The End of Data Chaos: Modernising Data Infrastructure to Revolutionise Clinical Research by eClinical Solutions

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Respiratory Disease Diagnosis and Testing Beyond COVID-19 Re-Evaluating Paediatric Cancer Endpoints What a Global Pandemic Taught Us About the Pharmaceutical Supply Chain Expediting Clinical Trials with Cloud-Based Metadata Repository and Study Automation Technologies

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Contents

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT Jerome D'Souza info@senglobalcoms.com EDITORIAL MANAGER Beatriz Romao beatriz@senglobalcoms.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Jessica Dean-Hill jessica@senglobalcoms.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Senglobal Ldt. J101 Tower Bridge Business Complex London, SE16 4DG

FOREWORD

WATCH PAGES 6

Virtual Town Halls Provide Timely Support to SARS-CoV-2 Test Developers

Since the onset of the COVID-19 public health emergency, the US Food and Drug Administration (FDA) has hosted a weekly “virtual town hall” meeting to provide the opportunity for stakeholders to ask questions about issues that arise as they develop and implement tests to detect SARS-CoV-2 or diagnose COVID-19. Deborah Komlos at Clarivate explains more about Town Halls Provide Timely Support to SARS-CoV-2 Test Developers. 8

Data Compliance or Rejection – Are you ready for September 15th?

Until recently sponsors have been able to submit nonclinical and clinical reports without datasets and without fear of rejection. In less than three months, the agency will begin to enforce their Technical Rejection Criteria for Study Data: “FDA plans to implement eCTD validation checks when submissions contain content under modules 4 and 5 beginning September 15, 2021. Submissions which fail this validation will be subject to rejection.” Melissa Rapp at Pharmalex analyses what are the impacts of this incident in the industry and why it is so important to the agency. REGULATORY 10 Respiratory disease diagnosis and testing beyond COVID-19

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Over the last year, the COVID-19 pandemic has placed healthcare for respiratory medicine firmly in the global spotlight. But even before this, over half a billion people worldwide (1) were living with chronic respiratory illnesses such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). Jonathan Lawson at Owlstone Medical analyses how to advance the diagnosis and treatment of these conditions? And how could non-invasive breath tests change our approach to respiratory care?

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14 The End of Data Chaos: Modernizing Data Infrastructure to Revolutionize Clinical Research

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The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright. Volume 13 Issue 4 August 2021 Senglobal Ldt.

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Clinical research organisations (CROs) are often buried under massive amounts of data that is difficult to analyse effectively and rapidly. Compounding this problem is that data often comes from multiple sources that are not inherently compatible or standardised and require additional transformations, which adds expenses and delays to the development of new drugs and therapies. Sheila Rocchio, at eClinical Solutions explains the different approaches that life sciences organisations can take to harmonise their data, eliminate delays, and achieve better outcomes. 16 What a Global Pandemic Taught Us About the Pharmaceutical Supply Chain As global supply chains strained under the pressure of intense demand and thinning resources created by the COVID-19 pandemic, both the public and private sectors had to think quickly and creatively about how to preserve the pharmaceutical supply chain. Along the way, we learned many lessons. Over the last several decades, the pharmaceutical supply chain has become increasingly complex. To be successful, it relies heavily on global trade and Journal for Clinical Studies 1

Contents international logistics. Reynaldo Roman at Marken explains what global pandemic taught us about the pharmaceutical supply chain. 20 Critical Considerations for Clinical Trial Safety Reporting Investments Naturally, safety event reporting and pharmacovigilance (PV) should be subject to detailed regulatory scrutiny as evidenced from the Food and Drug Administration (FDA) overseeing the protection of human subjects and improving trial conduct by ensuring appropriate safety procedures are in place. It's critical that the right information reach the right constituents for reporting adverse events in a clinical trial. Tim Billington at Pharmasol defines the key aspects that impact clinical trial safety reporting processes, such as excessive reporting by sponsors and the need to automate and intelligently integrate siloed information to facilitate safety document distribution. MARKET REPORT 22 Re-Evaluating Pediatric Cancer Endpoints The RACE for Children Act provides hope we can accelerate therapies to children, adolescents, and young adults with cancer. As precision medicine increasingly influences paediatric cancer care, we must consider which drugs to prioritise, how to develop them through global collaboration and novel trial designs, and how to measure success. Melissa Hansen, Joanna L. Perkins and Harris Dalrymple at PRA Health Sciences discuss the need to re-evaluate pediatric cancer endpoints. 26 Top 5 Innovations in Clinical Trials that are benefiting the Pharma Industry The current pace and scale of innovation that we are witnessing within the pharmaceutical industry has not been seen before. The speed at which COVID-19 vaccines have been developed is a testimony to the power of modern technology, scientific advancement, innovation, and collaboration across the industry. We are seeing a new age of innovation and experiencing significant transformation, for the better. Shrishaila Patil, at Navitas Data Sciences, indicates the Top 5 Innovations in Clinical Trials that are benefiting the Pharma Industry. THERAPEUTICS 30 Recent Advances and Future Challenges Using Biomarkers in Oncology Precision Medicine

have been created and conducted at an astonishing rate. At the time of writing, over 9400 clinical trials had been submitted to the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Kevin Burges at Formedix explores more about expediting clinical with cloud-based metadata repository and study automation technologies. 38 Digital adherence: Modern solutions to an age-old problem Despite spiralling drug development costs and timelines spawning industry-wide efficiency drives, tackling the multibillion-dollar problem of adherence has remained an untapped opportunity – until now. Advances in digital technologies are ushering in a new dawn in clinical trial adherence, promising to save time and money while improving patient experience and safety. Solutions such as connected smart packaging and data analytics are more accurate, more efficient, and more robust than traditional methods of compliance monitoring, such as pill counts, blood sampling, or self-reporting. Bernard Vrijens at AARDEX Group looks at the scale and impact of the problem, why traditional methods of monitoring are not up to the job, and how organisations are using digital technologies to finally overcome the age-old problem of adherence in clinical trials. 42 Digitising Healthcare: The Challenges and Benefits The market for IoT in healthcare is projected to reach $534 billion by 2025, driven in part by the fallout from Covid-19 and also by new societal attitudes. It’s clear that new technology has the potential to transform industries and every aspect of life from healthcare to retail, for instance. Artificial Intelligence, Machine Learning, IoT, Robotics and Industry 4.0 are all common buzzwords now and hold great promise. Peter Ruffley at Zizo Software analyses the challenges and benefits of digitising healthcare. LOGISTICS & SUPPLY CHAIN 44 COVID-19 Vaccines updates Cold Chain Logistics of Vaccine Distribution Developing COVID-19 vaccines was the first step in the fight back against the virus. The world then faced and continues to navigate, the significant challenges of having to protect, transport and safely store temperature sensitive pandemic payloads worldwide. Alongside cold chain challenges, further challenges remain relating to the equitable access to the various vaccines being produced and deployed on a global scale. Adam Tetz at Peli BioThermal talks about the updates on cold chain logistics of vaccine distribution.

Current and future cancer treatment is expected to be shaped and guided by the use of biomarkers that will guide researchers and physicians at every stage of development from the basic understanding of cell transformation to early cancer detection, to precision drug development, to long-term disease management. Historically, cancer treatment was empirical, driven mainly by the histology of the tumour and organs of origin, and how the average patient population responded to a treatment. Brian Huber at ICON explains the recent Advances and Future Challenges Using Biomarkers in Oncology Precision Medicine. TECHNOLOGY 34 Expediting clinical trials with cloud-based metadata repository and study automation technologies The COVID-19 pandemic put clinical trials firmly in the spotlight. Powered by the urgent need to combat this global threat, clinical trials 2 Journal for Clinical Studies

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Foreword Healthcare companies (device manufacturers, payors, and providers, among others) have long relied on technology as a core utility – for tracking R&D efforts and patient information, scheduling payments and services, launching new care options, and generally keeping the lights on. The digitization of products and processes, however, has dramatically changed the game for everyone. Consumers’ expectations about healthcare services are increasingly being informed by their experiences with large digital-born companies. With this “customer experience” frame in mind, healthcare companies are seeking to integrate the latest technologies into existing business models and IT architectures to improve services. The market for IoT in healthcare is projected to reach $534 billion by 2025, driven in part by the fallout from Covid-19 and also by new societal attitudes. New technology has the potential to transform industries and every aspect of life from healthcare to retail, for instance. Artificial Intelligence, Machine Learning, IoT, Robotics and Industry 4.0 are all common buzzwords now and hold great promise. Peter Ruffley at Zizo Software analyses the challenges and benefits of digitising healthcare

care, we must consider which drugs to prioritise, how to develop them through global collaboration and novel trial designs, and how to measure success. Melissa Hansen, Joanna L. Perkins and Harris Dalrymple at PRA Health Sciences discuss the need to re-evaluate pediatric cancer endpoints Current and future cancer treatment is expected to be shaped and guided by the use of biomarkers that will guide researchers and physicians at every stage of development from the basic understanding of cell transformation to early cancer detection, to precision drug development, to long-term disease management. Historically, cancer treatment was empirical, driven mainly by the histology of the tumour and organs of origin, and how the average patient population responded to treatment. Brian Huber at ICON explains the recent Advances and Future Challenges Using Biomarkers in Oncology Precision Medicine I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals. I hope that you enjoy reading this edition of the journal and keep well. Beatriz Romao, Editorial Manager Journal for Clinical Studies

Clinical research organisations (CROs) are often buried under massive amounts of data that is difficult to analyse effectively and rapidly. Compounding this problem is that data often comes from multiple sources that are not inherently compatible or standardised and require additional transformations, which adds expenses and delays to the development of new drugs and therapies. Sheila Rocchio, at eClinical Solutions explains the different approaches that life sciences organisations can take to harmonise their data, eliminate delays, and achieve better outcomes. In this issue, leaders in the field of pediatric radiation oncology provide important updates to the radiotherapeutic care of infants, children, and adolescents with a spectrum of cancers. The RACE for Children Act provides hope we can accelerate therapies to children, adolescents, and young adults with cancer. As precision medicine increasingly influences paediatric cancer

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

• Catherine Lund, Vice Chairman, OnQ Consulting • Cellia K. Habita, President & CEO, Arianne Corporation • Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe

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

• • 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

• Georg Mathis, Founder and Managing Director, Appletree AG 4 Journal for Clinical Studies

• Hermann Schulz, MD, Founder, PresseKontext • Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma.

• Jim James DeSantihas, Chief Executive Officer, PharmaVigilant • Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

• Maha Al-Farhan, Chair of the GCC Chapter of the ACRP • Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

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

• Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) • Stefan Astrom, Founder and CEO of Astrom Research International HB • Steve Heath, Head of EMEA – Medidata Solutions, Inc Volume 13 Issue 4

Our Vision Be the best patient focused solutions company for clinical trials worldwide. Our Mission Bring a unique combination of services to facilitate worldwide participation in clinical trials for all.

Patient

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

Watch Pages

Virtual Town Halls Provide Timely Support to SARS-CoV-2 Test Developers Since the onset of the COVID-19 public health emergency, the US Food and Drug Administration (FDA) has hosted a weekly “virtual town hall” meeting to provide the opportunity for stakeholders to ask questions about issues that arise as they develop and implement tests to detect SARS-CoV-2 or diagnose COVID-19. The FDA states that it “plays a critical role in protecting the United States from threats such as emerging infectious diseases, including the coronavirus disease 2019 (COVID-19) pandemic.” Given this context, the agency “is committed to providing timely guidance to support response efforts to this pandemic.” The Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised): Immediately in Effect Guidance for Clinical Laboratories, Commercial Manufacturers, and Food and Drug Administration Staff includes policies specific to this public health emergency. This guidance was issued on February 29, 2020, and subsequently updated in 2020 on March 16, May 4, and May 11. The town hall held on June 30 marked the sixty-second meeting since the series began on March 25, 2020. During these sessions, the FDA hosts typically begin with an overview of any pressing updates and then provide answers to selected questions that were submitted by e-mail in advance of the call (sent to CDRHWebinars@fda.hhs.

6 Journal for Clinical Studies

gov). The remainder of the session is slated for participants to ask questions live. Unsurprisingly, topics can recur within the individual calls and from week to week. One topic that has tended to arise is the FDA’s turnaround time for its review of applications or inquiries from test developers. While the agency’s Center for Devices and Radiological Health (CDRH) continues to have a backlog of emergency use authorisation (EUA) requests and pre-EUA submissions, and reviewers remain “just swamped,” the FDA is doing its “very best,” said Timothy Stenzel, MD, PhD, director of the CDRH’s Office of In Vitro Diagnostics and Radiological Health (OIR), during the June 30 call. The pre-EUA process is not required, but it is the recommended route to help reduce the risk to developers, Stenzel noted. As the agency states in its May 2020 immediately in effect guidance, the FDA will communicate any questions or concerns regarding a preEUA or EUA submission to the developer. In addition, the agency will work collaboratively to address any potential concerns or safety considerations that were raised in the pre-EUA submission or EUA request and will contact the developer regarding a final determination on the EUA request. On the topic of FDA response times, one caller during the June 30 town hall pointed out that it can take “a couple of weeks or so” to receive a reply from the FDA, which can be “a long time” for

Volume 13 Issue 4

Watch Pages Town Hall#

Topics Post-authorization software changes for home-use tests

39 (Jan. 13)

Semi-quantitative neutralizing assay requirements Conversion from EUA to 510(k) premarket notification FDA review of non-COVID-19 submissions Breadth of claims in EUA applications

42 (Feb. 10)

Authorization for SARS-CoV-2 variant testing FDA review prioritization Transferring from prescription to over-the-counter (OTC) use Limit of detection (LOD) determination

47 (Mar. 17)

Pooling of swabs Seroloqy testinq post-vaccination Updates to studies when EUA templates are revised Patient age groups in point-of-care (POC) tests

52 (Apr. 21)

Cycle threshold (Ct) values for antigen tests Saliva testing requirements Seroloqy home-use antibody tests Neutralizinq antibody testinq after COVID-19 vaccination

56 (May 19)

Direct-to-consumer at-home collection multianalyte test for SARS-CoV-2 and influenza EUA template for SARS-CoV-2 sequencinq assays Enrichment strategies for testing asymptomatic individuals OTC antiqen test for influenza A and B

59 (June 9)

Insufficient FDA responses to applications Updates to product while EUA under review Mobile applications for data reporting Table 1. Examples of Topics from Selected Virtual Town Halls in 2021

developers. “I feel for you,” Stenzel replied, noting that he spent more than 15 years “on the other side of the clinical development community working with the FDA.” Stenzel said that he tracks, at least weekly, “all of the volumes for the various submissions” and that he works with the CDRH team “to do the very best job that we can to get answers as quickly as possible.” Another caller thanked the FDA for its “hard work” and for doing its best. “But if the best is not good enough, and especially when you really don’t have enough resources to do it,” he said. The caller asked whether “anything” could be done to increase the efficiency and transparency of the review process. Stenzel replied that the FDA has authorised nearly 400 tests and that the public does not hear about the tests that the agency has not authorised. “We believe we’re doing a great job at meeting the public health need at this point,” Stenzel said. He explained that 100 people were moved from other areas within CDRH onto COVID-19 work. While that surge in staffing “had great success” in clearing the backlog in many cases for the priority reviews, it put “on pause” more than 100 regular non-COVID-19 submissions. Prior to the public health emergency, CDRH was not staffed to handle this increased volume of submissions, Stenzel noted. The OIR typically receives approximately 1,900 applications per www.journalforclinicalstudies.com

year. In the past 12 months, the OIR received more than 5,500 applications “with no substantial increase in staffing,” he said, because the work requires experts to perform the reviews. “We just had to do it faster and better than we had ever done it before, which I believe the team did,” Stenzel said. As of this late June meeting, it appears that the FDA plans to continue to host the virtual town halls for the foreseeable near future. Examples of topics that arose during the question-andanswer segments of selected past town halls are shown in Table 1.

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

Journal for Clinical Studies 7

Watch Pages

Data Compliance or Rejection – Are you ready for September 15th? Until recently sponsors have been able to submit nonclinical and clinical reports without datasets and without fear of rejection. In less than one month, the agency will begin to enforce their Technical Rejection Criteria for Study Data: “FDA plans to implement eCTD validation checks when submissions contain content under modules 4 and 5 beginning September 15, 2021. Submissions which fail this validation will be subject to rejection.”1 What does this mean for industry and why is it so important to the agency? Regulatory submissions in previous decades have progressed from the cumbersome and time-consuming paper volume review to electronic document review via computers and eCTD viewers. Such advancements have helped agency reviewers tremendously. The study data requirement seeks to further improve the review process as it aids the agency with organisational data tools. The advantage of using data standards for review is beneficial in several ways. “Having standard, uniform study data enables FDA scientists to explore many new research questions by combining data from multiple studies. Data standards also help FDA receive, process, review, and archive submissions more efficiently and effectively and the scientists at the FDA.”1 As industry stakeholders, we must keep ahead of the curve for the purpose of achieving important

research milestones. A technological hiccup such as a submission rejection can be easily avoided if industry is informed, equipped, and prepared. As the FDA Commissioner Stephen Hahn said in a speech to FDA staff on 30 Jan 2020, “One of the most important resources for our work lies in the power of data. I strongly believe that we need to do everything we can to attain more and better data for the work we’re doing, to be more proactive in gathering data, and to be more creative and thorough in our analysis of it. By harnessing this power, we can improve our regulatory decision-making…”2 Understanding the importance of this initiative to the reviewers is motivation for industry to strive towards data standards innovation. Now that the priority of data standards has been established, the next inquiry into this matter is determining how to achieve compliance. According to the guidance “Providing Regulatory Submissions in Electronic Format – Standardized Study Data,” NDA, BLA and ANDA submissions with studies that started after Dec. 17, 2016 and Commercial INDs with studies that started after Dec. 17, 2017 are required to be submitted in CDISC format following the FDA Data Standards Catalog “3. The agency has already begun to issue warnings like the one below if the correct data has not been submitted along with reports that require them. The following is a table that outlines the reports that require datasets and the type of datasets involved.

One prevalent aspect of the table below is the presence of the ts.xpt file. TS.xpt files should be considered as the “gatekeeper” dataset file for nonclinical and clinical study reports. The data provided in these files identifies the categories of data that the agency requires. For example, the ts.xpt file should contain the study start date. In a recent presentation with Pharmalex’s Adair Turner (Director, Regulatory Operations North America), these criteria were explained for a simplified ts.xpt file. The study start date allows FDA to determine that study data is not required to be in a CDISC standardised format. For a simplified ts.xpt file, there should be four variables (STUDYID, TSPARMCD, TSVAL, and TSVALNF) and one row of information. 8 Journal for Clinical Studies

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Watch Pages

Table 1: eCTD Technical Rejection Criteria for Study Data Expectations5

Table data from DIA RSIDM 2020 FDA Plenary Session – Technical Rejection Criteria for Study Data by Ethan Chen (OBI – CDER) Datasets consist of three different file formats. In the image below, the SEND dataset contains a define xml file, a Nonclinical Study Data Reviewer’s Guide in PDF format, and datasets in .xpt format. The define file can be viewed by web-browser in html format. The PDF can be opened by Adobe or any PDF viewer. The .xpt file can be viewed and reviewed in a SAS universal viewer that is available for free download.6 The amount of information provided and understanding what’s required may appear overwhelming; however, help is available. The agency has provided an “FDA Study Data Prep – Self Checklist”7 and provides detailed information on their website “Study Data for Submission to CDER and CBER”8.

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8.

https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ electronic-common-technical-document-ectd https://www.fda.gov/media/98907/download https://www.raps.org/news-and-articles/news-articles/2020/1/hahnstresses-importance-of-data-rwe-in-first-all https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/providing-regulatory-submissions-electronic-formatstandardized-study-data DIA RSIDM 2020 FDA Plenary Session - Technical Rejection Criteria for Study Data by Ethan Chen (OBI – CDER) https://support.sas.com/downloads/browse.htm?fil=&cat=74 https://www.fda.gov/media/123098/download https://www.fda.gov/industry/study-data-standards-resources/study-datasubmission-cder-and-cber

Melissa Rapp Melissa Rapp is a RegOps manager with 17 years of experience in submission publishing and management. At PharmaLex she has submitted over 400 sequences through the FDA gateway. She has successfully managed the submission activities of two simultaneous ANDAs and has experience with applications in the US, Health Canada and EU. Her managerial role has involved conducting issue resolution and managing global resources to ensure client and agency-mandated timelines are met. Email: contact@pharmalex.com

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Journal for Clinical Studies 9

Regulatory

Respiratory Disease Diagnosis and Testing Beyond COVID-19 Over the last year, the COVID-19 pandemic has placed healthcare for respiratory medicine firmly in the global spotlight. But even before this, over half a billion people worldwide1 were living with chronic respiratory illnesses such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). With an ever-increasing burden on healthcare systems, how can we advance the diagnosis and treatment of these conditions? In particular, how could non-invasive breath tests change our approach to respiratory care? Challenges in Respiratory Medicine The coronavirus pandemic has been the most significant global health crisis of modern times, affecting not just healthcare but every aspect of daily life. At time of writing, the SARS-CoV-2 virus has infected close to 150M people and been linked to over 3M deaths2. The pandemic has led to a dramatic increase in demand for respiratory care, with many severe cases requiring mechanical ventilation. For example, at the peak in the UK during January 2021, over 4000 COVID-19 patients had immediate access to mechanical ventilation3. What’s more, the emergence of socalled ‘long’ or ‘long-haul’ COVID, where symptoms persist beyond initial infection, is predicted to result in a marked increase in the demand for ongoing respiratory care.

Innovative solutions are needed to support chronic respiratory care as much as to detect acute infections. The critical challenge for diagnosing and treating chronic respiratory illnesses is that each condition is biologically complex and requires treatments to be suited to patient phenotypes. While the symptoms may be similar, the underlying mechanisms differ, and this has an impact on appropriate treatment and disease management. Current treatments are often found through trial and error, starting with affordable treatments that are most likely to succeed. This approach can take a long time to find an effective treatment and, during that time, a patient’s symptoms are poorly controlled5,6. When a treatment is found that the patient responds to, there’s also no certainty that it is the optimal solution for that patient.

Figure 2: Illustrating chronic inflammation phenotypes in respiratory diseases Chronic inflammatory airway diseases are often complex with a range of diverse phenotypes and overlapping symptoms. Underlying inflammation mechanisms can be a key distinguishing factor which can impact treatment, and being able to differentiate these subtypes could enable patient stratification and precision medicine. Finding biomarkers for these phenotypes could accelerate diagnosis and reduce the costs of treatment.

Figure 1: The impact of chronic respiratory diseases and COVID-19 A summary of key statistics around the number of cases and deaths associated with chronic respiratory diseases and COVID-19 infections as of May 2021. The number of deaths resulting from the pandemic is approximately equivalent to the annual number of deaths linked to COPD.1,2,4

While there is no denying the scale and impact of the pandemic, respiratory medicine faces many other challenges that existed before COVID-19 and will persist into the ‘new normal’. Current total COVID-19 statistics are comparable to annual numbers for common chronic inflammatory airway diseases. Most notably, statistics from the World Health Organisation estimate an annual 250M cases of COPD alone, leading to over 3M deaths per year4. In the last year, numerous efforts have been made to develop accessible diagnostic tests for COVID-19 and, thanks to unprecedented efforts, vaccines are now becoming widely available. Yet, diagnostics for asthma and COPD patients remain complex, unpleasant, and often unsuitable. 10 Journal for Clinical Studies

A key differentiator between chronic inflammatory airway disease phenotypes is the type of immune response responsible for causing inflammation7. These can include eosinophils, neutrophils, a combination of both, or sometimes neither. Treatments based on inhaled corticosteroids (ICS) are most often effective against eosinophilic cases, while the neutrophilic cases benefit more often from macrolide treatments. Another outstanding challenge for this area is predicting the onset, pattern, and recurrence of exacerbations, which present a significant and largely unpredictable risk for patients. Current Approaches for Respiratory Diagnostics There is currently no gold standard for diagnosing chronic inflammatory airway diseases. Traditional diagnostic approaches focus on the detection of symptoms such as wheezing, coughing and breathlessness, or on assessing lung function. Symptoms can Volume 13 Issue 4

Regulatory be assessed via questionnaires or through specialist observation. However, since symptoms vary over time, this can be a lengthy and imprecise approach. In 2011, a confirmatory study of 540 patients diagnosed with asthma by a physician found that 150 (28%) were misdiagnosed8. The paper went on to estimate that the additional cost of misdiagnosis exceeded $35,000 per 100 cases. Additionally, there can be unnecessary side-effects and negative impacts of treatment on misdiagnosed patients. Diagnosis now also typically involves more objective tests such as spirometry and peak flow tests which can assess lung capacity and function, as well as fractional exhaled nitric oxide (FeNO) which measures nitric oxide as a measure of airway inflammation. While these approaches provide indicators of lung health and disease, they are unable to differentiate the disease phenotypes that are critical for effective treatment. They also aren’t suitable for use with many patients, including young children with asthma. Currently the most widely accepted method for differentiating phenotypes involves assessment of eosinophils either from sputum or in the blood. Collecting airway eosinophils via sputum samples is an invasive and unpleasant experience for the patient, requiring time and specialist expertise to collect and analyse. It is typically only used in severe cases where there is an urgent need to improve symptom control but does provide a direct readout of eosinophil presence in the airways. Blood eosinophils are much easier to collect but less directly linked to the airways and accuracy of tests based on this approach has largely been insufficient to provide clinically useful results9. Sputum eosinophil counting serves to highlight another key consideration for these diseases too – suitability for use. Sputum collection often isn’t feasible for use with children and may be difficult for the elderly or those with severe breathing difficulties. Since these are all key patient groups for these diseases, the utility of this approach is significantly limited. If we are to treat these conditions more effectively, new tests are needed that offer specific results while still being non-invasive and suitable for all patients. Diagnosing Disease from Breath Existing efforts to accurately diagnose and stratify patients through non-invasive tests have achieved limited success. There may

be several reasons for this, but it may be in large part due to the reliance on single biomarkers which provide an incomplete picture of a patient’s biology. Both FeNO and blood eosinophils achieve sensitivities and specificities of 0.77 or less10. The non-invasive collection of exhaled breath represents a promising additional approach that provides access to a rich source of biological information. Work in the 1970s by Nobel prize-winner Linus Pauling demonstrated that breath contains much more than just atmospheric gases11, and we now believe that over 1000 different volatile organic compounds (VOCs) can be found on human breath12. Exhaled breath can also contain small aerosol droplets which have been a particular focus for SARS-CoV-2 detection, although VOCs are more suited to assess the long-term impact of infection. Their association with metabolic processes means that VOCs are of particular interest as biomarkers for different respiratory disease phenotypes. VOCs are typically small organic molecules that can be found throughout the body. They have many origins including exogenous sources such as food, pollution, perfumes and cleaning products, and endogenous production from metabolism. VOCs in the body can enter breath in the lungs either by passing from the bloodstream or directly from cells lining the airways. In the context of respiratory diseases, this means that breath can be used to assess both local and systemic aspects of disease. Collecting VOCs from breath has several other key benefits compared to existing diagnostic methods. First, VOCs can be captured during normal breathing, completely non-invasively, making it an appealing method for patients and suitable for use with a wider range of patient groups, including children, the elderly and those with severe respiratory symptoms. For example, a recent study from the East Midlands Breathomics Pathology Node (EMBER) consortium demonstrated that even patients with acute breathlessness were comfortable having breath collected using the ReCIVA® Breath Sampler13. Being non-invasive, breath sampling can also be used in a wider variety of applications. Breath can be collected without extensive clinical facilities or specialist expertise, making it well-suited for use in primary care and for public screening initiatives. In the future, at-

Figure 3: Volatile compounds on breath originate from endogenous and exogenous factors Over 1000 different volatile compounds have been reported in human breath. These have internal origins within the body as well as external origins influenced by diet, lifestyle and environment. As such, collecting and analysing VOCs on breath has great potential as a tool for disease detection, treatment and monitoring. www.journalforclinicalstudies.com

Journal for Clinical Studies 11

Regulatory home breath tests could also be commonplace. For chronic respiratory conditions, breath tests could be used for ongoing monitoring and, similar to blood testing for diabetes, could help to both assess current symptoms and predict exacerbations. Finally, certain VOCs on breath have already been shown to relate to particular biological processes involved in inflammation. In some cases, there are even defined mechanisms for the production of these VOCs, which can be either local or systemic. As such, changes to certain VOCs on breath can be strongly expected to relate to changes in disease activity and symptom severity. While breath analysis is still maturing as a diagnostic technique, there have been dramatic advancements in technology for breath collection and analysis over recent decades. Currently gas chromatography mass spectrometry remains the gold standard for reliable, high-sensitivity VOC detection and identification. The Breathe Free consortium of leading breath researchers also helped to create ReCIVA as a research tool for reproducible breath collection in the clinical setting. Various other approaches are also in development, including online analysis approaches, and chemicalsensor technologies. Demonstrating the Potential of Breath Tests for Respiratory Diseases VOCs on breath have been explored for applications across a wide range of illnesses, but perhaps none more so than chronic respiratory diseases. Many studies in the field have been proof of principle investigations, demonstrating the value of different collection and analysis methods. One of the largest studies to date investigated asthma phenotypes and was published by Schleich et al. in 201914. It is notable for both its size and the inclusion of an independent validation cohort. As with FeNO and eosinophil counting, Schleich et al. sought VOCs to differentiate asthma inflammatory phenotypes, particularly eosinophilic and neutrophilic. In total, the study involved over 500 asthma patients across the two cohorts. The first cohort was used to identify prospective VOC biomarkers, and models built using this information were then

validated with the second group. A range of different VOCs were found to be relevant in distinguishing phenotypes; however, the paper identifies four of particular interest. Nonanal, 1-propanol and hexane were elevated in the breath of neutrophilic asthmatics, while hexane was lower in eosinophilic asthmatics, as was 2-hexanone. The resulting models gave areas under the curve (AUC) for their receiver operating characteristic (ROC) plots of 0.88 and 0.71 for the discovery and validation cohorts, respectively. For eosinophilic cases, the study went on to draw comparison to existing diagnostic methods. The VOC model for eosinophilic asthma detection had an AUC of 0.72, comparable to blood eosinophils (0.71) and FeNO (0.70). The real strength in this comparison comes when the methods are combined, increasing the AUC to 0.87. This suggests a future approach where breath tests provide an initial moderately sensitive non-invasive diagnostic tool. Where more conclusive results are needed, breath test results could then be combined with more invasive methods if the patient’s health allows. Smaller studies have been carried out for other respiratory conditions, including using VOCs to differentiate asthma from wheezing in young children15, asthma from COPD, and interstitial lung abnormalities from IPF. Conference presentations from the Mayo Clinic have also shown data looking at changes to VOCs on breath resulting from physical lung stresses and inflammation induced by ultramarathon participation. Although existing studies have typically been small and have made use of a wide range of analytical approaches, a pattern is emerging where certain VOCs have repeatedly been linked to airway inflammation. Supported by insights into the underlying biological mechanisms, this represents the first step towards reliable, non-invasive breath tests for chronic inflammatory airway diseases. Looking to the Future of Respiratory Disease Diagnosis and Treatment There’s no doubt that both respiratory research and healthcare worldwide are at a point of considerable change. The COVID-19 pandemic has pushed limits far beyond what anyone had expected or planned for and seems likely to leave a significant, but as yet unquantifiable, legacy of patients with ongoing respiratory symptoms as a result of the long-COVID phenomenon. The pandemic has also

Figure 4: Breath biomarker performance is comparable to existing tests and can be combined for greater effect Receiver operating characteristic (ROC) curves for asthma phenotyping using blood eosinophils (orange) and FeNO (teal) compared to a test based on VOCs from breath (purple). Also shown is the result of combining methods demonstrating that diagnostic quality can be significantly improved by using methods together (cyan). AUC = area under curve, where 0.5 is random chance and 1.0 is a perfect diagnostic test. 12 Journal for Clinical Studies

Volume 13 Issue 4

Regulatory and as early warning systems for asthma attacks. Either approach, offline or online, could also have potential uses in primary care or even at-home settings to drastically increase the availability of screening while reducing burden on healthcare providers. This is a difficult time for respiratory medicine, and there are many unknowns about the future. Yet, the speed of progress on COVID research over the last year and recent research results around the diagnosis and treatment of chronic conditions also provide many reasons for hope. REFERENCES 1.

driven unprecedented advancements and innovation in respiratory healthcare and helped to highlight some of the directions that could shape the future of the field. After the pandemic, as before, chronic respiratory diseases will represent a major global healthcare burden with particular challenges in accurate diagnosis of phenotypes that can inform treatment decisions, where current methods are less than optimal. The effect that the ongoing presence of SARS-CoV-2 and long-COVID will have on this space is also yet to become clear. Though an emerging technology, breath tests have a lot to offer in terms of reliable and accessible analysis of biomarkers relevant for differentiating phenotypes. Existing data makes a strong case for the development of this option. In many cases it is already possible to achieve results of comparable quality to existing methods while still being easier to deploy for use with a wider range of patients. Breath tests also show their strength in their capacity to provide ongoing monitoring and, given the constant variation in symptom severity for these diseases, could help to predict acute exacerbations. It’s unlikely that breath could fully replace other diagnostic tools, but it is beginning to demonstrate that it could add a lot to the diagnostic toolkit for respiratory medicine. The precise form that breath tests could take is yet to be determined but is likely to vary drastically by clinical context and application. At the current stage of development, the most sensitive tools for VOC biomarker discovery rely on offline analysis – collection and analysis are separated and may be performed in different locations. This approach is common in most secondary and tertiary care settings, for example in blood or urine analysis, and may remain relevant to provide the best quality results for initial diagnoses. It is also possible, however, to envisage direct point of care devices that combine collection and analysis for more immediate results. This mirrors existing alcohol breathlysers as well as pregnancy tests and diabetic blood sugar tests and could be employed for daily monitoring www.journalforclinicalstudies.com

Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med, 2020. 8(6): p. 585-596. 2. COVID-19 Dashboard by the CSSE. 2021 [cited 2021 May]; Available from: https://coronavirus.jhu.edu/map.html. 3. Coronavirus (COVID-19) in the UK. 2021; Available from: https:// coronavirus.data.gov.uk/details/healthcare. 4. WHO COPD fact sheet. 2016; Available from: https://www.who.int/newsroom/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd). 5. Sidhaye, V.K., K. Nishida, and F.J. Martinez, Precision medicine in COPD: where are we and where do we need to go? European Respiratory Review, 2018. 27(149): p. 180022. 6. Custovic, A., J. Henderson, and A. Simpson, Does understanding endotypes translate to better asthma management options for all? Journal of Allergy and Clinical Immunology, 2019. 144(1): p. 25-33. 7. Schleich, F.N., et al., Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med, 2013. 13: p. 11. 8. Pakhale, S., et al., (Correcting) misdiagnoses of asthma: a cost effectiveness analysis. BMC pulmonary medicine, 2011. 11: p. 27-27. 9. Saglani, S. and A.N. Menzie-Gow, Approaches to Asthma Diagnosis in Children and Adults. Frontiers in pediatrics, 2019. 7: p. 148-148. 10. Korevaar, D.A., et al., Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med, 2015. 3(4): p. 290-300. 11. Pauling, L., et al., Quantitative analysis of urine vapor and breath by gasliquid partition chromatography. Proc Natl Acad Sci U S A, 1971. 68(10): p. 2374-6. 12. Phillips, M., et al., Variation in volatile organic compounds in the breath of normal humans. J Chromatogr B Biomed Sci Appl, 1999. 729(1-2): p. 75-88. 13. Holden, K.A., et al., Use of the ReCIVA device in breath sampling of patients with acute breathlessness: a feasibility study. ERJ Open Research, 2020. 6(4): p. 00119-2020. 14. Schleich, F.N., et al., Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma. Am J Respir Crit Care Med, 2019. 200(4): p. 444-453. 15. Smolinska, A., et al., Profiling of Volatile Organic Compounds in Exhaled Breath As a Strategy to Find Early Predictive Signatures of Asthma in Children. PLOS ONE, 2014. 9(4): p. e95668.

Dr. Jonathan Lawson Dr. Jonathan Lawson is the Head of Content at Owlstone Medical, the world-leader in breath biopsy. In his role, Jonathan leads on the creation of multimedia content to raise awareness of the potential for breath testing in both early detection and precision medicine across a range of diseases. He holds a PhD in genetics from the University of Cambridge and has previously worked at Cancer Research UK and the Babraham Institute. Jonathan joined Owlstone Medical in 2019 and enjoys the range of scientific topics that he gets to talk about. Email: breathbiopsy@owlstone.co.uk

Journal for Clinical Studies 13

Regulatory

The End of Data Chaos: Modernising Data Infrastructure to Revolutionise Clinical Research In the world of life sciences, data is everything. Better data leads to better research, which in turn leads to better outcomes that improve health and wellness. At least, that’s how it’s supposed to work. In reality, pharmaceutical companies and clinical research organisations (CROs) are often buried under massive amounts of data that is difficult to analyse effectively and rapidly. Compounding this problem is that data often comes from multiple sources that are not inherently compatible or standardised and require additional transformations, which adds expenses and delays to the development of new drugs and therapies. In many ways, it is a paradox that having more data sources has made research a less efficient process. However, there are a number of approaches that life sciences organisations can take to harmonise their data, eliminate delays, and achieve better outcomes. Why is there a problem in the first place? With many trials using six or more data sources, and much of that information originating from external or non-EDC sources, data chaos in clinical studies is now the norm. The exponential increase in the volume, variety, and velocity of data being used in trials has led to data integration, reconciliation, and review challenges that contribute to delays in trial timelines. To improve efficiencies across clinical studies, the life sciences industry needs to reimagine the clinical data ecosystem in a way that focuses on interoperability, simplifying complexities, and streamlining the flow of all clinical data. What is needed are new technologies and processes to centralise and manage disparate data sources. Building a data infrastructure designed for clinical development that automates the flow of data from collection to analysis enhances data quality, improves efficiencies, and promotes the ability to use artificial intelligence and machine learning techniques to predict risk. The Data Chaos Problem In theory, having more data sources should create better insights. After all, isn’t the goal to have as much data as possible to lead to richer views of the patient experience? The reality of clinical development is more complex. Data arrives from many different sources – real-world data, genomics, wearables, and more – each with its own formatting and standardisation. Each source has its own way of standardising its data, meaning that these sources are not ingested in a neat and organised way. This causes data managers and scientists – those responsible for ensuring the consistency, integrity and quality of clinical trial data streams – to devote significant time to cleaning and organising data and reviewing different sources in many different ways. In order to compare data with other similar trials to assess the safety of a new medicine, data must be standardised. That’s the only way to draw valuable insights from the information. The process of mapping data to standard formats and then analysing it can be both time- and cost-intensive. Despite industry standards, data across the product life cycle is highly varied, volumes are increasing, and the pace at which the data is being created is far faster than five years ago. For starters, information that is not easy to analyse requires multiple steps just to get it prepped adequately for researchers to work with it. Taking weeks or even months to do, it is a never-ending process because 14 Journal for Clinical Studies

new data is always ingested into the pipeline. This is actually one of the major sources of delays in getting therapies and drugs to market. In simple terms, if scientists do not have adequate data management protocols, they cannot access or analyse important information in a reasonable timeframe. These kinds of inefficiencies directly affect clinical trial operations when valuable research time needs to be devoted to what is essentially an IT problem. These increased cycle times are not only inefficient, they are expensive. Biopharmaceutical organisations increase their workforces just to stay ahead of the data onslaught. This directly affects cycle times, impedes speed to market, and also hits the bottom line. It is a lose-lose for everyone. In fact, there is a 40 per cent increase in last patient last visit to database lock cycle time for companies that incorporate data from five data sources, and most large trials have no fewer than eight sources. This creates extreme delays for important trials and therapies. It’s easy to think about this as a theoretical problem or a process issue, but it’s actually a significant business problem for life sciences companies. Organisations that don’t have effective data management tools in place cannot get important insights or analyse data in a reasonable timeframe. Both of these problems can lead to significant inefficiencies in clinical trial operations through increased cycle times and labour costs. New Impacts on Effective Data Management In recent years, with the advent of handheld computing, researchers have been trying to create new models for clinical trials that use technology to improve the patient experience in research, make participation in trials across the globe more accessible, and speed the pace of development. When the COVID-19 pandemic upended the clinical trial industry, shutting down trial sites and encouraging participants to stay home, the decentralised models of research accelerated. As it was nearly impossible for patients to actually visit hospitals and clinics for in-person visits, clinical development had to adapt – and quickly – to a new reality. Being an extremely controlled industry, the life sciences industry is notoriously slow to adopt technology. When it became a necessity, organisations came together to ensure that trials could continue remotely. Now, the industry is realising that the way forward is through decentralised and hybrid trials. Elements that were never even on our radar a decade ago have become almost commonplace. For example, wearables have gone from a fringe technology to a “must-have” approach for many trials that depend on real-time telemetrics. When you mix in things like validated instruments, genomics, and sensors, it’s clear that the current technology infrastructure and manual methods employed by many organisations to review these data is not advanced enough to manage the influx of new data sources. Today we are talking in terms of things like zettabytes and petabytes that weren’t even in the lexicon a decade ago. It’s not a snowstorm: it’s an avalanche, and the tools to handle this data need to evolve. The big question, of course, is whether or not we will return to the old model after the pandemic crisis is declared over. No one knows the answer, although the #NoGoingBack movement certainly has Volume 13 Issue 4

Regulatory The next key aspect is transforming and standardising the raw data for analyses with simplified workflows and self-service capabilities without the need for additional programming. Clinical organisations also require tools to curate and standardise data with built-in governance, and they need to be able to publish data for near-real-time consumption with governed access to all stakeholders. To dig a bit further into this, the key elements of a good data management strategy are: • its adherents. In fact, they correctly point out that no fewer than five vaccines for the novel coronavirus were developed in less than a year using an almost entirely decentralised approach. Whatever the methodologies and tools are going to be moving forward, what is exceedingly clear is that the real problem entails data and analytics tools that have simply not kept pace with changing data resources. Whether trials are held in one location, multiple facilities, or virtually, the method of information collection and analysis does not work as well as it should. This is no reflection on the quality of clinical researchers, many of whom I’ve seen do heroic work over the last 15 months. Rather it is an indictment of an approach to technology that has changed very little despite the industry revealing its inadequacies. If existing models aren’t working, what is the right approach? It comes back to technology that can manage multiple data sources, deliver high-value analytics, and help clinical organisations implement artificial intelligence tools with predictive capabilities. In fact, Gartner identified the ability to support audit trails and machine learning as top imperatives for CROs. At the crux of this conversation is how to improve interoperability between data sources and technologies. An Ecosystem for Clinical Data There's no single answer adequate to address the incredibly complicated problem of data chaos, but there is a relatively straightforward first step to help clinical trial organisations reduce work cycles and improve data management: create a modern data infrastructure that is capable of dealing with today’s large, complicated sets of information. The right infrastructure needs the ability to leverage artificial intelligence and machine learning to automate as much of the collection and analysis as possible, which in turn will reduce the time and cost associated with transforming clinical trial data into useful analytics. As decentralised and hybrid trials open the door for improved recruitment and retention, clinical trials are able to easily reach diverse patient populations, as they no longer rely on patient proximity to trial sites. Diversity in patient populations lead to more thorough data sets, and in turn, drugs and therapies that work for everyone – which is why many pharmaceutical companies are building the promise of diversity into their clinical trials. With standardised data sets, companies can monitor the race and gender of patients and ensure that diversity standards are being met. To truly achieve modernisation in clinical trials, two key factors are required. The first is building strong technology foundations that can handle the volume of data created in every trial. The second is a focus on automation to modernise the management of different components of the clinical trial data lifecycle. An automated clinical data pipeline is the solution to many problems that the life sciences industry faces. A robust data pipeline starts with automating the ingestion of information while easily cleaning and standardising various formats for efficient downstream processing. The goal is to achieve scalability while also eliminating manual intervention. www.journalforclinicalstudies.com

• •

•

The ability to automatically ingest and standardise data from any source in any format. This becomes more efficient if you have outof-the-box connectors to different clinical systems and metadata repositories via APIs. Ingestion capabilities should conform to data-enhancing standards (ODM) and include a mechanism to check on data structures’ compliance automatically while integrating with an MDR. The capacity to consolidate and organise raw data along with the metadata in flexible data stores to enable easier transformation and consumption. The ability to apply validation rules against the metadata to curate and enforce standardisation. Ideally, a data pipeline should also offer mature transformation and mapping capabilities to standardise the raw data for submission and publishing to data marts for end user consumption. Have interoperability capabilities for connecting to data-driven applications and analytics. Of course, the entire pipeline should support blinding/unblinding and audit trails — again in the context of data integrity.

Clinical trials have gotten infinitely more complex over the last five years, and they are going to get even more complicated over time, not less. A modern data infrastructure needs to enable data integrity and provide capabilities to maximise the benefits that come from data standardisation. Without technology and data infrastructure modernisation, companies will continue to struggle to take control of the data and extract its value. One thing we should all be able to agree on is that data is the currency of the life sciences industry; companies that lag with their investments into technology resources will not get the insights they need to drive the results they want to see. The Future of Data Chaos The clinical data deluge requires a modernised approach to clinical trials. This can be achieved by implementing a data and technologyfocused strategy, with modernised data management as the foundation. An end-to-end platform-centric approach – versus point solutions – will expedite data integrity and usefulness. But none of this is possible without investments into tools and technologies that are interoperable, standards-based, and can fit well into the existing infrastructure. The ability to evolve will be crucial as the industry continues to shift research priorities based on current trends and future needs.

Sheila Rocchio Sheila Rocchio leads global marketing for eClinical Solutions helping to inform clinical researchers on how cloud based technology and analytics can improve and accelerate their digital initiatives. She has twenty years of experience in product and marketing roles in software and services companies that help digitize the clinical development process. Email: srocchio@eclinicalsol.com

Journal for Clinical Studies 15

Regulatory

What a Global Pandemic Taught Us About the Pharmaceutical Supply Chain As global supply chains strained under the pressure of intense demand and thinning resources created by the COVID-19 pandemic, both the public and private sectors had to think quickly and creatively about how to preserve the pharmaceutical supply chain. Along the way, we learned many lessons. Over the last several decades, the pharmaceutical supply chain has become increasingly complex. To be successful, it relies heavily on global trade and international logistics. The COVID-19 pandemic highlighted some of the inherent strengths of the pharmaceutical supply chain but also exposed some of its weaknesses. It has been said that experience is a hard teacher because it gives the test first, the lesson afterwards.1 The events of the last year and a half provide evidence to support this notion. How the Pandemic Changed the Regulatory Landscape Looking back on 2020, it is hard to believe how quickly the regulatory landscape can change when faced with a global threat. It is no secret that regulatory change is usually a slow and tedious process. Even the slightest amendment or procedural adjustment can take months, if not years, of fleshing out, drafting and submitting through rounds of approvals before it can finally pass. However, the COVID-19 pandemic forced governments to discover a new capacity for regulatory decisiveness and swift action: a muscle they have always possessed but found difficult to flex. Trade Facilitation When it became apparent early in the pandemic that PPEs were in dangerously short supply, the World Customs Organization (WCO) strongly urged international customs administrations to facilitate the clearance not only of COVID relief goods, but goods in general, to help minimise the overall impact to the global supply chain.2 The U.S. and other countries quickly reacted by amending and or simplifying import and export rules to allow for faster global distribution of relief goods. In the U.S., for example, Customs and Border Protection (CBP) did a remarkable job of providing the trade community with resources to help expedite the import clearance of PPE. The agency created a CPB COVID-19 Updates and Announcements page on its website to guide importers and customs brokers on what they could do to ensure the timely release of PPEs and other relief goods.3 In turn, CBP prioritised the processing of COVID-related import shipments. Many other countries also implemented similar procedures to facilitate trade. Regulatory Flexibility The pandemic also forced public health agencies to embrace regulatory flexibility. Public health officials mobilised to expedite the regulatory approval and import admissibility, even if only temporarily, of relief products such as PPE and medical devices to address national shortages. 16 Journal for Clinical Studies

U.S. FDA, for example, invoked its Emergency Use Authorization (EUA) authority and enforcement discretion policies to lift some of the restrictions that apply to the manufacture, approval and import of specific PPE and medical devices.4 The agency also provided outreach to support the trade community and help clarify the import requirements that apply to these products. This additional support from customs administrations and public health regulators was vital for many companies relying heavily on sourcing PPE and other relief goods from around the world to meet demands. International trade was not the only area to implement regulatory flexibility. Regulators such as the FDA and European Medicines Agency (EMA) also advanced what the EMA called “the necessary flexibility and procedural simplifications needed to maintain the integrity of the trials, to ensure the rights, safety and well-being of trial participants and the safety of clinical trial staff during this global public health crisis.”5 The aim was to give clinical trial sponsors the freedom to explore new avenues for continuing clinical trials during a time when government authorities were enforcing travel bans and widespread shelter-in-place orders. As a result, innovations such as patient virtual site visits and direct-to-patient (DTP) models of investigational drug distribution moved from the frontiers of clinical trial study design to become commonplace and, in many cases, the only feasible approach. Not a Free-for-all While customs organisations and public health regulators were committed to facilitating trade and limiting regulatory barriers, they also clarified that flexibility did not mean a free-for-all approach to placing products on the market. Soon after the initial efforts to liberate trade, country officials began to reel in some of the slack and scrutinise COVID-related supplies more closely to avoid the introduction of unsafe products into the supply chain. For example, by May of 2020, the EU reminded the trade community that PPEs placed on the EU market must comply with PPE Regulation (EU) 2016/425 even when imported for COVID-19 relief.6 Here again, many other countries followed suit and issued similar announcements and enforcement policies. The regulatory changes continued well into 2021. As production of COVID-19 vaccines ramped up and global distribution loomed near, the EU Commission announced its intention to monitor the export of certain COVID vaccines and related materials. The commission would require EU countries to authorise the export of vaccines and associated materials manufactured under the EU Advance Purchase Agreement (APA): a European Commission programme that financed part of the upfront costs faced by vaccine producers in the form of funding in return for the right to buy a specified number of vaccine doses.7 The new export authorisation rule went into effect on January 29, 2021 and remains in force until June 30, 2021. Volume 13 Issue 4

Regulatory

The pandemic taught the trade community that commerce and regulatory policies can be elastic when necessary but that at some point, that elasticity must rebound. Trade regulations often shift and move in response to local and global pressures, so businesses involved in international trade must be ready to traverse the changing regulatory currents. Many companies learned that having a solid trade and regulatory team or department can mean the difference between navigating the storms of regulatory uncertainty or capsizing in their turbulent waves. Logistical Challenges One cannot understate COVID-19’s impact on global supply chains. Soon after the pandemic reached critical mass, many industries struggled as supply lanes became anaemic under pressure. The pharmaceutical supply chain was no exception. Travel bans, strained resources and a dwindling workforce threatened to put a chokehold on pharmaceutical and clinical supply distribution channels that have historically relied on well-established intermodal transport routes. Logistics companies, the pharmaceutical industry and regulators all had to think and act fast to find solutions. Logistics companies found ways to do more with fewer resources while ensuring the safety and wellbeing of personnel. The pharmaceutical industry embraced alternative and often costly www.journalforclinicalstudies.com

transport methods to maintain the supply chain. For example, when commercial flight cargo capacity began to evaporate, several companies switched to private charter aircraft, which came at a premium, but ultimately prevented critical drug supply shortages. Civil aviation regulators also played an important role. When commercial airlines reeled from the sudden decline in passenger travel, the Federal Aviation Administration (FAA) responded by allowing airlines to remove passenger seats from aircraft to accommodate more cargo transport capacity;8 a move that would simultaneously increase the bandwidth of cargo flight options and provide airlines with much-needed support during an unprecedented economic downturn. Maintaining Quality This collaborative effort to find novel solutions to supply chain disruptions, while laudable and necessary, did create some risks. While pharmaceutical companies rapidly pivoted to adopt alternative shipping and product storage arrangements, it was also incumbent upon them to ensure that their quality systems were robust enough to safeguard the integrity of products. EU regulators reminded the industry that any alternate shipping and storage methods for pharmaceutical products must comply with Good Manufacturing Practices (GMP) and particularly EU GMP Annex 13 for the distribution of investigational medicinal products.9 Journal for Clinical Studies 17

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www.mlm-labs.com

Regulatory lessons validated the merits of having a solid global logistics strategy, while others highlighted the need for better planning and disaster preparedness. As a result, many pharmaceutical companies are evaluating their supply chains and trading partners to see how they can improve disaster preparedness, security and overall quality. Governments are also examining the COVID-19 pandemic response as a study in how to strengthen national supply chains. In fact, under the Executive Order on America’s Supply Chains, the Biden administration has requested a full review of the nation’s supply chains.12 The goal is to ensure that the U.S. has more resilient supply chains that are secure and diverse and include greater domestic production, a range of supply, built-in redundancies, adequate stockpiles, safe and secure digital networks, among many other things. As the world slowly and gleefully returns to pre-COVID normalcy and as the dust settles, one question remains: Now that we have been tested, have we learned the lesson? REFERENCE 1. 2.

To meet these new regulatory demands, pharmaceutical companies closely examined their quality system to ensure it could and would cope with their new distribution models. They also had to confirm that their supply chain partners had quality systems that were equally robust and up to the challenge. Companies that had previously invested in quality-driven trade and global logistics strategies were uniquely equipped to face this new global threat. Transport Security Maintaining quality was not the only challenge faced by the industry. As global vaccine distribution commenced, transport security became a significant concern. Supply chain security has always been an essential part of worldwide trade and indeed the pharmaceutical supply chain. However, because of the pandemic, the stakes were higher than ever. The International Air Transport Association (IATA), with the support of other organisations such as the International Civil Aviation Organization (ICAO), WCO, WTO and World Bank, to name a few, published guidance in which quality and security of vaccines and pharmaceutical products were central themes.10 The guidance emphasised that vaccines are highly valuable commodities, so risk assessments should be performed to determine vulnerabilities and threats in the supply chain. Pharmaceutical companies had to coordinate quickly and carefully with their logistics service providers to ensure that transport lanes were secure. In several countries, even national and local law enforcement became directly involved in protecting vaccine transport by offering armed escorts and surveillance. In the U.S., for example, U.S. Marshals protected COVID-19 vaccines as they travelled throughout the country.11 Where We Go From Here The challenges faced in the last year and a half will change how both the public and private sectors think about the global pharmaceutical supply chain for many years to come. The pharmaceutical and trade community learned many lessons throughout the thick of the COVID-19 pandemic. Many of these www.journalforclinicalstudies.com

3. 4.

8. 9.

10. 11. 12.

Quote attributed to Vernon Law http://www.wcoomd.org/en/topics/facilitation/activities-and-programmes/ natural-disaster/coronavirus.aspx https://www.cbp.gov/newsroom/coronavirus https://www.fda.gov/emergency-preparedness-and-response/coronavirusdisease-2019-covid-19/covid-19-related-guidance-documents-industry-fdastaff-and-other-stakeholders GUIDANCE ON THE MANAGEMENT OF CLINICAL TRIALS DURING THE COVID-19 (CORONAVIRUS) PANDEMIC https://ec.europa.eu/health/sites/ default/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf COMMISSION RECOMMENDATION (EU) 2020/403 of Mar 13, 2020, on conformity assessment and market surveillance procedures within the context of the COVID-19 threat https://eur-lex.europa.eu/legal-content/EN/ TXT/?qid=1586260931727&uri=CELEX%3A32020H0403 Commission puts in place transparency and authorisation mechanism for exports of COVID-19 vaccines https://trade.ec.europa.eu/doclib/press/index. cfm?id=2239 Exemption No. 18584 https://www.faa.gov/coronavirus/regulatory_updates/ media/18584.pdf EU GMP Annex 13: Investigational Medicinal Products https://www.gmpcompliance.org/guidelines/gmp-guideline/eu-gmp-annex-13-investigationalmedicinal-products “Guidance for Vaccine and Pharmaceutical Logistics and Distribution” https:// www.iata.org/en/programs/cargo/pharma/vaccine-transport/ https://www.cbsnews.com/news/covid-19-vaccine-us-marshals-protect-drugtransportation/ Executive Order on America’s Supply Chains https://www.whitehouse.gov/ briefing-room/presidential-actions/2021/02/24/executive-order-on-americassupply-chains/

Reynaldo Roman Rey Roman, senior director of regulatory compliance, is a licensed U.S. customs broker and a certified customs specialist with over two decades of experience in brokerage and trade compliance and strategies. In his current role, Rey manages Marken’s trade compliance programmes, implementing trade strategies and best practices that enable smooth import processes resulting in more timely and cost-efficient delivery of clients’ imports. email: reynaldo.roman@marken.com

Journal for Clinical Studies 19

Regulatory

Critical Considerations for Clinical Trial Safety Reporting Investments Naturally, safety event reporting and pharmacovigilance (PV) should be subject to detailed regulatory scrutiny as evidenced from the Food and Drug Administration (FDA) overseeing the protection of human subjects and improving trial conduct by ensuring appropriate safety procedures are in place. It's critical that the right information reach the right constituents for reporting adverse events in a clinical trial. In this article, we will cover some of the key aspects that impact clinical trial safety reporting processes, such as excessive reporting by sponsors and the need to automate and intelligently integrate siloed information to facilitate safety document distribution. Nonintegrated clinical trial training and communication can negatively impact safety letter notification, regulatory document exchange, and cross-reporting between studies. There are also challenges involved in pharmacovigilance information technology. We will delve into a reallife use case for the effective distribution of critical drug safety event information. Centralised and automated SUSAR distribution has proven to be effective for delivering safety compliance information to sponsors, CROs and research sites. Pharmacovigilance IT and Business Process Support Throughout the drug development life-cycle, pharmacovigilance IT and business process support are critical components to ensure both drug and device safety. Clinical Research Organisations (CROs), pharmaceutical and medical device companies must proactively work and collaborate with all stakeholders to ensure a systematic approach to safety monitoring and reporting. This has helped to support the evolution of safety document distribution and technology breakthroughs, such as safety data communications hubs, portals, dashboards, etc. They centralise and automate distribution to increase the speed of clinical trials without compromising on safety and accuracy. The need for an increased collaborative approach, combined with a constantly changing regulatory landscape, has brought about additional requirements for managing risks. For instance, the industry has transitioned from passive to active safety surveillance and automated document distribution activities. Advanced technology in the form of communications hubs or smart portals can easily and seamlessly deliver documents to a variety of recipients within a specific timeframe, using predefined methods of delivery and in required formats, flawlessly. It is important to take into account the relevant global, regional or local regulations that apply, together with applicable internal business requirements by utilising quantitative methods to leverage data from all available sources (including Clinical Trial Management Systems). The Role of a Safety Data Communication Hub Pharmaceutical companies and CROs that utilise a safety data communication hub for drug safety document management today, are transforming the way in which they connect sponsors, CROs and sites across the clinical trials ecosystem. There has been a paradigm shift to more advanced technology like this, which is safeguarding companies and bringing greater efficiencies than ever before. They 20 Journal for Clinical Studies

are alleviating troubling inspections that can be risky and lead to penalties. Issues with sponsors burdening sites with needless or redundant reports of safety issues that have little to no relevance to the site can finally be eliminated. Cost savings can be achieved by no longer needing the trial staff to investigate whether a report of adverse events should be submitted to their institutional review board (IRB), a designated committee that protects the rights, safety and well-being of humans involved in a clinical trial, by reviewing all trial aspects and approving its start-up. It is no wonder that safety reporting is one of the largest hidden costs in the clinical trial industry. By simply decreasing any unnecessary safety letter distribution, cost savings can equate to millions of dollars. From our experience, we are finding that more than 50 percent of sites are spending 72-plus hours of staff time. This is time that could be invested in patient care. Additionally, we have found safety reports can average about $23 each to produce with budget expenses ranging about $40–$45 per report. Of course, these estimates can change depending on whether they involve global clinical trials where economies of scale can result or depending on how the trial unfolds in terms of its complexities. By reducing the complexities of safety reporting through the use of new technology for drug safety document management, substantial savings can be made through streamlining the reporting process and alleviating the burden on sites, CROs and sponsors. One CRO's Perspective In conversation with a Clinical Research Manager at a full-service global CRO they mentioned that they have successfully received from the FDA, as well as other international regulatory agencies, approval of more than 85 products since 2000. There has been tremendous benefit gained by replacing the legacy cloud-based collaboration platform with a "Smart Portal" that automates the sending of safety documents to the right people involved in a clinical trial, instead of multiple manual steps, as required with the previous solution. The CRO's involvement in more than one trial meant that they could expect to receive an average of 75 reports daily from some 3-4 hub users per individual site. With so many reports being generated and so many users utilising the information on a regular basis, this gives added importance to gaining auditable reporting and compliance tracking – all of which is handled through the hub where information can be centralised, and distribution of safety letters automated. The hub also groups messages where applicable. For example, in a large oncology program, there are multiple protocols, for the same compound, so by grouping messages together, sites receive only one safety alert and are not flooded with emails. This has also enabled the CRO to automate cross-reporting between multiple studies, a critical activity that the CRO struggled with previously. By centralising safety reporting within the organisation, they fixed their inability to track everything from every recipient, an instrumental activity for the clinical operations (CO) team who are working with the clinical sites directly. Now the CO teams no longer have to maintain compliance in another system but rather Volume 13 Issue 4

Regulatory

can do it through the same application doing the delivery. This has eliminated hours of lost time weekly and substantially reduced overspending. Safety documents like SUSARs, line listings and development safety update reports (DSURs) can be quickly sent and accessed by all recipients including sites, ethical committees or ECs and IRBs – thus reducing the number of outgoing messages. This is a great time savings when you factor in the CRO has about 200–300 internal users and thousands of site recipients. The safety documents can be automatically distributed using the embedded country rules and recipients’ language preferences. Out-of-the-box settings can be configured to user preferences, which helps in faster adoption and easier training, especially for large, global organisations. Safety reporting is a compound-level vs. study-level activity within drug safety operations. The hub handles study-level distribution using an approach that limits over-distribution especially when those sites are working on multiple studies with the same compound. Putting Actionable Insights into Practice In essence, the large CRO referenced said they advanced the automation of their drug safety document distribution process and appreciated that documents could be uploaded once and immediately made available to all appropriate recipients. The company was able to put actionable insights into practice and be able to track which recipients did what and when. By drilling into data sets, it was possible to see if particular countries, sites, users or studies are falling short of expectations regarding their obligations. Ultimately, it gave them better oversight on compliance and access information to potentially determine where targeted training may be needed for certain groups as well as possibly assessing whether wider issues exist at a site so that they can mitigate general risks. www.journalforclinicalstudies.com

To Conclude Innovative approaches to safety reporting processes should include monitoring and alert mechanisms to enable full compliance and also eliminate overspending together with comprehensive audit trails. Processes that build on existing safety delivery methods should also seamlessly implement and not require extensive site staff training. Often it is deemed instrumental to a clinical trial to achieve higher levels of user acceptance, automated compliance and save resources. Thus, why market research has shown that around 85% reduction in costs can be achieved along with a 90% reduction in resource requirements while experiencing compliance rates above 97% when able to fully automate the document distribution process. All of which gives credence to reevaluate current in-house systems for safety compliance.

Tim Billington T. Billington, Chief Sales Officer at pharmasol, which provides pharmacovigilance hosting services, and software, to their pharmaceutical and CRO customers. (www.pharmasol.de). He has been working in the pharmaceutical industry for more than 20 years. Starting his career at a CRO within data management and project management he then moved to Oracle where he led a number of global clinical software implementation projects. In 2001, he moved to pharmasol, where he co-developed the rapidLIVE implementation approach for accelerated application deployment. He now leads the sales team at pharmasol across all areas of the business. Email: tim.billington@pharmasol.de

Journal for Clinical Studies 21

Market Report

Re-evaluating Paediatric Cancer Endpoints The RACE for Children Act provides hope we can accelerate therapies to children, adolescents, and young adults with cancer. As precision medicine increasingly influences paediatric cancer care, we must consider which drugs to prioritise, how to develop them through global collaboration and novel trial designs, and how to measure success. The five-year survival rate for children's cancer has increased over eight-fold in 40 years. However, with improved treatments and supportive care, endpoints based on overall survival, disease-free survival, and progression-free survival do not fully describe treatment impacts such as secondary cancers resulting from initial therapy, or lifelong toxicities related to treatment. Now we must contemplate endpoints beyond simply survival. Endpoints need to be considered and chosen carefully. Years ago, emphasis was placed primarily on improvement of overall survival (OS), which alone would often lead to regulatory approval and insurance coverage. Now there are many more cancer agents that impact OS, so we need additional endpoints to help prioritise the right agent for the right indication. In addition, increases in the median overall survival, while good for patients, prolongs overall drug development time thereby reducing opportunity for uncovering drugs which are even more effective. While OS is the preferred standard for payers, if it is not used, the payers often insist upon a follow-up study to prove the link between OS and faster obtained endpoints such as progression-free survival (PFS), overall response rate (ORR), or another surrogate. When considering endpoints for future paediatric cancer trials, two main principles stand out: Firstly, endpoints that can be measured faster, and secondly, those endpoints that matter most to the patient and family. Faster Endpoints In 2018, the FDA granted accelerated drug approval for Amgen’s blinatumomab for paediatric and adult patients diagnosed with B-cell precursor acute lymphoblastic leukaemia in first or second complete remission. Efficacy was based on the primary endpoint of undetectable minimal residual disease (MRD) within one cycle of blinatumomab, and a secondary endpoint of haematological relapse free survival at 18 months1. Continued approval for the new indication was contingent upon verification of clinical benefit in subsequent, confirmatory trials. In January 2020, the FDA released Guidance for Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for the treatment of haematologic malignancies, and within it advised any sponsors considering planning a trial with such emerging endpoints meet with the FDA1. With the rapid advances in personalised medicine, we are increasingly able to distinguish forms of cancer in a way which was 22 Journal for Clinical Studies

barely conceivable a decade ago. The best-known example of this is breast cancer, for which 10 genes have now been identified, enabling better targeting of treatments. But breast cancer is one of our most prevalent cancers with, sadly, tens of thousands of patients diagnosed annually; conventional endpoints can reasonably be justified in such a setting. For paediatric cancers, we are not in the same situation. By definition, most paediatric cancers are rare, and gene profiling in many cases creates target populations which are too small to support conventional clinical trial models. In such cases, we may need to consider moving to the model used for gene therapy development: involving small (usually <30) numbers of subjects who are followed for five years, and an assessment is then made upon whether the treatment has been effective. However, we cannot abandon OS entirely, especially for those whose diagnosis offers no better survival rate or fewer toxic effects from chemotherapies than those for similar patients 20 or more years ago. For example, families with a child with diffuse intrinsic pontine glioma (DIPG), a uniformly fatal brain tumour of the brainstem, are seeking anything – really ANYTHING – which offers a better overall survival period greater than 18 months. A review of clinicaltrials.gov shows 96 studies addressing DIPG, 92 of them interventional. Of those, 32 are suspended, terminated, completed, or withdrawn; an additional five have status unknown. Of the 92 interventional trials, 49 are at Phase I or II. Historically, great emphasis has been placed on the overall survival timepoint of five years. However, although the five-year survival rate is currently nearly 85% for paediatric cancer3, many of those children relapse outside of the five-year mark, and there are too many others whose OS hasn't improved in years, such as those diagnosed with DIPG. What Matters to the Family In a high-level overview of five Phase I–III interventional paediatricincluded oncology trials on clinicaltrials.gov completed within the last four years or still running, researchers are including quality of life (QOL) input from patients and families. Two of the five random studies we identified included QOL patient-reported outcomes (PROs). The first looked at paediatric trials of progressive or refractory paediatric malignancies. The study compared metronomic therapy (low-dose oral chemotherapy) and standard of care with a placebo therapy and standard of care for paediatric patients with relapsed/refractory solid tumours4. The second study that included QOL was for those with the poorest stratification for their underlying germ cell tumour, which has an approximate 70% OS. This study is comparing accelerated therapy given every two weeks with standard therapy given every three weeks. Primary outcome is PFS, however secondary measurements are considering the patient and family's health-related quality of life and even treatment preference (assuming the two arms are equally effective)5. The other three trials which included recurrent or refractory ependymoma, novel therapy for relapsed or refractory tumours, or added therapy to already established standard of care therapy for those diagnosed Volume 13 Issue 4

Market Report

with some forms of high-risk leukaemia/lymphoma6 did not offer quality of life reported outcomes. The initial thought may be, well of course they are trying to raise the bar on overall survival of some tough diagnoses. But what if we do raise the bar and prolong OS and it is at a cost not acceptable to some or all of the patients and families? We'd then have no data to share with families when they ask – 'What will this treatment do to my son or daughter's, or my family's, quality of life now or in the future?' And consider this adult study in HR+/HER2 molecularly targeted therapy for advanced breast cancer: Badaoui and fellow researchers found that PROs for physical function were identified as prognostic factors for PFS in patients initiating abemaciclib. Specifically, higher patient PRO physical function could be an indicator for improved PFS7. Having more information like this could better guide families not only on future expectations but also the importance of good self-care. In an era when nearly 85% of childhood cancer survivors are living past the five-year OS mark, we are left to contemplate the ongoing needs of these patients: what can they look forward to, how can we support them, and – most importantly – can we reduce longterm risk for them? Children's Oncology Group (COG), the largest paediatric oncology consortium in the world, sets its goals not only to cure all children and adolescents with cancer and determine the cause and find ways to prevent childhood cancer, but also to reduce short- and long-term complications of cancer treatments. Their trials involve new and emerging treatments and supportive care measures and survivorship8. Nearly all children that survive cancer treatment will suffer some sort of late effect. Such effects can impact nearly any organ system to varying degrees and with differing www.journalforclinicalstudies.com

expectations depending on the subject’s age at, and specifics of, the treatment. In a recent article, researchers from Dana-Farber/ Boston Children's Cancer and Blood Disorders Center surveyed 95 parents of children with cancer and 41 physicians regarding five late effects of treatment: neurocognitive impairment, infertility, cardiac toxicity, second malignancies, and impaired growth and development. Avoidance of severe neurocognitive impairment was the predominant driver of parent and physician treatment preferences, even over an increased chance of cure, highlighting the importance of exploring parental late effects priorities when discussing treatment options9. There was a blog some years ago written by a mother whose teenage son had survived surgery, radiation, and chemotherapy for his high-grade brain tumour, who was left with the reality “…nobody prepared us for how difficult surviving a brain tumour would be for our son and our family.” Perhaps someday we can assume that with a lower disease burden or greater positive response to therapy, a patient's QOL or that of the caregiver, will improve, but that may not be possible until we are able to reduce if not eliminate entirely the toxic effects of the therapies we are giving to children. Closing With the RACE for Children Act there is no doubt a steep learning curve that all of industry will need to navigate over the coming months. When applying more molecularly targeted drugs to paediatric cancer therapies, we need to initiate the trials while fulfilling RACE for Children Act requirements. In many cases, an obvious approach is the inclusion of adolescents in adult trials. In Journal for Clinical Studies 23

Market Report such cases, what will the endpoints be? Should, or can, they be the same for adolescents and adults? Not only does a younger person have more years to lose by his or her diagnosis, but they also have more time for noticeable short- and long-term effects, as well as impact on their future should the trial be effective. Psychosocial, impacts on schooling, education, employment, living arrangements, and fertility all become more relevant. The blog from the mother mentioned earlier also highlights these impacts: Her son had dreamt his whole life of becoming a pilot, but because of severe neuropathies and significant learning challenges, he was no longer able to pursue his dream. In fact, due to the disruption and impact of his schooling, his employment options became very limited. Taken together, the condition and its treatment had resulted in the loss of control over his own future. This is another perspective from which we need to consider future therapies for our children diagnosed with cancer. The regulatory bodies undoubtedly place emphasis on the endpoints selected. The success of the trials and the future marketing of the product depend on solid, measurable outcomes. The authors of a recent publication evaluated 234 paediatric trials, with 171 distinct endpoints. The results of their analysis demonstrated that endpoint selection has an important impact on the outcome of a drug development programme. Two attributes of endpoints were identified as differentiating those trials that met their primary endpoint and were successful in obtaining paediatric labelling for the indication pursued compared to those that did not10. Those successful attributes were: 1. using an endpoint in a paediatric trial that was the same as the endpoint measure in the corresponding adult trial, and 2. having paediatric and adult patients enrolled in the same trial. In fact, the authors observed that incorporating unique endpoints into paediatric trials that differed from those measured in adult trials represented a risk factor for trial failure10. Sometimes, due to disease variability between paediatric and adult populations such as history, pathophysiology, or symptomatology, it may not be appropriate to include the same endpoints. However, in oncology when the biology and presenting history are comparable, similar endpoints should be heavily considered. It is said that change is the only constant, and the future of paediatric oncology drug development will certainly differ from what we know today. We need to find ways in which we can more rapidly ascertain whether a drug “works” in children, and we need to prioritise eliminating long-term impacts of medically successful treatment. We must contemplate the potential for personalised medicine to radically change clinical trial design. Much has been done – we have much more to do. REFERENCES 1.

3. 4.

FDA, United States Department of Health and Human Services Food and Drug Administration. FDA granted accelerated approval to blinatumomab for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. March 29, 2018. United States Department of Health and Human Services Food and Drug Administration. Regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment guidance for industry. January 2020. https://www.fda.gov/ media/134605/download www.curesearch.org/5-Year-Survival-Rate, visited on 05 Jun 2021. Pramanik, R. et al. Quality of Life in Paediatric Solid Tumours: A randomized Study of Metronomic Chemotherapy Versus Placebo. BMJ

24 Journal for Clinical Studies

Support. Palliat. Care. 2021, Jan 19: bmjspcare-2020-002731. Lawrence, N.J. et al. Protocol for the P3BEP trial (ANXUP1302): An International Randomised Phase 3 Trial of Accelerated Versus Standard BEP Chemotherapy for Adult and Paediatric Male and Female Patients with Intermediate and Poor-Risk Metastatic Germ Cell Tumours. BMC Cancer. 18, 854 (2018). 6. www.clinicaltrials.gov, visited on 05 Jun 2021. 7. Badaoui S. et al. Patient-Reported Outcomes Predict ProgressionFree Survival of Patients with Advanced Breast Cancer Treated with Abemaciclib. Oncologist. Published online April 29, 2021. Doi:10.1002/ onco.13806. 8. www.childrensoncologygroup.org/index.php/about, visited on 05 Jun 2021. 9. Greenzang, K.A. et al. Parental Considerations Regarding Cure and Late Effects for Children with Cancer. Pediatrics. May 2020, 145(5). DOI: https://doi.org/10.1542/peds.2019-3552. 10. Green, D.J. et al. Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA. J. Clin. Pharmacol. 2018 Jul; 58(7):885-890. DOI: https:// dx.doi.org/10.1002%2Fjcph.1109 5.

Melissa Hansen Melissa Hansen, MSN, APRN, PNP, Pediatric Strategy Liaison, Center for Pediatric Clinical Development at ICON, joined the company in 2019 as a paediatric strategy liaison. She has 25+ years of experience as a paediatric nurse practitioner, including 17+ years in paediatric haematology/ oncology providing care for infants through young adults diagnosed with haematologic and/or oncology conditions. Missy maintains her nursing certification in paediatric haematology/ oncology. Email: hansenmissy@prahs.com

Joanna L. Perkins Joanna L. Perkins, MD, MS, Director of Medical Affairs, Hematology-Oncology, ICON, joined the company in 2018 and serves as Director of Medical Affairs for Hematology-Oncology, Americas. Prior to joining ICON, Dr. Perkins was in clinical practice for 15 years with a focus on paediatric, adolescent and young adult leukaemias and lymphomas, and a clinical research focus on the long-term complications of childhood cancer treatment. Dr. Perkins is boardcertified in general paediatrics and in paediatric haematology and oncology. Email: perkinsjoanna@prahs.com

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

Volume 13 Issue 4

Corporate Profile

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

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

• •

• • • • • •

Medical Centre Ramus with Phase I Unit

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

• • • •

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

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

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

• • •

• •

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

, fast, correc t! Safe

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

Medical Diagnostic Laboratory Ramus Ltd

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

Ramus Medical Ltd Tu

to Cito

www.journalforclinicalstudies.com

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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 25 25

Market Report

Top 5 Innovations in Clinical Trials that are benefiting the Pharma Industry The current pace and scale of innovation that we are witnessing within the pharmaceutical industry has not been seen before. The speed at which COVID-19 vaccines have been developed is a testimony to the power of modern technology, scientific advancement, innovation, and collaboration across the industry. We are seeing a new age of innovation and experiencing significant transformation, for the better. The current pace and scale of innovation that we are witnessing within the pharmaceutical industry has not been seen before. The speed at which COVID-19 vaccines have been developed is a testimony to the power of modern technology, scientific advancement, innovation, and collaboration across the industry. We are seeing a new age of innovation and experiencing significant transformation, for the better. The pharmaceutical industry has evolved immensely over the last few centuries, starting with painkillers, Alkaloids, Antiseptics, Antibiotics (like Penicillin), small molecules through to more recent patient centric approaches such as Personalised Medicine, Gene Therapy, Antisense technology (primarily used so far to address rare diseases), mRNA technology, digital therapeutics, and App based treatments, to name but a few. We have witnessed greater innovation in the last two to three decades, thanks to programs such as the Human Genome project, which has led to the development of innovative new classes of medicines, with the exception of immunotherapies to treat underlying causes of diseases. In 2020, COVID-19 vaccines were developed in record time. Thanks to mRNA technology and a great collaborative effort by stakeholders from across the healthcare industry. Let us explore five of those key innovations that are benefiting Clinical Trials for the Pharma Industry. • • • • •

Digitisation of Clinical Trials Application of Data Science principles Real World Data (RWD) and Real World Evidence (RWE) Innovation in Standards Increased collaboration and partnership across Technology and Life science companies

1. Digitisation of Clinical Trials We are in an exciting phase of medical research, witnessing the Digitisation of Clinical Trials. Digitisation has helped reach required patient populations despite recent challenges owing to the COVID-19 pandemic, with patients and site personnel unable travel to clinical trial sites and hampering the progress of research. This is a significant shift in the traditional paradigm, where Clinical trials are taken to patients (Decentralised Clinical Trials (DCTs)/Virtual trials/Site-less trails/Hybrid Trials) through effective use of telemedicine, mobile applications, devices, sensors, eDiaries, 26 Journal for Clinical Studies

wearables, ePRO, eCOA, and other eSource technologies to collect necessary data remotely including eConsent, and other important elements of trial data. This shift has enabled patients to enrol in Clinical trials from anywhere and has greatly helped with patient recruitment, retention, and access to required patient pools. This is a great step towards patient-centric drug development and is, hopefully, here to stay post the COVID era. Drug development organisations, Pharma, Biotechs, and CROs have been quick to respond and have started showing great adaptation to digitisation. We are seeing teams working to update their clinical trial designs to enable successful virtual/hybrid trials, as well as updating internal processes, SOPs, and procedures in order to stay both up to date and relevant. “Digital Data collection methodologies (mobile technology, wearables, Electronic patient- reported outcomes (ePRO), Electronic Clinical Outcome Assessment (eCOA), etc.) have been instrumental, acting as game changers to enable robust data capture, improve the patient experience, reduce the burden on patients, and improve Data Quality in the era of COVID-19 and beyond” Global Regulators have extended their support to novel approaches and increased innovations through necessary inputs and guidelines. 2. Innovation in Standards Science comes to life through data. Data does not mean anything if you have to struggle to understand where it is located, how it is organized, or how to analyse it. One cannot harmonize anything or combine without standards. Standardisation helps in Data aggregation, accessibility, interoperability, reusability, and traceability. Ultimately, standardization helps regulators to focus on their scientific review and make patient centric decisions. What is needed is an endto-end data standardisation and integration strategy that considers all dimensions of clinical data. There are many Standards Development Organisations. When it comes to Clinical Trial Data Standards, CDISC (Clinical Data Interchange Standards Consortium) has played a significant role over the past two decades striving to achieve Data Quality (in order for us to trust the data to make credible and significant scientifically valid decisions) and also gain efficiency across Clinical Trial Data Life Cycle processing. CDISC standards are widely used across the biopharma industry and have become a requirement for data submissions to many Health Authorities (HAs). Originally focusing on common data domains in clinical trials (e.g. demographic information, adverse events, routine lab results, and subject status), CDISC has grown from PDFs to Machine readable standards, and from few safety domains to more Therapeutic Area specific standards (a great example of this is their COVID-19 guidelines). One of the strategic goals for CDISC to address in the coming years will be to “Develop multidimensional standards in an open, Volume 13 Issue 4

Market Report

transparent manner that allows community members to transition with as little disruption to their research as possible, while unlocking greater benefits of standardisation. Engage in concrete steps to achieve end-to-end standardisation.” Some of the initiatives in place to achieve this are: • • •

Another key strategic goal of CDISC is to expand and identify adjacent research areas that can benefit from data standardisation, i.e. with the evolution of the model, selectively extend CDISC standards to support new data types and/or new technologies.

• • • •

‘Mapping registry’, which standardises the conversion of proprietary device data to CDISC standards

•

HL7 and CDISC – CDISC is focused on Clinical trial Data standardisation, whereas Health Level 7 (HL7) standards focus on standards utilised in real-life healthcare services. With the advent of RWE or the inclusion of electronic health records in clinical trials, these two worlds now merger. With the publication of the Fast Healthcare Interoperability Resources (FHIR) draft standard, a paradigm change was introduced. The HL7 FHIR (Fast Healthcare Interoperability Resources) standard can serve as an interface between diverse Electronic Health Record (EHR) applications delivering RWD in support of RWE. Leveraging RWD, CDISC and other established and emerging standards (e.g. HL7-FHIR, BRIDG, OHDSI-OMOP, Sentinel, etc.) have the potential to transform the healthcare industry.

•

CDISC and Microsoft come together to plan the next generation CDISC Library: The next generation CDISC Library will provide machine-readable standards, standardised mapping to other data standards, and serve as a tool for community curation of standards that support data becoming accessible across geographies and disciplines, interoperable across systems and studies, and reusable for research today and tomorrow.

•

CDISC Partners with Gevity to Facilitate Use of Electronic Health Record Data in Clinical Research: The FHIR to CDISC project will leverage Fast Healthcare Interoperability Resources (FHIR), HL7’s standard for exchanging healthcare information electronically and CDISC’s standards for data collection (CDASH) and data tabulation (SDTM) to streamline the flow of data from EHRs to CDISC submission-ready datasets. The mapping and Implementation Guide will be available via the CDISC Library API (source of CDISC standards metadata).

CDISC 360 (to demonstrate the feasibility of standards-based metadata-driven automation across the end-to-end clinical research data life cycle) Evolve the expression of foundational conformance rules to an electronic format to increase consistency and instantiate multidimensional model artifacts in the CDISC Library. Initiate a process to build the model for machines first, people second. Commit to develop only end-to-end Therapeutic Area User Guides (TAUGs).

• • • •

•

Expertise in RWD/RWE Consumer wearables Medical devices Augment/replace patient-reported outcomes data from consumer wearables and/or medical devices Device registry, likely via collaboration, that uniquely identifies devices and enables automated mappings to CDISC standards CDISC-compliant registry toolkit that is built on the CDISC Library API

www.journalforclinicalstudies.com

Journal for Clinical Studies 27

Market Report

3. Application of Data Science principles Advances in technology (digitization) coupled with complexity in Clinical trials and acceleration of decentralized trials have necessitated the need to move to more advanced Clinical data science processes. Leveraging Big Data, Robotic Process Automation (RPA), Artificial Intelligence (AI), Machine Learning (ML), and Natural Language Processing (NLP) will help to unlock valuable new insights from our rich and diverse data. Some of the key technology enablers in new age Clinical trial management include: •

•

Adoption of AI based solutions like Clinical Data Management (CDM) Chatbots (intelligent virtual assistants) in Clinical Data Management. Based on ML, NLP, Voice recognition CDM chatbots can provide update on Study activities. For example: Ask a CDM Chatbot to “provide the counts of sites with more than 10 Serious Adverse events (SAE’s) reported on Study X”. RPA: RPA enables virtual robots to do predictable and repetitive human activities. For example: a Virtual Robot could be fed with details of external data reconciliation errors. The Virtual Robot could then login to the EDC with its own account (e.g. Login: CDM Robot) and post corresponding queries. The same technology could be applied to other simple CDM tasks. Virtual robots can become an unlimited virtual CDM workforce. Blockchain technology: Blockchain is a chain of interconnected blocks (i.e. data). Each block contains a time stamped and non-modifiable version of data. Blockchain can help establish a chain of digital trust between the patient, healthcare providers, and connected medical devices. Blockchain facilitates secure, real-time sharing of information within a trusted framework, preventing any misuse of medical or patients' personal data.

28 Journal for Clinical Studies

•

Managing Big Data: In terms of Data volume, we are moving from few datapoints per CRF to thousands, and millions of datapoints per patient, per week. In addition to EDC, we have data from multiple sources including RWD, biomarkers, genomics, imaging, video, sensors, and wearables (i.e. sequenced data), structured and unstructured data. Also, the speed at which the data is generated is near real-time, unlike eCRF data entered across days, weeks, and months. Data credibility and reliability plays an important role, with focus on what matters (i.e. critical to quality factor), riskbased data strategies, AI-driven automation of issue detection and resolution, and Fit-for-purpose solutions (scientifically plausible and strong enough to support reliability of trial results). RESTful Application Programming Interfaces (APIs) will provide interoperability between computer systems.

4. RWD and RWE RWD has the potential to provide answers to important questions. RWD may come from multiple sources including; EHRs, medical claims and billing activities, product and disease registries, patient-generated data (including in home-use settings), as well as data gathered from sources that can inform on health status, such as mobile devices. RWE is the clinical evidence regarding the usage and potential benefits, or risks of a medical product derived from the analysis of RWD. Global regulators, such as the US Food and Drug Administration (FDA), Japan’s Pharmaceutical and Medical Devices Agency (PMDA), the European Medicines Agency (EMA), India’s Central Drugs Standard Control Organisation (CDSCO), and China’s National Medical Products Agency (NMPA) are increasingly interested in leveraging the potential of RWD to complement randomised, controlled trials by providing insights into efficacy, safety, and postmarket surveillance as a means of supporting regulatory decision making across the product life cycle. Volume 13 Issue 4

Market Report Indeed, the US FDA is accepting observational data to support efficacy determinations, and the EMA is assessing the use of registry data for rare diseases. Case study for RWE using EHR Data: The PhUSE working group has demonstrated through a case study in 2019 that data typically collected in the real world (Ex. diabetes) studies can be extracted from medical records through FHIR resources and the process can be automated to populate eCRFs. They have developed a model and automated process to extract data from EHRs using FHIR resources and Application Programming Interfaces (API), and use this data as input for creating CDISC ADaM analysis datasets which, in turn, are used to generate analytics/reports. Case study for RWE using Clinical Trial Data: Bavencio® (Avelumab), a drug used to treat Merkel cell carcinoma, a rare and lethal form of skin cancer, provides an example of considering RWE for accelerated regulatory approval. Merck KGaA and Pfizer used RWE from a retrospective observational study to benchmark and contextualize results from their single-arm trial with respect to real-world outcomes in patients treated with chemotherapy. The FDA agreed that the trial efficacy and safety data presented in conjunction with RWE were sufficient to support Avelumab’s accelerated approval. As a result, Avelumab gained accelerated approval only 3 years after its Investigational New Drug (IND) filing, approximately 1.8 years shorter than the median for other drugs in expedited programs. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers’ confidence in evidence derived from RWD studies. 5. Increased collaboration and partnership across Technology and Life science companies The COVID-19 pandemic has triggered increased collaboration and partnership across the entire healthcare system from academic research institutions to life science companies, to hospitals, and health systems. A great example is how Pfizer collaborated with BioNTech (mRNA technology pioneer) and other Pharma companies in the manufacturing of their COVID-19 vaccine. This growing culture of collaboration in healthcare is starting to lead to partnerships, not only within life sciences, but also with other sectors, such as technology. For example: Boehringer Ingelheim is working closely with Google to apply the tech giant’s quantum computing expertise to pharma Research and Development (R&D). Technology can help streamline care and improve access to care. Technology enables data that was previously in siloes to be translated to insights that help to right disease. It can empower patients, caregivers, and providers to get the right information, at the right time, and improve decision-making, which leads to better outcomes. As we are witnessing many more collaborations and partnerships between big pharma giants and big technology companies, we certainly have exciting times ahead. Our hope is that these developments will further shorten drug development time to reach patients faster and save many more lives. www.journalforclinicalstudies.com

Summary Looking ahead, it is crucial for our industry to continue to work on priorities to prevent a possible future crisis (similar to COVID-19, or maybe much more challenging), enable patient centricity, maintain public trust, and save lives/prevent millions of deaths. We need to identify and encourage forward-looking ideas, facilitate innovations, bring them to life, and grow these ideas into potential solutions to save the precious lives of patients in need. Adoption of AI and ML technologies, RPA, Blockchain, using novel data collection instruments like wearables, sensors and eSource solutions, maximising the value of EDC, developing Intelligent CDMS to enable real-time, data-driven decision making are some of the technological aspects which need continued innovation. Patient safety and data integrity must be assured when dealing with technology. Innovation is needed in order to move away from any traditional inefficient processes and tools, towards efficient, simple, easy to implement, reliable, and cost-effective solutions. Collaboration across industry stakeholders is needed to develop better technology ecosystems and to agree on Validation and Regulatory benchmarks. REFERENCES 1.

Pharmaceutical Technology – “Collaboration not competition: is big pharma and big tech a recipe for success?” (https://www.pharmaceuticaltechnology.com/features/big-tech-big- pharma-collaboration-recipe-forsuccess/) 2. Nature Journal – “COVID has shown the power of science–industry collaboration” (https://www.nature.com/articles/d41586-021-01580-0) 3. SCDM (https://scdm.org/white-papers/) 4. PhUSE (https://phuse.global/Education) 5. CDISC a. https://www.cdisc.org/ b. https://www.cdisc.org/sites/default/files/resource/ CDISC_2019_2022_Strategic_Plan.pdf

Shrishaila Patil Shrishaila has done Masters in Biotechnology from Bangalore University & have more than 16 years of experience across Drug Development. He is currently working as Vice President at Navitas Data Sciences, the global Functional Service Provider of Navitas Life Sciences, heading the Statistical Programming Department, India. He is also working as "CDISC Volunteer" & “PhUSE India Membership” officer. He is also supporting “R Package Validation Framework” and “Open Source Technologies for Regulatory Submissions” Projects in PhUSE working group “Data Visualisation and Open Source Technology in Clinical Research (DVOST)”. He has authored an International book “FDA Clinical Outcome assessments and CDISC QRS supplements” under “Clinical disciplines” category with LAMBERT Academic Publishing group. He has exposure to various Analytical tools like SAS (Base and Advance Certified), R, PYTHON and CDMS Tools like Inform (EDC), Medidata Rave (EDC), Clintrial and Oracle Clinical LSH. He is a passionate Speaker & active in most of the conferences in the industry. His hobbies are Reading, playing Table tennis etc. Email: shrishaila.patil@navitaslifesciences.com

Journal for Clinical Studies 29

Therapeutics

Recent Advances and Future Challenges Using Biomarkers in Oncology Precision Medicine Introduction Current and future cancer treatment is expected to be shaped and guided by the use of biomarkers that will guide researchers and physicians at every stage of development from the basic understanding of cell transformation, to early cancer detection, to precision drug development, to long-term disease management. Historically, cancer treatment was empirical, driven mainly by the histology of the tumour and organs of origin, and how the average patient population responded to a treatment. Appreciation of pharmacologically tractable genetic lesions present in subpopulations of cancer patients was starting to be realised about 30 years ago. Demonstration of more and more exciting examples of lesion-specific targeted drugs effective in lesion–specific subpopulation of patients is becoming the norm in cancer therapy, as well as other therapeutic areas. The biopharmaceutical industry has also evolved their business model that historically assumed it should only develop drugs for “all comers,” even if they only worked for in a subset of patients. It was eventually realised that superior clinical outcomes justifies premium pricing, albeit restricted to a smaller sub-set of patients. In addition, it was quickly appreciated that many histologically different tumour types may also contain similar lesion-specific subpopulations that will expand the market size. Most importantly, significant benefits were also gained by collaterally avoiding treating patients that would likely only receive very marginal benefits, if any. This has decreased the size, time and cost of clinical trials yielding superior clinical results by avoiding treating patients that will have marginal benefits. This is the concept of Precision Medicine: choosing the right drug for the right patient at the right

dose. The foundation to enable this treatment strategy is having the companion diagnostic measuring a biomarker to identify/select the lesion-specific subpopulation of patients. The regulatory and 3rd party payer environments also evolved where companion diagnostics measuring specific biomarkers are fully integrated into the “label” of the drug, and reimbursement system appreciated the value of a companion biomarker to ensure the drug is being used selectively in the correct subpopulation of patients. This was coupled to the acceptance that premium was justified based upon superior clinical outcomes. Biomarkers and Precision Medicine Precision Medicine is now a routine therapeutic strategy where each cancer patient is screened for biomarkers to create a “cancer signature” that provides information to create a personalised treatment plan. Two figures below illustrate the shift in cancer care to a Precision Medicine approach using biomarkers: •

•

In 2005, personalised medicines associated with biomarkers in their respective labels, represented only five percent of the new molecular entities approved by the FDA. In 2019, the figure was 42 percent In 2000, only 15 percent of all oncology clinical trials involved the use of biomarkers. In 2018, this figure was 55 percent.

Figure #1 illustrated the broad applications that biomarkers have in oncology. 1.

Biomarkers have proved to be critically important as screening tools for the detection and diagnosis of cancer (i.e. screening for PSA levels to help detect prostate cancer) 2./3./4. Biomarkers have helped in our basic molecular understanding of cell transformation, resulting in the identification of new therapeutic targets and novel therapies directed at

Figure 1 Evolution and Broad Applications of Biomarkers in Oncology Precision Medicine 30 Journal for Clinical Studies

Volume 13 Issue 4

Therapeutics

these targets (i.e. breast cancer that express the estrogen receptor can justify the use of endocrine therapy) Biomarkers to drive efficiency and effectiveness of clinical trials in subject selection, enrichment and stratification.

Classification of Biomarkers Biomarkers are classified in a number of different formats. In the very broadest sense, there are 4 all-encompassing categories of biomarkers: predictive, prognostic, treatment and prevention subgroups. More times than not, a biomarker may fall into 2 or more subgroups. Predictive and Prognostic Biomarkers These terms have been utilised for many years with significant ambiguity and sometimes confusion associated with them. It is not uncommon that a specific biomarker may function as both a prognostic AND a predictive biomarker. •

•

Prognostic biomarkers are generally associated with the effects of patient or tumour characteristics on the patient outcome. Prognostic biomarkers facilitate cancer diagnosis, the assessment of the stage of the tumour and its potential malignancy, as well as the prognosis of disease remission. Hence, they help differentiate between patients with different outcome risks. Examples of a few prognostic biomarkers are: • presence of circulating tumour cells (CTCs) in blood, which leads to a poor prognosis; • Gene mutations whose products participate in DNA repair, such as BRCA1, BRCA2, ATM and P53 Predictive biomarkers are generally associated with the effect of treatment on the tumour and how a tumour may respond to a specific treatment. Predictive biomarkers help optimise therapy decisions by matching targeted therapies with the right patients, thereby increasing the likelihood of a response.

Integrated and Integral Biomarkers Another classification system for biomarkers are integrated and integral, terms that are increasingly used to describe the role of a biomarker in a clinical trial setting. •

•

Integral Biomarkers – Integral biomarkers are defined as biomarker that must be performed to enable the clinical study to be conducted or to enable the primary analysis or endpoint of the study. These biomarkers are essential to the conduct of the clinical study and will be performed on every study subject entered into the trial. They are likely to be part of the inclusion / exclusion criteria for patient randomisation into a trial, or what arm a patient is randomised to, or a measurement of a primary endpoint of the study. As such, integral biomarkers most likely have been extensively validated from previous investigations. Finally, if the study is a success, it is likely that the integral biomarker will become an essential part of the drug label which describes it proper use in clinical practice. Integrated Biomarkers – Integrated biomarkers test a specific hypothesis and are incorporated into a trial mainly to validate the biomarkers, confirm a hypothesis and have an associated prospective statistical plan to support confirmation of the hypothesis. By definition, integrated biomarker determinations are not associated with patient eligibility for the trial (not in the inclusion / exclusion criteria), not associated with subject assignment to treatment arms, not associated with treatment management and not associated with the analysis of the primary endpoints of the trial. The expectation is that integrated biomarkers may become an integral biomarker for a future trial. While integral biomarkers are likely to be associated with the

www.journalforclinicalstudies.com

primary objective of the study, integrated biomarkers are likely to be associated with the secondary objective of the clinical study. Impact of Multiplex Genotyping Technologies and Next-Generation Sequencing The first generation, real world use of biomarkers was typically binary and qualitative in nature. There was a one-to-one relationship between the presence of a lesion-specific biomarker and the use of a lesion-specific targeted therapy. The relationship was usually qualitative, not quantitative. If the lesion could be detected, then treat with that lesion-specific drug3. 1. The complexity has evolved to involve the interaction of multiple biomarkers assessing multiple molecular pathways, where the interactions are more accurately defined as a complex, quantitative algorithm that changes over time reflecting how the tumour becomes refractory or resistant. This complexity has necessitated the use of high-throughput technologies to assess many or all lesions in cancer cells, such as use of microarrays, next-generation sequencing, and mass spectrometry. Hundreds to thousands of markers can be multiplexed or sequenced to identify the unique lesion- signature in that specific patient and the algorithms on how best to intervene based upon the specific lesion-signature. Most importantly, there is a growing number of trials exploring pan-tumour biomarkers, such as microsatellite instability (MSI) and the NTRK gene family of receptor kinases that help regulate cell signalling. These “tumour type agnostic” biomarkers have justified the tumour agnostic approvals for such agents as pembrolizumab (MSI) and larotrectinib and entrectinib (NTRK). Paradoxical necessity of including marker-negative patients in clinical trials From a precision medicine perspective, it is very logical to prospectively exclude patients anticipated to fall into the biomarkernegative, non-responder subpopulation of patients. This is the theoretical premise of precision medicine. However, the fact that biomarkers can identify a more responsive, a more optimal patient population does not necessarily indicate that no benefit exists for the marker-negative remaining population. Significant value is generated on data in the non-selected, markernegative population to determine whether that population responds less well or indeed does not respond at all. Hence, the drug non-responders subpopulation can provide significant valuable information, despite being routinely excluded in study designs. Marker-negative populations have been included in efficacy studies utilising clinical design strategies - include a broad range of patients, including marker-negative subpopulations but prospectively designed to evaluate in its primary endpoint analysis in the enriched population subset. Stratify analysis on subpopulations. The feasibility of including marker-negative subpopulations is increased when there are early read-outs of efficacy or Proof of Mechanism allowing for an early cross-over to other therapies for the non-marker subpopulation. It is important to remember that a drug’s efficacy in nonresponders is crucial for risk-benefit assessments. Non-responders also give critical information on whether drugs from another pharmacologic class can be useful in previously unresponsive patients.2 It is also important to note that evaluation of drug efficacy in marker-negative populations can also help determine the degree of precision used to define marker positivity.2 Journal for Clinical Studies 31

Therapeutics Impact Impact on Key Stakeholders •

•

The physicians – helping the physician diagnose a lesionspecific subpopulation of patients, gain insights on prognosis, select the most appropriate treatment course, avoid marginally active treatment regimens and to be able to better assess efficacy and relapse. Biopharmaceutical companies. Deeper understanding of the molecular lesions causing tumour initiation and maintenance have been essential in developing more selective targeted therapies to enable more precision treatment options. Diagnostic companies – the role of companion diagnostics has been recognised as an equally essential component to the implementation of precision medicine. This appreciation extends to 3rd party payers where significant value is created in treating the right subpopulation of patients and not treating non-optimal subpopulations of patients. 3rd Party Payers - Third party payers have a clear incentive to evolve reimbursement mechanisms that help control costs without withholding potentially beneficial new medicines from patients. A major driver for cost containment should focus on ensuring the right oncology drug is selectively used in the right patient population, while incentivising that the drug is not used in patients with little hope of clinical benefit. Traditionally, bio-pharmaceutical companies were paid based upon units sold. Once regulatory approval for marketing is obtained, revenue is predominantly based upon volume, not how well the drug works in the indicated patient population in a real-world setting. More and more biopharmaceutical companies and payers are now partnering to make drug cost re-imbursements predicated on drug performance based upon a prospectively agreed clinical metrics. This shift is transitioning from a Volume Metric to a Value Metric, based upon clinical outcomes. In many cases, there are agreements between third party payers with drug companies that the drug company will be reimbursed at a set price, provided the drug meets or exceeds a clinical value metric. This is a Pay for Performance financial model. Importantly it incentivises the pharma company to develop, deploy and educate physicians on predictive biomarkers to ensure the drug is used in the correct subpopulation. It also incentivises the drug companies to educate physicians on: 1. 2.

•

in the current treatment of many cancer types, as an abbreviated illustration in the table below: Tumor Type

Biomarkers Impacting Precision Medicine Treatment decisions

Non-small cell lung cancer (NSCLC)

Epidermal growth factor receptor (EGFR) Excision repair-cross complementation group (ERCC) K-ras gene (usually mutation at position 13) Thymidylate synthase (TS) Rribonucleotide reductase (RRM 1)

gefitinib erlotinib Ras Raf, Mek Erk drug pathway platinum compounds

Melanoma

Braf

vemurafinib dabrafinib

Breast

ER PR HER2/neu (Erb-B2) BRAC-1/2

tamoxifen aromatase inhibitors fulvestrant olaparib trastuzumabt

Colorectal cancer (CRC)

EGFR K-ras B-raf UGT 1A1

imatinib cetuximab panitumumab

Chronic Myeloid leukemia (CML)

BCR-Abl

imatinib dasatinib nilotinib bosutinib ponatinib

Many solid Tumors

PD-1 PD-L1

pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab.

Additional targeted therapies will continue to be developed that specifically address targets in subpopulations of patients. However, as the field of precision medicine and biomarkers continues to advance, additional challenges will need to be addressed: •

avoiding treatment of inappropriate subpopulations of patients importance of compliance

The Patient – Most importantly, the cancer patient – for the patient, their treatment strategy is rapidly shifting from empiric in nature to mechanism-based - utilising biomarkerdriven treatment decisions. The overall objective is to ensure the correct patient is being treated with the right drug at the right dose for the right period of time. All being driven by utilising biomarkers for diagnosis, prognosis, treatment selection and response determination. Most importantly, not wasting valuable time by treating patients with drugs that will have marginal effects, instead of being treated with alternative therapies.

Future Challenges Biomarkers and Precision Medicine have had a tremendous impact 32 Journal for Clinical Studies

Multi-factorial, non-binary relationships – in the simplest situation, the relationship between a lesion and a targeted therapy is binary. Lesion positive (i.e. BRAF V600E mutation) indicates drug treatment (i.e. vemurafinib). However in most cases the clinical situation is much more complex, involving a multiple of potentially interacting lesions. This is where both: •

Multiplex genotyping technology platforms including NGS that can detect mutations, amplifications and rearrangements will be required

•

Coupled to complex AI driven algorithms needed to drive treatment decisions

•

Resistance – cancer cells can become resistant to targeted therapies, either the target itself can change and become less responsive to the drug or the tumour finds a new pathway to achieve growth that does not depend on the target. As we have found with anti-viral therapy, using synergistic combination therapy prior to resistance emerging may provide the best strategy to decrease emergence of resistance.

•

Temporal relationships – going forward, we need a much better understanding of how multiple lesions are related to initiation of tumour growth verse maintenance of the transformed phenotype and how this affects the tumour over time. Volume 13 Issue 4

Therapeutics

Non-drugable targets – finally biomarkers have identified targets present in recalcitrant tumours, like pancreatic tumours, but these markers have proved to be very difficult drug targets. An example of this is mutations found in the Ras gene. To date, Ras has proved to be very challenging in regard to drug target using the traditional way we have approached this. New and innovative technologies will need to be developed to overcome the challenge presented by Ras. REFERENCES 1. The Evolution Of Biomarker Use In Clinical Trials For Cancer Treatments; Personalized Medicine Coalition; www.PersonalizedMedicineC1710 Rhode Island Ave NW, Washington, DC 20036 2. FDA. Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products Guidance for Industry. March 2019. FDA-2012-D-1145 3. Li, T, Kung,HJ, Mack, PC, et.al., JClin Oncol 2013; 31 (8) 1039-1049. www.journalforclinicalstudies.com

Brian Huber Brian Huber, PhD is a leader in the Biopharmaceutical Drug Development, CRO Service and Investment Sectors, with over 35 years’ experience. His current position is the Vice President of Therapeutic Areas, Drug Development and Consulting at ICON. Dr. Huber’s experiences include VP & Managing Director at Quintiles/IQVIA; Global VP in Drug Discovery at GSK, CEO of Shionogi/GW Pharmaceutical Inc.; Director of Oncology at Burroughs Wellcome and Senior staff fellow at the National Cancer Institute, NIH, in Bethesda, MD. Dr Huber has 11 issued patents, 65 publications in peer-reviewed journals and a number of books and book chapters. Email: brian.huber@iconplc.com

Journal for Clinical Studies 33

Technology

Expediting Clinical Trials with Cloud-based Metadata Repository and Study Automation Technologies The COVID-19 pandemic put clinical trials firmly in the spotlight. Powered by the urgent need to combat this global threat, clinical trials have been created and conducted at an astonishing rate. At the time of writing, over 9,400 clinical trials had been submitted to the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)1. By challenging the traditional view on the structure and format of clinical trials and applying the Clinical Data Interchange Standards Consortium (CDISC) requirements, pharmaceutical, biotechnology and contract research organisations (CROs) have expedited trial timescales. Study automation platforms and nextgeneration, cloud-based clinical metadata repositories (CMDRs) have been at the centre of these changes, standardising and reusing metadata and automating manual and error-prone study builds. The learnings from the COVID-19 response are reinforcing the need for strategic change in clinical trial design and the generation of submissible metadata for regulatory approval. This article discusses how study automation platforms and all-in-one, cloudbased CMDRs can help organisations start trials quicker, deliver rapid insights and streamline regulatory approval. The Need for Speed in Clinical Trials The success of a pharmaceutical or biotechnology organisation rests on its ability to bring new therapies to market, and this, in turn, puts mounting pressure on businesses to push clinical studies through the pipeline faster and more cost-effectively. For contract research organisations (CROs), efficiency is everything and time is literally money; yet, for all companies, this focus on speed must not come at the cost of patient safety or robust efficacy evidence. For too long, fragmented internal processes, legacy systems and metadata siloes have created bottlenecks in clinical trial design and execution. Manual workflows and disconnected worksheets introduce transcription errors and repetitive work leads to delays. When metadata rules are reinvented for each project, the risk of inconsistencies increases, and trials don’t amass the knowledge or successes of previous trials. This lack of standardisation means extensive and expensive metadata rework before regulatory submission, adding further delays and costs. Although there are many technologies available to alleviate these problems, they are limited in scope and often aimed at individual issues, such as standards management, study design or data conversion automation. When solutions operate in siloes, disconnects restrict returns and organisations, overwhelmed by the potential risks, choose the path of inactivity. Only a holistic approach to metadata management and automated trial design can deliver the benefits needed to drive strategic change and maximise returns throughout the clinical trial process. 34 Journal for Clinical Studies

Viewing Standardisation as a Strategic Tool Since regulatory approval is reliant on the diligent evaluation of data, regulatory bodies, such as the Food and Drug Administration (FDA), stipulate data standardisation requirements in order to receive, process, review and archive submissions effectively. To begin to address metadata inconsistencies, CDISC2 was created, in collaboration with the FDA, to drive interoperability through data standardisation and accelerate the design, build, analysis and submission of clinical trials (see Figure 1). The items within the data tabulation and data analysis sections are regulatory requirements and refer to the standardisation of the structure and format of submissible data, including: • • • • •

Standard for Exchange of Non-clinical Data (SEND) – the content and structure of non-clinical data collected in a clinical trial, structured for submission. Study Data Tabulation Model (SDTM) – the content and structure of the data collected in a clinical trial, structured for submission. Analysis Data Model (ADaM) – the content and structure of the analysis datasets generated from SDTM data. Define XML – the metadata format used to describe the content and structure of the SEND, SDTM and ADaM datasets. NCI terminology3 – the consistent language used to make all terms in collected data clear.

Figure 1: CDISC standards model.

CDISC standards, implemented in the planning and data collection stages, are not regulatory requirements. Rather they’re integrative tools, defining the studies in common terms and creating the case report forms (CRFs) that are used to collect standardised data. Too often, organisations focus on the regulatory elements of CDISC, like a compliance afterthought or a tick-box exercise, rather than seeing it as a strategic tool to streamline the process and deliver efficiencies. By not incorporating CDISC standards into the process, compliance can cause considerable costs and delays as data managers rework data to meet the standards. Put simply, organisations feel the pain of compliance without reaping the rewards. When CDISC is viewed as the strategic tool that it was intended to be, clinical data teams can refocus trials, maximise Volume 13 Issue 4

Technology efficiencies by optimising system integration, and create preapproved data collection instruments that deliver automated, standardised data.

•

By automating the creation of submissible data, early safety views can be taken and in-trial adjustments made, allowing trials to become more flexible and adaptive. Standardisation becomes the central control, enabling organisations to focus on the real purpose of clinical trials: to bring life-saving therapies to people who need them in a faster and more cost-effective way.

•

The Power of All-in-one, Cloud-based CMDRs Although standards governance has been evolving over the past two decades, organisations have only recently started to see its value. And while technology has also evolved to keep pace, adoption is in its infancy. But attitudes are changing. If organisations are ready to transform and embrace standardisation as a tool for profound and long-lasting strategic change, then CMDRs and study automation technologies will become essential for effective and efficient clinical trial design, collection and analysis. An MDR creates a central hub for clinical trial metadata. It is a core, single-source-of-truth where forms, annotations, terminologies, datasets and much more are stored and can be accessed, anytime and anywhere by all who have the necessary permissions. Firstly, this secure bank allows visibility of all historic and current metadata, providing the information needed to build and conduct clinical trials in the most automated way, reusing content and decreasing the time and effort needed. Secondly, by having standards builtin and updated as new versions are released, the MDR ensures all stakeholders have access to compliant metadata that meets the needs of the current governance and requirements of regulatory bodies. Finally, the MDR provides a place for collaboration and controlled change management for future studies (see Figure 2).

• •

• • •

Cloud-based – with no need for server space, infrastructure or inconvenient upgrade cycles. Cloud-based systems are accessible from any location and can be built to give a personalised view based on user permissions. Control-based – an MDR must be the single-source-of-truth. Changes can only be made if they have been submitted and approved. Standardised – built-in templates, assets and data are automatically created in accordance with CDISC standards, with no rework. Configurable – to accelerate the construction of eCRFs and maximise the reuse of metadata, MDRs must be shaped to meet organisational structure and workflows. They can also be configured to generate existing specification formats, reducing the amount of retraining needed. Compliant – MDRs should be updated when new standards are released. Proposed changes should be mapped, showing owners the impact of new versions and facilitating migration to them. Analytical – when a metadata change is requested, its impact should be modelled across the system, allowing for subjective and evidence-based decision-making. Connectivity-driven – plug-ins can join the MDR to external systems to exchange data instantly.

MDRs Provide the Basis for Traceability, Consistency and Compliance By integrating CDISC standards and installing an all-in-one, cloudbased CMDR, organisations can maximise strategic empowerment. Improving the consistency, storage and compliance of metadata leads to quality enhancements and increased efficiencies within the clinical trial process. When reuse increases, processes become more streamlined and trial design and execution time decreases. High-quality, accurate metadata can become the basis for fast, rightfirst-time eCRF design before electronic data capture (EDC) system creation. The eCRF can be viewed and interrogated before the timeintensive EDC creation takes place. Some MDRs will allow EDC creation directly from the study specification, which further reduces the design time by removing manual builds and transcription errors. Investing in a cloud-based CMDR that enables eCRF creation for multiple EDCs further improves its usefulness and accommodates the nuances of differing trials. MDRs that combine study design automation with standardised data collection and analysis maximise their usefulness and return on investment (ROI). When standardised data is specified during trial design stages, it is created in a ready-to-submit format, allowing early views that can highlight any issues. Subsequently, with prompt intrial adjustment and early regulatory submission, drug development timescales can be dramatically reduced. By standardising metadata and automating trial builds and generation of submissible data, allin-one, cloud-based CMDRs can deliver faster, more accurate and more cost-effective trials.

Figure 2: An MDR system facilitates visibility, governance and collaboration.

MDRs have advanced with standardisation and can now deliver a holistic approach to metadata storage, control and automated trial design. A robust and effective CMDR will be: •

Fully integrated – built as an all-in-one software suite, removing the previously siloed approach to metadata construction, storage and transfer.

www.journalforclinicalstudies.com

Making Changes Now for the Long Term Despite the clear benefits offered by all-in-one, cloud-based CMDRs, the adoption of this technology has been lagging. Whether small or large, pharmaceutical, biotechnology and contract research organisations often evolve organically, absorbing expertise, workflows and even other businesses as they move through a changing medical landscape. The task of assimilating large, siloed datasets and manual processes is not to be underestimated, and the complexity of legacy systems can certainly add to the burden. However, the short-term benefits of inertia are quickly outweighed by the burden of continuing to use manually intensive and error-prone workflows. As clinical trials increase in number and as organisations respond to the needs Journal for Clinical Studies 35

Technology of a growing and ageing population, agility, speed, and cost will be key success factors in study design and operation, directly correlated to the ability of an organisation to increase its suite of marketable therapies.

heart of trial design, companies were able to gain rapid insights and adapt accordingly, dramatically reducing the time needed to bring vaccines to market.

Next-generation MDRs have certainly accommodated the valid concerns raised around integration, and have been designed to minimise the effort needed. Some MDRs offer seamless integration with existing platforms, and many feature application programming interfaces (APIs) and plug-ins to provide safe and secure data flow (see Figure 3).

Building All-in-one, Cloud-based CMDRs for the Future All-in-one, cloud-based CMDRs provide the stable foundation to deliver the strategic change that drives faster, more accurate and more cost-effective clinical trials. MDRs were created to integrate siloed systems and allow disparate users to create, view and consume metadata. And APIs are the tools through which this happens. Platform developers are already working on the technology that will deliver the clinical trials of the future, using the considerable knowledge amassed in the past few years. Automation is already supported by using data from external systems to trigger SDTM conversions, and returning generated datasets to the original system. APIs in external systems can also be used to push or pull data between platforms, using live data from EDCs to automate SDTM conversions throughout the trial lifecycle. As third-party solutions extract insight and APIs continue to feed metadata and data, more control and automation can be generated through the MDR. The CDISC 360 project4 is now looking to build on existing standards to drive end-to-end, metadata-driven automation and derive maximum ROI throughout studies.

Figure 3: The integration of all-in-one, cloud-based clinical MDRs with existing technology through the use of APIs.

The key driver behind MDR integration is to build a space for users to create, view and consume metadata. When MDRs are integrated with existing technology, they can be brought online quickly with minimal user training; with a staged approach to integration, stakeholders are aligned. Each benefit, such as data standardisation or EDC build integration, can be fully realised before moving to the next. With a focus on usability, MDRs can quickly realise their full potential and deliver fast ROI, sometimes within just a couple of trials. This short-term investment generates long-term wins as MDRs and study automation technology evolve and grow with the business, further improving clinical trial efficiencies and directly impacting clinical trial successes and regulatory approval rates. COVID-19 Vaccine Development: A Cloud-based CMDR Success Story Although the ability to automate standardised data collection came before the COVID-19 pandemic, the need to develop therapies at an unprecedented speed brought its usefulness into the spotlight. All-in-one, cloud-based CMDRs and study automation platform technologies have been used in several high-profile COVID-19 studies. MDRs were used to create eCRFs during trial design, for rapid review and approval, while also simplifying and expediting the build of multiple EDCs directly from the study specification. This process saw numerous studies get underway within weeks of vaccine development. However, in the race to reduce the typical 10-year development timeline, early indicators of trial success and accelerated approval were critical. Programmes began to release Phase I/II data as early as July and August 2020, and this was due in part to the rapid conversion of raw data to submissible SDTM files. The dynamic nature of these studies meant that metadata changes were frequent. Many trials began to deliver daily data to sponsors, enabling an early safety and efficacy picture to emerge and facilitating expedited approval. This rolling review of trial progression relied heavily on standardised data; when this was incorporated at the 36 Journal for Clinical Studies

Already, clinical trials are starting to make use of non-traditional, real-world metadata, such as that collected through wearable devices and patient-generated responses. As organisations make use of this real-world, less structured and semantically rich information, metadata standardisation will be ever more important for regulatory approval. As researchers extract real-world meaning from clinical trials, MDRs will be critical tools in the quest to structure, control, organise and extract these insights. Investment in all-in-one, cloud-based CMDRs already brings immediate benefits: faster ROI, expedited trials, more costeffective programmes and more accurate clinical data. But it is the wider and longer-lasting strategic benefits that will generate a competitive edge as organisations develop the clinical trials of the future. Investing in future-proofed technology that delivers both short-term and strategic benefits will ensure that organisations are prepared for the changes that will come. REFERENCES 1. 2. 3. 4.

https://www.who.int/clinical-trials-registry-platform, visited on 30 April 2021. https://www.cdisc.org/, visited on 2 May 2021. https://ncit.nci.nih.gov/ncitbrowser/, visited on 30 April 2021. https://www.cdisc.org/cdisc-360, visited on 2 May 2021.

Kevin Burges Kevin Burges, Head of Product Management at Formedix. In his 20 years at Formedix, CDISC has been a core focus for Kevin. He was a founding member of the CDISC XML Technologies Governance team, and helped drive the future technical direction of CDISC standards. Today, Kevin is a member of the Data Exchange Standards team, which includes ODM, Dataset XML and Define XML, and he works closely with customers to enhance the ryze platform and develop new features. Email: wecanhelp@formedix.com

Volume 13 Issue 4

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info@Astell.com +44 Journal (0)20 8309Studies 2031 for Clinical 37

Technology

Digital Adherence: Modern Solutions to an Age-old Problem Despite spiralling drug development costs and timelines spawning industry-wide efficiency drives, tackling the multibillion-dollar problem of adherence has remained an untapped opportunity – until now. Advances in digital technologies are ushering in a new dawn in clinical trial adherence, promising to save time and money while improving patient experience and safety. Solutions such as connected smart packaging and data analytics are more accurate, more efficient, and more robust than traditional methods of compliance monitoring, such as pill counts, blood sampling, or self-reporting. We take a look at the scale and impact of the problem, why traditional methods of monitoring are not up to the job, and how organisations are using digital technologies to finally overcome the age-old problem of adherence in clinical trials. The Problem It can take between 10 and 12 years and on average $1 billion to develop a new drug,1 with much of the cost driven by the number of patients needed to establish a treatment effect.2 Studies have shown that every Phase III trial participant is responsible for an average of $42,000 in costs.3 However, 30% are nonadherent, meaning they do not take the investigational product as set out in the study protocol, by day 100.4 Across all clinical trial phases, 50% of participants admit to not complying to the dosing schedule as directed.5 The consequences in terms of costs and timelines, not to mention patient safety, can be significant. “Medication adherence in drug trials is suboptimal, affecting the quality of these studies and adding significant costs. Non-adherence in this setting can lead to null findings, unduly large sample sizes and the need for dose modification after a drug has been approved,” said a paper published in the British Journal of Pharmacology last year.5 It can, for example, drain study power, and, with it, the probability of detecting a product’s true effect. Accurately calculating the statistical power of a study increases the chances of success, enables more informed go/no go decisions, and shortens the time to market. It’s a complex equation that involves the effect size of the drug, the variability in response, and, crucially, the sample size, which must be large enough to show the maximum effect size with the lowest variability. When subjects do not take their medication as directed, however, this decreases effect size, increases variability, and drains study power – to maintain that power, any decrease in adherence must be met with an expensive increase in study participants. 38 Journal for Clinical Studies

A typical Phase III study will last for one year and cover 50 sites; it will include 850 participants on a four-month follow-up – and will experience 20% non-adherence.7 In such an example, an additional 425 subjects would be needed to compensate for the associated drop in study power through increasing sample size. Aside from the direct participant costs of more than $18million, such an undertaking would delay the time to close the study, lengthening time to commercialisation and resulting in an important loss of revenue. In breakthrough drugs and rare disease products, strong early data can act as causal proof of concept, as well as enable the faster detection of adverse events. This information can be invaluable in making go/ stop decisions, but poor adherence will sully the integrity of the data, rendering it useless. Safety is paramount in any clinical trial, but poor adherence can lead to the underestimation of efficacy during the study. In turn, this can result in higher than necessary post-marketing dosing recommendations, and more frequent AEs. Adherence-informed drug trials, on the other hand, support the faster selection of the most appropriate dosing regimen, which is currently a leading cause of regulatory approval delay.6 Barriers to medication adherence, which might be intentional or non-intentional, are multiple. The problem might be related to the therapy, the condition, or to the patient themselves. It could stem from the relationship between the person and their research team, or a lack of understanding of the protocol. Whatever the reason, with traditional methods, poor adherence in clinical trials often goes undetected. “This can adversely influence the results of drug development, especially for treatments that have a narrow therapeutic window,” said a 2017 paper in Nature Reviews Drug Discovery.5 “However, regulators and drug companies have turned a blind eye to the crucial importance of patient adherence and are reluctant to acknowledge its importance in clinical trials, often hiding behind the use of intention to treat (ITT) analysis of data, which masks the problem.” Traditional Methods While the financial and practical implications of the adherence problem are wide-ranging, they are nothing new. Sponsors and CROs have grappled with these issues for decades, relying on methods such as pill counts, blood sampling, and HCP or self-reporting to monitor adherence. However, there is a growing body of data to suggest that these traditional approaches are simply not sensitive enough to provide real value. Counting returned tablets is the most commonly used adherence measure in clinical trials, but it is easily censored by participants.7 What’s more, it only provides a summary of medication taking behaviour between visits, rather than an overall understanding of treatment initiation and dosing patterns. Volume 13 Issue 4

Technology

Trial organisers may also opt for the self-reporting approach, with many asking participants to record their doses in a patient diary or conducting study exit interviews, for example. This method is not only intrinsically open to inaccuracies and bias, but it places additional burdens on the study participants. The same is true of asking site staff or healthcare professionals to record adherence. Monitoring drug or drug metabolites in blood, urine, or hair may seem a more evidence-based approach, but, again, it only provides a snapshot. Participants could engage, for example, in so-called “white coat adherence”, meaning they only take the investigational product the day before the visit. In addition, it is invasive, places additional burden on participants and staff, and is largely restricted to use in the active arms of a trial. Pill counts are a relic of primitive efforts to account for the disposition of the drugs being tested for efficacy and safety in randomised clinical trials, but they have been thoroughly discredited by methodologic advances, starting in 1989 by Pullar and repeatedly brought to light over the years by electronic monitoring.7 It is widely accepted that traditional methods are, at best, imperfect. But, until relativity recently, sponsors and CROs have had little option. Now, digital technologies have the potential to transform the landscape. In fact, studies have shown smart packaging monitoring to be 97% accurate. That’s compared to 70% for biological markers, 60% for pill count, 50% for HCP rating, and just 27% for participant self-report. www.journalforclinicalstudies.com

What is Digital Adherence Monitoring? Electronic monitoring is the most objective and precise way to fully understand medication adherence during a clinical trial. It consists of smart drug packaging, such as connected inhalers, blister packs, and container caps, and powerful data analytics. microcircuitry in the packaging records dose administration and transmits that information to the study team’s software for analysis. Connected pre-filled syringes, for example, collect and send essential information such as whether the injection was completed, the time and date of administration, type of drug, batch number, and expiration date. Once received, a cloud-based platform uses sophisticated algorithms to analyse medication-taking behaviours, and flag any erratic dosing patterns in the form of data visualisations. This technology allows site staff to identify those participants who may be at risk of poor adherence and take tailored action – whether that is more education on the protocol, offering tips on how to remember doses, or advice on managing side-effects. In essence, it is a closed feedback loop in which the packaging monitors, and the study team uses the resulting data to manage adherence. The data can also be integrated into third-party applications, such as patient-facing apps designed to build engagement and encourage adherence. Some systems feature onboarding screens to ensure participants have all the information they need to start and continue Journal for Clinical Studies 39

Technology

to follow the trial protocol. This might include dosing regimens, device use instructions, and information on the importance of adherence, as well as advice on developing strong medication intake behaviour.

And with the advent of evidence-based, proven innovations such as connected smart packaging and data analytics, doing just that is, finally, a possibility.

Throughout the trial, people can use the app to view their scheduled appointments, reminders, and medication history, transfer their data to the central system, and access the site team.

REFERENCES

This advanced approach is a feasible, reliable, and easily implemented method of quantifying medication adherence. It is continuous, so it provides an overall picture, and non-invasive, placing no additional burden on staff or participants. Maximising Return on Investment Digital adherence monitoring technologies can cost as little as $1 a day but can improve adherence to medication during clinical trials by up to 50%.9 More and more organisations are finding that this approach can help extract every drop of power from a study, thus reducing time to market, and increasing return on investment. AARDEX’s solutions alone have been used in 200-plus Phase II/III trials, and in research settings spanning more than 1 million study participants. Market-leading adherence management systems enable sponsors and CROs to measure and manage medication adherence throughout a trial. And at less than 1% of the cost of a trial, they are significantly less expensive, increasing sample size to compensate for adherence-driven dips in study power. Additionally, these systems improve data quality and integrity, support evidence-based risk mitigation strategies, and ensure compliance with FDA and ICH guidelines. They also give drug developers an insight into how their products are used “in real life”, providing behavioural data that can be utilised in the design of successful marketing strategies. Ultimately, for less than 1% of the trial cost, digital medication adherence management gives sponsors and CROs confidence in their data. It removes the adherence-related data quality issues that have been increasing study duration, delaying time to market, and decreasing return on investment, for decades. Win/Win According to Eliasson et al., addressing the adherence issue will benefit everyone involved. “For drug developers, it is likely to be more costeffective to identify and manage non-informative data or use trial enrichment strategies to increase study power than to manage the effect of non-adherence by increasing sample size. Patients stand to benefit from safer and more effective dosing regimens, which have been established based on adherence-informed results,” said the authors.5 40 Journal for Clinical Studies

7. 8.

Greener, M. Drug development: bench to bedside. (2013) https://www. magonlinelibrary.com/doi/abs/10.12968/npre.2010.8.2.46589 visited on 19 May 2021. Moore, T., Heyward, J. et al. Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015– 2017: A cross-sectional study. (2020). https://bmjopen.bmj.com/content/ bmjopen/10/6/e038863.full.pdf visited on 19 May 2021. Sertkaya, A., Birkenbach, A. et al. Examination of Clinical Trial Costs and Barriers for Drug Development. (2014). https://aspe.hhs.gov/system/files/ pdf/77166/rpt_erg.pdf visited on 19 May 2021. Blaschke, T. et al. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. (2011) https://pubmed.ncbi.nlm.nih.gov/21942628/ Eliasson, L. et al. How the EMERGE guideline on medication adherence can improve the quality of clinical trials. (2020). https://bpspubs.onlinelibrary.wiley. com/doi/full/10.1111/bcp.14240 visited on 19 May 2021. Breckenridge, A., Aronson, J. et al. Poor medication adherence in clinical trials: consequences and solutions. (2017). https://www.nature.com/articles/ nrd.2017.1 visited on 19 May 2021. Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets? Clin Pharmacol Ther. 1989 Aug;46(2):163-8. doi: 10.1038/clpt.1989.121. PMID: 2758726. Demonceau, J., Ruppar, T., et al. Identification and assessment of adherenceenhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and metaanalysis. (2013). https://pubmed.ncbi.nlm.nih.gov/23588595/ visited on 19 May 2021.

Bernard Vrijens Dr. Vrijens holds a PhD from the Department of Applied Mathematics and Informatics at Ghent University, Belgium. He currently leads a research program investigating (a) the most common errors in dosing using a simple but robust taxonomy, (b) particular dosing errors that can jeopardize the efficacy of a drug, and (c) the optimal measurementguided medication management program that can enhance adherence to medications and maintain long-term persistence. Dr. Vrijens is also the co-author of seven book chapters, over 100 peer-reviewed scientific papers, and named as inventor on 6 patents. He is a founding member of the International Society for Medication Adherence (ESPACOMP), and an active member of several EU- and US-funded collaborative projects around the theme of adherence to medications. Web: www.aardexgroup.com

Volume 13 Issue 4

INSIGHT / KNOWLEDGE / FORESIGHT

SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS IPI

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

www.international-pharma.com

JCS

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

PHARMA’S DNA

www.journalforclinicalstudies.com

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

IAHJ

IBI

www.international-animalhealth.com

www.international-biopharma.com

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

Peer reviewed, IBI provides the biopharmaceutical industry with practical advice on managing bioprocessing and technology, upstream and downstream processing, manufacturing, regulations, formulation, scale-up/technology transfer, drug delivery, analytical testing and more. Journal for Clinical Studies 41

Technology

Digitising Healthcare: The Challenges and Benefits The market for IoT in healthcare is projected to reach $534 billion by 2025, driven in part by the fallout from Covid-19 and also by new societal attitudes. It’s clear that new technology has the potential to transform industries and every aspect of life from healthcare to retail, for instance. Artificial Intelligence, Machine Learning, IoT, Robotics and Industry 4.0 are all common buzzwords now and hold great promise. New technologies such as these have helped the NHS to quickly adapt to the recent pandemic, giving teams the tools to allocate and deploy available resources more efficiently. IoT has also enabled the use of health and care devices to remotely collect data and monitor patients both in and out of hospital, reducing the number of hospital admissions and increasing patient satisfaction. As technology continues to flow into multiple aspects of everyday function, there are undoubtedly challenges that will arise, but the subsequent benefits far outweigh the challenges along the way. Peter Ruffley (CEO of Zizo) highlights these in the context of the digitisation of the healthcare sector. IoT Technology Transitioning elements of healthcare to the virtual clinic has been crucial in fighting the pandemic and reducing the strain on the NHS. IoT has enabled important new advances in remote monitoring through connected devices that can provide healthcare professionals with the ability to monitor ongoing patient health and vitals from home. Data can be accessible to clinical teams in real-time, also allowing them to monitor a range of key indicators, such as: glucose levels, temperature, heart rates, blood pressure and other key markers. Moreover, the ability to monitor behaviour changes, such as how many times an older individual uses the bathroom could indicate underlying health concerns before they escalate. Specialists can be alerted when there is a concerning change or a medical emergency to allow for immediate intervention. With IoT collecting and providing data automatically, staff need not use their time manually fetching data and reviewing information, freeing up time for clinicians and improving the efficiency of processes. In turn, this reduces the waiting time for patients and allows for smart prioritisation for those who require faster care. Paired with video conferencing and telephone calls instead of face-to-face appointments, doctors can reach and assess more patients per day to ensure that all health concerns are addressed. It has greatly improved accessibility and productivity in healthcare while keeping patients safe and in the comfort of their own homes. Improving Standards of Care Nationwide In rural and remote areas medical care has been known to fall behind standards elsewhere across the country, but technology can change this. Technology and healthcare applications can be used to provide healthcare workers with access to interact with and monitor people in places that have been traditionally harder to reach, and crucially Edge Computing can be used to increase performance and responsiveness for this digitisation. 42 Journal for Clinical Studies

COVID-19 has accelerated the adoption of digital technology throughout healthcare, meaning that it is now necessary that these organisations have the right processing capabilities in place for collecting, storing and analysing the mass volumes of data that will be collected. Traditionally, hospitals would transmit their data over a widespread network, which can present many issues within data distribution and security. Instead, Edge Computing can analyse and act upon this data at the point of collecting, helping to gather and interpret healthcare data, responding to any medical emergencies, in turn, presenting a more holistic insight. Extending Clinical Trials Clinical trials and research studies play a huge role in the advancement of healthcare, medicines and pharmaceuticals. Typical studies and trials can last a couple of weeks, but the opportunity to extend these into longitudinal studies provides much more value. From a scientific-pharmaceutical perspective, the idea of a connected device is to enable and enhance these types of studies. Edge computing can help to improve clinical trials by allowing the reach of these experiments to extend further than ever before, occur more frequently and accurately, and eliminate any unnecessary delays. The key to this is capturing data at the right time, in the right format, in the right way, which can be achieved through edge devices – where the data doesn’t have to go back to the cloud, creating small and contained networks within itself. Within the confines of clinical trials, a crucial element of achieving accuracy is ensuring patient compliance – taking medication at set times, for example, but the only way to truly know whether patients are being compliant is to have 24/7 contact and visibility of them. The idea of deploying analytics at the edge, whether that is through an edge device or edge infrastructure, enables the researcher to have this constant contact for a successful study. Additionally, this presents new opportunities to enhance precision medicine research by integrating wearables and sensors into the clinical trial process and therefore improving compliance and reporting. Taking the Patient out of the Lab When considering data collection and analysis within the health and personal care industries, this is typically a function restricted to laboratory and scientific environments. But if this data is designed to inform decision making, is such an environment providing the most granular and relevant insight for optimum decision making? What if we were to move away from the laboratory environment and take this data to the real world using innovative technology? There’s now an opportunity to integrate multiple data sources via IoT sensors with other data reference points, to really understand the context in which trial subjects use health devices and the other interactions that can come into play. For example; combining data from multiple types of IoT devices and pulling that data to a centralised point; using cross-sectional studies to generate volumes of data over a longer period of time, not only at a certain time each day; and using proactive questionnaires for a subjective measure of an individual’s activity and opinions. Volume 13 Issue 4

Technology sharing for this valuable decision making, but there must be agreed best practices in place to ensure that different devices from different teams can interact and exchange information with each other. The challenge lies in a lack of standards and data interoperability between IoT devices, as it results in inconsistencies in device implementation. There must be real checks and measures, along with known baselines based on real-world experience, to ensure that data is assessed correctly and used accurately. After all, patient care comes first, so regulations and processes must be in place to keep standards high across all settings. Patient Data Protection Data breaches and data mistrust are key terms in the media, as headlines often hit about the latest data leak, and data protection is a concern for many – especially when it comes to such a sensitive subject such as healthcare. Personal health records and location data are potential targets of cyberattacks, such as in 2017, many healthcare networks around the world were affected by the WannaCry ransomware attacks, which locked healthcare professionals out of patient health records. Overall, more than 230,000 computers in 150 countries were affected, causing billions of dollars of damage, virtually shutting down health systems worldwide. This is a critical challenge that the healthcare industry must address. Luckily, there are many basic security actions that manufacturers and providers of IoT devices can take to mitigate these risks, such as implementing security measures into the devices, including authentication and encryption. A recent study highlights that if IoT systems have adequate cybersecurity and resilience measures in place, these systems can reach the highest level of trustworthiness, providing users with confident healthcare services and continuing the advancement of technology within the industry. Conclusion Introducing further digitisation into healthcare clearly has great benefits, and by choosing the correct IoT providers, any associated challenges can be mitigated. We can expect to see technology adoption continue to rise in order to improve patient care, healthcare data analysis and importantly the speed at which patients are seen. Connected devices are the future and will leverage intuitive data analysis that ultimately saves lives and streamlines operational efficiency for health services across the nation. By reducing the myths surrounding the sharing of patient data and ensuring that connected devices are managed as part of one centralised system, healthcare providers can gain endless value and benefits from IoT.

Peter Ruffley Taking the science out of the lab and combining clinical data with behavioural data in people’s everyday environment will create vast amounts of new knowledge. It’s more than just a holistic approach – it’s a completely new approach that has never been done before, and this added insight can be powerful in terms of enhanced and evidence-based decision making and learning. Interoperability of Data There are of course challenges in the digitisation of the healthcare industry, and deploying IoT widely relies on crucial data integration of multiple points. Clinical teams must ensure the efficacy and accuracy of these tools at all times in order for data to be understood by all, and to drive informed and smarter decisions on patient care. Merging data across a central location allows for unobstructed www.journalforclinicalstudies.com

With over 40 years’ broad experience in the IT industry, including working with some of the biggest data technologies such as Oracle, IBM and Ingres Peter is the founder of Zizo Software. With a keen interest in Cloud analytic technologies, Peter understood the move to Cloud analytics was underway, and assembled a team to create a new type of technology, suited to deliver Big Data analytics and pattern database services at scale in the cloud. That technology is Zizo. With recent developments to the platform, Zizo is now moving into the IoT and Edge space to deliver insight on any device, wherever they may be.

Journal for Clinical Studies 43

Logistics & Supply Chain

COVID-19 Vaccines updates Cold Chain Logistics of Vaccine Distribution When the very first covid cases were reported it would have been impossible to predict the devastating impact this virus would wreak worldwide. Scientists globally worked tirelessly to better understand COVID-19, how it spread and mutated in a bid to discover and develop long term diagnostic and therapeutic strategies against the virus. The pandemic presented many major challenges including COVID-19’s rapid rate of transmission and ability to mutate into potentially more severe and contagious variants. An unsuspecting world was driven to galvanize a rapid response at an unprecedented rate in a bid to combat COVID-19 and develop new vaccines, therapeutics and diagnostics to try to fight the virulent virus. In an exceptionally short time frame scientists globally developed successful COVID-19 vaccines which were granted approval and being administered less than a year after the first cases of Covid came to light. This momentous medical milestone has been made possible by a global collaboration which has seen COVID-19 clinical trials conducted, vaccines developed, approved and deployed in a matter of months. Such accomplishments would ordinarily take years to achieve, however it was rapidly realised, with millions of cases and hundreds of thousands of deaths caused by covid, that the world was in a race against the virus. Developing COVID-19 vaccines was the first step in the fight back against the virus. The world then faced and continues to navigate, the significant challenges of having to protect, transport and safely store temperature sensitive pandemic payloads worldwide. Alongside cold chain challenges, further challenges remain relating to the equitable access to the various vaccines being produced and deployed on a global scale. With several COVID-19 vaccines already granted emergency use authorization to be administered, the race continues to vaccinate the world’s population, including its most vulnerable. Covid Cold Chain Challenges Developing effective COVID-19 vaccines is only part of the battle in the ongoing fight against the virus. Its imperative the cold chain is maintained during shipping and storage, ensuring approved vaccines can be deployed worldwide without effecting efficacy of any life-saving jabs. During the initial phased roll out of the first approved vaccines it was widely expected the majority would have extreme temperature requirements, for transportation and storage at medical facilities administering allocated jabs. 44 Journal for Clinical Studies

It had been anticipated that the first year of the international inoculation programme would be dominated by the need globally for a complex, costly infrastructure, including vast freezer farms providing storage at temperatures of -80°C. However this has not been the case as temperature requirements have changed according to the rising range of vaccines being developed, approved and administered. Collaborations with the pharmaceutical companies, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have resulted in the approval of the transportation and storage of vaccines at much more manageable temperatures, including -20°C and 2°C–8°C. The advantage of the introduction of vaccines which can be stored in a standard refrigerator at 2–8 degrees Celsius makes them more useful and accessible to developing countries, which may not be able to store large amounts of vaccine at low temperatures. Although some vaccines will still need extreme temperature requirements, which are more difficult and costly to maintain requiring more exotic coolants such as dry ice to achieve -80°C, what we continue to see are the various vaccines’ tight temperature shipping and storage requirements changing at a rapid rate. Whereas the industry expected all vaccines would need to be kept at -80°C in the first 12 months of inoculations, which would have been a significant drain on resources and made vaccines increasingly difficult to ship, that is no longer the case. Temperature conditions are determined by the requirement of the vaccine or therapeutic that’s developed and subsequently approved. We are now seeing the introduction of vaccines requiring more easily controlled temperatures during transit, storage and inoculation including -20°C or +5°C. These temperature requirements can be maintained via the existing infrastructure of refrigerators and freezers, which are already in place at clinics and hospitals. It also aids the ongoing deployment of vaccines to more remote regions which are harder to reach or do not have the necessary infrastructure in place to transport and store vaccines requiring extreme temperature protection. In an accelerated pandemic response pharmaceutical manufacturing and supply chain sectors continue to collaborate to contend with the often complex cold chain challenges involved with the safe transportation and storage of vital vaccines. Their collective objective of unbroken cold chain protection must be achieved throughout when shipping and storing vaccines. This includes every element involved from the temperature-controlled packaging utilised to ship vaccines, vehicles transporting the pharma payloads and buildings storing vaccines. To meet the stringent temperature requirements for vaccine distribution from manufacturer to clinics, hospitals or pop-up vaccination centres, specialised thermal packaging products have Volume 13 Issue 4

Logistics & Supply Chain

COVID -19

VACCINES IN COMPARISION UK Approved

Company

Oxford UniAstraZeneca

US Approved

Pending

Type Viral vector (genetically modified virus)

Doses

Storage

Regular fridge temperature 2 to 8°C (6 months)

Can be stored at -25C to -15C for up to 2 weeks (unpunctured vials) OR Undiluted / unthawed at +2C to +8C for 120 hours (US FDA - 1 month undiluted / unthawed) OR Room temperature (max +25C) for 2 hours

Additional Information Source: Respective Companies, WHO.

-70°C (7 months)

Source: Ministry of Health – Ontario, Canada (published 25th May 2021) US FDA (FDA report published 19th May 2021)

PfizerBioNTech

RNA (part of virus genetic code)

Moderna

RNA

Protein-based

Regular fridge temperature 2 to 8°C (6 months)

Source: Respective Companies, WHO.

Viral vector

Regular fridge temperature 2 to 8°C (3 months)

Source: Respective Companies, WHO.

-20°C (6 months)

Novavax

Pending

Janssen

Gamaleya (Sputnik V)

Pending

Viral vector

Sinovac (CoronaVac)

Pending

Inactivated virus (weakened virus)

Unpunctured vials can be stored in a refrigerator at +2C to +8C for up to 30 days. Punctured vials can be stored at +8C to +25C for up to 24 hours

-18.5°C (liquid form) Regular fridge temperature

Storage in a refrigerator at +2C to +8C for up to 2 months, future developments to extend storage to 6 months

Regular fridge temperature 2 to 8°C (12 months)

Room temperature not to exceed +25C

Source:- US FDA report (revised 31st March 2021)

Source:- TASS (Russian news agency)

Source: Government of Pakistan (guidelines published 22nd April 2021)

been adapted and produced within the industry that are designed to protect and perform for every step of these vaccine journeys. The temperature requirements for shipping and storage can be complex and as additional approved vaccines are produced the logistics of transporting temperature sensitive pandemic payloads plays a major part in ensuring the worldwide vaccination programme remains on track. Vaccines Providing Pandemic Protection Although the shipping and storage requirements of emerging temperature sensitive vaccines vary, they all need protection to mitigate potential temperature excursions during transportation. So how do the current approved vaccines compare when it comes to temperature transportation and storage requirements? •

Oxford – AstraZeneca – Currently approved for use in the UK, Europe and being administered in numerous countries worldwide. This viral vector vaccine (genetically modified virus) is administered in two doses. Can be stored at regular fridge temperature of 2°C to 8°C for six months. Temperature requirements make it more manageable to ship to more remote regions.

•

Janssen – Approved for use in the UK and US this viral vector single dose vaccine can be stored at a regular fridge temperature of 2°C to 8°C for three months.

•

Novavax – Awaiting approval for use in the UK and US this protein-based vaccine requires two doses and can be stored at regular fridge temperature of 2°C to 8°C for six months.

•

Gamaleya (Sputnik V) – This viral vector vaccine is currently being administered in Russia from where it originates, with Slovakia and Hungary also administering the two dose vaccine. Can be stored at -18.5°C (liquid form) and storage in a refrigerator at +2 to +8°C for up to two months, with ongoing developments to extend storage to six months.

•

Sinovac (CoronaVac) – China’s inactivated virus vaccine is currently being administered in several countries including Chile, Brazil, Indonesia, Mexico, Thailand and Turkey as well as China. It is the second Chinese vaccine (after the Sinopharm jab) to recently be granted approval for emergency use by the WHO. The vaccine can be stored at regular fridge temperature of 2°C to 8°C for 12 months and at room temperature not to exceed +25.

•

Sinopharm – This two dose inactivated virus vaccine has a temperature storage requirement of 2°C to 8°C.

Pfizer – BioNTech – The first COVID-19 vaccine approved for use in the UK and US, this RNA vaccine incorporates part of the virus genetic code and is administered in two doses. It can be stored at -70°C for seven months. It can be stored at -25°C to -15°C for up to two weeks (unpunctured vials) or undiluted/unthawed at +2°C to +8 for 120 hours (US FDA – 1 month undiluted/unthawed) or room temperature (max +25°C) for two hours.

•

Moderna – Also approved for use in the UK and US, this RNA vaccine is also administered in two doses. Can be stored at -20°C for six months. Unpunctured vials can be stored in a refrigerator at +2°C to +8°C for up to 30 days. Punctured vials can be stored at +8°C to +25°C for up to 24 hours.

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Journal for Clinical Studies 45

Logistics & Supply Chain •

Covaxin (Bharat Biotech) – Another inactivated virus vaccine administered in two doses with a storage requirement of 2°C to 8°C.

A summary of vaccine storage and transportation temperatures can be seen in accompanying infographic. In the US, to date, three vaccines have successfully secured emergency use authorization from the FDA, the first of which was a result of the partnership between Pfizer and German-manufacturer BioNTech. This was followed by a vaccine developed by Moderna in conjunction with the National Institute of Allergy and Infectious Diseases. The latest to join the approved trio is the Janssen jab from the vaccine division of Johnson & Johnson, which offers a one-dose vaccine. The latter does not require the complex cold-chain requirements to protect the vaccines from deteriorating, which the afore mention do with Pfizer and Moderna needing to be transported and stored at much lower temperatures. Like the Astra/Zeneca vaccine, developed with Oxford University, the Janssen jab requires much more regular temperature storage (2°C–8°C) making it an appealing option for cold chain logistics, especially when having to be deployed to regions which don’t have the infrastructure in place to protect the life saving vaccines.

In the UK the Pfizer, Astra/Zeneca, Moderna vaccines are being administered and the Janssen has also been approved. Vaccinating The World The latest pandemic statistics, as of July 20, 2021, according to the WHO reveal that globally there have been 190,770,507 confirmed cases of COVID-19 including 4,095,924 deaths reported to the organization. By July 19, 2021 it reported that a total of 3,436,534,998 vaccine doses had been administered worldwide.1 As of July 20, 2021 approximately 26.5% of the world population had received at least one dose of a COVID-19 vaccine, 3.69 billion doses have been administered globally, and 30.33 million doses are now being administered on a daily basis. However, it is estimated only 1.1% of the population in low-income countries have received at least one dose.2 The various vaccines are being developed, approved and deployed in a bid to minimise people’s chances of contracting the virus, getting ill, requiring hospital care or dying. While it is acknowledged that lockdowns globally have helped to break the chain of the virus spreading intermittently, administering vaccines worldwide is universally viewed as the exit strategy from the pandemic in the long-term. World leaders are making it their mission to ensure all countries have access to the billions of vaccines needed to protect people against the virus and help to break down the chain of transmission and ongoing emergence of new virus variants. Covid-19 vaccines were at the top of the agenda at the recent G7 meeting staged in the UK in June, where world leaders pledged to provide millions of Covid vaccine doses to low-income countries in a further step towards the goal to vaccinate the world. The doses would be donated directly or via the World Health Organization’s Covax scheme, whose main aim is to provide vaccines to the most vulnerable 20% of every nation worldwide. The communiqué issued by the G7 summit pledges to “end the pandemic and prepare for the future by driving an intensified international effort, starting immediately, to vaccinate the world by getting as many safe vaccines to as many people as possible as fast as possible”. It also stated that they will collaborate to strengthen their “collective defences against threats to global health by: increasing and coordination on global manufacturing capacity on all continents; improving early warning systems; and support science in a mission to shorten the cycle for the development of safe and effective vaccines, treatments and tests from 300 to 100 days”.3 While it is widely agreed the deployment and administration of approved vaccines is the most reliable exit strategy out of the covid crisis, for the world to emerge from this pandemic everyone needs to be vaccinated in order to help prevent the virus variants gain ground and reverse the vaccination programme progress made so far on an international scale. This collective objective to vaccinate the world’s population came a step closer when during the aforementioned G7 summit more than 870 million additional vaccine doses were pledged, which brings the collective commitments made since February this year to one billion. In response to the vaccine pledges made at the recent G7 meeting the head of WHO, Tedros Ghebreyesus, called for more doses to be

46 Journal for Clinical Studies

Volume 13 Issue 4

Logistics & Supply Chain

deployed faster and highlighted how many countries face another surge in cases without vaccines readily available to offer population protection.

successfully vaccinate the entire world to the level of 70%, which is the point where it is considered the transmission of the virus could be reduced substantially.

The call for increased vaccine donations to poorer countries comes as the US agreed to purchase 500 million doses from Pfizer-BioNTech at a not-for-profit price with 200 million of those doses due to be distributed before the end of 2021 and a further 300 million doses due for deployment in the first half of 2022.

Until the world is vaccinated the fight against COVID-19 will continue for some time to come.

Doses are due to be donated to approximately 100 low and lower middle-income countries including those in the African Union via the COVAX Facility.4 This is in addition to the 80 million doses the US had already pledged to provide countries globally.5 As part of the ongoing international donation drive, five million UK vaccines are due to be donated by the end of September this year with another 25 million to be added to that by the end of 2021 with 80% of the UK donated doses also being distributed via Covax. It was reported at the recent summit staged at the start of June by the Global Alliance for Vaccination and Immunisation (Gavi), that to date over 132 million doses have been shared by various countries worldwide. These included more than 54 million doses donated to lowerincome countries by Denmark, Belgium, Japan, Spain and Sweden. The summit helped raise funds to enable Gavi to secure 1.8 billion doses of COVID-19 vaccines for lower-income countries participating in the COVAX Facility. It is estimated the vaccines, due to be delivered during 2021 and early 2022, will enable COVAX to provide pandemic protection to almost 30% of the population in 91 AMC economies.6 Covax’s original aim was to provide two billion doses of vaccine globally by the end of 2021 however that objective has been reviewed with a new target to get 1.8 billion doses to 92 lower income economies by early 2022. Vaccine donation will need to continue to be ramped up as the WHO estimated that a total of 11 billion doses will be required to www.journalforclinicalstudies.com

REFERENCES 1. 2. 3. 4.

https://covid19.who.int/ https://ourworldindata.org/covid-vaccinations?country=OWID_WRL https://www.g7uk.org/wp-content/uploads/2021/06/Carbis-Bay-G7Summit-Communique-PDF-430KB-25-pages-3.pdf https://www.globenewswire.com/news-release/2021/06/10/2244894/0/ en/Pfizer-and-BioNTech-to-Provide-500-Million-Doses-of-COVID-19Vaccine-to-U-S-Government-for-Donation-to-Poorest-Nations.html https://www.whitehouse.gov/briefing-room/statements-releases/2021/ 06/03/fact-sheet-biden-harris-administration-unveils-strategy-forglobal-vaccine-sharing-announcing-allocation-plan-for-the-first-25million-doses-to-be-shared-globally/ https://www.gavi.org/news/media-room/world-leaders-unite-commitglobal-equitable-access-covid-19-vaccines

Adam Tetz Adam Tetz is the Director of Worldwide Marketing at Peli BioThermal and has more than 25 years of marketing experience. He is responsible for telling the story of Peli BioThermal to our worldwide audiences. His areas of responsibility include brand identity, product launch and communication strategy. Prior to Peli BioThermal, Tetz held positions in product management and marketing communication across a variety of industries, including medical software, financial software, information services and professional consulting services. He holds an MBA in Marketing from the University of Saint Thomas, a BA in Advertising from the University of Minnesota and is a veteran of the United States Coast Guard. Email: adam.tetz@pelican.com

Journal for Clinical Studies 47

Ad Index

IFC SGS

Page 3

Cerba Research

Page 5

Illingworth

Page 25

Ramus Medical Ltd.

Page 37

Astell Scientific

Page 18

MLM Medical Labs

Page 41

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IBC PCI Pharma

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