JCS Volume 12 Issue 3

Volume 12 Issue 3

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Regulatory Response to Accelerate COVID-19 Drug Development Serious Adverse Events in Lung Cancer Clinical Trials Thinking Outside the Box During the COVID-19 Pandemic Overcoming Clinical Development Challenges in Oncology with Innovative, Adaptive Trial Design

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Contents

JOURNAL FOR

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CLINICAL STUDIES U

Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITORIAL MANAGER Ana De Jesus ana@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Virginia Toteva virginia@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications 50 D, City Business Centre London, SE16 2XB Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

FOREWORD

WATCH PAGES 6

Observations on the Regulatory Fast Track to Speed up the Process with COVID-19 Vaccines/Treatment

Part of the prophylactic armoury against pandemic disease is a programme of surveillance for emergent pathogens. The current SARSCoV-2 outbreak may have been foreseeable as betacoronaviridae presagers which occurred in China and the Middle East, SARS (2002) and MERS-CoV (2012) respectively. Adrian Wildfire at SGS Life Sciences outlines a series of observations that aim to speed up the process with COVID-19 vaccines/treatment.

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FDA Focuses on Technology Modernisation Efforts

Under new leadership, the US Food and Drug Administration (FDA) is now focusing efforts on closing the gap between scientific advances and the computing solutions needed to translate advances into new therapies for patients, through the agency’s Technology Modernisation Action Plan (TMAP). Molly Spence at Clarivate Analytics emphasises the FDA’s focus on technology modernisation efforts in detail.

10 Strategies for Continued IRT Success During COVID-19 With the rapidly evolving nature of the coronavirus (COVID-19) pandemic, configurability and adaptability are key for IRT systems in order to minimise the impact to clinical trial patients. It is important to directly communicate with customers to help them mitigate the increasing challenges and avoid interruptions to their ongoing trials.

Kelly Knowles at Signant Health summarises her findings and best practices, in order to share with the industry at large.

REGULATORY 12 Regulatory Response to Accelerate COVID-19 Drug Development The FDA has created a special emergency programme for therapeutics known as the Coronavirus Treatment Acceleration Program (CTAP). This programme attempts to utilise all available methods to shepherd new treatments rapidly along the drug development pathway in an effort to reach patients as quickly as possible. Henry J. Riordan and Aman Khera at Worldwide Clinical Trials take a look at how the world has responded against COVID-19 in this regulatory report.

MARKET REPORT 14 Thinking Outside the Box During the COVID-19 Pandemic

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

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

Volume 12 Issue 3 June 2020 PHARMA PUBLICATIONS

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COVID-19 is a new virus with its own characteristics and the human population has showed its naivety. The number of individuals infected with COVID-19 continues to rise globally and healthcare systems have become increasingly stressed. Rossen Mihaylov at Ramus Medical explains why it is important to think outside the box during the COVID-19 pandemic, citing Ramus Laboratory as a good example of a company to watch.

18 The Human Side of Oncology Clinical Trials – Stories of True Patient-centricity The definition of being truly patient-centric is simply allowing a patient to participate in a clinical trial with minimal disruption to their personal and family lives. How this might look in practice will depend upon the indication itself. Within the realm of oncology this would be taking the visit to the patient’s home. Helen Springford at Illingsworth Research summarises actual real-life scenarios that demonstrate the human side of oncology clinical trials.

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Contents 20 COVID-19 and its Ripple Effect on Clinical Trials Whilst pandemics are fortunately not common, the global impact of COVID-19 has been profound. At the time of writing, global deaths have reached 420,000 whilst over 7.5 million people have been infected.

Sofie Vandevyver, Daniel Tanner and Mario Papillon at Cerba Research reflect on the impact on clinical trials, drug and diagnostic development and how the clinical trial market has rapidly adjusted to the new paradigm.

THERAPEUTICS 24 Overcoming Clinical Development Challenges in Oncology with Innovative, Adaptive Trial Design The field of oncology is expanding and changing rapidly. With increasing advancements in genomics and interests in precision-based medicine, more biomarker-guided treatments are being tested for new indications at an increasing rate. Jay JH Park, Adam Hamm and Ofir Harari at Cytel Inc. show how you can overcome clinical development challenges in oncology by using adaptive and innovative trial design.

28 Blood Pressure Monitoring in Clinical Trials in Obese Subjects The World Health Organization (WHO) classification system for obesity is based on body mass index (BMI). A BMI of 25.0 to 29.9 kg/ m2 is considered overweight, and ≥30 is considered obese. According to a 2016 WHO report, the worldwide prevalence of obesity nearly tripled between 1975 and 2016. Borje Darpo, Patricia Castellano, Robert Kleiman and Todd Rudo at ERT gives a short summary of the association between obesity, cardiovascular risk and hypertension.

34 Serious Adverse Events in Lung Cancer Clinical Trials Lung cancer is the leading cause of cancer death – 1.76 million lung cancer deaths occurred worldwide in 2018. More than 80% of patients were presenting with non-small cell lung cancer (NSCLC). Both NSCLC and small cell lung cancer (SCLC) are still frequently diagnosed at advanced stage. Maxim Kosov, Daniella Bajzath, Kamen Doxev and Maxim Belotserkovskiy at PSI CRO AG expand upon the serious adverse events that can occur in lung cancer clinical trials.

innovation, efficiency and speed to market. Noting the contrast between potential and progress in clinical trials vs post-marketing/ real-world monitoring, Peter Kohut at Arriello explores the main hurdles preventing greater automation of PV data capture processes within life sciences firms.

46 Notable Opportunities and Challenges of Wearable Technology in Clinical Trials Consumer-grade wearable devices offer the potential to continuously monitor many different physiological measures of health and fitness as individuals go about their daily routines. For a clinical trial, this could provide valuable insights between hospital visits, potentially enhancing the understanding of treatment response. Dr. Jennifer Bradford at PHASTAR offers insights into the notable challenges and opportunities of using wearable technology in clinical trials.

SPECIAL FEATURE 50 Translation Services – A Key Component in Successful Clinical Trials The language used in clinical trial protocols (CTPs) is becoming more and more differentiated as it blends medical, administrative and technical jargon not seen in other medical documents. However, inaccurate translations can happen and can affect human lives, credibility and economic revenue. Craig Brown at Dora Wirth Languages looks at the steps that companies can take to avoid faulty translations such as keeping communication channels open.

54 e-Learning Systems Revolutionising ‘teach’ and ‘learn’ in the Clinical Research Space Technology has revolutionised the way that we ‘teach’ and ‘learn’ in the clinical research space, because we now have a digital toolbox that can enable us to ‘learn online’. Whether that be through virtual e-learning systems or online courses, it’s no wonder statistics show that e-learning increases retention rates. Anthony Wilkinson at RQA showcases how RQA’s range of web-based, SCORM-compliant eLearning courses introduce Good Clinical Practice in the online training and clinical studies space.

38 Clinical Development in Inflammatory Diseases: Psoriatic Arthritis Psoriatic arthritis (PsA) is a specific form of chronic inflammatory arthritis associated with psoriasis, affecting both men and women equally but with a consistent geographic variability. Psoriatic arthritis is a potentially progressive, erosive, chronic, heterogeneous, and systemic inflammatory disease. Dr. Bhanu Priya Basavaraju, Dr. Vijayanand Rajendran and Dr. Mohamed El Malt at Europital outline the epidemiology, diagnosis and current clinical development in the treatment of psoriatic arthritis.

42 An Overview on Rare Disease Research With 350 million people affected worldwide, rare diseases represent a major unmet medical need. There is, however, no cure for the majority of rare diseases and many go undiagnosed. Tim Clark and Will Maier at ICON plc examine the key clinical, regulatory and commercial challenges associated with the development of therapies for the treatment of rare diseases in this compelling interview.

TECHNOLOGY 44 Five Barriers to Process Automation in PV & How to Overcome Them At the high-impact R&D end of life sciences, investment in technology is consciously linked to commercial priorities including 2 Journal for Clinical Studies

Volume 12 Issue 3

LIFE SCIENCE LIFE INSPIRED, QUALITY DRIVEN

CLINICAL RESEARCH SOLUTIONS

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SGS provides clinical research and bioanalytical testing, with a focus on early stage development and biometrics.

Delivering solutions in Europe and North America, SGS offers clinical trial services. SGS has its own clinical unit in Belgium including a viral challenge testing facility and two phase I patient units based in Belgium and Hungary.

SGS has a wealth of expertise in FIH studies, viral challenge testing, biosimilars and complex PK/PD studies with a high therapeutic focus in Infectious Diseases, Vaccines, and Respiratory. We offer a variety of tests that are bespoke, client-specific and support the full clinical development, from Phase I First-in-Human trials in our Clinical Pharmacology Units, to Phase II and Phase III studies in patients: • Drug Development Consultancy • Clinical Pharmacology Unit • Clinical Trial Management In Europe and Americas • Biometrics – Data Management, Statistics, PK/PD and Medical Writing

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Foreword The year 2020 started with a number of unfortunate events, and the most prominent to date is the COVID-19 pandemic. 2019-nCoV was named by the World Health Organization (WHO) on 7th January 2020 and was also given the official name: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of viruses (ICTV) on 11th February 2020. Whilst pandemics are fortunately not common, the global impact of COVID-19 has been profound. At the time of writing, global deaths have reached 420,000, whilst over 7.5 million people have been infected worldwide. As optimism increases that the virus is beginning to be controlled and the impact to life is understood, some forecasts predict grimmer longer-term societal and financial consequences, across many countries.

Although we should not overlook the tragic loss of life or the impact to quality of life, there are positives that we can take from this crisis. In the eyes of Rossen Mihaylov at Ramus Medical, the pandemic offered the opportunity to demonstrate to a wide range of people, companies and institutions its potential, professionalism, ethics, and advantages. According to Sofie Vandevyver, Daniel Tanner and Mario Papillon at Cerba Research, the COVID-19 pandemic has also revealed an urgent need for next-generation technology-driven clinical trials, citing virtual trials and digital healthcare as taking clinical trial management to a whole new level.

It is very likely that virtual trials and digital healthcare will become more mainstream as part of the new ‘normal’ beyond COVID-19, as remote patient monitoring gives participants the freedom and the peace of mind that they won’t be exposed to unnecessary risks.

The landscape of clinical trials never ceases to evolve, and COVID-19’s impact on clinical trials, drug and diagnostic development – and how the clinical trial market has rapidly adjusted to the new paradigm – has been vast. In fact the FDA has initiated a new programme to help expedite the development of drugs and vaccines for COVID-19, called the Coronavirus Treatment Acceleration Program (CTAP). Adrian Wildfire at SGS says that the CTAP aims to redeploy medical and regulatory staff to serve on review teams dedicated to COVID-19 and to streamline pathways for developers and scientists to progress inquiries and requests. This is a sentiment echoed by Henry J. Riordan and Aman Khera at Worldwide Clinical Trials, who claim that the programme seeks to shepherd new treatments rapidly along the

JCS – Editorial Advisory Board •

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

•

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

drug development pathway in an effort to reach patients as quickly as possible.

While the COVID-19 pandemic continues to strain clinical trials worldwide, a properly configured and adaptive IRT system can enable organisations to stay flexible and agile amidst a growing number of challenges. Kelly Knowles at Signant Health explains why configurability and adaptability are key for IRT systems in order to minimise the impact to clinical trial patients during the pandemic. However, improving the patient experience goes beyond COVID-19, as it is imperative that the human side of oncology clinical trials is taken into consideration, when putting true patient-centricity into practice. Helen Springford at Illingsworth Research summarises actual real-life scenarios that humanise the patient-oncology clinical trial experience, while Jay JH Park, Adam Hamm and Ofir Harari at Cytel Inc. focus on how you can overcome clinical development challenges in oncology by using adaptive and innovative trial design.

In order to humanise the patient experience, through adaptive measures, some experts have extolled the benefits of using wearable technology in clinical trials. Dr. Jennifer Bradford at PHASTAR offers insight into why consumer-grade wearable devices offer the potential to provide valuable insights between hospital visits, potentially enhancing the understanding of treatment response in clinical trials and even improving the dialogue between patient and caregiver. The positive impact of using digital technology has not gone unnoticed by Peter Kohut at Arriello either, who calls for greater automation of PV data capture processes within life sciences firms and how to overcome its barriers.

I hope you all enjoy our first summer issue, and I look forward to featuring more enlightening articles in the next edition coming out in August.

You may have noticed that we have changed the theme of the front cover picture of the JCS Journal. We started JCS with the unique goal of highlighting emerging countries and thoroughly analysed these countries as a clinical trial destination. Hence, we featured the national flower of one of the countries highlighted in that issue. Although we remain committed to bringing you a market analysis of emerging clinical trial destinations, JCS will now focus on therapeutic and regulatory aspects throughout 2020. The front cover picture will represent one of the therapeutic focuses that we have in this issue.

Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies

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

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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Catherine Lund, Vice Chairman, OnQ Consulting

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Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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

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

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

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

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Stefan Astrom, Founder and CEO of Astrom Research International HB

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

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Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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Hermann Schulz, MD, Founder, PresseKontext

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T S Jaishankar, Managing Director, QUEST Life Sciences

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Volume 12 Issue 3

THE CURE FOR THE COMMON CRO It’s hard to put a finger on what, exactly, makes Worldwide different from other CROs — but you start to get it when you experience the passion, expertise, and commitment in every team member.

We put everything into our projects. Our dogged determination to get it right. Our spirit of invention.

Our rigorous processes. Always curious. Always dedicated to delivering quality data. It keeps our customers coming back, choosing Worldwide as their partner time after time. We’re out to change how the world experiences CROs — in the best possible way.

Learn more at worldwide.com

AWARD-WINNING SERVICES Bioanalytical Services | Phase I-IIa | Phase IIb-III Phase IV | Rater Services | Real-World Evidence

THERAPEUTIC FOCUS AND EXPERTISE Central Nervous System | Cardiovascular and Cardiometabolic General Medicine | Rare and Orphan Disease Oncology and Hematology | Other Therapeutic Expertise

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Observations on the Regulatory Fast Track to Speed up the Process with Covid-19 Vaccines/Treatment Pandemic preparedness is a concept adhered to by global healthcare organisations and is perhaps best described by the World Health Organization (WHO) in their statement on pandemic influenza preparedness as being: ‘… an integral part of preparedness to threats to human health caused by any emergency, e.g. outbreaks of any disease....’ and as exemplified by the mission statement of the Coalition for Epidemic Preparedness Innovation (CEPI): ‘to stimulate and accelerate the development of vaccines against emerging infectious diseases and enable access to these vaccines for people during outbreaks’.

Part of the prophylactic armoury against pandemic disease is a programme of surveillance for emergent pathogens and an assessment of their likely impact on treatment-naïve populations.

The current SARS-CoV-2 outbreak may have been foreseeable as betacoronaviridae presagers occurred in China and the Middle East, SARS (2002) and MERS-CoV (2012), respectively. Coronaviruses (CoVs) are enveloped, positive-stranded RNA viruses comprising four structural proteins, namely: spike (S), nucleocapsid (N), envelope (E), and membrane (M). Vaccines against the S protein appear to be highly immunogenic but have also been linked to hypersensitivity in one mouse model1 and liver damage in ferrets.2 Previous experiences with accelerated pathways for H1N1/2209pdm influenza vaccines and Ebola (Ervebo – Merck) have leveraged proven and approved vaccine platforms and pre-qualified antigens to reduce time to authorisation.

Regulatory agencies have been prompt to support endeavours to accelerate vaccine candidates directed at breaking the SARS-2 transmission cycle. On March 24, 2020 (following recognition by the WHO of pandemic status March 11), the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA)

published a report by global regulators presenting the outcomes of a virtual workshop on COVID-19 vaccine development, convened under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA). The meeting offered practical advice including a decreased emphasis on efficacy and safety studies for proven platforms: “It is not required to demonstrate the efficacy of the SARS-CoV-2 vaccine candidate in animal challenge models prior to proceeding to FIH clinical trials.”3 However, the meeting did recognise and address the theoretical risk for SARS-CoV-2 vaccine-induced disease enhancement and requirements prior to proceeding to first in human (FIH) clinical trial. In addition to regulatory flex, the US FDA has initiated a new programme to help expedite the development of drugs and vaccines for COVID-19, called the Coronavirus Treatment Acceleration Program (CTAP). CTAP aims to redeploy medical and regulatory staff to serve on review teams dedicated to COVID-19 and to streamline pathways for developers and scientists to progress inquiries and requests.

As of March 13, 2020, the EMA announced full fee waivers for scientific advice applications from developers of potential therapeutics (to treat the disease) or vaccines (to prevent the disease) against the novel coronavirus disease (COVID-19). The EMA has also asserted that it is ready to review any applications for marketing authorisation within the ‘shortest possible timelines’ via mechanisms already in place such as the PRIME scheme, accelerated assessment and conditional marketing authorisation procedures. Other national regulatory authorities have reduced the timeline for clinical trial protocol review of COVID-19 studies, inclusive of emergency ethical or REC review. The Belgian Health Authority (the FAMHP) has reduced the review period to four days and the Danish Medicines Agency has reduced the review time for treatments relating to COVID-19 to three days. The usual assessment period for such studies is 14–35 days.

Source: Amanat, F. and Krammer, F. SARS-CoV-2 Vaccines: Status Report, Immunity (2020), https://doi.org/10.1016/ j.immuni.2020.03.007 6 Journal for Clinical Studies

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In the background, FDA, EMA and local authority site inspections are being delayed with current validation certification being rolled over until further notice and the European Commission has stated that it is working on a proposal to delay the entry into force of the new medical device regulations for one year, easing the burden of implementation and compliance.

Despite such proactive measures, with the SARS-CoV-2 pandemic ongoing and the likelihood of further pandemics exacerbated by increasing global travel and overpopulation, the final word should go to CEPI: “Though it’s unlikely, if the [COVID] pandemic appears to abruptly end before vaccines are ready, we should continue developing the most promising candidates to a point at which they can be stockpiled and ready for trials and emergency authorisation should an outbreak recur. A global financing system that supports end-to-end development … will be a critical component of future pandemic preparedness.”

REFERENCES 1.

2.

Tseng, C-T. and Couch, R. et al, Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus. PLOS ONE, April 20, 2012, https://doi.org/10.1371/journal. pone.0035421 Weingartl, H., Czub, M., Czub, S., Neufeld, J., Marszal, P., Gren, J., Smith, G., Jones, S., Proulx, R., Deschambault, Y. et al. Immunization with modified vaccinia virus Ankara-based recombinant vaccine against

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3.

severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets. J. Virol., 78 (2004), pp. 12672-12676 ICMRA: SUMMARY REPORT, Global regulatory workshop on COVID-19 vaccine development. A virtual meeting, held under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), convening experts from medicines regulatory authorities, the World Health Organization (WHO) and the European Commission. 18 March 2020. http://www.icmra.info/drupal/sites/default/files/2020-03/ First%20regulatory%20COVID-19%20workshop%20-%20meeting%20 report_March%202020.pdf

Adrian Wildfire Adrian Wildfire has worked as an infectious disease specialist for over 30 years, having trained and worked within the fields of bacteriology, virology, parasitology and mycology after obtaining his fellowship in medical microbiology in 1990, and a Masters in parasitology in 1998. He has specialised in human challenge models for nearly 10 years and is currently leading a multidisciplinary team manufacturing challenge agents for use in clinical trials. He is the author of numerous published papers and articles relating to HIV, ethics and viral challenge, amongst others.

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FDA Focuses on Technology Modernisation Efforts Under new leadership, the US Food and Drug Administration (FDA) is now focusing efforts on closing the gap between scientific advances and the computing solutions needed to translate advances into new therapies for patients, through the agency’s Technology Modernization Action Plan (TMAP).

“Data are the foundation of our most important work as a science-based regulatory agency – from reviewing medical products to identifying the source of a food-borne illness outbreak,” stated FDA Commissioner Stephen M. Hahn, MD, who began his term in December 2019. “Because data are so essential to what we do, we are committed to ensuring that our mechanisms for collecting, reviewing, and analyzing data are equally as sophisticated as the scientific advances that we are reviewing.”

Hahn stated that a main goal of his tenure would be to capitalise on scientific and technological innovation to speed product approval, while maintaining the FDA’s standards for safety and effectiveness. He aims to do this through continual modernisation of FDA information systems to provide reviewers and analysts with better data to accelerate assessments while ensuring information is accurate and high quality.

The TMAP1 encompasses three elements: 1.

Modernisation of the FDA’s technical infrastructure;

2.

Enhancement of the FDA’s capabilities to develop technology products to support its regulatory mission; and

3.

Communication and collaboration with stakeholders to drive technological progress that is interoperable across the system and delivers value to consumers and patients.

The FDA will combine its computing capability “with stateof-the-art approaches in data management, analysis, and decision-making,” said FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD. “We will work with internal and external experts on how to best approach important topics like data stewardship, strategy, standards, and more.”

A public meeting was slated for late March on the topic of data modernisation and strategy, but the FDA postponed it due to the COVID-19 public health emergency. The agency is seeking public input on topics such as standards and policy – including how the FDA can best use policy and common data standards to help ensure the effective and efficient use of data – and data security, privacy, and management. The FDA is also weighing how to design its data strategy and policy development to facilitate appropriate data access and appropriate reuse and repurposing of data to advance regulatory science priorities.

The need to modernise the FDA and its approach to drug development was stated recently by the Pharmaceutical Research and Manufacturers of America (PhRMA), a nonprofit group that represents the biopharmaceutical industry in the US and worldwide and advocates policies to facilitate the development of new medicines and treatments. PhRMA released a statement on the need for modernisation at the FDA, “to keep pace with scientific discovery, including catalysing the agency’s acceptance of innovative drug development tools (DDTs) and real-world evidence (RWE) to drive greater efficiency. This will yield a more competitive, innovative and sustainable biopharmaceutical ecosystem that better reflects patient experience and perspective.”

PhRMA advocates for regulatory acceptance of innovative approaches that go beyond the traditional randomised, controlled clinical trial design cited by Hahn as “the gold standard” for receiving FDA approval. The group stated that regulatory decisionmaking could be aided by appropriate use of RWE and the use of adaptive designs to increase clinical trial efficiency.

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In the TMAP, the FDA acknowledges that it will build the scientific and policy infrastructure to support increasing use of RWE2 to support regulatory decisions. The 21st Century Cures Act, enacted in 2016, highlighted the importance of RWE in the context of drug development. In late 2018, the FDA issued the Framework for FDA’s RWE Program3 for drugs and biologics. The FDA has also issued guidance4 on considerations related to the use of RWE in the context of regulatory decision-making for medical devices.

But RWE is only one area in which new technologies will shape future medical product development, the FDA stated.

Sophisticated data collection and analysis are also reshaping clinical trials, offering the ability to make clinical trials more efficient in the collection of data that is more representative of diverse patient populations. Novel and rapidly evolving technologies also promise to enhance the generation of evidence when the size of a clinical trial is limited – for instance, in the context of a rare disease, according to the TMAP. The TMAP provides a foundation for the development of the FDA’s strategy around data in general. In the coming months, the agency plans to engage with stakeholders to develop an overarching strategy for data modernisation and determine common priorities. www.jforcs.com

REFERENCES 1.

2.

3.

4.

https://www.fda.gov/media/130883/download https://www.fda.gov/science-research/science-and-research-specialtopics/real-world-evidence Framework for FDA’s RWE Program: https://www.fda.gov/media/120060/ download FDA Guidance for Industry and FDA Staff: Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: https:// www.fda.gov/regulatory-information/search-fda-guidance-documents/ use-real-world-evidence-support-regulatory-decision-making-medicaldevices

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

Email: molly.spence@clarivate.com

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Strategies for Continued IRT Success During COVID-19 With the rapidly evolving nature of the coronavirus (COVID-19) pandemic, configurability and adaptability are key for IRT systems in order to minimise the impact to clinical trial patients. Over the past few weeks, we have met with several customers to help them mitigate the increasing challenges and avoid interruptions to their ongoing trials. Now, we’re summarising our findings and best practices below, in order to share with the industry at large.

Distribution Challenges It seems that every day there are new distribution challenges for sponsors to address. Some of the most common issues are related to import delays due to closed distribution routes. These types of shortages require sudden changes to how sites are supplied. For example, if a depot in another country can import an item more easily than your current depot, this should be quickly updated in the IRT. Making these updates may require the addition of the new depot in the IRT, moving the medication, or more. Regardless, this must be communicated to your IRT provider as soon as possible.

A longer-term solution to prolonged import issues is to add a new sub-depot within an impacted country. The new subdepot could be a local pharmacy that has the ability to ship to sites within a region to avoid delays with customs or country

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import requirements while still considering all local pharmacy regulations. With this strategy, larger shipments can be sent to the new sub-depot to supply all the associated sites. This is similar to a central pharmacy design, but instead of requiring the sub-depot to ship for each patient visit, it would ship for all visits at a site within a set window of time.

In instances where a site is no longer able to dispense medication to patients, IRT resupply logic for the site should be quickly disabled to conserve supplies at the depot. Within the IRT system, threshold and/or predictive resupply logic to individual sites, specific countries or for the entire protocol can be turned off to limit the amount of resupplies sent to sites. These changes take effect immediately and manual shipments can still be created using the end-user interface to accommodate special circumstances.

Supply chain management parameters should also be reviewed to ensure that they align with current distribution challenges. With patients possibly taking home multiple visits worth of medication, IRT settings must account for the additional time the medication is with the patient. In addition, the resupply triggers surrounding resupplies for expiring medications may also need to be adjusted to allow more time. As distribution becomes more challenging, study medication shipped to a site should have a longer shelf-life to limit the amount of resupply shipments required due to expiry.

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The IRT can also help manage relabelling at the site to extend the expiry and ensure sites are using as much of their existing supply as possible.

Screening and Enrolment Challenges While updating the supplying depots or turning off resupply logic will help address distribution challenges, there may also be logistical challenges for patients attending site visits. There are many options to address this within IRT. The first option is to supply the patient with additional study medication so that they will not need to return to the site as often. This option is highly dependent on the way the study medication is administered and other protocol requirements (e.g. dosing, storage requirements, shelf-life, monitoring, etc.). However, if it is an option there are simple changes that can be made in the IRT to simplify this process for sites. This includes extending the predictive lookout windows and increasing the threshold amounts so that the sites are provided with extra study medication to give to patients.

Strategies like these must be coordinated with site staff, as they will need to record several visits in a row for the patient in order to permit the patient to take home the additional medication. If the system restricts the time between visits, unscheduled visits can be recorded to supplement the patient’s take-home medication.

Alternatively, the IRT can change hard visit windows to soft visit windows for patients in order to reduce the number of protocol deviations.

In addition to supplies, patients can also be moved to other sites to allow them to continue their visits. Within the IRT, the patient can be associated to a new site along with their visit history so that they can continue their treatment without interruption.

Another option is to implement a central pharmacy design where the ‘parent’ site is the study site and each ‘child’ site is a patient. To maintain patient confidentiality, no protected health information (PHI) should be entered into the IRT. This configuration would be another approach to implementing direct-to-patient (DtP) shipments in the IRT. We’ve heard that several studies are suspending screening and enrolment while allowing current patients to continue their treatment. To facilitate this, IRT systems can be used to quickly turn off screening and enrolment at the site, country or study level. To conserve supplies in these circumstances, sites can be www.jforcs.com

switched to a predictive-only resupply algorithm. This would limit the stock at site to only what is needed for the upcoming visits, and any buffer stock would be depleted as patients need additional, unscheduled or replacement medications. In addition, one-time manual shipments can be sent to resupply any site that exhausts their buffer supply.

Lastly, as mentioned earlier, organisations can update their IRT’s predictive algorithm to look for longer periods of time in an effort to account for more upcoming visits and create fewer, yet larger, shipments to the site. If certain countries or sites are consistently using more of their buffer stock than expected, the predictive check can run more frequently to mitigate the risk that the site will not have the necessary supply for a patient.

In Summary While the coronavirus (COVID-19) pandemic continues to strain clinical trials worldwide, a properly configured and adaptive IRT system can enable organisations to stay flexible and agile amidst a growing number of challenges.

As always, any changes in the IRT should always include cross-functional input from the clinical team including data management and statistics. Signant Health has a team of IRT designers, developers, supply experts and statisticians who are available to help consult on various study options to help support your clinical trial during these unique times.

Kelly Knowles Kelly Knowles is currently the Senior Director of Client Services at Signant Health and has been with the company for almost 12 years.

Prior to joining Signant Health she held project management positions at a contract manufacturing company in Philadelphia as well as within the Clinical Supplies and Process Development groups at Centocor.

She has her Bachelor degree in Biochemistry and Molecular Biology from Penn State University and her MBA from Villanova University.

Email: kelly.knowles@signanthealth.com

Journal for Clinical Studies 11

Regulatory

Regulatory Response to Accelerate COVID-19 Drug Development Citing concerns of both the alarming levels of spread and severity, and the distressing levels of inaction, the World Health Organization (WHO) declared that COVID-19 could be characterised as a pandemic on 11 March 2020. In response to this, various regulatory bodies – including the Federal Drug Administration (FDA) and European Medicines Agency (EMA) – have issued novel and streamlined guidance, operational processes and best practices designed to accelerate drug product development at this crucial time, given that there is no currently authorised treatment or vaccine.

At the time of writing this, April 10, the FDA has created a special emergency programme for therapeutics known as the Coronavirus Treatment Acceleration Program (CTAP)1. This programme attempts to utilise all available methods to shepherd new treatments rapidly along the drug development pathway in an effort to ensure that promising drug products reach patients as quickly as possible, but concurrently ensuring that both efficacy and safety are evaluated as rigorously as possible. The goal of CTAP is to immediately triage upon receipt any requests from drug developers wanting to develop new drug and biologic therapies by connecting them with essential FDA staff, often within a single day. FDA staff will then provide ultra-rapid and iterative input on the development plan with interactions prioritised based on scientific merit, stage of development, and identification as a priority product. This includes an ultra-rapid protocol review that typically occurs within 24 hours of submission. Single patient expanded access requests are also reviewed around-the-clock and generally completed within three hours. Additionally, the FDA will work closely with drug developers and other regulatory agencies to expedite quality assessments for drug products and to transfer manufacturing to alternative or novel locations to avoid any supply disruptions that may occur due to the pandemic.

This heightened support and ultra-fast turnaround times are made possible by the redeployment of medical and regulatory staff to review teams dedicated to COVID-19 therapies. This includes medical, operations, and policy staff to support the overall effort, as well as oversight by senior management. The FDA has also made it easier for healthcare providers and researchers to submit emergency requests to use investigational products for patients with COVID-19, given there has been a huge corresponding increase in the number of emergency use applications and ongoing trials.

The FDA remains committed to both enhancing and expanding the CTAP programme and pledges to post summary statistics and link to public information about ongoing clinical trials, in an effort to keep the public updated and to provide summaries of drugs in clinical and preclinical development when legally possible pending confidentiality concerns.

Being acutely aware that many hospitals and academic institutions had already begun initiating studies locally or treating patients as matter of urgency under compassionate use or similar emergency protocols, the EMA has also offered guidance designed to generate robust and interpretable evidence regarding safety and 12 Journal for Clinical Studies

efficacy for drug products designed for the treatment of COVID-192.

In a “call to pool EU research resources into large-scale, multi-centre, multi-arm clinical trials against COVID-19”, the EMA suggested that randomised controlled trials with a control arm without antivirals or other experimental agents (as none have proven efficacy yet) would supply data that could lead to timely regulatory decisions and best guide clinicians in determining treatment options for patients with COVID-19.

The EMA have also established a task force to take quick and coordinated regulatory action related to COVID-19 medicines3 that will assist EU Member States and the European Commission in dealing with the development, authorisation and safety monitoring of therapeutics and vaccines intended for treatment or prevention of COVID-19. The main purpose of the COVID-ETF is to draw on the expertise of the European medicines regulatory network and ensure a fast and coordinated response to the COVID-19 pandemic.

Unfortunately, a cursory review of the ever burgeoning number of studies that have recently launched, as seen on clinical trial registries such as https://clinicaltrials.gov/ and other websites such as Covid Trials Tracker4 and Oxford COVID-19 Evidence Server5, suggests that many of these studies do not meet these criteria. This is because they have relatively small sample sizes, no control arm without antivirals or experimental agents, or are forms of compassionate use and therefore, are not as likely to be able to generate the required level of evidence to permit sound regulatory and clinical commendations.

The EMA and WHO posit that such studies that are unable to generate an acceptable level of evidence to allow clear-cut recommendations and are not in the best interests of patients.

Rather, it is the multi-arm clinical trials investigating several agents simultaneously that have the potential to deliver results quickly across a range of therapeutic options according to the same evaluation criteria. Ideally, all EU countries would be considered for inclusion in such trials and adolescent subjects would at least be considered for inclusion in the large adult clinical trials. Studies of adequate size to assess safety and pharmacokinetics in the paediatric population would also be required.

It is acknowledged that a more coordinated approach across regions is needed to ensure appropriate efforts are geared towards larger multi-country randomised clinical trials that have the potential to generate this level of confirmatory evidence. To answer this call, many drug developers have partnered with private and public agencies/governments to launch large international trials.

In fact, four COVID-19 multinational adaptive trials are already underway; one starting with the investigational agent remdesivir, and two with the HIV drug combination of lopinavir-ritonavir.

The fourth, known as the Solidarity trial, will compare four treatment options against standard of care in one setting, in order to assess their relative effectiveness of remdesivir, chloroquine or hydroxychloroquine, lopinavir with ritonavir and lopinavir with ritonavir plus interferon beta-1a. Importantly, other drugs can be added based on emerging evidence. By enrolling patients across multiple countries, including Argentina, Bahrain, Canada, France, Volume 12 Issue 3

Regulatory instances inappropriate and should only be used for exploratory purposes and when no other options are possible. However, adjusted indirect comparisons such as mixed treatment comparisons using Bayesian statistical models to incorporate all available data for a drug can reduce uncertainty. Unfortunately, these techniques have not yet been widely recognised by researchers, or drug regulatory authorities. However this should not discourage drug developers from utilising already known (and if necessary, creating) novel and innovative clinical trial designs and analytic techniques that are efficient, flexible and robust enough in order to address this ongoing crisis in a rigorous and timely manner.

REFERENCES 1.

2.

3.

4.

5.

6.

Iran, Norway, South Africa, Spain, Switzerland and Thailand thus far, the Solidarity trial aims to discover as rapidly as possible whether any of the drugs slow disease progression or improve survival.

These massive trials demand herculean effort and resources and don’t typically permit much flexibility. It may also be possible to gain much-needed information by simultaneously launching new studies that permit the evaluation of multiple drugs (and most are combinations) in a single but relatively smaller study that does not use a factorial type approach to randomisation or analysis. The goal of these types of trials would be to utilise a more efficient and adaptive design that would enhance drug developers’ abilities to make comparative decisions very quickly regarding one drug or one combination over another. For example, utilising platform trials should enable drug developers to discover beneficial treatments and combinations with fewer patients, fewer patient failures, less time, and with greater probability of success than a traditional randomised controlled trial which doesn’t allow researchers to adapt to the results they are seeing throughout the study6.

Platform trials can be designed utilising an open master protocol which permits multiple treatments to enter or exit the trial over the course of the study, depending upon ongoing data – thus providing drug developers a chance to adapt to results that are observed throughout the course of the study. This heightened level of flexibility enables developers to drop treatments for futility, to assert certain treatments as superior to others, or add new treatments or combinations of treatments for assessment during a trial as they become available. This also allows developers to better meet the needs of patients within a study.

Another complementary strategy is to utilise various statistical methodologies that permit comparisons amongst studies that do not provide head-to-head evidence from a statistical point of view7. According to Kim et al., naïve direct comparisons are in most www.jforcs.com

7.

Coronavirus Treatment Acceleration Program (CTAP) https://www. fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatmentacceleration-program-ctap A call to pool EU research resources into large-scale, multi-centre, multiarm clinical trials against COVID-19. 16 March 2020 EMA/136815/2020 Committee for Medicinal Products for Human Use. https://www.ema. europa.eu/en/documents/other/call-pool-eu-research-resources-largescale-multi-centre-multi-arm-clinical-trials-against-covid-19_en.pdf Announcement of EMA task force. https://www.ema.europa.eu/en/ news/ema-establishes-task-force-take-quick-coordinated-regulatoryaction-related-covid-19-medicines Covid Trials Tracker https://covid19.trialstracker.net/about.html Oxford COVID-19 Evidence Server https://www.cebm.net/covid-19/ registered-trials-and-analysis/ Park JJH, Siden E, Zoratti MJ, Dron L, Harari O, Singer J, Lester RT, Thorlund K, Mills EJ. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.

Trials. 2019 Sep 18;20(1):572. doi: 10.1186/s13063-019-3664-1.

Kim H, Gurrin L, Ademi Z, Liew D. Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data.

Br J Clin Pharmacol. 2014 Jan;77(1):116-21. doi: 10.1111/bcp.12150.

Henry J. Riordan Henry J. Riordan, PhD is Chief Development Officer at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years. He has over 100 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology.

Email: henry.riordan@worldwide.com

Aman Khera Aman Khera is Global Head of Regulatory Strategy at Worldwide Clinical Trials. Ms Khera has over 23 years’ industry experience in providing global strategic direction in regulatory affairs. She has led a wide variety of regulatory projects providing regulatory strategy and development services for a variety of client sponsor companies in many therapeutic indications. Ms Khera is well versed in developing comprehensive regulatory strategies. Her career is built on helping client sponsor companies achieve their end-to-end regulatory strategies from study submission to commercialisation.

Email: aman.khera@worldwide.com

Journal for Clinical Studies 13

Market Report

Thinking Outside the Box during the COVID-19 Pandemic The year 2020 started with a number of unfortunate events, and the most prominent to date is the COVID-19 pandemic. 2019nCoV was named by the World Health Organization (WHO) on 7 January 2020. It was also announced with the official name: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of viruses (ICTV) on 11 February 2020.

COVID-19 is a new virus with its own characteristics and the human population showed its naivety. The number of individuals infected with COVID-19 continues to rise globally and healthcare systems have become increasingly stressed. The general advice to all of humanity is to “stay home”.

The urgent switch of priorities and the necessity to reorganise the work became eminent for all departments at the Ramus Corporation.

In this crisis, an essential role is dedicated to the clinical laboratory, contributing to patient screening, diagnosis, monitoring/ treatment, and epidemiologic recovery/surveillance.

SMDL-Ramus (Ramus Laboratory) was the first one of the private laboratories in Bulgaria dealing with COVID-19, based on PCR tests since 1 Mar 2020. The remarkable speed of the decision to implement testing for COVID-19 was based on the capability of Ramus Laboratory: • •

• • •

Highly qualified personnel of specialists in different medicinal fields; Employees trained in keeping biosafety standards in their everyday work – sampling, manipulations, testing – including in molecular biology sciences, keeping to the highest disinfection standards; Laboratory facilities and equipment appropriate to perform the necessary tests (PCR equipment); Emergency electric generation and key sensitive equipment protected by a USP; Accreditation from Ministry of Health (MoH), including for the Microbiology and Virology departments, mandatory for the task at hand.

collection, sample reception, laboratory testing. Comprehensive documentation of all stages was a crucial requirement.

In Bulgaria, the coronavirus epidemic manifested itself initially simultaneously with a full swing influenza B epidemic and diminishing influenza A epidemic. Thus, initially the hot topic was “Is it influenza or COVID?”! Following the necessity of the situation, Ramus Laboratory proposed testing for those possible causes of indisposition. Patients were advised to simultaneously test for other frequent respiratory pathogens using routine laboratory procedures.

Nowadays, with the diminishing risk of influenza occurrence, only a coronavirus test is performed.

According to the knowledge gained for the time being, it is considered that the most reliable diagnosis of suspected cases of COVID-19 is PCR testing (or stated more scientifically, real-time reverse transcription polymerase chain reaction – rRT-PCR). The rRT-PCR is a nucleic acid amplification test (NAAT). The goal is to search for the presence of unique for this particular virus molecules in respiratory tract specimens – upper respiratory tract specimens (nasopharyngeal swab), irrespective of the presence or absence of any symptoms.

One of the crucial steps in the analysis is the so-called extraction of the viral particles from the sample. When testing for COVID-19 started, this step was performed manually, which was a hard and time-consuming process. At best, up to 48 samples could be handled in three hours of work, which was acceptable due to low interest from society.

Shortly, in parallel with the worsening of the situation worldwide, the increased emigration of Bulgarian citizens from different hot points and growing media attention on the number of hospitalisations and mortality rates all over the world resulted in the laboratory experiencing the consequent growing desire from the general population for testing. This led to the inevitable need and decision to purchase an automatic extractor, facilitating the increased COVID-19 testing.

The ability to provide physically separated areas committed to the testing of COVID-19 was the crucial last grain that tilted the scales.

Two separate reception areas and medical offices for test collecting are established in order to protect patients undergoing routine laboratory test analysis from those being tested for COVID-19.

All procedures were arranged based on internal company risk assessments for each stage of testing – patient reception, sample 14 Journal for Clinical Studies

Volume 12 Issue 3

Market Report

Nowadays the available equipment and organisation of daily work and personnel of SMDL-Ramus achieve the unique possibility to perform more than 700 PCR tests in 24 hours.

reported to be useful for the monitoring of the health status of the COVID-19 positive potions – ferritin, PCT, CRP, hsTnI, D dimer, beta-2 microglobulin.

Moreover, our laboratory was the only facility, in that moment, testing asymptomatic persons, while the national institutes only tested patients showing symptoms.

When in contact with foreign substances, called antigens, the immune system produces an immune response – antibodies that appear in the bloodstream. Research has shown the detection of two types of antibodies – IgM and IgG antiviral antibodies in the serum samples from patients infected with COVID-19.

The PCR test might have been a bit pricy due to the sophisticated technologies applied, but it was still the same as the National Reference Laboratory analysis and had the same high standard of quality.

Subsequently, as the pandemic progressed, the idea of mass testing the population, or at least of certain high-risk groups, evolved. Moreover, the potential scenario of an asymptomatic course of the disease led to the need to propose tests for those people who may have generated immune response. This led to the introduction of cheaper options for the testing of COVID-19, sacrificing the highest quality for lower pricing, i.e. so-called “rapid testing”. Those quantitative tests for COVID-19 would give simple “Yes or No” results for the presence or absence of antibodies in the nasal swab. Such additional tests were included in the Ramus portfolio.

Besides the ongoing discussion worldwide about the reliability of “rapid testing” (very much depending on the manufacturer as well), the accessibility of the testing and the financial reasons were dominant for some people.

Following the Ramus Laboratory policy for providing the best possible quality of service, an intermediate option between PCR and “rapid testing” price-wise and quality-wise was discussed and utilised; namely, the quantification of the antibodies in the blood, showing reliable results for the state of the immune system.

This idea required the purchase of a new piece of equipment, MAGLUMI 800 – Snibe. This analyser is a fully-auto chemiluminescence immunoassay analyser for the COVID-19 clinical markers. The analyser also allows the testing of other parameters,

www.jforcs.com

Among them, IgM appears earlier in the course of the infection, and is mostly positive after 3–5 days of onset. After a few days the IgM titres decrease and the IgG potency rises rapidly. The titre of IgG antibody during the recovery phase may increase four times or more compared to the acute phase.

The MAGLUMI IgG/IgM assay is reliable and fully automated in the vitro antigen-antibody reaction, measuring the exact concentration of the COVID-19 specific antibodies. The risk of false negative or false positive results, inherent in “rapid testing” is negligible.

The whole duration of analysis is around 40 minutes, providing patients with quick results after a simple blood draw manipulation, facilitating the testing of a large patient population, protecting the safety of the laboratory employees simultaneously.

The role of the right equipment and facilities is indisputable, but our employees are the ones who made the “COVID-19 testing” challenge feasible. Our well educated and trained team demonstrated its competence, capacity, knowledge, and authority in working in high-risk conditions and under pressure.

For a short time, the personnel had to enrich the routine work process with a number of additional steps, mostly documentationwise and related to the more strict disinfection requirements, including, but not limited to: • •

Strict observance of a number of relevant protocols at all times; Additional interview of persons with probable or confirmed

Journal for Clinical Studies 15

Market Report

•

COVID-19, including collection of personal data, while complying with GDPR requirements; Collection of specimens from suspected COVID-19 patients (respiratory swabs or blood) under high safety requirements.

The engaged teams were re-trained on the appropriate standard operating procedures (SOPs) for collection, storage, packaging, and transport of specimens. New COVID-19 specific operational instruction and forms were developed, based on WHO and local authority recommendations, documented and available to relevant personnel. The staff were trained and monitored for efficacy in regard to the new document package.

Appropriate procedures for medical personnel to handle the additional protective equipment (for instance instruction about the correct way to put on and take off the protective clothing) was issued.

The staff in direct contact with patients being tested for COVID-19 or the collected samples were divided into separated teams with no physical communication between teams, following the WHO recommendation. Two types of teams – for taking samples and sample analysis – were structured. Each team for the sample analysis consisted of six individuals – a doctor who specialised in virology and microbiology, chemist or molecular biologists and a receptionist.

The work hours of a single team are limited to a maximum of four hours in an isolation ward. Two teams of both types work during the day without any contact between the team members, avoiding cross-contamination. A dedicated person reviewed the relevant and reliable sources for new available information on a daily basis, updated the documents used, when needed, and communicated the changes with the COVID-19 teams.

Each staff member is monitored for body temperature and respiratory symptoms before the beginning of their work at the laboratory, and only people with normal health status are allowed in. The Ramus staff working on the front line are regularly tested for COVID-19.

16 Journal for Clinical Studies

The WHO imposed requirements on protective equipment which was compiled in a letter. Adequate personal protection (PPE e.g., gowns, gloves, masks, eye protection) in accordance with BSL-2 laboratory protection requirements is available and obligatory to use for the staff dealing with coronavirus-19 according to the exposure risk level.

The provision of the PPE was an issue at the beginning of the crisis, because the PPE suppliers were unprepared with sufficient quantities of protective equipment, and the entire amount was redirected to government entities due to a change of priorities.

The medical director of the laboratory investigated, and market and manufacturers had to provide reliable funds in sufficient quantities to ensure the workflow for a few days ahead and to ensure the safety of our teams.

The sufficient availability of critical supplies is checked on a daily basis by a dedicated person.

Only appropriate disinfectants with proven activity against enveloped viruses are used. Disinfection of floors, walls, and all surfaces and objects is performed with chlorine-containing disinfectant three times a day and repeated any time when contamination is suspected. Air disinfection is performed by using ultraviolet lamps three times a day.

The location of the SMDL-Ramus central laboratory facility, near metro and bus stations, helps the patients to reach the facility.

The SMDL-Ramus central laboratory facility has its own large parking area offering its patients logistical ease, and facilitates the appropriate distance of 2 metres. Colour-coded signs were especially posted to demonstrate the necessary distance to be kept, while the entire process was constantly supervised by Ramus staff.

For those who were unable, for various reasons, to come to the central facility, SMDL-Ramus offer an in-home visit for sampling Volume 12 Issue 3

Market Report for coronavirus testing by three specially trained and equipped teams. Every team performs around 25 visits per day, so more than 1400 patients have used this service in under two months.

We take great pride that our colleagues from a number of hospitals in the country chose us for testing their medical and other staff.

The number of conducted tests from 15 March 2020 to 30 April 2020 is as follows: • •

10,148 PCR tests with 162 positive cases 7200 rapid tests with 213 positive cases

These numbers represent the higher percentage of tests conducted in Bulgaria (around 30%).

The reorganisation of the working process was in a way a challenge, but was to facilitate the implemented integrated quality management systems in the corporation.

SMDL-Ramus received accreditation from MoH for maximum duration, accreditation through EA BSA on ISO 17025:2017, and certification by Lloyds Register on ISO 9001:2015. SMDL- Ramus, in accordance with ISO 15189, is conducting an effective monitoring of the performance of diagnostic methods by using a third-party quality control – national and international, accredited to ISO 17043.

The new external quality assurance (EQA) programme was designed firstly by RANDOX in the UK, allowing the evaluation of laboratories’ ability to detect different coronaviruses including SARS-CoV-2 (COVID-19) using routine molecular methods, and our laboratory is already one of the participants.

A follow-up plan for Covid-19 patients is proposed by WHO, including a number of tests, expected to facilitate the health status monitoring of infected patients providing some base allowing prognosis of the disease outcome. Based on this, the medical director of SMDL-Ramus, with the collaboration of specialists in different fields, prepared a promotional package containing these additional laboratory parameters.

An information tempest erupted in society in Bulgaria. The media focused itself on the hot topics of the day, namely the shortage of protective face masks and other equipment (for both medical specialists and citizens), availability of tests and the risks of choosing one test over the other, prices of tests (free for patient with symptoms and governmental staff), what is happening with

the frontline staff...

Due to the apparent role of SMDL-Ramus in the COVID-19 issue, the national and local TV and radio media interviewed the CEO & medical director of SMDL-Ramus. The most pressing topics were those about the availability of tests for the citizens, informing people about how the testing is accomplished and the differences of the test options, which was shown to be a bit overwhelming for the participants.

The ongoing clinical trials performed by CRO Ramus Medical in the clinical phase are continuing, as agreed with the sponsors, following the “safety first” concept.

The official statement of the Bulgarian Regulatory Agency regarding its position during these strange times was not behind schedule, stating that trials should be postponed as much as possible. Various (online) training sessions with practical suggestions on how to minimise the damage followed as well.

Conclusion For the Ramus Corporation, the pandemic offered the opportunity to demonstrate to a wide range of people, companies and institutions its potential, professionalism, ethics, and advantages.

Our self-supporting departments, including medical laboratory with different fields of competence, logistical network, medical centre, CRO, integrated quality system and extremely stable management core made us stable during these unstable times.

The additional knowledge gained during the crisis will not only increase the positions of our PCR laboratory in Bulgaria, but will make us a more attractive choice for central and safety laboratory for various clinical investigations on the COVID-19 topic, that are, beyond doubt, just around the corner.

Be safe!

Rossen Mihaylov Assoc. Prof. Rossen Mihaylov MD, PhD in Medical Science, is founder and owner of the largest private medical laboratory in Bulgaria – Ramus and Ramus Medical – full service CRO. Has more than 30 years of experience in the field of clinical trials and laboratory activities.

Email: dimitar.mihaylov@ramusmedical.com

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Journal for Clinical Studies 17

Market Report

The Human Side of Oncology Clinical Trials – Stories of True Patient-centricity In this article I am going to ignore the typical metrics that are cited, such as the importance of clinical trial data being entered into the database, time to market and the cost of patent exclusivity. Instead, I shall focus on the influence of developing a truly patient-focused clinical trial, and the impact this has on the patient and their families. Whilst this is an aim we ought to strive for in all trials, it is especially important in the field of oncology studies, and even more so when the patient is terminally ill with a forecasted shortened life expectancy.

Instead of offering theoretical examples, I shall summarise actual real-life scenarios. These include the option for the patient of having visits at a location convenient for them. The traditional site is not completely replaced. Instead, having options really can have a positive impact on their lives and the lives of their families. Patients feel empowered and motivated to join or continue in their clinical trial.

What is Meant by a Truly Patient-focused Clinical Trial?

In my opinion, the definition of being truly patient-centric is simply allowing a patient to participate in a clinical trial with minimal disruption to their personal and family lives. How this might look in practice will depend upon the indication itself. Within the realm of oncology, this would be taking the visit to the patient’s home. In other areas it might be at school or at work.

This approach means taking the clinic to the patient and allowing the patient to build an optimum relationship with their visiting study nurse. This is often the same nurse throughout, thus giving the nurse a broader view of that patient’s wider health. This approach also enables the involvement of individuals that live in more remote locations to participate. They may previously have thought the distance to clinic would be too challenging. This type of service alleviates stress and improves the overall patient experience in studies where enrolment is typically an issue. A good example is in rare disease studies. Here sites can be few in number, indication-led issues a major issue, and often with substantial travel to site, in extreme cases even to a different country.

Typically, this approach has been successful in indications where enrolment has been challenging. That said, I feel the option should be offered more widely. Oncology trials have historically recruited well with patients driven by looking for a cure and supporting that effort.

However, as you’ll see below, there is great human benefit from being able take the trial to the patient in these instances. In my view it makes perfect sense to go to the patient at times when their immune system is vulnerable, and they are feeling physically weaker than usual.

This approach to clinical trials generally enhances recruitment rates as patients need to visit the site less regularly. It also enables those less mobile or who live further away to participate when they otherwise might not enter a clinical trial. Research nursing can also improve retention rates as patients build an open relationship with their visiting nurse. These factors provide extra support to the patient, whilst also enabling the drug to potentially reach the marketplace more quickly.

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Example 1 – Sheila The first situation involves a female patient with children and grandchildren who enrolled into a clinical trial for subjects with terminal ovarian cancer. I shall call this lady Sheila, for the sake of this article. As you would expect, Sheila became tired very easily and found trips to the site for visits difficult. Clearly, for anyone facing a terminal diagnosis, time is a very precious commodity. It is heartening to see people participate in clinical trials when there is clearly no gain for them personally. It is worth noting though that they consent to take part in trials of new drugs for the benefit of others in future generations. It is incumbent upon us all working in the clinical trials field to ensure that the burden on these patients is minimal.

This Phase I, first-in-human trial involved the patient travelling to site every day Monday to Friday to receive a subcutaneous injection. This was extremely onerous for the patient and family if they did not live in a short radius to the hospital site. Having to travel and park could mean the hospital appointment time would take several hours, if not the whole of the patient’s day! Following regulatory approval, it was agreed with the PI that following cycle 1 of the investigational medicinal product (IMP), the patient could receive the IMP off-site Tuesday to Friday, meaning that only one visit per week on a Monday had to be conducted at site. The IMP had to be administered under temperature-controlled conditions and transported at 2–8 degrees Celsius.

During one of the home visits, Sheila explained to our mobile research nurse the real impact this had on her in her final months of life. Every year in December, Sheila would make a Christmas pudding for each of her five grown-up children. It was a family tradition and extremely important to them all. Sheila laughed and said that it seems like such a trivial thing but for someone facing the end of their life with limited time left, the Christmas pudding ritual became extremely significant to them. Our nurse relayed what she had said: “If I had needed to travel to the hospital for all of these trial visits, I simply would not have had the energy left to prepare the Christmas puddings when I got home. Allowing the flexibility for me to be at home has made it possible for me to do this one last time for my children.”

Example 2 – Karen This example features another patient from the trial outlined above; here we have named her Karen. Karen had found the hospital experience very challenging and admitted to her research nurse she had thought about dropping out previously if this service had not have been available.

The demands of the hospital visits were becoming too much. The daily travel and time away from her family, which was often up to seven hours a day, were causing great distress. Karen’s husband was struggling to juggle the lengthy visits and time at the hospital with maintaining some sort of normal family life. This was also causing Karen great distress as she was labelling her visits a burden on her family.

Karen also had a needle phobia – not uncommon – but Karen’s was significant and heightened by the stress of being in a clinical environment. The waiting around, knowing the procedure would be happening but not quite knowing when, made it worse.

Volume 12 Issue 3

Market Report Research nursing at home really benefitted Karen. The same nurse was able to visit Karen each day, which reduced Karen’s anxiety levels dramatically, making the required visit procedures easier to perform.

Karen also reported feeling much more relaxed as the routine of the same nurse attending in a pattern had eased her anxiety. Karen built an excellent rapport with her visiting research nurse and she felt better able to ask any questions she had about the trial or drug.

Example 3 – Emily Another example of tailoring a trial to suit the subject is that of Emily (not her real name), aged 7. Emily had cancer and was enrolled into a clinical trial for a new chemotherapy agent.

Not unsurprisingly, Emily hated going to the hospital. The sterile, unfamiliar environment scared her. Even the thought of our mobile research nurse coming to the home to administer the chemotherapy was frightening. However, Emily loved fairies. At the next scheduled home visit, the family opened the door to our nurse and Emily was delighted to see that she was dressed in a fairy outfit! This made the visits more palatable and Emily felt slightly more in control of the situation. As our nurse recalled, “our paediatric patient would happily sit while I gave her intravenous chemotherapy as long as I was dressed as a fairy complete with tiara and wings! She said that I was her ‘get better fairy’ and that the trial medication was ‘magic potion’. I was very happy to comply. Home visits result in happier parents and increased compliance.”

Attention to detail and rapport is everything. If the nurse can speak to the child on their level, it makes for a more relaxed environment.

For Emily, being surrounded by her family, pets and a nurse dressed as a fairy while having the chemotherapy reduced her stress levels and made her participation in the trial far less unsettling.

Since then, our nurses carry cuddly teddy bears dressed up as nurses when they visit children at home. Performing role-play using the bears makes explaining study procedures more child-friendly and less intimidating.

The Sponsor Benefits Too… Although our primary focus here is the patient, sponsors are vital in ensuring this sort of service can be made available to patients and their appreciation of the added value to the patient is vital. The sponsor of Sheila and Karen’s trial commented: “The nurses were incredibly flexible, allowing patients to choose the time of the visit to fit around their daily activities of living, family and home life... Involving research home nursing improved the quality of life for those patients. At the end of life, enrolling in a trial is stressful, but with this patient-centric approach, it is a less stressful

A mobile research nurse explaining the procedures using our mascot, Illingworth Bear, before conducting any assessments on the child. www.jforcs.com

experience and helps to enrol and retain research patients when they know that this resource is available to them.”

In closing…

These three examples show that, by offering a more patientfocused approach to participation in clinical trials, one can make a significant, positive impact on patients and families.

Many people facing a terminal diagnosis will decide for the good of future generations to take part in studies of new drugs, whether or not it will help them directly. However, this does not mean that when designing these important oncology studies, we do not take time to consider and ensure the subject is not put under undue strain because of their involvement. It is only by the goodwill of the patient we can move forward with this pioneering vital research. By designing trials to ease the burden on the patients, this in itself has a positive effect on the very metrics that industry typically concentrate on, like patient enrolment and retention rates. Faster enrolment and a reduction in the dropout of patients subsequently allows for a drug study to close quicker and to reach the marketplace potentially faster than another compound. This is when the value of a truly patient-centric approach is most obvious. Finally, it is noteworthy that no less than 85% of all clinical trials fail to recruit enough patients. 80% are delayed due to recruitment problems. Even then dropout rates can be prohibitively high. Source biopharmadive.com.

It is not an exaggeration to state that the current situation cannot continue. Resources are indeed finite. This then is one of those wonderful situations where really placing the patient’s needs at the centre of the trial not only helps the patient and their siblings. It also increases efficiency in clinical trials and accelerates the drug’s progress to market.

Who then indeed would not want this?

Helen Springford Helen Springford, CEO, has been with Illingworth for 4 years, initially as Vice President, Strategic Development and then Chief Operating Officer. Helen has been pivotal in bringing process improvements and has developed a superb Business Development function to drive the company. Helen is a seasoned professional with 30 years industry experience. Helen graduated with an honours degree in Nursing Sciences and started her clinical trials career as a research nurse in London. Helen has managed an SMO and held various positions in CROs and big pharma within several functional areas including Clinical Operations, Project Management and Business Development. Her combination of nursing background, clinical and business skills will ensure Illingworth realise their goals over the coming years.

Journal for Clinical Studies 19

Market Report

COVID-19 and its Ripple Effect on Clinical Trials Whilst pandemics are fortunately not common, the global impact of COVID-19 has been profound. At the time of writing, global deaths have reached 420,000 whilst over 7.5 million people have been infected. As optimism increases that the virus begins to be controlled and the impact to life is understood, some forecasts predict grimmer longer-term societal and financial consequences, across many countries. Whilst we should not overlook the tragic loss of life nor the impact to quality of life, there are positives we can take from this crisis.

This article will reflect on the impact on clinical trials, drug and diagnostic development. However, many parallels with daily life can also be considered. Growing through adversity is an oft used aphorism and one which is true of people and industries alike. When faced with challenges, human ingenuity knows no bounds and COVID-19 has been both the mother of innovation but also the catalyst for the broader adoption of existing technologies.

It is no surprise therefore that the clinical trial market has rapidly adjusted to the new paradigm, one defined by limitation of social interaction, by looking to leverage technological mitigations. Before we explore this statement further, it is necessary to also reinforce that clinical trials were far from perfect. This has long been understood and the financial imperatives of this inefficiency propelled the industry to reevaluate the approach. This has materialised over the last decade with a greater focus on the patient as the centre of the trial. Whilst a truism that a clinical trial is not possible without the patients, the view that research should be designed around the patients, often as individuals, is something which is now being routinely built into studies.

Clinical trial participation remains low, with the US leading the way, with 5.4% as of 2016 (Statista); however, outside of the UK, Germany, France, Spain and Italy, only South Korea has a rate greater than 2% globally. The reasons behind this are complex, often idiosyncratic or culturally defined, however broadly stem from the awareness, social/moral compulsions and the burden of participation. The latter point is key and bringing studies to patients, and not the other way around, will be the cornerstone of future research, one which brings together digital health technologies with point-of-care testing and advanced supply chains. With the world in need of heroes, frontline workers across the world stepped up, with many placing themselves in clear personal danger. At the same time, the situation offered a degree of redemption for the increasingly vilified pharmaceutical industry. For many working within the industry at large, their critical roles in developing new vaccines, therapeutics and diagnostics never had such prominence, urgency or clarity of need. We saw unprecedented collaboration between competitors, regulators and academia to help solve the crisis. These new partnerships have the potential to revolutionise the way that we develop medicine in future. The hope is that all of this leads to a greater focus and commitment to human 20 Journal for Clinical Studies

health. Events of the last few months have only reinforced the fragility of our existence and a collective responsibility to help each other. We are still without any vaccine against the SarsCoV-2 virus and should not anticipate broad access to one for a long time yet. Antiviral medication to ameliorate the impact of infection is also in development; however, with the hope of repurposing existing treatments this may be sooner to arrive. Like the global economy, clinical trials are facing major disruption as research professionals seek to overcome unfamiliar challenges.

Processes taken for granted had to be speedily revisited.

Governments across the globe have instigated the necessary measures to ‘flatten the curve’ and limit the number and rise of COVID-19 cases. Alongside limits due to constrained supply chains, regional limitations and even company restrictions, hundreds of clinical trials have been significantly affected with the global average standing at -79% reduction in patients entering studies year-on-year (Medidata COVID-19 Report v.5).

Whilst anticipated, there is no assurance another pandemic will hit again, when that might be, or what the impact would be like. Taking the learnings from COVID-19, we know we can build on this opportunity to find innovative alternatives to set new standards that allow us to respond with flexibility and pragmatism. The industry has been historically slow to embrace new technology with EDC taking decades to become established.

The adoption curve for digital and virtual trials will hopefully be greatly expedited by the pandemic.

Pre-COVID-19 vs Post-COVID-19 – Clinical Trial Challenges Revealed Whilst the industry is focusing on developing vaccines and therapies in response to COVID-19, the crisis has significantly disrupted clinical trials in other therapy areas, most notably cardiovascular, dermatology and metabolic. Even though major regulatory agencies such as the FDA and EMEA have instigated guidelines and measures for maintaining the integrity of the trials, that seek to ensure the rights, safety and wellbeing of patients and healthcare staff during this COVID-19 pandemic, keeping clinical trials on track has been severely challenged. The COVID-19 pandemic has truly shaken up the world and the consequences on the conduct of clinical trials are many, including, but not limited to: •

Concerns about safety of the patient combined with the reallocation and hence lack of staff or resources to accommodate these patients have led to a decreased and/or delayed enrolment of patients

•

New study initiations were put on hold by either the industry itself, or forced by regional lockdowns, which resulted in patients being prevented from entering trials and visiting hospitals

•

Overwhelmed hospitals, resources, and systems

•

Reprioritisation of new test applications to only those that treat, diagnose, or prevent COVID-19; clinics allowing only these essential or critical visits, and refusing to take part in trials Volume 12 Issue 3

Market Report •

Have a clear view and understanding of the evolving situation

•

Reconsider standard trial design and setup to enable data capture

•

Be flexible and accelerate study start-up

•

Above all, maintain quality and supply chain.

At Cerba Research, we understand the situation is highly dynamic and region-dependent. We have integrated solutions in place to address each of these abovementioned challenges; from providing insights into metrics and trends, to virtual and nimble solutions and centralised data. Even though a remote workforce and disparate operations have become the new norm, we have taken first steps back to normal operations, and are building beyond standard to remain resilient and agile.

•

Conversion of physical visits into virtual visits

•

Extension of the duration of the trial, as the study was either interrupted or slowed down during recruitment

•

Recruited patients having to drop out of the trial

•

Vendors and contractors unable to meet obligations, such as delivering drugs to sites

•

Disrupted supply chain due to closed borders, also impacting shipment of clinical trial samples to be tested by a central laboratory

•

Risks of compromised data integrity if new procedures are deviating from the original plan

There is an obvious need to mitigate risks for patients and to support their inclusion into clinical studies. Flexibility, innovation and use of available technology will be of utmost importance to manage in this new paradigm. Beyond COVID-19, sponsors will be looking to dramatically accelerate patient recruitment and enrolment to catch up with lost time. Looking ahead, we believe the following challenges are pivotal for turning future clinical trials into a success: www.jforcs.com

Labs are Overwhelmed with Multitude of Assays for Identifying COVID-19 When it comes to the clinical trial space, we need to ensure inclusion/exclusion criteria are well defined as they set the framework for enrolment of patients. Given the current global prevalence, sponsors will need to consider routine inclusion of COVID-19 testing during screening in order to rule out positive patients in the course of the trial. Since the emergence of the pandemic, numerous tests have appeared on the market, which detect either the presence of the virus or the presence of antibodies against the virus. Both PCR and serology tests are becoming increasingly available as labs are scaling up their capacities. With a legion of assays available, many approved by FDA, and other regulatory bodies, the question arises which test will be the best to include in a study. The reliability, sensitivity and specificity of tests, are not always clearly demonstrated, documented or readily determinable. For this reason, Cerba’s scientists have performed a comparative study for different assays and technologies and have drawn up a list of tests which meet certain minimum criteria. Seeing differences in the respective Sars-CoV-2 gene and its mutations present on different continents, the need arises for a sequencing approach. It is important to note that the classification of cases is a surveillance tool that can be used to better understand the burden of the disease, and moreover the treatment suited for a certain individual. The use of current tests will evolve as we are increasing our understanding of the virus itself and newer tests are becoming available.

Technology and Decentralisation as an Alternative The landscape of clinical trials never ceases to evolve, and next to scientific breakthroughs, the COVID19 pandemic has revealed the urgent need for the next-generation technology-driven clinical trials.

Deviation from protocols is highlighting the risks of missing or delaying data collection from ongoing studies. This underlines the value of digital medicine, which is emerging by its advancements in cloud, mobile and IoT. Virtual trials are unfolding an extraordinary opportunity for pharma and healthcare, taking clinical trial management to a whole new level. It is very likely that virtual trials and digital healthcare will become more mainstream as part of the new ‘normal’ beyond COVID-19. There are numerous benefits to virtual trials, both short-term and long-term, though also limitations.

Remote patient monitoring gives participants the freedom and the peace of mind they won’t be exposed to unnecessary risks.

Journal for Clinical Studies 21

Market Report Virtual visits will allow the ability to reach a larger population of patients and will improve patient recruitment, engagement and retention. With the clinical trial ecosystem turned upside down, the emergence of virtual technology has the best chance to succeed and change the shape of clinical trials to be conducted for the coming years. Next to going digital, another solution to the current challenges includes deploying decentralised clinical trials, protecting both patients and medical staff. The FDA has published guidance back in March 2020 advising alternative methods while travelling to sites was heavily restricted, hence supporting the incorporation of decentralisation. For a couple of years now, some CROs as well as technology and software companies have been exploring this road of new patient-centric options. The COVID-19 pandemic has now paved the way for virtual trials and hybrid trials to become more widely accepted and perhaps eventually even become the norm.

Post-COVID-19: The Future is Now We are witnessing a true transformation of the clinical trial process and at a pace hitherto unforeseen. For the last decade, whilst some solutions were deemed too risky, the risk of not implementing them now has become greater. Change in this industry is a matter of survival, and many of the changes that were made during the COVID-19 pandemic will last and be for the better.

Case Study – Speed and Efficiency Were of the Essence Cerba Research was engaged by the Belgian government to participate in a government-led consortium. Working with a large team of software providers, pharmaceutical companies, CROs, laboratories and research institutes, we developed an approach for collecting and integrating data, aggregating and correlating it into focused dashboards, and setting up a framework to make relevant operational decisions. After setting up the initial framework and dashboard within only one week, we have supported the task force’s operational and scientific teams on a daily basis.

Led by the Federal Minister, the members of the task force worked (and are still working) to increase testing against COVID-19, an important tool in tackling the further spread of the virus, in order to flatten the curve. Cerba Research, the clinical trial & research division, with its headquarters in Ghent, Belgium, is providing the logistical support and organisation for this project, taking a pivotal role in the delivery of patient samples to pharma and academia for COVID-19 testing.

Key Achievements: •

Successful setup in only one week, including creation of a new database

•

Sourcing materials in-house for shipments on time despite current logistical challenges

•

Ability to quickly adapt to daily changes made and source new required supplies

Contingency planning and our flexibility to execute quickly and communicate effectively allowed us to meet all timelines. Risk identification and challenge mitigations proved helpful as the team were well prepared and showed an agile and determined mindset for this project.

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Sofie Vandevyver Sofie joined Cerba Research six years ago and holds a PhD in Science, biotechnology.

She combines her contracts and proposals experience with her scientific background to function as the Cerba Research head of business operations & marketing.

Daniel Tanner Daniel joined Cerba Research in 2018 having spent 15 years in the industry across several leading CROs in senior commercial roles. Daniel is Head of Business Development at Cerba Research.

Mario Papillon Mario is CEO of Cerba Research. Mario joined the Cerba HealthCare Group as the CEO of Cerba Research (formerly Barc Lab) in November 2017. A pharmacist by training, Mario has more than 25 years of experience in the pharmaceutical, biotechnology, and CRO industries.

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info@cerbaresearch.com www.cerbaresearch.com Journal for Clinical Studies 23

Therapeutics

Overcoming Clinical Development Challenges in Oncology with Innovative, Adaptive Trial Design Employing Adaptive Approaches to Reach Desired Clinical Objectives The field of oncology is expanding and changing rapidly.

With increasing advancements in genomics and interests in precision-based medicine, more biomarker-guided treatments are being tested for new indications at an increasing rate. Such research activity is dominating pharmaceutical pipelines, and is only growing in complexity and intensity. Oncology research now spans 450 immunotherapies and over 60 different mechanisms of action, with nearly 100 new next-generation biotherapeutics (NGBs) currently under investigation.

These complexities bring unique challenges. Oncology researchers struggle to source large enough patient populations for clinical trials, and there is often a lack of knowledge regarding a disease's natural history. This is especially true for rare cancers. The intricacy and changeability of endpoint analysis and clinical trials is growing, with the complexity of Phase I trials increasing by 20% in the past five years alone (measured as a combination of endpoints, eligibility criteria, and number of subjects). These problems are compounded for smaller companies that may lack the resources needed to plan and run clinical trials in an optimal and efficient way – a hurdle that is likely to worsen as trials become more complicated.

Given the environment of dynamic care in oncology, clinical development must be adaptable and dynamic, too. On top of this, there is a pressing need for earlier and longer-term planning that considers the entirety of a development plan, rather than individual trials that are planned and implemented on a step-by-step basis.

Trial developers can achieve this by using innovative, adaptive trial and programme designs, and involving quantitative strategists – statisticians, clinical pharmacologists and data scientists – early in the design and development process. Early involvement can hugely impact not only a single trial, but an entire development programme, enabling researchers to plan effectively, manage data optimally, and react to difficulties that threaten trial success.

The Challenges Facing Oncology Researchers Many of the difficulties prevalent in rare disease research are now evident for oncology trials, as more of these trials are now targeting specific subsets of the population with given biomarkers or characteristics. As a result, it is challenging to run randomised or larger-scale studies given that there is likely only a smaller pool of patients with biomarker targets to recruit. Many trials also have limited options in terms of comparator arms, making it challenging to compare and evaluate results. Due to scant knowledge of especially rare conditions, information on a disease’s natural history is often lacking, leading to reduced clarity over the outcomes, results and likely roadblocks.

Additionally, trial sponsors are calling for shorter, faster, and more streamlined development paths. Combined with the 24 Journal for Clinical Studies

competitive nature of the field, this pressure is having a significant effect: the median duration of the drug development process in oncology is declining, and some ‘breakthrough’ drugs are being approved at earlier stages of trials (Phase I, II, or combined II/III).

Furthermore, while time-to-event endpoints still dominate in oncology, additional endpoints, such as best overall response, are being more widely used earlier on in development programmes.

These capture different aspects of a disease and help characterise a product more accurately, facilitating its use and acceptance by stakeholders and authorities. While a variety of endpoints can capture more complete and detailed information, trial designers must be prepared to incorporate a more diverse, evolving range of endpoints and analyses than in the past, and at various stages of the trial.

With these challenges in mind, typical clinical development and regulatory pathways stand to benefit from new approaches that are optimised for the oncology research space — innovative, adaptive trial designs that offer new routes forward for organisations of any size. The development and use of such designs are encouraged and supported by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), and regulatory frameworks are evolving to reflect this1,2.

From Phase to Plan: Towards a Holistic Approach While clinical trials are traditionally separated into phases, this structure is becoming unsuitable for many rapidly evolving areas of research, with oncology being a standout example.

The different phases of trials are increasingly difficult to separate distinctly: initial studies in patients can often morph into dose escalations and expanded cohorts, and can provide evidence of both safety and efficacy in various specified subpopulations. While a science-based 'learn and confirm' mindset 3 remains present throughout the entire trial process, with a focus on understanding the functional relationships at hand, the delineation of distinct phases and stages of development is becoming less clear.

Rather than adopting a phased, study-by-study approach, oncology researchers now require a more overarching clinical development plan. Holistic perspectives enable a more adaptive, collaborative workflow within a fast-moving research and development environment, and offer flexible access to extensive complementary expertise and experience. This approach helps to identify and mitigate risk, which in turn leads to better preparedness and chances of long-term success. Compared to a phased approach, a holistic process can also help to cut clinical development timelines, lower the number of patients needed to address a research question, and reduce costs.

Cost is key in drug development. As the average annual investment required to produce new medicines increases, with Volume 12 Issue 3

Therapeutics per-product figures ranging up to US $300,000, sponsors are seeking ever-more streamlined production pipelines. Proving cost effectiveness is therefore essential to a product achieving a desired level of market access, coverage, value, and commercial success, as well as reaching the market in a timely, effective way.

Adaptations Bring Built-in Flexibility Clinical development plans allow researchers to better prepare for the trial ahead. Clinical development plans that incorporate innovative design features such as adaptive trial designs and Bayesian statistics can help maximise performance and efficiency. Adaptive trial designs allow for ongoing and datadriven decision-making throughout the trial process using prespecified adaptations to minimise potential risks while protecting trial integrity4. A Bayesian framework for analysis can offer more intuitive probabilistic interpretations of key clinical measures, formal incorporation of existing information, and flexibility in rules for adaptations5,6.

This kind of flexibility is especially important in oncology.

Given the absence of predecessor trials and data on many rare diseases and cancers, trials often lack the information needed to make accurate forecasts of expected outcomes. Even when agents being investigated in a trial are novel, or there is little information about characteristics or anticipated response7, oncology trials can adapt and move fast, highlighting the need for flexible data collection and decision-making.

Importantly, adaptive designs offer the ability to react and adapt dynamically to new findings mid-course. For example, trials with small patient populations operating under an adaptive Bayesian design framework can 'borrow strength' from previous trials8. This approach combines trial data with prior information and predecessor results to obtain better estimates of safety and effectiveness, and ensures that trials will not fail due to lack of power. Prior data can potentially reduce the necessary size or duration of a trial, allowing the same decision to be reached faster or with fewer participants. From a regulatory perspective, the FDA's Center for Biologics Evaluation and Research (CBER) appears receptive to Bayesian approaches9.

Adaptive designs can also allow for adaptive population enrichment, whereby eligibility criteria are adjusted throughout a trial using prospectively planned interim analyses so that, after an interim look at the data, only patients likely to benefit from a new treatment are enrolled. This can increase the power of a trial and allows trials to continue with smaller sample sizes and shorter durations than conventional approaches. Adaptive enrichment designs can overcome issues caused by differences in treatment effect between sub-populations10 by involving multiple parallel trial arms, and enriching for biomarker characteristics likely to predict for clinical success11.

One concern that is prevalent among trial participants, especially in oncology, is that they could be assigned to a placebo or a subpar treatment arm. This anxiety can delay patient enrolment and prevent trials from reaching ideal cohort sizes. Designs that incorporate external, synthetic or historical control arms can alleviate such fears. These designs leverage real-world data to model comparator arms based on previous studies, making them especially useful for early exploratory trials or other instances where the eligible size of the patient populations is low. Rather than needing to recruit real participants for control arms, trials can instead use synthetic arms based on health data gathered as part of routine care, records, claims, registries and historical trials. www.jforcs.com

Historical control groups ensure that the baseline characteristics in a treatment arm are comparable to that in previous standardof-care trials12, reducing the risk of trial participants being exposed to a treatment that is inferior. When announcing its 2019 strategic framework13, the FDA acknowledged the potential of real-word data in supporting the development of drugs and biologics, noting that such data can be used to advance medical research, generate evidence, and better analyse clinical outcomes.

Adaptations regarding changing endpoints are especially useful. Given the unknown nature of many of the diseases studied, oncology trials often rely on event-based endpoints on unknown timelines14. Selecting the right endpoints is crucial in bringing the right evidence when it comes to submission; complex endpoints must satisfy all stakeholders – patients, payers, prescribers, regulators – and must therefore be planned out at the early stages of conventional clinical development. Adaptive approaches, however, allow endpoints to be adapted and introduced at different stages of a trial. Multiple endpoints (for example, Overall Survival and Progression-free Survival) can also be combined to inform decision-making15. Reconsidering composite endpoints can help in overcoming the issue of scarce data and helping to better anticipate dynamic timelines and targets.

Quantitative Strategists Are Essential for Trial Success Quantitative strategists – from statisticians to clinical pharmacologists and data scientists – are essential in trial design. This is especially true for adaptive clinical trials, where it is paramount to ensure that any changes in trial parameters do not compromise integrity and statistical validity.

Often, statisticians are only involved when trial developers want to answer a specific question in the design process – when calculating required sample size, for example. However, it is difficult to know when statistical expertise is needed12, and to know what is unknown or unaccounted for. If a statistician is unaware that a trial faces a particular issue (defining the population, for example) they cannot suggest a solution (such as adapting for sample enrichment or using adaptive design to reduce the sample size needed). Involving a statistician from the start of programme development ensures they know the risks and can advise on how to address and mitigate them. For smaller organisations, this is even more important, where biostatisticians often need to pose questions that would come from elsewhere, such as outcomes research, data science, and clinical pharmacology in a larger organisation.

Additionally, as research trends towards precision medicine, an increasing number of trials select or stratify patients based on pharmacogenomics – where genetics is used to help determine or predict how an individual will respond to a drug. Statistical genetics experts thus have a potentially invaluable role to play in ensuring that clinical development plans are prepared for and navigating this emerging field appropriately and effectively.

Rather than just applying traditional biostatistics responses to specific queries, a collaborative, statistician-first workflow proactively identifies and avoids pitfalls and potential risks, ensuring that Statistical Analysis Plans are followed correctly – especially where adaptive methods are used in the study design.

This kind of approach also synthesises existing information to identify the potential for innovative design features that are datadriven.

Early involvement of quantitative strategists helps to provide information and clarity, and to determine and evaluate different Journal for Clinical Studies 25

Therapeutics ways to address key challenges. This reduces the risk of trials having to be re-run, saving time and money, and can help increase the likelihood of regulatory approval. For instance, the FDA and the EMA have approved approaches in which sample size is reestimated following interim analysis; these designs are proven not to undermine a study's integrity and statistical validity, and they enable sponsors to confidently proceed with expensive late-stage studies1,2.

Data Considerations and Complexity Oncology trials have highly complex considerations around data use and analysis. Trials utilize various categories and sets of external data, include elements such as dose escalations and cycles of therapy, and involve intricate data derivations and endpoints.

Data related to biomarkers and concomitant active treatments come from various sources, is stored across disparate external databases, and must be blinded to ensure trial and data integrity.

Some data is also subject to adjudication or confirmation. All of this complicates data handling processes, as it is crucial that data is blinded, aggregated, and accessible on a coordinated, transparent timeline. Here, statisticians can help – they can ensure that data is available throughout the development path as needed, and forecast the optimal timing for decision points through the trial process.

Trials require streamlined, clean, fit-for-purpose datasets that meet their specialised requirements, and researchers need constant, up-to-date knowledge of their data and its metadata to stay aware of data quality, accessibility, location, and status. Standardised approaches built around Data Management Plans can streamline workflows, bring preparedness and efficiency, and support pathways such as fast-track approval or data pooling16. This not only makes development plans more efficient but can improve their performance. Data pooling, for instance, brings together data from population-based or clinical settings for use in trials where sample sizes are inadequate. Given that large trials are not always possible, this enables a wider range of research questions to be addressed as accurately and effectively as possible.

26 Journal for Clinical Studies

Making considerations for adaptive trial design and other innovative trial design methods require technical capabilities. Some organisations, including smaller ones with fewer or limited resources, may find it beneficial to work with a collaborative CRO partner who can help them design and implement a robust data consolidation and analysis strategy. Combined with other services, such as historical or real-world evidence provision, this approach can ensure a trial is asking the right research questions, with the right data, for the right analysis.

Conclusion To keep pace with the rapidly changing landscape and abundance of new therapies emerging in oncology, researchers must think ahead – and think differently.

Oncology trials face numerous challenges, ranging from small patient populations to evolving endpoints to complex data handling and analysis. Overcoming these requires a holistic approach that considers an entire clinical development plan rather than fragmented trial phases. Trial design must be able to adapt and targeted changes be made in real time that maintain the statistical integrity of the analysis of data. Here, quantitative strategists are essential to ensure that, as a trial adapts, it remains focused on its objectives and does not compromise its integrity or statistical validity.

By involving statistical expertise from step one, oncology can now employ innovative, adaptive ways of reaching a whole host of desired clinical objectives. Small and large organisations alike can benefit from adaptive trial design. These innovative designs can reduce the inherent risk in clinical trial development and implementation, and target the populations who would benefit most from a new agent or therapy6 in order to bring products to market, and to patients, faster and more cost-effectively. After all, bringing benefit to the patient is the aim of any trial – and the more efficient and effective the trial, the better for patient health.

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https://www.fda.gov/regulatory-information/search-fda-guidance-

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documents/adaptive-design-clinical-trials-drugs-and-biologicsguidance-industry, visited on 15 May 2020 https://www.ema.europa.eu/en/methodological-issues-confirmatoryclinical-trials-planned-adaptive-design, visited on 15 May 2020 Sheiner, LB (1997). Learning versus confirming in clinical drug development. Clinical Pharmacology & Therapeutics (1997) 61, 275–291 Bhatt, D and Mehta, C (2016). Adaptive Designs for Clinical Trials. New England Journal of Medicine, [online] 375(1), pp.65-74. Available online: https://www.nejm.org/doi/full/10.1056/NEJMra1510061, visited on 15 May 2020 Gill, CJ, Sabin, L and Schmid CH (2005). Why clinicians are natural bayesians. BMJ 2005; 330(7499): 1080-3.

Jack Lee, J and Chu, C (2012). Bayesian clinical trials in action. Statistics in Medicine, [online] 31(25), pp.2955-2972. Available online: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3495977/pdf/nihms412608. pdf, visited on 15 May 2020 Cytel (n.d.) Flexible Dose Escalation Designs to Better Identify Maximum Tolerated Dose. Available online: https://www.cytel.com/ hubfs/0-library-0/cases/Case_10Flexible%20Dose%20Escalation%20 DesignsMini.pdf, visited on 17 March 2020 Gupta, SK (2012). Use of Bayesian statistics in drug development: Advantages and challenges. Int J Appl Basic Med Res. 2012 Jan-Jun; 2(1): 3–6.

Irony, T (2019). Issues in Clinical Trial Design for Cell Therapies, ACDRS-NIH Workshop: Cell-Based Immunotherapy, 22 January 2019.

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Cytel (n.d.). Innovative Phase 3 Adaptive Enrichment Design Reduces Development Risk in Rare Oncology Indication. Available online: https:// www.cytel.com/hubfs/0-library-0/cases/Case_11Innovative%20 Phase%203%20AdaptiveMini.pdf, visited on 17 March 2020 Cytel (n.d.). Designing A Complex & Innovative Trial to explore multiple options for a rare and aggressive cancer. Available online: https://www. dropbox.com/s/dyreiedjr4viofv/SignatureComplexCaseStudyprint. pdf?dl=0, visited on 17 March 2020 https://www.cytel.com/blog/keeping-clinical-trials-on-track, visited on 17 March 2020 https://www.fda.gov/news-events/press-announcements/statementfda-commissioner-scott-gottlieb-md-fdas-new-strategic-frameworkadvance-use-real-world, visited on 17 March 2020 https://www.cytel.com/blog/designing-event-based-studiesinterview-with-pantelis-vlachos, visited on 17 March 2020 Cytel (n.d.). Combining Bayesian Decision-Making with Frequentist Final Analysis in Phase 3 Oncology Trial. Available online: https:// www.cytel.com/hubfs/0-library-0/cases/Combining%20Bayesian%20 Decision-Making-webCase_9.pdf, visited on 17 March 2020 https://www.cytel.com/blog/specialized-data-oncology-trials, visited on 17 March 2020 Park, J et al (2020) An overview of platform trials with a checklist for clinical readers, https://doi.org/10.1016/j.jclinepi.2020.04.025, visited on 15 May 2020

Ofir Harari

Adam Hamm

Ofir Harari has been working in the field of statistics and data analysis since 2007. He has experience in the design and analysis of randomized and cluster-randomized clinical trials, Bayesian data analysis, adaptive designs, statistical emulation, Markov microsimulation models, synthetic control methods, survival analysis, statistical computing, geospatial analysis and network meta-analysis. At Cytel, Ofir is a Principal Statistician leading projects that utilize real-world evidence. Ofir also develops statistical software for Bayesian trial design, adaptive strategies and interim analysis, network metaanalysis, and causal inference from observational and longitudinal studies. Prior to joining Cytel, Ofir was a postdoctoral fellow at the University of Toronto and Simon Fraser University. His past work experience includes roles as a Fraud Analyst at Paypal and Yield Engineer at Optimal Plus. Ofir’s interest and expertise lie at the intersection of statistical methodology and software development.

Adam Hamm, PhD is a Senior Director of Biostatistics at Cytel and the Head of the North America Project Based Services group. He has more than 16 years of experience in statistical analysis and methodology across all phases of clinical research.

Responsibilities utilizing adaptive clinical trial designs have included strategic statistical consulting, development of statistical sections of protocols, and development of adaptive design plans including simulations and modeling. Adam has extensive experience in adaptive designs with trials involving survival endpoints. Prior to joining Cytel, Adam served in management and lead statistician roles at several contract research organizations. Adam has also had experience working in cross-functional team environments to develop protocols with innovative designs, and has a broad understanding of Bayesian and frequentist statistical methods in the statistical analysis of adaptive clinical trials. Adam attended the Medical College of Virginia at Virginia Commonwealth University for graduate school and received a PhD in Biostatistics in 2004.

Email: ofir.harari@cytel.com

Natasa Rajicic Natasa Rajicic is the Executive Director of Biometrics at Arrowhead Pharmaceuticals in Pasadena, CA. Until recently, Natasa was a Senior Principal at Cytel, where she helped clients explore and apply innovative study designs and address complex clinical development issues. Prior to Cytel, Natasa was at Pfizer in New York, where she led a team of statisticians responsible for late-stage endocrine products, providing statistical review of due diligence evaluations and co-development projects with external partners. She also oversaw statistical input on regulatory responses related to new or supplemental submissions, label extensions and safety. Earlier in her career, Natasa was a statistician on Phase 2–3 clinical trials at the Center for Biostatistics in AIDS Research at Harvard School of Public Health in Boston.

Natasa teaches a course in Research Design at the Columbia University’s Applied Analytics graduate program.

www.jforcs.com

Email: adam.hamm@cytel.com

Jay Park Jay is a Director at Cytel, affiliated with the Real World Evidence Group. His research interests include application of master protocols, adaptive trial designs, and real-world analytics to global health.

He currently teaches a course on adaptive trial designs and master protocols at McMaster University and is working on a book entitled, “Introduction to Adaptive Designs and Master Protocols,” that will be published by Cambridge University Press in 2021.

Email: jay.park@cytel.com

Journal for Clinical Studies 27

Therapeutics

Blood Pressure Monitoring in Clinical Trials in Obese Subjects The World Health Organization (WHO) classification system for obesity is based on body mass index (BMI). A BMI of 25.0 to 29.9 kg/m2 is considered overweight, and ≥30 is considered obese. According to a 2016 WHO report, the worldwide prevalence of obesity nearly tripled between 1975 and 2016.

39% of the world’s adult population aged 18 years and over (1.9 billion adults) are overweight and 13% are obese (650 million)1.

With the current trend, it has been estimated that the global prevalence of obesity will reach 18% in men and exceed 25% in women by 20252. Based on this very high prevalence in the general population and the tight association between obesity, hypertension and cardiovascular risk, it seems inherently important to understand whether new drugs cause an increase of systolic or diastolic blood pressure and more specifically, how such an effect translates into cardiovascular risk in obese subjects.

This brief review gives a short summary of the association between obesity, cardiovascular risk and hypertension and outlines the emerging FDA guideline on the need for blood pressure monitoring in the development of new drugs3.

Obesity and CV Risk Obesity is associated with an increased cardiovascular risk and obese subjects often suffer from other conditions, which also increases this risk, such as type 2 diabetes, hypertension, elevated plasma lipids, left ventricular hypertrophy, atherosclerosis and obstructive sleep apnea4. The physiologic and metabolic changes associated with obesity, which contribute to increased cardiovascular risk, include insulin resistance, dyslipidemia (lower HDL, increased triglycerides, smaller LDL particles, increased apolipoprotein B level), systolic and diastolic hypertension, obstructive sleep apnea, increased systemic inflammation, and endothelial dysfunction.

These changes manifest in varied conditions including coronary artery disease, stroke, left ventricular hypertrophy, heart failure, and atrial fibrillation. Consequently, obesity is categorised as an independent risk factor for cardiovascular disease according to 2013 Joint AHA / ACC / TOD guidelines for the management of overweight and obese adults5.

There is strong, consistent evidence in multiple epidemiological studies for the association between obesity and cardiovascular disease in general, individual cardiovascular disease outcomes, cardiovascular mortality and all-cause mortality4. As an example, 16,288 men and 7325 women were followed for up to seven years in the Münster Heart Study6. There was a graded and continuous positive relationship between BMI and coronary heart disease (CHD) with risk factors including age, total serum cholesterol, lowdensity lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. The increase of CHD death associated with BMI was completely accounted for and mediated by these risk factors.

In a meta-analysis of 21 cohort studies involving more than 300,000 patients that assessed the association of obesity and risk of CHD, a 29% increase of events related to CHD was observed for each fiveunit increase in BMI7.

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Obesity as a risk factor for CHD is confounded by the frequent comorbidities of hypertension, dyslipidemia, and diabetes.

However, even the metabolically healthy obese subjects, the risk for cardiovascular disease increases with every unit increase in BMI8.

Prevalence of Hypertension in Obese Subjects The association between obesity and hypertension is well recognised. In a Canadian cross-sectional, population-based survey published in 2010 of 2510 adults, aged 20 to 79 years, it was observed that the prevalence of hypertension increased with BMI and age. In the population older than 60 years of age, the prevalence of hypertension was of 51% for overweight subjects, 59% in obese subjects and 68% in severely obese subjects, as compared to 36% in lean individuals9. Using Framingham data, it has been shown that every 5% increase of weight was associated with a 20 to 30% increase of the incidence of hypertension10.

Emerging evidence suggest that obesity in itself causes hypertension through several different mechanisms, i.e., is a causative factor11. Main components involve i) overactivation of the sympathetic nervous system, ii) stimulation of the reninangiotensin-aldosterone system (RAAS), iii) insulin resistance, iv) alterations in adipose-derived cytokines, and v) structural and functional renal changes. Sympathetic nervous system overactivation in obese subjects is thought to be the result of abnormal adipokine secretion from adipose tissue, indirectly through stimulation of the RAAS, insulin resistance and baroreceptor dysfunction12.

Also, obstructive sleep apnea is frequent in obese subjects, which leads to intermittent hypoxia and upregulation of sympathetic nervous system activity through carotid body chemoreceptors.

There are several ways that activation of the RAAS may occur in obese subjects, which involves a bidirectional influence between the sympathetic nervous system and the RAAS leading to elevated renin levels. Levels of angiotensinogen, angiotensin-converting enzyme (ACE), and aldosterone are also elevated, which in turn induce systemic vasoconstriction and simulate the production of aldosterone from the adrenal cortex. This leads to increased renal tubular sodium reabsorption and water retention with expansion of intravascular volume and resulting hypertension. Insulin resistance and hyperinsulemia leads to sympathetic activation and renal sodium retention and blunted response to the normal vasodilatory effect of insulin through endothelial dysfunction, with increased vasoconstrictor tone13.

Emerging FDA Guidelines on Blood Pressure Monitoring in Clinical Trials Background In May 2018, FDA issued draft guidance on the importance of blood pressure evaluation in drug development3. To clarify the background and the underlying thinking, FDA and the Duke-Margolis Center for Health Policy arranged a public meeting in Washington DC in February 2019 with attendance from FDA, pharmaceutical sponsors and academia. At this meeting, sponsors were informed that FDA will institute an interdisciplinary review team (IRT) for blood pressure (BP) evaluation in clinical trials; this group will comprise of cross-divisional FDA staff and provide advice to reviewing divisions Volume 12 Issue 3

Therapeutics on study protocols in which blood pressure evaluation is included to ensure consistent advice across therapeutic areas. This is much the same approach that FDA has taken in regard to QT assessment, for which an IRT was established shortly after the endorsement of the ICH E14 guidance on this topic in 2005. At the meeting, there were several presentations from FDA staff from the cardiorenal division, who also are involved in the IRT for QT studies; these presentations have been summarised in a recent publication by Garnett et al.14.

FDA Guidance on BP Evaluation in the Clinical Development of New Drugs The FDA guidance distinguishes between drugs intended for short term, i.e., less than 12 weeks’ treatment, and chronic usage3. For drugs intended for short-term use, large blood pressure-increasing effects may be of concern, and careful assessment using cuff BP measurements during routine study visits is recommended with the objective to exclude, e.g., a mean increase of systolic blood pressure (SBP) of more than 4 mmHg. It is pointed out that when in-clinic cuff blood pressure measurement is deemed appropriate, accuracy can be improved by collecting triplicate measurements of sitting blood pressure in all subjects at baseline (predose), at several visits, at the end of the inter-dosing interval (trough measurement; predose), and at peak concentrations of the drug.

For drugs intended for chronic use, ambulatory blood pressure monitoring (ABPM) over 24 hours is clearly the preferred method.

The BP evaluation should be performed in the targeted patient population when the drug pharmacodynamically has reached steady state. In general, the results should be based on the integrated mean 24-hour blood pressure (i.e., area under the curve, a timeweighted average of the blood pressure throughout the day). If no effect is observed by ABPM in a patient study that is appropriately powered to exclude a small effect, subsequent studies (e.g., later Phase II, Phase III) can utilise monitoring by routine cuff blood pressure measurements. On the other hand, if the drug increases blood pressure in the overall patient population, the sponsor should obtain additional information about the BP effects in subsets of the population with potentially larger effects, e.g., patients with pre-existing hypertension, diabetes, renal impairment, AfricanAmerican and the elderly.

ABPM has several advantages as compared to BP measurements performed at study visits in the clinic or at home: •

• • •

ABPM allows for the assessment of blood pressure effects over a 24-hour period, thereby also capturing potential effect on the diurnal variation of BP as well as potentially variable effects of the drug on BP over the full dosing interval. It is thought that in most cases, drug-induced effects on BP can be seen as a shift over the full 24 hours, even though there are also examples where the effect is directly related to Cmax of the drug; ABPM devices can be programmed to collect measurements at specified time points; ABPM devices can be programmed to enable focus on prespecified time-windows for drugs with transient effect, i.e., with more intense collection; Importantly, ABPM, similar to BP assessment with other automated devices, is free of potential investigator bias.

As a preparation for the February 2019 meeting, members of the FDA’s cardiorenal division at the agency compiled a research database with data from 22 ABPM studies with more than 20 subjects per treatment arm14. Most of these studies (n=16) were old studies in patients with hypertension, conducted more than 25 years ago (between 1986 and 1995), but there are also more current www.jforcs.com

studies (n=6) in the database, including the Precision-ABPM study15 and the SYNERGY study16. Eleven of the studies included a placebo group with a total of 456 subjects. Each study had an ABPM session at baseline and at least one and up to three post- baseline visits with a median number of measurements of four per hour during daytime and three during the night and a median study duration of six weeks (range: two to 12 weeks). This research database was used as a data source from which a large number of studies with different assumptions were simulated. This approach allows for the evaluation of different design features of ABPM studies14,17, with the objective to understand how these can be conducted in an efficient way and yet with the power to exclude small BP effects18.

Primary endpoint: ABPM provides a large number of blood pressure measurements throughout the day, and by using an average across all time points a more precise assessment is obtained. Based on practical considerations, the device is often programmed to perform more measurements during daytime as compared to night and then a ‘weighted’ average should be used, taking into account the frequency of hourly values. However, for drugs that produce a transient effect on BP that is directly proportional to plasma concentrations, the peak BP effect would be expected to occur close to the peak plasma level of the drug. In such cases, the schedule of measurements using the ABPM device can be tailored to capture effects through more intense frequency over predefined timewindows, and the primary endpoint may focus on a more limited period of time14.

Placebo: In the original May 2018 FDA guidance, it is stated that in general, it is desirable to include a placebo group as the control group3. At the Duke-FDA meeting, FDA however presented data, which suggest that there is not much of a difference between the baseline assessment and on-treatment with placebo for study durations up to 12 weeks (Figure 1). The concern is also that through inclusion of placebo, variability of data increases and much larger sample sizes would be needed to exclude a small effect. Using simulated studies, it was shown that with no underlying BP effect of the drug, the sample size needed to exclude a 4 mmHg effect on the 24-hour SBP increased almost four-fold, from 30 subjects without placebo to 114 subjects in a placebo-controlled study. The recommendation at the meeting and in a subsequent publication14 was therefore that placebo in most cases is not needed for studies intended to exclude a small BP effect. Examples in which a placebocontrolled evaluation is warranted include studies in which procedures as such can have an effect, e.g., counselling on diet and exercise to achieve weight loss, studies of very long duration (e.g., more than six months) and when subjects with very high blood pressure are enrolled into studies to control regression-to-themean phenomenon. It should, however, be acknowledged that more

Figure 1, panel A: In both subjects with hypertension (black lines; H3) and in healthy volunteers (yellow lines; N1), there are only small changes from the baseline ABPM session (solid lines) to on-treatment visits, with unaffected diurnal pattern. Source:17 Journal for Clinical Studies 29

Therapeutics

Figure 1, panel B: Change-from-baseline of mean 24-hour systolic blood pressure in subjects on placebo across 11 studies in the FDA’s research database. Changes were overall small and in most cases below 2 bpm. Source:17

experience is needed to understand to what extent the inclusion of a placebo group may improve the ability to exclude a BP effect by accounting for trial conditions or period effects.

Number of BP measurements per hour and validity criteria: Using the simulation approach, data were also presented demonstrating that the accuracy and precision of ABPM studies using the 24hour endpoint were not materially influenced by the number of measurements per hour, or by reducing criteria for a valid ABPM session from the standard 70% of expected measurements in clinical practice to 50%18. It was, therefore, advocated that no more than two measurements per hour are needed and that criteria to define a valid ABPM session can be set to 50% of expected measurements.

It should be noted that even with two measurements per hour, day and night, the target of having 50% good measurements may be challenging if interpreted as a requirement of having at least one good measurement per hour, especially at night-time.

Cardiovascular Risk and the Threshold of Concern in Regard to Pressor Effect The FDA draft guidance does not define one single threshold of concern, i.e., which effect level should be excluded to claim that a drug is devoid of any safety concern in regard to BP effects. At the FDA-Duke meeting, SBP effect levels between 1 and 4 mmHg were discussed and it was pointed out that there are many factors that may influence this threshold, such as patient population and the extent and duration of the BP effect. A study that was thoroughly discussed and used as an example on how to perform ABPM studies was the Precision-ABPM study15. The Precision study compared the cardiovascular safety profile of three non-steroidal anti-inflammatory drugs – celecoxib, naproxen and ibuprofen – in more than 24,000 patients with osteoarthritis or rheumatoid arthritis with increased cardiovascular risk, by looking at the rates of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke during more than two years’ follow-up19. The ABPM sub-study enrolled 444 patients, who were randomly assigned to each of the three drugs and underwent an ABPM session at baseline and after four months’ treatment. Celecoxib did not have an effect on the mean 24-hour BP, in contrast to ibuprofen that exhibited a small, 3.7 mmHg effect on SBP (Figure 2, Panel A). Obviously, the ABPM sub-study was not powered to evaluate the effects on cardiovascular end points, but these were numerically fewer in patients treated with celecoxib (n=7) as compared to patients on ibuprofen (n=9). In the larger study, celecoxib was non-inferior to ibuprofen and to naproxen in terms of cardiovascular events after 30 months’ treatment (Figure 2, Panel B).

In the recent publication by FDA staff who presented at the meeting, the threshold of regulatory concern was further discussed and some interesting examples from approved drugs were given14.

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Figure 2, panel A: Change-from-baseline systolic blood pressure measured by ABPM in the PRECISION-ABPM study. Four months treatment with celecoxib did not have an effect on mean SBP over 24 hours, whereas ibuprofen caused a statistically significant increase of 3.7 bpm. Source:21

Figure 2, Panel B: In the main PRECISION study (19), celecoxib was non-inferior to ibuprofen and naproxen in terms of the primary composite outcome in the time-toevent analysis, i.e., the first occurrence of an adverse event that met APTC criteria (death from cardiovascular causes, including haemorrhagic death; non-fatal myocardial infarction; or non-fatal stroke), with a p value of <0.001 for both comparisons. Source:21 APTC: Antiplatelet triallists collaboration.

Bremelanotide is indicated for treatment of generalised hypoactive sexual desire disorder in premenopausal women. In an ABPM study, it was shown that the drug was associated with a transient, small effect on SBP of 3 mmHg within eight hours of dosing and thereafter returning to baseline. This effect level in a population with low cardiovascular risk should be of little concern. On the other hand, drugs with a more pronounced, albeit transient effect, can be of concern in a vulnerable population. Esketamine nasal spray, approved in conjunction with oral antidepressants for treatment-resistant depression, caused a mean increase of SBP of 7 to 9 mmHg, which lasted for four hours. However, in 8% and 17% of patients the increase of SBP and/or diastolic blood pressure (DBP) was larger than 40 and 25 mmHg at least once within the first 1.5 hours post-dose. Therefore, the label advises prescribers under Warning and Precautions that ‘patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects’. Small, but chronic effect may also be of concern when indicated in patients at a relatively high cardiovascular risk. APBM studies in men have shown that some testosterone replacement products, e.g., testosterone undecanoate and testosterone enanthate, caused a 5 mmHg and 4 mmHg mean effect on SBP, respectively, throughout the day. Since these products may be taken by older men with age-related low testosterone levels and with a high cardiovascular risk, there is a black box warning in regard to the risk of major adverse cardiovascular events, including non-fatal myocardial infarction, non-fatal stroke and cardiovascular death.

Volume 12 Issue 3

“Our paediatric oncology patient would happily sit while to have her intravenous chemotherapy as long as I was dressed as a fairy, complete with tiara and wings!”

“She said that I was her “get better fairy” and that the trial medication was a “magic potion”. I was very happy to comply.”

Illingworth Research Nurse

info@illingworthresearch.com www.illingworthresearch.com

Passion for research, Compassion for patients

Therapeutics Practical Considerations for ABPM in Obese Subjects Many patients struggle to tolerate ABPM monitoring. Wearing the device for 24 hours, even when placed on the non-dominant arm, is inconvenient, usually causes sleep disturbance and can be uncomfortable. As with any population, accurate blood pressure monitoring requires proper upper arm measurement and cuff size assignment. Incorrect sizing can lead to inaccurate BP results, poor cuff positioning, slipping, inflation failure or unnecessary discomfort.

While the patient is instructed not to remove the cuff anytime during the monitoring period, patients often do to rest their arm, especially when struggling to sleep or during their morning routine.

Obese patients in particular struggle with compliance. Big cuffs on big arms mean longer inflation and deflation times. While cuffs may be adjusted slightly to better fit the upper arm shape, it can be difficult to properly fit conically shaped arms. Hyper-inflation and inflation repeats are more frequent as the ABPM device tries to detect the systolic signal on larger and conically shaped arms, resulting in more discomfort. Another common complaint is excessive sweating on the cuffed arm, especially during summer months. All these factors explain why compliance challenges are more frequent in an obese population.

There are ways to help mitigate these issues and good compliance starts with good patient coaching. Site staff need to take the time to sit with the patient, explain the experience and set expectations in a realistic way. Allow the patient time to practise wearing the cuff and practise repositioning and self-applying the cuff. Disposable cuff barriers can help alleviate excessive sweating and position shifting.

Applying surgical tape on cuff edges can be used to reduce skin chafing on obese or skin-sensitive arms. Utilise cuffs that have a D-ring to enable self-application. When the patient returns to the clinic at the end of the monitoring period, blood pressure results should be reviewed immediately to assess whether there are a sufficient number of measurements to constitute a valid session, e.g., more than 50% of expected measurements.

Discussion The FDA guidance Assessment of Pressor Effects of Drugs has been debated within the agency for several years and it is not yet clear whether it will be universally applied across all therapeutic areas. The fact that an IRT for BP studies now has been established is however, in our view, a clear indication that the guidance is progressing and will be finalised within a foreseeable future. Meanwhile, it seems likely that there will be specific requests from the FDA forthcoming, and to-date we have seen such requests for development programmes of drugs intended for long-term treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus; indications that are highly relevant for the obese population. Additionally, individual sponsors have proactively chosen to perform such an evaluation in selected development programmes.

For drugs intended for more than 12 weeks’ use, ABPM sessions should be performed in the targeted patient population. In each patient, one valid ABPM session will be needed at baseline and one on-treatment at anticipated pharmacodynamic steady state, e.g., after four, eight or 12 weeks’ treatment. Given the numbers needed to exclude a small effect on BP (see below) and the population, it is advisable to place the BP evaluation in a Phase II study. An ABPM session is relatively cumbersome for the patient and sponsors should strive to utilise a strategy to minimise the number of patients with missing data; this can be achieved through education and training of sites and of patients, but also by performing the sessions in a way that will allow repeat of failed sessions. The baseline session can therefore be performed during the screening period, well in advance 32 Journal for Clinical Studies

of the days immediately before the first dose, with the option to repeat just before the first day of dosing; the same applies for the on-treatment session, which in a Phase II study can be placed at, e.g., four or eight weeks, with the option to repeat at 12 weeks. In support of this approach, the site should have the capability to immediately view the quality of the ABPM session to determine whether a session contains an acceptable number of acceptable measurements. It remains to be seen how strictly the criterion on having at least one measurement per hour, especially at night-time, will be implemented by the FDA. The power of an ABPM study is driven by the underlying effect of the drug, the observed variability and which effect level needs to be detected or excluded. In FDA’s research database, the observed variability, measured as the standard deviation of the changefrom-baseline SBP (∆SBP) was between 8.5 mmHg for mean 24 hour SBP and 11.6 mmHg for the night-time mean SBP. This is also consistent with our internal experience and a published sample size calculation for an ABPM study20. With this as a basis, the sample size of ABPM studies can be estimated across different effect levels on BP. For a drug with no BP effect at all (assumed underlying effect of 0 mmHg), a sample size of 122 subjects per group in a parallel designed study will provide 90% power to exclude a 3 mmHg drug effect, i.e., the upper bound of the 1-sided 95% confidence interval (CI) of the placebo-corrected ∆∆SBP will fall below 3 mmHg. Table 1 provides sample size calculation for SD of ∆SBP between 8 and 12 mmHg to achieve a power of 80% and 90%, respectively.

Table 1. Sample size per group required to exclude an effect of 3 or 5 mmHg change for SBP or DBP* *: The upper bound of the 2-sided 90% confidence interval of ∆BP falls below 3 mmHg; based on the assumption of no underlying BP effect of the drug. ∆BP: Change-from-baseline of 24-hour mean blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure;

We encourage sponsors to think proactively in terms of BP evaluation, particularly in therapeutic areas in which the target patient population, or subgroups thereof, may be seen as vulnerable.

Drugs intended for long-term use in young, relatively healthy patients may face less scrutiny than drugs intended for older patients with multiple risk factors for cardiovascular disease and stroke. In such cases, it is advisable to rule out that a new drug has a pressor effect, and to perform this evaluation strategically, which in most cases will mean during Phase II, and well before entering into pivotal, confirmatory trials.

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Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF et al. 2013 AHA/ ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.

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Schulte H, Cullen P, and Assmann G. Obesity, mortality and cardiovascular disease in the Munster Heart Study (PROCAM).

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Bogers RP, Bemelmans WJ, Hoogenveen RT, Boshuizen HC, Woodward M, Knekt P, van Dam RM, Hu FB, Visscher TL, Menotti A et al.

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Yeh TL, Chen HH, Tsai SY, Lin CY, Liu SJ and Chien KL. The Relationship between Metabolically Healthy Obesity and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis. Journal of clinical medicine. 2019;8(8).

Leenen FH, McInnis NH and Fodor G. Obesity and the prevalence and management of hypertension in Ontario, Canada. American journal of hypertension. 2010;23(9):1000-6.

Vasan RS, Larson MG, Leip EP, Kannel WB and Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet (London, England). 2001;358(9294):1682-6.

Shariq OA and McKenzie TJ. Obesity-related hypertension: a review of pathophysiology, management, and the role of metabolic surgery. Gland surgery. 2020;9(1):80-93.

Hall JE, do Carmo JM, da Silva AA, Wang Z and Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.

Circulation research. 2015;116(6):991-1006.

Muniyappa R and Sowers JR. Role of insulin resistance in endothelial dysfunction. Reviews in endocrine & metabolic disorders. 2013;14(1):5-12.

Garnett C, Johannesen L and McDowell TY. Redefining Blood Pressure Assessment - The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety. Clinical pharmacology and therapeutics.

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Ruschitzka F, Borer JS, Krum H, Flammer AJ, Yeomans ND, Libby P, Luscher TF, Solomon DH, Husni ME, Graham DY et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. European heart journal.

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Weber MA, Chapple CR, Gratzke C, Herschorn S, Robinson D, Frankel JM, Ridder AM, Stoelzel M, Paireddy A, van Maanen R et al. A strategy utilizing ambulatory monitoring and home and clinic blood pressure measurements to optimize the safety evaluation of noncardiovascular drugs with potential for hemodynamic effects: a report from the SYNERGY trial. Blood pressure monitoring. 2018;23(3):153-63.

McDowell TY. Placebo control in ABPM studies. Evaluating the Pressor Effects of Drugs and Ambulatory Blood Pressure Monitoring Studies Washington, DC. . https://healthpolicy.duke.edu/sites/default/files/ atoms/files/duke-fda_pressor_slides_updated_2019-02-05.pdf.

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Johannesen L. Design of efficient ABPM studies. Evaluating the Pressor Effects of Drugs and Ambulatory Blood Pressure Monitoring Studies Washington, DC. https://healthpolicy.duke.edu/sites/default/ files/atoms/files/duke-fda_pressor_slides_updated_2019-02-05.pdf.

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Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. The New England journal of medicine. 2016;375(26):2519-29.

Vollmer WM, Appel LJ, Svetkey LP, Moore TJ, Vogt TM, Conlin PR, Proschan M and Harsha D. Comparing office-based and ambulatory blood pressure monitoring in clinical trials. Journal of human

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21.

hypertension. 2005;19(1):77-82.

Borer J. Nested Blood Pressure Study to Assess Pressor Effects and Consequent Risks of Drugs Not Aiming at BP therapy: What does PRECISION tell us about Relevance of Such a Study for FDA Pressor Draft Guidance?. Evaluating the Pressor Effects of Drugs and Ambulatory Blood Pressure Monitoring Studies Washington, DC. https://healthpolicy.duke.edu/sites/default/files/atoms/files/ duke-fda_pressor_slides_updated_2019-02-05.pdf. Accessed April 30, 2020.

Borje Darpo As ERT’s Chief Scientific Officer, Borje Darpo, MD, PhD oversees ERT’s cardiology services and consults with external customers to ensure the cardiac safety of their compounds in development. He is board certified in cardiology and internal medicine and has 20 years of experience overseeing projects across all phases of clinical development.

Patricia Castellano Patricia Castellano is a Senior Director of Product Management at ERT. Patricia Castellano has worked in the pharmaceutical research industry for over 25 years. She has extensive experience with ECG, Holter, and blood pressure collection and is well-versed in the latest developments, including ABPM. Her leadership positions include Director of Operations and Vice President of Cardiac Systems Implementation. Most recently, Patricia has been ERT’s Senior Director of Cardiac Product Management, focusing on blood pressure monitoring services.

Robert Kleiman Dr. Robert Kleiman is a board certified cardiologist and cardiac electrophysiologist who has performed research in both basic cellular electrophysiology as well as clinical electrophysiology. Dr. Kleiman completed his training at the University of Pennsylvania and was a member of a cardiology practice for 12 years before joining ERT in 2003. Dr. Kleiman is currently ERT’s Chief Medical Officer and Vice President, Global Cardiology. His responsibilities include oversight of ERT’s cardiology services, consulting with external clients and managing overall satisfaction of ERT’s global customers, including all aspects of ERT’s solutions.

Todd Rudo Dr. Rudo has achieved board certifications in Internal Medicine, Cardiovascular Disease, Cardiac Electrophysiology, Nuclear Cardiology, and Echocardiography. His experience in drug safety / PV has spanned a broad range of therapeutic areas, including oncology, urology, endocrinology, cardiology, and immuno-inflammatory diseases, and has included support for early & late phase, global submission, and post-marketing PV activities. Currently, Dr. Rudo supports ERT’s cardiac safety consulting and business development teams, in addition to oversight of cardiac safety operations, including the ECG and holter monitor core lab services.

Journal for Clinical Studies 33

Therapeutics

Serious Adverse Events in Lung Cancer Clinical Trials Abstract: A limited amount of information is available about the structure of serious adverse events in lung cancer clinical trials and their influence on a selection of inclusion and exclusion criteria.

We performed a retrospective analysis of 1827 lung cancer patients from seven clinical trials to analyse the structure of serious adverse events. The most frequent fatal events were respiratory and cardiac disorders with a significant proportion of pulmonary embolism and pulmonary haemorrhage.

Considering risk factors for these conditions in inclusion and exclusion criteria may help to decrease the risk during clinical trials and improve patient retention.

Key words: clinical trials, serious adverse event, pulmonary embolism, pulmonary haemorrhage Lung cancer is the leading cause of cancer death – 1.76 million lung cancer deaths occurred worldwide in 20181. More than 80% of patients were presenting with non-small cell lung cancer (NSCLC) 1.

Both NSCLC and small cell lung cancer (SCLC) are still frequently diagnosed at advanced stage (stages III-IV in accordance with the American Joint Committee on Cancer (AJCC) classification), when despite the progress with treatment that occurred during recent years, the frequent and sometimes the only option is participation in a randomised clinical trial (RCT). The incidence and severity of serious adverse events (SAEs) together with whether treatment will be effective or not are two main questions for every person and institution involved in an RCT – study patient, investigator, regulatory and ethics authorities, and the study sponsor. A safety profile of a study drug is reflected in the investigator’s brochure, as the incidence and structure of adverse events (AEs) and SAEs that were registered at the previous stages of drug development, but it still does not give an understanding of expected incidence and structure of SAEs, and particularly of fatal ones. This is related to an important question of a feasibility of anti-cancer therapy in the clinical trial setting in patients with advanced lung cancer and selection of appropriate inclusion and exclusion criteria.

Materials and Methods We performed a retrospective analysis of 1827 lung cancer patients from seven Phase II-III clinical trials that were conducted by PSI in 2010-2016. Patients were treated with combination chemotherapy: in all studies, the experimental arm consisted of the study medication plus the approved chemotherapeutic agent and comparator arm, which also included the approved chemotherapeutic agent plus placebo in four trials and best supportive care in one trial.

Investigators graded AEs in accordance with Common Terminology Criteria for Adverse Events v3.0 or 4.0 (CTCAE). Causal relationship was evaluated as probably, possibly, unlikely, or unrelated.

Seriousness criteria were defined per the ICH E2A guidance2.

Results A total of 587 SAEs were reported in 445 patients. Of these 587 SAEs, 229 were deemed to be treatment-related, occurring in 142 patients. In accordance with seriousness criteria, SAEs were 34 Journal for Clinical Studies

distributed as follows: hospitalisations (49%), fatal events (48%), important medical events (2%), and life-threatening (1%). The most frequent SAEs not related to the study drug were those belonging to system organ class (SOC) of blood and lymphatic system disorders (neutropenia, anaemia, and thrombocytopenia) – 154 events (39% of all not-related SAEs) (Figure 1). Most frequent events were anaemia (64 events) and thrombocytopenia (61 events). In the majority of patients, especially those who had been pre-treated with chemotherapy, such disorders were already a component of medical history prior to enrolment into the trial and thus were listed as expected per the investigator’s brochure or the package insert for a comparator drug. Respiratory disorders contributed to 18% of all unrelated SAEs and most frequently these were clinical symptoms or conditions that were considered related to lung cancer: dyspnea, respiratory failure, haemoptysis, respiratory failure, and pulmonary embolism. More than half of cardiac SAEs had a reported diagnosis of cardio-respiratory failure, which is actually a syndrome that itself could be a manifestation of other conditions. The fourth most common SOC was infections, and predominantly infections of the respiratory tract: pneumonia and upper respiratory tract infections.

Figure 1. Distribution of not-related SAEs in accordance with system organ class (SOC).

Distribution related to the study treatment SAEs per SOC followed a similar pattern, with an absolute predominance of blood and lymphatic system disorders – 85% (thrombocytopenia – 59 events, anaemia – 54 events, and neutropenia – 11 events) (Figure 2).

In second place among related SAEs were infections with the same reported diagnoses of pneumonia, upper or lower respiratory tract infections, and general disorders with diagnoses of asthenia, fatigue, and injection site reactions. Interestingly, cardiac and respiratory disorders were considered related less frequently and were in fourth and fifth places, respectively.

Analysis of fatal SAEs showed that the most frequent causes of death were respiratory (38%) and cardiac (32%) disorders (Figure 3), which are for sure interrelated. SOCs of blood and lymphatic system disorders and infections were reported as a fatal condition in only 5% of cases each.

Figure 2. Distribution of related SAEs in accordance with system organ class (SOC).

Volume 12 Issue 3

Therapeutics The most frequent fatal respiratory AEs were: respiratory failure, pulmonary embolism, pulmonary haemorrhage, pulmonary edema, and dyspnea. Top five fatal cardiac AEs were: cardiopulmonary failure, cardiopulmonary arrest, cardiac failure, cardio-respiratory arrest, and myocardial ischemia.

Figure 3. Distribution of fatal SAEs in accordance with system organ class (SOC).

Discussion Safety of the study therapy is a universal requirement for RCTs and one of each study’s objectives. However, there is a very limited number of studies that describe the matter of SAEs in lung cancer RCTs3. Representation of related and not-related SAEs in analysed clinical trials were similar to the list of AEs from the reference safety information for the corresponding drugs. On the one hand, these AEs result from a patient’s underlying condition and on the other hand, drug toxicity, which most frequently affects blood, the immune system, and gastro-intestinal tract. It is important to understand the

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possible risk factors that may lead to the development of an AE, and, consequently to an SAE. Suina et al. showed that interstitial pneumonia and chemotherapeutic regimen are the risk factors in the prediction of SAEs3. In this study, and this is the limitation of this work, we did not analyse the patients’ profiles, but in approximately 50% of the patients from this study we assessed co-morbidities and showed that the most common co-morbidities in lung cancer patients enrolled in RCTs were hypertension (41%), coronary artery disease (24%), and chronic obstructive pulmonary disease (COPD) (13%)4. High incidence of cardiac and respiratory co-morbidities, which frequently worsen with the course of cancer, may explain predominance of cardio-respiratory fatal SAEs. Another limitation of such studies is that autopsy is not frequently performed in this group of patients and thus the immediate cause of death is sometimes difficult to establish. Such terms as “respiratory failure” or “cardiopulmonary failure”, that were the most common fatal SAE terms in our study, do not give a universal key to the real cause of death. Respiratory failure and cardiopulmonary failure are functional diagnoses or, rather, a “mechanism of death” and in our studies they were reported as AE terms in 32% of fatal SAEs, which corresponds to findings from other studies – 34.8%5 and 38%6. Nichols et al. showed that the most common immediate cause of death was tumour burden (30%), followed by infections (20%) and metastatic complications (18%), while diseases directly related to the respiratory system were less frequent: pulmonary haemorrhage (12%), pulmonary thromboembolism (10%), and

Journal for Clinical Studies 35

Therapeutics pulmonary diffuse alveolar damage (7%)6. Our analysis showed similar data: pulmonary embolism was reported as the SAE term in nine cases (10.7%) and pulmonary haemorrhage in six cases (7%), all events assessed as not related to the study drug by investigators.

If we speculate that cases of respiratory and cardio-respiratory failure, when not specified, could be attributed to lung cancer progression, and do not contribute to study drug safety profile, SAEs of pulmonary embolism and pulmonary haemorrhage are of particular interest. Pulmonary embolism is associated with increased death rate among lung cancer patients7. Risk factors for pulmonary embolism in lung cancer patients were summarised by Li et al. and include historical, clinical and laboratory parameters8.

Independent significant risk factors for pulmonary haemorrhage include squamous cell histology and lung cavitation9. Lung cancer clinical trial protocols normally do not consider such risks. We suggest taking this into consideration when elaborating on inclusion and exclusion criteria and study procedures. Such modifications, particularly at the early stages of drug development, will help to eliminate the potential influence of fatal events not directly related to progression of lung cancer.

Conclusion The population of patients with advanced and metastatic lung cancer is very fragile and characterised by a high number of SAEs and particularly fatal SAEs. The majority of them are attributed to the progression of lung cancer and are inevitable. At the same time, study protocols do not pay enough attention to such possible conditions as pulmonary embolism and pulmonary haemorrhage, that account for 17-20% of all fatal SAEs in lung cancer patients.

Considering risk factors for these conditions in inclusion and exclusion criteria (for example hospitalisation in the 12 months before diagnosis of lung cancer, surgery, chemotherapy, targeted drugs, central venous catheter), and introducing additional monitoring procedures (for example D-dimer), carcinoembryonic antigen (CEA) may help to decrease the risk during clinical trial and improve patient retention.

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World Health Organization, International Agency for Research on Cancer. Globocan 2018: Lung Cancer. International Agency for Research on Cancer. Available at http://gco.iarc.fr/today/data/factsheets/cancers/ 15-Lung-fact-sheet.pdf ICH E2A “Clinical safety data management: definitions and standards for expedited reporting”. Available at: https://www.ich.org/page/searchindex-ich-guidelines Suina K, Shukuya T, Koyma R et al. The risk factors for severe adverse events of chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 32, 2017 (suppl; abstr e19129) DOI: 10.1200/jco.2014.32.15_suppl. e19129. Published online January 31, 2017.

Kosov M, Kumar A, Belotserkovskiy M. Comorbidity in clinical trial patients with advanced or metastatic non-small cell lung cancer (NSCLC).

J Clin Oncol 34, 2016 (suppl; abstr e20606) Ogata R, Tanio Y, Takashima J et al. Retrospective analysis of immediate cause of death in lung cancer – two case reports of lung cancer deaths due to bowel necrosis. Gan To Kagaku Ryoho 38 (6), 2011: 987-990 Nichols L, Saunders R and Knollmann F. Causes of Death of Patients With Lung Cancer. Archives of Pathology & Laboratory Medicine 135, No 12, 2012: 1552-1557. DOI.org/10.5858/arpa.2011-0521-OA Chuang YM and Yu CJ. Clinical characteristics and outcomes of lung cancer with pulmonary embolism. Oncology 77, 2009: 100–106 doi. org/10.1159/000229503 Li Y, Shang Y, Wang W, Ning S and Chen H. Lung cancer and pulmonary embolism: what is the relationship? A review. J Cancer 9, 2018: 3046–3057 doi.org/10.7150/jca.26008 Ito et al. Risk factors associated with fatal pulmonary hemorrhage

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in locally advanced non-small cell lung cancer treated with chemoradiotherapy. BMC Cancer 2012, 12:27 doi:10.1186/1471-2407-12-27

Maxim Kosov Maxim Kosov, MD, PhD, is the Senior Medical Advisor at PSI CRO USA. He is a board certified physician in Pediatrics and Anesthesiology and Intensive Care. He is a member of ASCO. Maxim has more than 15 years of experience in the clinical research industry and has experience across a board range of indications. He is also the author/co-author of more than 50 publications.

Email: maxim.kosov@psi-cro.com

Maxim Belotserkovskiy Maxim Belotserkovskiy, M.D., Ph.D., MBA is the Head of Medical Affairs at PSI CRO AG. He has board certifications in Internal Medicine, Rheumatology, Anesthesiology and Intensive Care, and Hemodialysis. He is also a Certified Associate Professor of Pathological Physiology. He has more than 30 years of experience in clinical research as an investigator and clinical research professional. He is also the author/co-author of more than 170 publications.

Email: maxim.belotserkovsky@psi-cro.com

Kamen Doxev Kamen Doxev, MD, is a Country Manager/ Regional Director for Bulgaria, Greece, Turkey and Israel at PSI CRO AG. He has more than 20 years of clinical research and drug development experience gained from working as a Co-investigator, as well as in various roles in Project Management and Clinical Operations in both large pharma and CRO companies and in a large number of therapeutic areas including but not limited to Oncology, CNS, Cardiovascular, Psychiatry, Respiratory, etc. Dr. Doxev earned his medical degree from the Medical Faculty at Sofia Medical University. He is now acting as a Lecturer in(at) the same University at the Faculty of Public Health in their master’s degree Program in Clinical Research Management. He also has a post-graduate degree in Healthcare System Management at the same University.

Email: kamen.doxev@psi-cro.com

Daniella Bajzath Daniella Bajzath, PharmD, Safety Officer at PSI CRO AG, is a graduate from the Pharmaceutical Faculty, Semmelweis University Budapest.

Before joining PSI in 2016, she had worked for 4 years in public pharmacies in Hungary and Germany. She has experience in preparing and handing out prescription and OTC drugs, and in advising patients on medical subjects in several indications.

Email: daniella.bajzath@psi-cro.com

Volume 12 Issue 3

Medical Monitoring for your next Clinical Trial WHO WE ARE

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Journal for Clinical Studies 37

Therapeutics

Clinical Development in Inflammatory Diseases: Psoriatic Arthritis Psoriatic arthritis (PsA) is a specific form of chronic inflammatory arthritis associated with psoriasis, affecting both men and women equally but with a consistent geographic variability1,2. A systematic review and meta-analysis of 28 studies estimated that the mean global prevalence of psoriatic arthritis is 133 per 100,000 population and the incidence is 83 per 100,000 persons per year. A systematic review and meta-analysis of 266 studies concluded that worldwide, approximately one in four persons with psoriasis has psoriatic arthritis. However, prevalence of psoriatic arthritis internationally ranges widely depending on the population studied3. It was introduced in 1860 by the French physician Pierre Bazin (fr. psoriasis arthritique)4 and in 1964, psoriatic arthritis (PsA) was recognised as a separate disease by the American Rheumatism Association (now the American College of Rheumatology), and is now included as a member of the spondyloarthropathy spectrum. PsA was initially defined by Moll and Wright as ‘an inflammatory arthritis in the presence of psoriasis with a usual absence of rheumatoid factor’5. Early assessment of PsA remains limited and it requires multidisciplinary involvement. The objective of this article is to outline the epidemiology, diagnosis and current clinical development in the treatment of psoriatic arthritis.

Background Psoriatic arthritis is a potentially progressive, erosive, chronic, heterogeneous, and systemic inflammatory disease that develops in up to 30% of patients with psoriasis and can manifest in up to six different clinical domains, including peripheral arthritis, dactylitis, enthesitis, psoriasis, psoriatic nail disease, and axial disease6. It is an inflammatory disease in which the cutaneous manifestation of psoriasis coexists with arthritis, usually in the absence of rheumatoid factor4.

Etiology of PsA is still unclear but a number of genetic associations have been identified. Inheritance of the disease is multilevel and the role of environmental factors is emphasised and immunology of PsA is complex4. The major histocompatibility complex is a known susceptibility locus for PsA and psoriasis, as shown by the observation that nearly 25% of patients with PsA are positive for human leukocyte antigen (HLA)-B27. Specific HLA alleles are associated with different PsA manifestations.

Additionally, there is a strong familial aggregation of PsA with first- and second-degree relatives of affected individuals having increased risk of PsA6.

Immunological studies elucidate the interaction between hereditary and environmental factors in the development of psoriasis and PsA. They also explain the contribution of immune factors to the development of inflammatory lesions4. The pathophysiology of PsA is similar to that of psoriasis and involves important cytokines in the interleukin (IL)-23-Th17-IL-17 and tumour necrosis factor (TNF) pathway (e.g. IL-12, IL-17, IL-23, and TNF-a), as well as cytokines such as IL-226. There are stimulating factors (trauma, infection, some medications), resulting in rapid 38 Journal for Clinical Studies

activation of immunocytes, which set up a cascade of cytokines with tumour necrosis factor (secreted by dermal dendritic cells – macrophages) and interferon gamma (IFN-gamma), secreted by activated Th1 cells4. Thus, it is not surprising that many cytokinetargeting biologics and small-molecule inhibitors that provide effective skin clearance in psoriasis also improve joint symptoms and slow radiographic progression in PsA. Clinical Presentation and Diagnosis of PsA Although PsA was thought initially to be a relatively benign disorder, registry data has shown the destructive and progressive nature of the disease; it has a similar impact on quality of life and functional ability as in rheumatoid arthritis. PsA accounts for around 20% of referrals to the early arthritis clinic and presents a significant diagnostic and management challenge. Early diagnosis is important to prevent long-term functional disability and to ensure optimal management of arthritis and key comorbidities5, and management of PsA requires care by a multidisciplinary team including dermatologists, rheumatologists, physiotherapists and orthopaedic surgeons7.

Typically PsA involves joints of the axial skeleton with an asymmetrical pattern4 with musculoskeletal involvement, including arthritis, enthesitis, dactylitis and axial involvement as well as potential skin and nail disease. Different patterns of involvement of PsA can mimic different inflammatory arthritides5.

In up to 60% of patients, PsA begins with oligoarthritis (≤ 4 joints), but it may affect more joints as the disease progresses (polyarthritis, ≥ 5 joints)7. Peripheral arthritis can cause pain in a variety of joints in PsA and commonly involves the knee (41%), finger (26%), hip (19%), ankle (19%), and wrist (16%). Dactylitis is colloquially referred to as ‘sausage digit,’ and is a distinguishing feature of PsA, characterised by uniform swelling of an entire digit that occurs in up to 48% of patients. Another distinguishing feature of PsA, enthesitis is present in 35% of patients and is defined as inflammation where the tendon, ligament, or joint capsule inserts into bone. Psoriatic lesions can develop on the skin and may affect the nails (e.g. pitting). Axial symptoms, which may occur in up to 50% of patients with PsA, result in back stiffness and pain that improve with movement6. Clinical examination is crucial to diagnose PsA and on examination, joints affected by PsA are usually painful and tender but swelling does not always occur.

Moreover, patients often have morning stiffness7.

Table 1 above provides information about the subtypes of PsA7,8 Volume 12 Issue 3

Therapeutics 2 trial, secukinumab showed sustained improvement in clinical outcomes over two years13.

Surgical treatment can be beneficial in patients with severe and progressive pain, disability, restricted hip movements, hip or knee joint instability, and progressive loss of functional independence.

Orthopaedic procedures should be considered only when the best medical treatment has failed. Physiotherapy is important in the management of PsA. It may be used in addition to pharmacological treatment. The main goals of physiotherapy are to reduce pain and stiffness, prevent or delay deformity, and restore function.

Dermatologists, rheumatologists, and orthopaedic surgeons should work together to ensure that patients with PsA receive the best possible treatment7.

Table 2 above includes the characteristic signs seen on radiological examination7,9

Psoriatic arthritis is diagnosed according to the Classification Criteria for Psoriatic Arthritis (CASPAR). In Europe and North America, the diagnosis of PsA is missed in more than one-third of patients with psoriasis. Early diagnosis of PsA is important because delaying diagnosis even by six months, increases the risks of joint erosions and poor long-term physical function. When joint inflammation precedes psoriasis, PsA might be difficult to diagnose. Imaging and laboratory studies can help rule out rheumatoid arthritis, spondyloarthritis, osteoarthritis, and reactive arthritis.

Generally, laboratory tests are unhelpful for diagnosing of PsA: markers of systemic inflammation, such as the C-reactive protein or erythrocyte sedimentation rate, may be elevated in only 50% of cases and low titre rheumatoid factor and anti-cyclic citrullinated peptide may be found in up to 10% of cases. Current National Institute for Health and Care Excellence guidance for the management of psoriasis suggests that the Psoriasis Epidemiology Screening Tool patient-completed screening questionnaire (www. bad.org.uk/healthcare-professionals/forms-downloads) should be used annually to identify PsA7.

*if the treatment with arthritis without adverse prognosis fails – then treatment switched to arthritis with adverse prognosis

Figure 1: Treatment of PsA with pharmacological non-topical treatment14

Clinical Development ‘Treat to target’ is the concept that an outcome (or target) is objectively followed at each visit and therapies are adjusted to get the patient into a state of remission or low disease activity (whichever target is chosen). This concept was tested in a randomised controlled

Current Therapies The treatment of PsA has changed substantially over the past 10 years10. Management of PsA should be individualised for each patient7. New treatment recommendations for PsA were updated in 2015 by both the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Both of these recommendations are evidence-based and both broadly suggest a similar ‘step up’ approach to therapy. This approach uses therapies sequentially starting with simple therapies such as NSAIDS for pain or topical therapies for psoriasis, followed by single disease diseasemodifying anti-rheumatic drugs (DMARDs), then combinations of standard DMARDs, and finally biologic drugs if patients fail to respond to the previous treatment10.

Apremilast is a phosphodiesterase-4 inhibitor which has been approved by FDA and efficacy is lower than biologic therapies, but a favourable safety profile was demonstrated to position apremilast as an alternative to biologic therapy in patients perceived to be at high risk of infections or with other caution or contraindication11. Also, Apremilast maintained clinical benefit and a favourable safety profile for up to five years among patients with PsA12. Secukinumab is an interleukin-17A inhibitor used in the treatment of patients with active psoriatic arthritis. It is reported that multiple doses of secukinumab provide sustained improvement of signs and symptoms. In the Phase III FUTURE www.jforcs.com

Table 3A above provides details of Phase III compounds in development with their molecular targets and stage of development17,18 Journal for Clinical Studies 39

Therapeutics comparable efficacy when used in combination with methotrexate or other csDMARDs16.

Table 3B above provides details of Phase II compounds in development with their molecular targets and stage of development17,18

trial, TICOPA, which used minimal disease activity as the target10. The advent of newer mode of action therapies has provided additional choice for clinicians who can choose optimal therapies based on their efficacy for different musculoskeletal and skin manifestations and their side-effect profile. In recent years, biosimilars have been available for PsA. New biologics with alternative modes of action have also been tested in PsA5.

In DMARD-naive PsA patients, FDA approved ixekizumab, an IL-17A inhibitor, demonstrated early clinical improvement as early as week0115. In subgroup analysis of the SPIRIT-H2H study, ixekizumab showed greater improvement than adalimumab across multiple PsA endpoints when taken as monotherapy, and at least

40 Journal for Clinical Studies

Conclusion PsA is a heterogeneous, rapidly developing disease with potentially deleterious effects and frequently occurs within 10 years following the appearance of psoriasis6. Recent advances in PsA have emphasised that the disease is more common and more severe than previously thought. We now know that even a six-month delay in consultation with a rheumatologist results in untoward effects. One of the most useful aspects of the recommendations in treatment is the clarity they bring to the available evidence and the identification of critical gaps for which studies are needed for moving forward and improving patient outcomes10. New information on the pathogenesis of PsA has led to the development of new therapeutic interventions25. Although a number of medications are effective in the treatment of PsA, recent trials prove that there is potential treatment benefit in some drug classes and the new biologic agents have showed promise in the treatment of the DMARD resistant cases. Ongoing research studies attempt to answer these and other open questions and will provide more insight in the hope of increasing our understanding and improving treatment of PsA.

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Jung-Tai Liu, Horng-Ming Yeh, Shyun-Yeu Liu, Kow-Tong Chen.

Psoriatic arthritis: Epidemiology, diagnosis, and treatment. World J Orthop 2014 September 18; 5(4): 537-543.

Scotti L, Franchi M, Marchesoni A, Corrao G. Prevalence and incidence of psoriatic arthritis: A systematic review and metaanalysis. Semin Arthritis Rheum. 2018 Aug; 48(1):28-34.

Hammadi A A, Aljefri K. What is the global prevalence of psoriatic arthritis? www.medscape.com Sankowski AJ, Lebkowska UM, Cwikła J, Walecka I, Walecki J. Psoriatic arthritis. Pol J Radiol. 2013;78(1):7-17. doi:10.12659/ PJR.883763 Coates L C, Helliwell P S. Psoriatic arthritis: state of the art review.

Clinical Medicine 2017 Vol 17, No 1: 65–70 Gottlieb A, Merola J F. Psoriatic arthritis for dermatologists, Journal of Dermatological Treatment, DOI: 10.1080/09546634.2019. .1605142 Krakowski P, Gerkowicz A, Pietrzak A, et al. Psoriatic arthritis new perspectives. Arch Med Sci. 2019;15(3):580-589. doi:10.5114/ aoms.2018.77725 https://www.webmd.com/arthritis/psoriatic-arthritis.

Nunez-Atahualpa L, Matta E J. Psoriatic Arthritis Imaging. https:// emedicine.medscape.com/article/394752-overview#a6.

Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriatic arthritis. Rheumatology (Oxford). 2020;59(Supplement_1):i37-i46. doi:10.1093/rheumatology/kez383 Reed M, Crosbie D. Apremilast in the treatment of psoriatic arthritis: a perspective review. Ther Adv Musculoskelet Dis. 2017;9(2):45-53. doi:10.1177/1759720X16673786 Kavanaugh, A., Gladman, D.D., Edwards, C.J. et al. Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1–3 pooled analysis. Arthritis Res Ther 21, 118 (2019). https://doi.org/10.1186/s13075-019-1901-3 McInnes I B, Mease P J, Kivitz A J, et al. Long-term efficacy and safety of secukinumab in patients with psoriatic arthritis: 5-year (end-of-study) results from the phase 3 FUTURE 2 study. Tha Lancet Rheumatology; VOLUME 2, ISSUE 4, E227-E235, APRIL 01, 2020 Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update Annals of the Rheumatic Diseases 2016;75:499-510 Chandran V, Heijde D V D, Fleischmann R M, et al. Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1), Rheumatology, kez684,https://doi.org/10.1093/rheumatology/kez684 Rheumatology Network Editorial Staff, EULAR Report: Ixekizumab Approved for Axial Spondyloarthritis. June 4, 2020. https://clinicaltrials.gov.

GlobalData Healthcare, Late-stage PsA pipeline agents must prove their worth; 2020 Feb 6 Ritchlin C T, Kavanaugh A, Merola J F M, et al. Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial. The Lancet; VOLUME 395, ISSUE 10222, P427440, FEBRUARY 08, 2020 Paik, J., Deeks, E.D. Tofacitinib: A Review in Psoriatic Arthritis.

Drugs 79, 655–663 (2019). https://doi.org/10.1007/s40265-019-01091-3 EULAR 2020 https://www.congress.eular.org/ Rheumatology Advisor Contributing Writer. Clinical Improvement With Tildrakizumab in Refractory Psoriatic Nail Disease and Psoriatic Arthritis. 21Jan2020 Reddy, V., Thibodeaux, Q. & Koo, J. Certolizumab Pegol for Psoriasis and Psoriatic Arthritis. Curr Derm Rep 9, 100–106 (2020). https://doi. org/10.1007/s13671-020-00298-y Ismail FF, May J, Moi J, Sinclair R. Clinical improvement in psoriatic nail disease and psoriatic arthritis with tildrakizumab treatment [published online January 3, 2020]. Dermatol Ther. doi:10.1111/dth.13216 Gladman DD. Recent advances in understanding and managing psoriatic arthritis. F1000Res. 2016;5:2670. Published 2016 Nov 16. doi:10.12688/f1000research.9592.1

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Dr. Bhanu Priya Basavaraju Bhanu Priya is a Clinical Research Physician at Europital. She is a Clinical Pharmacologist and Research Physician with in depth knowledge of clinical trials, research methodologies, safety aspects, GCP and regulatory requirements, in addition to hands-on experience in a variety of Therapeutic Areas including, but not limited to, Auto-immune Diseases, Inflammatory Diseases, Oncology and Gastroenterology.

Email: info@europital.com

Dr. Vijayanand Rajendran Vijayanand Rajendran is the Senior Clinical Research Physician at Europital. Qualified physician with over ten years of clinical and research experience. Hands-on experience in safety monitoring of Phase I-IV trials in a variety of therapeutic areas including oncology, haematology, respiratory, gastroenterology and the musculoskeletal system.

Email: info@europital.com

Dr. Mohamed El Malt Oncology surgeon and expert scientific researcher with more than 33 years of experience as a medical doctor, including 18 years of clinical research and drug development experience in academic medical centers, pharma and CRO as investigator, project leader and medical director, in addition to 15 years of experience as general and oncology surgeon.

Email: info@europital.com

Journal for Clinical Studies 41

Therapeutics

An Overview on Rare Disease Research

JCS speaks with Tim Clark and Will Maier at ICON plc to examine the key clinical, regulatory, and commercial challenges associated with the development of therapies for the treatment of rare diseases Q1: With 350 million people affected worldwide, rare diseases represent a major unmet medical need. There is, however, no cure for the majority of rare diseases and many go undiagnosed.

What are the key clinical, regulatory and commercial challenges associated with the development of therapies for the treatment of rare diseases?

Tim: One of the obvious regulatory challenges is recruiting enough patients to generate an outcome that’s statistically strong enough to be deemed acceptable. You generally don’t get the strongest evidence from a small cohort, which explains the use of historical data in a synthetic cohort.

Will: From both a regulatory and clinical perspective, it can be challenging to know which outcomes to select. A primary defect in a specific disease can yield secondary, downstream effects in different body systems that may also be worth measuring.

In addition, we may want to expand outcomes beyond objective measurements to include patient impact.

Tim: It’s worth noting that there’s sometimes a discrepancy between the endpoint that a regulator wants to measure and the outcome that the patient thinks is most important.

Will: In terms of commercial challenges, in the last fifteen years or so, as the number of rare disease and oncology treatments has exploded, figuring out how to get your drug paid for has become a much bigger problem – especially with gene therapies that correct a primary genetic defect and carry a heavy, onetime price tag.

Q2: Since rare disease research seldom fits the traditional randomised clinical trial mould, collecting and communicating evidence that is compelling to regulators and convincing to payers is challenging. Therefore, how can companies use wearables, apps and electronic health records (EHRs) to generate real-world data (RWD) that fulfills regulatory and payer requirements?

Will: App technology is big in rare disease communities and can be used for everything from communicating disease information to recruiting for clinical trials to facilitating conversations among patients and providers.

In terms of EHRs, they’re not being used to full effect in the rare disease community. But as they become more widespread, they have the potential to help us find patients a lot faster and to improve the recruitment process.

42 Journal for Clinical Studies

As for wearables, we’ve seen a lot of interest in them for rare neurological conditions. Wearables can provide information about things like sudden movements, respiratory function, weight gain and sleep patterns, making it possible to monitor patients in a much more sophisticated way.

Q3: The FDA has published a guideline on the use of natural history studies in the study of rare disease mentioning the use of historical control groups in place of active or placebo control. How can companies evaluate and plan for the substitution or addition of a historical control in their rare disease clinical trial?

Tim: Both the FDA and EMA have shown a willingness to accept studies with historical controls. There are two primary ways to analyse historical data. One is to use a Bayesian approach. This involves using information in an external database to form your “prior belief” about what the outcome will be. That prior belief is then mixed with the data you generate from your study to form the posterior distribution, or outcome of your trial.

The other method is known as the frequentist approach. This involves setting up two groups – one external and one from your trial – and doing a standard comparison between the two groups using standard methodologies. This is the classical method that most people learn about.

The basic data used is the same for both approaches—the data are just used in different ways.

Will: Deciding whether or not to do a historical control comes down to a couple of things. First, what is the patient population like? Not all rare diseases fit the mould for being able to use historical data as their control. In some instances, it may be better to use a randomised alternative or placebo. You also need to determine the appropriateness of the historical data out there to ensure a valid comparison. What if you’re designing a novel outcome? Or what if available medical records don’t contain useful data? Often, there are holes in the data or there are temporal incompatibilities. These are a few things that can limit your ability in this area.

Tim: If there is an imbalance in covariates between the external source and your study data, the comparison will be biased. However, there are accepted methodologies for handling this.

Q4: The timely recruitment of eligible participants is a challenge for any rare disease. How does ICON effectively recruit participants through a partnership with patient organisations, patient contact registries, and clinician education to increase disease recognition and decrease time to diagnosis?

Volume 12 Issue 3

Therapeutics Will: We use a variety of strategies to find patients. For starters, we partner with rare disease patient groups such as NORD, EURORDIS and Orphanet. We also employ a digital engagement strategy, which allows us to recruit for clinical trials at specific points in time when patients are searching for information online – such as at the point of diagnosis.

In addition, we work with ongoing registries to help identify patients for clinical trials and to locate historical control data.

Designing a clinical trial that can meet enrolment goals and designating an appropriate comparator can make it difficult for rare disease drug developers to gather sufficient data. How can clinicians and statisticians collaborate to not only build a study design that is attractive to patients but also make trials simpler to enroll enough patients?

Tim: Speaking as a statistician, you want to work with your clinical colleagues to understand the best design for the trial and what the recruitment difficulties are. There’s no point in the statistician coming up with complex designs or sample sizes if the trial can’t feasibly be done.

It’s a case-by-case assessment based on the clinically relevant outcomes. At the end of the day, you’re always limited by the information you can generate. But regulatory authorities seem to be increasingly willing to work with companies to overcome these problems.

Q5: For many rare diseases, well-characterised efficacy endpoints are not available. Therefore, the responsibility resides with sponsors to select or develop trial endpoints based on their knowledge of the disease. Can you give JCS an insight into why the selection of appropriate endpoints is crucial to provide substantial evidence of the efficacy of a drug?

Will: If you don’t get the outcomes right, you’re going to miss the effect of the drug. Clinicians who treat particularly rare diseases will generally advocate for primary outcomes. If you can correct the primary genetic defect, you’d have a number of outcomes you could potentially measure. But, usually you can’t do that and you have to focus on downstream effects for your outcomes. We’ll usually design trials using the natural history data from an ongoing registry or a clinician’s collection. Many of these trials, interestingly enough, are single-arm studies. In diseases with a high level of unmet need, the FDA has been known to approve a drug even though there was not a statistically significant difference between outcomes from the single-arm study and the historical control.

Q6: In studies where disease heterogeneity is a characteristic challenge, trial protocols must be designed to accommodate the experience of the individual patient. Subsequently, why do you need strong patient engagement to mitigate risks for noncompliance or study dropout in the rare diseases clinical space?

Will: Although many patients with rare diseases are desperate for a treatment, strong engagement is still critical, as patients and their families have been perpetually desperate and get burned out over time.

Another problem we often face is that only a few specialists really know how to treat a certain patient population. www.jforcs.com

If patients don’t live near those physicians, you have to figure out how to engage patients in a valid way. That’s when you ask patients what’s important to them and what they can and cannot do. If we get them to participate in the trial design, sometimes they feel more committed to the study outcome. Adjusting your study design is different in a rare disease trial... because you can’t waste a single participant.

Q7: Consistent trial participation is contingent upon the patient’s ability to get to and from site appointments.

For success in a rare disease trial, the sponsor and other stakeholders must ensure there are no obstacles blocking patient compliance. So why is it imperative that contingencies to assist patients with transportation and accommodation costs be included in a company’s trial plan?

Will: We provide them with services to support every aspect of their lifestyle in relation to the trial such as travel, lodging, and periodic home health nurse visits. Somebody makes those arrangements so that patients don’t have to. It’s important to give patients the resources they need to continue in the study. We want to bring the trial to them.

William C. Maier William is Chief Scientific Officer, Head of Rare Disease Research, Commercialisation and Outcomes at ICON. William has over 30 years of experience with pharmaceutical companies in Europe, Canada, the United States and Asia. At ICON he works with pharmaceutical companies to provide regulatory, strategic and scientific guidance on medical treatment development and commercialisation. He is a member of the EMEA’s European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. He is a frequent speaker at medical conferences and is a member of the Royal Society of Medicine in the UK.

Timothy Clark Timothy is Vice President, Senior Consultant, Drug Development Services at ICON. Dr. Tim Clark gained his PhD in clinical trial methodology at the Institute for Medical Informatics, Biometry and Epidemiology (IBE), Ludwig-Maximilians-University, Munich. At ICON, he provides strategic drug development advice to customers and internal teams and specialises in clinical study design and protocol optimisation. Prior to joining ICON in 2009, he worked in clinical research and regulatory affairs for large French and American pharmaceutical companies and as an independent consultant advising on a range of drug development issues.

He has worked on small molecule and biological (including biosimilars) programmes indicated for cancer as well as CNS, autoimmune, cardiovascular and infectious diseases.

Journal for Clinical Studies 43

Technology

Five Barriers to Process Automation in PV & How to Overcome Them Noting the contrast between potential and progress in clinical trials vs post-marketing/real-world monitoring, Peter Kohut, Director of Drug safety at Arriello, explores the main hurdles preventing greater automation of PV data capture processes within life sciences firms, and suggests how to move beyond current inertia – touching on examples of how other heavily-regulated industries such as banking have overcome similar challenges to deliver process transformation.

At the high-impact R&D end of life sciences, investment in technology is consciously linked to commercial priorities including innovation, efficiency and speed to market. There is an appreciation of the value of automation in administering and reporting on clinical trials, for instance. Here, smart use of technology to accelerate what would otherwise be laborious manual processes ensures that data capture is robust, bears close scrutiny, and doesn’t tie up more skilled resources than is absolutely necessary.

By contrast, the post-marketing discipline of pharmacovigilance (PV), whose data intake requirements are multiplying by the week, has been largely passed over for technology-enabled automation. Although PV is seen as a more of a cost centre, a duty of care, rather than something competitively differentiating for organisations, this alone does not explain companies’ apparent reluctance to invest in its IT-based transformation. As a ‘cost centre’ the PV function must be run as efficiently as possible.

To fulfil its ultimate purpose – improving the safety profile of life sciences products – PV activities also need to be as reliable and complete as possible, satisfying regulators and patients that products are being monitored with due vigilance, and enabling confident next actions to be taken in R&D. With more and more safety data to capture, and a window of just 15 days to assess and report serious adverse events to health authorities, the case for automating the most labour-intensive aspects of PV is strong. So, what is holding companies back from investing in process transformation?

Below are five of the most common perceived barriers to technology-enabled data capture automation, and how and why they should be dispelled with a degree of urgency.

1. A lack of suitable solutions Look at most other industries, especially those that are highly regulated, and use of IT systems tends to be highly evolved. That’s because organisations have long realised the inefficiency (in cost, time and resources) of using people to manually input data into core business systems, and then physically re-enter the information into adjacent systems in other departments.

44 Journal for Clinical Studies

In banking today, increased digitisation of processes and services means that data (for example from customer transactions or loan applications) is captured electronically first time, and automatically flowed through into relevant back-office systems and associated workflow processes, keeping everything in sync and triggering next actions. This happens in insurance too, where increasingly, via client portals, customers are encouraged to enter more of their own information, even managing their own claims reporting (including uploaded photographic evidence), which can be flowed straight into case processing. As well as being more efficient for everyone concerned, this approach ensures that detail is captured more accurately first time.

In pharma, by contrast, core database systems tend to stand alone: companies are still figuring out how to connect them with tools that could transform and simplify data intake.

In some cases, the issue is that PV departments lack access to relevant technology expertise and knowledge, so they don’t have a picture of what’s available or what’s possible – including the scope for sourcing solutions and optimised business processes via cloud-based platforms and relationships with technology-empowered PV service partners. Meanwhile, larger companies which do have sufficient internal resources often believe that they need to build any tools themselves, something they may never get round to – especially if they haven’t tied down the business case.

Given that some very intuitive and easy-to-integrate data capture tools do exist out in the external market, with the precise purpose of transforming PV data capture efficiency and efficacy, it seems surprising that manufacturers/sponsors do not make more use of them – especially as the time and cost savings associated with digital solutions are shown to exceed 60 per cent when compared with processes that rely on manual data capture. As long as pre-built tools come from a reputable provider with proven PV experience, and integrate readily with companies’ safety databases, these offer a very credible option for firms looking to deliver PV more cost-effectively.

2. Regulatory complexity The increasing stringency and breadth of regulatory requirements are enough to make any life sciences organisation worry about inadvertent non-compliance. This anxiety can cause firms to view technology with caution. What if the chosen tool skips a vital step, or isn’t validated as fit for purpose/as meeting current GxP (good practice) criteria? Every regulatory inspection will include a thorough vetting of processes and tools, to ensure they meet expected standards and can be relied upon for completeness and accuracy – both now and in the future.

These concerns are easily addressed, however. When choosing data capture tools, or managed services which make strategic use of them, PV professionals simply need to check for certification/ documentation showing that any solution has been validated as meeting regulatory criteria. For the longer-term, continued validation Volume 12 Issue 3

Technology and system lifecycle management will be down to the provider’s support process, in other words how it manage updates and vetting on a continuous basis. So this is something else companies need to look for in a supplier.

3. Fear of the unknown Preoccupation with doing everything by the book can lead to inertia.

To ensure they stay the right side of regulators, PV teams prefer to play it safe and do things the way they always have – so they can be sure they haven’t missed anything, or used a bogus tool that lulls them into a false sense of security. For firms that have scant internal IT capabilities, this situation is magnified. PV teams don’t know quite what they’re looking for, or how to verify that the solution will stand up to regulatory scrutiny, or how to implement, integrate, use and get the best from it.

With the way the market is going, specifically the general acceptance that industries and companies that fail to get on board with process digitisation will lose ground to more nimble competitors, it is well worth life sciences firms investing in at least some internal IT resource – if only to be able to collaborate with external partners to ensure the right applications and approaches for the given need.

Without internal knowhow, firms risk feeling at the mercy of suppliers – therefore unsure whether to trust their advice, for instance.

With someone appropriately skilled on the inside, companies can begin to relax, knowing that they have a champion armed with the right questions and capable of ensuring that the target technology is appropriate and likely to deliver the desired results. This internal advocate can manage the supplier relationship, collaborating with developers to hone a solution in partnership with their counterpart at the provider organisation.

4. Cost For reasons mentioned in the introduction, post-marketing surveillance does not tend to attract big budgets. This means that any investment in PV IT needs to be tightly targeted, and seen to deliver improved results with greater efficiency – that is, controlling a drug’s safety profile and enhancing the company’s reputation, while simultaneously optimising resources. If companies choose not to invest in transforming PV data capture activity, they risk spending more than they need to, and consuming too much time of busy people who have other more critical tasks to be getting on with. That includes promoting and selling new medicines in the case of drug reps; or seeing patients, in the case of healthcare professionals. Data processors, meanwhile, could use their time more productively and expedite reporting if they didn’t have to keep going back to check or complete details missing from the adverse event (AE) reports that have been passed through to them.

While large life sciences organisations, which generally prefer to develop their own tools in-house, may question the cost/benefit trade-off of creating new data capture automation aids, bespoke development is not the only option. Taking advantage of a preexisting, pre-tested tool that’s ready to go today, and accessible on demand via a software-as-a-service delivery model, changes the economics considerably – especially if there is no associated support burden, because the provider takes care of everything.

5. Usability issues Companies’ inertia when it comes to trying new technology often also comes down to an aversion to change, of having to behave in different ways which may require staff retraining. Tools’ intuitive ease of use is paramount in overcoming this very real barrier, whether the data inputters are clinicians or drug sales reps on the front line, or backroom data clerks working for the PV department or an outsourced service provider. www.jforcs.com

Any industry that has embraced customer self-service, from banking to retail, has long understood that the key to encouraging more people to take up a new digital facility with positive results, is to make the experience as convenient and natural as possible for the user – so that they can complete tasks much more quickly and easily compared to the alternative/old way. Streamlined apps on smartphones which can populate forms quickly and efficiently, and which are effortless to use on the fly, have proved especially transformational for both service users and the brands serving them.

In PV AE case entry, it follows that tools need to be easy and intuitive for busy people to engage with as part of their daily work.

If users were able to enter patient information straight into a smartphone app – even by voice if typing is too onerous, capturing information directly into each of the required fields – this could be transformational for those called upon to report adverse events and provide the fullest picture they can about the patient’s experience.

For those users, the ability to tackle PV admin in the moment, instead of having to come back to it between appointments or at the end of a long day, a smartphone-based data capture app is an enticing proposition. For PV departments, meanwhile, this improved user engagement ought to result in more complete and more reliable patient/AE data, captured in a timely fashion and reducing the burden on data processing teams to chase up missing detail or any lack of clarity (e.g. due to illegible notes). With a single click to launch the app; drop-down lists; voice-based data capture into structured forms; and automated prompts to capture and check over each data entry, companies can be confident that cases submitted straight through for data processing are of good, actionable quality.

Why wait?

Looking for discrete tools such as this example of a voice-enabled smartphone PV data capture app – which are very easy to adopt and use, and which alleviate a substantial manual administrative burden – are a good way for life sciences firms to test the potential of process automation and amass some experience.

Embracing greater automation is going to be essential as PV reporting requirements continue to multiply and grow, placing an ever greater strain on resources. Automation offers a way to cope with rising demand, and to simplify demanding routine tasks, as firms expand their portfolios and market coverage, while controlling the safety profile of their products.

Yet, to take full advantage of the opportunities, companies need to overcome their historical barriers to technology adoption in pharmacovigilance – and there is no time like the present.

Peter Kohut Peter Kohut is the Director of Drug safety at Arriello and an experienced EU QPPV. His deep technical knowledge of pharmacovigilance helps Arriello’s clients understand the current PV framework, and enables the development of tailored PV systems that ensure effective risk management and compliance across the product lifecycle. Peter began his career in biochemical research, before entering the pharmaceutical industry where he has worked in both clinical trials and post-marketing safety roles.

Email: peter.kohut@arriello.com

Journal for Clinical Studies 45

Technology

Notable Opportunities and Challenges of Wearable Technology in Clinical Trials Consumer-grade wearable devices offer the potential to continuously monitor many different physiological measures of health and fitness as individuals go about their daily routines.

For a clinical trial, this could provide valuable insights between hospital visits, potentially enhancing the understanding of treatment response, delivering a rudimentary early warning system, providing objective measures of more subjective outcomes or even provide efficiencies in trial conduct.

Before the widespread adoption of such technology in clinical trials, however, there are several significant challenges from data access and interpretation to clinical validation. In this article, we offer insights into our experience and some of the specific challenges that exist, focusing on the collection and analysis of data including the interpretation and generation of meaningful clinical insights.

Wearable Activity Trackers There is considerable discussion around the use of patientgenerated data in health research and clinical studies, particularly from wearable activity trackers. Since around 2013 there has been a large increase in sales of consumer-grade activity tracking devices and it is estimated that over 22% of adults in the US alone will wear a smart watch for at least one month in 2019 according to eMarketer1, and the smart wearables market is predicted by Forbes to double by 2022 (October 2018)2. This popularity gives rise to a potentially under-utilised data source for clinical research.

During a clinical study, a patient is often closely monitored with a detailed analysis of their blood, vital signs etc. at specified timepoints, or visits to the clinic. However, with basic activity trackers providing accelerometer-based activity data and more sophisticated models capable of also monitoring heart rate and other features, these devices have the potential to provide insights into an individual’s health, fitness and sleep 24 hours a day, seven days a week. During a clinical trial, this would provide valuable information for each patient between clinic visits. Furthermore, there are subjective events that can be both under-reported and difficult to measure, for example fatigue, novel endpoints, or general wellbeing. From a physician’s perspective, a greater awareness of these events may help them with appropriate interventions or advice and more generally, this information could be important in defining the tolerability of new treatments from a patient’s perspective.

Limited Evidence Despite the potential around wearables, there is limited indication of how the data from consumer-grade devices might be used in clinical studies. Although wearable activity trackers are gaining traction in clinical trials, most focus on their use either as an intervention (e.g. in weight loss or behavioural studies) or in comparing consumergrade with medical-grade devices. There is potential for clinical teams to extract value from this data alongside the routinely collected data at visits. It is worth noting that there is much debate around the use of consumer-grade devices in clinical research and 46 Journal for Clinical Studies

the accuracy and validity of most devices has not been verified formally. As a result, their use within such research should be with the appropriate level of caution/awareness.

While consumer-grade activity trackers may have the potential to provide insights into patients’ general health and fitness and overall wellbeing between visits, there are, however, several challenges associated with the access to and utilisation of this type of data, for instance: 1.

2.

3.

4.

5.

6.

Data connectivity: accessing and extracting the data for an individual.

Types and frequency of data reported.

Missing data (including non-wear time).

Generating meaningful insights from the data.

Data privacy and security.

Clinical validation.

Despite these challenges, consumer-grade wearable data may provide benefits during clinical trials: 1.

2.

3.

4.

Valuable information alongside the standard clinical data collected during a clinical trial.

Improvement in recruitment because patients are actively involved in clinical research.

Better quality of the findings.

Greater impact because it empowers patients to donate their own data toward decision-making about their own health. This may have a positive impact on the patient's own experience of a clinical study and may improve the dialogue between patient and caregiver.

Effective extraction, processing and creating actionable healthrelated insights could potentially enable continuous monitoring of individuals outside of the clinic. This could empower the patient, as they will retain control over the additional information and data they provide to the clinical study team.

Four Key Challenges There are many challenges in utilising the data from consumergrade activity trackers as suggested above. The clinical validation is extremely important and should be a key consideration if planning to utilise these consumer-grade devices during a clinical trial as well as the data privacy and security. For the remainder of this article, however, we will focus specifically on the practical challenges around the data and the workflow; from data access through to meaningful analysis.

Challenge 1: Data Connectivity Challenges with Wearables Within data connectivity for wearables, there are two areas of concern. The first is what data the manufacturer will allow you to access, and the second is how to create a workflow for the secure transfer of the data from the device for analysis.

We conducted a small study where we provided full instructions so that volunteers could download their data from their device account to a secure server. They were able to select which data to Volume 12 Issue 3

Technology download and all participants opted to share their sleep and activity data in its entirety. This would not be a feasible approach in a larger study. The particular device used in this study provided data on a daily summary level - it would have been possible to access intraday data through an application programming interface (API), however this would be subject to review by the device company.

Our approach for this study was simple – volunteers would share their daily data with the investigators. Careful consideration would be required if this approach was scaled to a larger clinical trial, especially around how, with appropriate consent, an individual's data would be securely transferred and linked to existing data, all the while ensuring anonymity. Furthermore, consideration needs to be given to the appropriate, country-specific governing laws, for instance GDPR in the EU and the differing US laws depending on the grade of the device, be they medical grade or consumer grade.

Challenge 2: Types of Data Reported Although activity trackers essentially measure activity via an accelerometer (and, with some devices, a heart rate monitor), there are several marked differences in the available data from the various devices on the market.

There are also limitations in the use of such data, such as data being summarised as daily values, the definition of activity and sleep relying on the devices interpretation of the heart rate data and often the lack of any granular accelerometer or heart rate data.

It is imperative to consider these device-specific limitations when choosing which data should be included for analysis.

Challenge 3: Missing Data and Non-wear Time There are two types of missing data to be aware of with activity trackers. The first challenge arises where some data for a given day is reported, but the granular data is unavailable. An example is sleep data: the time to bed and wake-up times may be reported; however, the sleep stages may be missing. Alternatively, we may have activity data for each day but no sleep data at all, suggesting an individual removed their device at night.

The second challenge around missing data is non-wear time, where, for example, a device is removed for a short period of time during the day. Many wearables do not directly report non-wear time, however from the data it may be possible to approximate non-wear time per day for an individual based on a calculation over a 24-hour period. Such calculations can be based on the two assumptions: (1) an individual does not wake between the sleep start and end time (this, of course, is not strictly correct as individuals could wake in the night and remove the device for a time and then put it back on) and (2) If the device reports the number of sedentary minutes for a given day to be 1440 (the total number of minutes in a day) then it was assumed the user was not wearing the device.

In the study we conducted, we looked at the non-wear time over the month. We found that overall, the total non-wear time was low.

Questionnaire results suggested that most individuals only removed the device for charging and showering, with some choosing to not wear the device for prolonged periods such as for particular social occasions or to sleep.

Analyses should factor in non-wear time and missing data.

Thought should be given to what missing data there might be, how it will be calculated or detected and how to deal with the missing data. Certainly, it is important that the amount of missing data be made clear to those who are interpreting the data, along with any assumptions that have been made. www.jforcs.com

Challenge 4: Generating Meaningful Insights Directly from the Device Data Another major challenge in the use of wearable devices is around the interpretation of the data by clinicians. The volume of data generated by wearables could potentially be overwhelming to a physician or a clinical study team. For instance, many trackers can measure heart rate continuously over a 24-hour period, which over the course of a clinical study is a lot of data points.

There is still much to be done in this area in understanding how this data can be translated into something usable by the clinical and/or study team. Moreover, it is important to consider what medical intervention would result from the interpretation of such information.

It is known that sleep is an important measure of health3, activity can improve aspects of our wellbeing4 and physical activity impacts the overall quality of sleep5. If we look at the data generated at the single patient level it may be possible to look at changes in the sleep of an individual over time or a decrease in activity levels. The result from such insights may lead to an enhanced conversation between patient and caregiver with two-fold impact; firstly, the patient may feel more reassured that they are contributing to the consultation and secondly, there may be a medical intervention or a specific piece of advice the caregiver can provide that may help that patient. It must be noted that if the devices being utilised are consumer-grade devices, consideration must be given to the validity and accuracy of these measurements.

Examine the Trends A clinical study team may be interested in the data at the level of a population and want to consider potential trends in the data to provide meaningful insights. There are many ways to look at the data, such as the non-sedentary time on each day of the week. In our study with healthy volunteers, activity levels increased on the weekends, as one would expect. Translated to a clinical study, this sort of information could be utilised to study trends in the days following dosing, for example the general activity levels postdose across the trial population, which may provide insights into tolerability.

More generally we can look at the association between activity and sleep. There is no consensus on how to measure sleep quality; in our study, we applied the approach of Valenti et al.6 and defined sleep quality as the time spent in REM and deep sleep divided by the total minutes asleep, and looked at activity vs. sleep quality.

As mentioned previously, the volume of data from activity trackers can potentially be very large and it isn’t necessarily clear how a caregiver may consistently extract value from such data for an individual subject. It may be beneficial to use the activity/sleep data as an indicator of other health events. One potential application could be in the indication of a general sense of a patient’s wellbeing, which in turn could provide insight into drug tolerability.

Wellbeing is subjective, sometimes relying upon a dialogue between patient and caregiver. One approach used to measure wellbeing is a validated questionnaire, completed by the patient, which relies upon recall from a previous fixed duration. One such questionnaire is the WHO-57,8, which is a short self-reported measure of current mental wellbeing over the previous two-week period. During the study we conducted, we asked participants to complete an online version of the WHO-5. Although not a large enough sample size to be statistically meaningful, it provided some preliminary data on any possible association of activity tracking data to wellbeing.

Journal for Clinical Studies 47

Technology

Conclusion Consumer-grade wearable devices offer the potential to monitor an individual 24/7 as part of their daily routines, away from a hospital setting and include a myriad of physiological measurements from brain activity through to temperature. Although there are several clinical trials utilising wearable devices, often as an endpoint or as an intervention, researchers are only just beginning to understand how to extract value from such rich data to generate clinical insights. For instance, digitally-collected data from a wearable device may be transformed, through mathematical models and machine learning, into indicators of health outcomes. It may be possible that characteristics in an individual’s activity or sleep could form an objective measure of their general wellbeing or fatigue levels, which could then be used to inform their physician and/or provide insights across the study around general tolerability.

The role of wearable technology in healthcare and clinical trials is promising; the potential applications are diverse including enhancing our understanding of responses to treatment and efficiency gains in clinical trial conduct. However, there are significant challenges and the community would benefit from the regular exchange of learnings and experiences to facilitate the development of best practices around the deployment, collection, standardisation and analysis of such data for validated clinical applications.

REFERENCES 1.

2.

3.

4.

5.

Yoram Wurmser, Wearables 2019 “Advanced Wearables Pick Up Pace as Fitness Trackers Slow,” https://www.emarketer. com/content/wearables-2019 Paul Lamkin, Smart Wearables Market To Double By 2022: $27 Billion Industry Forecast https://www.forbes.com/sites/ paullamkin/2018/10/23/smart-wearables-market-to-doubleby-2022-27-billion-industry-forecast/-1ac6c7462656 R. Cooke, “Sleep should be prescribed': what those late nights out could be costing you,” September 24, 2017. [Online].

Available: https://www.theguardian.com/lifeandstyle/2017/ sep/24/why-lack-of-sleep-health-worst-enemy-matthewwalker-why-we-sleep. [Accessed September 2019].

“How to look after your mental health using exercise,” [Online].

Available: https://www.mentalhealth.org.uk/publications/ how-to-using-exercise.

P. D. Loprinzi and B. J. Cardinal, “Association between objectively-

48 Journal for Clinical Studies

6.

7.

8.

measured physical activity and sleep, NHANES 2005–2006,” Mental Health and Physical Activity, vol. 4, no. 2, pp. 65-69, 2011.

G. Valenti, A. G. Bonomi and K. R. Westerterp, “Quality Sleep Is Associated With Overnight Metabolic,” J Gerontol A Biol Sci Med Sci, vol. 72, no. 4, pp. 567-571, 2017. https://academic.oup. com/biomedgerontology/article/72/4/567/2629933 C.W. Topp, S.D. Østergaard, S. Søndergaard, and P. Bech, "The WHO-5 Well-Being Index: A systematic Review of the Literature," Psychoterapy and Psychosomatics, vol. 84, pp. 167–176, 2015. https://www.corc.uk.net/outcome-experience-measures/theworld-health-organisation-five-well-being-index-who-5/ WHO, "Wellbeing Measures in Primary Health Care/ The Depcare Project," WHO Regional Office for Europe, Copenhagen, 1998. http://www.euro.who.int/__data/assets/ pdf_file/0016/130750/E60246.pdf

Jennifer Bradford Jennifer Bradford, PhD is Head of Data Science for the CRO PHASTAR. She has worked for the Advanced Analytics Group at AstraZeneca, working alongside medical scientists, statisticians and s oftware developers to maximise the value from clinical trial data across therapy areas through data analytics, machine learning, text mining and data visualisation approaches. Jennifer led the development of AstraZeneca's interactive, visual tool for ongoing monitoring of clinical trial data (REACT). Jennifer also worked as part of the team at Cancer Research UK (CRUK) where the REACT tool was customised and delivered to other sponsors. She worked closely with patients and staff at the Christie Hospital, one of the largest cancer treatment centers in Europe, working on projects related to electronic data capture (EDC) in the clinic, App development and data collection from wearables, and understanding how this information can be analysed alongside routinely collected clinical data. Jennifer has a degree in Biomedical Sciences from Keele University and a bioinformatics Masters and PhD from Leeds University, with a focus on protein aggregation.

Web: www.phastar.com

Volume 12 Issue 3

Corporate Profile Ramus Corporate Group

is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of the International Standard for Quality Management System ISO 9001:2015.

Ramus Medical is working CTs in a variety of therapeutic areas and medical device.

•

• • • • • • • • • • •

Medical Centre Ramus with Phase I Unit

Full service CRO Medical writing for drugs and devices Scientific review of documentation GxP trainings Ramus Phase I unit Ramus Analytical laboratory Clinical trial management Monitoring Data management Biostatistics Regulatory advising and services during clinical trial

Medical Diagnostic Laboratory Ramus (SMDL-Ramus) • • •

20 clinical laboratories in Bulgaria and North Macedonia 300 affiliates for sampling in Bulgaria and North Macedonia 20 years experience in the CT flied as central and safety laboratory; , fast, correc t!

Safe

• • • •

Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

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

Others: • • • • •

Readability user testing Bridging report Archiving services DDD activities Transportation and storage of dangerous goods

Medical Diagnostic Laboratory Ramus Ltd

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

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

Dimitar Mihaylov Marketing Director

Journal Journal for for Clinical Clinical Studies Studies 49 49

Special Feature

Translation Services – A Key Component in Successful Clinical Trials

JCS speaks with Craig Brown of Dora Wirth (Languages) Ltd, on steps companies can take to avoid faulty translations Q1: The language used in Clinical Trial Protocols (CTPs) is becoming more and more differentiated as it blends medical, administrative and technical jargon not seen in other medical documents. However, inaccurate translations can happen and can affect human lives, credibility and economic revenue. What steps can companies take to prevent faulty translations?

It’s true that credibility is at stake when purchasing language services, not to mention the health and economic impacts bad translations can have.

Avoiding negative outcomes begins with procurement.

We have seen the gradual commoditisation of translation services over at least the last 10 years, reflected in RFIs attempting to benchmark language services according to price, quality and speed.

So, first of all we suggest better partnerships between business buyers who request translation services and their counterparts in procurement who are trying to identify the LSP best suited to their needs. In practice this may mean posing different questions: do I know the name of the person to contact when I am inevitably up against a submission deadline? Can we see anonymised CVs to check the background of your supply chain? What is the reputation of the LSP among the translator community? Are suppliers continuously evaluated?

How are non-conformances recorded and how do these affect the quality management system in place? How many pairs of eyes are checking your translations before delivery? Do you have any case studies to show where problem-solving ability can be demonstrated?

Lack of communication hampers translations.

Keep communication channels open so that an LSP may quickly resolve translation queries as they arise. Your source language documents are frequently open to interpretation, and the ability to resolve unclear wording on-the-fly will ensure that assumptions are not made about the intended meaning.

Doesn’t someone in accounts speak Flemish?

We frequently meet customers who recruit colleagues to translate documents, or review them. It could be seen as a cost-cutting exercise, or a way to ensure that the translation is in the hands of an expert. While it’s true that nobody knows your clinical trial better than you, it’s essential that a professional translator with adequate knowledge of source and target language, subject matter, register and tone be recruited to ensure a successful translation.

Success, of course, is the avoidance of misunderstanding, and ensuring patient safety and intact professional reputation. What you save in cost and time by getting your bilingual colleague to translate an informed consent form may be lost further down the line when translation errors need to be rectified at considerable expense.

50 Journal for Clinical Studies

Q2: How equipped was the translation industry for Covid-19 lockdown and will there be a longer-term effect?

Translation agencies are at the mercy of the industries they serve. Thus economic downturns affect different segments of the translation industry differently.

During the current pandemic, localisation and subtitling companies may feel greater pressure than specialist LSPs serving the pharmaceutical industry, as purse-strings in the former are tightened and the latter invests even more heavily in therapeutic solutions.

Certainly as an LSP specialising in translations for the life science sector we feel relatively secure, and continue to win business despite the global pandemic. We hear that more generalist agencies are putting pressure on linguists’ rates in response to the downturn and freelance translators are feeling the financial pinch.

The translation industry in general, however, is relatively well set up for this lockdown. Freelance linguists are, usually by definition, remote workers. In addition, supply chains are usually international and the translation management software we use is collaborative and web-based. So as long as LSPs are online, we are able to serve our clients.

In the longer term, we may find that the days of needing to house a team of project managers under one roof are no more.

We may thus see LSPs eschewing the traditional company headquarters and moving to fully remote setups. We already see companies in the pharmaceutical industry operating as corporations without fixed headquarters, and it will be interesting to see if this catches on, particularly if some form of lockdown persists.

There does seem to be a renewed sensitivity towards employee work/life comfort across many industries, as we all scramble to safeguard productivity and some sense of ‘team’ amid the pandemic. We look forward to a future, post lockdown where team engagement and social interaction are pushed higher up the list of business priorities.

Q3: When will machines replace human translators?

Since DWL was founded in 1962 we have seen the industry move from typewriters all the way to translation-at-the-touch-of-a-button. Computeraided-translation (CAT) is used extensively in the industry already, for consistency and speed, but it is a partnership retaining an essential human element behind the software.

Volume 12 Issue 3

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Journal for Clinical Studies 51

Special Feature

At a roundtable meeting with leading LSPs at a recent DIA conference in the States, I heard many industry stakeholders voicing a desire for disruption in the translation industry on a technological level. They didn’t know how, but they wanted translations faster, better and cheaper.

Machine translation (MT) is another tool in continuous development within the industry and there is no doubt that the accuracy of MT output has dramatically improved in recent years. You only need to take a look at Google Translate to know this.

This push for efficiencies in the processing of translations is no doubt fuelling developments in automation, machine learning and natural language processing. But how close are we to replacing the human translator in the life sciences vertical?

Some way off, DWL would argue.

Though big tech is driving forward improvements in the technology, so are translation companies and increasingly the pharmaceutical world, where research organisations are keen to develop solutions to translate vast amounts of data and remove the need for project management and human translators.

Translation memories are, after all, libraries of segments translated and maintained by linguists, terminologists, project managers and translation buyers. Vast investments in technology do not replace a watertight quality management system underpinned by human translators.

It must be borne in mind that, at the time of writing, the output of machine translation is most accurate for translating sentences out of context, and not for full documents. The flow and structure of the latter requires the intuition of a human translator. This is because it is just as hard for a human to guess the meaning of a sentence out of context as for a machine, so errors relating to textual cohesion will largely go unnoticed when evaluating MT output. For these reasons there is a real potential to exaggerate claims about the accuracy of MT as a reliable tool for translating clinical trial documentation.

The risk of mismanaging translation memory (TM) software was brought into the spotlight recently when the Canada Translation Bureau was sued by LSPs for contractually requiring them to use poor translation memories (TM) for discounted rates in return. The LSPs claim that the TMs they were obliged to use were polluted with bad translation units and thus required a disproportionate amount of time to use, despite the discounted rate they were expected to charge.

This has the potential to expose the risks of slavish use of TM software without due consideration for the quality of the translation work that should be fed into them.

52 Journal for Clinical Studies

As a result, we see human translators playing a key role in the future, both in evaluating the translation output of machines but also in editing it (post-editing) and preparing documents for the end user.

So yes, some translators may have to re-market themselves as post-editors of translations produced by machines. Yes, Volume 12 Issue 3

Special Feature technology solutions can enable us to cut corners and process huge volumes of data with fewer human touches, but with so much at stake in the life science industries, the role of the human translator is, for now at least, relatively safe.

Q4: Since DWL was founded in 1962, there has been a changing demand for target languages stemming from the establishment and growth of the European Union, and more recently the importance of emerging markets. Why do you think the demand for both localised and transcreated content is booming?

We live in an international world where media is transmitted rapidly and widely across countries and markets. Combined with record levels of literacy, this results in increased demand for translated or localised content worldwide.

Access to technology is higher than it ever has been, allowing developing nations access to information and content on a massive scale and in turn allowing companies access to markets and consumers of content outside of their traditional regions.

In the hands of the millions of displaced people around the world who have access to the internet, we are also able to offer life-saving support to populations speaking differing languages but who are not bound by traditional borders and yet require localised health information.

Emerging markets certainly play a role in this boom, and we see waves of demand for world languages as clinical trials are set up, and also as international pharmaceutical companies aim to market their products in European markets.

It is also logical that having access to learning materials in local languages will pave the way to employment which, in turn, benefits the economy.

The Indian government, for example, has recognised that although India has 22 official languages, most of its population of science and technology students do not learn in their own language. Thus it is investing around USD 65m to ensure that bilingual access to teaching and research materials is available to learning institutions. They plan to use a combination of machine and human translation to achieve this goal and this is expected to have a positive effect on the educated unemployed population.

Q5: With the growth of both the internet and e-mail and the advance of technology from typewriter to state-of-the-art IT, there has been a change in documentation for translation solutions. With that in mind, how can the translation industry upskill their offering and adapt to creating new types of translation projects?

Let’s not complicate matters. We translate the written word and the format is largely irrelevant.

What is important is that we fit seamlessly within our customers’ project management processes and work with them to handle any file or document type they need to translate. www.jforcs.com

LSPs are ready for changes in documentation and have an eye on future developments that will impact their businesses.

A recent example is the upcoming move to electronic product information (ePI) at the European Medicines Agency (EMA).

We react to industry developments like this by reaching out to experts, examining our capabilities and deciding whether our existing setup can handle any changes (see our blog for more).

In terms of technology, we are constantly reminded of the need to upskill and provide an ever greater array of machine translation solutions and automated processes. However, the translation industry has to strike a balance between the risks of lower efficiency and the risks of over-investment in technology and solutions that are not yet ready.

Craig Brown Craig Brown is the Director of New Business Development at Dora Wirth (Languages) Ltd., a specialist translation agency for the world’s top pharmaceutical firms. While at DWL he has managed the translation of documents relating to global clinical trials, European regulatory submissions and post-marketing activities. Having worked for over 10 years at two leading agencies, he has a good understanding of the translation industry and its relationship to life sciences. When he isn’t helping to shape DWL’s sales and operations strategy he is found running in the fells of Cumbria.

Email: craig@dwlanguages.com Web: www.dwlanguages.com

Journal for Clinical Studies 53

Special Feature

e-Learning Systems Revolutionising ‘teach’ and ‘learn’ in the Clinical Research Space

JCS speaks with Anthony Wilkinson at RQA on how web-based, SCORM-compliant eLearning courses introduce Good Clinical Practice in clinical studies Q1: Technology has revolutionised the way that we ‘teach’ and ‘learn’ in the clinical research space, because we now have a digital toolbox that can enable us to ‘learn online’. Whether that be through virtual elearning systems or online courses, it’s no wonder statistics show that elearning increases retention rates by 25% to 60%. With that in mind, can you tell JCS how RQA’s range of web-based, SCORM-compliant eLearning courses introduce Good Clinical Practice?

Introducing and promoting Good Clinical Practice (GCP) are critical aspects of RQA’s mission. As you rightly point out, an effective way of providing the required training is through eLearning. eLearning allows RQA to offer a training solution that can be easily consumed wherever and whenever the learner chooses. All RQA eLearning is SCORM-compliant which provides integration with a learning management system (LMS), all the courses have an assessment and, upon successful completion of the course, each offers a certificate.

All RQA eLearning is modular, allowing people to do as much or as little as they want in one sitting without needing to complete the entire course in one go. The Intro to GCP eLearning, for example, has six modules covering a range of topics, such as the history of Good Clinical Practice, an introduction to the ICH GCP Guidelines, the EU Clinical Trial Directives, and the Declaration of Helsinki.

Q2: 2020 has seen the rise of clinical research network capacitybuilding through implementing and evaluating training materials and courses to help independent researchers and research institutes strengthen their technical capacity in the clinical health management sector. Designed to empower individuals and institutions, what are the benefits of using online training for the purpose of capacity-building?

Most of RQA’s eLearning is purchased by organisations who want to train groups of people (often dozens) quickly, effectively and cost-efficiently.

Those organisations use RQA’s eLearning to provide new skills so that it may build the organisational capacity to suit new situations or improve current performance.

The advantage of buying multiple eLearning courses together, besides the available price discounts, is that each eLearning course doesn’t start until it is activated. So, the organisation feeds the eLearning to its staff as it is required. Each course purchase has an unlimited useage, but the assessment remains activated for one year.

Q3: While a successful capacity-building process will require fostering and incentivising collaborations to enhance research productivity, barriers to capacity development such as fragmented research systems, limited governance and regulatory capacity and inadequate material capacity, can deter potential researchers from applying for online courses. How can companies create a strategic plan framework to improve the efficiency of capacity development?

Capacity development is often about advancing the ability of individuals and teams to work more effectively by, for example, identifying and solving problems.

Any strategy relating to capacity development has to include elements such as infrastructure and leadership. But all capacity development strategies have to be built on the development and training of people; not as a one-off exercise but as an investment in the workforce of the future. All such strategies have to consider skills and knowledge transfer, learning, HR management, and leadership development.

RQA’s eLearning courses don’t require a massive investment, they don’t take people away from the workplace and can be consumed in bite-sized pieces. Any strategic framework for capacity development has to consider the workplace culture, and often the organisation has to change the culture to encourage people to learn.

Q4: As part of its effort to achieve global harmonised implementation of ICH Guidelines, ICH is working on ensuring that high-quality training is available based upon scientific and regulatory principles outlined in the ICH Guidelines.

Considering the updated ICH E8 guidelines, how can companies use training products such as face-to face courses, seminars, regional forums and more to support students in learning about general considerations for clinical trials?

It’s vitally important for training providers to offer a range of course subjects AND a variety of delivery methods. RQA firmly believes that learning should be consumed how, where and when the customer wants it. The pandemic has forced all trainers to deliver their material online, so we’ve seen a surge in people buying eLearning.

At the same time, for a more immersive learning experience, we’re offering remote courses where the tutors deliver the learning live

54 Journal for Clinical Studies

Volume 12 Issue 3

Special Feature and online. Such an approach provides an interactive course with chats, discussions, questions and answers – everything an excellent training course should have except the travel.

RQA’s GCP Auditing course is always popular; it offers an ideal training opportunity for anyone moving into the field of auditing clinical studies, and already has experience of GCP or auditing.

The remote course provides a clear understanding of the aims of Good Clinical Practice, an idea of what can go wrong with clinical trials and an understanding of the roles and responsibilities of the clinical trials auditor.

More and more, RQA is noticing that organisations want to be trained in groups. Obviously, eLearning is an ideal solution; it provides excellent, consistent training across a group of people.

Likewise, in-house courses, where the tutors deliver the training tailored to a particular client, is often an extremely efficient and cost-effective solution.

Q5: Good Clinical Practice (GCP) training is a key requirement for individuals involved in clinical research and is designed to ensure that those involved in conducting a trial are qualified by education, training and experience to perform their respective tasks. How does RQA’s Good Clinical Practice Committee educate members in understanding the importance of the interwoven laws, frameworks and guidelines, which govern the set-up and conduct of clinical research?

It’s a good question. RQA’s structure is actually quite complicated so I won’t go into too much detail about it. RQA has several committees that mainly focus on good practices. We also have course principals, who oversee the professional development courses with the support of a tutor group – one principal and one tutor group for each course. While the committees don’t have any direct responsibility for the course content, they’re often involved in any development work including the creation of new courses and learning material.

Coincidentally, the RQA GCP Committee is the most active in the association. It has around six or eight new products under development at any time. So, through a range of product types and topics, the GCP Committee delivers seminars and webinars regularly. Additionally, the committee runs a significant event within the RQA Conference – the GCP Clinic, where a panel of experts provide answers. It’s simple and extremely useful, and very popular. The committee members frequently write interesting and educational content for RQA’s quarterly magazine QUASAR, including an update on regulations and the regulators. Thanks to members of the GCP committee, RQA maintains an active discussion forum where anyone can post a question to the online forum and the experts will provide an answer.

Q6: A qualitative approach is essential for clinical pharmaceutical research specialists, which is why eLearning is vital as it not only enables the development of comprehensive training courses, but it also ensures a greater variety of procedures, not to mention compliance. Largely influenced by ‘microlearning’ and artificial intelligence, how does eLearning represent the future of ‘education’ and ‘training’, in the clinical research space?

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Over the past few weeks, due to the coronavirus, there has been a significant shift towards microlearning. There are many reasons for this – concentration levels, prioritisation, stress, and so on. Incidentally, we had already noticed that people were moving towards bite-sized learning before the pandemic.

The modular nature of RQA eLearning allows it to be consumed in small chunks. That’s one of the main features of our eLearning courses. I mentioned earlier that RQA firmly believes learning should be consumed how, where and when the customer wants it.

With shorter attention spans, eLearning is the ideal solution for education and training in the clinical research space.

Anthony Wilkinson Anthony is a successful Executive and Director with over 35 years of valuable business management experience. He has developed, supported and managed worldclass organisations across a diverse range of industries, products and services - manufacturing, automotive, engineering, FMCG, construction components, consultancy, certification, training, professional associations, not-forprofit, and testing/inspection bodies. With an excellent track record in building and managing businesses through corporate development, people involvement and continuous improvement in high-end global environments, Anthony specialises in the management and leadership of effective strategic planning, control of change, transferring knowledge, and empowerment.

Anthony has worked for organisations in the UK, Hong Kong, Munster, Toronto, Dubai, and various regions of Asia. In his spare time, Anthony is a prolific writer; he published three books in 2019. One on Change Management, one on Going Self-Employed, and one on his favourite pastime – Freshwater Fishing.

Journal for Clinical Studies 55

Ad Index

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IFC MLM Medical Labs

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Ramus Medical Limited

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Worldwide Clinical Trials

I hope this journal guides you progressively, through the maze of activities and changes taking place in the pharmaceutical industry

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Volume 12 Issue 3

GCP AUDITING:

PRINCIPLES AND PRACTICE

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For more information visit: www.therqa.com/learning/remote-courses

As an Association dedicated to informing and advancing its members, RQA provides status and visibility for individuals concerned with the quality of research and development concerning pharmaceuticals, agrochemicals, chemicals and medical devices.

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