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Considerations for Clinical Trial Design Involving Radiotherapy Plain Language Summaries of Publications – What Has COVID-19 Taught Us? Clinical Quality Management System (CQMS): A Framework for Compliance with Good Clinical Practice (GCP) Emerging Field Has Fast Become a Vital Component in the Medical Discovery Process

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Contents

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT Jerome D'Souza info@senglobalcoms.com EDITORIAL MANAGER Beatriz Romao beatriz@senglobalcoms.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Jessica Dean-Hill jessica@senglobalcoms.com ADMINISTRATOR Barbara Lasco

FOREWORD

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Scientific and Ethical Issues Surrounding the Enrolment of Pregnant People in Clinical Trials

Through recent actions, the US Food and Drug Administration (FDA) has signalled its commitment to advancing research in pregnant and lactating people, recognising that data is needed to inform labelling and benefit-risk determinations. To this end, the agency collaborated with the Duke University Robert J. Margolis Center for Health Policy to convene a February 2021 public meeting about scientific and ethical issues associated with enrolling pregnant individuals in clinical trials for drug development. Julie Odland at Clarivate explains the scientific and ethical issues surrounding the enrolment of pregnant people in clinical trials. 8

What is Cognitive Debriefing?

Cognitive debriefing is a language test of a linguistically validated questionnaire of healthy volunteers or patients with a specific disease to prove that the translation is indeed clear, easy to understand, relevant and culturally adapted to future users. Nataliya Nedkova at NN Translations EOOD explains more about the concept of cognitive debriefing REGULATORY

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10 Clinical Quality Management System (CQMS): A Framework for Compliance with Good Clinical Practice (GCP)

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What defines “quality” within the framework of clinical research? To answer this question, one has to step back and start with the definition of “quality” per se. Universally, quality is defined as the degree to which a set of inherent characteristics of a product fulfils requirements and “inherent”, as opposed to “assigned” means existing in the product. Amer Alghabban, the author of The Pharmaceutical Medicine Dictionary and The Dictionary of Pharmacovigilance amongst others analyses clinical quality management system.

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The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright. Volume 13 Issue 5 September 2021 Senglobal Ltd.

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14 Operationalising Decentralised Clinical Trials (DCTs) – the challenges and change management approaches, considering trial designs and timelines with decentralisation methods at the forefront While components of fully decentralised clinical trials and hybrid decentralised clinical trials existed prior to the COVID-19 pandemic, the ongoing public health crisis accelerated the demand for DCTbased approaches. During COVID-19, the pharmaceutical industry was focused on managing participant safety and ensuring data integrity for COVID-19 vaccine trials and other ongoing traditional trials, many of which were put on hold due to the inability of participants to travel to sites in the traditional trial model. Kamilla Posselt, Isaac Rodriguez-Chavez and E.B. McLindon at ICON plc. explain the challenges that need to be considered on trial designs and timelines with decentralisation methods at the forefront. 18 Overview: Pharmacovigilance and Risk Management Drug development is an expensive, lengthy, and high-risk business taking 1015 years and is associated with a high attrition rate. Approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Research on a new medicine does not end Journal for Clinical Studies 1

Contents when the discovery and development phases are completed, and the medicine is available to patients. Tahseen Khan and Tanveer Khan at LabCorp Drug Development overview the details to consider in Pharmacovigilance and Risk Management MARKET REPORT 24 Finding the right patients for primary care clinical studies Automated Recruitment Platforms (ARPs) offer primary care clinicians and allied health professionals’ opportunities for more time-efficient ways to engage with and recruit patients for clinical studies. Dr. Matt Wilson at uMed outlines the benefits of the technology and explains why the patient Electronic Health Record alone, although essential, is not a sufficient data set for successful clinical study recruitment in primary care. 28 Plain Language Summaries of Publications – what has COVID-19 taught us? The COVID-19 pandemic has significantly impacted the whole world and the public has had to struggle with understanding scientific data on a daily basis. The impact of scientific misunderstanding became painfully apparent with the decline in vaccine uptake and so the need for clear, understandable scientific information has never been more vital. Plain Language Summaries of Publications (PLSPs) could be an elegant and much needed solution to this problem. This article will explore what these documents are, the approaches taken to date, and the challenges that still remain. Lisa Chamberlain James and Rachel Beeby at Trilogy Writing and Consulting Ltd will aim to answer the question – what has COVID-19 taught us?

expectations. Add on the fact that many studies are conducted across international borders and involve more stakeholders than ever, and streamlining trial processes is even harder. Hugo Cervantes at Veeva Vault Clinical explains how clinical operations teams are advancing study management by adopting new strategies and technologies that bring together data, processes, and workflows to streamline trial execution 42 The Journey From Hesitancy to a Reliance on Real World Data As recently as just a few years ago, drug developers across the globe were hesitant of using world evidence (RWE) when pre-forming the clinical analysis of an investigator product. The gold standard of investigative analysis to determine the efficacy and safety of a new investigational drug remained the randomised clinical trial. Karen Ooms at Quanticate explores the rise in the use of real RWE in the pharmaceutical industry in recent years and argues that the concept of harnessing data from real-life patients has finally come of age. LOGISTICS & SUPPLY CHAIN 44 Emerging Field has Fast Become a Vital Component in the Medical Discovery Process Medical research has enabled healthcare professionals to successfully treat and prevent diseases, and the establishment of a reliable cold chain for the safe storage and transport of samples is essential for the continuation of such activities. Luc Provost at B Medical Systems, talks about the support of scientific and clinical research through a reliable cold chain and the importance of temperature-controlled shipments.

32 Clinical Evaluation of Ayurvedic Interventions: Current Scenario in Indian Market Ayurveda, the science of life, has evolved into a comprehensive system of healthcare based on high-quality scientific experiments with a sound and reproducible evidence base that has stood the test of time. Several strategies and road maps are being developed to carry forward the merits of this science in order to meet today's health needs and mainstream its core strengths in India and around the world through research and development. Koushik Yetukuri, Vikash Penki, M.S. Umashankar and Rama Rao Nadendla at Chalapathi Institute of Pharmaceutical Sciences evaluate the current scenario in Indian market. THERAPEUTICS 36 Considerations for Clinical Trial Design involving Radiotherapy Radiation therapy has been used for many years as an effective form of treatment against many cancer types; yet it remains less well researched and utilised than other well-known cancer therapies such as chemotherapy. Lucy McParland at PHASTAR focus on some of these challenges faced in general across all clinical trials involving radiotherapy, followed by a closer look at the different trial phases. TECHNOLOGY 38 Modernising Study Management for Greater Visibility and Speed in Trials Clinical trial complexity is growing as the industry adapts to COVID-19 disruptions, increasing data sources, and evolving patient 2 Journal for Clinical Studies

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Foreword The European Society for Radiotherapy and Oncology (ESTRO) seeks to improve cancer patients’ outcomes by promoting innovation, research, and dissemination of science and by developing initiatives to increase awareness and understanding of radiotherapy treatment, and therefore facilitate its access. After cardiovascular diseases, cancer is the main cause of death in Europe, worldwide. In 2012, there were 3.45 million new cases of cancer and 1.75 million deaths from cancer across the European Member States at that time. Radiation therapy has been used for many years as an effective form of treatment against many cancer types, yet it remains less well researched and utilised than other well-known cancer therapies such as chemotherapy. Lucy McParland at PHASTAR focuses on some of these challenges faced in general across all clinical trials involving radiotherapy, followed by a closer look at the different trial phases.

actions, the US Food and Drug Administration (FDA) has signalled its commitment to advancing research in pregnant and lactating people, recognising that data is needed to inform labelling and benefit-risk determinations. To this end, the agency collaborated with the Duke University Robert J. Margolis Centre for Health Policy to convene a February 2021 public meeting about scientific and ethical issues associated with enrolling pregnant individuals in clinical trials for drug development. I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals. I hope that you enjoy reading this edition of the journal and keep well. Beatriz Romao, Editorial Manager Journal for Clinical Studies

This volume explores the challenges of drug policy in the context of development. Drug development is an expensive, lengthy, and high-risk business taking 10 to 15 years and is associated with a high attrition rate. Approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Research on a new medicine does not end when the discovery and development phases are completed, and the medicine is available to patients. Tahseen Khan and Tanveer Khan at LabCorp Drug Development overview the details to consider in Pharmacovigilance and Risk Management As recently as just a few years ago, drug developers across the globe were hesitant of using world evidence (RWE) when performing the clinical analysis of an investigator product. The gold standard of investigative analysis to determine the efficacy and safety of a new investigational drug remained the randomised clinical trial. Karen Ooms at Quanticate explores the rise in the use of real RWE in the pharmaceutical industry in recent years and argues that the concept of harnessing data from real-life patients has finally come of age. In an article by Julie Odland at Clarivate we will discuss the enrolment of Pregnant people in Clinical Trials. Through recent

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Scientific and Ethical Issues Surrounding the Enrolment of Pregnant People in Clinical Trials Through recent actions, the US Food and Drug Administration (FDA) has signalled its commitment to advancing research in pregnant and lactating people, recognising that data are needed to inform labelling and benefit-risk determinations. To this end, the agency collaborated with the Duke University Robert J. Margolis Center for Health Policy to convene a February 2021 public meeting about scientific and ethical issues associated with enrolling pregnant individuals in clinical trials for drug development. The US Department of Health and Human Services (HHS) Federal Policy for Protection of Human Research Subjects (45 Code of Federal Regulations [CFR] 46, subpart A) – also called the Common Rule – has removed a reference to pregnant people as “vulnerable.” The FDA is working to harmonise its regulations with the Common Rule, as noted in the October 2018 Guidance for Sponsors, Investigators, and Institutional Review Boards: Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations (Final). The meeting supported the objectives of the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC). The PRGLAC advises the secretary of the HHS on gaps in knowledge about and research on safe, effective therapies for pregnant and lactating individuals.

safety, efficacy, and dosing; gestational age; the seriousness of the disease; and the availability of treatment options. Trials in the postmarket setting may be easier to conduct because investigators have more data to work with; areas to address include: • • •

Have the regulatory requirements been met? Opportunistic pharmacokinetic studies have minimal risk (e.g., blood samples from routine clinical care). Intervention trials may be appropriate if the benefit-risk is favourable.

Clinical trials for investigational new drugs applications (INDs) traditionally enrol males, postmenopausal individuals, and/or individuals of childbearing potential (with pregnancy testing and contraceptive use) within various study phases (see Figure 1). All reproductive studies, general toxicity, and genotoxicity are completed before pregnant individuals are enrolled. Generally, phase 1 enrols non-pregnant subjects and phases 2–3 enrol pregnant people.

Source: FDA slide presentation, 2–3 February 2021. FEED = fertility and early embryonic development; EFD = embryo-fetal development; PPND = pre/postnatal development

Figure 1. Timing of Reproductive Toxicity Studies During the IND

Labelling information for pregnant people typically is based on nonclinical data, “with or without limited human safety data,” the FDA states in its April 2018 Draft Guidance for Industry: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials. Lack of information based on clinical data can mean providers and patients decide against treating underlying conditions, “which in some cases may result in more harm” to the parent and the foetus than if they had received treatment. In other cases, individuals who use medically necessary drugs may do so without understanding the benefits and risks to themselves or their foetuses.

Further Information About the Draft Guidance The April 2018 Draft Guidance for Industry: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials identifies several reasons that justify including pregnant people in clinical trials:

As noted in the July 2020 Draft Guidance for Industry, Pregnancy, Lactation, and Reproductive Potential: Labelling for Human Prescription Drug and Biological Products – Content and Format (Revision 1), the pregnancy and lactation labelling rule requires sections 8.1 and 8.2 to include a risk summary, clinical considerations, human data (if available), and a summary of animal data. Section 8.3 for females and males of reproductive potential includes subsections about pregnancy testing, contraception, and infertility.

•

FDA speakers at the public meeting said that risk assessment and benefit considerations (e.g., gestational age, seriousness of the disease, availability of treatment options) may vary depending on the setting. These considerations include the amount of data available to inform 6 Journal for Clinical Studies

• •

The lack of accessible, safe, and effective treatment options for pregnant individuals is a significant public health issue. The health of pregnant people and their foetuses can be compromised if the dose/dosing regimen, safety, and efficacy of treatments used during pregnancy are not established. In some cases, pregnant people and their foetuses directly benefit from participation in clinical trials, in ways not possible outside the research setting.

A section of the guidance, FDA Regulations That Govern Research in Pregnant Women, identifies 10 conditions that must be met in trials supported or conducted by HHS, as laid out in subpart B of 45 CFR 46, Additional Protections for Pregnant Women, Human Foetuses and Neonates Involved in Research. They are: 1. Where scientifically appropriate, nonclinical studies (including in pregnant animals) and clinical studies have been conducted and provide risk information. Volume 13 Issue 5

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2. There must be the prospect of direct benefit to the pregnant individual or foetus; if there is no benefit, the risk to the foetus must be minimal and the purpose of the research must be the development of important biomedical knowledge that cannot be obtained by any other means. 3. The trial involves the least possible risk for achieving the research objectives. 4. Informed consent is obtained as described in 45 CFR 46, subpart A. 5. If the prospect of direct benefit is solely for the foetus, then additional consent from the father is needed, unless he is unavailable, incompetent, has temporary incapacity, or the pregnancy results from rape or incest. 6. Participants must be fully informed of the reasonably foreseeable impact of the research on the foetus or neonate. 7. For children who are pregnant, assent and permission must be obtained. 8. There can be no inducements for pregnancy termination. 9. Investigators are not to be involved in decisions regarding pregnancy termination. 10. Investigators are not to be involved in determining the viability of a neonate.

• •

Collection and monitoring of safety data. Stopping a clinical trial that enrols pregnant subjects.

The FDA has stated that it may use input from the February 2021 meeting to inform the finalization of the April 2018 draft guidance. According to the guidance, the agency “supports an informed and balanced approach to gathering data on the use of drugs and biological products during pregnancy through judicious inclusion of pregnant women in clinical trials and careful attention to potential foetal risk.” The document identifies scientific and ethical issues that should be addressed by sponsors who consider enrolling pregnant people in drug development trials. Related FDA publications for industry include the November 2020 final guidance: Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrolment Practices, and Trial Designs as well as two May 2019 draft guidance’s: Post approval Pregnancy Safety Studies and Clinical Lactation Studies: Considerations for Study Design.

Other sections of the guidance address:

In 2019, there were 3,745,540 births in the US, according to statistics by the Centers for Disease Control and Prevention (CDC). The fertility rate was 58.2 births per 1,000 females aged 15–44 years, the CDC reported. From 2018–2019, birth rates decreased for females aged 15–34, remained virtually unchanged for women aged 35–39, and increased for women in their early 40s.1

•

REFERENCES

• • •

General guidelines for including pregnant people in clinical trials. Disease type and availability of therapeutic options in the pregnant population. Timing of enrolment. Pharmacokinetic data.

Hamilton BE, Martin JA, Osterman MJK. Births: Provisional data for 2019. Vital Statistics Rapid Release; no 8. Hyattsville, MD: National Center for Health Statistics. May 2020. Available from: https://www.cdc. gov/nchs/data/vsrr/vsrr-8-508.pdf

Julie Odland Julie Odland is a writer and editor with more than 25 years of experience in publishing. She joined Clarivate in 2017 and specialises in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin. Email: julie.odland@clarivate.com U.S. Marine Corps photo by Sgt. Randall A. Clinton www.journalforclinicalstudies.com

Journal for Clinical Studies 7

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What is Cognitive Debriefing?

•

1. Purpose The purpose of each interview is to assess the clarity of the translation of the patient's questionnaire, its relevance to a specific culture, and whether it is appropriate for the target audience.

•

Note: The purpose of the interview is NOT to gather information on whether the patient is in good or bad health.

•

A language expert reviews the patient's responses and assesses whether the translation needs to be revised. The language expert makes the final decisions on whether further changes to the translation need to be made to ensure that any patient can understand each translated question. The revised translation is usually used in much larger future studies. It is important for the interviewer to keep in mind that the sole purpose of the interview is to confirm that the patient's questionnaire is clear and appropriate for the language and country in which it is being tested. The cognitive debriefing form provided should be used as a tool for interviewing respondents. 2. Interviews The purpose of each interview is to identify the questions and the possible answers in the patient's questionnaire that are problematic, to determine why, and to record the suggestions given by the respondents.

Completion of the patient questionnaire by the respondent

•

• • • • • •

Each interview consists of three parts:

•

Introductory part, in which the interviewer provides information about the interview to the respondent; 2. Filling in the questionnaire by the respondent independently; 3. Discussion of the point’s statement between the respondent and the interviewer.

• •

Presentation of the interview to the respondent

•

The interviewer explains that the purpose of the interview is to discuss the translation of the questionnaire in order to understand whether the way of expression is clear and easy to understand before distributing it to future respondents. The interviewer emphasizes that the information provided by the respondent will remain anonymous (i.e. his/her name will

8 Journal for Clinical Studies

The interviewer gives the questionnaire to the respondent and asks them to complete it independently. If the respondent asks for help, the interviewer should encourage them to answer as best as they can, but the interviewer does not help them understand the question. At the same time, the interviewer does not force the respondent to answer every question. The interviewer reminds the respondent that their main interest is not to answer each question, but it is their opinion and suggestion regarding the expression of the question (because it is translated from English). The interviewer reminds the respondent that their opinion and suggestion will be used to improve the translation. The interviewer notes the time each respondent takes to complete the questionnaire and writes it down in minutes.

Discussion of issues

The interviewer encourages respondents to focus on how the questions are expressed, rather than the order or structure of the possible answers.

not be recorded and will not be linked to what he/she says) and confidential (i.e. it will not be disclosed out of context of the translation project and will only be used to improve the translation). The interviewer reminds the respondent that his/her participation is voluntary, that he/she may refuse to participate or terminate his/her participation in the interview at any time and is free to refuse to answer some of the questions. The interviewer explains what will happen during the interview and what the expected duration of the interview is.

• •

General impression: the interviewer asks about the general impression of the respondent from the questionnaire: - is it clear and easy to understand? Is it easy to answer the questions, i.e. did he have difficulty choosing the possible answers (“No”, “Yes, to some extent”, “Yes, to some extent”) Is it too long? Is it suitable for the condition? Are the instructions clear? Review of the questions one by one: the interviewer goes through the whole questionnaire question by question and checks: Was the question difficult to understand and if so, why? Are there words that are difficult to understand, or is the meaning of the question unclear? How does the respondent interpret the question? The interviewer encourages them to explain what they think the question means, and what it refers to in their daily life or experience. Would the respondent express this question in any other way and how? Are the possible answers clear, are they sufficiently different from each other and are they compatible with the question? The client sends the project for cognitive debriefing stating the following requirements: Number of healthy volunteers or patients with a specific disease to be tested on the questionnaire (usually 5, in very rare cases 10) Age groups (usually 18 to 80 years old; sometimes children are included who need to be interviewed with their caregivers and/ Volume 13 Issue 5

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or parents) Education (people with both secondary and higher education should be involved) Male to female ratio (2: 3 or 3: 2)

The Provider makes an offer for the service by e-mail and upon approval of the Client the Provider contacts its doctor-consultant for the recruitment of patients with the respective disease and/or posts an ad on the internet. Once the Provider recruits the required number of patients according to the Client's requirements, he fills in the recruitment report stating the number of patients, the type of disease, the date of diagnosis, demographic data such as age, education and occupation and the name of the drugs that patients take currently (if any). Neither the Provider nor the Client collects personal data from patients such as names, address, personal identification number, medical records, etc. During the selection, the participant is informed that the interview would be recorded on audio media. The client then approves the recruited patients and sends the translated files ready for testing by the Provider. The provider contacts the recruited patients and arranges dates for the interviews, which take place at a convenient day and time for the participants. Prior to the interview, the participant fills in a Declaration of Confidentiality and Non-Disclosure of Personal Data, as well as the clinical questionnaire itself. During the interview, the interviewer asks questions about whether the text is clear and easy to understand, whether it corresponds to the patient's condition, how he can express the sentence in his own words and whether the questions and answers correspond to what has been said. After the interview, the Provider prepares and submits the following documents to the client: • • • •

• • •

•

Completed questionnaire from each interview (to be filled in by the patient); Declaration of confidentiality and non-disclosure of personal data (to be filled in by the patient); Completed cognitive debriefing form for each interview (to be filled in by the interviewer); A report on the recruited patients (although incomplete, it is submitted before the start of the interviews so that the client can approve the participants). At the end of the project, the provider submits the same report in its final version; Analysis of the results (the interviewer writes down the patient's remarks and makes suggestions for improvements in the translation); Audio recording of the interview (the patient is informed in advance that what he/she says will be recorded on audio media); Reconciliation report (it includes recording the patient's remarks, the interviewer's opinion regarding the patient's remarks and suggestions and making improvements in the direct and reverse translation); Updated translation of the clinical questionnaire in the target file.

Personal data is stored in a manner that ensures confidentiality, protection against loss, theft or destruction. In case it is necessary to use property belonging to external providers, the conditions for its management are determined in the contract/order for assignment of the implementation of the process. In cases where the property of a client or an external provider has been lost, damaged or otherwise found to be unusable, the manager shall inform the client or the external provider and store documented information about the incident. www.journalforclinicalstudies.com

Nataliya Nedkova Nataliya Nedkova is a translation company owner of NN Translations EOOD with a focus on medical and pharmaceutical translations for the Balkan languages and a well-established English-Bulgarian translator, proofreader, cognitive debriefer and linguistic validation consultant with 16 years of experience in the medical, pharmaceutical, law, technical, marketing and business industries as well as the fashion, cosmetics and tourism sectors. Nataliya Nedkova is passionate about the English language and in 2005 she also obtained a Bachelor’s Degree in English Language and Literature from the St. Cyril and St. Methodius University of Veliko Tarnovo, Bulgaria, and a Master’s Degree in Translation Studies from the same university. In 2011 she became a member of the Chartered Institute of Linguists, UK and in 2012 she became a Proz Certified Pro member. In 2013 Nataliya also joined the International Association of Professional Translators and Interpreters (IAPTI).

Journal for Clinical Studies 9

Regulatory

Clinical Quality Management System (CQMS): A Framework for Operational Excellence and Compliance with Good Clinical Practice (GCP) Foundational Introduction What defines “quality” within the framework of clinical research? To answer this question, one has to step back and start with the definition of “quality” per se. Universally, quality is defined as the degree to which a set of inherent characteristics of a product fulfils requirements and “inherent”, as opposed to “assigned”, means existing in the product. What are the quality “requirements” within the universe of clinical research? In the clinical settings, these are the applicable clinical research standards, regulatory requirements, and customer requirements as well as guidance and industry-wide practices and all these applicable requirements include the need for a Quality System (QS). Who are the “customers” in clinical research? Essentially, the “customer” can include the regulatory authorities, other clinical researchers and institutions, health insurance entities (governmental and/or private) and, most importantly, the public at large. What is the product of clinical research? In general, a product is an output from a process and the output from the clinical research process is “information”. Hence, for clinical research, the “inherent characteristics” need to be built in the clinical research system and its component processes (clinical trials) in order to produce the “correct information”; accurate, reproducible, reliable data with integrity and without errors that matter. Therefore, for the research to produce “quality” results, it needs to have a Clinical Quality Management System (CQMS). Fundamentally, a quality system (QS) is a set of policies, processes and procedures required for planning and execution (production/development/ service) in the area of an organisation (i.e., areas that can impact the organisation's ability to meet customer requirements)1, and for verification that the “requirements” are being fulfilled. While the International Council for Harmonization (ICH) has provided a guidance on a QMS for pharmaceutical manufacturing (ICH Q10), no such ICH or regulatory guidance exists for CQMS. Albeit a QMS can have same fundamental elements across different GxP-governed fields, managing quality varies tremendously between the different fields, such as, manufacturing, pre-clinical and clinical research. The extent of these differences reflects the difference in the risks associated with the research (e.g., procedures, investigational product, etc), to human subjects (participants), and conduct of the research team. For example, in a manufacturing setting, compliance with quality standards is largely dependent on the compliance of the manufacturing site and distributor employees, in clinical research it depends on the compliance of physicians, nurses, coordinators, designated study pharmacist (who may not always be a pharmacist by training), sponsor, and contract research organisation (CROs) and other external service provider (ESP) personnel and also, very 10 Journal for Clinical Studies

importantly, patients. The wide range of very different organisations/ participants and respective outputs is critical to the overall cumulative and, often, interdependent quality. This poses very different quality challenges and corresponding mitigation and quality management approaches. A diverse spectrum of individual entities, functions and organisations are responsible for the Total Clinical Quality (TCQ) and hence the TCQ is impacted by the quality output from each of these individual entities. There are usually several “independent” organisations participating in a study, each bringing their own experiences, interpretations of requirements including how quality is defined yet, as there is one final product for clinical research, results data, shortcomings in the quality constituent data could have an impact on the TCQ of the final results. Hence, a fundamental aspect of a successful CQMS is a shared responsibility for quality across functions within the sponsor organisation as well as with all the external entities/partners but while each is obliged to comply with the applicable regulations and GCP, the clinical research sponsor is ultimately responsible for the quality of output from all the contributing entities through risk-based activity oversight. So, the clinical research community has to establish, through consensus or as individual organisations a CQMS that fits its environment, respective regulatory requirements (and expectations), and works well with all the key stake holders and members of the research teams. So far, this journey has mostly achieved Clinical Quality Systems (CQS) but not a CQMS. So, what is the difference between a quality system and a quality management system? A Quality System typically focuses on a few areas of quality practices (techniques), such as organisational structure, responsibilities, written procedures (e.g., SOPs), processes, IT systems, and resources needed for implementing a Quality Management System (QMS). Quality management is hinged not only on service and product quality, but also on the methods to accomplish it. A Clinical Quality Management System (CQMS) can therefore be defined as “a system that should be used in clinical research to ensure Total Clinical Quality (TCQ) including; human subject protection, identification and reduction of recurring quality-related issues that undermine patient safety, data integrity and, hence, the reliability of clinical research results through ensuring that quality is built in the research systems (quality by design* (QbD)) and its component processes including clinical trial design (protocol), tools and methods for data collection, processing, data analysis and interpretation that are essential to decision making and data integrity. The CQMS should use a risk-based approach where methods used to control (QC) and then assure (QA) the research quality should be based on and proportionate to the risks. The QC and QA methods should be designed and timed to substantiate and assure that the design Volume 13 Issue 5

Regulatory (protocol) is scientifically sound, the personnel are appropriately qualified, the conduct (including outsource management and oversight) is well-controlled, the research documentation, data collection and systems used are robust, to ensure data accuracy, integrity, reliability, reproducibility, and verifiability throughout the lifecycle of a clinical trial. Clinical Quality by Design (CQbD), in clinical research, can be defined as a systematic quality methodology approach to clinical development that commences with predefined objectives and emphasises critical clinical processes, study data and process control, based on sound science and quality risk management. CQbD’s goal is to enhance the assurance of subject safety, effective delivery of quality data, and also significantly improve clinical research quality performance through quality risk management. To achieve all of the aforementioned objectives and deliverables, a Clinical Quality Management System (CQMS) should, at a minimum, have the following elements: 1. Clinical Quality Risk Management (CQRM) To build a QRM, the following principles have to be considered: • •

Clinical research sponsors should, using a risk-based approach, focus on trial activities essential to ensuring human subject protection and the reliability of study results. Identification and management of critical process and critical data.

Risk management Risk management concepts that have been described in scholastic settings, in other industries, and through standards such as ICH Q94, International Organization for Standardization (ISO) 310005, and ICH E6 (R2)3 provide, not surprisingly, different perspectives and scopes in risk management methods. A clinical research sponsor has to objectively and pragmatically assess and decide on an appropriate clinical quality risk management (CQRM) system, Quality Tolerance Limits (QTLs), and risk control that are fit-for purpose based on relevant attributes of the clinical research the sponsor intends to conduct. ICH E6 (R2) states, in Section 5.0.4, that the Sponsor should decide which risks to reduce and/or which risks to accept. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk. Research sponsors should establish predefined QTLs taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results. Detection of deviations from the predefined QTLs should trigger an evaluation to determine if action is needed.”3 A general risk management approach incorporates Risk Control, i.e., the methods for prevention of possible issues with the aim of mitigating undesirable consequences. Risk Control is a logarithmic decision-making process that should be incorporated in the QRM system to mitigate risk by avoiding it, reducing it to an acceptable level, or accepting it as is. Quality tolerance limits are included in ICH E6(R2) as a method of risk control.3 Risk minimisation should be built in, through early planning, by identifying early signalling metrics and mitigate the problems or mitigate the risks before they become active problems or issues. For example, appropriate Database/CRF edit checks can be added for critical exclusion criteria to avoid a potential safety impact of wrongly enrolling a subject. To achieve this, it is essential to utilise available relevant data and define QLTs for decision-making, then assess if they could cause problems and indicate whether corrective actions and preventive actions (CAPA) are warranted. www.journalforclinicalstudies.com

2. Clinical Quality Management Plan (CQMP) = Quality Control (QC) + Quality Assurance (QA): A Clinical Quality Management Plan (QMP) is required to conduct Quality Control (QC) and QA activities on key processes to realise more pre-defined, acceptable, and consistent quality of the output.2 A. Quality Control (QC): QC are the periodic operational techniques, checks and activities that need to be undertaken at each key step of clinical research within the framework of CQMS to verify that the requirements for quality of the trialrelated activities have been fulfilled, i.e., that clinical data are generated, collected, handled, analysed, and reported according to the protocol, SOPs, and GCP at each stage of the study.1 In clinical research, QC is the responsibility of the research team while QA is the responsibility of an independent entity. The latter exemplifies the concept of TCQ as a shared responsibility across the wide team. QC needs to be designed such that it can provide confidence that the: • Data generated from previous non-clinical and clinical studies that is relevant to the current study are thoroughly reviewed, analysed, and accurately reflected in the Investigator Brochure (IB), prior to developing a protocol for the current study. • Protocols, case report forms, and other operational documents are clear, concise, and consistent. • Data generated, during the study is the data stipulated in the protocol. • Data in the in the source documents have been accurately, completely, and faithfully entered into the study database via the case report form (CRF), i.e., to enable source data verification (SDV). The last two activities are covered by study data monitoring (at investigator sites and beyond). Risk-Based Monitoring (RBM) has revolutionised the way the monitoring part of QC is done through improving efficiency, focus on critical study processes and data, proactive, early, and real time risk assessment by leveraging existing data intelligence. RBM is a risk-based, methodical, individualised clinical trials monitoring system that is dynamic and adaptive. It’s based on a risk-based algorithmic monitoring plan that focuses on preventing or mitigating important and likely sources of error relating to trial-specific processes and data essential for subject protection and overall study quality6. The monitoring plan should be regularly and dynamically reviewed against clearly defined thresholds to adapt the monitoring. RBM should allow the establishment of intelligence trends to enable real-time decision-making.”6 • Data that will be “analysed” and “reported” is the (originally reported source) data recorded in the database. B. Clinical Quality Assurance (CQA): All those planned and systematic actions that are established to ensure that the trial is performed, and the data are generated, documented (recorded), and reported in compliance with GCP and the applicable regulatory requirement(s).1 QA includes the actions taken to ensure that the activity is conducted effectively and efficiently. Through reviews of the planned research protocols/plans, oversight (e.g., audits) of service providers, clinical investigator sites, etc. against the respective international standards such as GCP can ensure the scientific integrity, as well as protection of research participants’ rights, welfare, and safety. For CQA to successfully achieve these objectives, it needs to have the right expertise, a validated Journal for Clinical Studies 11

Regulatory independence from the operational research function and empowerment to effectively eliminate the risk of internal bias. The empowerment through positioning of the QA function as well as appropriate resourcing represents the sponsor organisation’s leadership commitment to quality. Independence should not preclude good added value interactive collaboration to ensure alignment of the unified objectives. To achieve its mission and objectives, CQA needs to have sound systems and tools including: • Quality Issue Management: i. Deviation management: Processes and tools for identification and escalation of protocol and GCP deviations and/or non-compliance with applicable regulatory requirements ii. Vigilant system able to swiftly identify, triage, and analyse issues iii. Sound Root Cause Analysis (RCA) methodology iv. Impact Analysis: Deviation/non-compliance Criticality Classification. Risk classification should be based on the impact of the issue/deviation/non-compliance as well as Probability and Detectability. Risk = Impact x Probability x Detectability So, for example, a “High” risk would be one which: • impacts the rights, safety, and well-being of trial subjects or data integrity, and • has high probability • is difficult to identify or often only detected by chance. While across the GxPs, deviations/non-compliances which are associated with a safety risk to human subjects are always considered as “critical”, risks are specific to the activity, and the respective impact. Different GxP-governed activities (e.g., GCP versus GMP or GLP) have different risks, different impact and, therefore, deviations and non-compliances should be assigned different criticality classifications within the different respective GxPs. Also, within the clinical functions such as clinical research (GCPgoverned) and pharmacovigilance (Good Vigilance Practice (GVP)-governed), the criticality classification of deviations and non-compliance criticality need to be specific to the activity concerned. Clear activity-based risk assessment can yield an equally distinct and clear definitions of criticality for that activity. v. Corrective Action and Preventive Action (CAPA) system based on a robust Root Cause Analysis (RCA) vi. Procedures for the identification, investigation, management and mitigation of scientific misconduct and fraud. Audits A risk-based, trial-specific, data-driven audit program that is interactive and works in tandem with other quality systems (e.g., Quality Control Monitoring, Central Data Monitoring, Statistical Data intelligence, etc.) will effectively achieve its intended objectives. The audit program should include auditing of: clinical operations systems, and component processes, clinical investigator sites, external service providers/vendors, essential documents (e.g. Protocols, Informed Consent Forms (ICFs)) and Clinical Study Reports (CSRs). The audit program should be agile for the research organisation conducting or sponsoring the clinical research. To this effect, it should incorporate audits of critical processes of the clinical system such as protocol development and review process, the CSR development including data generation and analysis and the review process, expertise and qualifications of the personnel involved, compliance with applicable regulatory requirements and internal procedures, etc. 12 Journal for Clinical Studies

It is essential to ensure that QC activities precede QA ones and not vice versa. 3. Resourcing, Expertise, Roles and Responsibilities, Training, and Partnering (including outsourcing): Organisations sponsoring clinical research should prospectively assess the necessary expertise, with clear accountability (roles and responsibilities) maintaining a robust infrastructure that is guided and governed by a CQMS: A. Expertise at the sponsor (e.g., Study Physicians, Safety Management, Medical Monitoring, Data management, Biostatistics, Medical Writing, and Subject Matter Experts (SME) experts, etc.) B. Qualification and Training: Training with focussed training content and a validated effectiveness (interactive delivery and validated with tests will pay dividends along the journey). A “read and understood” might neither suffice, as an effective training, nor has it been proven to be effective for several critical processes. For critical processes with a high potential impact, a verifiable training evaluation approach such as a “sign-off” “release to conduct the task unsupervised,” or a test should be considered.7 C. Clinical Research Organizations (CROs)/Vendor/External Service Providers (ESPs) Management and Oversight: This topic is covered in detail in another publication7 which provides a QA analytical perspectives and practical recommendations for the full cycle of Vendor/CRO/ESP management from the selection process through management and Vendor Oversight process.7 D. Investigator selection and management: Research sponsors need to challenge the traditional definitions and approaches and adopt pragmatic, verifiable data-driven selection process, not just a checklist. In other words, a selection process documented by (amongst other documents) a checklist rather than a selection process that is confined to a checklist. Considering that one of the most notable audit and inspection finding at investigator sites is lack of oversight by principal investigators, sponsor should ensure that the selection is based on verifiable (rather than merely declarative) ascertainment that the principal investigator has sufficient time to properly conduct (and/or supervise) and complete the trial. While Opinion Leaders are usually resourceful for input into certain aspects of trial design, it does not always follow that they would be good “trialists”. The sponsor should seek confirmation of availability of target patient population based on retrospective data and taking into consideration the trial´s inclusion and exclusion criteria. A good site is a site that delivers: • Correctly randomised subjects not just high number of randomised subjects. • Subjects that can be included in the Per Protocol analysis rather than numerous avoidable important deviations rendering substantial number of subjects illegible for Per Protocol analysis • Well-managed and tracked subjects ‘Good subject management’. • “Direct” access to trial subjects ‘records. Albeit, it sounds very straightforward, the numerous occasions where nondirect or problematic access is identified after the trial has started warrants a reflection on the site feasibility and selection methodology. The recent COVID-19 pandemic has left its additional footprint on the way sponsors and clinical sites need to adapt the whole monitoring strategies which must guarantee private data protection, validated technical tools, as well as adequate direct, yet remote secure access. • Quick response to queries Volume 13 Issue 5

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Protocol and GCP Compliance Accurate data based on correct use of study assessment tools (key effect parameter) and high-quality and timely safety reporting. • Good, usable (correct & precise) data. Absence of errors that matter. Good Site Management Practice (GSMP) is a life cycle process that should invariably include such elements as: • Pre-Site Feasibility (Interactive, evidence-based, and verifiable process), • Site Selection process based on a protocol-specific criteria, • Site Staff Training (protocol-based and includes real life examples of consequences of non-compliance). QA is best suited for GCP training of sites. • Site Initiation (interactive and equipped with emphasis on potential sources or error and pitfalls), • Site Risk- Based Monitoring (RBM) as mentioned above, • Appropriate sponsor protocol- and risk-based oversight plan • GCP QA risk-based site audits, and support before, during and after regulatory authority inspections. Site Management should be supportive but assertive taking into consideration that GCP “requires sponsors to secure compliance” and not just report it. 4. Research Design (clinical trial protocol): While GCP provides high level guidance on the calibre and bandwidth of the experts who should participate in developing study protocols, CRFs and planning the analyses (e.g., biostatisticians, clinical scientists, and physicians), only a robust CQMS will ensure that these experts achieve a scientifically validated as well as operationally sound protocol through am appropriate risk assessment and management, validated QC and QA processes (e.g. protocol audit) to ensure compliance with GCP, applicable ethical standards and regulations. Critical process and data identification: The first critical process and foundational block in clinical research is the design of scientifically sound but also operationally implementable clinical trial protocols, tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making. One of the most common myths and pitfalls that have been encountered, in recent years, is the assumption that the identification of critical processes could be done after a protocol has been developed. The first “critical process” in clinical research is “protocol development” followed by identification of critical processes (and data) relevant to that protocol. Robust protocol design should be coupled with identification of those processes and data that are critical to ensure human subject safety and trial data integrity. The sponsor must, therefore, during the protocol development, identify processes and data that are critical to ensure human subject protection, reliability of trial results (data integrity), and associated risks. Based on the identification of the critical processes, research sponsors should conduct a risk assessment and evaluation at both the Quality System level (as defined above) and clinical study level (e.g., trial design, data collection, informed consent process, etc.)3 to ensure that the identified risks are managed through targeted and effective risk mitigation and that controls are established to minimise and/or eliminate the errors that matter. 5. Management of Clinical Operations, Clinical Data Processing, and Documentation (Trial Master File (TMF)): Processes and tools for managing research documentation (e.g., TMF) should be developed to: www.journalforclinicalstudies.com

A. Enable efficient operations of research, accuracy of the documents, procedures and plans to be followed. B. Have a complete, operational and inspectable TMF to demonstrate compliance with GCP and appliable regulatory requirements and hence subjects’ protection, safety and reliability of data generated. A TMF should actually be used throughout the trial as intended, the “master file” rather than a file that is prepared solely for the purpose of regulatory inspections. This approach enables a win-win situation and successful outcome in that using the TMF operationally, throughout the trial life cycle, will act as a continuous dynamic QC and ensure its completeness in real time rather than discovering its shortcomings, its incompleteness, its difficulty of use, etc during a regulatory inspection. Finally, to ensure public health, governmental Regulatory Authorities (RAs) incorporated GCP into laws to provide parameters to protect the research subject and the integrity of the research and its data and conclusion. RAs enforce these laws through surveillance (routine ongoing monitoring and inspections) and enforcement actions when deemed necessary. So, the role of the RAs is a two dimensional one; public protection during the conduct of the clinical trials through provision of the regulations with corresponding enforcement if needed, guidance as well as being one of the “customers” for the output of clinical research, the outcome data which the RA assesses against scientific and quality criteria. REFERENCES 1. 2. 3.

4. 5. 6. 7.

Alghabban A. Dictionary of Pharmacovigilance (published May 2004 by Pharmaceutical Press), ISBN-13:978-0853695165. Alghabban A. Pharmaceutical Medicine Dictionary (published by Elsevier Health Sciences Apr 2001), ISBN: 9780443064753 International Council for Harmonization of Technical Requirements for Pharma-ceuticals for Human Use. ICH Harmonized Guideline. Guideline for Good Clinical Practice (GCP) E6(R2). Current Step 4 version dated November 9, 2016. ICH guideline Q9 on quality risk management, EMA/CHMP/ICH/24235/2006, September 2015. 21/30430517 DC BS 31100. Risk management. Code of practice and guidance for the implementation of BS ISO 31000:2018 Alghabban A. Unlocking the Potential of Risk Based Monitoring in Oncology Clinical Trials, Clinical Trials Arena (Nov 2017), http://bit.ly/2zobEhK Alghabban A. What to look for in selecting a CRO/CMO and how to ensure the right choice: a quality assurance perspective. Pharm Outsourcing. 2015;16(2):14-21.

Amer Alghabban Amer Alghabban, pharmacologist, is MD of GxP Compliance & Training Partners (GCTP) with over 30 years’ experience within pre- & clinical R&D, pharmacovigilance and GxP (GLP, GCP, GCLP & GVP) QA. Invited speaker at over 130 conferences, the author of The Pharmaceutical Medicine Dictionary and The Dictionary of Pharmacovigilance amongst others. Previous positions; VP QA Compliance & Training at Karyopharm, Global Head QA at Merck Serono, Global Head GxP QA at Arpida, Clinical QA Manager at Novartis, and first Pharmacovigilance Compliance Officer of the MHRA, Assistant Editor for 11 medical journals and Course Director-RQA Pharmacovigilance Auditing Course. Email: amer@gxpcomplianceandtraining.com

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Operationalising Decentralised Clinical Trials (DCTs) – The Challenges and Change Management Approaches, Considering Trial Designs and Timelines with Decentralisation Methods at the Forefront While components of fully decentralised clinical trials (full DCT) and hybrid decentralised clinical trials (hybrid DCT) existed prior to the COVID-19 pandemic, the ongoing public health crisis accelerated the demand for DCT-based approaches. During COVID-19, the pharmaceutical industry was focused on managing participant safety and ensuring data integrity for COVID-19 vaccine trials and other ongoing traditional trials, many of which were put on hold due to the inability of participants to travel to sites in the traditional trial model. These traditional trials were salvaged by amending them while implementing trial-related activities remotely following DCT principles. Nonetheless, many sponsors are still experiencing challenges with communication technologies, digital health technology tools, and operational processes used in DCTs as they retrofit ongoing traditional trials or set up new DCTs. The issue is that industry in many instances is still approaching trials in the same way as practiced for the past twenty years with the expectation that the new communication technologies, digital health technology tools, and operational processes will fit into the same mould and follow the same timelines as a traditional trial with in-person visits to traditional sites. For instance, some sponsors utilise certain remote participant assessment instruments supported by technology such as electronic Patient Reported Outcomes (ePROs) as an add-on instead of building it into the initial protocol design as part of the trial strategy and data architecture. DCT components, such as digital health technologies (i.e., wearable devices), communication technologies (i.e., telehealth visits via videoconference) and/ or inhome clinical services (i.e., home health nursing services), are not being added until the later stages of protocol development thereby creating challenges to operationalising the final protocol and impacting overall feasibility. By not having a cohesive DCT strategy that considers the wider perspective of trial endpoints, participant journey, data architecture that is fit-for-purpose, and regulatory requirements across multiple jurisdictions, trial inefficiencies will continue occurring such as trial delays due to enrolment and retention issues and inefficient use of DCT components. Persistent inefficiencies may be observed at the participant, research site staff and sponsor level unless changes occur to adopt DCT principles as customised solutions. For our industry to transform to DCTs there is a need for new methodologies that incorporate protocol development, enable the customisation of individual trials and an acknowledgement that over time traditional trial activities, framework and roles will be changed or replaced. How do we change our current approach while we await the industry, regulations and technology to align? To move forward, we must look beyond the past and current efforts to pandemic proof trials and focus on truly designing and implementing DCTs. A few approaches that we can take include: 1) re-assessing in-flight/ new trials to add fit-for-purpose DCT 14 Journal for Clinical Studies

components; 2) evaluate trials in early development (pre-protocol) or in pipeline through DCT principles and perspectives; and, 3) restructuring the current modus operandi to transform clinical development, enabling a more swift transition to approaching modern trial designs. To accomplish this, change management will be required not only for the industry but especially also to personnel in research sites (i.e., investigators and trial staff). The research participant may have never known about clinical trials before, so for them the change from traditional trials with inperson site visits to DCTs that may involve telehealth visits may not be equally revolutionary, as it would be for personnel in research sites and overall for trial teams. There needs to be an understanding that when introducing DCT components as contingency measures rather than mandatory/built in by-design, this will not necessarily reflect the actual potential and value of decentralisation of a trial. If neither personnel at research sites nor participants are obliged through circumstance to utilise the DCT components, such as we witnessed during the COVID-19 pandemic, then site personnel will fall back to their default ways of working. Much like neurons that wire together, fire together. Changing site personnel behaviour and habits will take time and is not to be underestimated. Although we are designing the DCTs with the safety and convenience of the participants first in mind, site personnel are the catalyst to a successful DCT deployment and they need to be part of the journey. To fulfil the promise of DCTs, we need to build trust with personnel at the research sites, which, in turn, will increase participant engagement and successful deployment of DCT components. If we look at current trials in-flight (retrofitting DCT components) or in early start-up, due diligence is needed to assess the feasibility of conducting participant-centric trials, and appreciation that DCTs may or may not be the most suitable solution. For example, the trial team may want to add eConsent to a trial, however, if this is the only DCT component added, you need to query will this justify the additional cost, effort and operational complexities for all stakeholders? Will this one DCT component bring value to a participant that will still need to travel to a research site for a screening visit, where Consent could be easily collected in-person? Does the additional technology the site personnel need to train and utilise reduce or increase their burden? Can the additional study costs, efforts, and operational complexities to deploy this one component be justified? Probably not. Another example we have seen is adding multiple apps and digital platforms to a trial for participants (and for site personnel and trial teams) to use, e.g. one with eConsent and the other one with an electronic clinical outcome assessment (eCOA). This is not a participant-centric approach and neither reducing the burden for site personnel or participant. Multiple technologies and login requirements may risk the opposite of the promise of DCT strategies and customised solutions. If a participant is required to use multiple digital platforms and wearable devices (i.e., use of multiple digital interfaces), especially with no Single Sign-On in place, we increase the participant burden, risk reducing participant recruitment and retention, and risk data entry compliance among many other aspects that translate into trial inefficiencies. While we wait patiently for the industry, regulations, and technology to align, we need to recognise that this will not be a sprint Volume 13 Issue 5

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but a marathon. However, we also need to continue to drive adoption of DCTs and keep reassessing if the strategies we implement truly bring value and reduce burden to all stakeholders (participants, investigators, site personnel, clinical operations teams, etc). This is where trials in early-development (pre-protocol) or in pipeline are a better fit to for decentralisation approaches than in-flight trials. While almost all clinical trials can adopt a hybrid DCT approach, in evaluating the best method – whether traditional, hybrid DCT, or full DCT – sponsors should follow five considerations outlined below to increase the probability of trial success. These considerations should be evaluated during early protocol development. The earlier the operational model considerations take place; the stronger the foundation is set for a successful implementation of a DCT. Choosing the study design The study design should consider the full participant journey from pre-screening to trial completion with the goal of reducing the participant burden, while collecting the data necessary to adequately assess the safety and efficacy of an investigational medical product. The trial design should inform which DCT components will produce the required data while considering the appropriate target population. For example, an interventional trial that has a high touchpoint and that involves specialised surgical procedures for participants, such as a neurology trial, may be suited for a hybrid DCT approach (some visits conducted away from the research site investigator), but may be less likely to transition to a full DCT approach. In contrast, non-interventional studies or low touchpoint interventional trials may be better suited to a full DCT programme. As part of the trial design, the data architecture needs consideration as well: the data flow, collection, storage and transfer all need to be considered. www.journalforclinicalstudies.com

Deciding endpoints and clinical assessments Sponsors will need to consider how endpoints, as well as clinical assessments will be measured, collected and confirmed. Will they be collected digitally (wearable devices, ePROs, etc.)? Can they be recorded or observed via telehealth (rash, fever, etc.)? Can they be collected via home-health visits by specialised medical personnel (blood pressure, blood draw, etc)? Finally, which technology solutions are accepted and authorised by regional and local regulatory authorities, and will that data be accepted by regulatory authorities? When selecting technology to support the trial design, help-desk support needs to be included by default to guide participants, site personnel and trial teams in case of technical queries, being cognizant that not all end-users are not experts in wearable devices, digital platforms, or applications that may be deployed. Considerations for language translations, as well as potential bandwidth constraints, should be also understood. Since more data is being collected using digital health technologies, telehealth, and mobile health applications, remote monitoring becomes more relevant as there is access to data in real-time or more frequently as specified by DCT protocols. Data monitoring becomes data science, and your clinical team needs to transform its operations to adjust to new dataflows. Considering the investigational medical product If a new drug that is being evaluated in a trial has a well-characterised safety and toxicity profile, then it could lend itself to a DCT approach. On the other hand, if there are concerns about the toxicity of the drug, a hybrid DCT approach may be a better strategy. In this case, a sponsor may choose to have the first dose administered in the clinic, allowing the participant to get accustomed to the drug and the Journal for Clinical Studies 15

Regulatory to occur beyond one protocol and for decentralisation approaches to become a mainstream in clinical research, these considerations among others should become part of our industry’s clinical operations processes.

Kamilla Posselt

physician to observe the participant post-dose for potential adverse reactions. Follow-up dosing appointments may be completed at home under the supervision of a nurse or other healthcare professional. Additional considerations include whether the drug evaluated in a trial is easy to self-administer which could include in home administration by home nurses or an existing, trained caregiver. This solution can be augmented by developing eLearning selfadministration videos which also direct the participant and caregiver to follow special storage requirements and return unused experimental medical products. Regardless of the trial’s design (whether hybrid DCT or full DCT) it is important to consider the logistics of clinical and non-clinical supplies directly shipped to the participant (Direct-To-Patient) without posing a burden or inconvenience and while in compliance with laws and regulations across multiple jurisdictions. Determining specific participant population needs Sponsors will want to consider the particular participant population enrolled in the trial. For example, in a rare disease trial, the participant population may require family, guardians or other caregivers to help them travel to a site. This would also apply for protocols targeting paediatric or elderly populations. Therefore, it is advisable to review what can be done to make it easier for the participant to remain engaged. One solution is to provide concierge services, and transportation services for participants with hindered mobility or for participants in remote geographic locations. In addition, incorporating digital health technology solutions (e.g., wearable devices), communication technologies (e.g., cell phone apps), or inhome services by medical professionals (e.g., home health nurse services) can further alleviate participant burden. Understanding jurisdictional laws and regulations When deploying a hybrid DCT or a full DCT approach, sponsors will also need to consider the fact that certain operational solutions may work in some but not all jurisdictions within a country or between countries involved in a particular DCT. Therefore, sponsors will need an understanding of the local and regional laws and regulations, where deploying specific DCT operational solutions, such as eConsent, make the most sense, and how quickly they can be engaged across multiple jurisdictions and in different countries. In conclusion, DCT solutions are not categorised as a one-size fits all trial designs. It is vital to understand the needs of the targeted participant population and gain the trust of the research site investigators and site personnel to ensure adherence to protocol operational procedures and utilisation of the chosen DCT components. For change management 16 Journal for Clinical Studies

Kamilla Posselt is Director of Decentralized Trials with proven ability to lead, develop and achieve successful operational business delivery and growth. She is passionate about streamlining the clinical research approach and identifying bespoke strategies and solutions that will suit patients, sites, study teams and bring benefits to clients. Since joining ICON in 2005, Kamilla has been engaged in various roles within clinical operations, as well as in strategic partnerships and alliance management. Kamilla has driven the development of operational strategy and framework solutions between ICON and several Top 50 Pharma clients. She is currently managing ICON’s decentralised trials vendor team by developing the infrastructure, technology and operational framework for success, as well as providing consultancy to clients on decentralised operational considerations.

E.B. McLindon E.B. McLindon is an accomplished senior executive with proven the ability to build, develop and achieve successful business growth. He is passionate about engaging patients and sites to simplify the research journey and supporting sponsors in recruiting and retaining patients. Since joining ICON, E.B. has driven the development of ICON’s site and patient strategy and led a large team of functions in the delivery of solutions including; Accellacare ICON’s global clinical research site network, Symphony ICON’s in-home health provider, patient recruitment and retention services and FIRECREST digital solutions. He is currently providing consultancy to help sponsors realise the potential of decentralized trials by developing the infrastructure, technology and operational framework for success. Previously EB had a key role in the development of Accelovance, a CRO that owns and operates clinical research sites

Dr. Isaac Rodriguez-Chavez Dr. Isaac Rodriguez-Chavez is a biomedical leader with expertise in Virology, Microbiology, Immunology, Vaccinology, and Viral Oncology. His expertise spans basic, translational, preclinical and clinical research (phase I–IV global trials). He also has expertise in digital health technologies, clinical research development and operations, regulatory affairs, approval or licensure of medical products, and quality control and quality assurance. Overall, Dr. Rodriguez-Chavez has over 32 years of work experience in several national and international organizations, including the U.S. Food and Drug Administration (FDA), National Institute of Health (NIH), industry and non-profit research organizations. He has a B.S. in Biology (Venezuela), M.S. in Microbiology (Venezuela), M.H.S. in Clinical Research (Duke School of Medicine), and a Ph.D. in Virology and Immunology (University of Delaware). He did two post-doctoral trainings in Viral Immunology and Viral Oncology at the National Institute on Aging (NIA) and the National Cancer Institute (NCI) at NIH.

Volume 13 Issue 5

KEEP YOUR STUDIES IN

MOTION

Agility. Flexibility. Reliability.

You Work Every Day to Find a Better, Faster, and Smarter Way to Bring Your Therapeutics to Patients in Need. Shouldn't your lab partner do the same? MLM Medical Labs is an industry-leading specialty and central laboratory with comprehensive standard and fully customizable biological research services and analytical capabilities across a wide spectrum of therapeutic areas. Our strong reputation for scientific expertise, agile solutions, passionate customer care, and quality data adds value at every stage of the drug development process. For three decades, we have empowered customers from emerging biotech to top ten pharma to reach confident clinical decisions that improve patient lives.

Find our team at these upcoming 2021 events! - BIO Europe | 25 - 27 Oct - OCT New England | 09 - 10 Nov - OCT Nordics | 26 - 27 Oct - OCT DACH | 24 - 25 Nov - Biomarkers UK | 08 - 09 Nov - American Society of Hematology | 11 - 14 Dec Learn what keeps #MLMinMotion at www.mlm-labs.com www.journalforclinicalstudies.com

Journal for Clinical Studies 17

Regulatory

Overview: Pharmacovigilance and Risk Management Drug development is an expensive, lengthy, and high-risk business taking 10 to 15 years and is associated with a high attrition rate. Approximately 1 in 10 drugs that start the clinical phase will make it to the market.1 Research on a new medicine does not end when the discovery and development phases are completed, and the medicine is available to patients. On the contrary, companies conduct extensive post-approval research to monitor safety and longterm side effects, and may also pursue research into new indications for the medicine in different disease areas, age groups, or other patient populations.2 Additional clinical value of therapies is realised over time through many different pathways, leading to expanded and improved use of a drug. One of the most important responsibilities of pharmaceutical companies is assuring the protection of human subjects. The history of egregious failures in this regard means that all stakeholders must remain ever-vigilant. The human experimentation in World War II Germany and Japan, and the Tuskegee syphilis study of 1932 to 1972 in the United States, bear witness to these failings. And it was followed by societal and institutional responses: the Nuremberg Code of 1947, the Declaration of Helsinki of 1964, and the Belmont Report of 1979.3 Pharmacovigilance is relevant for everyone whose life is touched in any way by medical interventions. The World Health Organization (WHO) defines pharmacovigilance as the science and activities relating to the detection, evaluation, understanding, and prevention of adverse reactions to medicines or any other medicine-related problems.4 The assessment of benefit versus risk begins during the preclinical evaluation of a medicinal product and extends throughout its full life cycle. As a result, there is added focus on safety and risk assessment after a product has received regulatory approval, when it is placed in the market and prescribed to large populations. Risk management is a set of activities performed for identification of risk, risk assessment, risk minimisation or prevention, and risk communication.5 Good pharmacovigilance identifies the risks in the shortest possible time after the medicine has been marketed and will help to establish and/or identify risk factors. When communicated effectively, this information allows for intelligent, evidence-based prescribing with potential for preventing many adverse reactions and will ultimately help each patient to receive optimum therapy at a lower cost to the health system.6 Operational Aspects of Pharmacovigilance and Risk Management Pharmacovigilance and risk management are essential part of pharmaceutical product development and commercialisation, the activities of which are highly regulated in many parts of the world. Rare adverse events may not be identified until large number of patients receives the product, so benefit and risk must be continually assessed as more data becomes available about the product through its use. Building pharmacovigilance and risk management capacity requires a systematic approach to ensure that all safety aspects are monitored and addressed properly (see table below).3 18 Journal for Clinical Studies

Activities currently included in the scope of pharmacovigilance: Category

Specific Activities/Functions

Phase(s)*

Supporting patient safety during the conduct of clinical trials

Informed consent, institutional review board, data monitoring committee

1 to 4

Selecting the first safe dose; first-in-human

Preclinical data, especially PK/PD parameters

Establishing the safety profile

Assessing all phases of development, focusing on dose-limiting toxicity, maximum tolerated dose, AEs of special interest, on-target and off-target toxicities

1 to 4

Communicating information to stakeholders

Maintaining standard formats: Investigator’s Brochure, Company Core Data Sheet, package insert, patient package insert, ClinicalTrials.gov

1 to 4

Attending to surveillance activities

Determining relationships between drugs and adverse events through passive and active methods

1 to 4

Monitoring safety-related issues that involve the quality of the manufactured product

Conducting health hazard assessments for manufacturing deviations, complaints

1 to 4

Managing risk: REMS, RMP

Understanding benefit-risk across patient populations and uses

1 to 4

Maintaining inspection readiness

Preparation for scheduled and unscheduled inspections of department activities

1 to 4

Training

Clinical investigators; internal customers throughout the company; vendors

1 to 4

Advertising and promotion review

Assuring consistency with important safety information

Providing medical information to health care professionals

Support for professional queries regarding product complaints, AE reports, product use

Conducting due diligence

Understanding critical safety information about products being considered for merger, acquisition, or licensing activities

1 to 4

AE = adverse event; PK/PD = pharmacokinetics/pharmacodynamics; REMS = Risk Evaluation and Mitigation Strategy; RMP = Risk Management Plan. *The phase(s) of the drug development process that include the described activities.

Three core functions of pharmacovigilance are: individual case safety reporting, signal management, and benefitrisk management. There are certain components and capabilities that are essential to have fully functioning pharmacovigilance system, regardless of how a company’s safety department is constructed.7 These include: • • • • • • • •

quality management plan (QMP) including standard operating procedures (SOP) and work instructions (WI) safety case processing and review safety systems (database) support global safety reporting medical writing and aggregate reporting signal management and risk analysis product quality complaints analysis a qualified person for pharmacovigilance (QPPV) (Europe)

The global pharmacovigilance market is segmented based on phase of drug development, type of reporting methods, and type of service providers. On the basis of phase of drug development, the market has been segmented into preclinical studies, clinical studies (phase I, II, III), and postmarketing surveillance (or phase IV). On the basis of type of reporting methods, the market has been segmented into spontaneous reporting, intensified adverse drug reactions (ADR) reporting, targeted spontaneous reporting, cohort event monitoring and electronic health records mining.8 Volume 13 Issue 5

Regulatory Following proactive measures could help to achieve effective operational alignment:9

Following proactive measures could help to prepare an effective risk management strategy:9

•

Align operational activities across different functional groups and reorganise it as needed for continuous improvement Implement well-defined decision-making models, escalation processes, and communication channels Retain key pharmacovigilance personnel with cross-disciplinary expertise and skill sets Establish corporate IT platform and have vision for a long term strategy

•

Risk Management Overall, risk management should ensure that the benefits of a particular medicinal product exceed the risks by the greatest achievable margin. The risk management plan (RMP; for European Union) and the risk evaluation and mitigation strategy (REMS; for the United States) are now a standard part of pharmacovigilance planning. The guideline intended to aid in planning pharmacovigilance activities (ie, ICH E2E)10 was originally created to achieve consistency and harmonisation, particularly during the early postmarketing period of medicinal products. Within the past few years, the United States and European regulatory agencies have increased their guidance on benefitrisk assessment and risk minimisation. The intent of both the RMP and the REMS is to minimise risks related to a medicinal product through interventions and to communicate those risks to patients and healthcare providers. Recently, regulatory authorities are emphasising more on effectiveness check of risk minimisation activities.

•

• • •

Develop an objective, data-driven, team-oriented approach to risk monitoring and evaluation Determine the pharmacovigilance workload and sufficiently resource the required effort Implement workflow management technology to ensure appropriate transparency and accessibility of safety information Select a vendor that best matches the pharmacovigilance operating model, business process and vendor/system selection criteria Develop risk management action plans based on pre-established risk scoring mitigation processes

Market Overview Pharmacovigilance has been fundamental to pharmaceuticals industry; however, it has been monitored and followed critically by regultory authorities and companies. The growing number of drug patient approval has made it tough for companies to monitor pre and post effect of each and every drug on the human. That is a prominent reason behind the splendid growth of the pharmacovigilance outsourcing market.11 The pharmacovigilance market was valued at approximately USD 5.6 billion in 2020, and it is expected to reach 8.6 billion by 2026, registering a CAGR (ie, compound annual growth rate) of nearly 7.54% during the period of 2021–2026.12 The key factors propelling this market are increasing drug consumption and drug development rates, growing incidence rates of ADR and drug toxicity, and increasing trend of outsourcing pharmacovigilance services. The increasing incidence of lifestyle-related diseases, such as diabetes, hypertension, and cardiac disorders, as a result of sedentary lifestyles, lack of physical activities, changing lifestyle patterns, and poor diets, leads to increased consumption of drugs, which indicates the high demand for drug monitoring and fuels the growth of the market. With the growing drug consumption, the need for regular monitoring of drugs has also augmented, eventually boosting the pharmacovigilance market.12 The emergence of COVID-19 has brought the world to a standstill. This health crisis has brought an unprecedented impact on businesses across industries. Rising support from governments and several companies can help in the fight against this highly contagious disease.13

Additional activities such as active surveillance, other clinical or epidemiological trials, specialised training, or restricted access may be included in the plan. The activities must be sufficient to minimise the likelihood of harm so that benefits still outweigh risks, and to ensure that the risk reduction procedures are communicated and implemented. Consequences of finding a significant safety issue may include any of the following activities:11 Pre-marketing actions include • • • • •

Amending the protocol Temporarily suspending enrollment Discontinuing the study Discontinuing development of the medicinal product Updating a development RMP/REMS

Post-marketing actions include • • • • • • • •

Enhanced monitoring Mechanistic safety studies Variation of CCSI / SPC / product information leaflet Post-authorization safety studies (active/passive) Update of the RMP Presentation of the signal in the PSUR Provision of the safety information to HCP and/or patients Suspension, withdrawal or revocation of the marketing authorization (with recall of the medicinal product)

CCSI = company core safety information; HCP = healthcare professional; PSUR = periodic safety update report; RMP = risk management plan; REMS = risk evaluation and mitigation strategy; SPC = summary of product characteristics

www.journalforclinicalstudies.com

The rising demand for drugs has significantly increased the need for new drug development via extensive clinical trials. Manufacturers are now focusing on remodelling their drug development processes to cater to patient needs across the globe. Presence of a competitive milieu has led to improved manufacturing operations, pharmacovigilance system, clinical data management, streamlined research and development (R&D), and medical writing. Manufacturers are rapidly considering outsourcing as a viable cost curbing tool. Moreover, organisations are targeting Asia Pacific countries, such as India and China, to conduct clinical trials owing to a wide presence of skilled labour, lower infrastructure & manufacturing costs, and presence of a large patient pool.14 Pharmaceutical companies are facing productivity crisis and their R&D investments have increased. Hence, the demand for postmarketing surveillance and safety services is increasing. Key Factors Driving the Global Pharmacovigilance Market Growing consumption of medicines: The primary driving factor for growth of the pharmacovigilance market is the significant increase Journal for Clinical Studies 19

Regulatory witnessed in the intake of medical drugs. Besides, increase in prevalence of acute and chronic diseases has consequently led to an increase in incidences of drug consumption, thereby leading to a rise in the number of adverse drug events and drug toxicity cases. This, in turn, has triggered the growth of the pharmacovigilance market globally.8 Increasing incidence of ADR and drug toxicity: The global pharmacovigilance market is primarily driven by the rising incidence of ADR, soaring patient awareness regarding safety of drugs, and stringent regulations by various agencies related to drug approvals. Strict guidelines related to clinical trials of new drug therapies and mandatory requirements to keep electronic medical records have propelled the growth of the pharmacovigilance market. Initiatives taken by regulatory agencies, such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA), and global organisations such as the WHO have mounted pressures on several biotechnology and pharmaceutical companies to manufacture safe drugs. This is expected to stimulate the demand for pharmacovigilance.15 Regulatory burden on manufacturers: The pharmaceutical industry operates in one of the world’s most regulated environments. Over the lifecycle of a drug, companies must adhere to both commercial compliance (such as Anti-bribery and Corruption [ABAC]) and industry specific compliance obligations (such as Good Clinical Practice [GCP], Good Pharmacovigilance Practices [GVP], and Good Manufacturing Practice [GMP]). Regulatory authorities continue to increase their compliance oversight and enforcement activities for existing laws. Indeed, those organisations who successfully implement an effective regulatory compliance framework are likely to be able to differentiate themselves from their peers, by articulating to patients the rigor invested in the development, and on-going manufacture and use of drugs, to deliver improved health and quality-of-life outcomes.16 Introduction of software services: A critical component of good pharmacovigilance practice is centred on acquiring complete quality data from reported source on adverse events. The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events. The development and use of standardbased pharmacovigilance system with integration connection to electronic health records and clinical data management system holds promise as a tool for enabling early drug safety detections, data mining, results interpretation, assisting in safety decision making, and clinical collaborations among clinical partners or different functional groups.9 The innovations created by the healthcare industry, such as artificial intelligence, next generation sequencing, and telehealth, are being used to combat everyday illnesses and conditions, and play a major role in the ongoing fight with the various diseases.17 Rising investment in R&D by healthcare companies: With the rising costs seen in the healthcare industry, there has also been a significant rise in health care R&D. In 2016, pharmaceutical firms spent $156.7 billion globally. Roche and Novartis were the largest investors in this space, spending $8.7 billion and $7.9 billion, respectively.18 Per the Center for Medicare and Medicaid, national healthcare spending in the United States is expected to grow at an average annual rate of 5.4% from 2019 to 2028.17 The research done by the pharmaceutical companies will lead to better and more innovative healthcare drugs, products, and services. Partnerships and collaborations: Prominent industry players operating in the pharmacovigilance outsourcing market are LabCorp Drug Development, ICON, Syneos Health, Parexel, PPD, IQVIA, Cognizant, and Tata Consultancy Services.19 These players are 20 Journal for Clinical Studies

actively indulged in several strategic initiatives including mergers and acquisitions, business partnerships and collaboration to strengthen foothold over the market and capitalise on market opportunities. In June 2018, Covance’s (now LabCorp Drug Development) acquisition of scientific process outsourcing company Sciformix strengthens its position in the later phases of drug development.20 During the same time in 2018, Genpact, a prominent player acquired Commonwealth Informatics, a leading provider of cloud-based drug safety analytics services. This move is expected to help Genpact strengthen its hold over pharmacovigilance artificial intelligence and cloud computing capabilities. Thus, ensure a strong hold over drug safety thereby fostering company’s growth.11 Market Restraints All new medicines introduced into the market are the result of lengthy, costly and risky R&D conducted by pharmaceutical companies.21 Regulatory policies vary across countries, thereby making it difficult for pharmaceutical companies to meet the specific requirements. Moreover, pharmacovigilance is a continuously evolving process and, therefore, researchers need to constantly educate themselves in line with the frequent changes in rules and regulations. Problems resulting from irrational drug use, overdoses, polypharmacy and interactions, increasing use of traditional and herbal medicines with other medicines, illegal sale of medicines and drugs of abuse over the internet, increasing selfmedication practices, medication errors, and lack of efficacy are all within the domain of pharmacovigilance. Additionally, the process of pharmacovigilance requires the use of skilled professionals to manage adverse events and clinical-trial activities, and contribute to ensure regulatory compliance.22 Some of the major challenges faced pharmacovigilance are as follows:23 •

• • •

• •

•

Quality and quantity of information received in post-marketing vary by sources and has inherent limitations – both the factors are challenging to deal with as they are required for critical decision making in risk management The globalisation of drug distribution and the increased exposure of massive populations to large volumes of medicines. The Internet, in addition to its many benefits, has also facilitated the uncontrolled sale of medicines across national borders. The scope of pharmacovigilance continues to broaden as the array of medicinal products grows. There is a realisation that drug safety is more than the monitoring, detection, and assessment of ADRs occurring under clearly defined conditions and within a specific dose range. Rather, it is closely linked to the patterns of drug use within society. There are shortcomings and at times conflicting interests within the pharmaceutical industry when dealing with public health concerns arising from drug safety issues. The generic sector, which is the largest supplier of essential drugs, has not fully recognised its responsibility to continuously monitor the safety of its products throughout the world. There is the erroneous belief that generic drugs are inherently safe even when they interact with other medicines. Current trends have dramatically changed the way in which medicines are used by society. The perception of risk versus benefit for medicines have not been considered in a meaningful way. The harm caused by medicines has been shown to be significant.

Existing systems need to evolve to address this broad scope adequately. A focus must be to empower health practitioners and Volume 13 Issue 5

Corporate Profile

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

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

• •

• • • • • •

Medical Centre Ramus with Phase I Unit

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

• • • •

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

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

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

• • •

• •

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

, fast, correc t! Safe

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

Medical Diagnostic Laboratory Ramus Ltd

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

Ramus Medical Ltd Tu

to Cito

www.journalforclinicalstudies.com

e re

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 21 21

Regulatory

patients themselves with useful information that improves individual therapy, aids the diagnosis and management of medicine-induced disease, which leads to a reduction of iatrogenic diseases. Outsourcing While Building Pharmacovigilance Capacity Pharmaceutical companies are increasingly outsourcing different activities to vendors as a strategy to stay competitive and flexible in a world of exponentially growing knowledge, new technologies and an unstable economic environment.24 Sponsors must ensure that vendors performing pharmacovigilance and risk management have the experience and capacity to perform required services. Services that are generally outsourced include performing safety audits; creation of SOPs and studyspecific procedures (SSP); medical and safety monitoring; individual case management; creating and maintaining databases; signal management; preparation and updating RMPs/REMS; trend analysis; organising and managing drug safety monitoring board (DSMB), data monitoring board (DMC), and clinical endpoint committee (CEC); and reporting of expedited and periodic safety reports to regulatory authorities, principal investigators, and institutional review boards.7 Major information technology companies are actively launching pharmacovigilance software to strengthen their market shares. Pharmaceutical and life sciences companies are forming strategic collaborations with key contract research organizations (CRO) to expand their market presence in various regions. This has also enabled them to gain a better foothold in major regions by effectively positioning their services to new clients.15 A Look Ahead The global pharmacovigilance is growing at a rapid pace. Marketing authorisation applicants are encouraged to plan from very early on in a product’s life cycle how they will further characterise and minimise the risks associated with the product in the postauthorisation phase.25 22 Journal for Clinical Studies

Owing to the factors such as high risk associated with data security, lack of global regulatory harmonisation, and lack of data standardisation for adverse event collection, the growth of the pharmacovigilance market is expected to get hindered.12 Selfmedication with over the counter and herbal medicines is a growing area and the possibility of experiencing an ADR or a safety concern following incorrect use should also be recognised. It should be easy to report a suspected reaction, also for individuals who do not obtain their medicines on prescription. With the unexpected apparition of COVID-19 and the search for a vaccine to combat this virus, the increased spending on innovation in the healthcare industry will lead to changes in modern medicine as a whole, transforming the way we currently prevent diagnose and treat disease.17 Some key points for future consideration which may be improved to make better pharmacovigilance practice:23 • Pharmacovigilance should be more focused on developing knowledge of safety and not just restrict itself in finding harm. • Complex risk-benefit decisions are amenable to, and likely to be improved by, the use of formal decision analysis. • Pharmacovigilance should operate in a culture of scientific development. This requires the right balance of inputs from various disciplines, a stronger academic base, and greater availability of basic training, and resource which is dedicated to scientific strategy. • Systematic audit of pharmacovigilance processes and outcomes should be developed and implemented based on agreed standards. • Improvement in signal detection and risk management practices by following risk based approach. Lastly, policymakers must engage in the difficult conversations about the important issues related to controlling the rising costs of healthcare and sustaining investment in R&D to develop new therapies and technologies. We must ultimately tackle the fundamental question of how much innovation for which we are Volume 13 Issue 5

Regulatory willing to pay. This conversation must be informed by the economic realities underpinning the business model of how new drugs and devices are developed. We must also weigh the costs of policies that could either hinder or hurt the development of new therapies and technologies for patients suffering from conditions without any existing treatments. This is where the ability to continue to innovate is critical to driving scientific advancement for patient benefit.26 REFERENCES 1.

Tamimi NAM and Ellis P. Drug development: From Concept to Marketing! Nephron Clin Pract. 2009;113:c125–c131. 2. PhRMA. Biopharmaceutical Research & Development: The Process Behind New Medicines. Available at: http://phrma-docs.phrma.org/sites/default/ files/pdf/rd_brochure_022307.pdf. Accessed on 12 August 2021. 3. Paul Beninger. Pharmacovigilance: An Overview. Clin Ther. 2018;40(12). 4. WHO Pharmacovigilance Indicators: A Practical Manual for the Assessment of Pharmacovigilance Systems. Available at: https://www. who.int/medicines/areas/quality_safety/safety_efficacy/EMP_PV_ Indicators_web_ready_v2.pdf. Accessed on 12 August 2021. 5. Jalali RK. Risk Management in Pharmacovigilance. 2018. Available at: https://www.sciencedirect.com/science/article/pii/ B9780128021033000316. Accessed on 12 August 2021. 6. WHO. A Practical Handbook on the Pharmacovigilance of Antiretroviral Medicines. 2018. Available at: https://www.who.int/medicines/areas/ quality_safety/safety_efficacy/handbook_pv_hiv.pdf?ua=1. Accessed on 12 August 2021. 7. Gagnon S, Schueler P, Fan JD. Pharmacovigilance and Risk Management. Global Clinical Trials Playbook. 2012. Available at: https://www.elsevier. com/__data/assets/pdf_file/0010/96967/Pharmacovigilance-and-risk_ link.pdf. Accessed on 12 August 2021. 8. Pharmacovigilance Market: Global Industry Analysis and Opportunity Assessment, 2015 – 2020. 2016. Available at: https://www.prnewswire. com/news-releases/pharmacovigilance-market-global-industry-analysisand-opportunity-assessment-2015---2020-300199799.html. Accessed on 12 August 2021. 9. Lu Z. Information Technology in Pharmacovigilance: Benefits, Challenges, and Future Directions From Industry Perspectives. Drug Healthc Patient Saf. 2009;1:35–45. 10. ICH Harmonised Tripartite Guideline Pharmacovigilance Planning E2E. Available at: https://database.ich.org/sites/default/files/E2E_Guideline. pdf. Accessed on 12 August 2021. 11. Pharmacovigilance Outsourcing Market: Notable Developments and Competitive Landscape. 2021. Available at: https://www.biospace.com/ article/pharmacovigilance-outsourcing-market-notable-developmentsand-competitive-landscape/. Accessed on 12 August 2021. 12. Pharmacovigilance Market – Growth, Trends, Covid-19 Impact, and Forecasts (2021–2026). Available at: https://www.mordorintelligence. com/industry-reports/pharmacovigilance-pv-market. Accessed on 12 August 2021. 13. Pharmacovigilance Market. 2021. Available at: https://www.marketwatch. com/press-release/pharmacovigilance-market-2021-industryanalysis-by-size-growth-share-trends-opportunities-key-playersbusiness-insights-competitive-landscape-regional-and-global-forecastto-2027-2021-05-27. Accessed on 12 August 2021. 14. Pharmacovigilance Market. 2021. Available at: https://www. grandviewresearch.com/industry-analysis/pharmacovigilance-industry. Accessed on 12 August 2021. 15. Pharmacovigilance Market. 2021. Available at: https://www.biospace.com/ article/pharmacovigilance-market-know-the-factors-that-will-hinderthe-market-growth/. Accessed on 12 August 2021. 16. Risk and Regulation: A Wave of Change for Pharma. 2014. Available at: https://blogs.deloitte.co.uk/health/2014/07/risk-and-regulation-a-waveof-change-for-pharma.html. Accessed on 12 August 2021. 17. A Significant Rise in Health Care R&D Provides Investors Opportunity in this Sector. 2020. Available at: https://www.nasdaq.com/articles/asignificant-rise-in-health-care-rd-provides-investors-opportunity-in-thissector-2020-07. Accessed on 12 August 2021. 18. Who’s investing in health care R&D? 2018. Available at: https://www. brookings.edu/blog/techtank/2018/04/23/whos-investing-in-healthcare-rd/. Accessed on 12 August 2021. www.journalforclinicalstudies.com

19. ISR Report. Pharmacovigilance Market Dynamics and Service Provider Benchmarking. 2014. Available at: https://isrreports.com/wp-content/ uploads/2014/11/ISR-Pharmacovigilance-Market-Dynamics-and-ServiceProvider-Benchmarking-Preview-Nov14.pdf. Accessed on 12 August 2021. 20. Strategic Acquisition. 2018. Available at: https://www.sciformix.com/ featured-stories/strategic-acquisition/. Accessed on 12 August 2021. 21. EFPIA. The Pharmaceutical Industry in Figures. 2020. Available at: https:// www.efpia.eu/media/554521/efpia_pharmafigures_2020_web.pdf. Accessed on 12 August 2021. 22. MarketWatch. Global Pharmacovigilance Market. 2021. Available at: https://www.marketwatch.com/press-release/global-pharmacovigilancemarket-2021-is-expected-to-register-a-cagr-of-128-with-top-countriesdata-industry-price-trend-size-estimation-industry-outlook-businessgrowth-report-latest-research-business-analysis-and-forecast-analysisresearch-2021-06-14. Accessed on 12 August 2021. 23. Jeetu G and Anusha G. Pharmacovigilance: A Worldwide Master Key for Drug Safety Monitoring. J Young Pharm. 2010:2(3);315–320. 24. Global Outsourcing and Vendor Management: Key Influence Factors and Strategies. Available at: https://www.jforcs.com/wp-content/ uploads/2021/02/Global-Outsourcing-and-Vendor-Management.pdf. Accessed on 12 August 2021. 25. EMA. Guideline on good pharmacovigilance practices (GVP). Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/ guideline-good-pharmacovigilance-practices-module-v-riskmanagement-systems-rev-2_en.pdf. Accessed on 12 August 2021. 26. High Cost of R&D Innovation in Healthcare. Available at: https:// objectivecp.com/high-cost-of-rd-innovation-in-healthcare/. Accessed on 12 August 2021.

Tahseen Khan Tahseen Khan is a Principal Regulatory Writer at LabCorp Drug Development in Mumbai. He did M.Sc. in Biotechnology, and has over 10 years’ experience in drug development. In his current role, Tahseen act as a lead writer authoring clinical documents including overview, summaries, study reports, investigator’s brochures, protocols, and other prepared for drug approval primarily for FDA submission. Email: tahsinkhan.bt@gmail.com

Tanveer Khan Tanveer Khan is Pharmacovigilance (PV) professional with 13+ years of experience in PV space, with right skill sets to manage and run the PV operations with a combination of process, people, and technology. He is designated as Manager Safety Operations at IQVIA, he is having experience in managing multiple projects with a team size of 50+ employees. He is also involved in process improvement with current technological enhancements in PV space and have got experience to face both PV audit and inspection. Email: tanveer.khan28@gmail.com

Journal for Clinical Studies 23

Market Report

Finding the Right Patients for Primary Care Clinical Studies Automated Recruitment Platforms (ARPs) offer primary care clinicians and allied health professionals’ opportunities for more time-efficient ways to engage with and recruit patients for clinical studies. This is compared to traditional ‘manual’ methods such as phone and paper-based approaches. Dr. Matt Wilson, who founded clinical research platform uMed, outlines the benefits of the technology and explains why the patient Electronic Health Record (EHR) alone, although essential, is not a sufficient data set for successful clinical study recruitment in primary care. Automated patient recruitment can benefit healthcare providers and their patients by helping to recruit the right patients with targeted studies more promptly, at greater scale and with less impact on practice workload in a data-secure way. What Automated Recruitment Platforms (ARPs) do Automated Recruitment Platforms are a relatively new health technology solution which use smart phone, text/SMS, social media and other electronic communications to engage with a patient in a more individualised, data-secure way than traditional manual approaches when recruiting patients for clinical studies. They are able to shorten, safely, the time span needed for a clinical study and, with a patient’s consent, combine their EHR with other data sources such as the patient’s digital engagement with a health provider over time. This enables a health provider, for example a local community health centre, to match eligible patients to appropriate clinical studies, providing more accurate and richer data for the clinical study sponsor. The challenges for patient recruitment in primary care A major challenge for delivering research in primary care settings is the limited capacity for healthcare providers to support the extensive logistics needed for clinical studies. It requires time, knowledge of the research process, and often capital expenditure to set up the infrastructure to deliver research programmes. Secondary care health services, for example clinicians in hospital settings, often have more infrastructure, capacity and experience in undertaking clinical studies, including randomised controlled trials. In primary care, the time invested in a clinical study equates to precious time and budget expended away from clinical demands. Primary healthcare professionals, for example GPs in the UK, family physicians, practice nurses and allied health professionals, often find it difficult to accommodate this time, given their operational model and more urgent clinical responsibilities. The result is that opportunities for clinical research in primary care are lost as potential study sites decide against involvement. Even when a study is successfully launched in a primary care setting, there is a risk of studies not recruiting sufficient patients with the result that studies can be cancelled, delayed, only partially recruited for, or are terminated midway. Arguably, a key hurdle when recruiting patients for primary care studies is the traditional ‘manual recruitment’ method still 24 Journal for Clinical Studies

employed by most health providers in primary care. This usually involves a member of the practice staff approaching a patient based either on their ‘local’ clinical records or using the patient’s EHR data which identifies them as relevant for a particular study. In either method, the primary care team would use a standard invitation script, effectively a ‘one size fits all’ approach when engaging with the patient. This may be a disincentive for patients who do not engage automatically with ‘template’ research approaches. These harder to engage patients could be from any demographic group but are likely to affect more marginalised populations. There is a growing evidence base to suggest that, particularly for ethnic minority populations in developed economies, there is a bias against their proper proportion in clinical studies. According to a recent US study published in Med, a clinical and translational research monthly journal published by Cell Press, researchers found that clinical trial enrolment remains “largely homogeneous”. “Unfortunately, clinical trial enrolment in the US remains largely homogeneous, with the majority of participants being non-Hispanic white men. Despite efforts to increase diversity in recruitment for clinical trials, enrolment of racial / ethnic minorities in this nation has decreased over the past two decades,” the authors wrote.1 Beyond ethnicity, there are other factors such as patients who are digitally excluded and those in troubled or chaotic situations such as drug addiction, domestic violence, homelessness or poverty. Equally, this may affect patients in socially or culturally marginalised communities or immigrant and some ethnic minority populations where language might be a barrier to access health services, and other hard to engage demographic groups. For example, a recent paper published by the UK-based King’s Fund noted that in England, “There are health inequalities between ethnic minority and white groups, and between different ethnic minority groups.” “The picture is complex,” the authors said, both between different ethnic groups and across different conditions, and understanding is limited by a lack of quality data.2 Another challenge is that the EHR does not provide all the data needed to determine the eligibility of a patient for a study. For example, symptom severity may not be registered in the EHR with sufficient accuracy given the format of the records. In contrast, ARPs can extract deeper information on a patient’s experience of a health condition through more substantive interaction with the patient via digital channels and data on a continuous basis. Finally, traditional recruitment methods also rely on ‘cold calling’ of patients. In the traditional approach, the patient may not be prepared for the invitation to join a study and so may not respond as positively as they would, had they been given an opportunity to consider the request through a non-intrusive communication ahead of a more formal call or invitation letter. This may weaken their inclination to participate when they receive a call. ARPs also have Volume 13 Issue 5

Market Report the ability to send automated SMS/texts branded to come from the clinician and so can help prepare the patient ahead of a call or other approach as to what participation involves, ensuring more receptiveness to the invitation when the approach happens. How ARPs can help A fully operational ARP is able to capture data remotely and directly from the patient, the patient’s EHR and their clinician. It automatically links this composite data back to a clinical study’s dataset (the overall data accruing from the clinical study), in doing so reducing the burden on clinicians and allied professionals who form the study site team. This is a significant benefit for primary care health providers and clinicians such as family physicians and GPs, reducing the time involved in clinical studies, safeguarding patient data, improving health provider oversight and contributing to a more empowered and safer patient experience. ARPs also open opportunities for ‘time-poor’ medical staff and practice nurses to participate in clinical studies to which they would not otherwise have been able to commit. Equally, it opens up opportunities for practices that have no heritage in research. ARPs, when fully operational, help study sponsors find eligible patients more quickly and in greater volume, replacing traditional communications channels such as manual phone communication and paper-based correspondence with automated engagement channels that enable real time capture of data. The technology also assists allied health workers such as a practice’s administrative and reception staff who are often the first contact point with patients. As mentioned, ARPs can automate important messages and deliver them to patients, appearing as if they originated from the practice team (similar to a ‘white label’ marketing approach where a contractor offers a service under the branding of their client) saving time for staff who would otherwise be the ‘front of house’ team members responsible for managing communications with patients. These benefits combine to make clinical study participation and recruitment of patients by primary care health providers more viable. ARPs also enable primary care health providers to scale up the numbers of patients who participate in clinical studies. In part, this is possible because they enable tailored communications based on the target demographic. For example, the patient cohort required by a study could be based on age, gender, ethnicity or other profile. Data gathered by an ARP enables precision targeting to find the right patients for the right study. This opens the possibility of hosting clinical studies across a larger number of research sites and creates capacity for healthcare providers to participate in more of these studies than would otherwise be possible. Patient consent is obtained through text or email via automated outreach on behalf of their recognised health provider, avoiding time consuming and slow hard copy correspondence and ensuring the patient recognises the message is from their clinician or practice team. More research is needed into patient experience and expectations – although some anecdotal feedback is emerging. For example, Geoffrey Taylor, a UK patient who had experienced using an ARP said: “It made me feel good that I was potentially helping others. Everything was easy to use and understand. It was a positive experience.” With ARP technology making it easier for primary care teams to engage in clinical studies, there is a further benefit in that many clinical studies involve payments by the study sponsor to the study site for the time and activity taken in support of the study, so potentially enhancing the income of a primary care health provider. It should be noted that the benefits ARPs offer apply whether the www.journalforclinicalstudies.com

practice has heritage in research or has no track record in research at all. Evidence base There is a growing evidence base around the challenges that have historically hindered patient recruitment in primary care, although clinical studies and data on how ARPs perform relative to manual methods of recruitment are yet to be published given the recent emergence of the technology. Several academic studies have examined the failure or delay rate of clinical studies on grounds of patient recruitment. The UK Health Technology Assessment Programme reported in 2017 in BMJ Open that 45% of 73 HTC/ Medical Research Council funded trials between 2002 and 2008 did not meet their recruitment number.3 Around the same time, a UK paper published in Primary Care Respiratory Medicine (Nature) which examined the participation rates of GPs in investigating the association between environmental exposures and exacerbations of Chronic Obstructive Pulmonary Disease (COPD) found significant reticence among GP practices to participate in studies because of the workload.4 In the study, 82 practices were invited to participate; 56 (68.3%) did not take part and, of these, 15 (17.9%) indicated that either they had ‘too much workload at present’ to complete the study activities or there were ‘insufficient resources’ or there was ‘not enough remuneration’. This effectively resulted in a loss of 2,073 (67.7%) patients who might otherwise have been considered in the study. Case example – Closed Loop Medicine Closed Loop Medicine (CLM) is a healthcare company focused on developing drug and digital combination products, secured by funding from Innovate UK Precision Medicine Accelerator, to run a clinical trial in partnership with Queen Mary University London for CLM’s integrated precision care solution for patients with hypertension (high blood pressure). The clinical trial, called Personal COVID BP, will see up to 1,000 patients recruited for a study investigating whether a combination product that links a drug to a smart phone app can enable patients to personalise and optimise their therapy regimen to treat hypertension. Importantly, the technology in the study allows patients shielding from COVID-19 to control their blood pressure remotely in a home setting environment. The company worked closely with the lead clinical team and used radio advertising to support recruitment but, given recruitment rates, CLM sought to improve patient participation further. The company approached uMed, with its Automated Recruitment Platform (ARP) technology, to increase and accelerate patient participation. uMed, working in partnership with Closed Loop Medicine and the team at Queen Mary University London, engaged patients on behalf of their recognised healthcare provider by text/ SMS to invite the most appropriate patients to volunteer for the study, making it easier for the patient to give consent. This ARP technology supported the acceleration of recruitment into the study and was key to the study hitting (and going beyond) recruitment targets. Through its ability to send individualised text/ SMS and online messaging, the uMed ARP technology supported the acceleration of recruitment into the study and was key to the study meeting and indeed going beyond its recruitment target. This enabled CLM to recruit the most relevant patients needed to move the study into its delivery phase. Patients recruited through this ARP platform found the process easy to navigate, allowing them the time to read the Patient Journal for Clinical Studies 25

Market Report Information Leaflet, to look up the study and become more confident and familiar with the research without the need for further consultation with a research nurse. By enabling and providing patients with the platform to make an informed choice to take part in the study, this empowered them to feel in control of how they engaged with the clinical research. The study team at Queen Mary University London (QMUL) reported patients were more motivated and better informed than other channels. In the future, it is hoped that all patients will be given the same level of control and comfort in participating in clinical research so making a conscious choice to ‘click the link’ and agree to take part; it is also possible that the patient felt more empowered to participate in the study – however this is an area for further research. Dr. Hakim Yadi OBE, CEO of Closed Loop Medicine, explained his company’s experience of using ARP technology, “At Closed Loop Medicine, we are developing novel drug and digital combination products prescribed on a single label. We are working at the forefront of the convergence of life sciences and health care technology, so it is important to us to be able to robustly and quickly validate our approach with patients. We used an automated recruitment platform5 to rapidly scale up and automate the recruitment of our clinical study, led by Queen Mary University London. Working in this way enabled us to scale and complete recruitment more effectively than traditional recruitment models – it was a simple integration for our team and the health professionals at Queen Mary University London and one which we will seek to engage with again.” Conclusion ARPs make it easier for clinicians supporting ‘study-eligible’ patients to communicate with them with more tailored and individualised messaging at greater scale and with reduced workload for the primary care team. In bridging the gap between the patient and the clinical study sponsor, ARPs make it much easier to find and communicate with patients at scale, potentially reducing clinical trial costs by over half. With radically cheaper and faster studies, ARPs also enable more researchers to take advantage of more opportunities in primary care. In summary, ARP technology has these benefits: Tailored engagement and individualised approaches – so not a standard script and so may receive a more positive response from the recipient patient. Finally, the benefit in opening the opportunity to screen patients for symptom severity and engage patients with bespoke questionnaires. For example, issuing letters to older, less digitally engaged, patients explaining that they may receive a text message; and sending text at times for different demographics. For example, many older people who have a mobile/cell phone prefer to receive texts in the morning and younger people in the afternoon. ARP technology enables different text messages to be sent at different times. Reduced workload – for primary care clinicians and allied health professionals when participating in a clinical study. Scale and speed – a fully operational ARP has the ability to send 10,000 texts in one issue and reduces the time taken to reach patients. Ability to issue ‘from clinician’ communications – where communications to patients are branded as from the clinician including texts and other communications on behalf of clinicians. 26 Journal for Clinical Studies

REFERENCES 1.

Med Leanne Woods-Burnham, Jabril R. Johnson, Stanley E. Hooker Jr., Fornati W. Bedell, Tanya B. Dorff, Rick A. Kittles https://www.cell. com/med/fulltext/S2666-6340%2820%2930075-1#secsectitle0010 Published: January 08, 2021 DOI: https://doi.org/10.1016/j.medj.2020.12. 009 The Role of Diverse Populations in US Clinical Trials. The Kings Fund Veena Raleigh, Jonathon Holmes. https://www. kingsfund.org.uk/publications/health-people-ethnic-minority-groupsengland The health of people from ethnic minority groups in England BMJ Open Stephen J Walters, Inês Bonacho dos Anjos HenriquesCadby, Oscar Bortolami, Laura Flight, Daniel Hind, Richard M Jacques, Christopher Knox, Ben Nadin, Joanne Rothwell, Michael Surtees, Steven A Julious. https://bmjopen.bmj.com/content/bmjopen/7/3/e015276.full. pdf Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme. Nature / NPJ Primary Care Respiratory Medicine Jennifer K. Quint, Elisabeth Moore, Adam Lewis, Maimoona Hashmi, Kirin Sultana, Mark Wright, Liam Smeeth, Lia Chatzidiakou, Roderic Jones, Sean Beevers, Sefki Kolozali, Frank Kelly & Benjamin Barratt; npj Primary Care Respiratory Medicine volume 28, Article number: 21 (2018). https:// www.nature.com/articles/s41533-018-0089-3 Recruitment of patients with Chronic Obstructive Pulmonary Disease (COPD) from the Clinical Practice Research Datalink (CPRD) for research. Closed Loop Medicine used uMed for its project with Queen Mary Hospital, London

Dr. Matt Wilson Dr. Matt Wilson is a former accident and emergency doctor, anaesthetist and medical officer in the UK’s Royal Marines. He founded the uMed platform in 2018, recognising the benefits to clinical research of automating key parts of the clinical study process by using electronic health record data. The platform is engaging with two million patients in approximately 200 primary care sites in the UK and will soon include some US health systems.

Volume 13 Issue 5

People service Science, Science serving People

Banook Group is one of the few established international providers capable of supplying Cardiac Safety, Central Imaging, Endpoint Adjudication and eCOA/ePRO solution services to pharmaceutical, medical device and biotech companies, CROs and nonprofit organizations.

OUR MISSION IS TO HELP OUR CLIENTS INVENT TOMORROW'S HEALTHCARE By using qualitative, reliable and innovative solutions in early to late stage clinical trials, we bring new solutions to the market for the benefit of patients worldwide. Our medical and regulatory expertise, quality-driven approach and team availability make Banook Group a key player for your clinical trial. Founded in 1999 (under the former name of Cardiabase), we operates on an international scale, maintaining offices at its headquarters in France, Canada and China.

CARDIAC SAFETY

CENTRAL IMAGING

We have been involved in : over 950 trials 75 countries since 1999 more than 1 500 000 ECGs analyzed We also have gathered experience in phase I-IV studies in all therapeutic areas.

We have many years of experience in : onco-radiology cardiac imaging nuclear medicine in international clinical trials.

www.journalforclinicalstudies.com

ENDPOINT ADJUDICATION We are involved in the adjudication process since 2004. We have been participating in a large number of endpoint adjudication protects for various therapeutic classes.

France - Canada - China www.banookgroup.com

eCOA / ePRO We have an unique e-health platform, flexible and adaptable with a large solution of Clinical Outcome Assessments in various therapeutics fields : Patient-Reported - ePRO Performance - ePerfO Clinician-Reported - eClinRO Patient-Diary - eDIARY

Journal for Clinical Studies 27

Market Report

Plain Language Summaries of Publications – What Has COVID-19 Taught Us? The COVID-19 pandemic has significantly impacted the whole world and the public has had to struggle with understanding scientific data on a daily basis. The impact of scientific misunderstanding became painfully apparent with the decline in vaccine uptake and so the need for clear, understandable scientific information has never been more vital. Plain Language Summaries of Publications (PLSPs) could be an elegant and much needed solution to this problem. This article will explore what these documents are, the approaches taken to date, and the challenges that still remain. The authors will aim to answer the question – what has COVID-19 taught us? The development, approval, and dissemination of COVID-19 vaccines has been in the forefront of our lives for a long time now. The discussions around potential side effects and efficacy of the vaccines have been many and varied, and have sometimes been delivered with a startling lack of scientific evidence or even basic understanding. The resulting public mistrust and ensuing reluctance to have one or any of the vaccines was swift and devastating, and will undoubtedly have cost lives. This has highlighted the need and demand for scientific research to be delivered accurately and plainly. The public’s demand for more and better scientific information is not new, and the Regulatory Agencies have already responded with an increase in transparency and patient engagement. The most recent and largest changes from a documentary point of view have been the inclusion of a new patient-friendly part of the Risk Management Plan (mandated by the EMA in 2013)1, which was closely followed by the introduction of Regulation (EU) 536/2014, which mandates the production of a Lay Summary of Clinical Trial Results.2 This is not currently mandated by the FDA, but patient friendly summaries of clinical trial results are recommended. With this in mind, it is unsurprising that there is a growing demand for Plain Language Summaries of Publications (PLSPs). What are Plain Language Summaries of Publications (PLSPs)? PLSPs are short summaries of research papers written in language that is understandable to a non-specialist audience. A PLSP aims to improve access to the results of an original research article in such a way that non-specialist healthcare professionals, patients, and consumers of health care without a medical background can readily understand the findings and recommendations. It is not specifically aimed at patients or the general public, but it is likely that these audiences will take a keen interest in PLSPs. Although there is a growing demand for PLSPs, there is no requirement to produce or publish one alongside a manuscript in peer reviewed journals. There is also no standard guidance available on how to prepare a PLSP. In 2013, Cochrane Methods3 and in 2017 the Canadian Frailty Network4 issued very helpful guidance, but even PLSPs following the Cochrane guidance remained highly heterogeneous with very low adherence to these standards.5 However, other guidance and best practice documents 28 Journal for Clinical Studies

have been (or are currently being) developed, e.g. by Patient Focused Medicines Development and Open Pharma, and the update to the Good Publication Practice Guidelines is expected to include a new section on information to the patient. With increasing guidance being made available, it is hoped that the awareness and quality of these documents will increase. Why should we care about PLSPs? PLSPs do not only benefit the general public and patients, they benefit researchers, study sponsors, healthcare providers, and healthcare professionals. For the general public and patients, these patientcentric documents can help the lay audience understand complicated issues, so that they are empowered to actively participate with their healthcare provider about their treatment: “No decision about me without me” has been a mantra in the UK since 2010, supported by government and the NHS.6 For time-poor and overstretched healthcare professionals, it can be difficult and time-consuming to extract key messages from scientific papers. Therefore, PLSPs are a good way to increase scientific learning by assimilating complex information quickly and easily, in turn promoting good evidence-based medicine. Both patient empowerment and evidence-based medicine are also likely to promote patient engagement, meaning that patients are more likely to comply with their treatment, which ultimately improves clinical outcomes. In 2019, US citizens rated the pharmaceutical industry as ‘the poorest regarded industry’ out of a list of 25 industries, ranking lower than the oil and gas industry, the federal government, and the US healthcare system.7 For researchers and study sponsors, PLSPs are a keyway of communicating research results to a wider audience, increasing accessibility to their work, and aiding transparency, which in turn may help ease negative opinions of the pharmaceutical industry. A survey among physicians, patients and caregivers showed that scientific journals were the third most common source of healthrelated information online (47%).8 It also identified the value of PLSPs in facilitating a patient-physician dialogue. In the US, a survey identified that 73% of Americans obtain health-related information from the internet,9 and in the EU, another survey showed that within a 3-month period, 52% of EU citizens aged 16 to 74 reported they sought online health information.10 As the demand for information about health-related topics continues to rise, it is important to optimise its dissemination and reach. However, despite the benefits related to the availability of healthrelated information, one survey showed that respondents had concerns about the credibility of the information: fears that it was false or misleading (52%), that it was trying to sell products or services (47%), confusion over research studies that seem to contradict each other (43%), difficulty understanding the information (31%), and that companies were tracking the information being searched for (29%).9 Despite roughly two-thirds of respondents reporting that they see health information on social media, the majority (83%) were concerned that this information was incorrect or misleading. These Volume 13 Issue 5

Market Report

surveys highlight the fact that the quality of health information available to patients is a major concern and increasingly important. It is vital that when the public search for information, it is accurate, reliable, and presented in a way that they understand and can engage with. This will aid clarity and help to avoid misinterpretation. This growing demand for clear and unbiased information is pushing the drive for PLSPs. What is out there and what approaches are being taken? PLSPs are increasingly being considered as part of the publication plan.11–13 Over recent years there has been an increase in the number of PLSPs produced, an increase in journals including PLSPs in their requirements, and a more visible inclusion in their guidelines for authors. Although journals such as Autism has been producing PLSPs since 2011, and PLOS medicine since 2004, prior to 2016 there were only approximately 100 PLSPs available on Pubmed, which slowly began to grow year on year to over 400 available in 2018, and this number had doubled by 2020 to approximately 800.14 Various approaches are being taken to communicate these clinical data to a wider audience. These include PLSPs that are text-only, a combination of text and visuals, infographics, videos, and podcasts. Gardner et al.15 investigated patient format preferences of PLSPs and identified that infographic style summaries were the first choice followed by medium complexity PLSPs (reading age of 14–17 years) in all patient groups investigated. Bredbenner and Simon11 found that original abstracts and graphical abstracts are not as successful as video abstracts and plain language summaries at being understood, giving a feeling of understanding, or enjoyment. However, visual PLSPs are more expensive and difficult to produce. There are also problems with visual PLSPs being www.journalforclinicalstudies.com

‘found’ by search engines since these engines search by text. The importance and effectiveness of infographics has been demonstrated most recently during the COVID-19 pandemic, when they were the medium of choice to convey important messaging quickly to the public, whether related to COVID symptoms, handwashing, or results of clinical trials and vaccinations. However, even when it was of the most importance- in a pandemic – governments struggle to use data visualization well.16 Publishers and individual journals vary dramatically in how they approach PLSPs. Some journals include a PLSP as part of the manuscript submission process or on acceptance of the main article, for others it is optional or not required at all. Some companies have developed their own guidelines,17 and some publishers have produced short articles on how to write PLSPs (e.g., Elsevier’s ‘In a nutshell: how to write a lay summary’18 and Wiley’s ‘How to write a lay summary for your research’).19 However, the majority still provide little to no guidance for authors. In general, journals most frequently specify length of the PLSP and target audience only, and the guidance itself varies widely. The target length of the PLSP can vary from ‘60–80 words’,20 to ‘250 words or less’.21 The target audience for the PLSPs varies between journals with some aiming to be ‘understandable by media and educated patients’, ‘someone in high school’, or ‘an interested person without a scientific background’,22 or advise to ‘pretend you’re trying to explain your article to a distant family member who works in retail/fashion/ hospitality’.23 Generally, most journals target a higher reading age or ability than is expected in the general population. Very few journals give guidance on language, and when it is offered it varies dramatically from journal to journal. One journal Journal for Clinical Studies 29

Market Report publicly available or easy to find.25 Journals and databases rarely have a dedicated ‘PLSP’ category, and Fitzgibbon et al 2020 identified that only 2 out of 11 PLSPs were visible on PubMed.26 Another factor that may contribute to the difficulty in discovering PLSPs is the lack of a standardisation of terminology, making searching difficult. PLSPs are referred to by a number of different terms, including lay summary, plain language summary, plain English summary, patient summary, author summary, general scientific summary, non-technical abstract, significance statement, highlights, or blog. Some journals have also been found to use more than one term for a PLSP26 and these terms also have different meanings for different people. This lack of visibility and discoverability is a huge challenge, and is frustrating for the general public. Patients feel that there is not enough open access material online to be useful and that it is difficult to find.27 The challenges for medical writers and the value they bring Many medical writers have been trained in the scientific writing of complex documents that convey information to specialist audiences who are experts within their fields. However, writing for a non-specialist audience requires far more than a translation of difficult vocabulary into simpler terms. It requires a completely different skillset, necessitating training and practice. Once the documents have been produced, the teams reviewing them must also be aware of, and skilled in providing for, the needs of a nonspecialist audience so that their review is meaningful and helpful, and most review teams are far more used to reviewing highly complex documents aimed at regulatory agencies. It would help both writers and review teams to have the PLSP available as part of the manuscript, and peer reviewed alongside it. The lack of guidance on the content of PLSPs drives the huge variation in quality and length of the current offering. Medical writers are trained to provide documents complying with a variety of requirements, but best practices are needed to help provide standardisation of PLSPs across the industry. In particular, guidelines are needed on the best format to use, text length, structure of infographics, reading age, and where the information should be made available. Beyond this, even standalone PLSPs should not contain more information than that presented in the main manuscript, but should include some context to allow non-specialist readers to fully understand the messages. Therefore, it’s important that the main manuscript is also written well! recommended using a readability analyser24 to get an indication of the reading age level of the given text, but in general, the content and structure of the PLSPs is based on the abstract of the manuscript, and the advice is to simply summarise the impact/importance/ relevance/key findings of the study. Challenges Non-specialists have access to a vast amount of medical content online, but how discoverable and easy is it for them to find peerreviewed content of published research? Information is commonly found on websites, social media, etc. Despite publishers increasingly publishing PLSPs, their availability, accessibility, visibility, and discoverability are still challenging. Most journals have tried to make PLSPs easily accessible and open access, however there are some that do not make them available at all, or place them behind a paywall. For the general public, who may not be aware of publishers’ websites, PLSPs are generally not 30 Journal for Clinical Studies

Conclusion It’s clear that there is a growing demand and need for information for non-specialist audiences, and it is equally clear that we face many challenges to be able to provide fit for purpose information in the form of a PLSP. However, this effort is vital – for without it, the PLSP will not be read or understood, and the monumental effort will be wasted. Although many publishers have responded and are making great strides towards this goal, more can be done to help industry, authors, and ultimately the non-specialist audience. If journals require PLSPs and insist on high quality, fit for purpose documents, this will drive uptake and PLSP quality. The journals’ demand for PLSPs may also ease company compliance issues and the danger of companies being accused of cherry-picking journals with no requirement for PLSPs. Whatever the decisions made by publishers on this issue, it is clear that PLSPs should be made available free of charge and should be a routine part of publication planning. Volume 13 Issue 5

Market Report Medical writers are uniquely placed to bring data to life and help non-specialists to visualise them and put them into context. Writing for non-specialists is part of the evolution of the medical writing profession, and as communication experts they should be involved in the production of PLSPs right at the start of publication planning. The lack of PLSP availability and visibility could in part be due to the lack of standardised guidance on terminology, language and content of PLSPs, all of which have been called for by the medical writing profession. Perhaps a simplistic view, but many of the challenges could be solved by simply producing the abstract in plain language. In this way, non-specialist audiences would have an easily accessible summary of the paper in language they can understand, which would also be appreciated by time-poor HCPs. This would have the added advantage of having more in-depth detail available (directly attached to the abstract) with no risk of de-coupling detailed scientific information from the summary, and a much lower chance of misunderstanding and confusion. This should be the ultimate aim. If we are to learn any lesson from COVID-19, surely, it’s this. REFERENCES 1.

https://www.ema.europa.eu/en/documents/regulatory-proceduralguideline/guidance-format-risk-management-plan-european-union-partvi-summary-activities-risk-management-plan_en.pdf 2. European Medicines Agency. Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, Version 2. Amsterdam: European Medicines Agency; 2017.https://ec.europa. eu/health/sites/default/files/files/eudralex/vol-1/reg_2014_536/ reg_2014_536_en.pdf 3. Cochrane. Standards for the reporting of Plain Language Summaries in new Cochrane Intervention Reviews (PLEACS). 2013. Available at: http:// editorial-unit.cochrane.org/sites/editorial-unit.cochrane.org/files/ uploads/PLEACS_0.pdf 4. https://www.cfn-nce.ca/wp-content/uploads/2017/09/cfn-guidelinesfor-lay-summaries.pdf 5. Kadic AJ, Fidahic M, Vujcic M, Saric F, Propadalo I, Marelija I, Dosenovic S, Puljak L. Cochrane plain language summaries are highly heterogeneous with low adherence to the standards. BMC Medical Research Methodology. 2016;16(61):61. 6. Department of Health. Liberating the NHS: No decision about me, without me – Government response to the consultation. 13 December 2012. Available from: https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment_data/file/216980/Liberating-theNHS-No-decision-about-me-without-me-Government-response.pdf [Accessed 07 July 2021]. 7. McCarthy J. Big pharma sinks to the bottom of U.S. Industry ranking. 3 September 2019. Available from Gallup site: https://news.gallup.com/ poll/266060/big-pharma-sinks-bottomindustry-rankings.aspx [Accessed 07 July 2021]). 8. Pushparajah DS, Manning E, Michels E, Arnaudeau-Bégard C. Value of Developing Plain Language Summaries of Scientific and Clinical Articles: A Survey of Patients and Physicians. Ther Innov Regul Sci. 2018;52(4):474-481 9. The Great American Search for Healthcare Information. 2018. https:// www.webershandwick.com/wp-content/uploads/2018/11/HealthcareInfo-Search-Report.pdf#:~:text=The%20Great%20American%20 Search%20for%20Healthcare%20Informationis%20a,firm%20Weber%20 Shandwick%20in%20partnership%20with%20KRC%20Research [Accessed 07 July 2021] 10. Eurostat. 53% of EU citizens sought health information online. 27 Mar 2020. https://ec.europa.eu/eurostat/web/products-eurostat-news/-/ddn20200327-1 [Accessed 7Jul2021]). 11. Bredbenner K, Simon SM. Video abstracts and plain language summaries are more effective than graphical abstracts and published abstracts. PLOS ONE. 2019;14(11):e0224697; www.journalforclinicalstudies.com

12. Chapman SJ, Grossman RC, FitzPatrick ME, Brady RR. Randomized controlled trial of plain English and visual abstracts for disseminating surgical research via social media. Br J Surg. 2019;106:1611-6. 13. Gardner J et al. Poster presented at ISMPP Annual Meeting 2019 14. Havran LM, Morgan CH. Lay and plain-language summary trends in the medical literature. Poster presentation at ISMPP Annual Meeting. March 2019. 15. Gardner J, Silvagnoli LM, Shepherd C, Pritchett J. Evaluation of plainlanguage summaries (PLS): optimizing readability and format. JPLS. 2019;1(1):1-10. 16. https://www.ucl.ac.uk/news/2020/nov/analysis-data-visualisationexpert-whats-wrong-uk-governments-coronavirus-charts 17. Rees T, Richter CA, Dennis N, James J, Gokool N. Development of a framework for publishing patient lay summaries in medical journals. Poster number 3 2017. European Meeting of ISMPP, 17–18 January 2017, London, UK. 2017. 18. Tancock C. In a nutshell: how to write a lay summary. Elsevier Connect 2020 19. Green S. How to Write a Lay Summary for Your Research. Wiley Apr 2019 https://www.wiley.com/network/societyleaders/research-impact/howto-write-a-lay-summary-for-your-research 20. Author guidelines, Autism Research. https://onlinelibrary.wiley.com/ page/journal/19393806/homepage/forauthors.html 21. Guidance, Taylor & Francis https://authorservices.taylorandfrancis. com/publishing-your-research/writing-your-paper/how-towrite-a-plain-language-summary/?utm_source=google&utm_ medium=sem&utm_lk C, Gaskarth M. Where are biomedical

research plain-language summaries? Health Sci Rep. 2020;9999:e175.

22. https://onlinelibrary.wiley.com/page/journal/19393806/homepage/ ForAuthors.html#_Lay_Summary; https://onlinelibrary.wiley.com/ page/journal/13652133/homepage/ForAuthors.html 23. https://www.elsevier.com/connect/authors-update/in-a-nutshellhow-to-write-a-lay-summary 24. Autism Research https://onlinelibrary.wiley.com/page/journal/ 19393806/homepage/ForAuthors.html#_Lay_Summary 25. Penlington, M., Silverman, H., Vasudevan, A. et al. Plain Language Summaries of Clinical Trial Results: A Preliminary Study to Assess Availability of Easy-to-Understand Summaries and Approaches to Improving Public Engagement. Pharm Med 2020;34:401–406 26. FitzGibbon H, King K, Piano C, Wilk C, Gaskarth M. Where are biomedical research plain-language summaries? Health Sci Rep. 2020;9999:e175. 27. Nunn E and Pinfield S. Lay summaries of open access journal articles: engaging with the general public on medical research Learned Publishing, 2014, 27(3): 173–184

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

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Market Report

Clinical Evaluation of Ayurvedic Interventions: Current Scenario in Indian Market Abstract Ayurveda, the science of life, has evolved into a comprehensive system of healthcare based on high-quality scientific experiments with a sound and reproducible evidence base that has stood the test of time. Several strategies and road maps are being developed to carry forward the merits of this science in order to meet today's health needs and mainstream its core strengths in India and around the world through research and development. When designing clinical trials to test the safety and efficacy of Ayurvedic approaches, the fundamental aspects of holistic systems must be analysed properly. The concepts and methods are developed in course of time adding several new drugs, interventions and approaches right from Vedic period, Samhita period, medieval period and current era enriching the Ayurvedic pharmacopoeia and pharmaco-therapeutics. In light of the above it is crucial to adopt an interdisciplinary approach for validation of Ayurvedic drugs and therapies without losing core fundamentals of Ayurveda. Keywords: Ayurveda, Clinical trials, Safety and Efficacy. Introduction The clinical research in traditional medicines broadly developed based on the validation of fundamental principles involved in Ayurveda. A critical review of Ayurvedic literature reveals Ayurveda's robust approach to Research & Development and its reflection of epistemology. Darshanas (Doctrines of Philosophy) methodical approaches form the foundation of research tools for evidence generation and development of classical Ayurvedic texts, such as Samhitas.

They are as follows: 1. 2. 3. 4. 5.

Aptopadesa (Evidence base on therapeutic leads) Pratyaksha (Direct evidence) Anumana (Logical inference) Upamana (Analogy: Comparative /Control design) Yukti (Reproducible Experimental Evidence)

Clinical trials have their roots in the two-way approach of experimentation and drug trials mentioned in the Samhitas. As a result, Sushruta Samhita narrated the methods and approaches for testing an intervention and interpreting observations in the context of Kriyakala (stages of etiopathogenesis of a disease), which reflect reverse pharmacology, such as feasibility of test intervention (Tatlingatwat), observational design (Dristaphalatwat), and system validation (Agamaatsya). This could be useful as a quick test intervention screening method. Given the foregoing, it is critical to take an interdisciplinary approach to the validation of Ayurvedic drugs and therapies without losing sight of Ayurveda's core principles. The model that has been suggested is in Figure 1. Therapy/Procedure as per AYUSH Following factors may be considered while designing efficacy studies/validation of the therapy or procedures General consideration for Panchakarma/other Procedures 1. Suitable, unsuitable persons for the therapy/procedures/ diseases 2. Pre and post therapeutic procedures 3. Ideal season/periods 4. Possible errors by the performers/participant and their prevention 5. Duration of each procedure based on individual constitution/ severity of disease condition 6. Possible complications/adverse events and their management 7. Dietary life style guidelines before, during and after performing Therapy/Procedures 8. Quality of medicine 9. Subjective and objective parameters of evaluation A. Panchakarma procedures: i. Poorvakarma (Preparatory procedures) Deepana (Appetizer), Pachana (Digestive), Snehana (internal/ external use of oil/ghee) and Swedana (Medicated sudation) • Source of procurement of trial drug • SoPs for the preparation of drug(s) • Dose and Dosage form • Route of administration • Time of administration • Duration

Figure 1: Evidence base in Ayurveda: Suggested Approach by Ministry of AYUSH Figure 1: Evidence base in Ayurveda: Suggested Approach by Ministry of AYUSH 32 Journal for Clinical Studies

ii. Pradhanakarma (Main procedures) Vaman Karma (Therapeutic Emesis), Virechan Karma (Therapeutic Purgation), Anuvasan Basti (Oil/Unctuous Enema), Asthapana Basti Volume 13 Issue 5

Market Report (Decoction based enema) and Nasya Karma (Nasal administration of medicaments) • • • • • • • •

Source of procurement of trial drug SoPs for the preparation of drug(s) Dose and Dosage form Route of administration Time of administration Duration Vehicle along with justification (classical/published data) End point of the Procedure (Samyak lakshan)

iii. Paschatkarma (Post Therapy Procedures) • Specific Paschatkarma according to Pradhan karma • Samsarjana karma (Special Dietary regimen) with duration • Pathya-apathya (Diet and Life style) Assessment of Participant compliance with study Intervention, Procedure for monitoring the participant compliance to therapy and Protocol for any other procedures like Shirodhara, Shirobasti, Janubasti, Uttarabasti, Janudhara, Katibasti, Tarpana, Vidalaka, etc. may be designed as per above said Panchakarma guidelines. iv. Samsarjana karma (Special Dietary regimen) with duration After Pradhan karma, digestion power diminishes, hence as per Ayurvedic principles researcher should advise the participants to take diet in a specific manner gradually increasing from liquids to semisolids and then to solid materials in a specific time according to the Pravara/ Madhyama/Avara shuddhi (Detoxification) achieved in the procedure. Special diet can be given in the meal timings (Twice/day) which start after Pradhan karma from the evening of that day. It may last for 7 days in Pravara, 5 days in Madhyama and 3 days in Avara Shuddhi. Later, the person may be allowed to take normal diet. B. Parasurgical procedures: i. Ksharasutra • Description of material and method • Source of procurement if any • SOPs for Preparation • Time of administration • Duration • Pre and post-operative procedures ii. Agni karma • Description of material and method • Time of administration • Duration • Pre and post-operative procedures iii. Rakta Mokshana • Description of material and method • Time of administration • Duration • Pre and post-operative procedures • Samyaka Lakshana Clinical Research protocol: The pre-clinical and clinical trials for new ayurvedic drug formulations have been prescribed by the Indian Government Department of AYUSH (India) with the intention of providing appropriate evaluation methods to facilitate the development of regulation and registration in ayurveda and other traditional systems of medicines. The standard protocol for conducting clinical research for Ayurvedic drugs has been provided in Table 1. www.journalforclinicalstudies.com

Title:

Include title of the study with type of trial (e.g., dose-ranging, observational, double-blind, etc.)

Objectives:

Include study objectives Primary: ------ Secondary: ---------

Outcome measures:

Include primary/secondary outcome measures and method by which outcome will be determined. Primary: ------- Secondary: --------

Population:

Include sample size, gender, age, general health status, geographic location, etc

Phase:

Mention the phase of the study (I, II, III, IV)

Number of Sites:

Single/ Multi-centre

Study Design:

Open label, Randomized, Masking etc.

Study Duration:

Provide time from when the study initiation and until the study completion with close out.

Participant’s participation Duration:

Provide time it will take to conduct the study for each individual participant.

Description of study intervention:

Include name of the intervention along with reference, dose, dosage form, Anupana (vehicle), route of administration and references along with the name of the intervention.

Estimated time to complete the enrollment:

Provide estimated time from enrolment into study of the first participant to enrolment into study of the last participant.

Utility of the study outcome:

Report

Table 1: Clinical Research Protocol

Phases of clinical trial for Ayurvedic drug/Patent or Proprietary Medicines Registration of Clinical Trials: A systematic study of Ayurvedic drugs/Patent or Proprietary Medicines on human participants – (whether participants or nonparticipant volunteers) – with the goal of discovering or verifying the clinical, pharmacological (including pharmacodynamics/ pharmacokinetics), and/or adverse effects, with the objective of determining their safety and/or efficacy. Human Pharmacology (Phase I) The primary objective of these studies is to determine the safety and tolerability of Ayurvedic Drugs/Patented or Proprietary Medicines when they administered initially to humans (s). Therapeutic exploratory trials (Phase II) The primary objective of Phase II trials is to assess the efficacy of an Ayurvedic drug/Patent or Proprietary Medicines for a specific indication or indications in participants with the condition being studied, as well as to determine the drug's common short-term side effects and risks. Therapeutic confirmatory trials (Phase III) The primary objective of Phase III studies is to show or confirm therapeutic benefits (s). Phase III studies are intended to confirm the preliminary evidence obtained in Phase II that a drug is safe and effective for the intended indication and recipient population. Post Marketing Trials (Phase IV) Post Marketing studies (other than routine surveillance) are conducted after a drug has been approved and are related to the approved indication (s). These trials go beyond demonstrating the drug's safety, efficacy, and dose definition in previous studies. These trials may not be required in the process of Ayurvedic drug approval /Patent or Proprietary Medicines approval, but they considered necessary by the Licensing Authority to optimise the drug's use. Registration of clinical trial in India: The Clinical Trials Registry-India (CTRI), which is placed at the ICMR's National Institute of Medical Statistics (NIMS), is a free and open-access public record system for clinical trials conducted in India (www.ctri.nic.in). Journal for Clinical Studies 33

Market Report formulations have been known to have curative benefits on many health disorders, but such results have not been rigorously pursued via research investigations to determine the effect of such medications in many complicated biological systems. As a result, the notion of reverse pharmacology (RP) aids in addressing the problem in which the effect of an Ayurvedic formulation on a health condition is recognised but the mechanism of action is unknown. In this strategy, the drug candidate travels from ‘clinics to laboratory' rather than the traditional ‘laboratory to clinics.' This concept has three phases as follows: Before the first participant is enrolled, the trial investigators, sponsors, interventions, participant population, trial site, and other details must be publicly declared and identified. Trial registration in the CTRI requires submission of ethics approval as well as Ministry of AYUSH approval (if applicable). Designs Amenable to test Ayurvedic Therapies: Black-box design In general, Ayurvedic remedies are more than just the solitary administration of a therapeutic molecule or a single drug; they are a set of drugs/procedures that comprise a therapy for a specific medical condition for a specific individual. As a result, a traditional treatment involving a number of therapeutic procedures should be viewed as a single module that is compared to either a placebo or a standard treatment. This allows Ayurvedic treatments to be determined within a conceptual framework without jeopardising the fundamental principles of traditional medicine. Reverse Pharmacology Design In the field of traditional medicines, many herb-based medicinal

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RP-Phase I: This study includes an experiential phase in which comprehensive clinical observations of the effect of standardised Ayurvedic drugs on biological systems are documented. RP-Phase II: The objective of this phase is to assess the target activity of the Ayurvedic formulation/drug/Therapy in in-vitro and in-vivo models, as well as to conduct exploratory studies for tolerability, drug-interactions, and dose-range. RP-Phase III: This phase's objective is to conduct basic and clinical studies at various levels of biological organisation in order to identify and correlates of drug safety and efficacy. Based on relevant science, studies in this phase should be able to decipher mechanisms of action at multiple biological systems and optimise the safety, efficacy, and acceptability of the leads in natural products. Conclusion Evidence of the efficacy of traditional medicines may be factual rather than speculative. The goals of these recommendations

Volume 13 Issue 5

are to facilitate scientific evaluation and eventual integration of traditional medicine into the national healthcare system, as well as to significantly aid in the eventual rational use of traditional medicine through the development of technical guidelines and international standards. As a result, it is recommended that clinical trials on Ayurvedic medicines be conducted in accordance with the guidelines provided by regulatory authorities such as AYUSH. It can be driven to compete with pharmaceutical products. REFERENCES 1. Guideline’s series 3, General guidelines for clinical evaluation of Ayurvedic Medicines. Central council for Research In Ayurvedic Sciences Ministry of AYUSH. (https://www.ayush.gov.in/) 2. Anonymous, Quality control methods for Medicinal plant materials, WHO, Geneva 1998 3. Anonymous, Guide lines for methodologies on research & evaluation of research of Traditional medicine, WHO, Geneva., 2000 4. Anonymous, Ethical guidelines for biomedical research, ICMR, New Delhi, 2000 5. Charaka, Charaka Samhita, Choukhamba Sanskrit Series, Varanasi. 1997 6. Susruta, Susruta Samhita, Chowkhamba Sanskrit Series, Varanasi. 1962 7. Sharangadhara, Sharangadhara samhita, Choukhamba publications, Varanasi. 1984 8. Vagbhata, Astanga hridaya, Choukhamba publications, Varanasi. 1992 9. Quality control methods. In: Remington: the science and practice of pharmacy, 19th ed. Easton, PA, MACK, 118-119 (1995)

Koushik Yetukuri Assistant Professor, Department of Pharmaceutical Regulatory Affairs, Chalapathi Institute of Pharmaceutical Sciences (AUTONOMOUS) Guntur, and also a Research Scholar in Department of Pharmaceutics, SRM Institute of Science and Technology (SRM Deemed to be University), Chennai, India. Email: yetukurikoushik@gmail.com

Vikash Penki Pursuing Masters in Department of Pharmaceutical Regulatory Affairs, Chalapathi Institute of Pharmaceutical Sciences (AUTONOMOUS) Guntur, India. Email: vikashpenki39@gmail.com

M.S. Umashankar Professor, Department of Pharmaceutics, SRM Institute of Science and Technology (SRM Deemed to be University), Chennai, India. Email: umashans@srmist.edu.in

Rama Rao Nadendla Professor, Head – Department of Pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences (AUTONOMOUS) Guntur, India. Email: principalclpt@gmail.com

www.journalforclinicalstudies.com

Therapeutics

Considerations for Clinical Trial Design Involving Radiotherapy Radiation therapy has been used for many years as an effective form of treatment against many cancer types; yet it remains less well researched and utilised than other well-known cancer therapies such as chemotherapy. Radiotherapy works to shrink or completely eradicate cancer cells with the aim of reducing the risk of recurrence or to cure the cancer completely. When used in this setting, the intent is known as “radical” or “curative” treatment. Radiotherapy can also be given in the palliative setting when a cure is not possible to relieve symptoms caused by the cancer. Radiotherapy can be used alone or in combination with other treatments such a chemotherapy, which is known as chemoradiation. It is also often given prior to (neoadjuvant) or post (adjuvant) surgery. It is a very versatile treatment coming with its own nuances compared to other commonly used cancer therapies such as chemotherapy, surgery, and immunotherapy. The amount or dose of radiotherapy delivered is measured in grays (Gy) per fraction. For example, a patient treated with 62Gy in 28 fractions would receive 2.2Gy of radiotherapy per fraction/ administration. Typically, patients would receive one fraction per day, Monday to Friday. These differences need to be well understood when it comes to designing and conducting clinical trials of radiotherapies, meaning trials for radiotherapy, can require unique strategies and methodologies, and can often present challenges not faced in other settings. This article will focus on some of these challenges faced in general across all clinical trials involving radiotherapy, followed by a closer look at the different trial phases. General Considerations for Radiotherapy Trial Design When designing radiotherapy clinical trials, there are some general considerations to be aware of, among them: •

•

Access to treatment Radiotherapy machines are not always available on a local level. This is particularly the case for newer forms of radiotherapies such as intensity modulated radiotherapy (IMRT) and proton beam therapy (PBT). Therefore, feasibility of recruitment and the generalisability of the trial results need to be considered, particularly when it comes to conducting large scale definitive trials. More novel and efficient trial designs need to be considered to optimise the availability of patients. Assessment of adverse events and duration of follow-up Side-effects from radiotherapy come in the form of short-term and late/long-term effects. The definition of these will differ between cancer types, but short-term side-effects are typically those experienced during and up to 6 weeks after the end of treatment. Whereas late/long-term side effects can present or

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•

still be present years later depending on the type of radiotherapy given and cancer being treated. Therefore, it’s important that clinical trials incorporate sufficient follow-up for toxicities and patient reported outcomes to fully capture the extent of the incidence and duration of these side-effects. A variety of methods for data capture should be considered including the use of electronic devices and follow-up phone calls to try and maintain compliance throughout the duration of the study. Bias Minimisation of bias (e.g., selection, attrition, and assessment bias) is a key consideration for all clinical trials. However, radiotherapy can bring some additional challenges. Radiotherapy technology is continuously advancing, and newer forms of treatment such a PBT, have been subject to much interest in the media. External biases such as these could impact the equipoise of a patient when considering participation in a trial and feasibility of randomisation should the patient have a strong treatment preference. This must be carefully addressed through unbiased patient-facing material and training of participating site staff. Another consideration is the feasibility of ‘blinding’. Unlike many cancer drugs, depending on the comparator, it may be more difficult to blind a patient to treatment allocation with radiotherapy, again increasing the risk of bias within the study. This could be minimised by ensuring assessments are conducted independently and blind to treatment allocation where feasible.

Considerations for Phase I Trials The main aim of Phase I trials (sometimes known as “first-in-human trials”) are to establish the safety of a treatment and recommended dose level for further evaluation at Phase II. This will usually involve treating small cohorts of patients in escalating doses until the ‘maximum tolerated dose’ (MTD) is determined i.e., the highest dose of a drug or treatment that does not cause unacceptable side-effects. These unacceptable side-effects are known as dose limiting toxicities (DLTs) and require patients to be followed up for long enough to be able to observe any DLTs, which may prevent escalation to the next dose level. Typically for drug trials, patients are usually observed for DLTs during their first cycle of treatment e.g., 4–6 weeks. But radiotherapy trials require a longer period of follow-up to ensure DLTs, many of which will occur post-treatment, are observed. Many Phase I ‘rule-based’ designs, such as the Standard 3+3 Design and Accelerated Titration Design, require all patients within a cohort to be followed up for the same length of time before assessing the potential for dose escalation. In the radiotherapy setting, this could lead to lengthy Phase I trials, which is not desirable. Model-based Phase I designs can provide a more efficient way of assessing patients within each dose level. For example, the Time-toEvent Continual Reassessment Method (TITE-CRM) design allows dose decisions to be made without the need for all patients to be fully followed-up and faster entry of patients into the study based on the accumulating toxicity data. The downside of this approach is that these types of designs are more complex and intensive from Volume 13 Issue 5

Therapeutics both a statistical and practical perspective compared to the more conventional methods. Considerations for Phase II Trials The main objectives of Phase II trials are to further establish the safety profile of an intervention and generate preliminary evidence of short term efficacy to determine if the intervention is worthy of taking forward for a definitive assessment within a Phase III trial. Importantly, a Phase II trial should act as a screening tool for Phase III, for example, selecting an optimal dose to take forward out of a number of “acceptable” doses. Phase II trials require a larger number of patients than Phase I, anywhere between 10s–100s patients. Depending on the type of radiotherapy being delivered and accessibility to treatment, recruiting large numbers of patients within a timely manner might pose challenging. Therefore, strategies are needed to try and reduce the overall numbers of patients required whilst still generating sufficient data on the experimental treatment(s). Phase II trials provide the opportunity to be more flexible with certain statistical design parameters, to address these recruitment challenges, whilst at the same time, still being statistically robust. Three approaches could be: • • •

Inflation of the type 1 error rate 1-sided test for statistical significance 2:1 randomisation

The type 1 error rate or significance level is the probability of observing a ‘false-positive’ result. It is typically set at 5% for Phase III and many Phase II trials, which represents the probability that you are willing to accept of observing a false positive result. But since the Phase II trial is not the end of line when it comes to evaluating a treatment, and a promising intervention will undergo further rigorous testing during Phase III, inflating the type 1 error at Phase II (for example to 10%) is considered an acceptable approach. In turn, if all other statistical parameters are kept constant, this will reduce the overall required sample size, as effectively you are saying you would be willing to accept more uncertainty around the result. Another approach to reduce the overall sample size could be to perform a 1-sided test for statistical significance, as opposed to a standard 2-sided test. By doing this you would be seeking to demonstrate a difference in a specific direction i.e., experimental > control, as opposed to any difference between the two groups, positive or negative. A 1-sided test gives you more statistical power than a 2-sided one, which in turn reduces your sample size if all other parameters are kept constant. It is however a less conventional approach and may come under scrutiny for not allowing effects to be demonstrated in either direction. It may be considered acceptable, however, at Phase II if there is strong case to believe the direction of the effect will be in one particular direction and there is little interest in the alternative. Finally, if there is already sufficient prior evidence and knowledge on the control arm, a 2:1 randomisation ratio could be employed, giving patients twice as much chance of receiving the experimental treatment. Whilst this will not lead to a reduction in sample size, it will increase the amount of data and evidence for the treatment of interest, and potentially have a positive effect on recruitment into the trial. Master Protocols – Challenges and Benefits Master protocols incorporate multiple trials and/or interventions into one single overarching clinical study protocol and are designed to answer multiple research questions. Trial designs which could make www.journalforclinicalstudies.com

use of a master protocol could be platform, basket, and umbrella trials, the latter of which will be the focus here. Umbrella trials are designed to study multiple therapies in parallel for a single disease, which may be divided into different subgroups based on the presence of a specific biomarker or mutation, stage of disease, or risk group. When treating patients with radiotherapy in the past, it was standard practice to treat all patients with a particular type of cancer with the same dose and schedule of radiotherapy, regardless of the stage of the disease or presence of known prognostic factors. This could mean that patients with early-stage disease may be being overtreated, and patients with more advanced, later-stage disease who might benefit from an increased dose of radiotherapy, may be being undertreated. Advances in radiotherapy technology now means that different doses of radiotherapy can be delivered to different parts of the tumour and surrounding tissues, allowing for a more personalised medicine approach. Umbrella trials are particularly suited for personalised medicine approaches as they allow the study of multiple therapies within a single disease, targeted at patients who are most likely to benefit i.e., patients with the same stage of disease, or with a particular genetic mutation. For example, a study of patients with anal cancer, might divide patients into three groups, i.e., those with low, medium and high risk disease, where risk is determined by how advanced the cancer is. Three separate trials may be run under a single clinical protocol, where three different experimental doses of radiotherapy are studied alongside the standard control. This type of design is not only efficient compared to running three separate individual studies but also increases the likelihood of a positive result by personalising treatment towards those patients who are most likely to benefit. As with any new approach, there are both challenges and benefits. Challenges may include more complex designs and methodology, more upfront investment to design and set-up the trial, a single independent data monitoring committee (IDMC) for the duration of the trial, and multiple IDMC reports to be delivered at one time. The benefits of the umbrella approach, however, are significant. Multiple research questions can be answered more efficiently, and it allows for a more personalised medicine approach potentially leading to greater interest by patients in participating. It optimises infrastructure across trials resulting in cost savings vs. running individual trials and allows patients with potentially rarer disease types to take part in a trial which may not have been feasible to conduct on its own, outside of the setting of a master protocol. In Summary Design of clinical trials for the evaluation of radiotherapies can bring up some unique challenges not seen with other cancer therapies. These nuances need to be well understood, and novel or less conventional approaches may need to be employed to try and overcome them.

Lucy McParland Lucy McParland is a Principal Statistician at PHASTAR (www.phastar.com), a contract research organization (CRO). Lucy joined the company in 2019, following a move from the University of Leeds where she was involved in leading the late phase oncology portfolio for radiotherapy research. Lucy has over 13 years of experience working in clinical trials, in both the academic research setting and for CROs. She also provides statistical consultancy for key industry partners.

Journal for Clinical Studies 37

Technology

Modernising Study Management for Greater Visibility and Speed in Trials Clinical trial complexity is growing as the industry adapts to COVID-19 disruptions, increasing data sources, and evolving patient expectations. Add on the fact that many studies are conducted across international borders and involve more stakeholders than ever, and streamlining trial processes is even harder. Coordinating between sponsors, CROs, multiple sites, and patients has become almost unmanageable using paper-based and manual processes. Clinical operations teams are advancing study management by adopting new strategies and technologies that bring together data, processes, and workflows to streamline trial execution. The Problem Complexity at the heart of clinical operations Today’s trials have complicated protocols, generate larger amounts of data, and span several geographies and diverse regulatory requirements. This makes real-time reporting a significant challenge since insights are required within shorter timeframes more often. (Figure 1) Most clinical operations teams cannot cope with these requirements because of legacy solutions that support outdated, paper-driven, and onsite processes. Key challenges include: • •

Delays: Too much time is spent capturing and tracking protocol deviations or follow-up items for trip reports, reconciling information, and double-checking reporting accuracy. Productivity issues: Clinical teams are turning to disparate systems and processes, including local file shares and emails, to collaborate because existing systems are too hard to use or cannot adapt to changes quickly enough.

•

Lack of transparency: Insufficient visibility due to data and system siloes, including poorly integrated external databases, can have an impact on study oversight.

The Solution Applying piecemeal upgrades to legacy systems has not supported innovation or led to transformation in clinical operations. As many reach the end of their useful life, a new breed of digital clinical trial management system (CTMS) is transforming how studies are conducted. Modern, cloud-based applications that can easily share data and documents with other applications like electronic trial master file (eTMF) and study start-up are now available, removing the need for integrations. They ensure all milestones during study startup and conduct are aligned across clinical applications and share site information, document lists, and reports with key stakeholders. Bringing together documents and data Unifying trial documents and operational data in a single system centralises clinical processes, improves accuracy, and enables strategic planning. For example, if team members can see all information for an upcoming planned site initiation visit, the team can use the combined data to decide how to prioritise their actions. That might be a contract that needs to be developed and reviewed; documentation that must be gathered for an investigational medicinal product release; or a monitor who needs to be briefed in order to conduct the study initiation visit. The work can be done in the optimal sequence quickly because team members can all access realtime operational data and documents. Historically, these processes have been tedious and manual, requiring reconciliation of document management systems and data. This slows essential actions or stops them from happening at all. The workflow of documents, for example – creating, reviewing, and

Figure 1. Trends in Clinical Trial Complexity 38 Journal for Clinical Studies

Volume 13 Issue 5

Technology

Figure 2. Common Clinical System Architecture distributing – provides essential information that must be combined with the project management data in the CTMS, a task that would require a heavy administrative lift if teams manage trials across two systems. A modern application with strong document and data management capabilities can bridge the gaps that persist across older methods of managing trials. The form of the data no longer matters and combining information does not require manual steps. Having a complete view of the trial allows clinical operations teams to make timely, better decisions, improving the speed and quality of trials. Just one platform The cloud CTMS (Figure 2) sits at the heart of the information architecture of a clinical trial, providing a centralised source of truth. Traditionally, a monitor might have to wait for hours while three or four systems updated before being able to access a site report. Using a modern system, information is immediately available as soon as it is entered. Monitors and study teams can move seamlessly between a visit report in CTMS and the associated casebooks in their electronic data capture (EDC) to perform source data verification (SDV) or review. Adopting clinical applications built on a common platform also helps to remove software integration bottlenecks. With a CTMS application that can easily connect to other solutions, there is no need for clunky integrations or customisations. Even upgrades are simpler, ensuring the latest functionality without costly professional services or consultants. Change is Happening The industry is looking ahead Clinical leaders are already taking action to unify clinical systems as 83% say that they already have, or plan to have, an initiative in place to bring together their clinical operations landscape. For CROs, this percentage was even higher with 90% saying that they plan to www.journalforclinicalstudies.com

integrate and streamline their systems and processes in the next 12 months. Most CROs acknowledged that they need to improve information sharing among study partners to reduce manual processes, speed up study execution and improve collaboration. Unsurprisingly, the use of CTMS has also grown dramatically in this group. In 2020, 73% of CROs said that they were using a CTMS, compared with only 58% in 2017. Case study: ARG One such CRO, Atlantic Research Group (ARG), was able to execute studies in less time, with fewer errors, when it upgraded to a modern cloud CTMS. The organisation provides clinical programme development services focused on oncology, immunology, rare, and neurodegenerative diseases. As the operational arm for sponsors’ clinical studies, ARG aims to make every engagement highly individualised. With a focus on innovation and speed, ARG sought to eliminate manual processes to better serve sponsors and study partners. Hunter Walker, chief technology officer, says “our goal with automation is to free our resources to tackle challenging tasks and solve bigger problems, not reduce headcount.” Following success with Vault eTMF, ARG felt they could drive even greater efficiencies and service levels by modernising their CTMS. They chose to replace their proprietary system with Vault CTMS. “We wanted to keep our IT team small, nimble, and focused on clinical research processes, not server architectures, operational systems, and security,” explains Walker. Moving to a unified platform enabled ARG to execute studies in a more efficient way. Clinical research associates (CRAs) previously spent long durations on every trip report, and with 10 CRAs and 100 reports over the life of the study, this became a significant cost. Adding in QC hours to review work done by the CRAs exacerbated Journal for Clinical Studies 39

Technology

costs. Now that the entire trip report and confirmation letter process is automated in Vault CTMS and auto-filed in Vault eTMF, these inefficiencies have been eliminated. Trip reports are now much easier for CRAs to perform and they can focus on more important activities during monitoring visits. Collaboration is a Key The industry has recognised that improving how information is shared between all study stakeholders is critical to long-term success. Organisations are looking to reduce manual processes, improve visibility and oversight, and speed trials. Because so many critical trial processes are still managed with legacy systems and trackers, the industry is in search of a better way of working together. By adopting applications that automate information flow, sponsors and CROs can connect their clinical systems directly to streamline processes. For example, working with a unified clinical solution enables sponsors to immediately create site candidate lists from CTMS and use site performance data from EDC and CTMS to target the best sites. Sponsors can easily collect input from investigators on study feasibility, allowing them to spend less time coordinating and tracking surveys. Milestones are aligned and shared between CTMS and the study start-up application so key activities are automated, site activation is faster, and documents are automatically filed in eTMF. By transforming information exchange from manual and paper-based to digital and automated, the industry can improve collaboration in studies. The continued adoption of decentralised approaches in trials is also improving information sharing across study stakeholders. For example, many companies still manage patient informed consent manually, in person, and on paper. Solutions like eConsent provide a complete digital experience, making it easier for patients to 40 Journal for Clinical Studies

understand and provide informed consent, and for sponsors, CROs, and sites to exchange documents and data. Looking ahead, the organisations that embrace a modern CTMS system that easily connects to other key systems – not only within the sponsor, but CRO, site and remote patient data collection as well – will accelerate trials and reduce overall costs. A modern CTMS is the foundation that enables a patient-centric digital clinical trials strategy. If the core infrastructure is outdated, inflexible and hard to integrate, it makes patient-centric studies much more complex to run. By bringing together sponsors, CROs, sites, and patients, the industry is enabling better collaboration and faster execution across trials. We’re only scratching the surface, but the advancements will continue to be swift. The industry is moving quickly toward trials that are fully digital, connected, and fast. This is benefitting the industry as a whole and will help speed the delivery of medicines to the patients that need them.

Hugo Cervantes Hugo Cervantes is the vice president of Vault Clinical Strategy, Europe, at Veeva Systems. Vault CTMS is part of Veeva Vault Clinical Operations Suite, enabling sponsors and CROs to seamlessly share information and documents across CTMS, eTMF, study start-up, and payments for better collaboration and increased efficiency throughout the study lifecycle.

Volume 13 Issue 5

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info@Astell.com +44 Journal (0)20for 8309 2031 Clinical Studies 41

Technology

The Journey from Hesitancy to a Reliance on Real World Data Karen Ooms, Head of Statistics at Quanticate explores the rise in the use of real world evidence (RWE) in the pharmaceutical industry in recent years, and argues that the concept of harnessing data from real-life patients has finally come of age. As recently as just a few years ago, drug developers across the globe were hesitant of using RWE when pre-forming the clinical analysis of an investigator product. The gold standard of investigative analysis to determine the efficacy and safety of a new investigational drug remained the randomised clinical trial. However, many statistical consultants have for a long time argued the merit of using real world data (RWD) to help create more efficient trial designs and provide, potentially, even more reliable data to inform clinical trials. The debate is ongoing. However, the COVID-19 pandemic has forced a new-found reliance on RWD. Sponsors and their CRO partners are seriously considering harnessing RWD to help the world overcome COVID variants and ensure new vaccinations for these variants get to market quickly and safely in the continuing fight against the global pandemic. With this in mind, has the use of RWD and RWE finally come of age? The drawbacks of clinical trials While randomised clinical trials are a crucial feature of any drug development process, providing valuable information about both the performance and safety of an innovative drug candidate, they do present drawbacks. These limit their utility with regards to developing a full understanding of the real-life performance of new therapies. For instance, they have narrow inclusion criteria, which often means that patients under concomitant treatments, with comorbidities or organ dysfunctions, or over a certain age limit are left out of studies. This is designed to reduce confounding factors and to produce data that is applicable to the average patient. However, in the real world, many of the patients taking the therapy will have other conditions that require treatment with other medications. Not including these means that it is impossible to gain a full picture of how the treatment will work. Further complicating matters is the issue of finding enough patients for the study to ensure adequate representation of all the possible patients who will benefit from the drug candidate. This is a particular problem for treatments for rare diseases, or for demographics such as children, older people, or pregnant women due to ethical concerns. Actual patient adherence to the therapy is another factor that clinical trials cannot take into account on their own. During trials, participants tend to be more compliant with instructions. However, patients at home may take and manage their medications quite differently – they may take their dose at different times of the day, or 42 Journal for Clinical Studies

they may forget to take it altogether. They may even struggle when self-administering – such as failing to inject or inhale an entire dose, leading to uneven dosage quantities. Varying perceptions of what constitutes a meaningful impact on symptoms and quality of life among both healthcare professionals (HCPs) and patients is also not typically addressed through clinical trials. With all of this in mind, clinical trials leave significant gaps in our understanding of the true performance of new treatments. During the COVID-19 pandemic, with the need to access data rapidly about the efficacy of treatments for patients hospitalised by the disease, the need to fill these gaps became particularly acute. It is no surprise that more and more drug developers took to exploring RWE as a means of addressing this issue. Explaining RWE To assess what is happening in the real world, rather than using clinical trials to collect data, the researcher may use data which has come directly from the market – RWD – to provide RWE for their treatments. The US Food and Drug Administration (FDA) defines RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials”.1 This RWD includes electronic health record data, insurance claims, device data and other patient-generated information. It also includes genuine ongoing conversations between doctors and their patients about day-to-day experiences of their conditions, and of their treatment. Such data can be collated from a wide range of sources, from medical databases kept by state healthcare systems or private HCPs to records of health insurance claims held by medical insurers. Patient-generated data from wearables or medical devices used at home can also be harnessed to generate real insight into how patients respond to treatments. The benefits of RWD Observational longitudinal databases of RWD allow for in-depth analysis by expert clinical research organisations (CROs). These databases contain de-identified medical records for many patients – the largest one Quanticate works with contains information about more than 100 million patients – over a period of at least a few years. This is a much larger scale than regularly used in clinical trials. Such a wealth of long-term information allows for analyses of rare diseases, treatment pattern changes and other factors, such as treatment performance alongside therapies for other conditions. However, unlike in clinical trials, the researcher will not be able to randomly assign patients to a given therapy nor collect all characteristics that may be of interest. This is one reason why RWE should act as a complement to clinical trial data. Volume 13 Issue 5

Technology In addition, the de-identification process of these data needs to follow country specific guidelines for protecting individual health care information.2 This means the available data does not include any information that could potentially be used to identify a person. RWE is quickly demonstrating its value to the pharmaceutical industry and proving that it can be used alongside clinical trials to measure the efficacy of new treatments. For example, in 2019, the first drug was approved by the FDA – Pfizer’s Ibrance – using analysis largely based on RWD.3 Previously, drugs were approved based on data derived entirely or almost entirely on traditional clinical trials. RWE in the age of COVID-19 The COVID-19 pandemic has provided an ideal scenario to highlight the genuine positive impact of RWE on pharmaceutical innovation. A number of CROs have seen demand increase significantly over the past year for RWD from drug companies working on treatments and vaccines for COVID-19. This includes demand for evidence of treatment performance in patients hospitalised with serious cases of COVID-19, to information about the long-term efficacy of the vaccines already introduced in the market. RWD can provide pharma companies with a wealth of information that can inform the search for improved therapies for in-patients with respiratory complications, as well as potential treatments for long-COVID symptoms. As more data becomes available, we can expect further innovation to be fuelled, benefiting COVID sufferers in the future.

Electronic medical records (EMR/EHR) databases, on the other hand, contain patients’ medical records drawn together for multiple facilities or across networks all collated by one entity. Consequently, they are disorganised and difficult to compile into a single comprehensible database. Different approaches to define certain health events may be used by each originating database. Records may also be incomplete. However, the data they offer provides incredible insight into the unique attributes of patients, such as lung volume or pain scores, which may impact on their response to treatments. With this complexity in mind, an individual, customised approach is vital when it comes to analysis of RWE. Working closely with an expert CRO with experience capturing and analysing RWD is vital if pharmaceutical companies want to ensure they get the most out of this new source of information and evidence. Time to harness the power of RWE While randomised clinical trials will always have a crucial part to play in any drug development project, we can expect RWE to have a far more important role in the future.

Most importantly, RWD has the potential to provide life sciences professionals with rich data about the impact of existing vaccines on new variants as and when they arise. Armed with this information, they can pinpoint which variants pose the highest threat to public health, which variants require boosters, and exactly where and when intervention is needed.

Such rich data, gathered in the field, over the long term and from a far wider selection of patients, offers an exciting opportunity to advance our knowledge of treatment efficacy. It also provides us with the chance to circumvent the limitations of clinical trials when studying rare diseases, helping us to deliver therapies and orphan drugs successfully.

As a result of all this comprehensive real-world information, pharmaceutical companies will be able to play an even more effective role in helping us to live with COVID-19 in the future. We will hopefully be able to save thousands of lives and turn the disease from disruptive pandemic into a manageable seasonal issue, as with influenza. The use of RWE in the pandemic even holds lessons for pharmaceutical companies focusing on the treatment of chronic or rare diseases, as well as cancer.

Harnessing RWE effectively is complex and challenging. However, with expert support, pharmaceutical companies can ensure they make the most out of this rich new source of information, so they can go even further towards transforming patients’ lives for the better.

The future of RWE RWD and RWE offers tremendous potential for improving our understanding of the effectiveness of the treatments we offer. However, the use of RWD is still in its infancy for the simple reason that the data itself – what and how much is collected, how and where it is stored, and how it is analysed – is a long way from being standardised. Efforts are being made to counteract this, but they consistently sacrifice some database specific advantages. But it does mean each database has its own structure, advantages and limitations. For instance, administrative healthcare databases compiled by medical facilities to be sent to insurance companies for billing of private medical care are clean, consistent and standardised, making them easy to study. However, they are restricted in terms of the information they offer, as they are limited only to data required by the insurance company. www.journalforclinicalstudies.com

REFERENCES 1. 2.

https://www.fda.gov/media/120060/download e.g. in the United States: Final Privacy Rule of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), American Recovery and Reinvestment Act of 2009 (ARRA) https://www.pharmaceutical-technology.com/comment/real-worldevidence-in-pharma/

Karen Ooms Karen Ooms is Executive Vice President and Head of Statistics at Quanticate, whi is responsible for overseeing the Statistics department at Quanticate. She is a Chartered Fellow of the Royal Statistical Society and has a background in biostatistics spanning more than 25 years. Prior to joining Quanticate in 1999 (Statwood), she was a Senior Statistician at Unilever. She earned her MSc in Biometry from the University of Reading.

Journal for Clinical Studies 43

Logistics & Supply Chain

Emerging Field Has Fast Become a Vital Component in The Medical Discovery Process Medical research has enabled healthcare professionals to successfully treat and prevent diseases, and the establishment of a reliable cold chain for the safe storage and transport of samples is essential for the continuation of such activities. Here, Luc Provost, CEO of B Medical Systems, talks about the support of scientific and clinical research through a reliable cold chain and the importance of temperature-controlled shipments. Medical research has enabled medical professionals to create therapeutics that can treat and even prevent a vast range of diseases and conditions that have before plagued communities the world over. The development of the first smallpox vaccine in 1796,1 the discovery of insulin in 19212 and DNA in 19533 are examples of events that have had a profound impact not only in medical research, but on the everyday life of billions of people worldwide. Biomedical discoveries have increased our knowledge of the world and with that, created new therapeutics to fight off infections and other diseases. This in turn enabled communities themselves to develop and flourish, leading to economic and social development.4 To this day, new technologies such as gene editing through techniques like CRISPR-Cas9 and AI applications in fields such as proteomics, are helping scientists create more advanced remedies for diseases and conditions.

The same can also happen to specimens but in this case, entire biological systems may break down irreversibly. Moreover, bacteria and fungi may find ideal growth conditions under high temperatures which can contaminate samples. Flammable or explosive chemicals also need to be stored at the correct temperature in a reliable and safe refrigeration environment to mitigate the risk of ignition. This is why medical refrigerators, freezers, and even ultra-low freezers are utilised so extensively in laboratories around the world. Laboratory refrigeration equipment is required to meet very high standards and are built specifically to safely store fragile biologicals. Refrigeration needs for laboratories can vary widely depending on the biologicals that need cold storage, which typically is divided in three main ranges: • • •

The regular cold chain which provides storage in the range of +2°C to +8°C usually provided by refrigerators Laboratory freezers or plasma freezers that offer temperature ranges reaching as low as -41°C Ultra-low freezers that can reach -86°C (cryogenic freezers offering freezing storage environment with temperatures as low as -150°C also exist, although these products aren’t used as frequently as their counterparts)

Specimens that require refrigerated temperatures (+2°C to +8°C) are the simplest thermosensitive ones to store.

Throughout the development of modern medicine, a new specific field has emerged which has fast become a vital component during the various stages of the medical discovery process – the medical refrigeration industry.

In these temperature ranges, medical refrigerators provide the necessary cold chain infrastructure. This type of equipment is especially designed to maintain a set temperature in the range from +2°C and +8°C, depending on the biological requiring storage, along with its temperature requirement.

The medical refrigeration industry has for decades been one of the catalysts that has enabled the discovery of new biomedical technologies. Indeed, major laboratories around the world utilise some sort of refrigeration solution for their samples – whether it’s a refrigerator, a freezer, an ultra-low freezer, or a combination of all three. Recently, because of the COVID-19 pandemic, the need for medical refrigeration has been brought to the attention of the public, specifically the various temperature and storage requirements of vaccines.

Laboratory refrigerators provide a uniform and stable temperature, usually via a forced or a controlled air-cooling system which allow them to perform well. Other features, such as gaskets, insulations and thermostats, ensure that temperature is maintained inside the cabinet while alarm systems alert associated stakeholders in the event of a change in the cabinet’s storage conditions. Remote monitoring solutions – which send automatic alarms via SMS and email directly to laboratory professionals/technicians in case of issues – are being used at a growing rate.

The Medical Refrigeration Cold Chain The importance of a reliable, medical cold chain that guarantees the safety of samples and compounds and the role of refrigerators and freezers in biomedical research cannot be overlooked. Many laboratory compounds are thermosensitive, which requires them to be kept at a certain temperature else they degrade. As temperatures rise, molecules can become unstable and give rise to chemical reactions. This can irreparably change the nature of the samples or compounds.

Thermosensitive compounds and samples, such as blood plasma or tissues and cells that are suspended in appropriate stabilising solutions, require freezing temperatures ranging from -41°C to -20°C. At ambient temperatures, these biologicals would spoil very quickly, therefore impeding research and clinical efforts.

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Medical freezers are the ideal cold chain solution for this temperature range. They deliver a uniform and stable temperature Volume 13 Issue 5

Logistics & Supply Chain

distribution and a fast recovery time in case of door opening. A reliable model should also feature advanced defrosting technology, enabling a stable cabinet temperature even during the defrosting cycles, a system to reduce heat transfer during door openings (such as automatic switch-offs of evaporator fans) and an extended autonomy in case of possible power failures. Alarm systems need to be highly sophisticated as in most cases they will store expensive and complex biologicals. Alarms should be audio-visual and ideally, connected to a remote transmission system which, in an emergency, can forward an alert via SMS or email. There are many energy efficient models on the market which boast eco-friendly performance ratings with features such as insulated inner doors, sealed gaskets and other structural features to minimise cold air loss and heat conduction. These, combined with the use of natural refrigerants, ensure freezers are more sustainable to run compared to other refrigeration equipment. Laboratory refrigerators that use natural refrigerants and conform with the US SNAP and EU F-Gas regulations are not only kinder to the environment but allow research institutes to save on operating costs. The most energy intensive laboratory refrigeration appliance is the Ultra-Low Freezer (also referred to as ULT), which is typically used for the long-term storage of samples with temperatures reaching as low as -86°C. However, advanced units will usually be able to reach less severe temperatures (as high as -20°C). Biologicals stored within these devices ranges from genetic material, such as DNA and RNA, to cell and tissue samples. This makes ULTs extremely important for www.journalforclinicalstudies.com

advanced medical research and for scientists who need to preserve important specimens for extended periods of time. New advances in vaccines research related to COVID-19 have expanded the use of these products to include the storage of thermosensitive mRNA vaccines, as well. ULTs are the epitome of advanced cooling systems that allow even and constant temperature distribution. Coupled with insulated inner doors and strong gasket seals, they ensure a reliable storage environment for optimal sample safety. Furthermore, the best ULTs provide a rapid pull down and strong door opening recovery and holdover times, which assist in maintaining a stable interior temperature during openings or even adverse events such as power outages. Because of the extreme temperatures they need to reach, ultra-low freezers can consume as much energy as an average family household and, because of this high energy consumption, the CO2 emission potential is high – typically, an ultra-low freezer and related HVAC can produce up to 100 tons of CO2 in their life span. To reduce the carbon footprint of its products, manufacturers need to invest in creating products that use green refrigerants with low Ozone Depletion Potential (ODP) and Global Warming Potential (GWP). Obtaining certifications such as Energy Star and abiding by the US SNAP and EU F-Gas regulations would be a great start towards energy efficiency for a lot of manufacturers regarding their ultra-low freezers. Training customers on how they can efficiently run a ULT is also recommended. B Medical Systems calculated that Journal for Clinical Studies 45

Logistics & Supply Chain

simply switching a product’s setpoint from -80°C to -70°C, could ultimately save customers 6.13 kWh/day.5 Transport of Biologicals via the Cold Chain Although biomedical research is carried out in laboratories around the globe, compounds, samples, and other materials need to be safely shipped to and from each setting to ensure discoveries can be applied to the clinical world. Pharmaceutical companies require the use of temperaturecontrolled shipments to ensure their products reach their target destination without having degraded during transport. In many cases, such as for medicines and vaccines, this is a complex operation that requires all necessary precautions to be considered to ensure products remain at the intended temperatures. Many vaccines are spoiled during transportation due to cold chain failures. To address this, medical transport boxes and temperature-controlled containers are widely used around the world. Transport boxes cater to the small sized shipments while temperature-controlled containers cater to the large-scale transportation requirements. Medical grade transport boxes are necessary during the transportation of thermosensitive specimens, compounds, or vaccines. Typically, there are two types of transport boxes. Passive products maintain certain temperatures due to their insulating properties while those in the active category utilise a compressor to maintain the intended temperature. These products are far superior to non-medical boxes as they are designed to maintain precise temperatures for extended periods of time. They offer reliable protection from temperature excursions and physical shocks during transport, long-term durability, and tend to have user friendly designs, ensuring the usability is always front of mind. Phase Change Materials (PCMs) or dry ice keep shipped samples at the correct temperature for the duration of the journey. Generally, dry ice is utilised to reach temperatures as low as -80°C, while PCMs can support a wide range of temperatures, including -32°C, +4°C, +22°C and +37°C. It’s noteworthy to highlight the use of temperature boxes during clinical trials is dependent on regulations which can vary widely between countries. Conclusion It is extremely important that biomedical research institutes and laboratories provide their researchers with reliable medical refrigeration products for the safe storage and transport of thermosensitive medicines, vaccines, samples, and compounds. The uniformity and stability can’t be matched by household equivalents. Moreover, when choosing the right medical refrigeration solution, it is important to not only consider what biologicals require storage, but also the reliability, convenience and energy efficiency these cold chain products offer. 46 Journal for Clinical Studies

B Medical Systems S.à r.l (formely Dometic/Electrolux) is a global manufacturer and distributor of medical cold chain solutions. Across the three major business portfolios of Vaccine Cold Chain, Medical Refrigeration, and Blood Management solutions, the company currently offers 100+ models including Laboratory Refrigerators, Laboratory Freezers, Pharmacy Refrigerators, Ultra-Low Freezers, and Transport Boxes. Throughout its over 40 years of experience, the company provided equipment to support its partners in vaccinating more than 350 million children in developing countries, and to enable clinical and biomedical research in tens of thousands of universities and research institutes worldwide. REFERENCES 1. 2. 3. 4. 5.

https://www.who.int/news-room/feature-stories/detail/smallpox-vaccines https://www.diabetes.org.uk/research/research-impact/insulin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379645/ https://www.frontiersin.org/articles/10.3389/fmicb.2020.01526/full https://www.bmedicalsystems.com/en/white-papers/sustainablelaboratory-ult-freezers/

Luc Provost Mr. Luc Provost believes in a vision that fosters innovation and customer-centricity. He is a hands-on leader who focuses on perfecting every customer interaction with efficiency and effectiveness. He has a proven executive management track record and over 20 years of experience in driving sales growth. He is passionate about helping save lives by providing solutions in the remotest areas and is also a prominent speaker and thought leader in the field of medical refrigeration. Mr. Luc Provost, CEO of B Medical Systems, a global medical refrigeration device manufacturer has been with the company for more than 20 years. He possesses a wealth of knowledge in business ownership, technology, operations, and sales and is at the core of the company’s reputation as an end-to-end medical cold chain provider. Since joining the company, he has played a pivotal role in the company’s revenue growth, geographical expansions and has signed various global commercial agreements for the company including with major corporations like Toyota. He was also instrumental in the launch of 50+ new products, many of which even created new WHO PQS standards. In his official capacity as CEO, he has travelled to 100+ countries and has worked closely with several central governments, ministries of health, international humanitarian and procurement organizations like UNICEF, WHO etc. Luc Provost holds a degree in Business and Management from University of Louvain in Belgium and has studied International Marketing at Laval University in Quebec. He is a Belgian citizen and has also worked for the Belgian Army. He speaks English, French, German, Dutch and Spanish.

Volume 13 Issue 5

INSIGHT / KNOWLEDGE / FORESIGHT

SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS IPI

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

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JCS

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

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IBI

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Peer reviewed, IBI provides the biopharmaceutical industry with practical advice on managing bioprocessing and technology, upstream and downstream processing, manufacturing, regulations, formulation, scale-up/technology transfer, drug delivery, analytical testing and more. Journal for Clinical Studies 47

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Volume 13 Issue 5

Sample Transport Packaging Complete Solutions for Clinical Trials

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