JCS Volume 14 Issue 4 by Senglobal1

PEER REVIEWED Volume 14 Issue 4 Delivering on the Promise of Digital Trials Simplified Experiences for Sites and Patients What Passive Packaging Options Are Available When Shipping Clinical Trials at Frozen Temperatures? Clinical Trial Feasibility in a Changing World Current Trends and Prospects Bridging the Gaps in the Analytical Procedure With Bayesian Statistics Journal for Clinical Studies www.journalforclinicalstudies.com

YOUR BRIDGE BETWEEN LIFE-CHANGING THERAPIES AND PATIENTS OUR INTEGRATED CLINICAL SERVICES INCLUDE: • Drug Development • Drug Product Manufacturing • Primary and Secondary Packaging • Labeling • Global Storage, Distribution and Returns THE PCI WAY Delivering unmatched expertise and flexibility, allowing a customized approach to your unique trial requirements. www.pci.com talkfuture@pci.com

REGULATORY 14 Early Adoption of an Integrated Product Development Strategy will Reap Dividends

Volume 14 Issue 4 July 2022 Senglobal Ltd. Contents Journal for Clinical Studies

Journal for Clinical Studies 1www.journalforclinicalstudies.com MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT info@senglobalcoms.com EDITORIAL MANAGER Beatriz beatriz@senglobalcoms.comRomao DESIGNER Jana www.fanahshapeless.comSukenikova RESEARCH & CIRCULATION MANAGER Jessica jessica@senglobalcoms.comChapman 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: Journalwww.journalforclinicalstudies.cominfo@senglobalcoms.combyClinicalStudies–ISSN1758-5678 is published bi-monthly by Senglobal Ltd. 4 TALKINGFOREWORDPOINT 6 Talking Point with PCI Pharma Services: Journal for Clinical Studies Established in 1971 and trading as Packaging Coordinators Inc. (PCI), the company provided contract packaging solutions to the pharmaceutical industry. Over the last decade, PCI has made a number of strategic acquisitions to both increase global packaging footprint as well as adding manufacturing capabilities. Alan Lahaise at PCI Pharma Services talks about the values and principles of the company. WATCH PAGES 10 The Importance of Conducting Diverse US Trials for US Cancer Patients

12 An Open Letter of Appreciation to Clinical Trial Participants, Patient Advisors, Caregivers and HealthCare Professionals

Since the early 1990s, overall cancer death rates have declined for most cancers in the US. According to the Annual Report to the Nation on the Status of Cancer – issued in March 2020 as part of a joint effort between the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the North American Association of Central Cancer Registries (NAACCR), and the National Cancer Institute (NCI) – rates decreased by 1.8% per year among men and 1.4% per year among women from 2001 to 2017. Children aged 0 to 14 years also experienced a decrease in deaths, down 1.4% per year. Among common cancers with declining death rates from 2014 to 2018, lung cancer and melanoma showed the largest decreases. Many factors have contributed to these decreases, such as tobacco cessation, early detection, genetic testing, and annual screening for high-risk individuals, but perhaps the largest contributor has been the introduction of targeted immunotherapies, such as CAR T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies, immune system modulators, and treatment vaccines. However, some cancers are experiencing increases despite these advancements. Jaime Gavazzi at Clarivate shows the importance of conducting diverse US trials for US cancer patients.

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright.

2 Journal for Clinical Studies Volume 14 Issue 3

30 Powerful Techniques Promoting Gene Therapy and Genemediated Cell Therapy Progress Gene therapy and gene-mediated cell therapy (e.g. CAR-T cell therapy) approaches hold great promise for treating debilitating diseases with unmet clinical needs. The drive to address the genetic cause of a disorder has brought about a gamut of innovative tools that can correct a cell’s function at the DNA level or engineer a cure via in vivo or ex vivo methodologies. Dr. Chelsea B. Pratt at Bio-Rad Laboratories discusses the fundamental principles of gene and gene-mediated-cell therapies, addresses the challenges associated with in vivo and ex vivo gene delivery approaches, and presents tools the industry can use to support product development.

26 Clinical Trial Feasibility in a Changing World: Current Trends and Prospects

One of the best ways to ensure that a sponsor’s clinical and commercial programs reflect how patients experience a disease or a treatment is to interview patients directly over time. This practice – longitudinal qualitative research – is an emerging science that can guide development efforts as well as inform communication strategies for treatments in any therapy area. Sally Lanar and Alexia Marrel of ICON, outline what longitudinal qualitative research is, when and how it can be used and the key factors for success when using this type of research.

Intellectual property is an intangible business asset that often helps set companies apart from their competitors. Unfortunately, few businesses know precisely what their IP is worth, or how to protect it.Let’s step into the world of IP and explore the risks that you could be facing –and how you can build resilience for your business. A guide by Hanna Beaumont at Partners& will be putting together in collaboration with CFC Underwriting, a leading provider of insurance solutions for life science and technology companies. &

A fundamental factor that underpins the successful execution of clinical trials is site quality, and delays in, or the failure of, trial participant enrolment represent significant risks in product development. Therefore, a critical success criterion of clinical trials is the selection of sites with the requisite capabilities: access to a well-characterised population of potential trial participants, experienced and well-motivated investigators and study staff, and adequate site facilities, all located within countries with a favourable regulatory environment. Dr. Arash Ghalamkarpour and Dr. Otawale Salami at SGS summarise the pitfalls associated with current methodologies of clinical trial feasibility and highlight how SGS Health Science's data-driven and multidisciplinary clinical trial feasibility approach supports many trial sponsors in optimising trial planning across various therapeutic indications.

Within the clinical trials sector, there is an increasing demand for high-performing thermal packaging to meet the rising requirements of protecting pharma payloads, needing to be shipped at extremely lower temperatures. Consequently, thermal packaging vendors are responding to the growing trend to transport clinical trial materials at significantly lower temperatures including frozen, deep frozen and ultra-deep frozen. The main driver for this rising demand for such specialist shippers is the rapidly rising rate of clinical trials being conducted. After the initial impact of the pandemic, the industry is now seeing multiple trials initiating from their first phase and successfully moving through all four phases. Ross Gregory at Peli BioThermal explains what passive packaging options are available when shipping clinical trials at frozen temperatures.

34 Delivering on the Promise of Digital Trials: Simplified Experiences for Sites and Patients

20 Understanding How Intellectual Property Insurance Can Protect Your Business

Bruno Boulanger at PharmaLex, discusses how Bayesian statistics and interpretation bridge the gaps in the guidelines.

24 Longitudinal Qualitative Research – Capturing the Patient Voice; Enhancing Patient Centricity

THERAPEUTICS

36 What Passive Packaging Options Are Available when Shipping Clinical Trials at Frozen Temperatures?

DEVELOPMENT

Contents and cost-effective path to market. But while more organisations are adopting an IPD strategy, a recent industry survey found most aren’t doing so early enough. Frédéric Pailloux at PharmaLex examines the IPD journey.

16 Bridging the Gaps in the Analytical Procedure with Bayesian Statistics

RESEARCH

TECHNOLOGY

SUPPLY CHAIN MANAGEMENT

Contact us Clinicalsgs.com/healthcommunitysgs.com/healthsciencehealthscience@sgs.com SolutionsResearch Health QualityInspired,Driven. Delivering solutions in Europe and North America, SGS offers clinical trial services. SGS has its own clinical unit in Belgium including a viral challenge testing facility and two phase I patient units based in Belgium and Hungary. SGS has a wealth of expertise in FIH studies, viral challenge testing, biosimilars and complex PK/PD studies with a high therapeutic focus in Infectious Diseases, Vaccines, and Respiratory. We offer a variety of tests that are bespoke, client-specific and support the full clinical development, from Phase I First-in-Human trials in our Clinical Pharmacology Units, to Phase II and Phase III studies in patients: • Full Service CRO • Drug Development Consultancy • Clinical Pharmacology Unit • Clinical Trial Management • Biometrics • Medical Safety & Regulatory • Clinical Trial Analytics SGS provides clinical research and bioanalytical testing, with a focus on early stage development and biometrics.

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

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

• Catherine Lund, Vice Chairman, OnQ Consulting

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

The concept of a “digital clinical trial” involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomised intervention allocation and has the potential to transform clinical trials and lower their cost.

In this journal, we will also explore more about intellectual Property. Intellectual property is an intangible business asset that often helps set companies apart from their competitors. Unfortunately, few businesses know precisely what their IP is worth, or how to protect it. Let’s step into the world of IP and explore the risks that you could be facing – and how you can build resilience for your business. A guide by Hanna Beaumont at Partners& will be putting together in collaboration with CFC Underwriting, a leading provider of insurance solutions for life science and technology companies.

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

• Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

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

• Deborah A. Komlos, Principal Content Writer, Clarivate

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

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

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

The shift toward decentralised trials (DCTs) was not caused by COVID-19 but has certainly been accelerated by it. DCTs should result in a more patient-centric experience. Since they do not need to travel to clinical research sites to participate in studies, patients are empowered to share clinical data from varied caregiving settings. Remote clinical trials are enabled through the use of digital applications, which are the how of DCTs. But such a rapid shift has introduced challenges, with patients juggling multiple technologies during a Patientstrial.are not the only ones facing challenges. Sites also find it difficult to realise the operational benefits of DCTs. Hugo Cervantes at Vault EDC analyses simplified experiences for sites andWithinpatients.the clinical trials sector, there is an increasing demand for high-performing thermal packaging to meet the rising requirements of protecting pharma payloads, needing to be shipped at extremely lower temperatures. Consequently, thermal packaging vendors are responding to the growing trend to transport clinical trial materials at significantly lower temperatures including frozen, deep frozen and ultra-deep frozen. The main driver for this rising demand for such specialist shippers is the rapidly rising rate of clinical trials being conducted. After the initial impact of the pandemic, the industry is now seeing multiple trials initiating from their first phase and successfully moving through all four phases. Ross Gregory at Peli BioThermal explains what passive packaging options are available when shipping clinical trials at frozen temperatures. – Editorial Advisory Board

• Stefan Astrom, Founder and CEO of Astrom Research International HB

JCS

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

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

4 Journal for Clinical Studies Volume 14 Issue 3 Foreword

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

• Georg Mathis, Founder and Managing Director, Appletree AG

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions.

• Hermann Schulz, MD, Founder, PresseKontext

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

• Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

www.journalforclinicalstudies.com Full Service Delivery Early Phase Oncology Specialists Technology Driven Clinical Consultancy A Full ClinicalServiceCRO as Advanced as your Therapy +44contact@aptusclinical.com(0)1625238662

By eliminating the requirement for preformulation activities, excipient compatibility and associated stability studies, as well as simplification of method development processes, utilizing the Xcelodose® technology allows products to be manufactured and delivered to clinic up to 6 months faster than the more traditional route. Dosing directly into capsules also helps to reduce the amount of API required, helping to eliminate wastage of often-valuable APIs which is particularly important at the early stages of proof of concept if API is in short supply.

Talking Point

PCI Pharma Services is a trusted partner for global integrated CDMO services. Can you tell our readers the brief history of your company, how the company got started and your growth so far?

The structural complexity of modern biologics presents packaging manufacturers with a new challenge when it comes to ensuring the drug remains stable throughout its designated shelf life. Can you explain how PCI supports multiple delivery forms from Phase I through commercialisation?

Through facilities in North America, Europe and Asia Pacific, PCI provides a global service with localized focus, delivering over 200 protocols a year in over 100 countries, utilising best-in-class technologies combined with experienced and dedicated teams.

Talking Point with PCI Pharma Services

PCI’s “Contained Micro-Dosing Xcelodose® Technology” is a very innovative solution. Can you explain what that is, and why do you claim that this technology leads to faster first-in-human studies?Xcelodose® is a precision powder micro-dosing system that allows API to be filled directly into capsules and vials. This approach removes the need for development of a powder blend, as would be the case for a more traditional development processes. At PCI, we operate both the Xcelodose® 120 and the 600S models, filling up to 120 and 600 capsules per hour respectively, making them ideal for clinical manufacture from early to later stage clinical programs. We have also invested in Xcelohood™ and Xceloprotect™ containment systems, further enhancing our world class engineered contained manufacturing capabilities for the safe processing of highly potent drug products.

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Addressing the growth in the biologics market and their varying complex requirements, PCI continues to invest in developing new solutions and adding capacity for the manufacture, packaging and temperature controlled storage of these specialist drug products. With many biologics presenting stability challenges we are investing significantly in large scale lyophilization technologies which are essential to improve stability and reduce the complexity associated with cold chain logistics.

Established in 1971 and trading as Packaging Coordinators Inc. (PCI), the company provided contract packaging solutions to the pharmaceutical industry. Over the last decade, PCI has made a number of strategic acquisitions to both increase global packaging footprint as well as adding manufacturing capabilities. One such acquisition in 2014 was Penn Pharma, bringing with it a state-of-theart contained manufacturing facility for the safe processing of highly potent drug products. In 2015, the organisation rebranded under the name PCI Pharma Services and has since continued to grow both organically and by way of further acquisitions, with Lyophilization Services of New England (LSNE) being the most recent acquisition building upon its expertise in specialty manufacturing, delivering on the company strategy to become a truly integrated, global, CDMO.

Today, PCI Pharma Services is a global $1 billion CDMO with 30 GMP facilities throughout North America, Canada, UK, Europe, and the Asia Pacific region. We are proud to serve in excess of 1,700 customers with unparalleled expertise and experience in taking compounds from the earliest stages of development through to successful commercialisation, delivering speed-to-market and commercial success for our customers. Our continued growth enables us to support over 3,100 clinical trials, over 450 commercial molecules, and each year launch over 90 commercial products. Our industry leading experience, operational flexibility, commitment to safety, supported by innovative technologies and our exemplary quality and regulatory record make us the partner of choice for biopharmaceutical companies around the world.PCI is committed to supporting clients at every stage of the of the clinical cycle, delivering best-in-class services efficiently and effectively. What are the core clinical trials services you provide andOurwhere?clients come to us seeking solutions to often complex and unique opportunities due to our reputation in offering unmatched flexibility, a client-centric experience and consultative approach. We deliver a seamless clinical service for almost all dosage forms and drug products including pharmaceutical development, clinical manufacturing, packaging, labelling, storage and distribution. Our scalable solutions ensure we are able support our clients from early first-in-human (FIH) studies through to late phase clinical trials and ultimately commercialisation.

Through our global network, PCI is able to provide integrated end-to-end solutions for both sterile and non-sterile drug products including development, manufacturing and packaging across the entire drug product lifecycle, from early phase clinical trials to commercialisation, meeting the needs of our clients and bringing life-changing therapies to patients faster.

PCI is active in Cold Chain management. You provide specialist expertise in the packaging, labelling, storage, and distribution of temperature-sensitive clinical supplies including biologically derived and parenteral products. Temperature controlled logistics was vital in the distribution of Covid-19 vaccines worldwide. What role did PCI play in this undertaking, and what lessons have we learnt?PCIis a true expert in Cold Chain management and is a trusted partner to many biopharmaceutical companies having built the expertise and reputation that we have over many years. We also have a philosophy of invest now for the future, which has served us well and meant that when the pandemic hit, we were able to offer seamless solutions to our customers because although we had not planned for a pandemic, we had planned based on the general market growth trends.

In terms of regulatory support, we provide a completely bespoke service whereby we can assist our clients with the composition of their Drug Product (DP) Common Technical Dossier either writing the entire DP section or assisting with certain sections pertinent to activities undertaken at PCI. Furthermore, our Regulatory team can provide an integrated support service where a designated team member embeds within our clients’ project team, providing regulatory support and facilitating decision-making at key stages throughout the product development lifecycle. Should support be required at pivotal scientific meetings with regulators we can assign a designated team of subject matter experts to ensure product quality questions are addressed seamlessly. What major events have occurred in the industry and what has been its effects. The COVID-19 pandemic has and continues to affect almost every aspect of the pharmaceutical industry. On a positive note, we have seen vaccines being developed and available for commercial use in a timescale that would have been almost unthinkable prior to the pandemic. We have also witnessed just how responsive the industry can be, using innovative technology and processes to develop new ways of working and ensuring ongoing regulatory compliance for example with the hosting of virtual audits. Unsurprisingly, the pandemic has also created many challenges, with the most disruptive affecting global supply chains and shortages of both raw materials and consumables. To overcome some supply chain challenges, pharmaceutical companies and CDMOs alike are now looking to source from domestic suppliers, which not only has a positive ESG impact by reducing the company’s carbon footprint but can also assist in reducing lead times. At PCI, we have navigated potential supply chain challenges by utilising our integrated and predictive supply chain management platform, pci|bridge™. Utilising this innovative technology, we were able to work with our clients, adjust forecasts, order additional supplies and leverage existing relationships and partnerships to source materials. This meant that project milestones were met and an uninterrupted supply of lifesaving therapies to patients.

www.journalforclinicalstudies.com

Can you explain your Regulatory and Analytical Support Services? What are you offering, and how do you make a difference in the industry? Our specialist in-house Regulatory and Analytical teams provide essential support services to our clients across the full drug product lifecycle from development through to commercialization helping to reduce complexity and expedite timelines.

Talking Point Supporting the downstream processing of biologics and providing an integrated solution to our clients, our European and US Biotech Centers of Excellence, provide scalable and flexibility packaging solutions to cater to the range of packaging needs of our clients from standard vials to more patient-centric drug delivery pack formats such as pre-filled syringes, auto-injectors, medical device and kits.

Amid supply chain uncertainties, PCI works with clients to utilise just-in-time labelling allowing total flexibility of clinical trial inventory management allocating investigational medicinal products where they are needed. For clinical studies where the demand may be unpredictable and location of patient population unclear, justin-time principles have demonstrated to be significantly impactful to ensuring both supply continuity as well as supply optimisation, reducing waste and saving costs for our clients.

Our global network of sites boast a range of analytical laboratories equipped with world-class fully GMP and ICH compliant technologies that provide a broad spectrum of analytical testing from method transfer, through method development and validation to drug product release and ongoing stability studies for all dosage forms including high potent and sterile drug products.

PCI offers over 30 years of experience in the Pharmaceutical Storage and distribution of clinical trial materials, effectively storing and distributing thousands of patient kits to over 100 countries worldwide. What challenges are you facing post Covid-19, and what strategies have you implemented henceforth?

It is clear that the pandemic affected all levels of pharmaceutical distribution. In terms of clinical phases of development with patients unable to attend a clinical site, site-to-patient and directto-patient distribution are gaining momentum – as is the concept of decentralised trials. At one time deemed to be a theoretical notion, clinical trial sponsors are now looking to site-to-patient and direct-topatient transfers as a viable method to deliver medicines to patients and keep their trials on track, which in return means complex supply chains with temperature management considerations being key.

At PCI, we work with clients to develop a flexible and dedicated service to meet the needs of each and every clinical trial, irrespective of size or global requirements. Dedicated teams of logistics experts ensure complete accountability and supply chain integrity throughout the clinical lifecycle.

Journal for Clinical Studies 7

Talking Point

And on a smaller scale but no less important, demonstrating our flexibility was that in March 2020 when crisis point hit Milan, PCI supported the shipment of emergency medicine to patients when commercial flights from the US where drastically scaled back. PCI secured permits and arranged for courier jets, drivers and trains to deliver the life-saving drugs to the patients in WhatMilan.does the future hold for PCI? What is your vision in the next 5 years? As an innovative end-to-end solution provider, and to fulfil our mission to be the bridge between life-changing therapies and patients, we will continue to invest and evolve our services and facilities to meet the needs of existing and future clients.

Alan Lahaise Alan started his career at Ciba-Geigy as a sales representative and progressed through a variety of business development leadership roles at Medeva PLC, Quintiles, Aptuit, Patheon and Thermo Fisher Scientific (Fisher Clinical Services). Alan joined PCI Pharma Services in July 2021 where he is VP Business Development for global Manufacturing and EMEA Clinical Services. Alan brings over thirty years sales team leadership experience within the CRO/CDMO sectors in North America, EMEA and APAC regions. His responsibility for services has ranged across small molecule API, large molecule biological drug substance development and manufacture through to formulation development, clinical and commercial manufacture of drug product (oral solid dose, soft gel capsules and sterile products). to support the development, manufacture and packaging of both small and large molecules will ensure we are able to provide the right solutions to our customers when they need them. The industry will continue to focus on personalised medicine and treating orphan designated diseases, which will mean more niche products and smaller batch sizes with increasing pressure on delivering speed to market.Withover $250m planned on capital investments over the coming years to deliver enhanced manufacturing and packaging capabilities and capacities together with our flexible, integrated approach to scalable development and manufacturing, we will continue to support our clients to deliver these specialized products to the market in the most cost and time efficient way.

One example of how we supported would be that having invested over $25m prior to the pandemic hitting, the PCI Pharma Services’ biologic Center of Excellence in Philadelphia was well equipped to support the unprecedented surge in demand for specialist Cold Chain storage and processing of temperature sensitive drug products.Another example includes our clinical and commercial Cold Chain capabilities as throughout the pandemic, PCI played a major role in the specialist packaging, labelling and distribution of various Covid-19 vaccines, not only supplying hospitals and clinics throughout North America but also in Europe.

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In terms of the future, we believe there will be a continued growth in biologics including mRNA technologies with a focus on patient centric delivery systems. We also believe that the continued focus in the area of oncology will remain and so our ongoing investments

Corporate Profile Medical LaboratoryDiagnosticRamusLtd 26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel/Fax: +359 2 944 82 06 email:www.ramuslab.cominfo@ramuslab.com Ramus Medical Ltd 26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel./Fax: +359 2 841 23 69 email:www.ramusmedical.comoffice@ramusmedical.com Journal for Clinical Studies 9 Dimitar Mihaylov Marketing Director S! act fe er ,r fo ac st, to TutoCiVere Ramus Corporate Group is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in the Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of ISO 9001:2015. Ramus Medical is full service CRO, working CTs in a variety of therapeutic areas and medical device. • Medical writing for drugs and devices • Scientific review of documentation • Clinical trial management • Monitoring • Data management • Regulatory advising and services during clinical trial Medical Diagnostic Laboratory Ramus (SMDL-Ramus) • 30 clinical laboratories in Bulgaria and North Macedonia • 325 affiliates for sampling in Bulgaria and North Macedonia • More than 20 years’ experience in the CT field as central and safety laboratory; • Largest PCR laboratory in Bulgaria • Laboratory System integrates cluster generation, sequencing, and data analysis • Total laboratory automation with Abbott GLP-System • Bioanalytical laboratory – ISO/IEC 17025:2017 accredited Medical Centre Ramus with Phase I Unit • PK/PD studies • Medical devices investigations • Phase I–IV • Non-interventional studies Others: • Readability user testing • Bridging report • Carriage and storage of dangerous goods in compliance with ADR principles www.journalforclinicalstudies.com

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met in April 2021 to discuss whether confirmatory trials have demonstrated clinical benefit for multiple immune checkpoint inhibitors approved under the accelerated approval pathway. The committee agreed that some of those products should remain on the market but recommended that others be removed after they did not demonstrate clinical benefit.

• The foreign data are applicable to the US population and US medical practice.

• Clinical investigators of recognised competence have performed the studies.

• The FDA can validate the data through an onsite inspection or other appropriate means.

The FDA also relies on consensus guidelines from the International Council of Harmonisation of Technical Requirements

Watch Pages

Trials Conducted Outside the US

Since the early 1990s, overall cancer death rates have declined for most cancers in the US. According to the Annual Report to the Nation on the Status of Cancer – issued in March 2020 as part of a joint effort between the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the North American Association of Central Cancer Registries (NAACCR), and the National Cancer Institute (NCI) – rates decreased by 1.8% per year among men and 1.4% per year among women from 2001 to 2017.1 Children aged 0 to 14 years also experienced a decrease in deaths, down 1.4% per year. Among common cancers with declining death rates from 2014 to 2018, lung cancer and melanoma showed the largest decreases.2Manyfactors have contributed to these decreases, such as tobacco cessation, early detection, genetic testing, and annual screening for high-risk individuals, but perhaps the largest contributor has been the introduction of targeted immunotherapies, such as CAR T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies, immune system modulators, and treatment vaccines. However, some cancers are experiencing increases despite these advancements. When Accelerated Approval Gets It Wrong To help address the cancer burden in the US, the US Food and Drug Administration (FDA) offers various routes to accelerate the development of cancer treatments, the most notable of which is accelerated approval. Sponsors of drugs that treat serious conditions and fill an unmet medical need can seek considerably earlier FDA approval based on a surrogate endpoint.3 These companies must still conduct confirmatory studies to confirm clinical benefit; if that is not achieved, the FDA can withdraw approval, prompting removal of the product from the market by the sponsor.

At the ODAC meeting, the FDA noted an “increasing number of single-country trials” submitted to support US approval, which the agency considers “me-too trials.” This practice is “a departure from decades of multiregional clinical trials as the consistent approach to drug development.” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence (OCE), spoke about the lack of racial and ethnic diversity in ORIENT-11, which he stated was a “lack of diversity by design,” and said he was “very unhappy to have this discussion” during Black History Month in the US. He noted the importance of including racially and ethnically diverse populations in clinical trials designed to approve products for use in USUnderpatients.21CFR 314.106(b), sponsors must meet 3 requirements for using foreign data as the sole basis for marketing approval in the US:4

10 Journal for Clinical Studies Volume 14 Issue 3

Two products were subsequently voluntarily withdrawn from the market: 1) Keytruda (pembrolizumab), from Merck Sharp & Dohme Corp, for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 and 2) Opdivo (nivolumab), from Bristol-Myers Squibb Company, for the treatment of patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib.

After reevaluating multiple products to treat cancer in 2021, the FDA convened the ODAC in February 2022 to consider a new product to treat cancer – sintilimab from Innovent Biologics (Suzhou) Co, Ltd, for use in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of patients with stage IIIB, IIIC, or IV non-squamous non-small cell lung cancer (NSCLC) with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumour aberrations. In a new biologics license application (BLA) submission, the sponsor sought approval based on a single confirmatory trial conducted in China (ORIENT-11). The committee agreed that sintilimab appeared to be safe and effective, adding value over chemotherapy alone. The primary endpoint for the study was progression-free survival (PFS), but the standard endpoint for firstline treatments of NSCLC with immune checkpoint inhibitors is overall survival (OS). The FDA’s primary issue with the BLA, however, was that the trial was conducted in a single country lacking the diversity of the US population. Ultimately, the ODAC voted 14–1 that additional clinical trial(s) demonstrating applicability to US patients and US medical care should be required prior to a final regulatory decision. The panelists also agreed that a lack of unmet need in the associated patient population contributed to their decision. The FDA subsequently issued a complete response letter recommending that the sponsor conduct a multiregional clinical trial and use OS as an endpoint.

The Importance of Conducting Diverse US Trials for US Cancer Patients

4. Title 21, Chapter I, Subchapter D, Part 314, Subpart D, § 314.106. Code of Federal Regulations. subchapter-D/part-314/subpart-D/section-314.106https://www.ecfr.gov/current/title-21/chapter-I/

7. Cancer Statistics. National Cancer Institute Website. https://www.cancer. gov/about-cancer/understanding/statistics

While the burden of oncology in the US is still immense – accounting for 602,350 deaths as of January 2022 and maintaining the status of the second leading cause of death7 – the importance of adequate representation in clinical trials to reflect the diversity in the US cannot be overwritten by fast-track methods to bring products to market. This is especially true for products that do not fill an unmet medicalSomeneed.products, such as those that receive accelerated approval, could address an unmet need in certain cancers, but the data must support safety and effectiveness in the relevant patient population. For the US, this should include underrepresented racial and ethnic populations that have largely been ignored in the clinical trial realm. Whether the FDA will consider additional applications with singlecountry studies is up for debate – and hinges on the opinion of the ODAC in many cases.

Jaime Gavazzi Jaime Gavazzi is a Principal Content Writer for the Cortellis suite of life science intelligence solutions at Clarivate. Her previous roles include writing and editing for books, online magazines, educational coursework, government proposals, and government regulatory publications. Her primary assignments at Clarivate include reporting on FDA drug/device advisory committee meetings and drug approvals.

3. Accelerated Approval Program. Food and Drug Administration accelerated-approval-programhttps://www.fda.gov/drugs/information-health-care-professionals-drugs/Website.

5. Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials Guidance for Industry. Food and Drug Administration. https://www.fda. gov/media/157635/download

Diversity in Clinical Trials

Email: jaime.polychrones@clarivate.com for Pharmaceuticals for Human Use (ICH) for its evaluation of foreign data. The acceptance of foreign data from single countries is addressed in the ICH’s E5 Ethnic Factors in the Acceptability of Foreign Clinical Data guidance and the FDA’s E17 General Principles for Planning and Design of Multiregional Clinical Trials guidance.

Maintaining a Regulatory and Ethical Balance

In April 2022, a year after the ODAC meetings to discuss certain oncology products with accelerated approval and months after the committee recommended a US trial for sintilimab, the FDA announced its continued commitment to enrolling underrepresented racial and ethnic populations in the US into clinical trials and published a draft guidance for industry, Diversity Plans to Improve Enrolment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials, to provide sponsors with recommendations on how to achieve this goal.5 The intent of the guidance is to provide guidance to sponsors “to enroll representative numbers of participants from underrepresented racial and ethnic populations in the United States, such as Black or African American, Hispanic/Latino, Indigenous and Native American, Asian, Native Hawaiian and Other Pacific Islanders, and other persons of color, in clinical trials.”

REFERENCES 1. Cancer Statistics. National Cancer Institute Website. https://www.cancer. gov/about-cancer/understanding/statistics

Journal for Clinical Studies 11www.journalforclinicalstudies.com Watch Pages

6. Singh H, Pazdur R. Importing oncology trials from China: a bridge over troubled waters? Lancet Oncol. 2022;23(3):323-325. com/journals/lanonc/article/PIIS1470-2045(22)00071-7/fulltext#%20https://www.thelancet.

Ahead of the February 2022 ODAC meeting for the sintilimab BLA, Pazdur published a comment in The Lancet Oncology noting that at least 25 applications from China are in the drug development phases, planned to be submitted, or already under review.6 This veers from the agency’s initiative to increase diversity in clinical trials, which is attempting to address a “disproportionate disease burden” in underrepresented racial and ethnic populations “for certain diseases relative to their proportional representation in the general population.”

2. Decrease in Cancer Death Rates Infographic - Annual Report to the Nation. National Cancer Institute Website. https://seer.cancer.gov/report_to_ nation/infographics/mortality.html

Those of us who have dedicated our careers to medical and health sciences share a mission to improve the lives of people everywhere through the development of innovative vaccines and medicines. We recognise that to be our very best for patients, we cannot do it alone. We want to express our sincere appreciation to those who participate and conduct clinical trials and the advisory support we receive from patients, caregivers, their families, and healthcare professionals (HCPs) around the world. Through their guidance and participation, we are better at what we do. Simply put, thank you! Research and Development (R&D) teams have been notably increasing the levels of collaboration with patients, caregivers and advocacy organisations. These collaborations are front line to identifying ways to bridge the academics of clinical research with the day-to-day realities associated with clinical trial participation. As a result, clinical trials are more inclusive, incorporate innovative solutions to ease participation, reflect endpoints and outcomes data most relevant for patients and, as a result, accelerate the pace of developing new healthcare solutions. Patient centricity can be defined as ‘the commitment to listen and translate patient insights into actions that develop new healthcare solutions with meaningful outcomes, address unmet needs, and improve health-related quality of life’.1 Perhaps at no other time in history, has the need to work together with patient and healthcare communities been more important. These collaborations ideally begin in the early stages of scientific research and continue through all aspects of a medicine’s development.Thepandemic, economic, and geopolitical crises have established new norms and created new challenges for healthcare interactions, clinical trial participation, health related decision making and access. These dynamics have increased the need for personalised and shared decision making and accelerating the pace of innovation. It has also brought to light health disparities among traditionally underserved and diverse communities which need to be urgently solved.2,3 As such, understanding firsthand, the health-related experiences and priorities of patients, their loved ones, and caregivers – and collaborating with them and their communities – is essential. As an example, in 2021 alone, our4 collaborations with patients spanned over 100 patient advocacy organisations across 33 countries and their support helped inform and align 100% of our clinical development programs.4

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Additionally, collaborations informed endpoints and outcomes to help our researchers answer patients' most pressing questions related to health care options. Despite the adversity of the pandemic, research organisations that co-created study designs and logistical solutions continued to accelerate the development of health care solutions. Thanks to these partnerships, it was possible to improve the pace of study execution and enrollment compared to industry benchmarks despite the challenges.5Patientsand their stakeholders are key advisors to research teams and therefore it is imperative that industry listen and act. When it is made a priority, it is reasonable to see 100% of all ‘patient’ studies reflect designs that better integrate with real life. Innovation exists, and continues to evolve, so that easy to use remote and digital capabilities are systematically built into each trial. And industry should not stop there. Investments in the development of other innovations such as digital biomarkers hold the potential to integrate research into a participant’s daily life. This not only helps reduce logistical challenges but also helps enable data integrity, while ensuring data privacy and the advancement of science when access to a trial site may create undue burden, such as distance to travel. Building trust and access across all communities, is a priority. Listening to patients and their representatives6 have re-written ways of working across the industry and regulatory landscapes, to ensure the needs of diverse communities are understood long before studies are initiated. Early and proactive discussions with diverse, community-based advisors help better the understanding of local social determinants of health and unmet needs. Thanks to these insights, and the support of community stakeholders, it is possible to co-create, long term, meaningful solutions. Recognising the need to monitor progress, technology can now make it possible to track, in real-time, the patient diversity represented across studies. Prioritising inclusion, notably in all US clinical trials, leads to early and achievable diversity goals with more studies showing increased participation reflecting real world disease demographics. Of course, it is important for clinical trial participants, their caregivers, and sites to have a positive experience. Industry relies on feedback from surveys and benchmarks to improve how clinical trials are conducted and perceived.7 Knowing where we need to focus, provides a roadmap for improvement, and motivates us to do even better on patient's behalf. By committing to act for patients and having the partnership of patients and their stakeholders, we will continue to find new ways to expedite development of new medicines for those who are counting on Onceus. again, we say thank you.

Watch Pages

These important and diverse engagements identified the most pressing priorities for patients & investigator sites so that teams were able to implement effective study site centric solutions thus making clinical trials more inclusive and accessible for participation.

Thank you!

An Open Letter of Appreciation to Clincial Trial Participants, Patient Advisors, Caregivers and HealthCare Professionals

REFERENCES 1. Sanofi R&D definition of Patient Centricity 2. Deloitte, PhRMA Enhancing Clinical Trial Diversity; 2021

4. Sanofi patient informed development metrics 5. CMR 2022 6. Various Sanofi and Patient Group Advisory panels 7. 2021 CenterWatch Global Site Relationship Benchmark Survey Watch Pages

Victoria DiBiaso Victoria DiBiaso MPH BSc Nursing is the Head of Patient Informed Development & Health Value Translation at Sanofi. Based in Paris France, she heads a global team dedicated to collaborating with patient advocacy groups and their communities. This work informs broadly, the research and development programs across all key research and all development staged indications.

Engaging

Journal for Clinical Studies 13www.journalforclinicalstudies.com

review. Implementation

Kelly Simcox Kelly Simcox, BS, MA, is the Global Head of Clinical Operations at Sanofi. Based in US, she leads a global team working directly with investigative sites in >30 countries, bringing the country & site voice to the table to inform development programs across all therapeutic areas. Bombard, Y., Baker, G.R., Orlando, E. et al. patients to improve quality of care: a systematic Sci 13, 98 (2018).

Creating a Road Map for the Future

Waiting until after regulatory approval to create an IPD strategy puts companies at risk of missing opportunities to change or adapt processes that could prevent budget or deadline blowouts.

Implementing an IPD strategy early in clinical development can help determine important points along the drug development journey, including:

• The best global regulatory strategy for client and business Adoption of an Integrated Product Development Strategy will Reap Dividends

When leaders from different disciplines and departments are brought together to form a cross-functional team at the start, a road map encompassing all areas of drug development can be created.

Early

Almost all (98%) believe IPD is integral to their ability to innovate across research and development (R&D). Indeed, innovation is essential in an industry that has seen the price of bringing a drug from conception to market double in a decade –a journey that takes more than 10 years and costs almost $2.6 billion.1

By inviting input from all parties, companies develop a clearer understanding of potential pitfalls at each stage of development, as well as a multidisciplinary approach to finding solutions. This, in turn, means decision makers are not stuck in silos, where counter-intuitive steps can be taken without knowledge of what is happening outside their self-imposed walls, but have a clear picture of the broader development program. This enables activities and decisions to be conducted in parallel across different functions, thus improving efficiencies.

But while companies are clearly warming to the value of a crossfunctional approach that dismantles silos and promotes an agile and decisive response to myriad challenges, the data shows that most are starting their run too late. Only a third believe IPD should begin early in clinical development, while almost half (48%) believe IPD should start at Phase 3, or after they have received regulatory approval.

• Data required to address pharmacology, safety and toxicology further downstream

This is despite an overwhelming number of those already in the process of implementing IPD believing that the strategy will help them meet key milestones (96%) and to identify where therapies could be marketed earlier (94%).

The respondents work across a range of fields, at all sizes and stages of development, including biostatistics, clinical, regulatory affairs, patient safety, market access, medical affairs and CMC (chemistry, manufacturing and controls).

In a recent survey commissioned by Pharmalex and conducted by Censuswide, almost half of the 107 senior leaders from US pharmaceutical and biotechnology companies polled had already implemented an IPD program or were conducting a pilot. Another third expected to roll out an IPD program within the next year.

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By pushing the adoption of IPD later in the drug development phase, companies are making it harder to capitalise on those key areas, which represent potentially huge savings in both time and money.

• Compressing time to market • Increasing productivity • Delivering on innovation

With both the cost and time to bring a drug to market ballooning, the importance of an integrated product development (IPD) strategy is gaining traction. This multidisciplinary approach to drug development brings key stakeholders together, breaking down barriers to an efficient and cost-effective path to market. But while more organisations are adopting an IPD strategy, a recent industry survey found most aren’t doing so early enough. Frédéric Pailloux, Senior Director, Head of Integrated Product Development and Consulting at PharmaLex examines the IPD journey.

Biopharma companies are increasingly recognising the ability of a strong IPD strategy to transform drug development, inviting participation from internal and external stakeholders across different platforms for the greater good.

Unlike the long-established approach to drug development, which is phase driven with functions working in silos, IPD uses a holistic framework that integrates all functional teams, including clinical, regulatory and commercial.

Over the next 12 months, industry leaders say they plan to bolster their IPD strategies, with the development and implementation of target product profiles (TPPs) or end goals; improved management of timelines, costs and resources; and the creation of more detailed strategic and operational plans to underpin a robust IPD.

Those who have already invested in IPD and are starting to measure their returns believe the strategy will reap dividends in three key areas:

The response to COVID-19 demonstrated how quickly and effectively new drugs can be released. While the circumstances were exceptional – nothing mobilises forces like a global pandemic – companies that embrace transformational strategies in drug development can also reduce timelines and costs. Key to this is the early adoption of an integrated product development (IPD) strategy, a multidisciplinary approach designed to improve efficiencies from start to finish.

With the push for change needing to come from the top, leaders can help initiate a shift in entrenched culture by:

The earlier this holistic approach is adopted, the more likely the integral pieces will complete the puzzle – and bring life-changing therapies to those in need in the safest, most efficient and cost-effective way.

Similarly, an early understanding of the regulatory environment and how it might affect a drug’s development can provide a smoother path to approval.

Overcoming the Biggest Hurdle Industry leaders cited several obstacles to implementing IPD, including budget constraints and operational limitations.

Email: frederic.pailloux@pharmalex.com

It is also critical that functions associated with the end of the cycle, such as commercialisation, be brought into the planning room from the start of clinical development.

The incentive to work together as a team is also seen to be hindered by overly complex processes (32%), the inability to keep plans current as factors change (32%) and the lack of technology to collaborate (30%).

The TPP is critical to the strategy because it forms the foundation for all the steps needed to move a drug through development and requires input from internal and external stakeholders, including regulatory and market experts.

objectives, as well as meeting agency expectations

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Moreover, when the early adoption of an IPD strategy is closely aligned to business objectives, industry leaders can:

But what is seen as the biggest hurdle to an effective IPD strategy is the same across all organisation types, stages and sizes, with almost 40% identifying culture as the main impediment to transformational change.

• Designing processes that don’t require an extended or laboured chain of approvals

leaders should consider all functions and stakeholders when developing an IPD strategy to maximise the chances of a successful drug rollout and minimise waste and cost blowouts. An IPD strategy that is stage appropriate, with the right subject matter experts at hand at the right time, will be more adaptable and better equipped to deal with new challenges. For example, CMC is often overlooked as part of the strategy but a cross-functional model that involves CMC can help ensure adequate product supply and prevent bottlenecks at the launch stage.

• Encouraging early input from internal and external stakeholders, including investigators and patients

• Determine changes that will drive greater efficiency – this includes promoting more innovative clinical trial designs, as well as collaborative and integrated processes Bringing Everyone Along for the Ride

• Suitable countries for clinical trials from a regulatory standpoint, global data acceptance and clinical cost perspective

One way around this is to form strong partnerships with likeminded external organisations, an approach that more than half the respondents have already adopted.

• Creating a cross-functional team that can be assembled and disbanded based on deliverables

While it requires considerable commitment from leadership, it is clear an IPD strategy is a powerful tool for changing both culture and outcomes.Bydriving new ways of thinking, and encouraging the dismantling of silos, industry leaders can build a multidisciplinary framework for current and future challenges in drug development, helping to lower costs and improve the chances of commercial success.

Frédéric Pailloux Frédéric Pailloux, PharmD, Senior Director, Head of Integrated Product Development and Consulting, at PharmaLex. He has extensive experience in regulatory science and quality assurance, both within the pharmaceutical industry and as a consultant

When an organisation has traditionally operated in silos, with each department staking out its territory and fiercely defending it from perceived attacks on capability, accountability or performance, it is even harder to break down those walls.

While it will naturally evolve with the project, the earlier the TPP is incorporated into a company’s IPD program, the better equipped the multidisciplinary team will be in an increasingly competitive landscape. It provides important context for the drug’s position in the clinical setting, as well as the marketplace.

Those respondents already implementing an IPD strategy report a strong focus on team alignment, efforts supported by cross-functional technology infrastructure (62%) and the contribution of cross-functional teamsWhile(58%).most involve all the key departments that support a drug’s development, the degree to which certain functions are included in the multidisciplinary team depends on the company’s size and stage. Only about a third reported involving patient safety, medical affairs andIndustryCMC.

More than half the respondents already implementing IPD have identified commercial considerations as integral to the strategy, with 56% reporting that market access, pricing and reimbursement strategies were in scope. However, to be truly effective, commercial considerations need to be incorporated from the get-go. While even the best-case scenarios can fall short, and clinical trials can still fail, a comprehensive riskbenefit analysis provides companies with more surety for the return on their considerable investment.

• Empowering functional teams and the core program team, with each being positioned as the primary decision maker on specific deliverables

• Cultivating the sharing of information and ideas, to show that integration is not only beneficial to everyone but rewarding

While almost half of respondents say they plan to make their target product profiles (TPPs) a priority during the next 12 months, they should be identified early and referred to regularly.

• Align all stakeholders with the end goal – ensuring new therapies can be released without delays or budget over-runs and reducing duplication, such as repeated studies.

In pharmaceutical manufacturing, it is this concept of uncertainty, or Target Measurement Uncertainty, that allows the user to determine with a high probability (for example 95%) that the true value of the batch or sample is within a pre-specified quality range. So, if an analytical procedure is used to release a batch of a drug product and the specification limits are that it must fall within +-2mg, then the uncertainty associated with a result should be much smaller than the +-2mg in order to keep the risk acceptable. (See figure 1). In keeping with Six Sigma thinking, the rule of thumb is that TMU should not be greater than one sixth of the specifications of the product to reduce the risk of making a wrong decision.

Strict

The importance of this has been underscored by the International Organization for Standardization, which states in its standard AcceptanceZoneIndecisionZone IndecisionZoneZoneRejection ZoneRejection Results

Strict

But, as opposed to ICH-Q8 that starts with the target product profile (TPP) or the properties that a product and its related process should achieve, both ICH-Q2 and Q14 miss the central point that applies to all analytical procedures: defining what is a good fitfor-purpose measurement or reportable value. The fact that the actual aim of analytical procedure is not clearly defined causes misunderstanding and confusion about various concepts such as accuracy, linearity and range. Bayesian statistics and interpretation address these misunderstandings, helping to bridge the gaps that exist in these two guidelines.

Reportable

Uncertainty of Measurement

5% Strict

The ICH-Q2 (R1) describes the linearity of an analytical procedure as “its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample”.1 The idea is that by increasing the quantity or the potency, the result will be proportional to the increase. Trust in the result during routine use of a validated method is the concept of uncertainty of a measurement – a concept routed in Bayesian statistical theory.

Applying Bayesian statistics allows the user to take results obtained during the validation of the analytical procedure and predict the uncertainty around any future result.

The ICH-Q2 has stated that the objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose, yet it – as well as the ICH-Q14 – fails to clearly define the actual aim of analytical procedure, leading to misunderstanding and confusion. Bruno Boulanger, Ph.D., Global Head Statistics and Data Science at PharmaLex, discusses how Bayesian statistics and interpretation bridge the gaps in the guidelines.Inearly 2022, ICH released two important guidelines for comments: ICH-Q2 “Validation of Analytical Procedures” and ICH-Q14 “Analytical procedure development”, both of which are closely interconnected through the concept of the Analytical Target Profile (ATP), which is used to assess the quality of results generated by analytical methods. The ATP and ICH-Q14 are intentionally more aligned with the Quality-by-Design (QbD) ICH-Q8 document on process development, qualification and control. This introduces the concept of QbD applied to analytical procedures (AQbD).

= specifications for sample (e.g., lot) = the acceptance limits for the reportable values should be made “smaller”, to keep the risk acceptable (less than the 0.05 probability true value µ being outside specifications-> concept of guard bands or grey area or indecision zone A product measured with a reportable value inside the dotted blue range has at least (say) 95% probability to pass its specs.

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Going back to the concept of AQbD, elements of which are employed in the Q14, the point is to be sure that for any future test the product will be within specifications. However, what is missing from the Q14 and the Q2 guidelines is they don’t define what the specifications on the uncertainty should be in relation to the quality of the product, which means that the fit-for-purpose concept is not explicitly defined.

AcceptanceLowerLimit LimitAcceptanceUpper USP <1220>

BridgingRegulatory the Gaps in the Analytical Procedure with Bayesian Statistics

Figure

Decision Making Process with Speci cations 1

-12.5-15-10-7.5-5-2.502.557.51012.515

(%)ErrorRelative Concentration (1) ? ? ? ?

Because we’ll have to analyze an unknown sample! So its true concentration is unknown.

Journal for Clinical Studies 17www.journalforclinicalstudies.com Regulatory

The question for diagnostic tests is, how to determine the probability of an outcome (for example, does the patient have cancer

The objective of an analytical procedure is to be able to provide any reportable value close enough to any future unknown quantity (within a predefined range), with a high probability. Since ICH-Q2 is about validation of analytical procedures, it’s important to work with a known sample to try to determine the accuracy of a result (a combination of bias and precision). By applying Bayesian theory, the reviewer uses predictive distribution – the distribution of possible future values given the results observed in validation – to evaluate future uncertainty. As long as the uncertainty of future measurement is small in validation, assuming there is a definition of “small” in the TPP of the analytical target performance, the analytical procedure can be accepted. But this is missing in the ICH-Q2.

Perhaps the clearest example of measurement during the validation versus routine phases is with diagnostic products. Specifically, diagnostic tests deal with sensitivity and specificity and are important indicators of test accuracy. On one hand, sensitivity is the proportion of true positives versus false negatives in tests of patients with a given condition, while on the other, specificity is the percentage of true negatives versus false positives of all subjects who do not have the condition.

Figure 2 Figure 3

0 100 200 300 400 500 600 700 800

The issue is different when moving to the routine, where use of a validated analytical procedure requires trust in the measurement – unless there is some evidence showing a problem occurred during the analytical procedure when generating that reportable value. Therefore, the only way to trust a result during the routine phase on an unknown sample is by referring to the analytical procedure and its performance, as assessed during the validation.

(%)ErrorRelative Concentration (1) Why is it mandatory to go through the TMU?

Diagnostics and Drug Products in Validation and Routine

ISO 21748: “Without quantitative assessments of uncertainty, it is impossible to decide whether observed differences between results reflect more than experimental variability, whether test items comply with specifications, or whether laws based on limits have been broken. Without information on uncertainty, there is a risk of misinterpretation of results.”2

So given its concentration is unknown, its intrinsic uncertainty is unkown.

0 100 200 300 400 500 600 700 800 -12.5-15-10-7.5-5-2.502.557.51012.515

Regulatory

The yes/no measurement scenario, which is standard in diagnostics, gives the reviewer all the reportable values (Xi) given the sample is positive. In routine, the reviewer needs to determine where, with high probability, the true unknown content of the sample will be, given there is one measurement. A decision needs to be made for each reportable value. Through the Bayesian theory of uncertainty in measurement, reviewers can determine the distribution of the unknown true value with 95% reliability.

Returning to pharmaceutical manufacturing, an analytical procedure could be used for the release of a batch of drug product based on its potency or concentration, to assess the stability of batches, to evaluate the dissolution of tablets, and so on – all with the purpose of supporting low-risk decision-making about the batch. The specifications applied to any reportable value will be directly derived from the specifications of the product or the test as defined in the TPP. First, though, it is important to define the target measurement uncertainty or greatest uncertainty allowed over an intended range of true values to be covered in the future. During the validation, it’s necessary to characterise the uncertainty based on different levels of concentration. However, given unknown samples will be used during routine, the bias, precision and uncertainty will also be unknown.Figures 2 and 3 shows a range between 40 and 800. The reviewer may have a sample at a concentration of 600, but if they have never carried out validation at 600 they don’t know what the uncertainty is. What they do know is that between specified concentrations measured during validation – in this example between 40 and 800 – there is a high probability that the sample is within the target measurement uncertainty (the two black horizontal lines in figures 2 and 3). It is only the TMU that allows the reviewer to know the risk made during a decision in the routine. So, using Bayesian statistics, the reviewer can say given the result during validation using the known sample, it is possible to predict over a range the probability that a future unknown sample will be within the TMU.

1. Validation of Analytical Procedures: Text and Methodology, June 2-r1-validation-analytical-procedures-text-methodology-step-5_en.pdfhttps://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1995, 2. Guidance for the use of repeatability, reproducibility and trueness estimates in measurement uncertainty evaluation, ISO, 2017, https://www. iso.org/standard/71615.html

Bruno Boulanger Bruno Boulanger, Ph.D., is Global Head Statistics and Data Science at PharmaLex, where he draws on his many years of experience in several areas of pharmaceutical research and industry including discovery, toxicology, CMC and early clinical phases. Bruno has authored or co-authored more than 100 publications in applied statistics. He organizes and contributes to Non-Clinical Statistics in Europe and, in 2010, set up the First Applied Bayesian Biostatistics conference. or not) given the result is positive. During the validation phase, the result is based on the known sample, while in the routine it is inverted to ask what is the probability of the sample being truly positive given the positive result? This inversion is built on Bayesian theory. During validation, therefore, the sensitivity and specificity of the device is tested to demonstrate its performance, while during routine, the manufacturer needs to prove what is called the predictive positive value (PPV) and negative predictive value (NPV).

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REFERENCES

The ICH-Q2 asks manufacturers to prove that different concentration levels work, but does not show how that is feasible with unknown future samples. Using Bayesian theory and given the result from the validation of the known sample it is possible to say, with a probability of more than 95%, that it will be within the TMU. The target measurement uncertainty should be the objective of Q14 and by defining the TMU, or the quality of the measurement in future, it is possible to connect the objectives of the ICH-Q2 and Q14, which ultimately should be to support decision-making about capability of an analytical procedure to provide reliable results. Unfortunately, ICH-Q14 uses the wording Total Analytical Error instead of Uncertainty because errors during validation with known samples are still confused with future uncertainty of a measurement about an unknown sample. Using Bayesian statistics helps to make thisBayesianlink. theory helps to bridge the gaps and address the questions posed by many regulations and guidelines, including the ICH-Q2 and Q14. Among the problems it helps to solve are ensuring reportable values can be routinely trusted given the validation results and helping to define the TMU and be confident it can be achieved in future results. Certainly, in the case of validation of analytical procedures and ICH-Q14 analytical procedure development Bayesian is the best way to address the gaps in understanding and reduce risk in decision making.

Journal for Clinical Studies 19www.journalforclinicalstudies.com Qualifications & Validations Multilayer thermal blanket for PMC ULD Euro and Block pallets Temax 4000 blanket with integrated 4x multiple reflection technique Stress tested in summer (+46°C) and winter ( 15°C) profiles Tarmac tested on solar power and greenhouse effects Ecological notes Recyclable + Low ecological footprint NON laminated composition = easy to dismantle Re manufacturing of recycled compounds Development and manufacturing Thermal Blankets for the temperature protection of pharmaceuticals and healthcare products in airfreight (+15°C +25°C) and (+2°C +30°C) Worldwide available at freight forwarder s KRAUTZ - TEMAX Group Development and WebsitePhoneBelgiummanufacturingEurope+3211.26.24.20www.krautz.orgEmailinfo@krautz.org Temax Americas LTD Hanover park Illinois USA ISO 9001:2015 certified

IP insurance provides cover for claims alleging infringement of IP rights, including patents, trademarks, copyright and trade secrets. It can also provide cover for contractual indemnities, the enforcement of IP rights and the costs associated with loss of IP rights or loss of profits. The insurance will only cover claims which the insured was not aware of at inception.

• Loss of IP right cover • Loss of future profit

Businesses are also investing more in intellectual property – like research and development, software, branding and design – than they are in physical assets, creating more value in IP.

Defence of Patent and IP Infringement

• Contractual indemnities cover • Pursuit of infringers

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How does IP insurance work?

Intellectual property is an intangible business asset that often helps set companies apart from their competitors. Unfortunately, few businesses know precisely what their IP is worth, or how to protect it. Let’s step into the world of IP and explore the risks that you could be facing – and how you can build resilience for your business. This guide is put together in collaboration with CFC Underwriting, a leading provider of insurance solutions for life science and technology companies. What is intellectual property? Intellectual property (IP) is a broad term used to describe the legal rights arising out of intangible creations and assets, such as a product or process, a piece of software, a brand or even a customer database.

SMEs may also find themselves targeted by large competitors who want to prevent competition and who have more established IP portfolios because of their size and age. IP can present a classic David versus Goliath scenario, and without sufficient resources, the smaller organization can face more dire consequences.

Covering a wide range of areas from inventions and algorithms to products, manuscripts and design including a name, image, symbol or logo, intellectual property rights allow the original creator to apply for legal protection of their IP in the form of a patent, copyright or trademark. Intangible assets, including IP, now make up to anywhere from 70 to 80 percent of a typical company’s balance sheet.1

The cost of simply defending a claim can be significant for a small business even if they believe they are not infringing.

• Patent and IP infringement liability

Typical IP insurance policies include:

It’s not just Large Organisations that Need to Worry About IP Risks

Contractual Indemnity For many companies, their main exposure arises out of their obligations under contracts, typically with customers or licensees. For instance, a supplier's customer may insist that the supplier warrants that the product does not infringe on IP rights, otherwise the customer will refuse to buy the product. Ideally, the supplier should negotiate to minimise this contractual risk, but the balance of power between the parties may not allow for such negotiation, and in some sectors it is more or less standard to provide non-infringement indemnities. IP

A claim of IP infringement can have a devastating impact on a firm’s finances and reputation. Protecting your business with IP insurance can help fund legal action against an infringer or defend a patent’s validity. Simply having IP insurance in place can be a powerful deterrent to any potential infringer.

UnderstandingRegulatory How Intellectual Property Insurance Can Protect Your Business

This part of the policy will cover the costs of defending against allegations of infringement by a third party and can also cover the out of court settlements, or damages awarded by a court, as a result of the claim. Defence costs are often substantial due to the complexity of IP litigation and expertise required by lawyers. Aside from infringement allegations, the defence cover can also include claims of entitlement by employees and certain elements of contract breach arising out of IP. Directors and officers are also automatically included should a claim involve both the company and the director.

Understanding IP Risk

Smaller businesses can present an easy target for IP infringement claims because they lack the resources to properly address or defend them. Many SMEs could struggle to survive an IP dispute.

• Let’s explore these in more detail.

The biggest IP exposure a small or medium-sized enterprise (SME) will often face is a claim of infringement by another company, rather than a direct threat to their own IP. Many businesses assume they’re immune to this risk because they hold some form of IP rights (i.e., a patent, copyright or trademark) or because they simply don’t understand what constitutes infringement. Infringement can arise out of a business activity – i.e. the import, sale or manufacture of a product – or the delivery of a service. It doesn’t matter whether a business holds IP rights or not. Holding a patent, copyright or trademark doesn’t protect a business from infringing on someone else’s IP. Given the volume of IP rights in existence, it’s nearly impossible to guarantee that a company isn’t infringing on someone else's IP. IP rights also often overlap, and patents rarely cover an entire product. For example, a business may think that it holds the IP rights for a pen, but may lack the rights to the cap, the ink or the spring. Intellectual property is highly relevant to companies of all sizes and in all industries.

Consider what would happen should your business face an injunction preventing you from selling your product? Or if you were required to pay significant damage or royalties to the rights holder?

The renewable energy company had purchased an IP insurance policy with pursuit coverage included from CFC. This pursuit coverage provided legal costs cover for any costs incurred enforcing intellectual property rights against third-party infringers.

Not only did the company save money on their pursuit action, but they secured a future revenue stream having had access to quality legal representation at a competitive price with the support of an experienced claims team who were able handle the claim on the insured’s behalf saving many hours of their management’s time.

The company worked with CFC’s claims handlers to appoint a suitable legal representative in a timely manner. Initially they considered using an IP lawyer they had used previously, however CFC’s claims team were able to recommend three additional law firms to ensure the company had the best legal representation. The company selected one of the recommended law firms because they had the most extensive experience in handling patent infringement disputes in the US, despite the company operating in the UK.

IP Insurance in Action – A Aase Study Renewable energy company pursues competitor’s patent infringement

Regulatory insurance will cover the insured if a claim is made against them, but also if a claim is made against their customer, or further down the line of contracts if it is a complex supply chain. This section can insure a single contract exposure or a number of contracts and exposures. It is particularly relevant for companies operating in traditional supply chains (e.g. automotive).

and development is very important for the company’s business model and their innovations are protected by registering patents in territories worldwide. This strategy provides the company with exclusive rights to their proprietary technologies. They commercialise their technologies by manufacturing products containing the technologies themselves, as well as licensing a small number of their patents to third party partners better positioned to commercialise the technology.

The cost of using the legal representative was negotiated and monitored by CFC’s claims team throughout the process. This service was a benefit to the company because it improved the value for money of the legal representative’s work and the company’s IP insurance claims history was in a healthier position going

While defence cover will typically cover historical damages or settlements arising out of a covered claim, this clause provides cover for the loss that may be incurred after final disposition, for example, if the company is prevented from selling a product due to the infringement.

Theforward.legalrepresentative was able to undertake a preliminary assessment of the competitor’s product and the technologies protected by the company’s patent. The costs of the investigation were £3,500 which was paid by the insured but eroded their £10,000 policyBetweendeductible.thelegal representative and CFC’s claims team it was successfully established that: 1. Patent infringement was likely to be occurring 2. There were good prospects of success pursuing the competitor 3. The infringement was likely to be causing lost revenues for the insured so enforcing their patent against the third party was commercially proportionate.

The CFC claims team approved legal representative’s legal expenses to communicate and negotiate with the third-party infringer.After issuing a cease-and-desist communication, followed by subsequent correspondence to outline the company’s intention to issue proceedings, the competitor agreed to negotiate a license agreement with them. The terms of the license agreement firstly required a compensatory payment of £50,000 to reflect extent of infringement to date and it also required ongoing royalty payments to the company on all future sales of the heating device.

The legal costs for the case amounted to £125,000 which was the least the energy company would have had to pay if they did not have IP insurance. Instead, the energy company paid £33,000 and the insurer paid the remainder of the fees.

This section covers the enforcement of intellectual property that is owned by or licensed to the insured, as long as the claim has reasonable prospects of success and is commercially justified. This includes the legal costs of negotiating with the alleged infringer or taking court action, as well as the costs of defending a counterclaim if the infringer claims that the right should not be valid. If an infringer alleges that the insured is actually infringing on their rights, then this type of linked claim may also be covered by the insurance.

A small UK domiciled renewable energy company develops and sells energy saving devices for use in renewable energy enabled housing. These devices incorporate machine learning to capture and assess data which provides the most effective heating programmes all year round. The company’s routes to market include distribution via energy consultants and direct marketing to large landowners. Their goal is to incorporate their products into new build projects globally.Research

IP Insurance and M&A Mergers and acquisitions activity (M&A) can involve a buyer acquiring an entire business or simply the acquisition of specific assets. In both cases, M&A will have implications relating to IP. IP will often play a significant role in an acquisition, as for many businesses much of their value lies in their IP which is what makes themWhenunique.an acquisition takes place, the buyer will obtain representations (reps) and warranties from the seller regarding the

Pursuit of Infringers

Loss of Future Profit

The £50,000 settlement received was also split between the company and insurers, with the energy company retaining £10,000 and the insurer receiving £40,000. This meant the total outgoings for the company during this case were just £23,000, all for the successful resolution of the infringement of their patent.

www.journalforclinicalstudies.com

Journal for Clinical Studies 21

Loss of IP Rights

If the insured’s registered right is invalidated as a result of a covered infringement claim, then the policy can cover the costs that the insured incurred in registering and maintaining the right up until the point that it was invalidated.

The company, insured with CFC, became aware of a competitor selling a household heating kit in the US. They believed this product was likely to be infringing one of their US patents.

In many cases, IP insurance can act as a deal facilitator by helping the buyer avoid protracted IP reps and warranty negotiations, or by acting as a bid differentiator at auction.

Hanna Beaumont Hanna is an expert in commercial insurance for science and technology firms and is a fellow of the Institute of Risk Management. She has worked with a huge range of inspiring businesses to support their growth and development, from helping ground-breaking start-ups to advising long-standing clients as they expand internationally and encounter new risks.

The IP protection under R&W insurance can vary depending on the scope of the IP reps and warranties in the acquisition agreement. For instance, the relevant IP reps and warranties may include knowledge qualifications (i.e. may be subject to seller awareness) and will likely be historic or ‘retro’ in nature.

On the other hand, IP insurance is designed to cover the legal expenses and damages arising from any allegations of infringement, both historic and prospective, regardless of seller awareness.

REFERENCES 1. intangible-asset-businesswww.businessweekly.co.uk/blog/business-weekly-guest-blog/rise-

In most cases, these reps and warranties will include statements in relation to the target company’s IP. It is common for the seller to represent and warrant that the operation of the target business does not infringe, misappropriate, or violate any other party's IP rights; that no other party is infringing, misappropriating, or violating the target’s IP rights; and that there is no litigation or claims covering any of the foregoing that is pending or threatened.

22 Journal for Clinical Studies Volume 14 Issue 3 Regulatory

Email: hanna.beaumont@partnersand.com assets being acquired. This is primarily a means of risk allocation, providing the basis for which they can recover damages if those reps and warranties are false. Frequently buyers will purchase R&W insurance to protect themselves against financial loss resulting from breaches of the reps and warranties.

In Summary Apart from helping protect what you already own, intellectual property insurance can also help your business grow. Allowing you to licence your idea to others can make your business attractive to potential investors, knowing your invention or unique idea can’t be stolen by someone else. Intellectual property insurance is key to supporting your business when defending itself against claims of IP infringement and can help you pursue those who are infringing on your patent, copyright or trademark.

With this in mind, IP insurance can be an invaluable tool for a buyer in establishing or enhancing protection against IP associated risk during M&A transactions as the policy will cover infringement allegations that would not be otherwise covered by R&W insurance. It is also provides peace of mind that any IP infringement allegations relating to the target’s new business activities will be covered going forward.

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Journal for Clinical Studies 23www.journalforclinicalstudies.com

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One of the best ways to ensure that a sponsor’s clinical and commercial programs reflect how patients experience a disease or a treatment is to interview patients directly over time. This practice – longitudinal qualitative research – is an emerging science that can guide development efforts as well as inform communication strategies for treatments in any therapy area. Here, Sally Lanar and Alexia Marrel of ICON plc, outline what longitudinal qualitative research is, when and how it can be used and the key factors for success when using this type of research.

• Documenting the impact of a potential therapy from a patient perspective

The qualitative data gathered via patient interviews can be valuable in any therapeutic area but are particularly useful in studies of rare diseases, chronic diseases, and surgical interventions. Possible objectives of such research include:

Longitudinal Qualitative Research –Capturing the Patient Voice; Enhancing Patient Centricity

• The natural history of the disease is poorly known or not welldescribed in the literature

The benefits are compelling, so how best to go about designing such studies? These must be designed carefully to produce clear and replicable results, the data must be analysed according to scientifically valid methods, and the findings must be communicated in a way that gives voice to patient views.

A Maturing Field of Research

• Evaluating patient/physician relationships over time

When to Use

First and foremost, what is longitudinal qualitative research? Put simply, this research is conducted through interviews with patients at various time points during their study participation. The interviews should be conducted by qualified interviewers who have been trained in how to establish rapport with a patient, how to remain objective while eliciting feedback, and how to follow an interview guide and adapt it as needed to the patient. This research is important in clinical development for two reasons. Firstly, the life sciences industry is committed to taking a patient-centric view of clinical development. Secondly, qualitative research methodologies have matured. Interviewing patients in clinical trials is a valid approach to understanding the patient perspective of a disease or treatment, providing context for explaining and interpreting quantitative clinical data, and informing future outcome assessment strategies and trials.1

24 Journal for Clinical Studies Volume 14 Issue 3 Research & Development

• Regulators are likely to challenge the clinical meaningfulness of the magnitude of change or difference

Qualitative longitudinal research does just that – it uncovers how patients experience healthcare over time, providing the context and details needed to understand and assess meaningful change in their condition. This includes capturing the critical moments patients go through that cannot be captured by quantitative patient reported outcomes (PROs).3 The research can be applied to:

The practice is in line with the US Food and Drug Administration recent guidance that recommends interviewing patients enrolled in clinical trials at screening and at exit in order to assess change over time.2

• Studying complex phenomena in rare diseases, for example the onset and duration of symptoms when this is not described in the literature

• A small patient sample and lack of valid, specific Clinical Outcomes Assessment measures will limit benefit/risk assessment and value communication

The approach has the advantage of giving a much fuller picture of the patient experience than a single interview conducted at one point in time. Holding multiple interviews also avoids the recall bias that can be present in exit interviews. The depth and frequency of the conversations yield granular data that can offer an extremely vivid picture from a relatively small sample of patients.

• Insights will be sought on clinical parameters not measured in a trial (such as the onset of action or duration of therapy)

• It will be important to develop strategies to promote adherence to the therapy Designing Qualitative Studies

The research question and a clear vision of how the data will be collected and analysed should guide the study design. Once the purpose is clearly defined, the next step is to develop the interview guide which calls for the experience of a qualitative research scientist to ensure that the questions will elicit meaningful answers. The interview guide should be the same for all patients for the first interview, as it will set the foundation for further assessments and serve as a baseline in following the patient journey. Then, for subsequent interviews, the interview guide can either continue to be the same for all patients, or it can be customised for each patient based on the results of the baseline interviews. In either case, there should be sufficient flexibility in the protocol design to allow for openness in the interview – as directed by a trained and skilled interviewer. The frequency and timing of interviews could either align with the time points for collecting patient-reported outcomes (PRO) in the trial, or synchronise with the timing of expected effects of the Longitudinaltherapy.qualitative research can be performed as a standalone study, or it can occur within a quantitative study in conjunction with the collection of clinical data, for example within a clinical trial or an observational (natural history) study. In the latter case, the results can be triangulated with the clinical data.3

• Lanar, S. and Marrel, A. (8Feb2022) Webinar: Qualitative longitudinal research in patient-centred research - a powerful tool for understanding the patient experience. ICONplc.com/LQR-webinar

• Enlist the advice and involvement of experts as neededqualitative research scientists, trained interviewers, and professional communicators.

Sally Lanar Sally has over five years of experience in patient-centred outcomes. Her expertise is in longitudinal qualitative research, qualitative research embedded in clinical trials, and the use of qualitative analysis software. She has worked on six projects with longitudinal interviews embedded in clinical trials. For each project, she has developed tailored approaches to interview guide development, interview conduct and interview analysis. She has conducted longitudinal interviews herself and led interview teams and analysis teams in this field.

The richness of the data gathered requires that sponsors have a distinct plan for how it will be analysed – a decision that must be founded in an understanding of the types of analyses available and what each entails and generates. There are three types of analyses commonly used with qualitative longitudinal data.

RESOURCES

Journal for Clinical Studies 25www.journalforclinicalstudies.com Research & Development

2. Domain-level analyses: These look at change in concepts within a theme, most often a domain of health-related quality of life.3 This type of analysis still examines the results for one patient at a time. However, change over time can be examined between two time points or across multiple time points.

• Share the findings to increase the body of best practices in this emerging field.

Key Success Factors The design of these type of research studies and methods of data analysis are key components to be considered. When determining these, we recommend that a number of basic principles are followed to ensure that the research yields valid insights:

3. Group-level analyses: These aggregate results for all patients in the study as a whole and are therefore the most macro, or abstract, level of analyses. They are designed to answer the “big picture” questions about the most prominent and meaningful changes for all the patients in the course of the entire study.3

Determining the best analytical strategy is a matter of working backwards from what data is needed and how best to report that data. Will it be most useful to describe the change in particular symptoms or in broader domains of quality of life? Or, is the goal to understand and relay what matters most to patients collectively? Usefully, the three types of analyses are not mutually exclusive and the same dataset can be used to tell all three types of stories – provided that the right data was collected. Collecting the most specific, micro-level data through a patient-specific follow-up interview allows for this type of analytical and storytelling flexibility.

• Remember that the results are subjective by design. Find creative, narrative and visual ways to communicate the results so that the patient voice is evident.

2. Patient-Focused Drug Development: Methods to Identify What Is Important to Patients,” US Food & Drug Administration, Feb. 2022.

Alexia Marrel Alexia has over 15 years of experience, with significant expertise in the management of international projects in the field of patientcentred outcomes. At ICON plc, she is responsible for the direction of patient reported outcomes (PRO) projects and proposals, with specialised interest in qualitative research, specifically in patient interviews within clinical trials, also known as mixed methods research. This work covers a wide range of disease areas, including several rare diseases. Alexia has also co-authored a number of manuscripts published in peerreviewed journals, as well as delivered presentations at international scientific conferences.

1. Concept-level analyses: The most micro level of analysis looks at a concept, such as a symptom or an impact on the patient, over time. The goal of a concept-level analysis is to evaluate change between two points in time, for one concept at a time, for one patient at a time.

• Keep the end goal in mind when developing the interview guide. The type of data collected will determine both the type of analysis that is possible and the scope and richness of the findings.

• Think critically about the analysis so that the process will be clear, precise, and replicable. Anticipate how the data will be managed, given that it will be voluminous. Analysts must be trained on the concepts of the study and be monitored over the course of the project.

Conclusion – An Important Role to Incorporate the Patient Voice into Clinical Trials Direct interaction with patients to elicit their thoughts can significantly enhance patient centricity in clinical trials. For those life sciences companies striving to increasingly incorporate the patient voice in their development programs, evidence dossiers, and commercial messaging platforms, longitudinal qualitative research can be an important tool in helping the voice of the patient really come to the fore.

Strategies for Data Analysis

3. Shah, N., Delforge, M., San-Miguel, J., Moshkovich, O., Braverman, J., Dhanda, D.S., Lanar, S., Miera, M., Williams, A., Murphy, R. and Devlen, J., 2022. Patient experience before and after treatment with idecabtagene vicleucel (ide-cel, bb2121): qualitative analysis of patient interviews in the KarMMa trial. Leukemia Research, p.106921.

1. Shah, N., Delforge, M., San-Miguel, J., Moshkovich, O., Braverman, J., Dhanda, D.S., Lanar, S., Miera, M., Williams, A., Murphy, R. and Devlen, J., 2022. Patient experience before and after treatment with idecabtagene vicleucel (ide-cel, bb2121): qualitative analysis of patient interviews in the KarMMa trial. Leukemia Research, p.106921.

REFERENCES

• Lanar, S. and Marrel, A. (2022) “Using longitudinal qualitative research to capture the patient voice – methods for collecting, analysing, and reporting patients’ perceptions of change over time”. ICONplc.com/LQR

In recent years, there has been an upsurge in the number of (bio) pharmaceutical products under development globally, reaching an estimated 7,471 products in 2021, which represents a 2.3fold increase compared to 2017 (Figure 1). This unprecedented expansion in the pipeline of innovative therapeutics and vaccines across a broad spectrum of diseases has in turn increased the number of clinical trials. During the same period, the number of industry-sponsored studies increased by 56%, from 6,307 to 9,870 clinical trials (Figure 2). The number of trial participants has also increased, with over four million healthy subjects and patients in COVID-19 and non-COVID-19 studies in 2020 due to the impact of the pandemic (Figure 3).1 A fundamental factor that underpins the successful execution of clinical trials is site quality, and delays in, or the failure of, trial participant enrolment represent significant risks in product development. Therefore, a critical success criterion of clinical trials is the selection of sites with the requisite capabilities: access to a wellcharacterised population of potential trial participants, experienced and well-motivated investigators and study staff, and adequate site

Clinical Trial Feasibility in a Changing World: Current Trends and Prospects

26 Journal for Clinical Studies Volume 14 Issue 3

To assess the contribution of recruitment failure to the global toll of clinical trial termination, we analysed global trends over five years from January 1, 2017 to January 1, 2022 by evaluating all terminated interventional Phase 1, 2, and 3 and industry-sponsored studies posted on ClinicalTrials.gov. A total of 1,156 studies were included. The results outlined in Figure 4 and Table 1 show that a majority (42%) of clinical trials over the last five years were terminated due to business or strategic decisions. Furthermore, recruitment delays accounted for 22% of trial terminations globally over the previous five years. Other causes of trial termination were lack of efficacy of the intervention (10%), safety (8%), failure to meet the primary endpoint (8%), futility (3%), COVID-19 related reasons (2%) or FDA request (2%). Less common reasons for early trial termination include Data Safety Monitoring Board (DSMB) and Independent Data Monitoring Committee (IDMC) recommendations, investigational medicinal product (IMP) issues, poor pharmacokinetic (PK) data, principal investigator (PI) exit, or no reason was specified.

Figure 1 – Number of medicinal products under development from discovery to preregistration Figure 2 – Number of industry-sponsored clinical trials over time

Research

Recruitment Failure: A Critical Risk to Clinical Trials Globally Premature termination is a common phenomenon in the clinical trial landscape. For example, approximately 40% of clinical trials in oncology are terminated prematurely.2 Other authors have estimated that up to 23% of trials cannot follow their patient recruitment as initially planned and fail the study timeline, and about 13% of clinical trial sites do not enrol a single patient in the study.3 Recruitment failure can seriously impact the product innovation lifecycle, with significant implications in terms of research costs, corporate revenues and delays in access to life-saving innovations.

Figure 4 – Aetiology of clinical trial termination: A global view, 2017–2022 facilities, all located within countries with a favourable regulatory environment.Inthisarticle, we summarise the pitfalls associated with current methodologies of clinical trial feasibility and highlight how SGS Health Science's data-driven and multidisciplinary clinical trial feasibility approach supports many trial sponsors in optimising trial planning across various therapeutic indications.

Figure 3 – Number of clinical trial participants over time

& Development

In recent years, attention has focused on a deeper understanding of the data sources that are critical to increasing the accuracy of trial enrolment planning and risk management. The increasing availability and use of digital real-world data (RWD), including electronic health records (EHRs) and insurance claims, has facilitated the application of advanced analytical tools to identify eligible populations and subpopulations of patients with clinical indications of interest.4 Newer statistical and machine learning algorithms are being deployed to derive even greater insights from existing data.

Journal for Clinical Studies 27www.journalforclinicalstudies.com Research & Development Figure 5 – Workflow of feasibility assessment, SGS Health Science Table 1: Aetiology of clinical trial termination: A global view, 2017–2022 Reason For Trial Termination Number Of Trials % Business/Strategic Decision 489 42.3 Delayed Recruitment 253 21.9 Lack Of Efficacy 113 9.8 Primary Endpoint Not Met 94 8.1 Safety 91 7.9 Futility 34 2.9 COVID- 19 25 2.2 FDA Request 17 1.5 IDMC Recommendation 13 1.1 IMP Issues 11 1 No Reason Given 8 0.7 PI Exit 5 0.4 Poor PK Data 2 0.2 DSMB Recommendation 1 0.1 Total 1,156 100

Many trials sponsors in the (bio)pharmaceutical industry experience delays in clinical trial completion mainly because their enrolment plans are based on poorly validated information. In many instances, the enrolment rate needed for developing the country/site/patient analysis and subject accrual duration is extrapolated from either raw data from databases without in-depth analysis or directly from site feasibility surveys. However, this linear approach omits several critical components vital for an accurate trial feasibility workflow. Using pharmaceutical intelligence databases without further investigation or heavy reliance on trial investigators’ selfassessment of recruitment capacity may result in overly optimistic enrolment estimations. Furthermore, in a recent publication that explored clinicians’ perspectives on the persistence of barriers to patient enrolment in Phase 3 oncology studies, some trial investigators considered the completion of site feasibility questionnaires as a very time-consuming activity, often without any guarantee of eventually participating in the study,5 highlighting the critical role of questionnaire design in the feasibility process.

The integration of data-driven analytics and decision-making into the clinical trial feasibility planning process can help maximise the enrolment potential of clinical trials and mitigate the risks of premature termination. Furthermore, the operational efficiencies gained by optimising the feasibility planning process at the trial or portfolio level may potentially reduce drug development costs.

A Data-driven Approach to Clinical Trial Feasibility Planning

UMIN-CTR into feasibility planning, combined with well-curated epidemiology and market size information, supports holistic strategic and business decision-making.

The workflow of data-driven clinical trial feasibility at SGS Health Science is outlined in Figure 5. The start of the feasibility planning process is based on the receipt of a request for proposal (RFP) from a sponsor. The protocol-related information is reviewed by crucial internal departments, resulting in identifying potential recruitment obstacles, an initial, high-level selection of suitable regions/countries and a first estimation of the anticipated recruitment rate. The overall process is managed by a dedicated feasibility team and supported by medicalFurthermore,staff.

a second feasibility evaluation is performed that incorporates critical details like the targeted indications, trial design, subjects’ inclusion and exclusion criteria, study assessments, type of investigational medical product, and estimated start and end dates, which are subjected to inhouse intelligence and benchmarking analyses incorporating proprietary and publicly available databases as well as relevant published scientific literature. The output is cross-referenced with information collected directly from sites. The result is a detailed clinical trial feasibility assessment report tailored to the sponsor's needs that optimises trial efficiency and minimises the risks of recruitment failure.

SGS Health Science: Delivering Data-driven Clinical Trial Feasibility

Furthermore, incorporating data from clinical trial registries like ClinicalTrials.gov, the EU Clinical Trials Register and Japan

Email: healthscience@sgs.com

The author acknowledges the contribution of SGS colleagues in the manuscript: Dr. Arash Ghalamkarpour, Associate Medical Director; Elke De Rijck, Global Feasibility Manager; and Barbara Buls, Executive Manager Clinical Operations.

28 Journal for Clinical Studies Volume 14 Issue 3 Research & Development

REFERENCES

With the increasing availability of large, patient-level datasets on electronic platforms, a more significant role for artificial intelligence and deep learning algorithms in the feasibility planning process is anticipated.6 New sources of information on disease incidence, such as social media, are likely to play increasing roles in patient recruitment. Furthermore, as trials become larger and more globally distributed, regional data privacy laws like the European Union (EU) General Data Protection Regulation (GDPR) will become increasingly relevant when it comes to assessing trial feasibility.

4. Inan, O.T., Tenaerts, P., Prindiville, S.A. et al. Digitizing clinical trials. npj Digit. Med. 3, 101 (2020). https://doi.org/10.1038/s41746-0200302-y.

1. GlobalData Plc 2022; John Carpenter House, John Carpenter Street, London, EC4Y 0AN, UK. Registered in England No. 03925319; https://pharma.globaldata.com; Access 25 April 2022.

6. Artificial Intelligence for Clinical Trial Design - ScienceDirect. (n.d.). Retrieved April 4, 2022, from science/article/pii/S0165614719301300.https://www.sciencedirect.com/

Acknowledgement

There is increasing recognition of the central role of data-driven feasibility in (bio)pharmaceutical product development. Improving efficiencies in targeted feasibility support that meets the innovation cycle needs of evolving personalised and precision medical products represents a critical priority for clinical research organisations. The response of competent authorities to the COVID-19 pandemic – shortening review timelines and providing novel, accelerated pathways – exemplifies the need for adaptation to the emerging patient and public health priorities. Feasibility plans will need constant updating to keep up with these trends.

5. Barriers to patient enrolment in phase III cancer clinical trials: interviews with clinicians and pharmaceutical industry representatives - PMC. (n.d.). Retrieved April 3, 2022, from https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC8860011.

Clinical Trial Feasibility: Future Directions

Dr. Olawale Salami, Head of Project Management and Feasibility at SGS Health Science, is an experienced physician. His post-doctoral research at the University of Lausanne, Switzerland, focused on the impact of lung microbiota on respiratory infections and drug development in chronic lung diseases. Over the last 10 years, Dr. Salami has worked on phase one to phase four studies on a variety of therapeutic areas in adults and children.

Dr. Olawale Salami

2. Stensland KD, McBride RB, Latif A, et al.: Adult cancer clinical trials that fail to complete: An epidemic? J Natl Cancer Inst 106:dju229, 2014.

3. Tufts Center for the Study of Drug Development; Impact Report January/February 2020, Vol. 22, No. 1 (csdd.tufts.edu); published on 28 Jan 2020.

Journal for Clinical Studies 29www.journalforclinicalstudies.com CPHI Frankfurt is back, Autumn!this Don’t miss your chance to meet the entire pharma supply chain in the heart of Europe. Register now and join Connect to Frankfurt, online on 28th September, to get a head start on making Thenconnections.joinusin Frankfurt on 1-3 November for 3 days of in-person networking and learning to help you grow in your knowledge and expertise, face-to-face! cphi.com/europeSpecialOffer:Registernow and receive a 20% discount on your Attendee EARLY ACCESS pass! From 28 September 2022 | Online Event 1-3 November 2022 | Messe Frankfurt, Germany

30 Journal for Clinical Studies Volume 14 Issue 3 Therapeutics

Currently, there are two FDA approved gene therapy products (GTPs), both of which are examples of in vivo gene augmentation therapy using adeno-associated virus (AAV) vector to deliver functional copies of a gene to alleviate symptoms caused by a dysfunctional protein.2 Luxturna (Spark Therapeutics), was approved in 2017 for the treatment of biallelic retinal pigment epitheliumspecific 65 (RPE65) mutation-associated retinal dystrophy, which can result in blindness.3 Luxturna can restore normal retinal cell function by supplying an RPE65 transgene thus restoring protein function. Following Luxturna, Zolgensma (Novartis) received marker approval for treatment of spinal muscular atrophy (SMA) in 2019. SMA is the leading inherited cause of infant death resulting primarily from biallelic loss-of-function of survival motor neuron 1 gene (SMN1). Zolgensma works by supplying a functional copy of the SMN gene from which a fully functional protein can be produced. Both clinical trials and post-approval studies assessing the longterm safety and efficacy of Zolgensma treatment demonstrated a significant increase in survival rates and quality of life in infants with the disease.4,5 Numerous pre-clinical and clinical trials are currently underway exploring how gene editing or suppression can alleviate symptoms of genetic conditions caused, for example, by toxic gainof-function of proteins, such as in the case of Huntington’s disease. Protein overexpression can be treated by gene ‘silencing’ or by post-

Powerful Techniques Promoting Gene Therapy and Gene-mediated Cell Therapy Progress

Gene therapy and gene-mediated cell therapy (e.g. CAR-T cell therapy) approaches hold great promise for treating debilitating diseases with unmet clinical needs. The drive to address the genetic cause of a disorder has brought about a gamut of innovative tools that can correct a cell’s function at the DNA level or engineer a cure via in vivo or ex vivo methodologies. Since 2021, the US Federal Drug and Food Administration (FDA), approved a record number of five gene- and chimeric antigen receptor (CAR)-T cell-therapy products. While there are thousands of clinical trials currently on the horizon, progress of such therapies to the market is hampered by safety, efficacy, and reproducibility concerns. Market approval relies on consistently presenting robust and reliable data displaying the highest levels of purity, potency (i.e. intended biological activity and/or therapeutic effect), and, ultimately, safety of the products throughout all phases of development. Harnessing the ability of specific techniques, providing accurate and precise data on product characteristics, is key to extending product accessibility to more patients across a wider range of genetic disorders. This article discusses the fundamental principles of gene and gene-mediated-cell therapies, addresses the challenges associated with in vivo and ex vivo gene delivery approaches, and presents tools the industry can use to support product development.

Over the past two decades, advances in gene therapy and genemediated cell therapy have led to the development of versatile treatment strategies which fundamentally involve the delivery of

nucleic acids into specific cells using gene delivery vectors. Using an in vivo approach, a gene therapy product is delivered directly into a patient, while ex vivo gene delivery combines a gene therapy product with allogeneic (patient-derived) or autologous (healthy donor-derived) cells, resulting in engineered cells which can be then transferred into the patient (Figure 1). Depending on the underlying cause of genetic disease, delivery of genetic material into a cell can result in gene augmentation, editing or suppression (Figure 2).

Figure 2. Outcome of gene therapy approaches

Figure 1. Gene therapy and gene-modified cell therapy approaches

transcriptionally targeting a specific mRNA sequence.6 Gene editing is a powerful approach that can also be used to restore gene function. Pre-clinical and clinical trials are currently underway, assessing the efficacy of these tools, such as small interfering RNA (siRNA), CRISPR-Cas9 and zinc finger nucleases.7

Safeguarding Therapeutic Potential

Demonstrating purity and potency of a GTP or GMCTP throughout all pre-clinical and clinical stages, and following market approval, is critical to ensuring product efficacy and safety. With gene delivery being a key component of these therapies, use of a safe and specialised gene delivery vector is imperative to product success. An ideal gene delivery vector would be characterised by its ability to encapsulate a transgene, safely deliver it to a target cell without triggering host immune response and releasing its cargo via endocytosis to either the cytoplasm or nucleus. Viral vectors, commonly used during gene therapy and CAR-T cell therapy development, are costly to manufacture and can come with the risk of insertional oncogenesis (e.g. retroviruses), and high immunogenicity (e.g. adenoviruses) following transduction. AAVs are some of the most extensively researched viruses, and with modified characteristics making them safe to use as gene delivery vehicles, are widely used in clinical in vivo gene therapy applications. AAV has unique biological abilities which render it invaluable in the field, such as lack of immunogenicity and pathogenicity in humans. Engineered AAV vectors used in gene therapy, lack 96% of the viral genome and are essentially recombinant protein-based shells unable to replicate or integrate into the human genome.9

testing, ddPCR can be used to assess plasmid quality prior to transfection, and precisely measure viral vector titre during the virus production and recovery process – all of which are vital for determining therapeutic efficacy downstream. Through the final quality assurance / quality control steps, ddPCR can confirm potency of the purified viral titre, and assure sample safety through reducing mycoplasma false positives and detecting residual host DNA. Beyond the manufacturing process, and into the clinic, ddPCR can be used to verify the therapeutic delivery of the GTP or GMCTP and assess transgene expression.

During the process of generating CAR-T cells, an ex vivo gene therapy, a CAR is delivered into either autologous or allogeneic T cells via lenti- or retro-viral vectors.8 This type of gene-mediated cell therapy product (GMCTP) has revolutionised the field of immunooncology. Four out of five CAR-T cell therapy products were granted FDA approval in 2022; most recently, Breyanzi (Bristol-Myers) was authorised for the treatment of patients with B-cell lymphoma and works by identifying and eradicating CD19-positive cells, i.e. B cells.2

Techniques Assisting Therapeutic Product Development

There are currently over 2400 cell and gene therapy trials taking

Therapeutics

Application of Droplet Digital PCR Throughout Development

Utilising a water-in-oil droplet system and a single low-volume sample, ddPCR counts nucleic acid molecules partitioned in over 20,000 individual volumetrically defined droplets, each serving as individual PCRs. Each droplet is then analysed to determine the fraction of PCR-positive droplets in the original sample. The concentration of target DNA template in the original sample can then be calculated using Poisson statistics. This method is suitable for the analysis of samples throughout GTP and GMCTP development.During‘in-process’

Real-time quantitative PCR (qPCR) utilises a standard curve to estimate nucleic acid quantities. Although widely use, this method has inherent limitations with reliable data acquisition being susceptible to template quality, reaction conditions and sample variability. Compared to real-time qPCR, droplet digital PCR (ddPCR) delivers higher rates of reproducibility, offering absolute nucleic acid quantification across the lifecycle of a product (Figure 3). Crucially, ddPCR does not rely on a standard curve or perfect DNA amplification efficiency, meaning significantly less variation compared to real-time qPCR. As such, ddPCR is deemed the ‘gold standard’ for measuring viral titration within the gene and genemediated-cell therapy field.13

Journal for Clinical Studies 31

www.journalforclinicalstudies.com

Challenges Associated with Gene Therapy Approaches

Finally,removed.themanufacturer needs to verify therapeutic delivery of the transgene into the target cell and assess biological effect by measuring its expression. Ex vivo gene therapy that uses genome integrating retro- or lenti-viruses for cell transduction can provide long-term therapeutic benefits through prolonged transgene expression. Viral vector genome integration is, however, typically associated with a higher risk of insertional oncogenesis10. Addressing such concerns, the FDA recommends that GMCTPs are accompanied by transgene integration and transduction efficiency studies. Specifically, the integration copy number should be no more than five copies per cell to minimise any health risks, while still ensuring a potent therapeutic product at lot release.10

Using reliable techniques capable of addressing all the challenges during GTP and GMCTP development is essential for ensuring product safety and efficacy. SDS-PAGE followed by protein staining and western blotting is commonly used to validate both viral vector purity and identity. Using stain-free protein gels assist in expediting this process and enable rapid estimation of the capsid protein ratios in viral samples.11 Western blotting can also be used to verify product identity and assess transgene protein expression during early-stage product development, while flow cytometry, can be employed to detect protein expression on target cells during pre-clinical or clinical stages via high-throughput, high-speed cell phenotyping.Oneofthe most established techniques commonly used to measure transgene or viral messenger RNA (mRNA) expression is reverse transcription quantitative PCR (RT-qPCR).11 A onestep RT-qPCR approach combines the reverse transcriptase and quantitative PCR steps in a single reaction, resulting in reduced sample manipulation and faster data acquisition. Alternatively, if the cDNA needs to be isolated and used for any downstream experiments or reserved for auditing purposes, a two-step RT-qPCR approach should be taken, whereby the two processes are separated. Depending on the manufacturer’s objectives, each method has its own merits; the two-step approach offers higher sensitivity and efficacy, while the one-step approach can generate data at a faster rate with less external interference.12

Due to their intrinsic characteristics and versatility of applications, AAVs are likely to remain the leading tools for in vivo gene therapies for years to come. Despite their potential, AAVmediated gene therapy is accompanied by safety and efficacy concerns raised during the manufacturing and clinical process. During the initial steps of both in vivo and ex vivo gene therapy development, confirmation of the identity, integrity and purity of the viral vector and assessment of viral titre is critical and will impact the success the final product. During the product purification phase, contaminants derived from common cell culture procedures, such as residual host DNA, bacteria or other viruses, can be present in the final batch posing a significant health risk to the patient and must be

Email: chelsea_pratt@bio-rad.com place across the globe, with rare cancers being the main target for treatment14. Novel therapeutic modalities have undoubtedly contributed to the growing number of products entering the market every year targeting diseases with unmet clinical needs. Despite the promising future ahead, the progress of such therapies is stalled by safety and reproducibility concerns.

9. Li, C. & Samulski, R.J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 21, 255-272 (2018).

Downstream efficacy and safety of any GTP or GMCTP relies heavily on consistently demonstrating purity and potency throughout earlier stages of development and following lot release. Collaboration and transparency between regulatory bodies, GTP/ GMCTP manufacturers, and tool or reagent providers is imperative to the development of such life-changing therapeutics.

7. Blighe, K. et al. Gene editing in the context of an increasingly complex genome. BMC Genomics. 8, 595 (2018).

12. Clarner, P. & Mansfield, K.M. PCR-Based Methodologies to Characterise AAV Gene Therapy Vectors. Am. Pharm. Rev. (2022).

Specifically, reproducible data quantification and reliable product verification requires tools that comply with regulatory requirements. Adhering to a set of stringent, product-specific standards, that fulfil applicable regulatory requirements associated with medical devices, such as ISO 13485, will guarantee the highest levels of quality when it comes to product development. Moreover, data must be documented electronically and stored securely to ensure it is readily available for auditing, as outlined in the US FDA Code of Federal Regulations (CFR) Part 11. Making certain these processes are in place from the start, can aid in providing access to Figure 3. Application of ddPCR in gene therapy approaches reliable and trustworthy data throughout therapeutic development and manufacturing, maximising the chance of success.

8. Wang, X. & Rivière, I. Clinical Manufacturing of CAR T Cells: Foundation of a Promising Therapy, Mol. Ther. Oncol. 3 (2016).

REFERENCES

32 Journal for Clinical Studies Volume 14 Issue 3 Therapeutics

Dr. Chelsea B. Pratt Dr. Pratt is the Biopharma Market Development Manager at Bio-Rad Laboratories. In this role, she works with leaders in the biotech and pharmaceutical industries to understand how Bio-Rad can accelerate drug discovery and development in new therapeutic areas. She is a recognised expert in chromatography and protein purification, and serves as a regular panellist at conferences, seminars, and webinars. Dr Pratt holds a PhD in Biological Chemistry from the University of Texas Southwestern Medical Center.

3. Rodrigues, G. A. et al. Pharmaceutical Development of AAV-Based Gene Therapy Products for the Eye. Pharm. Res. 36, 29 (2018).

5. efficacy/,https://www.zolgensma-hcp.com/clinical-experiences/str1ve-trial-visitedon26July2022.

2. Julyproducts/approved-cellular-and-gene-therapy-products,https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-visitedon112022.

10. Zhao, Y. et al. Development of the First World Health Organisation Lentiviral Vector Standard: Toward the Production Control and Standardisation of Lentivirus-Based Gene Therapy Products. Hum. Gene. Ther. Methods. 28(4), 205-214 (2017).

11. Bulletin_5782B.pdf,https://www.bio-rad.com/webroot/web/pdf/lsr/literature/visitedon28July2022.

6. Ghosh R. & Tabrizi S.J. Gene suppression approaches to neurodegeneration. Alzheimers Res. Ther. 9, 82 (2017).

1. Anguela X.M. & High K.A. Entering the Modern Era of Gene Therapy. Annu. Rev. Med. 27, 273-288 (2019).

4. Waldrop, M. A. et al. Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics 146, 3 (2020).

14. https://alliancerm.org/sector-report/2021-annual-report/, visited on 11 July 2022.

13. https://alliancerm.org/manufacturing/a-gene-2021, visited on 11 July 2022.

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Patient Effort Still High New processes and technology (including patient-facing applications) were introduced rapidly at sites during the pandemic so ongoing trials could continue. This included wearables, digital patient diaries, electronic monitoring, and electronic consent (eConsent) forms, which are now standard tools for patients and site teams. But, if introduced as separate applications, they shift the burden onto patients, who become responsible for downloading apps to document their progress and communicate with study teams. Some struggle with the day-to-day experience of multiple logins and passwords. Others, particularly in Europe, need reassurance around privacy implications, such as how their health data is being stored and accessed. Greater Capabilities, More Complexity Digital transformation has also increased operational complexity for sites, particularly those running large numbers of trials. Without close coordination with sponsors, it’s difficult to cultivate technology expertise at sites. Instead, clinical research sites spend disproportionate time training their teams to navigate dozens of platforms introduced by different sponsors. Site staff, who thrive on patient interaction, are instead troubleshooting technology issues for patients. Some sites have even hired platform managers and technology liaisons to free up research nurses to focus on patients. Lacking standardised or connected systems, many sites struggle to operate efficiently.

2. Collaborate early and often with users. Before adding a new resource, widen the conversation to teams, sponsors, and patients. This will help incorporate new criteria in software decisions that could boost user adoption, including functionality, user-friendliness, and workload.

4. Improve the patient experience. Making trial participation more accessible and convenient will improve patient enrollment and retention. Innovative patient-facing applications could be used to keep patients informed and connected through a single application for all their trial activities. Study information should flow seamlessly between sponsors, CROs, sites, and patients, eliminating paper and manual processes.

Patients are not the only ones facing challenges. Sites also find it difficult to realise the operational benefits of DCTs. As one sponsor at a recent Veeva roundtable noted: “Decentralised trials burden sites with more technology and processes. We need to provide a helping hand for more efficient execution.”

34 Journal for Clinical Studies Volume 14 Issue 3 Technology

At a recent Veeva roundtable of clinical operations leaders, Joana Claverol, who leads the clinical research unit at Barcelona Children’s

Sponsors should seize the opportunity to reduce the technology burden on patients and sites. Here are four steps to simplify the experience and deliver on the promise of digital trials: 1. Build standard operating procedures (SOP). Identify universal ways of working and standardise SOPs before introducing new technology. For example, develop a login pathway that minimises the number of times a team member or patient will have to log into applications.

Hospital SJD, depicted the scale of the challenge: “Every year, we conduct roughly 200 trials, and we use the sponsor’s technology for each. A trial can require us to use different platforms for feasibility, documentation, electronic data capture, patient randomisation, travel expenses, imaging, invoicing, and others.”

An emerging priority is gaining access to a system that aggregates real-time data in one place. This would address sites’ data quality concerns by ensuring all uploaded data from multiple applications are brought into one platform. Investigators would benefit by being able to make decisions quickly. Site leaders pinpoint the potential impact on efficiency: “We estimate that 20% of our time would be saved if we could use one platform to simplify our work,” Claverol said.

Sponsors acknowledge the heavy burden on sites of multiple siloed applications: 99% of those surveyed agreed that technology adoption is a major barrier to decentralised trials.1 As the systems are disconnected and lack interoperability, this can result in data access and quality issues for site teams and CROs: for example, if the same data is manually entered into different systems.

Effective Data Management at the Core

Four Steps to Simplify the Experience

3. Identify dedicated resources for site support. Create a digital support team as a single point of contact for sites. Make sure they work directly with new technology vendors and are trained to troubleshoot for sites.

Delivering on the Promise of Digital Trials: Simplified Experiences for Sites and Patients

The shift toward decentralised trials (DCTs) was not caused by COVID-19 but has certainly been accelerated by it. Research indicates that just 28% of sponsors and CROs ran DCTs before the pandemic.1 Now, 87% run DCTs, with estimates of an increase to 95% in years to come. DCTs should result in a more patient-centric experience. Since they do not need to travel to clinical research sites to participate in studies, patients are empowered to share clinical data from varied caregiving settings. Remote clinical trials are enabled through the use of digital applications, which are the how of DCTs. But such a rapid shift has introduced challenges, with patients juggling multiple technologies during a trial.

Hugo Cervantes As vice president Vault EDC, Hugo is responsible for Vault EDC strategy, market adoption, and customer engagement. Hugo has spent the last 15 years in management consulting and professional services, helping biopharmaceutical organizations increase their productivity, innovate and grow.

Journal for Clinical Studies 35www.journalforclinicalstudies.com Technology

Collaborate and Consolidate The shift to decentralised clinical trials was already underway but has been accelerated by the pandemic. As a result, patients are more empowered to participate in studies and contribute data from different settings. DCTs also offer great potential to improve collaboration between patients, sites, sponsors, and CROs, for better trial and patient outcomes. There is a significant opportunity to convert willingness to use new tools into improved operational efficiency at sites, and a seamless patient experience. It requires a more collaborative approach and a willingness to consolidate existing systems. Only then will digital trials start to deliver on their huge potential. 1. Veeva, Digital Clinical Trials Survey Report, 2021 2. Veeva, Digital Clinical Trials Survey Report, 2021

With paperless trials now the norm, sites increasingly see the need for flexible, modern electronic data capture (EDC). One sponsor observed that this is underestimated by teams when they move from paper to electronic processes. “People can do whatever they want with paper, but when you try to do something electronically all your decisions have to be made upfront. This can slow down implementation.”

REFERENCES

Within the clinical trials sector there is an increasing demand for high performing thermal packaging to meet the rising requirements of protecting pharma payloads, needing be shipped at extreme lower temperatures. Consequently, thermal packaging vendors are responding to the growing trend to transport clinical trial materials at significantly lower temperatures including frozen, deep frozen and ultra-deep frozen.

COMPLEXITY OF

What Passive Packaging Options Are Available when Shipping Clinical Trials at Frozen Temperatures?

Through the second and third phases the quantity of participants is increased alongside the emphasis on effectiveness. The fourth phase of a trial for drugs or devices takes place after the FDA agrees the trial results are positive and approves their use.

As a trial moves through its phases, the quantity of participants increases as does the spread of countries these participants are located in. This presents considerable challenges from a logistics standpoint to ensure the drug remains at the right temperature.

36 Journal for Clinical Studies Volume 14 Issue 3 Supply Chain Management

As a device or drug's effectiveness and safety are monitored in large, diverse populations this can present temperature challenges for pharma payloads being deployed. Throughout all the phases of a clinical trial, the temperature requirement can change across, cryogenic frozen (-180°C), deep frozen (-80°C), frozen (-20°C), 2–8°C and even 15–25°C.

The main driver for this rising demand in such specialist shippers is due to the rapidly rising rate of clinical trials being conducted. After the initial impact of the pandemic, the industry is now seeing multiple trials initiating from their first phase and successfully moving through all four phases. A clinical trial starts initially with an experimental treatment on a small group of often healthy people to judge a developed drug’s safety, side effects and establish the correct drug dosage required.

Clinical research organisations (CROs) need to ensure they can meet some if not all of these temperature requirements if they are to be chosen to manage the clinical trial. To do this they will need to assess the packaging options they have, and which packaging is the most appropriate to utilise to protect the valuable medical materials being shipped. Temperature Requirements More recently there has been an increase in trials materials needing to be kept at a frozen temperature and this can create additional complications. There are considerations to take into account including what packaging is available within the industry, how does this packaging work and crucially, how long will it maintain the set temperature for? LOGISTICS

• Refrigerated: (freeze point of PCM 4°C) This would require EPS boxes with a PCM for specific temperature requirement of +2°C to +8°C. To maintain this demanding temperature a VIP would be used as the insulation.

Many of these passive packaging solutions currently being deployed within the marketplace have extensive qualification to demonstrate their cold chain capabilities.

Deciding what packaging to use will be based on the drug’s temperature stability, the temperature band the drug can be exposed to without impacting on its performance and effectiveness when administered.Themajority

Journal for Clinical Studies 37www.journalforclinicalstudies.com

•• Frozen: (freeze point of phase material -20°C) This would require EPS boxes with a PCM for specific temperature requirement of below -15°C. To maintain this challenging temperature a VIP would be used as the insulation.

The passive packaging options available are uncontrolled ambient, controlled ambient, refrigerated, frozen and deep frozen.

Later in the clinical trial, when the stability data is available, there might be a move to packaging which is able to maintain a temperature of 2°C–8°C.Another key driver for the rising requirement for frozen packaging systems has been due to increasingly stringent Good Distribution Guidelines (GDP) that organisations need to comply with when storing, transporting and handling medical materials within the supplyUpdatedchain.GDP regulations resulted in the introduction of CRT, a newer temperature level implemented within the clinical trial space with mandatory requirements to demonstrate temperature control is inWithplace.the advent of more stringent guidelines, pharma products must be kept frozen by using specialised temperature-controlled packaging (TCP) engineered and designed for this purpose. The subsequent rise in requests for TCP for frozen shipments is in response to ensure adherence to these increased regulatory requirements. There has also been a rise in requests for ambient controlledThereforeshippers.thermal packaging providers have had to respond to the requirements within the clinical trial industry by adapting product portfolios or engineering and designing new packaging products.

Chain Management

• Controlled ambient (referred to as “controlled room temperature” or “CRT”): This would require EPS boxes with a PCM for a specific temperature requirement of +15°C to +25°C. (freeze point of phase material 20°C)

CROs and cold chain organisations will want to partner with TCP vendors who can offer a breadth of products to meet the varying temperature requirements within trial phases to eliminate excursions and ensure the developed drug is effective and safe for patients.

of packaging being utilised for clinical trials will use foam and/or vacuum insulation panels (VIP) for insulation and a phase change material (PCM) for the engine and power of the packaging to maintain temperature. The different materials used will affect the thermal performance the systems can achieve with the following systems being used during clinical trial phases:

• Uncontrolled ambient: A simple expanded polystyrene (EPS) box with the no specific temperature control and a large tolerance of drug stability.

• Deep frozen: Traditionally deployed would be EPS boxes with use of dry ice for a deep frozen requirement of -80°C. Or for -50°C temperature requirements a PCM with an enforced VIP would be used as the insulation. With all these various options available with variable performance and price points, it can be a challenge to decide what packaging to use.

Supply

Clinical Trial Trends Companies operating in the clinical trials space want to have a bandwidth to maximise their options and will start as many clinical trials as they can that have as much chance of being successful as possible.Therefore, they are now starting clinical trials with much less tolerable stability data. Because there is less stability data available, trials are often started at frozen temperatures, utilising frozen performance packaging to ensure the efficacy of that drug or pharma product is met.

Email: ross.gregory@peli.com

These logistical challenges, coupled with the rising trend whereby we are seeing a lot of the active pharmaceutical ingredients (APIs) and drugs being manufactured in North America, can present complications when shipping into Asia.

dry ice, the moment the box is opened or the dry ice escapes, the amount of temperature control you have is limited.

Ross Gregory Ross Gregory joined Peli BioThermal in 2011 where he works as a Business Development Manager. With over 15 years of experience in commercial sales; customer account management and long-term strategic planning, Ross is a key member of the Peli BioThermal business where he specialises in helping customers facing difficult pharma distribution challenges. Since Ross joined the organisation, Peli BioThermal has experienced significant sales growth throughout its comprehensive single/reusable parcel and bulk shipper products, specially developed for the pharmaceutical and clinical trials market. Before joining Peli BioThermal, Ross spent five years working in retail and the consumables industry as a sales representative and team leader.

38 Journal for Clinical Studies Volume 14 Issue 3

Affect Another trial trend emerging is that the clinical industry is increasingly enrolling participants for trials from Asia and Asia specific countries. Many more clinical trials are being conducted in Asia because there are numerous different diseases, which are more prevalent in the region than other countries, because these illnesses are being eliminated elsewhere due to vaccine advances.

Consequently the TCP deployed will need to withstand the various external temperature environments that will be encountered en Clinicalroute.

Supply Chain Management Asia

Longer duration capabilities is needed for TCP being deployed to Asia as payloads being transported within the region will have to contend with very different climates. As FDA approval requires proven drug data including its efficacy, ability to work and correct patient dosage, data is needed from all ethnicities of differing age groups, depending on the illness you are trying to prevent or Thereforecure.it’s

trial companies must cover off many elements including managing and manufacturing developed drugs while taking into consideration logistical challenges to ensure they reach participants on a global scale. These companies will look to TCP vendors who can demonstrate they have a breadth of shipper solutions for all temperature needs and can manage the temperature-control requirement to withstand any external environment temperature challenges. While TCP designed several years ago might be sufficient for shipping within Europe, with the effects of global warming impacting the climates of different countries, it’s essential TCP products are fine tuned to provide high-performance and withstand changing climate challenges. TCP Trends The industry is seeing a move away from utilising dry ice as companies explore alternatives within the TCP space. A key driver for the shift is because dry ice is a hazardous chemical, a gas, so there are specific safety measures that must be in place when packing a box using it. PPE needs to be worn and packing of the payload must take place in an aerated room so when the dry ice melts, it sublimates, it disperses into the air and is not inhaled. During shipment clinical trials have a lot of regulation, certification and custom points to navigate, therefore during its journey a box may need to be stalled or held at customs for checks.Ifusing

This enables you to freeze panels in advance of shipment without the need to use dry ice or its associated safety measures. The coolants can be packed in a box with standard handling processes and during shipment, should there be a delay, that box can be placed in a freezer and the PCM will stop thawing, won’t sublimate so no temperature changes will occur. Once the box continues its journey it will maintain the previous temperature control.

essential to be able to ship drugs globally and once a clinical trial enters phase three drugs will need to be shipped worldwide to multiple patients employed over a period of time.

Looking ahead we will continue to see the increased incorporation of technology, computers and mobile devices being utilised to make it easier to collect and store live data. This is vital as it allows the CRO to improve the design and conduct of future clinical trials. While the COVID-10 pandemic impacted all aspects of clinical trials, the speed of the trials for developing vaccines proved that processes can be conducted at pace and at a rate not seen before. There are numerous regulatory systems and automated data capturing involved that has been improved as a result of the advancements made during the pandemic, which will improve processes for the future.

A lot of infrastructure has been learned through the pandemic response within the clinical trial world and a key development is the public understanding of clinical trials has increased considerably.Thepublics’ interest of clinical trials has improved people’s awareness overall. This has helped clinical trial companies increase the number of trial participants, which will help improve the success rate of future trials and drug development.

We are seeing PCMs being tailored to specific lower temperature requirements so the performance is available without the potentially hazardous risks related to dry ice, as there is no danger associated withAsPCM.more new PCMs blends become available and packaging advances, we will see dry ice usage reduce further.

Asia also appeals due to the low cost of conducting studies and growing patient population, however an Asia-centric approach to clinical trials poses challenges when shipping pharma products, at much lower temperature ranges, to the region.

Some of the latest industry developments relate to PCMs, a liquid that will freeze and change phase at a set temperature, negating the need to use dry ice. Newly developed PCMs incorporating different chemical elements will see the liquid freeze at -50°C or -40°C and there’s an emerging trend for a -35°C temperature requirement and standard -20°C.

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