JCS Volume 14 Issue 5

Volume 14 Issue 5

Journal for Clinical Studies PEER REVIEWED

How the FDA Sped Up Cancer Product Development and Reviews During a Global Pandemic How to Streamline a Complex Process: The Value Add of Experienced Medical Writers for Oncology Dossiers Asia’s Clinical Trial Industry Developments and Challenges Optimising Trials Assessing Cognitive Post-Acute Sequelae of SARS-CoV-2 Infection (PASC-Cog)

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Contents 4

FOREWORD

WATCH PAGES 6

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

How the FDA Sped Up Cancer Product Development and Reviews During a Global Pandemic

Amid the ongoing COVID-19 public health emergency, the US Food and Drug Administration (FDA) has emphasised the importance of caring for patients with established conditions – particularly for those requiring chronic medical care and/or with weakened immune systems, such as cancer patients. Deborah Komlos at Clarivate outlines how the FDA sped up cancer product development and reviews during a global pandemic.

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How to Streamline a Complex Process: The Value Add of Experienced Medical Writers for Oncology Dossiers

Oncology is one of the most common areas of drug development in the pharmaceutical industry. In 2020, the majority of new drugs approved by the FDA were cancer treatments. Existing cancer drugs are also regularly being approved for additional indications. Julia Forjanic Klapproth and Maurice Löwens at Trilogy Writing & Consulting outlines the value add of experienced medical writers for oncology dossiers.

REGULATORY 10 Achieving Simultaneous New Drug Document Submission for the FDA and EMA International Conference on Harmonization (ICH) guidance makes it feasible to construct a new drug submission dossier that can be used for applications to multiple countries. Two of the largest markets with the most evolved regulatory landscapes, the U.S. and Europe, have similar documentation requirements, but with important considerations to recognise that need special attention. Steve Sibley at Certara Synchrogenix explains how to achieve simultaneous new drug document submission for the FDA and EMA. 14 Turning Pharmacovigilance into a Strategic Advantage Safety science complexity is on the rise as the volume of safety data explodes (case volumes are growing at a pace of 15 to 20% per year), regulatory scrutiny continues to increase, and consumer demands grow. The pandemic and national health emergencies like Monkey Pox have put safety and public health benefit-risk discussions in the spotlight, and stricter regulations have emerged from local regulators as a result. Sharmila Sabaratnam at Veeva Systems discusses how to turn pharmacovigilance into a strategic advantage.

The opinions and views expressed by the authors in this journal are not necessarily those of the Editor or the Publisher. Please note that although care is taken in the preparation of this publication, the Editor and the Publisher are not responsible for opinions, views, and inaccuracies in the articles. Great care is taken concerning artwork supplied, but the Publisher cannot be held responsible for any loss or damage incurred.

This publication is protected by copyright.

Volume 14 Issue 5 September 2022 Senglobal Ltd.

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Journal for Clinical Studies 1

Contents

RESEARCH & DEVELOPMENT

THERAPEUTICS

16 Why Do We Need Patient Diversity in Clinical Trials?

28 Optimising Trials Assessing Cognitive Post-Acute Sequelae of SARS-CoV-2 Infection(PASC-Cog)

In the commercialisation of new medications, the paramount legal responsibilities of the pharmaceutical company are, firstly, to prove that the pharmacology is safe and well understood, and, secondly, to prove effectiveness against the targeted disease. Within the European Union, for example, each pharmaceutical company has a Qualified Person for Pharmacovigilance (QPPV) representing them in each country in which they legally operate and market medications. Douglas Drake at Clinerion Ltd clarifies why do we need patient diversity in clinical trials.

20 Improving Health Literacy to Transform Clinical Trials The healthcare industry struggles with resolving fundamental patient communication challenges. Approximately 50% of adults cannot read at a high school level and 88% of adults are not proficient in health literacy. There is a global need to develop culturally sensitive, relatable medical education resources for patients, caregivers, and their families.

Columba Quigley at Jumo Health will discuss successful strategies that have been employed to improve patient recruitment and retention in clinical trials.

MARKET REPORT 24 Asia’s Clinical Trial Growth – Industry Developments and Challenges Clinical trials within Asia are on the rise again, however the effects of the COVID-19 pandemic continue to have a significant impact within the industry. While the number of clinical trials and countries involved is increasing post pandemic, there remain key challenges that need to be navigated to support the surge. Kazuo Ishizuka at Peli BioThermal shows that while having to contend with these ongoing challenges, companies may seek alternative solutions which can be conducted virtually or rely more on the local production of clinical drugs.

2 Journal for Clinical Studies

Post-acute COVID-19 syndrome has recently been recognised as a complex chronic clinical entity in subjects who have experienced the SARS-CoV-2 infection. It is currently defined as the presence of symptoms for more than twelve weeks developed during or after SARSCoV-2 infection which are not explained by an alternative diagnosis, usually presenting with clusters of symptoms that can affect any system in the body, including the central nervous system. Henry J. Riordan and Tomislav Babic at Worldwide Clinical Trials show how to optimise trial assessing cognitive post-acute sequelae of SARS-coV2 Infection.

TECHNOLOGY 32 How Digital Health Can Reshape Pharma’s Role in Healthcare With analysts predicting that patient numbers could double in the next few decades, hospital lead times will need to be cut by 50% simply in order to maintain care provision at its current levels. But given the rate at which personnel are leaving the profession, even this feels like a tall order. To address this challenge, smarter diagnostic tools and a growing role for remote care will be of huge importance in the new healthcare environment. In light of the proposed shift to value-based healthcare, Gérard Klop and Marcos Gallego Llorente at Vintura set out their vision for how pharma can grow its role in digital health provision.

APPLICATION NOTE 34 PCI clinicalSMART™: A SMART Solution to Clinical Supply Management With the number of registered clinical trials increasing significantly each year, it’s not surprising to learn that the clinical trials supply and logistics market is predicted to grow exponentially in the years ahead.

PCI Pharma Services presents clinicalSMART™ as SMART solution to clinical supply management.

Volume 14 Issue 3

Foreword Clinical trials are the engine of progress in the development of new drugs, procedures, and devices for the detection, monitoring, prevention, and treatment of cancer. A wellconceived, carefully designed, and efficiently conducted clinical trial can produce results that change clinical practice; deliver new oncology drugs, interventions, and diagnostics to the marketplace; and expand our understanding of cancer biology. A poorly done trial does little to advance the field or guide clinical practice, consumes precious clinical and financial resources, and challenges the validity of the ethical contract between investigators and the volunteers who willingly give their time and effort to benefit future patients.

Amid the ongoing COVID-19 public health emergency, the US Food and Drug Administration (FDA) has emphasised the importance of caring for patients with established conditions – particularly for those requiring chronic medical care and/or with weakened immune systems, such as cancer patients. Deborah Komlos at Clarivate outlines how the FDA sped up cancer product development and reviews during a global pandemic

medications. Douglas Drake at Clinerion Ltd clarifies why we need patient diversity in clinical trials Clinical trials within Asia are on the rise again, however, the effects of the COVID-19 pandemic continue to have a significant impact on the industry. While the number of clinical trials and countries involved is increasing post-pandemic, there remain key challenges that need to be navigated to support the surge. Kazuo Ishizuka at Peli BioThermal shows that while having to contend with these ongoing challenges, companies may seek alternative solutions which can be conducted virtually or rely more on the local production of clinical drugs.

I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals.

Beatriz Romao, Editorial Manager Journal for Clinical Studies

Enormous advances have been made over the past decade in the diagnosis and treatment of cancer. Many people are living longer and better lives due to advances made in the prevention and early detection, surgical techniques and procedures, newer forms of radiotherapy and systemic drug therapies. Oncology is one of the most common areas of drug development in the pharmaceutical industry. In 2020, the majority of new drugs approved by the FDA were cancer treatments. Existing cancer drugs are also regularly being approved for additional indications. Julia Forjanic Klapproth and Maurice Löwens at Trilogy Writing & Consulting outline the value added by experienced medical writers for oncology dossiers.

In this journal, we will also explore more about patient diversity in clinical trials. In the commercialisation of new medications, the paramount legal responsibilities of the pharmaceutical company are, firstly, to prove that the pharmacology is safe and well understood, and, secondly, to prove effective against the targeted disease. Within the European Union, for example, each pharmaceutical company has a Qualified Person for Pharmacovigilance (QPPV) representing them in each country in which they legally operate and market 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, Principal Content Writer, Clarivate

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

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

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

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

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

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Stefan Astrom, Founder and CEO of Astrom Research International HB

Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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Volume 14 Issue 3

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Journal for Clinical Studies 5

Watch Pages

How the FDA Sped Up Cancer Product Development and Reviews During a Global Pandemic Amid the ongoing COVID-19 public health emergency, the US Food and Drug Administration (FDA) has emphasised the importance of caring for patients with established conditions – particularly for those requiring chronic medical care and/ or with weakened immune systems, such as cancer patients.

In a July 2020 message to healthcare providers and patients with cancer, the FDA’s Oncology Center of Excellence (OCE) stated that it recognises that cancer patients represent a vulnerable population at risk of contracting COVID-19.1 The OCE acknowledged that although the nation’s emphasis is on the need to combat SARS-CoV-2, the virus that causes COVID-19, “patients with cancer and their unique needs continue to be a top priority.”

Authorised by the 21st Century Cures Act of 2016 and established in January 2017, the OCE collaborates with the three FDA product centres – the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH) – in an integrated regulatory approach to enhance cross-centre coordination for the clinical review of oncology products.

The OCE’s director, Richard Pazdur, MD, commented in February 2022 on the fifth anniversary of the centre that the OCE looks forward to continued progress toward achieving its “vision to create a collaborative scientific environment to advance the development and regulation of oncology products for patients with cancer.”2 Since its inception in 2017, the OCE has created more than 30 externally facing programs and projects to educate, inform, conduct research, and collaborate, Pazdur noted. He said the OCE “is committed to driving change in cancer drug development that results in more efficient and accessible clinical trials, more effective and safer medical products, and better outcomes” for cancer patients.

In 2021, the OCE developed additional research and development projects addressing various aspects of cancer drug development, as summarized in the 2021 OCE Annual Report.3 Among these were Project Optimus, an initiative to reform the dose optimisation and dose selection paradigm in oncology drug development, and the Rare Cancers Program, which works in conjunction with CDER’s Office of Oncologic Diseases (OOD) to promote the development of safe and effective new drugs and biologics to treat patients with rare cancers.

Pazdur noted that, despite the challenges of the second year of the COVID-19 public health emergency, the CDER and CBER oncology review teams granted a total of 80 drug approvals in 2021. This included 15 new molecular entities (NMEs), one original biologics license application (BLA), 50 supplemental approvals for 6 Journal for Clinical Studies

new indications, eight supplemental approvals in new populations, and six 505(b)(2) approvals. Eight approvals included indications for pediatric patients. The CDRH, also collaborating with the OCE, authorized 16 oncology-related in vitro diagnostic devices, including 12 companion diagnostics.

Facilitating Regulatory Reviews Other endeavors in the OCE aim to facilitate the regulatory review process, potentially allowing patients to receive earlier access to medical products. Among these initiatives is Project Orbis, which the OCE began in May 2019 to provide a framework for concurrent submission and review of oncology products among international regulators. Another is the Real-Time Oncology Review (RTOR) program, which the OCE, in collaboration with the OOD, commenced in February 2018.

Through participation in the voluntary RTOR program, applicants can submit components of individual modules (e.g., portions of the clinical module) at separate times. This differs from the existing mechanisms for rolling review in which, generally, complete modules (e.g., the complete clinical module) are submitted prior to a complete application submission. According to the FDA, by providing the agency with earlier access to key safety and efficacy data, it can identify data quality and potential review issues and provide feedback to the applicant, which can permit a more streamlined and efficient review process. In July 2022, the FDA published the draft guidance for industry, Real-Time Oncology Review (RTOR), to provide recommendations to applicants on the process for submission of selected new drug applications (NDAs) and BLAs with oncology indications for review under the RTOR program.4 To initiate an RTOR submission, the FDA requires the top-line efficacy and safety results from the applicant’s pivotal clinical trial(s). At this stage, the applicant should have already completed the database lock for the clinical trial(s). The agency noted that RTOR is not designed to receive live updates of clinical trial data.

Furthermore, RTOR may not be suitable for certain biological products (e.g., cell and gene therapies) for which the FDA must consider complex manufacturing and product characteristics in evaluating the safety and efficacy of the product. For these types of products, the FDA recommends that the applicant discuss the product’s suitability for RTOR with the appropriate review division.

For RTOR submissions, the FDA prefers that applicants use the Assessment Aid, a voluntary submission to facilitate the agency’s assessment of the NDA/BLA application, including supplements.5 Based on the FDA Multidisciplinary Review template, the Assessment Aid is intended to focus the FDA review on critical thinking (assessment), increase review efficiency and consistency, and decrease review time spent on administrative tasks (e.g., formatting).

Volume 14 Issue 3

Watch Pages Cancer Therapeutic Approvals Under OCE Programs To date in 2022, several CDER and CBER product approvals with cancer indications have involved OCE efforts, including: •

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January 25: Kimmtrak (tebentafusp-tebn), from Immunocore Limited, a bispecific glycoprotein 100 (gp100) peptide, human leukocyte antigen (HLA) – directed CD3 T-cell engager, was approved for HLA-A*02:01 – positive adult patients with unresectable or metastatic uveal melanoma.

The FDA’s review was conducted under Project Orbis and involved collaboration with the Australian Therapeutic Goods Administration (TGA), Health Canada, and the United Kingdom’s Medicines and Healthcare product Regulatory Agency (MHRA). The review also used the RTOR program and the Assessment Aid. February 28: Carvykti (ciltacabtagene autoleucel), from Janssen Biotech, Inc, was approved for the treatment of adult patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Carvykti is a B-cell maturation antigen (BCMA)–directed genetically modified autologous T-cell immunotherapy. This review used the Assessment Aid. March 18: Opdualag (nivolumab and relatlimab-rmbw), from Bristol-Myers Squibb Company, was approved for adult and pediatric patients aged ≥12 years with unresectable or metastatic melanoma. Opdualag is a fixed-dose combination of two IgG4 kappa monoclonal antibodies: nivolumab, a programmed death receptor-1 (PD-1)–blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3)– blocking antibody. This review occurred under Project Orbis and involved collaboration with the TGA and Switzerland’s Swissmedic. The review also used the RTOR program and the Assessment Aid. March 23: Pluvicto (lutetium Lu 177 vipivotide tetraxetan), a radioligand therapeutic agent from Advanced Accelerator Applications USA, Inc, a Novartis company, was approved for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic castrationresistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. This review used the Assessment Aid.

More recently, on August 5, the FDA approved Enhertu (famtrastuzumab deruxtecan-nxki), from Daiichi Sankyo, Inc, for the treatment of adult patients with unresectable or metastatic HER2low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. Originally approved in December 2019, Enhertu is the first approved therapy targeted to patients with the HER2-low breast cancer subtype, which is a newly defined subset of HER2negative breast cancer, the FDA stated in the announcement of the recent approval.6 This review was conducted under Project Orbis and involved collaboration with the TGA, Health Canada, and Swissmedic.

Advancing the Fundamental Understanding While broadening the cancer treatment armamentarium is crucial, it requires expanding the knowledge of the underlying science.

The National Cancer Institute (NCI) notes that certain people with cancer, especially those who are receiving treatment for cancer, www.journalforclinicalstudies.com

may be more likely to have severe illness from COVID-19. To advance the understanding of COVID-19 in people with cancer, the NCI is conducting the NCI COVID-19 in Cancer Patients Study (NCCAPS), a longitudinal natural history study in approximately 2,000 participants.7 The study collects blood samples, medical information, and medical images from patients with a prior or current cancer diagnosis and with a positive SARS CoV-2 test within 14 days of enrollment. The goals of NCCAPS include the following: • • • •

Learn more about the risk factors related to serious illness from COVID-19 in people who are receiving treatment for cancer.

Study how COVID-19 affects cancer treatment and the results of the treatment.

Find genetic risk factors and markers of serious illness from COVID-19 in people with cancer.

Create a bank of data, blood samples, and images from people with COVID-19 and cancer for future research.

The knowledge acquired via NCCAPS “will help doctors better manage treatment for people with cancer and COVID-19 in the future,” according to the NCI. “It will also help doctors understand how COVID-19 and cancer affect one another.”8 NCCAPS began in May 2020 and is projected to complete in May 2023.

REFERENCES 1.

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8.

A Message to Patients With Cancer and Health Care Providers About COVID-19. Food and Drug Administration Webpage. https://www.fda. gov/about-fda/oncology-center-excellence/message-patients-cancerand-health-care-providers-about-covid-19 OCE Director’s Message. Food and Drug Administration Webpage. https://www.fda.gov/about-fda/2021-oce-annual-report/oce-directorsmessage OCE 2021 Annual Report. Food and Drug Administration Webpage. https://www.fda.gov/about-fda/oncology-center-excellence/2021-oceannual-report Real-Time Oncology Review (RTOR) Draft Guidance for Industry. Food and Drug Administration Webpage. https://www.fda.gov/media/160186/ download Assessment Aid. Food and Drug Administration Webpage. https://www. fda.gov/about-fda/oncology-center-excellence/assessment-aid FDA Approves First Targeted Therapy for HER2-Low Breast Cancer. Food and Drug Administration Webpage. https://www.fda.gov/news-events/ press-announcements/fda-approves-first-targeted-therapy-her2-lowbreast-cancer NCI COVID-19 in Cancer Patients, NCCAPS Study. ClinicalTrials.gov Webpage.https://clinicaltrials.gov/ct2/showNCT04387656?term=NCCAPS& draw=2&rank=1 NCI COVID-19 in Cancer Patients Study (NCCAPS). National Cancer Institute Webpage. https://www.cancer.gov/research/key-initiatives/ covid-19/coronavirus-research-initiatives/nccaps

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

Email: deborah.komlos@clarivate.com

Journal for Clinical Studies 7

Watch Pages

How to Streamline a Complex Process: The Value Add of Experienced Medical Writers for Oncology Dossiers Oncology is one of the most common areas of drug development in the pharmaceutical industry. In 2020, the majority of new drugs approved by the FDA were cancer treatments.1,2 Existing cancer drugs are also regularly being approved for additional indications.2 The submissions needed to get these approvals are the result of large numbers of oncology studies that are being run all over the world. The summary documents for these submissions are often large and complex and having experienced medical writers working with the clinical teams, who are aware of the unique aspects of oncology studies and have an understanding of the principles underlying cancer therapies, will help pull these documents together more easily and ensure they are communicating the key messages clearly.

Cancer is a disease that is frequently treated over the long term, and even when the cancer has been eliminated, follow-up continues for years. As a result, the endpoints to assess efficacy tend to look at the effect over time and its endurance, not just a static assessment of whether the disease is cured, as in many other therapeutic areas.

The challenges associated with this in the context of submission dossiers arise from the fact that there are often multiple interim study reports, in addition to the final CSR, and multiple data cuts over time (sometimes with different data cuts across multiple studies, which can be tricky to explain to the reader of a submission).

Cancer therapy is also a very dynamic area with developments in biotechnology rapidly shifting the approach to treatment. The medical dogma in many cancer types can shift swiftly, which means that the scientific rationale, currently available treatments, and medical need descriptions often need to be updated frequently – sometimes changing considerably, even within a 12-month period, as new treatment options change the therapeutic landscape.

The role of the medical writer in the dossier-writing process is to collaborate with the clinical experts to understand their vision for the treatment being studied and to crystallise the messaging from the clinical program. The medical writers need to come to terms with the oncology specific terminology, acronyms and efficacy endpoints (progression-free survival, overall response rate, duration of response). They also need to work with the clinical teams to know where current changes in the medical opinion might need to be reflected in the medical need discussion and to understand how the product under assessment needs to be positioned in the overall picture of available therapies. Frequently, because the clinical experts are often deeply involved in the research going on in their area, the medical writers need to help the experts step back from the minutiae and look at the big picture in the context of a registration dossier. It is important that the regulatory documents stay focused on what is needed to get regulatory approval of the target product profile (TPP) and not get bogged down and off target in academic questions (that can be very interesting but should be saved for publications).

To do this effectively, it is essential that submission teams have a clear and well developed TPP from the start of a clinical development program. Ideally, the program should be reverse engineered to specifically collect the data that will be needed to support the 8 Journal for Clinical Studies

intended claims of the TPP. At the latest, it should be ready by the time writing on a submission dossier begins. Without the TPP, it can be challenging to know what aspects to focus on in the Module 2 summaries. If written in parallel, it often gets in the way of writing the dossier as the team chases a moving target. Having the TPP ready and agreed on well in advance gives the team clarity on what issues to focus on throughout the clinical program, in general, and when writing the CTD summaries, in particular.

During an oncology clinical program, it is not uncommon to have multiple dose modifications as the investigators adapt to manage AEs and slowly home in on the optimal dose regimen. Early studies can have different dosing regimens than later studies. As a result, treatment groups can be very fragmented, making it very difficult to interpret the data, particularly in a pooled dataset, because the data cannot be easily compared across different doses. Changes in dosing can also mean that the proposed dose has less exposure time than earlier doses. These problems affect the interpretation of both efficacy and safety and need to be considered carefully when planning how to present the data in the dossier.

Another hurdle that teams often grapple with when writing oncology dossiers is how to handle adverse events of special interest (AESIs). Due to the different organs effected with different cancers, there is often little consistency in the AESIs collected in different studies. This presents a challenge when summarising them across studies in Module 2.7.4. Do you try to find a consistent grouping of these across studies in different cancer types, or do you just present AESIs from the pivotal trial? In oncology, the AESIs will be driven by the risk factors from the underlying disease (cancer type) and in a large dossier, you will need to find a way to bring some very diverse safety data together. This should be thought about as early as possible when the team begins to plan for the dossier, and it certainly needs to be discussed in the statistical analysis plan (SAP) for the safety summaries.

Kaplan Meier plots are widely used in oncology programs for the depiction of overall survival as well as the time to onset and time to resolution of adverse events. These plots can be very useful in visualizing how much of a difference there is for the duration of survival in patients treated with the drug under assessment vs other treatment options. Similarly, in the context of adverse events, Kaplan Meier plots can help make clear the periods of risk for drug-related events. It is helpful for medical writers to understand how Kaplan Meier plots work, so they can provide useful context when writing about these.

Something else to keep in mind when planning for and writing oncology dossiers, is whether there is a likelihood of submitting in other regions (e.g. Japan). If so, it is a good idea to have a discussion with the colleagues from those other regions while developing the SAPs for the efficacy and safety summaries to be sure that all analyses will be planned as required or expected by their local agencies. There is nothing more frustrating than thinking the dossier is fit-for-purpose for a global submission, only to find out that you need additional analyses to be run and incorporated into the files.

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Watch Pages

The value of having an experienced medical writer on the team is that they will be thinking about many of these challenges in advance and can bring meaningful advice and guidance to the dossier team.

While subject matter experts are focused on their particular area of expertise, a medical writer is far enough away from the minute details to be able to add value to ensure the documents stay focused and fit for purpose. Medical writers often come to the project with a fresh pair of eyes and they can ask the naïve questions that the team may have completely overlooked. Their experience in writing submission dossiers can streamline the planning and writing process, helping the team navigate a minefield of potential problems and letting the subject matter experts spend more time on crafting the messages.

With a strong regulatory lead who has a good vision of the target, and clinical experts who understand the therapeutic benefits to be gained, a strong medical writer rounds out a dossier team by advising on how to present the information with clarity that will direct agency reviewers to what they are looking for and aid the approval process.

Julia Forjanic Klapproth After receiving her PhD in developmental neurobiology, Julia started her career as a medical writer in the regulatory group at Hoechst Marion Roussel (later Sanofi) in 1997. Since then she has been president of the European Medical Writers Association (EMWA) twice (2001–2002, 2007–2009). In 2002, Julia co-founded Trilogy Writing & Consulting, a company specialised in providing regulatory medical writing. In addition to managing the company as President/Senior Partner, she writes a wide array of clinical documents including study protocols, study reports, and is specialised in the clinical parts of CTD submission dossiers.

Email: julia@trilogywriting.com

REFERENCES

Maurice Löwens

1.

Maurice studied Natural Sciences at Cambridge University and spent 4 years in pharmaceutical manufacturing before discovering the world of regulatory writing. He now has over 14 years’ experience as a medical writer and has been with Trilogy Writing & Consulting for 3 years.

He has worked on numerous types of clinical regulatory documents and enjoys collaborating with diverse teams of experts from across drug development. In his current role as a Senior Medical Writing Manager, he leads teams of writers on a wide variety of regulatory writing projects.

2.

New Oncology Drug Approvals in 2020. Clinical Oncology News. 15 Dec 2020 In the Pipeline: Specialty Drugs to Watch in 2021. Accessed online at In the Pipeline: Specialty Drugs to Watch in 2021 (navitus.com)

Email: maurice.loewens@trilogywriting.com

www.journalforclinicalstudies.com

Journal for Clinical Studies 9

Regulatory

Achieving Simultaneous New Drug Document Submission for the FDA and EMA International Conference on Harmonization (ICH) guidance makes it feasible to construct a new drug submission dossier that can be used for applications to multiple countries. Two of the largest markets with the most evolved regulatory landscapes, the U.S. and Europe, have similar documentation requirements, but with important considerations to recognise that need special attention.

By planning for simultaneous document submissions, drug developers can minimise rework, maximise efficiencies, compile optimal data packages, and create the most direct path to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval. Many other countries follow FDA or EMA approvals, further extending the benefits of a combined approach.

While Module 1 of the ICH Common Technical Document contains regional information and will therefore present significant differences between FDA and EMA submissions, Modules 2, 3, 4, and 5 are similar in comparison. However, terminology and seemingly small grammatical distinctions can loom large if overlooked. Careful planning is crucial if not pivotal. A submission team can greatly accelerate global document submission by first creating and reviewing a checklist of differences, agreeing on the best approach to address each difference, planning the summary documents based on these decisions, and collaborating closely in pursuit of a successful outcome.

With any submission dossier, some aspects are under the developer’s control, and some are not. Timing, authoring differences, and regulatory requirements can be accounted for in the planning phase, whereas the standard of care and unmet need, regulatory interactions and agreements, and marketing and product regional differences may have to be addressed on the fly.

Regardless, the first step is to consider simultaneous document submission up front.

Most drug developers seek new drug approvals in both the U.S. and Europe. They are two of the largest markets, with the most evolved regulatory landscapes and highest uptake of new medicines.

Approvals in the U.S. and Europe also provide a gateway to other countries that follow FDA or EMA guidelines.

Historically, submission teams have viewed and managed the two document submissions separately. After all, the U.S. and Europe are an ocean apart, with different policies and their own regulatory bodies in the FDA and EMA, respectively. Meanwhile, the number of people involved in any submission dossier can create complexities and – let’s face it – inefficiencies in the crucial phases of document preparation. Add in comparing, contrasting, and completing FDA and EMA submissions, and those inefficiencies become doubled and magnified.

10 Journal for Clinical Studies

Is there a better way? The question always breeds critical thinking and often leads to new solutions. In this discussion, it can entirely rewrite the approach to, and relieve many of, the common pitfalls experienced during dossier development for the U.S. and Europe.

Before plunging headlong into submission preparation, consider your whole global submission plan and the feasibility of simultaneous document submission to optimise the process. It takes more planning and deliberation up front but streamlines each step thereafter.

Why It’s Possible The traditional two-lane mindset served its purpose when the U.S. and Europe truly represented two completely different regulatory environments with little to no crossover. That changed in 2000 with the finalisation and adoption of ICH guidance facilitating mutual acceptance of clinical data between the regulatory bodies of the U.S., European Union (EU), and Japan to make new drug registration less resource intensive.

“ICH's mission is to achieve greater harmonisation worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner,” ICH says on its website. “Harmonisation is achieved through the development of ICH Guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side.”

ICH’s leading Article of Association hinges on “the interpretation and application of technical guidelines and requirements for pharmaceutical product registration and the maintenance of such registrations.” While licensing, joint ventures, and globalisation were previously softening the borders of clinical data, ICH was the turning point enabling simultaneous document submission particularly to the FDA and EMA. All drug developers are familiar with ICH guidance from a regulatory perspective, and most have been pursuing simultaneous submissions for the past 15 to 20 years. However, that harmonisation has been drifting apart the past several years. Dossiers for the FDA and EMA can still be merged to start and managed as one for the bulk of the work before later being adjusted as necessary to suit the final submissions, but few address up front what is required from a tactical standpoint to do so efficiently.

Main Differences The FDA and EMA dossiers have their differences, giving simultaneous document submission its limitations. The most notable difference is Module 1 of the ICH Common Technical Document.

This consists of regional information that will need to be compiled separately. Module 1 is best set aside so it doesn’t hinder the rest of the information that can be compiled simultaneously.

The significant differences in Module 1 may be the reason submission teams assume FDA and EMA submissions are different Volume 14 Issue 3

Regulatory undertakings altogether. However, there are some very specific differences in requirements across other Modules, including: • • • • •

Clin Pharm Highlights checklist (FDA only, submitted outside of eCTD) TQT checklist (FDA only, submitted outside of eCTD) eSub package (FDA only. Clinical CDISC and BIMO placed in Module 5, SEND datasets in Module 4 and ECG wave forms submitted outside of eCTD to the ECG warehouse.)

EMA Module 5.3.5 (Overview of Clinical Efficacy (tabular format)) Justification document (May be needed for EU to justify missing or excluded components of an eCTD. Can be appended to summaries in Module 2 for Nonclinical or Clinical.)

It can also be helpful to understand how the FDA and EMA review submissions through different lenses. The FDA is very datadriven, with robust requirements for data sets and programs used to generate statistical analyses. They first look at individual listings, case report forms for patients with adverse effects, and other deep documentation, working from the bottom up to arrive at a decision.

EMA reviewers, on the other hand, tend to take a more top-down approach. They prioritise key messages and information in the clinical overview to develop their interpretation of what a drug is doing for patients and modern medicine. The EMA does not require data sets or case report forms like those required by the FDA. In general, the EMA is more qualitative while the FDA is more quantitative.

More Similarities Aside from Module 1, submission teams should be happy to hear that Modules 2, 3, 4, and 5 are similar between FDA and EMA submissions.

The U.S. and Europe are two of the most similar regions in the world when it comes to their submission requirements, again thanks to ICH guidance on summary documents and submission format.

The main differences discussed above are really the exceptions, so we can (and should!) reframe our approach to assume that 75% or more of the compilation can be conducted simultaneously. But don’t dive in just yet! Remember that small details can become big headaches in these large and technical documents. Careful planning is pivotal to gain an understanding of where the risks and opportunities lie.

Biggest Risks With any submission dossier, some aspects are under your control, and some are not. Those that are not in your control are effectively the risks, or things you will have to roll with as they arise. During simultaneous document submission, the key risks are: Regulatory Interactions and Agreements Your team may be well into the process of creating shell documents alongside pre-submission meetings when the FDA and/or EMA might ask for additional information or analyses. This is more common from the FDA due to its detail-oriented approach.

It’s a good idea to review the regulatory interaction history for each agency and note any commitments that were not addressed.

Cite specific agreements, such as endpoints, time points to be analysed, pooling of data, relevance of patient subsets, and studies considered supportive of efficacy or safety. Plan when all pre-submission meetings will occur relative to your final data availability, document preparations, and submissions. Even when taking these measures, regulatory interactions are ultimately out of your control. www.journalforclinicalstudies.com

Standard of Care and Unmet Medical Need Other product approvals can cause untimely changes in the Standard of Care and Unmet Need. Are the standard of care, disease definition, and affected patient population the same across both submissions? To what extent can the wording of the proposed indication be identical across all planned countries? Can you write one unmet medical need section for Module 2.5 that will work in all submissions? These are important and productive questions to ask to mitigate – though not fully eliminate – the impact of any unexpected changes along the way.

Marketing and Product Regional Differences The marketing of your product can potentially be similar in both the U.S. and Europe, but oftentimes, there are standout differences that impact the two submission documents. These differences include indication wording, brand name, and dosage form or even dose.

Brand name is perhaps the key piece in this area, with the question for marketing and product purposes being whether you were or will be able to get adoption of a single brand name globally.

Awareness of these factors folds into the proactive planning that follows and can help buffer against unwanted surprises so they can at least be taken in stride en route to on-time and ultimately successful submissions.

Examples of Missteps It’s a lot less painful to learn from others’ mistakes than your own.

Here are a few simplified examples of real-life teams running into submission roadblocks that could have been avoided: •

The Afterthought: A sponsor completed a full regulatory history review, accounting for all agreements and resolutions for successful NDA submission. However, they completed the NDA without considering the MAA planned 3 to 6 months after NDA submission. This resulted in extensive rework of approved NDA versions to create MAA versions. (To make matters worse, they had outsourced preparation of the NDA and MAA submissions to different vendors.)

•

The Comment Carousel: With the goal of writing documents in a way that one version would work or at least require minor revisions for all countries, the team took off running…and spinning…and sputtering. They were unable to stop commenting on standardised global introductory text, derailing a wellintended plan when version control between submissions finally caught up with them and caused delays.

•

The Caveat: Starting with the assumption of no differences in Module 2.7 documents and identifying differences in Module 2.5, a submission team built a combined BLA/MAA version up to point of first draft, including specific MAA sections highlighted.

For BLA Draft 1, they removed the MAA sections. Once BLA Module 2.5 was approved, they used that approved version as the initial draft for MAA and replaced BLA-specific content with MAA-specific content. But by the time of MAA creation, data presentation agreements with EMA and team agreement to include a label Adverse Reactions table in Module 2.7.4, that Module required tedious EU-specific modifications as well.

How can you avoid missteps like these? Quite simply, with planning.

Planning You Can Control The key takeaway to this point has been that the FDA and EMA submission dossiers are more similar than they are different. Now, Journal for Clinical Studies 11

Regulatory •

Fourth, and more involved is whether you will account for reviewer tendencies noting the differences in the FDA’s and EMA’s respective approaches discussed in the “Main Differences” section of this article.

Throughout the submissions, writers know how to find workarounds to be as universal as possible with language; they just need the instruction and guidelines in advance to minimise the work and uncertainty for editors later.

Regulatory Requirements Over the years since ICH introduction, regulatory requirements in the U.S. and EU have slowly drifted apart. Still, the requirements are known, clearly stated, and can thus be planned for in the submission process.

For example, in considering the inclusion of integrated summary of efficacy (ISE) and integrated summary of safety (ISS), it’s easier if the ISE and ISS are just the outputs. However, there are no issues with including ISS and ISE in an EMA submission after these pieces were developed for an FDA submission.

Separately, for the Benefit-Risk sections, you can convert the content of an FDA table into subsections with the exact same text to fulfil the comparable EMA description.

These are just a few glimpses of efficiency with simultaneous document submission, knowing and accounting for the regulatory requirements. the important message is that more of the documentation process is in your control than not. You can plan for: Timing You don’t necessarily control your deadlines per se, but you know what they are and can plan accordingly. How soon after the first submission do you want (or need) to make the second submission?

How long is the duration between submissions, and will that lead to additional study data being available or the need for a new cut-off date for safety data? What are the plans for supplements if filing for multiple indications? These are just a few of the many questions to ask early regarding timing of final submissions.

Authoring If there is one component that is undeniably in your control, it’s your process for authoring your dossiers. Possible strategies include generating one version that can be re-used mostly unchanged, generating a full version for one with the goal of minimising any revisions needed for the other, or generating a core version followed by country-specific versions from that core for global simultaneous submissions beyond the U.S. and Europe.

There are four immediate considerations for authoring FDA and EMA dossiers simultaneously. Three of them are almost laughably simple but can cause significant rework if overlooked.

•

First, deciding whether to use British or American English is much easier before starting submissions than it is to address after the documents are underway.

•

Second, note the name of the submission, e.g., BLA vs MAA and use of “application” or “submission” as a generic identifier.

•

Third, consider cross-referencing, e.g., sNDA & Type II variation cross-referencing.

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Identifying and Managing Differences The goals of simultaneous document submission are to minimise rework, maximise efficiencies, compile optimal data packages, and create the most direct path to FDA and EMA approval. It starts with assessing and identifying all possible country and regional differences while also keeping in mind timing. Develop a checklist and discuss it in detail with the entire submission team, followed by a timeline.

Review the full regulatory history and highlight any gaps that may need to be filled or could potentially present obstacles to successful submission and approval.

Given the similarities between FDA and EMA submissions, it’s quite feasible to write one global version excluding Module 1, and then make specific edits for the key differences in the two final submissions – or it can be equally effective to write one version first and then edit that version into another. It’s a significant undertaking by any measure and means, but the first step is one that any team can implement off the bat – consider simultaneous document submission up front to help ensure on time and successful submissions.

Steve Sibley Steve Sibley is Vice President of Global Submissions at Certara Synchrogenix. Steve has 30+ years of pharmaceutical experience focused on regulatory writing, consulting, and project leadership roles. He has successfully supported projects from discovery through approval and life cycle management. He has played significant roles in 75+ submissions and, in several cases, led the entire submission team, overseeing all documentation from Modules 1–5, publishing, and transmission to the regulatory authority.

Volume 14 Issue 3

Corporate Profile

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Journal for Clinical Studies 13 13

Regulatory

Turning Pharmacovigilance into a Strategic Advantage Safety science complexity is on the rise as the volume of safety data explodes (case volumes are growing at a pace of 15 to 20% per year),1 regulatory scrutiny continues to increase, and consumer demands grow. The pandemic and national health emergencies like Monkey Pox have put safety and public health benefit-risk discussions in the spotlight, and stricter regulations have emerged from local regulators as a result.

COVID-19 and growing health concerns have made it critical for marketing authorisation holders (MAH) to be able to act quickly on patient safety issues since it only takes hours to days for a local problem to impact patients globally. The demand for greater transparency and comparative benefit-risk analysis throughout the product lifecycle has shifted questions of ownership and accountability beyond the qualified person for pharmacovigilance (QPPV) and head of safety to the C-level.

Chief medical officers and safety leaders are becoming critical for end-to-end safety processes to drive timely and transparent communications. This means clear and transparent data sharing on drug benefits versus risks to patients, healthcare providers, and stakeholders. As regulations continue to evolve, more companies are leveraging technology to enable real-time information exchange, coordinated inspections, and seamless collaboration with regulatory agencies worldwide. Here are some of the regulatory changes brought on by the globalisation of pharmacovigilance and examples of how technology can help drive innovation for greater patient safety.

Upcoming Regulatory Changes Elevating Safety Beyond the PV Team Emerging rules are shifting ownership of health information in accordance with federated governance models, which will result in more product benefit-risk and safety data not being managed by pharmacovigilance alone.2 Simultaneously, outside statistics that are just being introduced to drug safety teams, such as data collected from social media and sales, will become an increasingly vital component of pharmacovigilance.

Several efforts in Europe will have considerable repercussions for the data surrounding the safety of drugs, and more generally, for healthcare data. These include: •

•

•

The European Union (EU) Health Data Space would facilitate the safe sharing of data such as electronic health records, genomics, and disease registries while maintaining patients' right to confidentiality.3 The EU Data Governance Act establishes guidelines for the reuse and sharing of data among data intermediaries that serve as service providers.4 Companies are embracing data altruism and the availability of data by making use of a standard framework.

The European Medicines Agency's (EMA) strategy for the EU's telematics network sets the path for regulatory master data, governance, interactiveness, digitalisation, and regulatory innovation in the EU, which will boost quality, speed, and collaborative integration.5

14 Journal for Clinical Studies

•

•

The EUDAMED database, founded on the EudraVigilance paradigm, offers data openness, patient participation, and realtime communications regarding the performance of medical devices already available on the market.

The EUs Electronic Product Information (ePI) initiative to improve drug risk and benefit communication by creating more efficient labels and product information sheets that are directed toward end users via digital channels. This will allow the initiative to better integrate data accessibility and governance efforts.6

This points to patients and healthcare providers taking a more active role in decision-making as new models for information management emerge. Strategic transformation intends to affect each facet of healthcare, from improved patient access to questions regarding therapeutic interventions, safety, and open public communication.7,8 As such, data related to one's health is a valuable commodity that will be used to generate innovative solutions to problems relating to safety and public health, as well as preventative measures.

With distributed data ownership, there is less of an opportunity to mine insights from safety data and conduct a cumulative benefitrisk analysis of the product during its entire existence. Medical safety teams may play a significant part in reducing or managing risks and improving patient outcomes when they have access to real-time data, analytics, and insights. With the right technology, safety teams can benefit from agile and flexible ways of using data to take action on patient insights.

Advancing Predictive PV and Data Visibility In lieu of retrospective audits and corrective action and preventive action (CAPA) plans, an increasing number of businesses are employing artificial intelligence (AI), data analytics, and predictive models.9 Long-established processes, such as the standard practice to collect and report key pharmacovigilance risk indicators to enterprise risk committees remain key. It is also becoming increasingly important to identify the leading indicators earlier in the research and development stage to protect patient safety. The use of innovative technologies allows for the rapid analysis of massive data sets by safety teams, and the discovery and dissemination of insights that may decrease risk.

With an advanced cloud-based safety system, companies can find answers to important pharmacovigilance questions, such as: •

How can we manage new risks when using AI and predictive algorithms across the research and development, commercialization, and post-market surveillance stages of the product lifecycle?

•

What effects would the combination of federated data governance and an increasing amount of benefit-risk data that is stored outside the organization have?

•

How can we develop an integrated pharmacovigilance system capable of monitoring performance and contributing to early interventions?

Volume 14 Issue 3

Regulatory

Under the present market conditions, it is even more important for pharmacovigilance teams to maintain the integrity of data. Using a safety system on a single cloud platform integrates content and information across the end-to-end value chain, from patients to product development, delivering transparency into actionable data.

This enables safety leaders and C-level executives with a more holistic perspective of pharmacovigilance and in the end, can help improve information exchange, aggregation, and insights across healthcare.

7.

8.

9.

underway EMA, “EMA Regulatory Science Strategy to 2025,” www.ema.europa.eu/ en/about-us/how-we-work/regulatory-science-strategy#regulatoryscience-strategy-to-2025-section Cumberledge Report, https://www.immdsreview.org.uk/index.html EMA, “Joint HMA/EMA Workshop on Artificial Intelligence in Medicines Regulation,” https://www.ema.europa.eu/en/events/joint-hmaema-workshopartificial-intelligence-medicines-regulation

REFERENCES

Sharmila Sabaratnam

1.

Sharmila Sabaratnam is responsible for Veeva Vault Safety Strategy in Europe, helping customers transform their business through a unified safety solution. She is a physiologist by training with research experience in oncology and arthritis. Sharmila has over 10 years of experience in safety, previously leading safety and regulatory advisory services for Top25 and Top-100 companies at Ernst & Young and Navitas. Her experience includes operating model design and safety strategy, PV automation, benefit-risk management, and performance benchmarking.

2.

3.

4.

5.

6.

FDA, FDA Adverse Event Reporting Public Dashboard, https://fis.fda.gov/ sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/7a47a261d58b-4203-a8aa-6d3021737452/state/analysis Patient and Public Involvement Strategy 2020-2025 https://assets. publishing.service.gov.uk/government/uploads/system/uploads/ attachment_data/file/1022370/Patient_involvement_strategy.pdf EC, EU Health Data https://ec.europa.eu/health/ehealth/dataspace_en “Proposal for an EU Data Governance Act,” iapp.org, iapp.org/news/a/ proposal-for-an-eu-data-governance-act-a-first-analysis/ EMA, “EU Extended Telematics Strategy Implementation and Roadmap,”www.ema.europa.eu/en/documents/other/extendedtelematics-strategy-implementation-roadmap-2019-2020_en.pdf P. Chaudhary and V. Shetty, “E-Labeling: Change is Underway,” Pharmaceutical Executive, June 29, 2020, /www.pharmexec.com/view/e-labeling-change-

www.journalforclinicalstudies.com

Journal for Clinical Studies 15

Research & Development

Why Do We Need Patient Diversity in Clinical Trials?

Ensuring Drug Safety, First and Foremost, Even Ahead of Drug Efficacy In the commercialisation of new medications, the paramount legal responsibilities of the pharmaceutical company are, firstly, to prove that the pharmacology is safe and well understood, and, secondly, to prove effectiveness against the targeted disease. Within the European Union, for example, each pharmaceutical company has a Qualified Person for Pharmacovigilance (QPPV) representing them in each country in which they legally operate and market medications. The QPPV is legally responsible for the safety of a pharmaceutical product marketed for human usage in their country and do so by investigating adverse drug reactions (ADRs) – especially life-threating ones – reported by patients or their physicians in the country, associated with the use of their product(s). The identification of these emerging 'safety signals’ guarantees the safety profiles of products marketed in that country.1 Pharmacovigilance consists of monitoring and ensuring drug safety across what are often diverse populations following a drug’s market authorisation. As an example, in oxidative metabolism (a mechanism by which compounds are broken down in the body), there is extensive population variability in the key cytochrome P450 (CYP450) liver enzymes. A medication’s metabolism and clearance (pharmacokinetics) are important factors when determining appropriate dosage for clinical efficacy. If an individual patient´s CYP450 enzyme activity is lower than anticipated, they will receive a comparatively higher dose, as, for them, the molecule will be metabolised and excreted at a relatively lower rate. Hence, repeated administration of the medication could lead to accumulation of the drug and increase the potential for toxicity.2,3 CYP450 enzymes are just one example of differential gene expression leading to varied pharmacodynamics and drug response.

As drug treatments become increasingly personalised and often genetically focused, such as in cancer and many rare diseases, understanding genetic diversity across populations in countries in which the drug is marketed is increasingly critical. Taking it one step further, relatedness of populations and genetic ancestry across borders are also becoming important to trait mapping and the understanding of underlying genetic dependencies in populations of target countries, especially those with mixed populations.

As an illustration, there are significant differences in optimal dosing for East Asian populations, compared to populations of European, Latino or African descent when prescribing Warfarin.

The medication is widely prescribed as an anticoagulant to prevent thromboses and embolisms, but there are population differences associated with genetic polymorphisms in the Warfarin metabolic pathway. As an example, there can be significant variations in the 16 Journal for Clinical Studies

Vitamin K epoxide reductase complex gene which regulates Vitamin K as part of the inverse clotting synthetic pathway. Individuals of Asian descent require a lower dose of Warfarin compared to Latinos, who are still more sensitive to the medication than patients of European and African descent, which results in the need for specific per patient dosing and diet monitoring.4,5,6 Nature versus Nurture Accounting for this genomic variability is therefore of importance for clinical trials, and the underlying reason for the need to ensure diversity in clinical trial patient populations. Additionally, the social and economic determinants of health must also be considered for the population of each country: there are significant differences in incidence of disease because of location, race, social status, and proximity to care. As an example, the incidence of Chronic Obstructive Pulmonary Disease (COPD) and other respiratory diseases is higher in metropolitan areas with high smog and poor air quality than it is in rural areas. In many countries, there are persistent racial disparities in health coverage, chronic health conditions, mental health, and mortality. The COVID-19 pandemic is further highlighting significant social boundaries and differences in access to, and quality of, care based upon race, resulting in poor outcomes in racially and ethnically diverse communities, especially in the United States.7,8 Need for Diversity and Inclusion While the need to include diverse populations in randomised clinical trials is increasing, this also increases the legal responsibility of drug development companies to ensure patient care for diverse groups beyond the clinical trial care setting.9 Once patients are part of the drug treatment regimen delivered by the clinical trial, they have the right to continued care until the drug is available on the market, under the ethical guidelines of the World Medical Association’s Declaration of Helsinki 2013 Article 34, which states, In advance of a clinical trial, sponsors, researchers, and host country government should make provisions for post-trial access for all participants who still need a product identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.10 Unfortunately, this creates an inherent conflict between commercial focus, which may be on ‘high reimbursement’ countries (i.e., countries where patients can usually afford expensive treatments due to high levels of health insurance coverage), and patient care in emerging markets and Low- and Middle-Income Countries (LMICs), where health insurance reimbursement for drugs and care are more restricted or limited to government or single-payer care systems. We can take an example of targeting drugs for people of African descent in high reimbursement regions such as Western Europe and North America. To better understand genetic disease dependency by conducting trials on high numbers Volume 14 Issue 3

Research & Development of patients for statistical relevance, one would need recourse to larger populations in Western or Central Africa, where genetic ancestry can be traced. However, many African nations have low to moderate drug reimbursement compared to more developed nations and therefore the drug companies may be reluctant to site their trials there, as the principle of continuity of care would insist on them continuing to provide the same drugs to the trial participants even if they cannot be reimbursed.11 This is especially true for many genetically dependent rare diseases. The per capita diagnosis of many genetically rare diseases is higher in many emerging markets and LMICs than in developed countries, however the focus for many of the newer higher reimbursement gene therapies for rare disease is on high reimbursement markets, not on the populations in geographies most often in need.

Diversity has several different meanings and a wide context. In the United States, diversity in clinical trial recruitment is measured against US census diversity metrics. This is the classification used in the recent guidance by the Food and Drug Administration (FDA).12 The problem is that US census classifications do not match global racial categories,13 a point further developed in a paper on “race” definition recently published in JAMA.14 Applying US census race metrics globally ends up treating race generally and removing many racial and ethnic subgroups.

Specifically, US census race metrics characterise race and ethnicity based upon where populations migrated or moved into the US from, not the actual ancestry of the populations.

For trials assessed by the FDA, the challenge is how, or if, this guidance can be translated to trials outside the USA, where racial diversity within populations is not defined the same way. For example, the category “Caucasian” has little to do with the countries of Georgia or Armenia, where the Caucasus mountains lie.

The category “Hispanic or Latino” does not refer to European Spaniards (who would be classified “White” under US census terms), but rather individuals with ancestry from the Caribbean, Mexico, Central America, and South America. In fact, Hispanic or Latino populations from North America, the Caribbean, Central and South American are often various mixtures of the original local indigenous pre-Columbian tribes with Europeans from Spain, as well as African slaves, and later further population migration from Europe and Asia.

Most African Americans have ancestral relatedness to slaves that were shipped from Western Africa, not only into America, but also the Caribbean islands and South America. However, genetically, these slaves were collected from at least four distinct West, West Central, Southwest, and Southeast African population groups, not a homogenous population. Today, many African Americans can trace their ancestry through genetic linkage to African, European, and Native American populations.15,16 The issue is that race and/or ethnicity are not always recorded in medical records in countries around the world. In fact, the EU General Data Protection Regulation (GDPR) explicitly prohibits collecting this information, even for clinical trials, unless explicitly justified and approved by the respective data protection authorities.

As an example, in Poland, where a clinical trial enablement study was recently completed, the population diversity breakdown based upon US census data categorisation is as follows: the majority are White European, and locally of Eastern European origin, or Caucasian. In many countries within Clinerion’s own global www.journalforclinicalstudies.com

network, race and ethnic data are captured when available, but are not always mandatory and therefore often incomplete. The question is how this diversity, if captured, overlaps with the FDA census categories, and thereby aids diversity from the perspective of US clinical trial diversity metrics.

This is important because the FDA is the world’s largest medicine and medical device regulatory agency sheerly because of the size of the US healthcare market. Global healthcare projections for 2022 state that the US will be 42% of the global market, with Western Europe at 23% and Asia and Australasia at 24%.17 In the EU, the EMA ICH-E5: ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA regulations are focused on intrinsic and extrinsic ethnic factors that will impact the safety and efficacy of a medication in any of the ICH member and observer countries.18 Essentially, intrinsic, and extrinsic factors model nurture (associated with environment or cultures) versus nature (associated with genetic polymorphism, age, gender, sex, body mass and other physical metrics). The intent of the ICH-E5 regulations (released in 1998) was to incorporate targeted foreign population diversity into trial design to include sufficient test metrics to validate safety and efficacy in specific countries. The regulation’s Appendix C highlights 3 major ethnic groups within founding ICH regulatory (Japan, US, and EU) members, Asian, Black, and Caucasian) and treats EU countries as ethnically Caucasian, but reviews differential ethnic diversity in the other countries where approval is requested. In summary, the EMA, in accepting foreign Country Argentina Australia Austria Belgium Bulgaria Canada Croatia Czech Republic France Georgia Germany Greece Hong Kong Hungary Iceland India Ireland Israel Italy Japan Malaysia

Activated Sites 1 19 2 8 4 7 4 5 24 3 26 5 4 8 1 50 5 12 13 50 7

Country Mexico Netherlands New Zealand Norway Poland Portugal Romania Russian Federation Serbia Singapore Slovakia South Africa South Korea Spain Sri Lanka Sweden Switzerland Taiwan Ukraine United Kingdom United States

Activated Sites 1 9 7 1 25 8 11 14 5 5 5 3 12 15 4 2 2 12 17 16 100

Example showing global site diversity for trial: Gilead diversity Crohn’s disease trial sites20 Journal for Clinical Studies 17

Research & Development data for drug approval, also reviews ethnic population impact in the countries submitted for safe and efficacious use to harmonize approval and drug medication use when possible. Although not as ethnically explicit as the more recent FDA advisory guidance, the EMA guidance does represent broad ethnic groups and country/ member population inclusion for clinical research and trial inclusion.19 Diversity Means Inclusion One approach toward achieving diversity would be to include diverse populations and as well as diverse geographies that insure diverse genetic population inclusion. From an industry perspective, there is value in sponsors developing the diversity of sites globally, as it helps to gain regulatory approval by addressing race and ethnic diversity, if not through direct race and ethnicity identification, then through inclusion of diverse populations, geographically. Sites external to the US can lend intelligence on populations originating from Europe, Africa, Asia, and Polynesia. Although it is hard to trace exact pharmacogenomic phenotypes within diverse populations, broad sampling is critical as the next step forward to understanding healthcare, safety, and efficacy.

Lastly, the increase of decentralised clinical trials (DCTs) due to technological advances and the pressures of the COVID pandemic offers an encouraging trend to support clinical trial recruitment diversity. Individuals and populations who previously did not (or could not) have access to centralised trial sites now have more options to participate in trials. This offers local alternatives to patients, wherever they are in the world, to join trials they would otherwise be restricted from, due to access, transportation, work, social or other physical and economic limitations. The potential benefits of remote patient center trial management were recently highlighted in a report21 on a recent Janssen study based upon a remote patient center trial structure.22,23 Conclusion Genetics are increasingly part of not only disease treatment, but also response to treatment. Understanding and representing genetic

18 Journal for Clinical Studies

diversity, not just population diversity, is therefore increasingly needed in clinical trials. Understanding genetic contribution to disease, as well as incidence of disease – because of location, race, social status, and proximity to care – are important aspects for diverse patient recruiting in clinical trials. The approach to diversity that focuses only on finding diverse populations based upon US census metrics is not sufficient. Census metrics do not represent genetic background, and US trials often do not recruit a sufficiently diverse population to represent global patient populations. The only mechanism to ensuring diversity is to include not just distinct ethnic groups, but also diverse global trial sites that ensure the inclusion of diverse genetic populations in trials. Additionally, the capabilities of DCTs will also enable broader social economic patient inclusion by bringing the trial treatment and data collection to the patient rather than requiring patients to always attend a centralized RCT site.

It is a small world, after all.

Acknowledges The author would like to acknowledge and thank the following individuals for their help and review of the manuscript: Sébastien Wischlen, CancerDataNet William Caddy, ESCMID Michael Kangas, Novartis Le Vin Chin, Clinerion Kamila Novak, KAN Consulting REFERENCES 1.

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Signal management, European Medicines Agency, available at: www.ema. europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/ signal-management Bachtiar, M., Lee, C.G.L. Genetics of Population Differences in Drug Response. Curr Genet Med Rep 1, 162–170 (2013). https://doi.org/10.1007/ s40142-013-0017-3 Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong XB, Tien YC, Jeong H, Pan X, Shireman LM, Tay-Sontheimer J, Lin

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YS. Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism. Drug Metab Dispos. 2016 Mar;44(3):343-51. Doi: 10.1124/ dmd.115.067900. Epub 2015 Dec 17. PMID: 26681736; PMCID: PMC4767386.

Roden DM, Wilke RA, Kroemer HK, Stein CM. Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011 Apr 19;123(15):1661-70.

Doi: 10.1161/CIRCULATIONAHA.109.914820. PMID: 21502584; PMCID: PMC3093198.

Wilke RA, Dolan ME. Genetics and variable drug response. JAMA. 2011 Jul 20;306(3):306-7. doi: 10.1001/jama.2011.998. PMID: 21771992; PMCID: PMC3539154.

Gross, AS, Harry, AC, Clifton, CS, Della Pasqua, O. Clinical trial diversity: An opportunity for improved insight into the determinants of variability in drug response. Br J Clin Pharmacol. 2022; 88( 6): 2700- 2717. doi:10.1111/ bcp.15242 Frederick R. The Environment That Racism Built. Center for American Progress. Published May 2018, available at www.americanprogress.org/ article/environment-racism-built Abraham P, Williams E, Bishay AE, Farah I, Tamayo-Murillo D, Newton IG. The Roots of Structural Racism in the United States and their Manifestations During the COVID-19 Pandemic. Acad Radiol. 2021 Jul;28(7):893-902. doi: 10.1016/j.acra.2021.03.025. Epub 2021 May 12. PMID: 33994077.

Kelman A, Kang A, Crawford B. Continued Access to Investigational Medicinal Products for Clinical Trial Participants—An Industry Approach. Camb Q Health Ethics. 2019 Jan;28(1):124–33. doi: 10.1017/ S0963180118000464. PMCID: PMC6317109.

World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.

JAMA. 2013 Nov 27;310(20):2191-4. Doi: 10.1001/jama.2013.281053. PMID: 24141714.

Funding Environment for Rare Diseases in Low- and Middle-Income Countries.IQVIA White Paper. Dec. 2021. Available at: www.iqvia.com/ locations/asia-pacific/library/white-papers/funding-environment-forrare-diseases-in-lmics Collection of Race and Ethnicity Data in Clinical Trials. Guidance for Industry and Food and Drug Administration Staff. FDA Office of Minority Health. October, 2016. Available at www.fda.gov/consumers/minorityhealth-and-health-equity/clinical-trial-diversity Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity. Executive Office of the President, Office of Management and Budget. October 1997, available at www.whitehouse.gov/wp-content/ uploads/2017/11/Revisions-to-the-Standards-for-the-Classification-ofFederal-Data-on-Race-and-Ethnicity-October30-1997.pdf Flanagin A, Frey T, Christiansen SL, AMA Manual of Style Committee.

Updated Guidance on the Reporting of Race and Ethnicity in Medical and Science Journals. JAMA. 2021;326(7):621–627. Doi:10.1001/jama.2021.13304

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Zakharia, F., Basu, A., Absher, D. et al. Characterizing the admixed African ancestry of African Americans. Genome Biol 10, R141 (2009). https://doi. org/10.1186/gb-2009-10-12-r141 Stefflova K, Dulik MC, Barnholtz-Sloan JS, Pai AA, Walker AH, Rebbeck TR (2011) Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas. PLoS ONE 6(1): e14495. https://doi.org/10.1371/ journal.pone.0014495 Global Health Care outlook. Deloitte. 2019. Available at: www2.deloitte. com/content/dam/Deloitte/global/Documents/Life-Sciences-HealthCare/gx-lshc-hc-outlook-2019.pdf ICH Members and Observers. Available at: www.ich.org/page/membersobservers Ethnic Factors in the Acceptability of Foreign Clinical Data E5(R1). ICH Harmonized Tripartite Guideline. February 1998. Available at: www.gmpcompliance.org/files/guidemgr/E5_R1__Guideline.pdf Filgotinib in the Induction and Maintenance of Remission in Adults with Moderately to Severely Active Crohn’s Disease (DIVERSITY1).

ClinicalTrials.gov Identifier: NCT02914561. Available at: https:// clinicaltrials.gov/ct2/show/NCT02914561 Clinical Research as a Care Option (CRAACO) White Paper. Accelerated Enrollment Solutions. Available at: https://globalaes.com/clinicalresearch-as-a-care-option-craaco-whitepaper A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure (CHIEF-HF). ClinicalTrials.gov Identifier: NCT04252287. Available at: https://clinicaltrials.gov/ct2/show/ NCT04252287 Spertus, J.A., Birmingham, M.C., Nassif, M. et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med 28, 809–813 (2022). https://doi.org/10.1038/ s41591-022-01703-8

Douglas Drake Douglas Drake, MS, MBA, is originally a life science researcher with a passion for digital enablement of better patient care. For over 30 years, Douglas has worked in various aspects of diagnostics, therapeutic research, drug discovery and global business development. He has broad experience in transformative technologies, data sciences, digital healthcare and applying these to improving patient engagement and the patient journey.

Journal for Clinical Studies 19

Research & Development

Improving Health Literacy to Transform Clinical Trials The healthcare industry struggles with resolving fundamental patient communication challenges. Approximately 50% of adults cannot read at a high school level and 88% of adults are not proficient in health literacy.1 Health literacy is defined as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.’’2 As a result, more than 80% of health information provided in the doctor’s office is forgotten before patients or their parents get home, and more than 50% of the recalled information is remembered incorrectly.3 Paucity of knowledge, misunderstandings, and forgotten information have led to poor healthcare outcomes and the erosion of patients’ trust in medicine. Traditional approaches to medical education clearly have not worked. A fresh approach is required, both to improve health outcomes and curb costs from poor communications resulting in reduced patient recruitment and retention, and avoidable delays.

Within clinical trials alone, the numbers are staggering: every day that a trial is delayed, due to slower than expected patient recruitment or other issues, costs an additional $600,000 to $8 million.4 There is a global need to develop culturally sensitive, relatable medical education resources for patients, caregivers, and their families. This article will discuss successful strategies that have been employed to improve patient recruitment and retention in clinical trials.

Low patient recruitment and retention rates pose considerable challenges to the success of clinical studies and advancing medical science and healthcare practices. Worldwide, 90% of studies fail to enroll the target number of participants within the proposed time.5 Slow recruitment can prolong the enrollment period, inflate costs, and possibly result in early trial termination. A 2013 analysis of listings posted on ClinicalTrials.gov found that 12% of studies were terminated early, and 57% of those studies were ended prematurely due to insufficient patient enrollment.6 Dropout rates can reach 30% or higher in some studies, which may lead to biased results and impact the validity of the study findings.7 Enrolling minorities can also be a challenge, and patients with minority racial/ethnic backgrounds are considerably underrepresented in clinical studies.8,9 Poor health literacy is a significant part of the problem recruiting and retaining participants for clinical studies. Nearly half of Americans have limited health literacy10 and as a result are less informed about how to manage their condition, have poorer health, and are less likely to be involved in health promotion and disease prevention.11,12,13 Exacerbating this issue, healthcare materials are often written at the tenth-grade level or higher, and yet the average reading level of U.S. adults is eighth grade.12,13,14 Furthermore, even people who are highly health literate may have difficulty understanding health information presented to them while they are feeling stressed or anxious.

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Providing Accessible Educational Materials A lack of understanding of their health condition and of how participating in a clinical study could benefit them presents a significant hurdle to recruiting and retaining patients in clinical studies. One proven strategy to address this issue is to provide accessible patient educational materials at appropriate reading levels throughout the clinical trial process.15,16,17,18,19 With access to clear information, patients can better understand their health, its management, and the benefits and risks of joining a clinical study.

Engaging patients with educational materials that are clear, easy to comprehend, and age appropriate equips them with the tools they need to make an educated choice about how to best manage their health.12,20,21,22,23 Supporting Informed Consent Some patient materials, such as the Informed Consent document, can be particularly difficult to understand. The Informed Consent Form is not only a legal document confirming that the patient agrees to participate in the clinical study, but it also serves as a tool to educate them about the study purpose, procedures, and risks and benefits, thereby make an educated choice about whether participating in the study is right for them. Unfortunately, in many cases the Informed Consent document is too long and uses medical jargon, making it challenging for non-experts to read and understand, further reducing the number of people that can absorb and process the information.

The American Medical Association and the National Institutes of Health recommend that patient education materials are written at sixth to eighth grade reading levels or lower.20,24 The reading level of a document can be assessed based on criteria such as sentence length, word count, syllable count, and use of familiar words.21,22 Health education materials should also reflect sensitivity to patients’ social, emotional, and cultural needs. A patient may be overwhelmed by a new diagnosis or the sheer amount of information they need to process to decide whether to join a clinical study. Furthermore, the patient may prefer to digest information in a particular format, be it through direct discussion, learning online, watching videos, reading brochures, or listening to podcasts.23, 25,26 Regardless of the way in which the patient best absorbs information, all materials should be presented in a straightforward way to encourage learning. Patients should also be given sufficient time to digest and review the materials on their own.

Providing Ongoing Communications Clinical studies can be an endurance test for patients. An important strategy for maintaining patient participation is to provide educational materials throughout the study. These can focus on what happens at each stage of the study and update patients on the study progress and results. Ongoing communication can help to build trust and promote patient awareness of their role in the study.

Following these recommendations will help to create effective patient education materials: Volume 14 Issue 3

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Create age-appropriate materials that include visual aids, such as comic books and animation, to help reinforce the written word. Partner with youth advocates to make sure that the chosen messaging and format resonate with them.

Develop content at the fifth and sixth grade reading level, ensuring that it is accessible to everyone.

Prepare materials that combine visual and verbal elements, enabling readers to gain the requisite knowledge even if reading is difficult for them. Offer materials in a larger font for people who are visually impaired.

Partner with patient advocacy groups and community advisory boards throughout the development process to ensure that all the information is clear, inclusive, and culturally sensitive.

Develop a broad range of educational materials – both print and digital – to support clinical study recruitment and retention.

These can include recruitment posters, booklets describing the medical condition, study brochures and welcome guides, informed consent/assent flip book discussion guides, videos describing the study and the informed consent/assent process, activity books, study passports so that children can track their progress through a study, and study schedule planners. Patient websites, podcasts and newsletters can also help to promote disease awareness, knowledge sharing, and create a sense of community among patients in a study.

Medical Education in Action Enhancing Patient Recruitment Recruiting patients who had tested positive for COVID-19 within the previous five days but did not require hospitalisation for an NIAID-sponsored Operation Warp Speed study of multiple drugs

for use as potential therapeutics was challenging. Not only did the sponsors need to recruit participants for a COVID-19 therapeutics study when the national focus was on vaccine campaigns, but trust in pharma was extremely polarised, especially amongst minority communities.

As COVID-19 was infecting Black and Hispanic people at 3.5 times the rate of other members of the public, it was imperative that the candidate therapeutics were shown to be safe and effective in those populations. To ensure that, needed to be appropriately represented in the study. Underscoring the urgency of this work, during the first six months of the pandemic, COVID-19 lowered the life expectancy of Black and Hispanic people by three years.

This was a massive study involving multiple government agencies, academia, and pharmaceutical companies and more than 200 clinical trial sites.

Community Advisory Boards were created so that key opinion leaders could partner with trusted members of the local communities, including barbers and hairstylists, to learn more about the barriers preventing people of color from enrolling in clinical studies. These relationships spurred grassroots outreach in the local neighborhoods and helped to overcome the prevalent mistrust of clinical trials.

The resulting multi-lingual medical education campaign, which prioritised recruiting a diverse patient population, included digital, print, licensed multi-media and custom educational resources.

The campaign empowered patients to overcome their fear, take control of their lives and seek care for their COVID-19 infection by participating in clinical trials. It inspired hope and helped participants to transition from victim to victor as they played a critical role in developing new therapies.

This medical education program was quickly expanded from 10 clinical trial sites to 150. In eight months, it created 55 million social media impressions, 16 million search impressions, and more than 1 million website views. This resulted in a patient referral rate of 44% (three times greater than a chain pharmacy), a screen rate of 29% (20% greater than a CRO), and 64% of patients being randomised to enter the trial.

Facilitating Patient Screening A Phase 3 randomised, double-blind, placebo-controlled study of the safety and efficacy of a new drug candidate to treat pulmonary arterial hypertension was expected to screen 385 patients at 191

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Journal for Clinical Studies 21

Research & Development sites in 26 countries. A screen fail rate of 33% was anticipated due to complex inclusion and exclusion criteria.

While most screen failures are due to inclusion/exclusion criteria, some aspects of site operations and training can also negatively impact conversion rates.

A series of site resources were developed to facilitate prescreening, explain the protocol, and train study investigators. These tools helped the sites better determine which patients were likely to qualify for the study before the formal screening process began. That step reduced the site burden during the actual screening process.

This multi-faceted educational program lowered the study screen fail rate by 9%, producing an estimated ROI of 9:1. Improving screening and enrollment processes can lead to reduced trial costs, shorter study timelines, and better study performance.

Improving Patient Retention Retaining enrolled participants in a clinical trial is always important but when the study is of a rare disease with a very small patient population the future of the trial could depend upon it. When a patient drops out, their valuable clinical trial data are no longer usable. If several patients leave, regulatory authorities may stop the trial due to insufficient results or evidence.

For a Phase 2a safety, tolerability, pharmacokinetic and pharmacodynamic study of participants with MELAS (mitochondrial

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encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, the goal was to enroll 20 patients and ultimately have 12 evaluable patients. The study involved a 29-day treatment period and 14-day follow up. A significant drop out rate was anticipated because the study involved quite an intensive schedule of protocol visits and procedures including neuroimaging, blood draws, patient-reported outcome assessments, and lifestyle restrictions.

Patient educational materials were developed for pre-consent, screening, and enrollment, explaining the study, outlining the appointment schedule, and setting appropriate expectations.

Most importantly, these new resources, which promoted ongoing compliance and retention, were produced using a variety of media that were visually engaging, easily understandable, relatable, and empowering to this small patient population.

As a result, patient retention rates exceeded the sponsor’s expectations by 40% and delivered an estimated ROI of 4:1. The educational resources helped to keep participants in the trial and the study on track, which ensured better data quality and integrity, and saved time, money, and other resources.

Conclusion Having a limited understanding of medical concepts or poor health literacy increases stress, confusion, and anxiety amongst patients, their caregivers and family members. Those combined factors make it hard for patients to make informed decisions regarding possible treatments and clinical trial participation. That can lead to sponsors

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Research & Development having difficulty recruiting and retaining patients in clinical trials.

It may also result in poor patient compliance with medical staff instructions during the trial.

The solution to all these problems is medical education. But that new information must be delivered in the right format using a combination of text and visual elements – which are age-appropriate, culturally sensitive, and relatable so they easily understood. The medium selected is also important and can range from comic books and animation to virtual reality experiences and patient interviews, depending on the audience’s age and experience.

Partnering with patient advocacy groups and community and youth organisations when developing these materials helps to ensure that the messaging resonates and is authentic.

An increasing emphasis on improving health literacy will raise the public's level of healthcare knowledge and understanding, which will not only benefit society today but also future generations.

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https://www.washingtonpost.com/news/answer-sheet/wp/2016/11/01/ hiding-in-plain-sight-the-adult-literacy-crisis/ Ratzan and Parker. National Library of Medicine Current Bibliographies in Medicine: Health Literacy. 2000. https://www.researchgate.net/ publication/230877250_National_Library_of_Medicine_Current_ Bibliographies_in_Medicine_Health_Literacy https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC539473/#:~:text=40%2D80%25%20of%20medical%20 information,that%20is%20remembered%20is%20incorrect. http://www.pharmafile.com/news/511225/clinical-trials-and-theirpatients-rising-costs-and-how-stem-loss Institute of Medicine. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. 2010. Washington, DC: The National Academies Press. https://doi.org/10.17226/12900.

Williams RJ, Tse T, DiPiazza K, Zarin DA. (2015) Terminated Trials in the ClinicalTrials.gov Results Database: Evaluation of Availability of Primary Outcome Data and Reasons for Termination. PLoS ONE 10(5): e0127242. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127242 National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. Washington, DC: The National Academies Press. 2010. https://doi.org/10.17226/12955 Society for Women’s Health Research and FDA Office of Women’s Health. Dialogues on Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials. September 22–23, 2011.

Washington, DC. Clark et al. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers. Curr Probl Cardiol, May 2019. Pages 148-172.

Kutner M et al. National Center for Education Statistics. The Health Literacy of America’s Adults. Results from the 2003 National Assessment of Adult Literacy. September 2006.

DeWalt et al. Literacy and Health Outcomes: A Systematic Review of the Literature. J Gen Intern Med 2004;19:1228–1239.

Institute of Medicine. Health Literacy: A Prescription to End Confusion.

Washington, DC. 2004. The National Academies Press. https://doi. org/10.17226/10883 Kirsch et al. National Center for Education Statistics. Adult Literacy in America: A First Look at the Findings of the National Adult Literacy Survey. April 2002.

Hadden et al. Improving Readability of Informed Consents for Research at an Academic Medical Institution. J Clin Transl Sci. 2017 Dec;1(6):361-365. https://doi.org/10.1017/cts.2017.312.

Chhatre et al. Patient-centered Recruitment and Retention for a Randomized Controlled Study. Trials. (2018) 19:205. https://doi.org/10.1186/ s13063-018-2578-7 Huang et al. Clinical Trials Recruitment Planning: A Proposed Framework from the Clinical Trials Transformation Initiative. Contemporary Clinical Trials. 66 (2018) 74-79.

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Contemporary Clinical Trials Communications. Volume 9, March 2018, Pages 33–39. https://www.sciencedirect.com/science/article/pii/ S2451865417301564?via%3Dihub#!

Caldwell PHY, Hamilton S, Tan A, Craig JC (2010) Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review.

PloS Med 7(11): e1000368. https://journals.plos.org/plosmedicine/ article?id=10.1371/journal.pmed.1000368.

Sacristan et al. Patient Involvement in Clinical Research: Why, When, and How. Patient Preference and Adherence. 27 April 2016. http://dx.doi. org/10.2147/PPA.S104259 NIH U.S. National Library of Medicine. MedlinePlus. Health Literacy. https://medlineplus.gov/healthliteracy.html CDC. Simply Put: A Guide for Creating Easy-to-understand Materials. April 2009. https://www.cdc.gov/healthliteracy/pdf/simply_put.pdf.

Program for Readability In Science & Medicine (PRISM) Readability Toolkit. https://www.kpwashingtonresearch.org/about-us/capabilities/ research-communications/prism Harris and Kelly. Patient Education in Clinical Trials and Throughout the Product Lifecycle. Medical Writing. Volume 25 Number 4. December 2016.

Weiss. Health Literacy: A Manual for Clinicians. American Medical Association, American Medical Foundation, Chicago, 2003.

NIH U.S. National Library of Medicine. MedlinePlus. Choosing Effective Patient Education Materials. https://medlineplus.gov/ency/ patientinstructions/000455.htm Guise et al. Using Health Literacy and Learning Style Preferences to Optimize the Delivery of Health Information. Journal of Health Communication, 17:122–140, 2012. https://pubmed.ncbi.nlm.nih. gov/23030566/

Dr. Columba Quigley Dr. Columba Quigley is Associate Vice President and Editor In Chief at Jumo Health.

The company develops evidence-based, age-appropriate, and culturally sensitive educational resources for patients and caregivers. Jumo Health has experience serving diverse populations and has covered 160+ health topics in 75+ countries covering 90+ languages. Jumo Health collaborates globally with 180+ advocacy groups and community organisations to ensure authentic patient experiences are accurately represented. Dr. Quigley works from the Company’s London office.

Journal for Clinical Studies 23

Market Report

Asia's Clinical Trial Growth – Industry Developments and Challenges Clinical trials within Asia are on the rise again, however the effects of the COVID-19 pandemic continue to have a significant impact within the industry.

While the number of clinical trials and countries involved is increasing post pandemic, there remain key challenges that need to be navigated to support the surge.

As clinical trials increase in the region, this upturn is not being matched by the recovery of the aviation industry, which is resulting in a shortage of flights to transport clinical trials’ samples.

Air freight space and cost is still the main headache when it comes to international transportation, and it is not anticipated the demand for air travel will pick up soon as it is predicted it will not reach the levels seen pre-pandemic.

Another challenge causing disruption is the lacking number of patients and trial volunteers, due to the perceived transmission risks associated with attending healthcare facilities and any necessary travel.

Standard Operating Procedures (SOPs) implemented during the pandemic have restricted physical movements by patients and volunteers to hospitals and laboratories. This in turn has led to a demand for temperature-controlled packaging (TCP) to facilitate direct-to-patient (DtP) and direct-from-patient (DfP) services by Clinical Research Organisations (CROs).

While having to contend with these ongoing challenges, companies may seek alternative solutions which can be conducted virtually or rely more on the local production of clinical drugs.

China’s Covid Crackdown As China’s Zero-Covid restrictions continue to impact supply chains, the ripple effect is impacting clinical trials in the region.

Supply chains disruption have become the new norm due to different levels of COVID-19 movement controls.

As countries continue to adapt to the new post pandemic world, we’ve seen a substantial rapid rise in home deliveries and huge e-commerce growth because people are increasingly ordering online. A reflection of these developments is being seen within the clinical trial sector including sending samples from the participating patients or trial volunteers, and such processes will have to be part of the “new normal”.

As a result we will continue to see the rise in remote consultations, rather than face to face, via video calls between the patient and doctor, to progress the clinical trial process.

These will become the more mainstream measures going forward if movements continue to be heavily restricted in China. Alongside these limitations within the region, there is a fear of attending health care facilities in person due to a risk of infection and consequently people want to stay away from such facilities. Therefore, the option of the remote contact touch points is vitally important.

The digitalisation of such services and how easily it can be to authenticate and validate the identities and secure the data of the patients and the volunteers is a key consideration within these ongoing developments.

As clinical trials are increasing in Asia, we are seeing more centralised hubs where big Pharma are becoming increasingly established.

However there remain challenges in relation to the infrastructure for clinical trials in Asia, which is continuing to improve, and it is acknowledged what the region currently has in place is getting better.

These essential elements are improving. However, compared to US and Europe’s approach, when it comes to the different distribution of drugs, Asia tends to use other solutions.

Traditionally Asia would utilise and rely on temperaturecontrolled vehicles, rather than deploying TCP solutions. However, given the greater need to deliver direct to the patient’s door, these requirements clearly cannot be met alone by utilising the traditional temperature-controlled vehicles.

With no sign of the situation changing in the near future, the challenges will continue to affect the clinical trial sector in Asia in a number of ways.

Consequently, those companies who need to conduct clinical trials with DtP need to utilise and deploy TCP shippers transporting deliveries directly to the trial participant’s home, ensuring there is no breakage within the cold chain.

This can include creating further obstacles with regards to potential patients and participants reporting to hospitals or laboratories as part of the clinical trial process. This in turn will necessitate a step up in Asia in the DtP and DfP model and an overall more patient centric approach.

While it is acknowledged there are challenges to contend with, in comparison to the traditional cold chain processes which had been incorporated previously, what we are now seeing is the Asian countries are catching up with the drug delivery approaches taken

by Western countries.

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Market Report

With the increased move to DtP and DfP, whether facilitating a decentralised clinical trial or collecting samples from a patient in their home, within the TCP space is a greater use of single-use and reusable refrigerated shippers.

These innovative TCP products are simple and easy to use at remote sites. By incorporating push-button temperature-controlled packaging solutions, which require no conditioning, makes cold chain accessible to patients and untrained medical professionals alike.

Utilising such touch of a button technology to activate the cooling process for refrigerated samples, brings room temperature samples gradually to +2 to +8 degrees Celsius. This is helping to facilitate the increasing drive for more patient centric processes within the clinical trial sector.

As the pandemic has accelerated the move to online ordering in numerous sectors of everyday life, so too is the face of healthcare changing to accommodate the growing need for convenience, which is where easy-to-use TCP supports the requirement for at-home care for patients and clinical trial participants, making the option more accessible to all.

While TCP ease of use is important, it is also essential to ensure those organisations conducting clinical trials, or shipping pharma payloads within Asia, can maintain the international and national compliance conditions to meet the good distribution practice (GDP) requirements.

This can be achieved by delivering perfect conditioning within the packaging deployed during the clinical trial process and ensure the temperature conditions are maintained at all times to prevent contamination of the pharma payloads. www.journalforclinicalstudies.com

Supply Chain Challenges Unlike regions such as Europe or United States, countries in Asia are geographically more fragmented. Therefore, when it comes to the distribution of clinical drugs, site-centric clinical trials often face challenges upon cross-border transportation and travelling of patients even before the pandemic.

Although regulations are easing in many parts of Asia, we are still seeing many constraints on logistics or passenger flights. When trade returned between China Europe and the US in 2021, logistics space was centralised within the shipping lanes between China and Europe/US. Other countries in Asia faced space constraints and consequently the freight costs rose drastically, which impacted parties who conduct, engage in, or operated within the clinical trials sector.

Due to a strict Zero-COVID policy in place, some pharmaceutical and healthcare products faced the risk of being damaged due to a breakdown within the cold chain. Container bulk shippers were often opened at the airport or seaport to conduct COVID19 virus checks and sanitisation. As a result, many companies postponed shipments or tried to source suitable bulk shippers to transport their pharma payloads.

The network support for clinical trials within the region continues to grow and there are major CROs and specialty couriers in Asia. They are equipped with current Good Manufacturing Practices (GMP) facilities, digital prowess and temperaturecontrolled packaging specifically designed for increasing DtP and DfP services.

In addition to these developments, we are seeing more airports, forwarders and warehouses operating within Asia which are Journal for Clinical Studies 25

Market Report

certified as IATA’s – the Center of Excellence for Independent Validators in Pharmaceutical Logistics (CEIV Pharma) – which meets international and national compliance to keep pharmaceutical products protected and effective.

Healthcare facilities providers and governments have also improved their services in Asia to enable a safe clinical trial experience for patients and volunteers.

Post Pandemic Developments The pandemic has certainly created a greater awareness about the need for more healthcare facilities to be available throughout many countries. As we witnessed during the pandemic, countries globally had to rapidly set up healthcare hubs and facilities for mass vaccinations and testing.

These facilities, after the pandemic, would be redundant and ideal for conversion to clinical trial centres or associated trial facilities.

Alongside an abundance of physical facilities, there is also an abundance of trained personnel who have been deployed during the pandemic for testing, for collection of samples and delivery of those samples.

In terms of trained manpower and facilities, these countries will be left with a lot of infrastructures that would be left redundant once the need for mass testing and vaccinations is scaled down. These could be utilised for the purposes of future clinical trials that are to be conducted.

As highlighted, due to the difficulty to secure patients’ access to designated sites during the pandemic, companies faced challenges with on-site-centric clinical trials. Those companies continue to see more opportunities to conduct patient-centric clinical activities with the help of advancements in digital tools and technologies, including but not limited to: connected devices, eConsent schemes and eAdverse events.

Not all the clinical trials are replaceable by digital tools and technology, and the distribution of clinical drugs to a patient’s 26 Journal for Clinical Studies

personal location will require further financial investments and procedures to ensure the safe delivery of pharma payloads.

To reduce travel, associated costs, inconvenience and future disruptions to patients and volunteers, patient-centric models such as DtP and DfP will become the norm in the next few years, with remote consultations replacing in-facility physical interactions.

It is expected patient-centric clinical trials will continue to increase. Due to differences of drug distribution, history and regulations, the utilisation of TCP solutions is on the increase in many countries and regions in Asia.

With the anticipated rise in patient-centric trials in Asia, companies operating within the clinical trials space will be required to adopt new solutions and improve their existing systems to deliver vital pharma products to patients in the right condition that meets international and national compliance and most importantly, is safe for the patient.

One late delivery or temperature fluctuation can compromise a study or endanger a patient.

Kazuo Ishizuka Kazuo Ishizuka is Peli BioThermal Asia’s Business Development Manager & Distribution Manager in North Asia and is based in Japan. He joined the company in 2019 looking after the markets in China, South Korea, Taiwan and Japan and global customers in the region. He has more than 17 years of experience in the freight forwarding industry in Japan and Singapore, in Japanese and western companies and experienced operation, sales, customer service and a director position. His role includes closely monitoring and following up the emerging markets and companies to assist their business growth.

Email: kazuo.ishizuka@pelican.com

Volume 14 Issue 3

Healthcare Events The ultimate events for the pharmaceutical and biotechnology community to discover how to excel in clinical supply strategy as well as form key connections for long-term success

CLINICAL TRIAL SUPPLY EUROPE 2023

TEMPERATURE CONTROLLED LOGISTICS IN BIOPHARMACEUTICALS EUROPE 2023

Milan, Italy 15th-16th March, 2023

Milan, Italy 15th-16th March, 2023

2023 will see the return of the Clinical Trial Supply Europe conference to Milan where pharma, large and small, alongside biotechs will have the opportunity to discuss, debate and consider new technologies and processes to streamline supply chain operations.

The two-day in person event for industry leading updates on a series of topics around temperature-controlled logistics.

www.arena-international.com/ctseurope

There’s never been a better time to exchange case studies, meet sociallydistanced thought leaders, and discover the latest solutions from our selection of experienced exhibitors to create a robust clinical supply chain.

www.arena-international.com/pharmatemp

This includes how to avoid excursions, using data to monitor temperatures, shipping products at deep frozen temperatures and how your peers are coping with new Brexit regulations affecting the supply chain in and out of the UK.

Register now

Register now

Use reference code: JCSJKG

Use reference code: JCSJKG

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Journal for Clinical Studies 27

Therapeutics

Optimising Trials Assessing Cognitive Post-Acute Sequelae of SARS-CoV-2 Infection (PASC-Cog) Long COVID-19 syndrome has recently been recognised as a complex chronic clinical entity in subjects who have experienced SARS-CoV-2 infection. It is currently defined as the presence of symptoms for more than twelve weeks developed during or after SARS-CoV-2 infection which are not explained by an alternative diagnosis, usually presenting with clusters of symptoms that can affect any body system, including the central nervous system.1 The prevalence of Post Acute Sequalae of SARS-CoV-2 infection (PASC) has shown significant variation among studies ranging from 33% in community-based studies2 to 75% in hospitaldischarged subjects.3–5 Several important risk factors for PASC have been recognised including not only hospitalisation itself, but also increased age and obesity.1 Further, observational studies indicate a higher risk of PASC among middle aged women,3–5 subjects with type 2 diabetes, subjects with the presence of autoantibodies during infection, and subjects that experienced more than five symptoms during the first week of initial infection.6–7 A recent study suggested the presence of PASC in 52% of young adults who were isolated at home during the infection, indicating the occurrence of PASC appears to be independent of the severity of initial illness.8 Pathophysiological Processes Involved in Neurological Manifestations of PASC It is well known that coronavirus enters the host cell using clathrinmediated endocytosis (CME) that is triggered by the binding of the virion to host receptors, such as angiotensin-converting enzyme 2 (ACE2), and to host proteases, such as transmembrane serine protease 2 (TMPRSS2)9 or furin10 that are present in the secretory pathway and CME compartments. Exactly how SARS-CoV-2 invades the central nervous system (CNS) is not clear and needs to be established, but possible neuroinvasive mechanisms include hematologic spread, retrograde transport from the peripheral nervous system (PNS), and blood–brain barrier (BBB)-mediated spread.11 Studies on CoVs strongly favour retrograde neuronal transport as a viable route for viral invasion of the CNS.12–13 A characteristic feature of PASC is the emergence of new symptoms that fluctuate over time. Several hypotheses have been put forward to explain this including: (a) the presence of a defective immune response which would favour viral replication for a longer time; (b) the existence of systemic damage secondary to an excessive inflammatory response or an altered immune system (cytokine storm syndrome); c) the presence of physical impairment or mental/ psychosocial sequelae (anxiety, depression, post-traumatic stress disorder, effects of confinement or social isolation); and unfortunately d) reinfection with the same or a different variant of SARS-CoV-2.14–15 The immunological mechanisms of neurocognitive presentation of PASC include immune exhaustion leading to chronic inflammation, 28 Journal for Clinical Studies

autoimmunity, and mast cell activation syndrome.16 Patients with PASC may develop a dysfunctional immune response, with increased interferon-γ, interleukin-2, B-cell, CD4+ and CD8+ T-cells, and appear to have effector T-cell activation with pro-inflammatory features.17 Post-mortem analysis of COVID-19 patients show hypertrophic astrocytes and activated microglia18 and astrocytes likely play a pivotal role in the neuropathology of COVID-19, being involved in the virus’ CNS spread, immune responses, and neuronal function.19 Both neuroinflammation and neurodegeneration in PASC are associated with reactive astrocytosis leading to failure of synaptic functions particularly in glutaminergic, GABA-ergic and glycinergic neurons following by disruption of short-term or/and long-term synaptic plasticity contributing to the development and perpetuation of neurocognitive symptoms.20 Microglia also play an important role in the development of PASC through the direct effects of microglia activation as initiators of reactive astrogliosis; via realisation of ATP from distressed cell (through hyperactivation of P2X7 receptors),21 and subsequent activation of NF-kB in microglia and astrocytes; increasing reactive oxygen species (ROS) production; activation of NRLP3 inflammasomes, and upregulation of proinflammatory cytokines.22 This hyperinflammatory stage is associated with high energy demand leading to a high degree of mitochondrial stress and eventually to cell death. COVID-19 patients with dysfunctional mitochondria are likely to exhibit a prolonged hyperinflammatory phase of sepsis, which may cause increased production of proinflammatory cytokines also resulting in increased cell death.23 This ROS-induced mitochondrial stress negatively affects mitochondrial metabolism and ATP synthesis and increases mitochondrial fragmentation.24 Cells with dysfunctional mitochondria may also have an impaired immune-tolerant phase repair responses, as well as reduced responsiveness to treatment.23 Thus, the interplay between inflammation and mitochondrial ROS-dependent oxidative stress is important for regulating inflammatory and antiviral immune responses.11 One proposed mechanism for persistent CNS dysfunction following even mild COVID illness suggests that neuroinflammation may result in hypometabolic lesions as seen on PET imaging.25 In one patient with a history of mild COVID, hypometabolism in the cingulate cortex was associated with diminished executive control and loss of attention.25 Similarly, a PET study examining several patients with persistent cognitive and emotional impairment six months after recovery from COVID-19 encephalopathy found hypometabolism in the frontal, anterior cingulate, and insular cortices as well as the caudate. These results suggest that COVID can have lasting negative effects on cognitive networks and that clinicians should maintain an index of suspicion for prolonged neurocognitive symptoms in patients who have recovered from the acute phase of COVID encephalopathy.26 Some authors have also suggested that neuroinflammation caused by mild COVID infections could even lead to neurodegenerative illness.27 Consequently, long-term follow up is recommended in all patients who experience neurologic derangement during COVID infection to detect persistent symptoms.25 Volume 14 Issue 3

Therapeutics Assessing Cognitive Post-Acute Sequelae of SARS-CoV-2 Infection (PASC-Cog) To date most CNS drugs have registered labels for a recognised specific disease or syndrome, and for the most part these claims tend to be focused on the disease entity rather than any specific features of the disease. More recently, however, regulatory agencies have approved development programmes for indications reflecting specific features of a disease such as negative symptoms, suicide ideation, and cognitive impairment in schizophrenia and depression; agitation in bipolar disorder and autism; and impulsive aggression in ADHD. Given that these indications have been considered valid targets for drug developers, many have maintained that cognitive impairment associated with other disorders would also represent a legitimate target for drug developers.

The term 'brain fog' is probably the most common moniker used to characterise the cognitive dysfunction associated with PASC-Cog. It is also generally agreed that the underlying neurocognitive domains in PASC-Cog reflect difficulties in areas including but not limited to organisation and planning, working memory and self-monitoring, sustained attention / divided attention or vigilance / distractibility, and processing speed. Further, many of these cognitive domains seem to be related to many of the cerebral pathophysiological findings outlined above suggesting some degree of brain structure function correlates. Of note almost all the cognitive domains affected in PASC-Cog seem to be related to frontal system functioning and these measures are often referred to collectively as executive functioning. However, other behavioural aspects typically seen in frontal executive dysfunction such as disinhibition, impulsivity, and preservation do not seem to be particularly relevant in PASC-Cog suggesting a possible unique “cognitive signature” of PASC-Cog that represents a distinct and legitimate target for drug developers.

Ideally the cognitive signature of PASC-Cog should be reflected in diagnostic nomenclature that signifies this cognitive construct as being different from any other constructs that regulatory bodies may be currently entertaining in PASC or other disorders. It is important to note that the frontal executive dysfunction associated with PASCCog is also a key symptom across many other disorders and is readily apparent in ADHD, Parkinson’s disease, bipolar/unipolar depression, traumatic brain injury, as well as in non-nervous system disorders such as HIV and primary breast cancer.

Cognitive domains can be accurately measured by a number of validated and reliable standardised pen and paper as well as various computerised neuropsychological and behavioural measures, suggesting that reliable changes associated with novel drug intervention can be measured effectively in a controlled clinical trial setting. Given the vast number of tests with numerous associated outcome measures for each, cognitive test composites are often created to minimise Type 1 error (by reducing the number of outcome measures to a more manageable level) and importantly to improve signal detection by being more sensitive to treatment effects and change while reducing sample size. Composite cognitive endpoints have several other advantages including being more highly correlated with putative biomarkers such as neuroimaging and cerebral spinal fluid (CSF) measures in other cognitive indications. Importantly, the use of a composite score does not preclude an examination of individual domains within the composite as an exploratory analysis.

Transforming data into a common metric based on standard scores such as Z-scores helps to ensure that the psychometric properties of the various components that comprise the composite have similar psychometric properties. This Z-transformed data for each cognitive composite can be analysed in a manner similar to that for nonwww.journalforclinicalstudies.com

transformed data through the use of multivariate statistics. Importantly, this type of analysis permits a shape or profile analysis that can help determine if treatment affects one cognitive composite (e.g., executive function) to a greater degree than any or all of the others. If there is no difference across cognitive composites there would be no difference from zero (corresponding to the mean of the normative data) and this would be represented by a flat line across composite measures.

However, if a non-flat line is apparent, a significant within-subject profile shape can be tested for via standard multivariate analysis of variance (MANOVA) or mixed model repeated measures (MMRM) techniques that detect significant differences between drug and placebo groups for all cognitive composites at baseline and over time.

A significant profile shape-by treatment group-interaction could then be decomposed using univariate ANOVA techniques and Bonferroni corrected t-tests. A measure of premorbid intellectual functioning can be used as a covariate to control for general intelligence which has been shown to correlate highly with performance on almost all cognitive measures. Revealing a treatment-by-profile shape interaction would represent an achievement that could not be easily realised when examining a sole cognitive measure or single composite alone.

Salient Aspects of PASC-Cog Study Designs Randomisation into clinical trials designed to establish the efficacy of pro-cognitive drugs on PASC-Cog should be limited to those patients with documentation of prior COVID infection(s) via SARS-CoV-2positive diagnostic test with an established SARS-CoV-2 antigen, RT-PCR, or molecular diagnostic assay. Further, it will be important to establish the timing of the acute infection(s), the variant if known, symptom cluster by medical history, therapeutic treatment, and vaccine history. The presence of cognitive dysfunction for more than twelve weeks developed during or after SARS-CoV-2 infection is paramount and of course, there should not be any acute SARS-CoV-2 infection at the time of randomisation nor during the study conduct.

Vaccination status and known variant/timing may be related to symptom cluster and may serve as important covariates in analyses based on recent data.

This notion is supported from a recent attempt to assess longterm COVID symptoms in a naturalistic setting that analysed selfreported symptoms from 1,459 people who had COVID symptoms for more than twelve weeks, and found that the largest group of patients reported a cluster of nervous system symptoms such as fatigue, brain fog, and headaches.28 Of note, the most common variant among this group was the Alpha variant, which was dominant in winter 20202021, and the Delta variant, which was dominant in 2021, suggesting that it may be possible to enrich on nervous system symptoms based on type of variant or time of illness. Three distinct cluster of symptoms in both vaccinated and unvaccinated people based on the variants investigated thus far were found, indicating that the overall risk of long COVID was reduced by vaccination.

Confirmation of both objective and subjective/perceived cognitive dysfunction is essential and should be based not only on self-reported measures of overall cognitive dysfunction but also on measures related to organisation and planning, working memory and selfmonitoring, sustained attention / divided attention or vigilance / distractibility, and processing speed. Performance on at least two of these cognitive areas should fall between 0.5 and 2.0 standard deviations below age and education-related normative data to avoid both ceiling and floor effects related to putative treatments. Ideally there should be some congruence between self-report/informant report and objective neuropsychological measures as well.

Importantly, it is critical to assess PASC related symptoms such as fatigue/daytime sleepiness and depression/anxiety. Although Journal for Clinical Studies 29

Therapeutics patients should not be included or excluded based on these measures, there may be some utility in stratifying patients on these important variables that are known to affect cognitive outcomes. These noncognitive symptoms have also been seen independently in PASC and represent important secondary outcome measures that may also be amenable to treatment. Other measures related to presenteeism/ worker productivity should also be gathered as these are vitally important patient-reported outcomes that may reflect changes in cognitive function in participants who are largely still working.

Notably, data establishing non-response can also help to provide evidence to regulatory agencies that the intended target is not pseudo-specific. Pseudo-specificity claims are misleading because they seek to promote a distinction without meaning; consequently, these claims are rejected because they are held to be in violation of the requirement that a product’s labelling not be false or misleading.

While it is relatively easy for many clinical trialists to acknowledge that specific cognitive domains are more likely to be associated with particular indications, few appreciate that even widely recognised cognitive enhancers typically affect multiple cognitive domains preferentially improving some domains while possibly causing impairments in others even when seen against a backdrop of improved overall cognitive function.

Treatment duration should be at least six months in order to allow for reliable and durable effects to develop. It is reasonable to expect that the Z-score composites assessing change in the treatment versus placebo groups will provide evidence of reduced cognitive impairment in the treated group after a time frame of approximately 24 weeks across cognitive domains. This is a similar time frame needed to see durable cognitive changes in studies of mild cognitive impairment associated with HIV-associated neurocognitive disorder (HAND). The milder level of cognitive impairment in HAND is similar in nature to PASC-Cog, with difficulties noted in concentration, planning/organising, and decision-making. Like PASC-Cog, HAND usually remains stable over time, rather than progressing as in the mild cognitive impairment typically associated with Alzheimer’s disease. Monthly assessments should be sufficient to assess the slope of change over time and to ensure that patients have adequate data from serial testing for visit wise analyses.

Relevant Biomarkers for PASC-Cog As there are no diagnostic tests nor treatments for PASC-Cog, the role of putative biomarkers in the design of clinical trials is critical.

Electrophysiological biomarkers involving event-related potentials (ERPs) can serve as useful surrogates for cognition, and there is some evidence in early stages of the cognitive decline associated with neurodegeneration that electrophysiological measures may actually be more sensitive to treatment-related changes than many cognitive tests. As such, non-invasive biomarkers such as ERPs are routinely used to understand the connections between brain networks and treatment effects in early clinical trials and in proof-of-concept settings. ERPs measuring brain response to specific events such as auditory stimuli can provide data on cognitive potentials such as P300, a component resulting from decision-making thought to reflect higher level cognitive processes associated with stimulus evaluation or categorisation.

Although more invasive, CSF biomarkers, particularly inflammatory biomarkers, have also shown some diagnostic utility in PASC.29 Researchers have reported that participants with PASC had elevated levels of the CSF immune activation markers interferongamma-inducible protein, interleukin-8, and the immunovascular markers vascular endothelial such growth factor-C and VEGFR-1, although differences compared to the control group were not 30 Journal for Clinical Studies

statistically significant. Overall, 77% of participants with cognitive PASC had a CSF abnormalities compared with 0% of cognitive controls suggesting that CSF biomarkers could potentially be used for inclusion purposes, or to enrich patient samples, and of course as an outcome measure when measured serially. Notably, CSF biomarkers of neuronal injury may also be associated with PASC-Cog; and one biomarker neurofilament light protein (NFL) has been shown to be elevated across several cognitive disorders with associated declines in NFL seen following successful treatment.

Finally, both structural and functional imaging should be considered as a useful exploratory outcome measures in PASCCog. In the first longitudinal imaging study comparing structural brain scans acquired from individuals before and after SARS-CoV-2 infection to those scans from a matched control group, researchers described both imaging and cognitive longitudinal effects following COVID even after excluding cases who had been hospitalised.30 This group investigated structural brain changes in 785 UK Biobank participants imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, as well as 384 controls. They reported a reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus, and a greater reduction in global brain size in SARS-CoV-2 cases compared to controls. Notably, the participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points than controls. Although structural changes are unlikely to be evidenced over relatively short Volume 14 Issue 3

Therapeutics trial durations as suggested above, functional changes via PET metabolism or resting state via functional MRI may prove to be more beneficial in this time frame, especially given the nature of the cognitive deficits noted in PASC-Cog. In addition to PET, resting state functional connectivity may have some unique applicability given that this measures the temporal correlation of spontaneous signal among spatially distributed brain regions, and as such provides a much broader network representation of the functional architecture of the brain. Unlike traditional fMRI, resting state fMRI is more reliable and reproducible, has no task demands, and therefore, is more standardised and better suited for multi-site investigations.

Summary In sum, PASC is a complex heterogeneous condition affecting mainly respiratory, cardiovascular, and very commonly the central nervous system. The most common nervous system symptoms of PASC are fatigue, cognitive dysfunction, and anxiety/depression.5,14 The neurocognitive symptoms associated with PASC seem to be distinct and persistent, significantly affecting patient quality of life.12 Data thus far on PASC-Cog suggests a unique “cognitive signature” that may represents a distinct and legitimate target for drug developers.

Randomised controlled clinical trials of various nootropics are currently being designed and deployed with the hopes of ameliorating the cognitive dysfunction associated with PASC. Careful selection of entry criteria and the use of appropriate outcome measures and biomarkers as suggested above should help increase the chances of trial success of drugs designed to treat PASC-Cog.

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Whitaker M, et al. Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people. medRxiv 2021.

Sigfrid L. et al. Long COVID in adults discharged from UK hospitals after COVID-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg. Health Eur. 2021, 8, 100186 Huang, L, et al. 1-year outcomes in hospital survivors with COVID-19: A longitudinal cohort study. Lancet 2021, 398, 747–758.

Huang, C. et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021, 397, 220–232.

Sudre CH et al. Attributes and predictors of long COVID. Nat. Med. 2021, 27, 626–631.

Su Y. et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 2022, 185, 881–895.

Blomberg, B, et al. Long COVID in a prospective cohort of home-isolated patients. Nat. Med. 2021, 27, 1607–1613.

Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271–280.e8.

Kielian M. Enhancing host cell infection by SARS-CoV-2. Science 2020;370:765–766 Swain O et al. SARS-CoV-2 Neuronal Invasion and Complications: Potential Mechanisms and Therapeutic Approaches. The Journal of Neuroscience, June 23, 2021 • 41(25):5338–5349 Guadarrama-Ortiz P, et al. Neurological aspects of SARS-CoV-2 infection: mechanisms and manifestations. Front Neurol 2020;11:1039; Li YC, at al. he neuroinvasive potential of SARSCoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020;92:552–555 Oronsky B, et al. A review of persistent post-COVID syndrome (PPCS).

Clin Rev Allergy Immunol 2021 Feb 20: 1-9. [Epub ahead of print].

Salmon-Ceron D, et al; APHP COVID-19 research collaboration. Clinical, virological and imaging profile in patients with prolonged forms of COVID-19: a cross-sectional study. J Infect 2021; 82: e1-4.

Afrin LB et al. COVID-19 hyperinflammation and post-COVID-19 illness

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may be rooted in mast cell activation syndrome. Int. J. Infect. Dis. 2020, 100, 327–332.

Seeßle J. et al. Persistent symptoms in adult patients one year after COVID-19: A prospective cohort study. Clin. Infect. Dis. 2021, 1–8 Lee MH et al. Microvascular Injury in the Brains of Patients with COVID-19. N. Engl. J. Med. 2021, 384, 481–483.

Tavcar P et al. Neurotropic Viruses, Astrocytes, and COVID-19. Front.

Cell. Neurosci. 2021, 15, 123 Verkhratsky A et al. Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol. Dis. 2016, 85, 254–261 Ribeiro DE at al. Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology. Mol. Psychiatry 2020, 26, 1044–1059.

Mohamad MS et al. Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Feature. Int. J. Mol. Sci. 2022, 23, 4275. https://doi.org/10.3390/ijms23084275 Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–1034 Scott L, et al. Trumping neurodegeneration: targeting common pathways regulated by autosomal recessive Parkinson’s disease genes. Exp Neurol 2017;298:191–201.

Hugon J, et al. Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex. Journal of Neurology. 2022; 269: 44–46.

Kas A et al. The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study. European Journal of Nuclear Medicine and Molecular Imaging. 2021; 48: 2543–2557 Heneka MT, et al. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimer’s Research & Therapy. 2020; 12: 69.

Canas LS et al 2022 . Profiling post-COVID syndrome across different variants of SARS-CoV-2.https://www.medrxiv.org/ content/10.1101/2022.07.28.22278159v1 Apple AC, et al. 2022. Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19. Ann Clin Transl Neurol. 2022 Feb;9(2):221-226. doi: 10.1002/acn3.51498. Epub 2022 Jan 19.

Douaud G, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022 Apr;604(7907):697-707. Epub 2022 Mar 7.

Dr. Henry J. Riordan Dr. Riordan is Chief Development Officer and co-founder of Worldwide Clinical Trials. He has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years. He has over 125 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology.

Email: henry.riordan@worldwide.com

Dr. Tomislav Babic Dr. Babic is a board-certified neurologist and clinical pharmacologist, with particular interest in drug development of various neurodegenerative disorders. He is the author of more than 60 peer-reviewed articles and books and has been integral to the development of many approved drugs across a number of neurologic conditions. His expertise has been widely noted in clinical neuroscience in both industry and academia for the past 25 years.

Email: tomislav.babic@worldwide.com

Journal for Clinical Studies 31

Technology

How Digital Health Can Reshape Pharma’s Hole in Healthcare In light of the proposed shift to value-based healthcare, Gérard Klop and Marcos Gallego Llorente of Vintura set out their vision for how pharma can grow its role in digital health provision.

With analysts predicting that patient numbers could double in the next few decades, hospital lead times will need to be cut by 50% simply in order to maintain care provision at its current levels. But given the rate at which personnel are leaving the profession, even this feels like a tall order. To address this challenge, smarter diagnostic tools and a growing role for remote care will be of huge importance in the new healthcare environment.

The pharma industry is already growing its role in delivering hybrid solutions combining therapies with diagnostic and smart solutions and devices, and it could play a significant role here – not just in creating and providing medication, but also in providing smart solutions and data-related tools.

Secondary prevention (slowing the progress of existing conditions or avoiding relapse) presents a particular opportunity for pharma to add new value in the real world. For instance, diabetes management is already well established as an example of digital health in remote care, but smart monitoring and targeted interventions are also making inroads into the management of auto-immune disorders such as inflammatory bowel disease, cardiovascular health issues and cancer – both in monitoring the progression of those conditions and in averting flare-ups.

As well as doing more to proactively support healthcare providers and patients, digital health opportunities provide a chance for pharma companies to capture and become a trusted source of important data about patients’ behaviour/trends and their wider wellbeing.

One example is Cosmo Pharmaceuticals’ GI Genius AI-enhanced endoscopy aid device, which detects colorectal lesions during a colonoscopy and is now approved for use in Europe, the US and Canada. The device is marketed worldwide via a partnership with Medtronic. It works in real time, as an adjunct to the gastroenterologist, highlighting regions with visual characteristics consistent with different types of mucosal abnormalities – such as colorectal polyps of all shapes, sizes and morphology.

An even greater game-changer using smart diagnostic tools would be its potential impact in incidental diagnoses – for example the ability to spot nodules on the X-ray of a 25-year-old athlete presenting with broken bones. Potentially this is something a smart algorithm could do with minimal additional expense as part of a standard set of tests.

Pharma’s role in such scenarios is linked to the wider theme of how the industry can become more deeply embedded at the different stages of clinical pathways, relieving pressure on healthcare resources and being present as part of the solution.

Straightforward drug sales will play a decreasing role in the future of pharma, so it is clear that the industry must work harder to be indispensable across a greater range of touchpoints, and to maximise the scope for reimbursement. Leveraging digital solutions to move innovative medicines up from third-line treatment options to secondor even first-line would be an important strategic win.

Helping patients with Chronic Illness Chronic conditions has been the area most transformed by digital health, and this area is attracting strong investment. Diabetes solutions have had highest profile up to now, as the parameters are relatively straightforward to measure. But other disease areas are also seeing success, including Multiple Sclerosis (MS), with digital solutions helping both with the monitoring of patients’ physical symptoms and in maintaining good mental health.

Significant Impact Digital health solutions can have a significant impact in two major ways. The first is at the healthcare provider level, where the latest advances in genetic testing and biomarker measurement might boost early detection of conditions and inform decision-making about treatments. The second is at the patient level, once an individual has entered treatment. Applications here include tele-consultations, remote monitoring of chronic conditions, and chronic disease selfmanagement, including associated education, reminders and prompts to modify and maintain desired behaviour.

When it comes to mental health, Sanofi’s partnership with mental health app provider Happify Health is a good example, extending support to patients to help them cope with depression and anxiety (people with MS may be up to five times more likely to develop severe depression than the general population, studies suggest). Working together, the two companies have developed a promising proof of concept for an app that uses cognitive behaviour therapy to help improve mental health through education and other activities.

In a hospital/speciality care setting, digital health can transform the early detection of serious diseases. Teams managing targeted screening programmes, such as checks for lung cancer in high-risk populations, may already use artificial intelligence and machine learning to ‘read’ high volumes of medical images efficiently, and detect even minute traces of the disease that may be invisible to the human eye.

Meanwhile, Merck’s SmartPatient/adveva multi-channel patient support system connects MS patients all over the world with a range of support services, including round-the-clock access to instructional videos on how to safely handle medication, tips for living with MS, personalised reminders to keep patients on track, and a built-in diary to facilitate discussions about their treatment.

32 Journal for Clinical Studies

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Technology

Tools for maintaining a close connection with patients affected by broader mental health conditions are also attracting a lot of interest. During the height of the Covid-19 pandemic, Boehringer Ingelheim and Click Therapeutics announced the collaborative development of a prescription-based digital therapeutic tool for use in the treatment of schizophrenia, filling a gap in support for patients who cannot always easily access tailored psychosocial intervention therapies.

Although respecting patient confidentiality is paramount, companies providing digital solutions will automatically be capturing a wealth of real-world data which, as anonymised trend insights, could inform their own development and commercial strategies: these findings will also be of interest to clinicians, as pharma organisations work towards more of a trusted partnership with physicians and hospitals.

If, using digital channels and tools (even if applied in the third line of care), pharma is able to identify when an initial/alternative treatment is failing to deliver the intended benefits, the benefits for patient, healthcare provider and pharma could be considerable, helping to trigger new, targeted interventions, so that the affected patients are redirected in a timely fashion to a more effective therapy.

A good example is in the case of auto-immune diseases like Crohn’s, where it is relatively common for patients to develop resistance to therapies: close monitoring could help identify the point of drop-off or decline at an earlier stage.

Untapped Opportunities To maximise the opportunities linked to digital health, pharma companies should examine the current care pathway and see where there might be an untapped opportunity to improve value for patients, linked to their own brand strategy and claims for their product. Guided by this convergence of interests, they can start to design a solution to fill the gap.

The new solution will require a different business model from established products, and will involve partnerships with both the care provider and a digital technology specialist. www.journalforclinicalstudies.com

Lastly, it will be important to consider the scalability of the proposed solution and how readily and efficiently it could be replicated across other hospitals/regions/countries.

Traditional pharma’s involvement in digital health is still at an early stage, and optimal delivery and partnership models are still being worked out. But this market is brimming with opportunity for those with the vision and agility to reinvent themselves.

Gérard Klop Gérard Klop is a partner at Vintura, which provides strategy consultancy to pharma and healthcare providers embracing transformation. Gérard has been a strategy consultant to the pharma and medical devices sectors for two decades, and is a published expert on value-based and value-managed healthcare.

Email: gklop@vintura.com

Dr. Marcos Gallego Llorente Dr. Marcos Gallego Llorente is a senior consultant at Vintura, specialising in digital health. A life scientist and healthcare consultant, he helps big pharma companies and hospitals hone their strategies to improve efficiency, or to ensure that their patients have a better quality of life throughout their treatment and their journey as a patient.

Marcos is also an adjunct professor at Madrid’s IE University in Spain, lecturing on the topic of biotech entrepreneurship and the future of health. He holds a Bachelor’s degree in biochemistry and pharmacy and a PhD in genetics from Cambridge University in the UK. Email: mgallego@vintura.com

Journal for Clinical Studies 33

PCI clinicalSMART™

Application Note

PCI clinicalSMART™: A SMART Solution to Clinical Supply Management With the number of registered clinical trials increasing significantly each year, it’s not surprising to learn that the clinical trials supply and logistics market is predicted to grow exponentially in the years ahead. Recent data suggests that by 2030 this market will be valued at approximately $12.4 billion, up from $5.1 billion in 2020; this translates to a Compound Annual Growth Rate (CAGR) of 9.1% from 2021 to 2030.1 Such growth places huge pressure on drug discovery companies, CROs and CDMOs to find supply management solutions which ensure seamless, efficient delivery of clinical trial materials worldwide, whilst navigating the challenges of more complex study designs and the ever-evolving regulatory landscape. PCI Pharma Services’ clinicalSMART™ is one such solution.

Experience, Expertise and Services PCI’s clinicalSMART™ team has a collective experience of almost 400 years, with an average of 16 years’ clinical trials supply experience per Clinical Supply Manager (CSM). In a recent survey, CSMs noted their level of experience and expertise in terms of therapeutic areas supported, previous employment, dosage forms supported, and a list of the services provided in their tenure with PCI’s clinicalSMART™, as outlined in Figures 1 to 4 below.

What is clinicalSMART™?

PCI’s clinical Supply Management And Readiness Team (SMART) is a department of experienced Clinical Supplies professionals who manage clinical drug supply on behalf of clients. At the time of this writing, PCI's clinicalSMART™ are supporting 74 clients and 214 studies globally. Designed with flexibility at its core, clinicalSMART™ is able to support sponsor requirements either throughout the entire study lifecycle, from protocol development through to final destruction of materials, or at time points when sponsor teams require additional resources to supplement in-house supply management expertise.

It does so by collating all key information from external parties (such as trial design, drug stability, and recruitment assumptions) and utilising in-house expertise to develop optimal supply strategies.

Whether it’s working with client’s internal teams in a consultative role, or assuming full ownership of supply chain management, clinicalSMART™ services are immediately available, preventing the need to recruit new staff, delivering the agreed contracted hours per month as required by the client.

Figure 1: Category Other includes reproductive, pain management, liver disease, hypertension, autosomal recessive disorder, gastrointestinal, rare diseases, cell and gene therapy, generic products, central nervous system

Established in 2016, clinicalSMART™ addressed the industry’s growing need for integrated clinical supply management services.

At that time, the two highest ranking therapeutic areas in terms of clinical trial cost per patient were hematology and oncology, with a median cost of over $200k and over $100k respectively.2 As of September 2022, there were 174,669 registered interventional clinical trials using drug or biologic therapies.3 Considering the sheer numbers involved here, any delays, miscommunications or errors in the clinical trials management process would be extremely costly in financial terms, not to mention the most important factor: the risks to the patients themselves.

Due to its initial successes, and a growing need from clients outside the US for the kinds of services offered by clinicalSMART™, the European and Asia Pacific team was established in 2019 to create a global team.

34 Journal for Clinical Studies

Figure 2 Volume 14 Issue 3

PCI clinicalSMART™

Application Note

How does clinicalSMART™ operate?

The effectiveness of clinicalSMART™ is best described via two realworld case studies.

Case Study #1: Integration and Embedded Support In one instance, PCI was performing packaging and global distribution for a client with a very aggressive clinical plan involving 7 global trials, complex multi-dose carded kits, and many inventory items. At a crucial stage, the client’s CSM resigned, creating a gap in support. In response, a clinicalSMART™ CSM was contracted to provide supply study oversight.

The clinicalSMART™ CSM’s role included: • • Figure 3: Category Other includes novel dosage forms, combination therapy with pump for Parkinson’s, topical ointment/semisolids

RFQ Support Services In addition to clinical supply chain management, clinicalSMART™ is also able to initiate RFQ document writing to support outsourcing requirements on a client’s behalf. After reviewing key study assumptions and estimates in order to establish an initial study plan, the RFQ and relevant supporting documentation is prepared for the client; due to a thorough knowledge and evaluation of the study requirements, a high level of accuracy within the quotation is assured. As with the study plans, RFQs are then submitted to the clinicalSMART™ team for peer review, drawing on the vast experience within the team to ensure a high level of accuracy.

• •

Responsibility for planning and creating demand and supply schedules; Working with the Project Manager to allocate inventory and stabilise the packaging schedule per trial; Working with the Distribution Project Manager to establish planned depot shipments; Eliminating rushed packaging and shipments.

Not only did the clinicalSMART™ CSM’s involvement maintain the drug supply for all trials without slowing the enrolment process, but they also worked with the client to recruit their own CSMs and trained them to assume all responsibilities going forward.

This seamless integration into the client’s supply chain is key to the clinicalSMART™ philosophy, as is the multifaceted nature of the clinicalSMART™ CSM’s role. They serve as a Project Manager,

Figure 4: Category Other includes On-boarding and interviewing new sponsor staff, supporting client CSMs, FIFO Assessment, Import/Export including Duty/Tax implications, supporting client vendor selection. www.journalforclinicalstudies.com

Journal for Clinical Studies 35

PCI clinicalSMART™

aiding communication between PCI, CMC, the Clinical team, Regulatory, CRO partners and IRT vendors; a client advocate who understands the needs of both the client and PCI and will bridge the gap between the two parties, ensuring that nothing is lost in translation; a continuous liaison throughout the trial lifecycle; a team member able to provide a Full-Time Equivalent (FTE) without the overheads involved in adding headcount; and an unblinded resource, which is critical to managing a controlled supply chain.

These services are underpinned by a high level of reassurance that the clinical supply management is in the hands of a highly experienced team, with almost 400 years collective experience in this field of expertise.

Case Study #2: Plan, Execute, Review – A Post-Go Live Intervention Limited staff resources within client organisations is another potential cause of delays, threatening the timing of trial execution.

One client contracted a SMART™ CSM to manage unblinded IRT activities and drug inventory at sites, with the contract established as the trial started when the client realised they had no unblinded personnel.

This began as an IRT support related role for the CSM, with the client responsible for all planning and packaging oversight, and the PCI CSM’s role commencing after sites had been seeded with initial supplies. Almost immediately, the PCI CSM determined that the quantity of drug packaged and supplied in initial site shipments was insufficient to support ongoing site re-supplies until the end of treatment period. The PCI CSM alerted the client to this critical risk only weeks into the trial lifecycle.

The SMART™ CSM immediately started working with the Project Manager and Distribution PM to establish a solution for the client, which involved: 36 Journal for Clinical Studies

Application Note

• • • •

Creating a new supply plan to fit the trial needs; Preparing a rushed packaging operation to generate more drug supply; Performing a number of site-to-depot returns and site-to-site drug transfers; Maintaining manual monitoring of drug inventory and site shipments.

Following the implementation and execution of the new plan, trial activities were maintained without interruption. Sites continued to open on schedule, enrolment continued without any slowing down, and the trial design was expanded to increase the number of patients.

The final delivery of this clinical trial led to this client contracting a portfolio of trials to the PCI clinicalSMART™ team.

This case study is an illustration of clinicalSMART™ performing their Plan, Execute, Review (PER) model, which is a core process that can be applied throughout the study lifecycle. It ensures a balance of the actuals of a clinical trial against the initial assumptions and realtime reactions to any potential risks to the study.

This experience-lead planning involves a deep understanding of stakeholder needs, and the ability to challenge vendors to ensure all aspects of the supply chain are being considered. These plans are then peer-reviewed, a process of internal critique which ensures that plans are robust and any risks are identified, assessed, and managed appropriately. During execution, clients benefit from full-time supply chain support and back-up support where necessary, with optimal issue avoidance resulting from the support of almost 400 years experience across the team. Plans are then reviewed after execution to assess lessons learned, and to share these lessons within the team.

Overall, this creates a proactive supply chain management process, instead of a reactive one where issues are not identified in good time.

Volume 14 Issue 3

PCI clinicalSMART™

Application Note When to get SMART Regardless of the level of CSM involvement contracted to the client, the critical objective remains the same: to provide a seamless, integrated clinical supply service at the level required by the client, at any stage or throughout the study lifecycle, whilst leveraging PCI’s extensive experience in this area of expertise.

However, to gain maximum benefit from clinicalSMART™ it is recommended that services are contracted as early as possible, preferably prior to study start up. This enables the PCI CSM to collate and analyse key information from external study stake holders, and to review the protocol, the drug stability, the availability of comparators in the marketplace, the countries involved in the study, the labeling and distribution strategy, and recruitment projections.

This comprehensive assessment will help the clinicalSMART™ CSM identify the least wasteful kit design and create an initial packaging forecast, which can be modified as changes arise. The CSM will also ensure the forecast is ‘fit for purpose’ by assessing it against the potential drug utilisation in the IRT. The PCI CMS will typically review the IRT specifications and recommend initial shipment triggers and re-supply values, ensuring best use of available drug product, adjusting values when live study data becomes available, and when changes arise from unplanned protocol revisions, or variance between projected vs actual site activity. This enables the PCI CSM to flag potential supplies risks, and present corrective measures.

The Future of SMART Since its conception, clinicalSMART has grown exponentially with the number of trials supported globally increasing year on year. PCI is committed to an ongoing recruitment plan to help facilitate this growth in the years to come. PCI is proud to have clinicalSMART™ as part of its service offering, and its continued excellence in providing seamless, integrated services aligns perfectly with the wider organisation’s goal of providing true end-to-end CDMO services for clients around the globe. If you want to learn more about clinicalSMART™ and how it may assist you, please get in touch today.

Please get in touch today at www.pci.com or email talkfuture@ pci.com.

REFERENCES 1.

2.

3.

https://www.biospace.com/article/clinical-trial-supply-and-logisticsmarket-size-share-growth-trends-forecast-2021-to-2030/?keywords= COVID+19+vaccine https://www.statista.com/statistics/1197095/clinical-trial-cost-per-patientby-therapy-area/ https://www.clinicaltrials.gov/ct2/resources/trends#TypesOf RegisteredStudies

Carolyn Timpany Carolyn Timpany, Senior Supplies Manager for the International Region at PCI Pharma Services, joined PCI in July 2022 from PPD, where she held the positions of Client Oversight Manager and Senior Supplies Manager. She has a breadth of experience in Clinical Supplies Management spanning a period of 17 years, and was formerly a Project Manager, Business Development Manager and Integrated Process Manager IRT/ Supplies at the Almac Group.

Email: carolyn.timpany@pci.com

Lisa Spence Lisa Spence, Director, Clinical Supply Chain for the International Region at PCI Pharma Services, joined PCI in March 2019 and has over 25 years clinical supply experience within in the pharmaceutical industry which was gained whilst working at GSK, Merck Sharp & Dohme, Pfizer and MedImmune. Lisa has industry expertise in clinical supply manufacturing, packaging, labeling/distribution, clinical supply chain project/programme management, regulatory and clinical operations. Lisa also has a BSc. Hons. degree in Pharmaceutical Science, which she gained at Greenwich University in 1995. Since joining PCI Lisa has created a new team of clinical supply managers that provide clinical supply management support for PCI’s EU/ ROW customers.

Email: lisa.spence@pci.com

Ed Groleau Ed Groleau, Director, Clinical Supply Chain for North America at PCI Pharma Services, has over 30 years of experience in the Pharmaceutical industry. He joined PCI Pharma Services in 2018 and became the director of his group in 2019. Ed leads the Supply Management And Readiness Team (SMART) at PCI where his team partners with clinical trial sponsors to provide any clinical supply management services from protocol development through destruction. Prior to PCI, Ed worked in numerous departments at Eli Lilly, spending 15 years in various laboratories before moving into the Clinical Trial Supplies group in 2003. In 2011 he became part of a highly integrated CM&C team responsible for overseeing the development of compounds from discovery through the proof-of-concept stage. In 2016 Ed moved to Elanco, Lilly’s animal health division, where he established a global clinical trial supplies group for developing companion and food animal projects.

Email: edward.groleau@pci.com

www.journalforclinicalstudies.com

Journal for Clinical Studies 37

Events Preview

CPHI Frankfurt 2022: At the Heart of Pharma Event Overview CPHI Frankfurt (previously called CPHI Worldwide) – the world’s largest pharma event – returns to Germany in 2022. It remains the go-to event for global pharma attracting industry wide participation, making this event the best place to source, network and collaborate.

The 2022 edition brings a raft of exciting changes – including a full schedule of onsite content and in person sessions for the first time since 2019 – with event numbers expected to meet or exceed pre-pandemic levels as the pharma community turns out again en masse.

The three day exhibition and in-person conference will be hosted at Messe Frankfurt, Germany, 1–3 November 2022 and will run in hybrid form – fusing the best elements of the traditional show with interactive online features to help attendees maximise their CPHI experience.

Extending the value delivered, CPHI opened its networking and learning platform on 28 Sep 2022 with the 'Connect to Frankfurt' digital platform that began the countdown to CPHI Frankfurt. Connect to Frankfurt will feature over 40 on demand session covering topics from all aspect of the pharma supply chain. The online platform is accessible to anyone registered for CPHI Frankfurt (November 1–3, 2022) and will remain open post event until 18th November.

What’s New at CPHI Frankfurt One significant change, that will be immediately clear, is that the event has been rebranded as CPHI Frankfurt and the onsite experience enhanced for attendees’ ease of navigation. For example, the collocated events have been replaced by descriptively named zones for packaging, outsourcing, machinery and more.

“One of the reasons behind the new identity is that we wanted to deliver the smoothest possible onsite experience so that attendees and exhibitors can concentrate on maximising opportunities. Everything we have done is to help the industry to match with exactly the right partners and to be able to do this more quickly,” Orhan Caglayan, Group Director CPHI Frankfurt.

Highlights at CPHI Frankfurt 2022 Who attends: It’s truly the heart of pharma with participants from over 145 countries; with 78% having purchasing responsibility and 47% from the C-suite.

CPHI Frankfurt has been designed to empower attendees to more connections and make them count, with a full platform of enhancing digital tools to use pre-event.

38 Journal for Clinical Studies

Who exhibits: CPHI Frankfurt is the beating heart of the entire global pharma/biotech supply chain – with everything from ingredients and finished dosage drugs to machinery, outsourcing providers, packaging, clinical services and even bioprocessing at BioProduction.

CPHI Awards 2022: Held on 1st Nov 2022, the CPHI Awards will feature a welcome reception and ceremony to celebrate the industry’s achievements and brightest stars – with categories spanning a total of 10 awards.

Attending CPHI Frankfurt Event Opening Hours: 10:30am to 6:30pm Early Access: 9:30am to 6:30pm VIP Access: 9:30am to 6:30pm To register kindly visit: https://registration-smartevents.iiris.com/CPHI%2F2022 Digital Features Connect to Frankfurt: Take the first digital step on your journey to CPHI Frankfurt Connect to Frankfurt marks the launch of the digital platform, a companion to CPHI Frankfurt, the online meeting place to connect with the entire supply chain. The platform empowers visitors to source suppliers, browse the exhibitors list and discover the full content agenda.

The CPHI Frankfurt App provides both attendees and exhibitors with a timetable of each day’s activities, a full list of exhibitors and onsite navigation (including hall locations).

Content Overview Connect to Frankfurt agenda This year the CPHI Frankfurt content experience begins online on 28th September, with Connect to Frankfurt – an online platform for expert content, to get a head start on your networking and to help plan your in-person experience. Highlights include a ‘trends outlook’ session hosted by leading marketing intelligence companies (including IQVIA and Accenture), the CPHI Learning Labs – with insights from leading pharma companies on new products & solutions – and an overview of the German pharma market and the CPHI Award finalists.

The on-demand webinars will span more than 40 sessions covering the entire lifecycle of drug development from ingredients to clinical trials services and outsourcing providers.

CPHI Frankfurt (November 1–3) Content Agenda – The First Full Schedule of In-person Content Since 2019 The conference agenda – the largest ever put together by CPHI – will span some five tracks across three days in the main Conference Volume 14 Issue 3

Events Preview

theatre, with an additional theatre dedicated to ‘Product Innovation and Sustainability’. Running alongside CPHI Frankfurt content will be 3-days of +30 talks, biologics sessions curated by the team at BioProduction.

Reflecting the hottest trends in the industry and attendees’ interests tracks cover: ‘Ingredients and Formulation (Track 1), Future Therapies (Track 2), Digital (Track 3), Manufacturing Excellence (Track 4), and Patient Centricity (Track 5).

The opening day keynote explores the glut of recent research into Psychedelic therapies to treat an array of mental health issues from depression to anxiety and post-traumatic stress.

David Erritzoe, Clinical Director and Deputy Head at the Centre www.journalforclinicalstudies.com

for Psychedelic Research presents an ‘Introduction of Psychedelic Therapies into Mental Health – Current Status and Future Perspective’.

The final morning of the show is focussed on Patient Centricity and will open with a keynote address from the National Coalition of Organisations for Patients with Chronic Conditions of Romania (COPAC), & the European Patient's Forum Board.

This will be followed by a roundtable on ‘Latest Trends in Consumer Health’, a session from On Demand manufacturing covering ‘Supply Chain Resiliency & Patient-Ready Medicine Delivery’ and closes with Deloitte Consulting analysing the use of AI for ‘Advanced Digital Customer Segmentation’.

Journal for Clinical Studies 39

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Journal for Clinical Studies

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Volume 14 Issue 3

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