelihood risks occurring to prioritize the plans

Plan risk responses

Determine actions to address the Risks • Negative – avoid, reduce potential negative impacts • Positive – exploit potential beneficial opportunities • Both – it needs time and budget • Approval risk plans to be gain • Monitor the risks, status, triggers regularly

Planning

• Executing

Control and monitor risks

Closing

Report or close outcomes

•

Introduction of previously unidentified risks to evaluate new risks or any changes with risk analysis process Have risk plans ready to execute with a change control process

• •

Complete documentation has required Summarize the outcome of risk effort

Source: MED DEVICE ONLINE (Guest Column | September 12, 2018) Managing Risk For Medical Device Clinical Trials

• • •

We tend to focus on the negative impact of various events, so we cannot make good use of opportunities to improve the project schedule, apply more solutions, and leverage resources.

We have to understand the ways of communicating to provide an important update for stakeholders.

Have you ever performed risk analysis for the first time? Create a small table with a few categories at a critical crossroads.

Tier 1 first, then Tier 2, then Tier 3. All of the risks should be quantified into ranges of cost increases, schedule delays, and quality impacts.

Clinical Study Plan Risk Management When you are an individual doing a clinical study for development of a new virus diagnostic instrument under the leadership of a project leader at the IVD firm, the purpose of this research is to collect data that could be used to submit an application to the Food and Drug Administration (FDA). So, we are identifying risks to minimise them.

Pre-market Clinical studies information plays a crucial role in the design validation, verification and implementation of risk mitigation measures. With respect to the medical device type, intended use, and risk classification, and with the aim of supporting device risk analyses, acceptability determinations and post-market surveillance activities.

Post-market Clinical research/data/evidence is part of monitoring and risk management activities after a drug has been approved for sale.

Regulatory expert decisions include clinical evidence, risk benefit analysis, and licensing circumstances.

A key point of medical device clinical studies is the inclusion of this trial information with your evaluation of the risk for product rejection and safety assessment. This tip provided in this article can help clinical trial managers more precisely organise a procedure to meet pre-market and post-market requirements.

The Clinical Trial Manager and Medical Device Product Risk Management ISO 149714 shows the process of consumer product risk management. Project risk management has the basic components

Clinical Trial Risk Management Considerations Objective

Managing

Clinical trial examples

Scope

The work requirements and deliverables of the project

Definition of in-scope and out-scope should be documented

Quality

The outcomes and deliverables of project should meet acceptance criteria

Trail outcome and data should not meet acceptance criteria. Analysis handling methods, adequacy of protocols & tools to obtain, manage and verify the data

Time

Schedule

Data willingness to meet 510k submission date. Achieving patient enrollment timings and site engagement

Cost

Budget

Product development or trial risks that could impact on budget.

Resources People & more

www.jforcs.com

The resources are available at the right time. Not only people but also skill sets like materials, equipment, services and supply chain.

Journal for Clinical Studies 23

Market Report of plan, identify, analyse, control, monitor, and report. ISO focuses on preventing medical accidents caused by product defects.

Example 1: Non-standard of Care Testing with Clinical Study Sample concludes an experimental study focused on a project end about one of those types of tests.

Identify and Assess: There are misused assessments, since the places are not used to gathering these assessments and / or outcomes for this category of topic.

Mitigate: To alleviate this risk, the traditional method is to guarantee personnel involved are educated and qualified properly. Study workers will be qualified on the procedure; however, the prolonged workers of the core laboratory or central laboratory may also have to be qualified.

Another option would be to conduct primary on-site observing appointments that include exact attention to the non-standard testing; these appointments would guarantee correct procedure steps were being tracked to collect this data.

Review: At each site, examinations have to be assessed for the duration of the study for the risk of unused examinations. Some of the projects may not have any problem and if some sites do have problems, additional training and visits may be necessary to address the issues. The sponsor should identify what further competency actions will be required.

In the example given above, we will indeed start by assessing the desired use and potential risks from a variety of sources: performance, and much more.

Possible harm is evaluated in terms of severity and probability (likelihood of occurrence).

Detection accuracy of hazards, situation or events may be introduced to provide crucial information to the risk analysis.

Risk mitigation by design, and preventative measures are put in place when possible within a device. Evaluating a control after its introduction has to be analysed and addressed accordingly, with the assessment of a risk.

Devices are used in diagnosis, in which accuracy must be the primary concern. Product safety management continues for the remainder of the life cycle of the product.

There are various ways the clinical trial manager can positively affect product risk management: • • •

A crucial part of offering any pharmaceutical product is to collaborate closely with our medical advisers and liaise with the clinical department.

Test the device both clinically and functionally, and explain how certain user interfaces may cause harms.

Coordinate with researchers' managers to navigate potential risks and possibilities.

ISO 14971 Medical Device Product Risk Management Process

24 Journal for Clinical Studies

Volume 13 Issue 3

Market Report

In Summary Clinical study managers can effectively control risk for medical device projects by taking a methodical approach. Risk management is necessary for meeting the objectives of medical devices projects.

The Food and Drug Administration and European Medicine Agency released guidelines that describe the implementation of the concepts into the scientific experiment process, technique execution and closure of risk management strategies in clinical trials industry. Combining good principles, norms, and excellent behaviours has strong influence on clinical trials that will save time, cash, troubles, and difficulty.

REFERENCES 1.

Campbell-Matland, C. 3Sixty Pharma Solutions, September 12, 2018, Managing Risk For Medical Device Clinical Trials, https://www.meddeviceonline.com/ doc/managing-risk-for-medical-device-clinical-trials-0001 2.

Haglund, E. Clinical Auditor, IMARC Research Inc., Risk Management in Clinical Research Process and Application, https://www.imarcresearch.com/ hs-fs/hub/149400/file 2584753550pdf/doc/mastercontrol whitepaper_ riskmanagment.pdf 3.

2018-2020 Strategic Priorities, U.S. Food & Drug Administration, Center for Devices and Radiological Health, January 2018. https://www.fda.gov/ media/110478/download 4.

MEDDEV 2.7/1 Revision 4, 2016, Clinical Evaluation: A Guide for Manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/ EEC. https://www.document-center.com/standards/show/MEDDEV%202.7.1 5. E. N. ISO 14971: 2012, Medical Devices - Application of risk management to medical devices (ISO 14971:2007, Corrected Version 2007-10-01), https:// infostore.saiglobal.com/preview/98701458424.pdf?sku=856997_SAIG_NSAI_ NSAI_2038661 6.

Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications, Guidance for Industry and Food and Drug Administration Staff. Issued August 24, 2016. https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/factors-consider-when-making-benefit-risk-determinationsmedical-device-premarket-approval-and-de 7.

A Guide to the Project Management Body of Knowledge (PMBOK® Guide), Fifth Edition. 2013 Project Management Institute, Inc.® https://www.oreilly. com/library/view/a-guide-to/9781935589679/ www.jforcs.com

Balamuralidhara. V Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research.

Mysuru-57001, Karnataka, India Email: baligowda@jssuni.edu.in

Prasannakumar P Bhat Research Scholar in Pharmaceutical Regulatory Affairs, JSS College of Pharmacy, JSS Academy of Higher Education and Research.

Mysuru-570015, Karnataka, India Email: bhatprasanna97@gmail.com

Suhas S Joshi Research Scholar in Pharmaceutical Regulatory Affairs, JSS College of Pharmacy, JSS Academy of Higher Education and Research.

Mysuru-570015, Karnataka, India Email: joshisuhas96@gmail.com

S. S. Tarun Nag Research Scholar in Pharmaceutical Regulatory Affairs, JSS College of Pharmacy, JSS Academy of Higher Education and Research.

Mysuru-570015, Karnataka, India Email: tarunnag9844@gmail.com

Journal for Clinical Studies 25

Market Report

Nursing Report Sheet: An Essential Tool for the Clinical Research Nurse Introduction The clinical research nurse's areas of expertise are defined by the NIH (National Institute of Health) and are shared internationally. However, nursing practice in clinical research has only recently begun to be formally defined.1 In the past, the research nurse had little time to read the entire protocol and, in order to manage scheduled visits, they developed the nursing summaries of clinical trials. Discussing nursing summaries can help assess research workload, allowing for better planning and resource allocation.2 Documenting care is not only a legal obligation but, above all, a mature, responsible and ethical way of acting professionally.

Properly documenting, then, is the best way to protect the two components of healthcare: the citizen on the one hand, and the professional on the other.3 Institutional and professional purposes determine what information should be documented and how it should be documented.6 Although the content of nursing documentation is an expression of the functions indicated in the professional profile,7 the related documentation will vary according to the contexts in which nursing activity is expressed and actualised (inpatient, freelance, home, day hospital, etc.). Thus, nursing documentation becomes a simple repository of information delivered to the decision-makers of other professions as a tool for scientific problem-solving applied to nursing.8 In clinical research, it is essential to adopt good documentation practices that must be accurate and appropriate to ensure that study results are built on credible and valid data.9 The question to ask is, "do we have good documentation and how do we use it"? Any basic training in clinical research will surely include these phrases: "What is not documented is not done!" "Document what is done and what is not done!"

Objective The objective of this article is to describe the experience of creating nursing records as an essential tool for collecting good-quality data in clinical trials.

Methods In 2014, in a diabetes clinical research unit at San Raffele’s Hospital, the research team decided to introduce the nurse report sheet (NRS).

Before that, nursing documentation had not been adopted; the role played by the research nurse in the areas of autonomy, competence, and responsibility was not documented. It was the physician who documented all activities performed (including nursing activities) during the visit of the patient involved in the clinical trial. At the end of 2014, there were twenty active clinical trials, and there was one research nurse following these protocols, primarily on type 2 diabetes, divided among five investigators. As a result of her education through the Master in Clinical Research Nursing, the research nurse developed the idea of creating the NRS. 26 Journal for Clinical Studies

Initially, a "literature review" was conducted. The purpose of the literature review was to find material related to "research nursing documentation" in general and more specifically regarding the NRS. The literature review was developed through databases (PubMed and Cinhal).

Unfortunately, no examples of nursing documentation related to clinical trials have emerged (likely due to the inevitable "customisation" of NRSs based on trials).

However, it is essential to remember that documentation of the research nurse's activity is established in CP4 of the clinical practice dimension,10 is therefore a necessary competency of the clinical research nurse (CRN), and is already recognised as such.

Preparation of the NRS is one of the most time-consuming of all activities performed by the CRN.11 In fact, it is necessary to study the protocol and prepare documents for each visit required by the clinical trials. That also constitutes a very useful checklist that allows the research nurse to perform all the planned activities of the visit, according to the protocol, minimising the risk of error and especially certifying and tracking any data. To structure the NRS, the reference model was the definition of source document according to GCP (Pto.1 .52): 'Original documents, data, and records (e.g., hospital records, clinical and administrative records, laboratory notes, memoranda, subject diaries or evaluation forms, drug distribution records, data recorded by automated equipment, copies or transcripts certified after verification of their adherence to the original, microfiches, negatives of photographs, microfilm or magnetic media, x-rays, subject records, and records kept in the pharmacy, laboratories, and medical-technical departments involved in the clinical trial)."

[12] In addition, according to Food and Drug Administration (FDA) standards, the term ALCOA is an acronym that stands for: A – Attributable. The source document must be attributable and unequivocal.

L – Legible. Readable; written documents must be clearly legible.

C – Contemporaneous. Complete and consistent. Contemporary, complete and consistent with the data you want to insert so that you can clearly understand when the information was collected and recorded. So even for any type of correction made to the source document, an abbreviation (to identify the one who corrects) and a date (to establish the chronological order of events) is required.

O – Original. Original.

A – Accurate. Accurate.

Table 1 summarises the key principles of the common/ transversal parts of the NRS, with an example of NRS in Figure 1.

The basic steps for creating an NRS can be summarised in Table 2.

Results To objectively assess the impact, in terms of the number and severity of findings (i.e., errors or deviations from the protocol), Volume 13 Issue 3

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Table 1. The key principles of the common parts of the NRS

Figure 1

Table 2. The NRS creation process

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Journal for Clinical Studies 27

Market Report pharmacogenetic specimen collection, notes have been added specifying the time of collection and the "not collect" option if no longer requested. This was to make the NRS as accurate as possible to avoid omissions or errors.

the "follow-up letter" was used as an evaluation tool. These letters were produced and sent by the various CRAs, based on the data monitoring process done during periodic monitoring visits to our site. The monitoring and follow-up letters were periodic in time but overall variable in frequency, depending on the number of active protocols. It was estimated that annually there were approximately 20 active protocols at our centre.

A retrospective review of all follow-up letters was performed, starting from the end of 2009 until December 31, 2019. Only results closely related to the nursing procedures required by the research protocol and associated samples management (including laboratory manual) were considered.

Deviations from laboratory manual procedures were considered, as the research nurse is often also responsible for the management of biological samples (collection, processing, storage, shipping, and documentation) and some of these procedures are included in the NRS. Findings specified in the follow-up letters could be generated by any action not in line with the research protocol or laboratory manual, any requested but performed inconsistently procedure, or omitted procedures. A total of 13 findings were found. This number is small compared to the number of follow-up letters, and demonstrates a good quality of the site, which has also improved with the implementation of the NRS. Findings found can be categorised into: -

Failure to meet the sample submission timing (biological samples shipment to the central laboratory); Laboratory kit not appropriate for the visit – incorrect use of lab kit; Biological specimens incorrect collection; Failure to comply with storage method of biological samples; Procedures to be performed during the visit (nursing assessments).

The case of "failure to meet sample submission timing" was the most frequent case (seven hits) and primarily involves frozen samples that were sent later than requested. The risk of its recurring has been eliminated by making a reminder in the NRS regarding the timing of sending frozen samples. We emphasise that each biological sample has its own storage times and methods, specified in the laboratory manual, which must be respected in order to perform the correct analysis.

The case of "lab kit not appropriate for the visit" involved the use, for the collection of biological samples, of incorrect kit. There were four separate findings and some involved the collection of pharmacokinetic/pharmacogenetic samples. The risk was eliminated by adding a reminder in the NRS, specifying, if necessary, which kit is to be used at each visit, and also adding the use of any optional kits, such as pharmacokinetic/pharmacogenetic, DNA, etc. In addition, in the case of mandatory pharmacokinetic/ 28 Journal for Clinical Studies

The case of "biological specimens incorrect collection" (one finding) involved the collection of the FMV (first morning void) urine specimen; the patient had not been sufficiently instructed and FMV urine collection wasn’t done. This risk was eliminated by providing a reminder in the NRS specifying the type of urine specimen to be collected at home, and the need to give to the patient the related containers and appropriate directions to collect the FMV. The "procedures to be performed during the visit" case involves two separate events. One case involved the failure to perform an electrocardiogram (a procedure required by the protocol), and the other involved measuring vital signs at a certain frequency and determining a reference arm. The risk was eliminated by including in the NRS all procedures and methods to be performed. The protocol flowchart and detailed description of how the various procedures are performed are always considered. This ensures the accuracy and consistency of the collected data.

The "storage method of biological samples" case involves only one event. It was not possible to include a reminder or description in the NRS because handling of blood samples is complex, the number of blood samples to be handled is large, and all necessary information is included in the laboratory manual. Failure to comply with the indications of the laboratory manual are the responsibility of the operator who manages the samples collected and, in this regard, but separately from the NRS, in our centre has been subsequently implemented by the CRN with the purpose of preventing these types of errors, a specific form, where all the steps of the biological sample management process are traced and documented, from collection to shipment.

Discussion The introduction of the NRS was gradual, beginning in 2014, was institutionalised in January 2015, and to date has become a key tool for the research nurse and the entire research team for the quality of work performed. In fact, the NRS lists useful reminders and procedures (and how to perform them) for the entire research team. Without these reminders/procedures, important visit planned activities and assessments might be omitted. Its structure and included notes have been refined over time, sometimes as a result of the findings. Retrospective evaluation of errors found before and after the creation of the NRS found that, although they occurred even after the introduction of the NRS as data collection tool and checklist, the findings were reduced/eliminated as it was gradually refined. Some findings in 2014/2015 were related to studies that began before the introduction of NRS. It should be noted that starting in mid-2015, there were no more relevant findings related to nursing assessments or activity. In addition, the quality of our research centre has always been good and overall there were no relevant findings, either during monitoring visits or audits. NRS aims to ensure excellent quality of the data collected and the best quality of a study conduction by following the correct procedures.

Conclusions The combination of the efforts of the clinical research nurse and the principal investigator (PI) is critically important to the success of the clinical trial. [13] In this case, PI’s approval is also essential in nursing documentation in order to support the clinical research nurse in the process of developing these documents, that become very useful for the entire research team. In our reality, this has Volume 13 Issue 3

Market Report

Table 3. Findings found in follow-up letters Finding

been the case and it would be interesting to conduct a nursing survey to map if and how many CRNs are using the NRS, how they are structured, and if those who are not using them yet might be interested in implementing the NRS, and then analyse the opinions of fellow research nurses on the usefulness of this tool.

REFERENCES 1.

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K. Castro, M. Bevans, G. Cusack, F. Loscalzo, A. Matlock, H. Mayberry and C. Hastings, "Building the foundation for the clinical research nursing domain of practice.," Scottsdale, AZ, 2008.

C. Rinnone, "Documentazione infermieristica: un approccio giuridico," 2016. [Online]. Available: https://www.nursetimes.org/documentazioneinfermieristica-un-approccio-giuridico/19994. [Accessed 15 dicembre 2019].

P. Di Giulio, C. Arrigo, H. Gall, C. Molin, R. Nieweg and B. Strohbucker, "Expanding the role of the nurse in clinical trials: the nursing summaries," Cancer Nursing, vol. 5, no. 19, pp. 343-7, Oct 1996.

M. Casati, La documentazione infermieristica, 2005.

D.M. n. 739, Regolamento concernente l'individuazione della figura e del relativo profilo professionale dell'infermiere, 14 settembre 1974.

F. Polverini, P. Di Giulio and D. Gragari, "Esperienza di validazione dell’indice di complessità assistenziale (ICA) presso un’Azienda Sanitaria Ospedaliera della Regione Liguria," L'Infermiere, vol. 24, no. 1, pp. 26-33, 2009.

R. Currel and C. Urquhart, "Nursing record systems: effects on nursing practice and health care outcomes," Cochrane Database Syst Rev., 2003.

C. Bargaje, "Good documentation practice in clinical research," Perspectives in clinical research, vol. 2, no. 2, pp. 59-63, 2011.

A. Milani, K. Mazzocco, S. Stucchi, G. Magon , G. Pravettoni, C. Passoni, C. Ciccarelli, A. Tonali, T. Profeta and L. Saiani, "How many research nurses for how many clinical trials in an oncology setting? Definition of the Nursing Time Required by Clinical Trial-Assessment Tool (NTRCT-AT)," International Journal of Nursing Practice, vol. 23, no. 1, Feb 2017.

V. Henderson, "The nursing process--is the title right?," Journal of Advenced Nursing, vol. 7, no. 2, pp. 103-109, 1982.

National Institutes of Health Clinical Center, Nursing and Patient Care Services, "CRN 2010 Domain of Practice Committee 2009.Building the Foundation for Clinical Research Nursing: Domain of Practice for the

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Sceciality of Clinical Research Nursing," 9 4 2004. [Online]. Available: https://www.cc.nih.gov/nursing/crn/DOP_document.pdf. [Accessed 10 12 2019].

European Medicines Agency, "Guideline for good clinical practice E6(R2)," 1 Dicembre 2016. [Online]. Available: https://www.ema.europa.eu/en/ documents/scientific-guideline/ich-e-6-r2-guideline-good-clinicalpractice-step-5_en.pdf. [Accessed 14 12 2019].

R. Poston and C. Buescher, "The essential role of the clinical research nurse (CRN)," Urologic Nursing, vol. 30, no. 1, pp. 55-63, 77, Jan-Feb 2010.

Michela Melissa Stuccillo Michela Melissa Stuccillo graduated at University of Milan with a Bachelor of Nursing and later obtained a Master in Clinical Research Nurse at Bicocca University, Milan.

She has 12 years' experience as Senior Clinical Research Nurse in the field of Diabetes Research and, in addition, she has been collaborating for 4 years as Lecturer at the Master in Clinical Research Nurse from Vita-Salute San Raffaele University.

Email: stuccillo.michela@hsr.it

Diana Sufragiu Diana Sufragiu, after the Bachelor of Nursing at Vita-Salute San Raffaele University, Milan, obtained in 2011 a Master in Evidence-Based Nursing and Clinical Research Methodology at Bologna Alma Mater Studiorum University. She has 6 years’ experience as Diabetes Clinical Research Nurse and, in the last 4 years, also as a Lecturer at the Master in Clinical Research Nurse at Vita-Salute San Raffaele University.

Email: sufragiu.diana@hsr.it

Journal for Clinical Studies 29

Therapeutics

From Little Acorns: A Scandinavian Study’s Implications for Paediatric Development In December 2020, a paper1 was published in the journal BMJ Paediatrics Open, a respected journal with a relatively modest impact factor of 2.496, regarding paediatric medicinal product availability in Scandinavia (Norway, Sweden, Finland and Denmark). The study described in the article contained extremely informative data, so enlightening that it could – and should – trigger a wide-reaching review of our approach to the development of and access to new paediatric medicines. Lepola and her colleagues examined the marketing status of new paediatric medicines listed in the European Commission’s ten-year report on the implementation of the Paediatric Regulation, as initially authorised between 2007 and 20162, and assessed the products’ availability in these four countries. The main findings of this study were: • • •

21%–32% (16/76–24/76) of the new medicinal products were not marketed, Of the new formulations relevant to children, 29%–50% (16/56–28/56) were not marketed, A significant proportion of these products had never been marketed.

The authors conclude that similar data from other countries are needed to evaluate the overall European status of marketed paediatric approvals. How true!

Traditionally, the pharmaceutical industry has targeted approvals from the “big five” in Europe (France, Italy, German, Spain, UK), which have populations ranging from 47 to 83 million.

Contrast that with these four Scandinavian countries which have a combined population of some 23 million. The authors recognise that Scandinavia may offer limited financial opportunity to manufacturers, which may be a factor in decisions not to market new products for paediatric patients in these countries. The generation of similar information for the “big five” would help to clarify the extent to which commercial considerations may be a causative factor. These Scandinavian countries fill four of the top five places in the Legatum Prosperity Index™ 20203. Most of the countries in south-east Europe, with populations broadly similar to the Scandinavian countries, fall between 20 and 50 in the Index, so a comparison of the marketing authorisations in those countries would be equally enlightening. A similar review in the US would be informative given it is the home of the majority of pharmaceutical manufacturers. The US also has a unique reimbursement system and drugs are priced according to what the market will bear.

The authors’ analysis of the Scandinavian data indicated that most products not currently marketed had never been marketed.

This finding led them to suggest decisions to enter specific markets are made at the outset of paediatric development programmes. They 30 Journal for Clinical Studies

postulate that regulatory obligations in addition to national pricing and reimbursement systems may impact such decisions, together with the readiness of physicians to prescribe off-label. One might reasonably infer the investment necessary to develop countryspecific packages and negotiate national pricing and reimbursement mechanisms would produce a substantially greater return in each of the “big five” than would be the case for any of these Scandinavian or south-eastern European countries. However, there appear to be no published pan-European data which would enable comment on the potential impact of off-label prescribing.

The study also found the medicinal forms or strengths not marketed in any Scandinavian country were often the paediatricspecific ones (lower strengths, oral liquids, chewable tablets) whereas a significant proportion of the new forms and strengths that were marketed appeared to optimise the entire product line rather than fulfilling a specific paediatric need. The authors also point out, correctly, that the marketing authorisations for paediatric products in Europe allows manufacturers to market the drug in all EU member states but does not compel them to do so. Marketing is, therefore, not specifically encouraged, and potential rewards, e.g., extended patent protection, are granted nationally, rather than on a pan-EU basis, for the whole product rather than any specific formulation.

Do Lepola’s findings raise a potential ethical concern? Lepola’s paper lists the new medicinal products and the new pharmaceutical forms and strengths which have marketing authorisation but have not been marketed in these four countries. The paper does not indicate whether any of the clinical trials necessary for approval of these new products were conducted in any of these countries. Given the relative sizes of the paediatric populations, it is conceivable that the trials did not involve any of them. The principle of distributive justice requires perceived fairness regarding how rewards and costs are shared by group members. If children in Scandinavia have borne the cost, risk, or burden by participating in clinical trials, then the group of which they are members, i.e., Scandinavian children, should all receive the benefit. Moreover, Kantian ethics – deontology – requires respect for persons as ends in themselves, and not merely or exclusively as a means to an end. If the authors’ suspicion is correct and decisions regarding the countries in which these drugs should not be marketed for paediatric use were made propter hoc and the necessary clinical trials were then conducted in these countries, that would appear to raise an ethical concern.

Following its publication, the European Commission’s tenyear report on the implementation of the Paediatric Regulation was criticised in some quarters as being self-congratulatory4. The Regulation imposed a requirement to file and execute a paediatric investigation plan (PIP) for almost all new drugs as a condition of receiving a marketing authorisation approval (MAA) for the drug in adults. As a result, many more paediatric trials were initiated, resulting in an increased number of new paediatric drug approvals.

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info@Astell.com +44Journal (0)20 8309 2031 for Clinical Studies 31

Therapeutics

However, little progress has been made in diseases which affect only children, or which show biological differences between adults and children, and particularly in rare diseases such as childhood cancers. Lepola et al. conclude that the reported success of the Paediatric Regulation in terms of new authorised products is only partially valid, and that the access to medicines for children, in practice, is still limited. In practice, it remains the case that paediatric development follows the manufacturer’s plan for development of the adult indication. Again, this would be consistent with commercial considerations underlying decisions to invest in particular countries.

Despite hailing the Paediatric Regulation as a success, the European Commission (EC) is now undertaking a joint evaluation of the Paediatric Regulation and the Orphan Regulation. In its Working Document5, the EC concludes that, while the Regulations have played their intended role, they did not ensure patient accessibility to authorised paediatric medicinal products. Accessibility refers to both the actual marketing of a product (availability on the market) and market access (pricing and reimbursement). This seems somewhat contradictory, as the explicit aim of the Paediatric Regulation was to improve the health of children in Europe by facilitating the development and availability of medicines for children. The Working Document also concludes that ill-tailored rewards are the main point of criticism for the Paediatric Regulation.

The extension of the term of the supplementary protection certificate (SPC) is the main paediatric reward. An SPC extension brings greater benefits for products with larger sales volumes.

Medicinal products developed for use in both adults and children, rather than exclusively for children, will normally generate a larger sales volume in countries with larger adult populations. The EC’s Pharmaceutical Strategy for Europe6 foresees that, as part of the review of the pharmaceutical legislation, future incentives would be linked to obligations, and “market launch” is expressly mentioned in this context. The Joint Evaluation suggests that the Paediatric Regulation will not be amended in a focused manner through revisions of other regulations. Consequently, replacing the SPC extension as the main reward is unlikely as this would be a key change to the Paediatric Regulation. Offering a paediatric reward for new medicinal products without SPC would support the development of exclusively paediatric products. An alternative might be to follow the Swiss model and create a “paediatric SPC”.

Several statements in the Joint Evaluation suggest the adoption of a specific legal regime to address (high) unmet medical needs 32 Journal for Clinical Studies

and propose that more differentiated tools may be needed to direct investments to specific areas, as not enough “purely” paediatric products are being developed. The Joint Evaluation classes antibiotics with orphan and paediatric medicinal products due to the lack of return on investment, perhaps revealing that the EC has already decided the main cause for the problem. The Commission could also propose a new regulation on (high) unmet medical needs to cover certain orphan and paediatric medicinal products as well as antibiotics. This would be in line with the EC’s Pharmaceutical Strategy but would be a challenging exercise. The EU and the US already collaborate in areas of high unmet medical needs, including paediatrics, and the EU could consider the US orphan drug and paediatric ideas as a model or an inspiration for future regulation. For example, the US has a “voucher” programme to incentivise sponsors to develop new active ingredients to treat rare paediatric diseases.

If detailed qualifying criteria are satisfied, at the time of paediatric product approval the sponsor receives a “voucher” which entitles the sponsor to a priority review for another product. The voucher can be sold to another developer to expedite the review of any product and not necessarily one for an unmet medical, or paediatric, need.

The reported price range for vouchers sold since February 2017 was $M80 to $1307, but why would a manufacturer not wish to purchase a voucher to expedite the review of a drug for adults predicted to earn a billion dollars per annum, rather than spend it on a paediatric drug which may bring in one-tenth of that?

A second example from the US is the five-year add-on period of market exclusivity for adult approvals. This includes a “fast track” designation yielding enhanced regulatory interactions and priority review of submitted applications to encourage the development of new antibacterial and antifungal drugs to treat serious or lifethreatening conditions. Such an approach could be applied to drugs intended to treat conditions seen only in children, providing an incentive to market drugs for these relatively small populations which do not benefit from the development of drugs intended for adult use. If the EU does adopt aspects of the US approach, convergence to support global development will be critical for the pharmaceutical industry, in particular companies developing medicinal products for small populations.

Historically, paediatric drug development has been impeded by a lack of coordination among regulatory authorities. This has been resolved to an extent by the creation of a “Paediatric Cluster” (EMA, FDA, Health Canada, JPMA, TGA)8. The cluster is clearly active and issues a number of (non-binding) common commentaries providing an agreed position amongst the participants regarding Volume 13 Issue 3

Therapeutics specific development programmes. However, its true impact is difficult to assess due to a lack of transparency of communications among regulators and the fact that manufacturers are not yet permitted to attend. Yet, global development is key for gene therapy products, paediatric and orphan drugs, and many other medicinal products with a small target population. More transparency would be welcome.

Some key differences remain between the two main agencies on particular topics in paediatric development. For example, the FDA still seems inclined toward placebo-controlled trials, whereas the EMA is reluctant to approve such studies if an approved treatment exists, except for the most trivial conditions. Official EMA guidance indicates a default position of commencing paediatric studies in all age groups simultaneously, whilst the FDA mostly favours a progressive approach from adolescents to younger children. The FDA will grant a waiver if the necessary studies in children are impossible or highly impracticable, or if reasonable attempts to produce a paediatric formulation for the relevant age group have failed; the EMA does not recognise these as grounds for a waiver.

In Europe, if the benefits to the participating minor outweigh the burden, the trial is considered acceptable, whilst a similar condition does not appear in the FDA’s 21 CFR §50.53.

Earlier this year, a new common commentary template9 was issued, giving a framework for seeking scientific advice from both the EMA and the FDA on new paediatric development plans. The FDA now recommends manufacturers of new cancer products submit their plans simultaneously to FDA and EMA “to promote global coordination and international research collaboration”, and both agencies clearly encourage rapid initiation of paediatric oncology drug development. However, the essence of these plans clearly remains enabling the assessment of the benefit/risk of new drugs in the target population, rather than making them available to that population. Both agencies experience competition among companies to conduct trials in small populations, resulting in delays to the completion of most paediatric programmes. This could be resolved if the same paediatric trials for different active substances were better scheduled or even considered as not required if several medicinal products are already available for the condition/disease.

Perhaps a similar recommendation to that for oncology drugs would support all paediatric drug development.

The International Congress for Harmonisation was intended inter alia to harmonise the regulations relating to the development of new drugs thereby bringing them to the market more rapidly. Increasingly, it seems that US and EU perspectives are diverging to the point that true global protocols are becoming increasingly challenging (e.g., do you age-stagger enrolment or not?). This risks reducing the flow of new medicines, and as Lepola’s paper illustrates, an additional but ill-defined hurdle exists to ensuring that drugs which are developed for paediatric use do then become available to that vulnerable population they were intended to benefit. The future of paediatric drug development depends upon alignment between the major agencies, and will be impeded by the apparent divergence which is increasingly evident. The investigation of Lepola and her colleagues will, perhaps, plant the seed which will grow to a towering oak tree, stimulating consideration of the actions necessary to ensure “new drugs for children” is more than a catch-phrase.

2.

3.

4.

5.

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Open;4:e000880 (2020). doi:10.1136/ bmjpo-2020-000880.

European Commission’s ten-year report on the implementation of the Paediatric Regulation (2017). Available at https://ec.europa.eu/health/ human-use/paediatric-medicines_en. Accessed 8th April, 2021.

Legatum Prosperity Index 2020. Available at https://www.prosperity. com/rankings.

Pearson, A.D.J., Heenen, D., Kearns, P.R. et al. 10-year report on the European Paediatric Regulation and its impact on new drugs for children's cancers. Lancet Oncology, 19, 285-287 (2018); Taylor, P. EU’s 10year paediatric meds report - not bad, but can do better (2017). Available at http://www.pmlive.com/pharma_news/eus_10-year_paediatric_ meds_report_-_not_bad,_but_can_do_better_1209899 Accessed 8th April, 2021.

European Commission, Joint evaluation of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, 11 August 2020. Available at https://eurlex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52020SC0163.

Accessed 8th April, 2021.

Affordable, accessible and safe medicines for all: the Commission presents a Pharmaceutical Strategy for Europe. Available at https:// ec.europa.eu/commission/presscorner/detail/en/ip_20_2173. Accessed 8th April, 2021.

Livornese, D.L. The Value of Priority Review Vouchers – GAO’s Two Cents (2020). Available at https://www.fdalawblog.net/2020/02/thevalue-of-priority-review-vouchers-gaos-two-cents/ Accessed 8th April, 2021. Accessed 8th April, 2021.

US Food & Drug Administration. International Collaboration / Pediatric Cluster. Available at https://www.fda.gov/science-research/pediatrics/ international-collaboration-pediatric-cluster. Accessed 8th April, 2021.

Oakes, K. FDA, EMA team up on pediatric oncology drug development template (2021). Available at https://www.raps.org/news-and-articles/ news-articles/2021/4/fda-ema-team-up-on-pediatric-oncology-drugdevelop?utm_source=MagnetMail&utm_medium=Email%20&utm_ campaign=RF%20Today%20%7C%201%20April%202021 Accessed 8th April, 2021.

Dr. Harris Dalrymple Dr. Harris Dalrymple, PhD (Med), PhD (Law), Executive Director, Center for Pediatric Clinical Development, PRA Health Sciences, has nearly 40 years’ experience in the pharmaceutical and CRO industries, and over 20 years’ paediatric trial involvement. Originally a pharmacologist, he holds a master’s in medical law and ethics and PhDs in medicine and law. His interests include assent/consent/dissent, clinical trials in pregnancy, and ethical issues in clinical trials. He lectures on medical law and ethics for the British Association of Pharmaceutical physicians.

Email: dalrympleharris@prahs.com

Dr. Mark Sorrentino

REFERENCES

Dr. Mark Sorrentino, MD, Vice President, Center for Pediatric Clinical Development, PRA Health Sciences, has 20 years of experience in the pharmaceutical and biotech industries. Prior to joining PRA, he spent five years as the global chair and founder of the paediatric practice area at a leading CRO. In addition to working at CROs, Dr Sorrentino has served as the global chief medical officer at ADMA Biologics and as director of medical science at MedImmune.

1.

Email: sorrentinomark@prahs.com

Lepola, P., Wang, S., Tötterman, A.M. et al. Does the EU’s Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? A cross-sectional study. BMJ Paediatrics

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Journal for Clinical Studies 33

Therapeutics

The Use of Psychedelics in Neuropsychiatry – A New Era in Research Introduction The use of psychedelics is an extremely promising evolution in the field of neuropsychiatry, especially since most of the psychiatric drugs available today were developed decades ago, at a time when the understanding of the pathophysiology of neuropsychiatric disorders was more limited than it is today.

In our current arsenal of medicines for treating conditions like depression, even the most effective only provide relief to a subset of patients, and usually only for a limited amount of time. Psychedelic drugs are currently under research in several neuropsychiatric disorders, including major depression, substance use disorder (SUD), and post-traumatic stress disorder (PTSD).1 Background Psychedelics or serotonergic hallucinogens are a group of substances with a common mode of action: serotonergic 5HT2A receptor agonists. These substances can be found in nature (such as psilocybin, present in mushrooms of the genus Psilocybe and many others; dimethyltryptamine/DMT, present in the botanical preparations ayahuasca and jurema; and mescaline, present in peyote and San Pedro cacti), or they can be of synthetic origins (such as the diethylamide of lysergic acid/LSD). Naturally occurring botanical psychedelics have been part of the traditional medicine of many cultures in the Americas for centuries.2 An Opportunity for Treatment-resistant Patients Hallucinogens/psychedelics could present an opportunity for patients who do not respond to currently available psychiatric medications. A treatment-resistant patient is defined as having

34 Journal for Clinical Studies

shown no improvement after treatment with at least two different medications; often they have been treated with more than two.

Treatment failure means no improvement in existing symptoms, and also leads to increases in symptoms over time. Chronic, treatment-resistant patients frequently suffer from comorbidities and have a diminished quality of life.1 Psychedelic substances are a source of great interest for science and the pharmaceutical industry due to their promising antidepressant, anxiolytic, and anti-addictive effects. Based on research, psychedelic drugs appear to produce both rapid and long-lasting beneficial effects in several neuropsychiatric disorders, including major depression, SUD, PTSD. Recent open-label studies showed that psilocybin reduced depressive and anxious symptoms in treatment-resistant depression (TRD) and in major depressive disorder (MDD). Depression and anxiety symptoms were also reduced in controlled trials in terminal cancer patients. Psilocybin also showed positive effects in open-label trials for the treatment of alcohol and tobacco dependence.1 Researchers in many fields (chemistry, neuroscience, psychology, molecular biology, and clinical science, to name a few) will need to focus their efforts to understand exactly how these powerful drugs affect brain function, and the appropriate treatment conditions to ensure patient safety. Additionally, regulatory agencies, governments, and public health authorities will also be looking to a deeper scientific understanding in order to inform public policy decisions.

Current Knowledge and Understanding Psychedelics are small molecule drugs, and as such their functional properties are dictated by their chemical structures, making

Volume 13 Issue 3

Central & SpeCialty lab

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www.mlm-labs.com Journal for Clinical Studies 35

Therapeutics

structure−activity relationship (SAR) studies essential for fully understanding how they affect the nervous system. SAR studies help to identify human abuse potential of drugs, and they are for fully understanding and optimising the therapeutic properties of psychedelics. A large body of work has been completed over the years by scientists (David Nichols, Richard Glennon, and others), into how the structures of psychedelics produce their hallucinogenic effects.1 Researchers are now discovering that psychedelics not only induce hallucinations, but also can produce a variety of other important biological effects that may contribute to their therapeutic properties. Notable among these effects is potential activity that promotes neural plasticity (psychoplastogenic effects). In 2020, the first SAR study aiming to characterise the psychoplastogenic pharmacophore of psychedelics was published.1 Many stress-related neuropsychiatric disorders are characterised by the atrophy of neurons in the prefrontal cortex, and the psychoplastogenic effects of psychedelics demonstrate potential in treating these disorders. Another study published in 2020 showed that ketamine and LSD produced sustained neuronal growth after only a short period of cortical neuron stimulation, which may help explain why psychoplastogenic psychedelics can produce longlasting behavioural effects after only a single administration.1

(TRD) showed that ayahuasca administration reduced depression, anxiety, and suicidality.2 Similar results are being observed with the N-methyl-Daspartate (NMDA) glutamate receptor antagonist ketamine in TRD. Ketamine is also a psychedelic/hallucinogen that demonstrated fast and long-lasting antidepressant effects.2 Most of these clinical trials involved the administration of a single or very few doses, and the beneficial effects were fastacting (in hours to days) and long-lasting (weeks to months). All the investigative substances showed a good safety and tolerability profile, producing mostly mild/moderate and transient effects, such as vomiting and nausea, anxiety, confusion, and headache.2 In the 1980s, another class of serotonergic drugs with mindaltering and therapeutic properties appeared: the “entactogens”.

These substances are not hallucinogenic; they increase empathy and emotional openness. The most intensely studied drug of this

Another area where psychedelic therapy is being looked to for potential benefit is in suicidality. A 2021 randomised controlled study by Ross et al. showed that “psilocybin-assisted psychotherapy (PAP) produced rapid and sustained improvements in depression, demoralisation, and hopelessness in people with cancer. Converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment.”1 Ayahuasca has also been the subject of study. A controlled trial in healthy normal subjects showed that it reduced panic-like and hopelessness symptoms. Two trials (one open-label and one placebo-controlled) in patients with treatment-resistant depression 36 Journal for Clinical Studies

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Therapeutics class is MDMA (3,4-methylenedioxymethamphetamine), commonly referred to as “ecstasy”. MDMA is being researched for the treatment of social anxiety in autistic adults and in the treatment of end-of-life anxiety (NCT00252174), as well as being developed as a prescription medicine for the treatment of PTSD. Both MDMA and psilocybin have been designated as breakthrough therapies by the FDA, and MDMA has been authorised for use as a compassionate medicine by both the FDA and the Israeli Agency of Medicines.2 Similar results are being observed with the N-methyl-Daspartate (NMDA) glutamate receptor antagonist ketamine in TRD. Ketamine is also a psychedelic/hallucinogen that demonstrated fast and long-lasting antidepressant effects.2 Most of these clinical trials involved the administration of a single or very few doses, and the beneficial effects were fastacting (in hours to days) and long-lasting (weeks to months). All the investigative substances showed a good safety and tolerability profile, producing mostly mild/moderate and transient effects, such as vomiting and nausea, anxiety, confusion, and headache.2 In the 1980s, another class of serotonergic drugs with mindaltering and therapeutic properties appeared: the “entactogens”.

These substances are not hallucinogenic; they increase empathy and emotional openness. The most intensely studied drug of this class is MDMA (3,4-methylenedioxymethamphetamine), commonly referred to as “ecstasy”. MDMA is being researched for the treatment of social anxiety in autistic adults and in the treatment of end-of-life anxiety (NCT00252174), as well as being developed as a prescription medicine for the treatment of PTSD. Both MDMA and psilocybin have been designated as breakthrough therapies by the FDA, and MDMA has been authorised for use as a compassionate medicine by both the FDA and the Israeli Agency of Medicines.2 Mechanisms of Action The therapeutic effects of psychedelics are related primarily to the fact that they are serotonergic receptor 5HT2A agonists, and also have impact at 5HT1A and 5HT2C receptors, although to a lesser extent.2 Agonists of 5HT1A receptors are thought to be responsible for passive adaptive response (tolerability to a source of stress), while 5HT2A agonists are thought to be responsible for the active adaptive response (dealing with the source of the stress). Considering that psychedelics have agonistic activity at both receptor sites, an overall increase in adaptability could be attributed to their therapeutic effects.2

In addition, 5HT2A agonists induce the release of glutamate, which modulates activation of the amygdala, hippocampus, and prefrontal cortex. The increase of glutamate in these brain areas also stimulates the synthesis of brain-derived neurotrophic factor (BDNF), which increases neuroplasticity.2 Psychedelics also appear to reduce activity of the default mode network (DMN) and enhance functional connectivity between otherwise distinct brain networks, which also demonstrates enhanced neuroplasticity.2 The anti-depressive properties of ayahuasca can be attributed to modulation of BDNF, cortisol, and inflammatory biomarkers in depressive patients. In one ayahuasca study, subjects performed an imagination task with eyes closed. The brain activation pattern that was recorded in occipital areas was similar to the pattern observed when looking at an object with eyes open. This could contribute to its therapeutic effects by making inner experiences, such as biographical memories, feel more real.2 LSD and psilocybin reduce the recognition of negative emotions through amygdala modulation, while they increase positive effect and mood. The areas of the brain related to emotional processing seem to be most affected by this mechanism of action, producing anxiolytic and antidepressant effects.2 MDMA has a different mechanism of action from the classic hallucinogens. MDMA is not a cortical 5-HT2A receptor agonist, instead it inhibits monoamine (serotonin>norepinephrine>dopamine) reuptake, and enhances oxytocin release. The therapeutic effects of MDMA on PTSD seem to be related to fear extinction and memory reconsolidation. Although MDMA is not a truly “classical hallucinogen”, it is of interest to mention briefly here because it is in Phase III of clinical trials for the treatment of PTSD and is a scheduled substance. Therefore, the challenges related to its medical use are similar to those of classic hallucinogens.2 Psychological mechanisms also seem to be involved in the therapeutic effects of hallucinogens. Decentring and mindfulnessrelated processes have been associated with positive therapeutic outcomes in studies of acute drug administration and in long-term users. Positive change in personality, such as increase in the traits of openness to experience and self-transcendence, is also related to the therapeutic effects of these compounds.2 Additional Therapeutic Mechanisms The psychological effects of these drugs, which often include mystical experiences, increased empathy and sociality, ego dissolution, and increased acceptance, openness, and psychological flexibility, are new drug-induced therapeutic mechanisms that are both acute and enduring. Those new pharmacological and psychological perspectives are relevant to clinical practice, and to psychopharmacological and psychological theories of psychiatric disorders.2 Many people agree that set (personality and internal expectations of the subject) and setting (environment in which the substance is used) are critical elements of a psychedelic experience, although more research is needed to develop a comprehensive understanding of these elements. Other potential indicators of success were identified in a literature review by Aday et al. Their research found that patients exhibiting preoccupation, apprehension, and confusion were more likely to experience adverse effects, while those characterised by baseline openness, absorption, acceptance, and surrender were more likely to have mystical-type experiences.

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Journal for Clinical Studies 37

Therapeutics providers, is occurring around the world. Traditional medical systems and scientific biomedical approaches exist in parallel.

Western medical practices and processes are being shared with indigenous communities, while traditional indigenous medical approaches are gaining popularity in Western societies. Indigenous doctors and shamans perform ayahuasca/iboga rituals in the West, while Westerners travel to South American and African countries in search of healing, psychological appeasement and spiritual enlightenment.2

They further concluded that participant gender was not responsepredictive, while other biological variables such as 5-HT2AR binding potential and rACC volume were important factors.1 Also in 2021, a study was published regarding the first nonhallucinogenic psychedelic analogue with sustained therapeutic properties. There is healthy and ongoing debate as to whether the subjective effects of psychedelics are a necessary element of their therapeutic impact, since the subjective effects are often regarded by patients as being profoundly meaningful and transformative.1 As research continues into the use of psychedelics as medicines, establishing robust biomarkers for efficacy evaluation, and understanding the impact of these drugs on brain function are of critical importance.

Health Policy Opportunities and Challenges The opportunities offered by psychedelics/hallucinogens are accompanied by several challenges. One of the most relevant is the legal status of these compounds worldwide. Psilocybin, DMT, LSD, and MDMA are in the Schedule I of the United Nations Convention on Psychotropic Substances from 1971. Schedule I substances are deemed to lack therapeutic effects and have a high potential for abuse/dependence coupled with serious adverse effects.

Accordingly, there are costly and time-consuming bureaucratic processes to perform, and approvals to obtain for both preclinical and clinical studies with these drugs, which sometimes ultimately fail before any study can be conducted. Synthesis, storage, transportation, and use of these substances are all subject to stringent and complex regulations. Some researchers have suggested that these drugs should be reclassified to allow for full investigation of their therapeutic potential.2 In fact, there are already some interesting and practical pathways to exploration of their potential as medical treatments. One such pathway is allowing medical administration under compassionate use conditions and restrictions. This pathway is already being used with LSD, psilocybin, and MDMA in Switzerland, the United States, Canada, and other countries.2 The different medical systems that are implicated in psychedelic practices present a significant additional challenge. Biomedical practices are validated by the means of clinical trials, while traditional practices have a long history of ritual and ceremonial use.

Globally, medicalisation of psychedelics co-exists with community/ traditional use. The therapeutic administration of ethnobotanicals by mental health professionals, lay persons with experience in traditional contexts, and a wide range of other practitioners and 38 Journal for Clinical Studies

Conclusion To fully comprehend how these powerful drugs impact brain function and human health, and whether their therapeutic potential can be realised safely, medical science will need to embrace myriad perspectives, work across length scales, and make full use of the latest scientific tools. Developing effective medicines for treating diseases such as depression, PTSD, and SUD, which are among the greatest contributors to disability worldwide1, would be a major neuropsychiatric breakthrough, and provide relief to millions of patients around the globe. While psychedelics have demonstrated significant potential for treating these serious, challenging disorders, we must advance slowly on the path toward development of therapeutics, and most importantly, conduct rigorous scientific research with all the tools at our disposal.

REFERENCES 1.

2.

David E. Olson. The Promise of Psychedelic Science. ACS Pharmacol.

Transl. Sci. 2021 XXXX, XXX, XXX−XXX C. https://doi.org/10.1021/ acsptsci.1c00071 Rafael Guimarães dos Santos et al. Risk Management and Healthcare Policy 2021:14 901–910. http://doi.org/10.2147/RMHP.S300656

Dr. Beatrice Setnik Dr. Beatrice Setnik, PhD, has been working in the area of clinical drug development and abuse potential assessment since 2005. She is an Adjunct Professor at the University of Toronto (Department of Pharmacology and Toxicology), and she earned her doctorate degree in Pharmacology and the Collaborative Program in Neuroscience from the University of Toronto. During her career she has been responsible for scientific input on early phase clinical trials and in strategic initiatives in business growth and development. Dr. Setnik led the clinical development, regulatory filing, and lifecycle management, including abuse potential evaluation, of several pain compounds, including abuse-deterrent opioid formulations, and also provided scientific input on various specialty phase I/II clinical trials, including abuse potential studies for CNS drugs. She is currently the Chief Scientific Officer at Altasciences, an early phase CRO/CDMO with U.S. and Canadian locations. Dr. Setnik has published numerous research articles in internationally recognized peer-reviewed journals, and has presented at over 200 scientific meetings and conferences.

In addition, she is the Managing Director and Clinical Subgroup Lead for the Cross Company Abuse Liability Council and chair of the Clinical Pharmacology Community of the Drug Information Association (DIA). Dr. Setnik is also an active member and participant in several congresses, including the College on Problems of Drug Dependence. She has also been actively engaged in many aspects of abuse potential assessment, including development of patient reported outcome instruments and contributing to postmarketing surveillance studies.

Volume 13 Issue 3

INSIGHT / KNOWLEDGE / FORESIGHT

SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS IPI

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

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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.

PHARMA’S DNA

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Listen to industry experts on the latest in drug discovery, development, research, industry regulations and much more at Pharma,s DNA, the podcast channel by Pharma Publications, available on Sound Cloud, Spotify, iTunes and YouTube.

IAHJ

IBI

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

www.animalhealthmedia.com

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.

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Journal for Clinical Studies 39

Technology

The Central Role of Interactive Response Technology in Today’s Clinical Trials Introduction The clinical trial process has been undergoing substantial change in recent years – even more particularly in the past 12 months.

The first signs of the evolution began in the 2000s when protocol complexity significantly increased. In the ten-year period from 2005-2015, the number of protocol endpoints increased by 86% and the number of planned subject visits increased by 25% (Ref: Tufts). A second key change is the move towards a patientcentric approach to trial management. In a recent ICON survey, 30% of subjects indicated a preference for hybrid or decentralised trials, with a further 33% indicating no preference to remain with the traditional site-based model. Thirdly, drug development costs have increased by 145% in the past ten years, with the average cost of bringing a single drug to market now standing at $2.6 billion. Thus, sponsors and their partners have been under increasing pressure to accelerate timelines in the clinical trial process and subsequently reduce costs. The demand for timeline reduction has been further driven (and thankfully realised in many trials), with the onset of the global COVID-19 pandemic.

The use of technology is a key enabler in this clinical trial evolution. Here we examine the critical delivery elements required from Interactive Response Technology (IRT) providers to support this evolution, with particular focus on the needs of COVID trials.

What is the Role of IRT? In a clinical trial, the selected IRT must provide an effective and efficient technology solution for managing subject enrolment and randomisation, as well as enabling the effective management of the trial drug supply and dosing regimen. The platform must deliver some standard elements including a user-friendly and stable interface. Regardless of trial complexity, the IRT must offer solutions to support all dosing algorithms and it must be supported by a robust information technology infrastructure to enable secure and rapid access for all system users. The IRT is always the first to know. It is the first step for the investigator in triggering the subject enrolment; the data created is required to feed many other critical sources in a real-time fashion.

What Key Elements must an IRT Provider Deliver?

According to a recent publication from Industry Standard Research (ISR) published in August 2020, the top five criteria for sponsors when selecting an IRT provider are: (1) ability to integrate with EDC, ePRO, CTMS and other data systems, (2) startup timelines and speed of build, (3) flexibility in study design, (4) low cost, and (5) integration with sponsor drug supply. This ISR report indeed hits many of the important delivery elements required from an IRT solution. In recent COVID trials, these five elements were certainly of huge importance.

40 Journal for Clinical Studies

(1)

On integration: IRT solutions must have strong integration capabilities with the ability to feed study data in a real-time fashion to other systems. This generates efficiencies and enables rapid decision-making. The IRT platform is vital for many stakeholders including site users, data managers, clinical supplies managers, and statisticians as well as the sponsor and broader study team. In recent COVID trials, data integration allowed for real-time data transfer from the IRT to the EDC, sending screening and randomisation information to the EDC as these transactions occurred in the IRT. The automation of this data entry provided an efficient way for the sponsor and clinical team to view data in the EDC in real time and relieved the sites of the burden of entering the same data across multiple platforms.

(2)

On timelines: With COVID-19 studies in particular, the need to expedite timelines is critical. In a typical IRT situation involving design, development and validation, timelines for a study build of average complexity range from 10 to 12 weeks. With COVID trials, IRTs are often needed in four to five weeks. In order to meet such timelines, IRT teams must be able to operate in an agile fashion. This means that study requirements are often still evolving when development work has commenced. This presents a challenge to the team with a high demand for rework when requirements change. Development and validation must be completed to an extremely high standard with zero quality findings. When the system is provided for user acceptance testing, minimal findings should be identified. With the growing demand to expedite timelines, not just for COVID trials, IRT providers must move towards decreased build times for all studies.

(3) Flexibility is critical and the ability to adapt the IRT midstudy is vital as subject and protocol changes need to be accommodated whilst the trial is ongoing. Many protocols are now designed with multiple cohorts, in which doses are still to be determined. Thus, the IRT must be able to accommodate such changes with no interruption, whilst maintaining complete fluidity of the original study design. Additionally, throughout the duration of the trial, the IRT must enable the project teams to open and close screening, randomisation and resupply in a real-time fashion on the project, country, and/ or site level. End users must have the ability to adjust initial, trigger, and resupply quantities in real time to ensure sites have adequate IP stock on hand throughout the duration of the trial.

(4) Costs must be managed carefully and sponsors must be informed promptly of the cost impact of any protocol or scope changes. This should be a standard feature of all IRT providers and again, must be done at high speed, particularly during fast-paced COVID trials.

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Technology

(5) Integration with the sponsor or third-party drug supply is vital to ensure that drug supply is where it is needed, when it is needed, in the correct quantities, thus enabling maximum enrolment on to the trial. IRT providers must play a collaborative role with IP manufacturers and distributors, as well as have the ability to rapidly pivot to varying enrolment needs. More broadly, relating to decentralised trials, flexibility is key. During the pandemic, IRT providers have been required to collaborate strongly with all drug supply chain stakeholders to fulfil needs where necessary, to provide IP direct to patients’ homes.

Additional Critical Elements Based on COVID-19 Experience Based on recent COVID-19 trials, additional factors should be considered when selecting IRT providers. Most important amongst those are: (1)

IT Infrastructure In COVID trials in particular, an IRT platform and the supporting infrastructure must be able to withstand significant demands. Trials typically involving many months to enrol hundreds of subjects are now not the norm. IRT solutions must hold up to the stern test of enrolling as many as 30,000 subjects in a four- to six-week period. This must be achieved in an extremely secure system, with zero waiting time. Frequent and diligent monitoring of server loads and application performance in a timely manner is vital and in recent experience provided important recommendations for optimising the system on various levels of the technology stack to assist with transaction and report load times. This ensures thousands of randomisations can be supported in as little as an hour.

(2) Team Experience and Expertise With trials moving at a fast pace, critical thinkers and decision-makers must be on hand to support the needs of the broader study team and to provide solutions for oft complex challenges including design solutions. This is not a time for rounds of discussions and drawn-out decision-making processes. Key team members must have the expertise to make informed and educated decisions at great speed and with confidence. Therapeutic expertise is important and the ability of an IRT team to work hand in hand with their clinical www.jforcs.com

project management counterparts can have a significant and positive impact. Teams with years of IRT experience are important in this regard, with access to a well-structured management system who can step in to support at short notice.

(3) 24/7 Cover and Ability to Rapidly Manage Site and Subject Needs A 24/7 call centre is a standard offering with most IRT providers. This, in COVID trials, is of course also critical, but it must be supplemented with appropriate levels of support to ensure questions can be answered rapidly and data changes can be made around the clock and around the globe. Emergency un-blinding is often required in a matter of minutes. Thus, it is critical to supplement 24/7 support with experienced team members including application support and other subject matter experts. This can significantly maximise prospects of enrolling subjects into a trial.

Conclusion Careful selection of an IRT provider that can partner with sponsors to provide a robust and flexible IRT platform, with a team of experts to support it, is vital in today’s clinical trials, none more-so than COVID-19 trials. IRT professionals are extremely dedicated to their cause, and choosing an IRT partner with the appropriate technology, expertise and infrastructure can make or break a trial’s success.

Michelle Lynskey Michelle Lynskey is Global Head of Interactive Response Technology and Clinical Supplies Management at ICON plc, leading the delivery of ICON’s proprietary IRT solutions and CSM services. Michelle’s prior experience includes operational and client oversight roles in ICON’s Central Laboratory, as well as several years’ experience in Strategic Project delivery, including technology innovations.

Michelle holds a B.Sc. in Biotechnology, B.Sc. Technology Management, M.Sc. Science Communication and she is PMP and Lean Six Sigma Black Belt Certified.

Journal for Clinical Studies 41

Technology

Flexible Virtual Trials for Patientcentricity, Efficiency, and Better Data Before the pandemic, virtual and hybrid trials were a novelty. Although enabling technologies such as bring your own device (BYOD), electronic patient-reported outcomes (ePRO), and direct data capture (DDC) have been in place for several years, the implementation of these hybrid approaches stagnated. Now, remote trials are a proven and valuable necessity. While the idea of a clinical trial in which certain strategies and technologies reduce the need for patient site visits is simple, the details of design and implementation are not. This article discusses practical considerations in virtual and hybrid trials and how these trials can help reduce cost, deliver cleaner data, and improve patient acceptance and engagement.

Decentralised, Virtual, and Hybrid Trials – What’s the Difference?

Clinical trials designed to leverage a variety of methods that limit the need for patients to visit investigator sites go by many names.

Confusion arises because these terms, such as decentralised, virtual, and hybrid, are used inconsistently. For some, decentralised might mean there is no central clinical research site, only a decentralised coordinator. Others equate decentralised clinical trials with any trial that applies a patient-centric approach and requires fewer patient clinic visits. For some, virtual trials enable patients to avoid site visits altogether – a design that is, in fact, very rare – whereas hybrid trials utilise a combination of traditional and virtual methods.

Others use virtual loosely to mean the same thing as hybrid.

In the end, all these terms refer to clinical trials that employ any number of methods to allow for more flexibility in how patients join and participate than the traditional clinical trial model wherein all patient interactions occur at an investigational site. Strategies range from digital consenting tools to remote monitoring and telemedicine to direct-to-patient distribution of clinical trial materials to home health visits to cell-phone apps. These solutions aim to ease burdens associated with patient participation, provide access for a greater variety of patients, and improve compliance and retention, resulting in better data, reduced site burden, and faster trial completion.

Innovative Approaches That Promote Patient Recruitment and Retention Finding patients, keeping patients, and engaging with patients – these are critical for any clinical development programme. One of the best ways to find and retain patients is to offer a different clinical trial model – one where patients can be involved in the study in a way that allows them to enroll and stay in it while also balancing a busy schedule. For some patients, avoiding medical facilities may also be a priority. With the technologies available today, more organisations could embrace a site-visit limiting approach, which I believe would have a significant impact on the industry’s chronic inability to attract and retain a sufficient number of patients.

If you think about a complete and flexible patient journey, it’s all about options. Variety is key for clinical trials; since no two are the same, it takes a range of solutions to arrive at the constellation 42 Journal for Clinical Studies

that fits. However, a toolbox of solutions isn’t enough. Experience with virtual studies and the know-how to implement them are also crucial. To understand the range of activities that might comprise the conduct of a decentralised trial, consider the following scenarios.

Hybrid Virtual Visit With patients who have already been screened, consented, and enrolled in a study, sites interact remotely, often using an online video platform such as Zoom or Doxy.me. In this model, sites record patient observations and capture study data via electronic clinical outcome assessments (eCOA) as they would during an on-site visit. This setup allows patients to engage in the trial with minimal effort. At the same time, these direct patient interactions are key for patient retention, as they allow study teams to stay engaged and follow up with timely encouragement, appreciation, and reminders to stay with the study.

Patient interactions may include testing during the visit and/ or be supplemented with self-administered data collection (e.g., a home blood pressure cuff) or sensor-based data collection devices.

Carriers specialising in logistics and supply chain for virtual clinical trials can be engaged for secure, documented, timely, climatecontrolled home delivery and pickup of clinical trial supplies and clinical samples. For patients not yet consented, eConsent by telemedicine may be possible. Explanations, ID verification, and reviewing of eConsent can all be done remotely.

Site-to-Patient Direct Data Capture (DDC) Another option is to conduct home visits, bringing the site to the patient. The travelling study coordinator captures data electronically at the point of care. Data entry is guided by edit checks and data may be uploaded and made available to study teams immediately.

In cases where no internet connection is available, visiting coordinators can download patient data collection forms in advance and upload collected data later. This DDC model has been successfully used in many therapeutic settings to reduce patient burden while still maintaining control over the protocol execution and data capture.

It’s important to understand that DDC is distinct from electronic data capture (EDC). In many trials, data from various sources must be transcribed into the EDC tool – a time-consuming, error-prone process. With DDC and other eSource data capture methods, the original source data is entered directly into the electronic record, saving time, reducing errors, and eliminating the need for later verification. The success of virtual trials – and many of their advantages – hinges on this clean operational approach. ePRO Configured to Engage Patients and Improve Data Quality Electronic patient-reported outcomes (ePRO) are an excellent tool for promoting patient adherence and retention while improving data quality. Patients record real-world data on mobile electronic devices, such as smartphones. The applications can be configured to deliver edit checks and reminders that promote adherence to study protocols. In addition, they can deliver study information and other communications that enable study teams to keep in touch, promoting patient retention. An additional advantage is that realVolume 13 Issue 3

Technology time data visibility and alerts can give study teams the opportunity to contact patients promptly when data entries are incomplete.

Bring Your Own Device (BYOD) ePRO BYOD-enabled ePRO takes advantage of the devices (smartphones) already in people’s pockets to gather data, send information and instructions, and maintain patient engagement for better retention.

Particularly in a situation like the pandemic, the logistics and supply chain issues of getting devices to sites (and ultimately to patients) can be problematic. Additionally, reusing devices among patients increases concerns about infection risk. But even more importantly, patients prefer using their own devices and are more compliant when they do so.(1) Note that these studies must always have provisioned devices available so as not to exclude patients unable to take advantage of BYOD. Through greater patient-centricity, virtual trials reduce the clinical trial burden on patients, making participation more convenient and more attractive. They also offer a variety of opportunities to improve patient engagement and adherence to study protocols, increasing retention and data quality.

Case 1: COVID-19 Vaccine Trial in Long-term Care Facilities Decentralised trials enable some studies that would be otherwise impossible. One example is a Phase III vaccine trial for a leading pharma company including more than 1000 patients at 82 sites. Participants were over 60 years of age, lived in long-term care facilities, and had been exposed to the SARS-CoV-2 virus. They were unable to attend off-site visits, and televisits were not feasible.

As a virtual solution, travelling nurse coordinators were deployed with data-capture devices that did not require internet access. Data was captured directly into the electronic record, avoiding the need for transcription. Elderly patients were able to participate with minimal burden. The electronic interface allowed collection and automatic storage of nontraditional data types, such as images and source notes. This data capture solution was deployed in 11 weeks.

Flexible Study Design Is Key for Virtual Trials Design needs for virtual trials are highly variable. The vast majority of studies require some in-person site visits for activities such as screening, baseline, and end-of-study assessments, while intermediate and follow-up assessments are virtual. This structure of time and events is set up in a way that enables the use of the proposed modalities at the desired frequency and time points. Because they limit visits, virtual trials ease site burden and – with eSource DDC – eliminate most data transcription work: data only needs to be entered once.

Virtual study coordinators can use both voice and video to connect securely with patients based on an agreed-upon schedule for collecting the needed data. Depending on the specific data requirements for the study, the coordinator can either meet with patients at their homes or at a convenient location to perform study procedures, much like a home health nurse. Using DDC tools, coordinators can also collect needed audio and video and enter it directly into the electronic research record with all the other data.

As an added option, lab work not done at the patient’s home may be performed at nearby commercial laboratories.

Rapid study implementation requires an agile, interactive design-build cycle for the eCOA, ePRO, and DDC questionnaire screens. These can be made to appear as familiar, document-based forms. This approach offers intensive collaboration to configure prototypes and updates, which are reviewed directly on the relevant device. Typical bottlenecks include standard assessment licenceholders, translations, and hardware availability. Engaging licenceholders early to get buy-in and agreement can avoid delays. A good working relationship with a top translation vendor can expedite screen translations and migrations. It’s also important to plan ahead for devices, including provisioned options. Where video visits are part of the protocol, this may include providing some patients with tablets.

A few additional best practices for virtual trial design: • • •

Allow for flexible use of televisit solutions – let sites use what they are accustomed to.

Choose eSource DDC for the greatest all-around efficiency.

Utilise solutions that enable direct capture of data regardless of patient location.

Figure 1. Hybrid virtual trials can allow data collection with edit checks and reminders wherever the patient happens to be, and in some cases, on the patient and study coordinator’s devices of choice. www.jforcs.com

Journal for Clinical Studies 43

Technology

• •

Embrace a BYOD approach, where possible.

Ensure there is an integrated, easily accessed helpdesk.

Real-time Data Enables Timely Decisions in Clinical and Data Management Clinically, eSource DDC solutions for hybrid virtual trials provide earlier insights into patient well-being and protocol adherence.

Real-time capture and access to clinical trial data including ePRO responses enable clinical teams to monitor for and respond to questions and safety concerns immediately. In contrast, with a paper-based system, by the time the team learns of an event, it is long past. Frequent engagement allows teams to identify issues proactively. For example, certain patient diary responses could trigger an alert regarding potential safety concerns, and the team would follow up right away.

Data managers and monitors can also take advantage of this technology for remote monitoring and oversight. Monitors can travel far less, reducing expenditure of time and funds. At the same time, they can ensure the integrity and quality of the data captured as a part of the virtual trial. Monitors can provide oversight across numerous virtual sites and issue manual queries – all while using the same tools deployed by the virtual coordinator to collect the data. Real-time access to the collective data should enable monitors to focus on source data review (SDR) and trends and outliers, a more proactive approach to addressing potential issues within the wider context of the clinical trial. Source document verification (SDV) is unnecessary as DDC has never been transcribed.

From a data quality perspective, eSource DDC achieves much more reliable documentation for virtual trial entries and helps teams verify that the protocol is being followed correctly. Many kinds of data may be entered into the electronic research record and preserved for later reference or compliance purposes. Unalterable UTC time stamps mark entry times, ensuring that the assessment happened when indicated.

From a compliance and data integrity standpoint, automatic time stamps and reminders to complete tasks are a dramatic improvement over paper-based records, which may have been completed in the parking lot five minutes before the patient visit.

All these efficiencies add up to easy review of source documents and audit trails with reduction in data queries, faster resolution, cleaner data, and accelerated database lock. Other DDC methods, such as physician notes, drawings, audiovisual recordings, 44 Journal for Clinical Studies

ECGs, lab results, or other kinds of data can also be entered into the electronic research record with ease to be preserved for later reference or compliance purposes. For investigator sites, process simplifications like these give time back to study teams for patient care – a consideration of special importance when some teams are overwhelmed, as during the pandemic.

Case 2: CNS Studies Losing Patients and Struggling with Recruitment During Pandemic The constraints of the pandemic put many clinical trials in jeopardy. This pharma company needed to pivot – fast. Their two Phase II studies and two Phase III studies involving nearly 2000 patients at 250+ sites were originally designed as traditional on-site investigations, but participants were reluctant to come to the site. Studies in neurology are notoriously complex. In this case, 10 different assessments had to be configured for home use to limit the number of on-site visits. That meant building and deploying 10 different collection forms for BYOD use at home, for all four studies, as quickly as possible. Furthermore, the licence-holders for all these standardised assessments had to approve the conversions.

Through an agile study development approach with no more than two rounds of user acceptance testing, a virtual trial eSource solution was designed, developed, and deployed in 10 days. The study could move forward, despite the pandemic.

Regulatory and Privacy Considerations for Virtual Clinical Trials Over the years, regulatory authorities have discussed data capture frequently with the industry. With the advent of tools, technologies, and approaches that embrace a more direct capture of data, the FDA, the EMA, and other regulatory agencies have issued eSource-related white papers and guidances, embracing this type of approach (see table). In 2019, the EMA came out with a qualification opinion on eSource in which the Clinical Ink platform is referenced more than 10 times in relation to its use in multiple eSource studies conducted in Europe.2 Throughout, the agency makes it clear that not only is eSource a very viable method for data collection, it is the preferred method.

Of course, systems must be compliant with applicable privacy regulations – 21 CFR Part 11, GDPR, HIPAA, and any other relevant guidance set forth by local regulatory agencies.

Volume 13 Issue 3

Technology

When eSource DDC is used for a virtual trial, data is captured directly, cleaned during the patient visit (via edit checks), and digitised. It can then be consolidated into a single data set and uploaded to the portal in real time, ready to be reviewed remotely.

The data need only be entered once; no paper, transcription, or SDV is needed – getting you to database lock faster.

Virtual Trials Give Patients, Sites, and Sponsors Flexibility and Options With the right technology, decentralised trials are not only possible, but can also reach more patients and ease data collection while improving data monitoring, data quality, and integrity. These trials ease the study burden on patients and sites by leveraging timely advancements including a vast technology toolkit. DDC, BYOD, ePRO, electronic clinical outcome assessments (eCOA), timely risk-based management (RBM), eConsent, telemedicine, home health visits, connected devices/wearables, and more can all be implemented and supported as part of a hybrid virtual trial design. A system that works seamlessly and a team with experience applying it in a variety of environments, from remote areas to highrisk countries, can strengthen the application further.

Sponsors and CROs benefit from cleaner data, site and monitor efficiencies, reduced cost, improved clinical management and patient engagement, and accelerated results. These advantages, along with the reduced need for in-person clinical and monitoring interactions, have allowed pharma research to continue during the COVID-19 pandemic. Given that 70% of patients live more than two hours from a research site,5 continuing this trend even after the fear of coronavirus exposure subsides should ease recruitment of a wider variety of patients for greater equity in clinical research.

REFERENCES 1.

Pugliese, L., Woodriff, M., Crowley, O., Lam, V., Sohn, J. & Bradley, S. Feasibility of the Bring Your Own Device Model in Clinical Research:

www.jforcs.com

2.

3.

4.

5.

Results from a Randomized Controlled Pilot Study of a Mobile Patient Engagement Tool. Cureus. 8(3), e535 (2016). doi: 10.7759/cureus.535.

EMA/CHMP/SAWP/483349/2019 Product Development Scientific Support Department, European Medicines Agency, 25 July 2019, www. ema.europa.eu/en/documents/regulatory-procedural-guideline/ qualification-opinion-esource-direct-data-capture-ddc_en.pdf, accessed 13 Apr 2021.

EMA/INS/GCP/454280/2010 GCP Inspectors Working Group (GCP IWG), Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials, 09 June 2010; https://www.ema.europa.eu/en/documents/regulatoryprocedural-guideline/reflection-paper-expectations-electronic-sourcedata-data-transcribed-electronic-data-collection_en.pdf,accessed 13 Apr 2021.

Guidance for Industry, Electronic Source Data in Clinical Investigations, September 2013, https://www.fda.gov/media/85183/download, accessed 13 Apr 2021.

Alper, J., Khandekar, E. & Shore, C. (Rapporteurs), Virtual Clinical Trials: A New Model for Patient Engagement, National Academies of Sciences, Engineering, and Medicine, August 2, 2019.

Jonathan Andrus As Chief Business Officer, Jonathan Andrus leads Clinical Ink’s solution management and commercial teams to help sponsors and CROs leverage DDC, eCOA, and ePRO data. With 25+ years of experience, Andrus develops eClinical services that integrate data and technology, helping life science companies optimise study execution. Andrus is responsible for P&L across Clinical Ink’s products and services, and forges strategic partnerships with sponsors, CROs, regulatory bodies, and clinical research professionals.

Email: jonathan.andrus@clinicalink.com

Journal for Clinical Studies 45

News Fueled by COVID drug manufacturing revenues, CDMO Jubilant HollisterStier invests in upgrades, expansion Since the onset of the coronavirus pandemic, Jubilant HollisterStier has been busy churning out COVID-19 treatments and more recently vaccines. Now it's turning those revenues from the increased business into an investment in the future.

Source: Fierce Pharma Study: Poor care access, higher costs more likely with private than public insurance People with private insurance report poorer access to care, higher costs and lower satisfaction as compared to those with public insurance plans, a new study shows. As the debate over health insurance reform continues, policymakers should consider efforts that expand Medicare and increase protections for those with private insurance.

Source: MedCityNews Main improvement work to start on £40m development at trust Work will now start on the main phase of the £40m development, at Walsall Healthcare NHS Trust, following the completion of enabling works at the site. This will see major improvements to the emergency care facilities and capacity, on what is regarded as an outdated building.

Source: National Health Executive Cellarity: Transforming Drug Development at the Confluence of Biology and Machine Learning Rather than the traditional target centric approach to drug discovery, Cellarity works at the level of the cell to understand how disease impacts cell behaviour via a target agnostic approach that can help illuminate the most complex diseases science has not yet been able to crack.

Source: BioSpace FDA authorizes machine learning software to help diagnose autism The system, developed by digital health startup Cognoa, uses information from questionnaires and videos to help pediatricians diagnose autism. It received marketing authorization from the FDA on Wednesday.

Source: MedCityNews Seroprevalence study of SARS-CoV-2 infection in domestic cats Along with humans, dogs and cats have tested positive for COVID-19 (coronavirus disease 2019). In spite of this, we don't know for certain whether pets are involved in the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, SARSCoV-2, the etiological agent of COVID-19 has infected over 173 million individuals and claimed over 3.72 million lives worldwide.

Source: News Medical Life Sciences

Hydroxychloroquine + Azithromycin therapy at a higher dose improved survival by nearly 200% in ventilated COVID patients Treatment options have been limited in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Earlier optimism regarding immunomodulatory drugs such as azithromycin (AZM) and hydroxychloroquine (HCQ) seemed to be undermined by results of large interventional trials.

Source: News Medical Life Sciences Lynparza® improves invasive disease-free survival in high-risk early breast cancer trial In the Phase III OlympiA trial, Lynparza® (olaparib) reduced the risk of cancer recurrences or death by 42 percent in patients with BRCAmutated high-risk early breast cancer. AstraZeneca and Merck & Co. (MSD outside the US and Canada) have revealed that the OlympiA Phase III trial showed Lynparza® demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) versus placebo in the adjuvant treatment of patients with germline BRCA-mutated (gBRCAm) high-risk human epidermal growth factor receptor 2 (HER2)-negative early breast cancer.

Source: European Pharmaceutical Review Bayer at ASCO: Vitrakvi Effective in TRK Fusion Cancers Regardless of Tumor Type Bayer is presenting four abstracts related to its Vitrakvi (larotrectinib) across TRK fusion cancer patients of all ages, ranging from 0.1 to 84 years, and for multiple tumor types. Vitrakvi is a first-in-class TRK inhibitor for TRK and presenters are supporting the drug’s effectiveness in a range of cancers with TRK gene fusions regardless of tissue type or patient age.

Source: BioSpace The balancing act: accessibility and sustainability in packaging design Drug innovation has come on in leaps and bounds over the years, yet the way in which consumers access medicines has not. Packaging design remains stubbornly inaccessible to the cognitively challenged, making complex medication management impractical and even dangerous.

Source: European Pharmaceutical Review Alzheon doses first patient in oral drug trial for Alzheimer’s disease Alzheon has dosed the first patient in its APOLLOE4 Phase III study evaluating the efficacy and safety of oral anti-amyloid drug ALZ-801 in early Alzheimer’s disease (AD) patients. With a novel anti-amyloid oligomer mechanism of action, ALZ-801 is an optimised prodrug of tramiprosate that has shown promising results in analyses of Phase III clinical data.

Source: Clinical Trials Arena

With expansion, UK dermatology CDMO MedPharm will double its presence in the US With business thriving at MedPharm, a U.K.-based company that specializes in the development of dermatology, nail, mucosal membrane and transdermal products, there is a need for more physical space, both at home and in the United States.

Ten recommendations to foster the UK’s medicinal cannabis market The acknowledgment that cannabis has medicinal properties has resulted in it being legalised to varying extents in over 50 countries worldwide. This legitimation has created a global medicinal cannabis industry that was valued at £16.5 billion in 2019 and is expected to reach over £55 billion by 2027.

Source: Fierce Pharma

Source: European Pharmaceutical Review

46 Journal for Clinical Studies

Volume 13 Issue 3

News Vasopharm’s ronopterin fails in traumatic brain injury trial Vasopharm has reported that its Phase III trial of ronopterin (VAS203) failed to meet the pre-specified primary goal in traumatic brain injury (TBI) patients. Ronopterin lowers the increased production of nitric oxide through upregulated inducible NO synthase, targeting both blood vessels and tissue of the injured brain.

Source: Clinical Trial Arena NIH SBIR Grants Key in Providing Fuel to Novel Innovative Therapies Targeting Pending Crisis such as NASH People in the U.S. and in some other countries are headed toward a “NASH” crisis, a not very well-known but pervasive disease associated with many of the lifestyle elements of America that turn up in diagnosis ever more frequently. That’s when the liver starts storing fat in what becomes Nonalcoholic Fatty Liver Disease (NAFLD) plus the addition of hepatitis (inflammation) added to the fat accumulation, and the disease becomes Nonalcoholic Steatohepatitis (NASH).

Source: Trial Site News Everything you need to know about the A1C test The A1C test is a test for diabetes to measure a person’s average blood glucose level over about 3 months. Doctors can use it to diagnose type 2 diabetes and to monitor people’s diabetes.

Source: Medical News Today Eiger to add Peginterferon Lambda to Covid-19 trial in Brazil Eiger BioPharmaceuticals has said that its investigational agent, Peginterferon Lambda, will be added to the Phase III TOGETHER platform study of Covid-19 outpatients in Brazil. A type III interferon (IFN), Lambda induces immune responses required for developing host protection during viral infections. Eiger licensed the therapeutic from Bristol-Myers Squibb.

Source: World Pharma today

with the delta variant, it said. Data also indicate that the variant is spreading rapidly through England’s schools.

Source: BMJ Israel finds a ‘probable link’ between Pfizer vaccine and myocarditis cases The cases, observed mostly in young men who had received the Pfizer/BioNTech jab, have a ‘probable link’ to the second dose of the vaccine, according to Israel. Israel’s Health Ministry reported that it was aware of 275 cases of myocarditis occurring between December 2020 to May 2021, with 148 of these cases happening within a short time frame after receiving the Pfizer/BioNTech vaccine.

Source: PMLiVE University of Georgia Takes Lead on $2.57m Grant to Launch Effectiveness of Medicaid-based Alcoholism Use Disorder Treatment Program Researcher Christina Andrews, an associate professor of health services policy and management at the University of South Carolina, teams with a University of Georgia associate professor who just received a four-year, $2.57 million R01 grant to investigate the effectiveness of Medicaid-covered alcohol use disorder treatment. That’s Amanda Abraham, an associate professor of public administration and policy, and her study takes on a real growing crisis as “Alcohol-related morbidity and mortality are on the rise in the United States.

Source: Trial Site News MorphoSys expands oncology pipeline with $1.7bn acquisition of Constellation Pharmaceuticals MorphoSys will pay $34 a share to acquire Constellation Pharma, which will see it gain two lead drugs, including BET inhibitor pelabresib and second-generation EZH2 inhibitor CPI-0209. Both product candidates are in mid- to late-stage clinical trials, with ‘broad therapeutic potential’ across various haematological and solid tumours.

Source: PMLiVE

New treatment option offers disease control and extends life in patients with advanced prostate cancer Cancer researchers say they have established a new, life-extending treatment option for men with prostate cancer that has spread and become resistant to hormone therapy. The injected treatment combines a targeting compound with a radioactive isotope to irradiate and kill cancer cells.

Rise in cost and usage of antidepressants sparks concern Researchers conducted a study to investigate the trends in prescriptions and costs of various antidepressants in England during the COVID-19 pandemic. Following the analysis, the scientists have said that it is vital for the country ‘s mental health interventions to create strategies optimising the use of antidepressants.

Source: News Medical Life Sciences

Source: Health Europe

Henry Ford Hospital cardiologists are first in the U.S. to implant circulatory support device Cardiologists at Henry Ford Hospital are first in the U.S. and second in the world to implant a circulatory support device that is being investigated in a clinical trial for patients hospitalized with acute decompensated heart failure (ADHF) and worsening kidney function, a condition known as cardiorenal syndrome.

Digital tool will reduce the cost of developing new medicines In a vital step for the development of new medicines, the cuttingedge digital tool, called Quantitative Understanding of Bio-molecular Edge-Shift (QUBES) and developed by scientists at the University of Bath, will enable pharmaceutical companies to predict protein stability in a more cost-efficient manner.

Source: News Medical Life Sciences Covid-19: Delta variant is now UK’s most dominant strain and spreading through schools The delta covid-19 variant (B.1.617.2), which was first detected in India, has overtaken the alpha variant, better known as the UK or Kent variant (B.1.1.7), to make it the most dominant strain circulating in the UK, Public Health England has said. This is a concern because there is evidence that the risk of hospital admission is higher in people www.jforcs.com

Source: Health Europe “Black fungus’ and COVID-19: Myths and facts In India, COVID-19 has led to a surge in cases of a potentially fatal fungal infection called mucormycosis, popularly known as “black fungus.” The infection is every bit as dangerous as the media have portrayed it, but several myths are circulating on social media about potential sources of the infection and its treatment.

Source: MedicalNewsToday Journal for Clinical Studies 47

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