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Volume 12 Issue 1


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


Emerging Treatments For Spinal Cord Damage The Biggest Regulatory Moments of 2019 And How They’ll Impact 2020 Rescue Trials When Should You Call for Help? Unified Trial Governance Why CTMS is the Jewel in the Crown

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


Volume 12 Issue 1 January 2020 PHARMA PUBLICATIONS

Boosting Trial Success through Blinded Data Analytics: What Can We Learn from CNS?

Research scientists know that data alone does not lie – but data can mislead. That’s especially true in clinical trials that rely on subjective endpoints to assess drug efficacy. Psychiatry studies, which often centre around the clinician’s assessment of disease progression or severity, have modest success rates. While the reasons are multifactorial, Dr. Anthony T. Everhart at Signant Health pinpoints excessive placebo response rates and the lack of precision in the measurement of symptom severity as root causes of trial failure, exploring how we can use central nervous system (CNS) clinical trials to boost trial success. 8

FDA Guidance on Less Common Viral Hepatitis Type

The US Food and Drug Administration (FDA) recently revisited the topic of drugs for liver infection through a newly issued guidance document on hepatitis D virus (HDV) in October 2019. Deborah Komlos at Clarivate Analytics illustrates how the guidance document, titled ‘Chronic Hepatitis D Virus Infection: Developing Drugs for Treatment’, provides recommendations regarding clinical trial designs for the development of drugs and biologics to support an indication for the treatment of chronic HDV infection. 10 IDMP at a Crossroads Providing annual reviews on IDMP progress has proved painful in recent years because momentum has not always been where it should be, due to shifting timescales and fluctuating focus and alignment among the various stakeholders. While 2019 saw a crystallisation of ideas about what needs to happen next, Frits Stulp at Iperion Life Sciences Consultancy calls for focus and mutual support during what will be a critical year for the regulatory network’s improved patient safety initiatives in 2020. 12 Merger and Acquisition in Healthcare Healthcare mergers and acquisitions have been the cause of extensive debate across the medical industry, calling into question the tools and scale necessary to thrive in current care models in healthcare. While there are two types of consolidation that can enhance clinical integration and management in the healthcare merger and acquisitions division, Adhiti Soni, who works in the healthcare and government sector, examines how vertical integration and horizontal consolidation can have a negative impact on patient experience. 14

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.


The Use of Modelling and Simulation Studies in Early-phase Clinical Trials

Improving experimental drug success rate and accelerating clinical development are top priorities for pharmaceutical and biotech companies. Careful and considered decision-making is essential early on in the process to minimise development time, manage a project’s costs and improve the probability of commercial success. Bruno Speder at SGS Clinical Research showcases how the use of modelling and simulation tools can be a very useful strategy to mitigate such risks and make better-informed decisions. REGULATORY 16

The Biggest Regulatory Moments of 2019 and How They’ll Impact 2020

2019 saw many noteworthy changes in the regulatory industry. In April 2019 it was announced that the FDA’s Office of New Drugs (OND) would create enhanced review zones that would intersect

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Contents disease areas and divisions, to maximise access to more focused and innovative areas of regulatory expertise. While this article is by no means an exhaustive listing of all the changes globally, Aman Khera at Worldwide Clinical Trials seeks to provide the reader with an insightful snapshot of a selection of the changes that have impacted the industry last year and how they’ll impact 2020. 22 Rescue Trials – When Should You Call for Help? Although previously very rare, more and more trials are becoming in need of 'rescue' as competition for resources means less experienced staff are left to manage unforeseen problems or ensure projects keep to their timelines. No one seems sure how to deal with all the delays and the CRO is beginning to run out of ideas. David Ng and Leslie Jones at WuXi Clinical stress the importance of reviewing some of the scenarios that typically cause a tipping point to be reached, before constructing a ‘rescue package’. MARKET REPORT 24 Ensuring Effective Financial Management in Sponsored Research in Malaysia A critical part of managing clinical trials is a solid, well thought out clinical trial budget. A successful budget to ensure a good quality clinical trial should not only entail careful detailing of costs that are in line with the trial protocol, but should also include a financial management system that executes this budget in an efficient, timely and transparent manner. Yau Yit Huan and Audrey Ooi at Clinical Research Malaysia delve into how effective financial management can positively facilitate the initiation of clinical trials. THERAPEUTICS 26 Exploring the Limb Girdle Muscular Dystrophy Clinical Trial Landscape With the recent advent of adeno-associated, virus-based gene therapy treatments, limb girdle muscular dystrophy (LGMD) is currently attracting the attention of the biopharmaceutical industry, especially with the goal of restoring full or partial proteins that are otherwise dysregulated. Raymond A. Huml, Siddharth Aras, Marie Trad, Tiffany Chow, Olja Tanjga and Jill Dawson at IQVIA, describe the results of a proactive, global LGMD feasibility study with insights from investigators currently providing LGMD patient care. 32 Emerging Treatments for Spinal Cord Damage Injuries to the spinal cord can cause permanent paralysis and even lead to death, with little or no hope of regaining lost functions once the trauma has occurred. Dr. Jerry Silver at Case Western Reserve University looks at his spinal cord research to try and understand why nerves that are damaged through spinal injury don’t regenerate, as well

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as identifying non-invasive, easy-to-administer strategies that can promote robust functional recovery. 34 Chronic Lymphocytic Leukaemia: Current and Emerging Treatment Options With the advent of new targeted and cellular therapies, the treatment landscape for patients with chronic lymphocytic leukaemia (CLL) has considerably changed in the last few years. Current CLL management considers genetic aberrations, previous treatments, as well as disease relapse, in addition to the clinical stage. Oana Draghiciu and Inka Pawlitzky at CATO SMS describe contemporary CLL management, with a focus on current and emerging therapies in first-line disease and subsequent settings. TECHNOLOGY 44 Unified Trial Governance: Why CTMS is the Jewel in the Crown In today’s extremely regulated and progressively global life sciences marketplace, managing clinical trials requires an end-to-end system that offers oversight into trial costs and regulatory risks, while being flexible and compatible with other technologies. Ricky Lakhani at Pharmaseal shows how using CTMS can integrate data from disparate sources to help people make proactive and informed decisions. 48 The New Healthcare, Digital by Design Our healthcare is becoming increasingly interconnected as technologies allow us to be more connected to our devices, to other people and healthcare services and providers. Our digital footprint is now part of a larger digital ecosystem that promises to enable better patient care through clearer insights. Douglas Drake at Clinerion looks at how the healthcare sector can improve patient care and outcomes through the use of data technologies, connected medical devices and biomarker metrics through to IoT. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 52 Temperature Challenges in Clinical Supply: Examining the Cold Chain to Ensure the Efficacy of IMPs and Patient Safety Supply chains for investigational medicinal products (IMPs) are becoming more complex. As clinical trials change rapidly, maintaining product integrity and quality at every stage is challenging. Anthony Mistretta and Bryan Thompson at Almac Clinical Services examine the temperature challenges associated with biologic products and address how emerging cold chain management solutions are helping sponsors ensure specified temperatures are maintained throughout the supply chain.

Volume 12 Issue 1

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Foreword Consolidation in the CRO space is relatively common, though recent M&A among CROs has been around building out capabilities either in data analytics or in key CRO functions such as patient recruitment or site management. Much of the growth has been concentrated in the large full-service players as well as the small/niche CROs, while mid-size full-service companies have generally trailed market growth, which is where a lot of the consolidation has been happening. The largest services provided by CRO’s are site management, study monitoring, and data management comprising 22%, 20%, and 12% of total industry revenue, respectively. Many of the largest outsourced services are generally mature and to an extent, commoditized. The CRO industry is expected to grow ~6%, driven by ~2%–3% from increasing R&D spending by the biopharma industry and ~3% from increased penetration of drug development budgets. The industry remains fragmented in 2019 and looks to see continued opportunity for value-accretive M&A.   According to a recent study in March 2019 from the Tufts University Center for the Study of Drug Development (CSDD), leaders in the analysis of the CRO industry, the top 10 largest CROs, according to CSDD, controlled 57% of outsourcing spend in 2018. This demonstrate a 12% increase from seven years ago, suggesting the top CROs, with geographic scale and broad therapeutic expertise are taking share. Of note, in a previous survey, R&D projects managed by CROs have shorter cycle times, with study initiation duration 39 days faster for established CRO relationships (77 days faster for new relationships) as compared to sponsor-run trials. The dynamics further emphasize the value proposition of clinical trial outsourcing, helping to offset the growing complexity of clinical trials and expanding scope of studies. It also noted that sponsor layoffs alongside building R&D pipelines as well as sustained biotech demand continue to support R&D outsourcing penetration. Adhiti Soni, who works in the healthcare and government sector, examines how vertical integration and horizontal consolidation can have a negative impact on patient experience. The Regulatory Section begins with an article by Aman Khera at Worldwide Clinical Trials who seeks to provide the reader with

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

an insightful snapshot of a selection of the changes that have impacted the industry last year and how they’ll impact 2020, and Deborah Komlos at Clarivate Analytics illustrates how the guidance document, titled ‘Chronic Hepatitis D Virus Infection: Developing Drugs for Treatment’, provides recommendations regarding clinical trial designs for the development of drugs and biologics to support an indication for the treatment of chronic HDV infection. A very informative article by Raymond A. Huml, Siddharth Aras, Marie Trad, Tiffany Chow, Olja Tanjga and Jill Dawson at IQVIA, describes the results of a proactive, global LGMD feasibility study with insights from investigators currently providing LGMD patient care and Dr. Jerry Silver at Case Western Reserve University looks at his spinal cord research to try and understand why nerves that are damaged through spinal injury don’t regenerate, as well as identifying non-invasive, easy-toadminister strategies that can promote robust functional recovery. I hope you all enjoy the 1st edition of JCS in the year 2020, and I look forward to featuring more enlightening articles in the next issue coming out in March. Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies You may notice that we have changed the theme of the front cover picture of the JCS Journal. We started JCS with the unique goal of highlighting emerging countries and thoroughly analysed these countries as a clinical trial destination. Hence, we featured the national flower of one of the countries highlighted in that issue. Although we remain committed to bringing you a market analysis of emerging clinical trial destinations, from 2020, JCS will focus more on the therapeutic and regulatory aspects. The front cover picture will represent one of the therapeutic focuses we have in that issue. Research and Treatment of Spinal Cord injury is one of the articles we have featured in this issue and the front cover picture represents that theme.

• 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

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

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

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

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

of Europe

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

• • Elizabeth Moench, President and CEO of Bioclinica – Patient

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

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

Recruitment & Retention

• Francis Crawley, Executive Director of the Good Clinical Practice

Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

• Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) • Stefan Astrom, Founder and CEO of Astrom Research International HB

• Georg Mathis, Founder and Managing Director, Appletree AG

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

• Hermann Schulz, MD, Founder, PresseKontext

• T S Jaishankar, Managing Director, QUEST Life Sciences

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Boosting Trial Success through Blinded Data Analytics: What Can We Learn from CNS? Research scientists know that data alone do not lie – but data can mislead. That’s especially true in clinical trials that rely on subjective endpoints to assess drug efficacy. Psychiatry studies, for example, which often centre around the clinician’s assessment of disease progression or severity, have modest success rates. Just 24% of Phase II and 56% of Phase III psychiatric studies1 demonstrate a statistically significant drugplacebo separation. But is it true that so many medications, having moved so far through the development pathway, do not work, or is something else at play? In truth, the reasons for these modest success rates are multifactorial, but often excessive placebo response rates and lack of precision in measurement of symptom severity are root causes of trial failure. Electronic clinical outcome assessment (eCOA)-based technology, combined with sophisticated data analytics, has the potential to address many of them.

Common Problems with Endpoint Data Quality For a trial to yield meaningful results, the most relevant outcomes need to be measured in the most consistent manner. To that end, ensuring endpoint data quality rests upon establishing and maintaining precision of symptom measurement and early detection and remediation of poor-quality endpoint data.

Quality Data Signant’s clinical data experts have demonstrated in central nervous system (CNS) clinical trials, including schizophrenia, Alzheimer’s Disease and major depressive disorder, that data quality markers are predictive of measurement error, placebo response and diminished drug-placebo separation. This is likely to be equally true in other therapeutic areas that are reliant on subjective or “soft” endpoints.

Traditional outcome scoring lends itself to error, as the AD example of raters recording two values for the same measurement when using different scales illustrates. Paper-based assessments and manual calculations can result in collection of incomplete or erroneous data: mathematical mistakes or the omission of vital information, for example.

Illustrative of this point are data collected on 4245 subjects participating in six atopic dermatitis (AD) trials across 286 investigative sites. The data were analysed for anomalies in the body surface area (BSA) assessments obtained during the administration of two rating scales, the Scoring Atopic Dermatitis (SCORAD) and the Eczema Area and Severity Index (EASI). Using blinded data analytics, sites with aberrant measurement technique were identified. These sites recorded notably discordant body surface areas (BSA) on the same patients, utilising the SCORAD and EASI, despite each measure asking for the same assessment. The analysis was also able to identify erratic results, such as extreme fluctuations in symptoms and assessment scores from visit to visit, recorded by individual clinicians, or raters. These common data quality errors have the potential to significantly undermine the success of a clinical trial. Signant has worked with numerous CNS sponsors to help embrace data analytics programmes, informed by clinical insight and coupled with remediation, to significantly improve endpoint reliability. The same methodologies could now lead to similar benefits for any nonCNS fields which also struggle with low success rates. 6 Journal for Clinical Studies

When raters are insufficiently trained and monitored on administering an instrument, trials can collect poor quality data. This can be a challenge. In today’s world of global, multi-site investigations, each study could have hundreds of raters speaking dozens of languages in multiple countries, yet data integrity requires each of them to carry out the assessment and record the results in the same way. Endpoint Quality Solutions As has been demonstrated in CNS trials, integrated clinical trial software combined with clinical expertise and sophisticated data analytics can improve endpoint reliability. Intelligent electronic clinical outcome assessment (eCOA) systems replace paper data collection and calculations. Quality platforms can include mandatory fields and provide memorynudging hints and tips on performing the scale at hand, for example, and can monitor data input to flag quality issues in real time. Similar systems will also be accessible to trial participants, meaning they can collect rich data from sources such as patientreported outcomes (PROs) and symptom diaries and subject them to the same level of scrutiny. Volume 12 Issue 1

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Sponsors and CROs also need to know that every rater understands and administers the clinical assessment in the same way every time. Best practice, systematic rater training and certification ensures sponsors can be confident that they are collecting like-for-like data across multiple sites, in multiple languages and cultures. As many trial organisers will appreciate, data quality issues often remain hidden until the end of a study, which is why no trial strategy should ignore the importance of data quality monitoring. Clinically informed, blinded, evidence-based data analytics can detect and remediate a lack of precision in subject interviews, improper diagnosis and symptom measurement, protocol noncompliance, procedure violations, and fraud. Blinded Data Analytics – Success and Potential Monitoring data quality for aberrant or illogical patterns of symptom change has been performed unobtrusively in the background of CNS trials, where it has informed the remediation of aberrant raters and sites. In the AD analysis, for example, blinded data analytics were able to identify erratic scoring. This alerts sponsors to training needs before any lasting damage is done to the trial. This success can be replicated across any therapy area where trial failure is a result of the collection of poor quality data, or poor data collection processes, rather than a lack of drug efficacy.

Much like CNS studies, trials in immune-mediated conditions such as rheumatoid arthritis and inflammatory bowel disease, for example, rely heavily on rater-dependent assessments and patientreported outcomes. And as such, they lend themselves well to similar blinded data analytics. Data collection issues are common in areas such as cardiorespiratory disease, where manual collection often results in the rounding up or down of assessed values. And oncology, for so long dominated by the “hard” endpoint of tumour response, is starting to embrace “soft” endpoints and PROs as a therapy’s impact on quality of life becomes ever more important. Ultimately, blinded data analytics can be employed in all these areas to improve endpoint quality. This avoids costly trial failure, and, crucially, ensures new treatments are available to the people who need them as quickly as possible. REFERENCES 1.

Clinical Development Success Rates 2006-2015 - BIO, Biomedtracker, Amplion 2016.pdf Development%20Success%20Rates%202006-2015%20-%20BIO,%20 Biomedtracker,%20Amplion%202016.pdf Accessed April 9, 2019.

Anthony Todd Everhart Anthony Todd Everhart, MD, FACP, is the internal medicine leader at Signant Health. Dr. Everhart is board-certified in internal medicine and a fellow of the American College of Physicians with over 23 years of experience in the practice of medicine and over 12 years of experience in clinical development. Prior to joining Signant, Dr. Everhart held positions of Vice President, Medical Affairs and Vice President, Medical Informatics at Chiltern and Covance, and consulted independently in the areas of medical monitoring, medical data review, data analytics, and physician adoption of technology. He has worked in all phases of clinical development in numerous therapeutic areas including allergy & immunology, cardiovascular, hematology & oncology, infectious disease & HIV, neurology, ophthalmology, psychiatry, respiratory, and rheumatology. Email:

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FDA Guidance on Less Common Viral Hepatitis Type The US Food and Drug Administration (FDA) recently revisited the topic of drugs for liver infection through a newly issued guidance document on hepatitis D virus (HDV). In October 2019, the FDA released the draft guidance for industry, Chronic Hepatitis D Virus Infection: Developing Drugs for Treatment, which provides the agency’s current recommendations regarding the overall development programme and clinical trial designs for the development of drugs and biologics to support an indication for the treatment of chronic HDV infection. In November 2018, the agency released the draft guidance, Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment, which contains information relevant to HDV drug development, but focuses on drugs and biologics to treat chronic hepatitis B virus (HBV) infection. The Centers for Disease Control and Prevention (CDC) explains that infection by HDV (also known as hepatitis delta virus) is uncommon in the US, occurring only in people who are infected with HBV. This is because HDV is a replication-defective virus that uses the HBV surface antigen (HBsAg) as its envelope protein. Therefore, HDV infection only occurs in the setting of concurrent HBV infection. In July 2019, the World Health Organization (WHO) noted that at least 5% of people with chronic HBV infection are co-infected with HDV, resulting in a total of 15-20 million persons infected with HDV worldwide. However, the WHO stated, this is a broad global estimate since many countries do not report the prevalence of HDV. According to the WHO, HDV-HBV co-infection is considered the most severe form of chronic viral hepatitis due to more rapid progression toward liver-related death and hepatocellular carcinoma. HDV is transmitted via the same routes as HBV: percutaneously or sexually through contact with infected blood or blood products. HDV infection can be an acute, short-term infection or a long-term, chronic infection. Vaccination against HBV prevents HDV coinfection, and hence expansion of childhood HBV immunisation programmes has resulted in a decline in hepatitis D incidence worldwide, the WHO states. Drug Development Programmes In its October 2019 guidance, the FDA noted that because chronic HDV infection is considered serious and life-threatening and there are no approved treatments, investigational anti-HDV drugs may be eligible for the FDA’s expedited programmes, such as fast track, breakthrough therapy, and priority review designations. Given that trials demonstrating clinical benefit of an HDV therapy would likely require a prolonged follow-up period, the FDA anticipates that development programmes may opt to pursue accelerated approval pathways based on a surrogate endpoint. According to section 507(e)(9) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the term ‘surrogate endpoint’ is defined as “a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement of clinical benefit, and — (A) is known to predict clinical benefit and could be used to support traditional approval of a drug or biological product; or (B) is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug or biological product in accordance with section 506(c).’’ As explained by the FDA, clinical trials are needed to show that surrogate endpoints can be relied upon to predict, or correlate with, clinical benefit. Surrogate endpoints that have undergone this testing are called validated surrogate endpoints and these are accepted by the FDA as evidence of benefit. 8 Journal for Clinical Studies

For HDV infection, no surrogate endpoints have been definitively shown to predict clinical benefit, the FDA stated in the October 2019 guidance. An appropriate surrogate endpoint for the treatment of HDV should provide evidence of both a decline in virologic replication and an improvement in associated liver inflammation as evident by biochemical response, the agency explained. As precedent, the agency noted in the November 2018 guidance that HBV DNA suppression with or without HBsAg loss is considered a validated surrogate endpoint that has been demonstrated to predict clinical outcomes, and that this endpoint could be used to support a traditional approval. Regarding drug development programmes in general, the FDA advises that they should include a diverse and representative clinical trial population. In the October 2019 guidance, the FDA pointed to the global presence of HDV infection, with the greatest burden of infection occurring in Eastern and Mediterranean Europe, the Middle East, the Amazon Basin, and parts of Asia and Africa. Sponsors are advised to consider the following points in relation to trial populations: •

Although foreign data may be acceptable as a sole basis for marketing approval under certain circumstances (see 21 CFR 314.106), the FDA encourages sponsors to include US patients in development programmes to provide additional experience relevant to the US population.

Eligibility criteria should allow the clinical trial population to reflect the diversity of the patients who will be using the drug if it is approved, the FDA said. For additional information, see the draft guidance for industry, Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs, issued in June 2019.

The FDA accepted public comments on the October 2019 draft guidance to Docket No. FDA–2019–D–4042 until December 31, 2019.

Deborah Komlos Deborah Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis suite of life science intelligence solutions at Clarivate Analytics. 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:

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IDMP at a Crossroads

In 2020, will growing urgency around veterinary regulations disrupt progress on human medicinal product standards, and will anyone at last speak up for patients? Frits Stulp of Iperion Life Sciences Consultancy calls for focus and mutual support during what will be a critical year for the regulatory network’s improved patient safety initiatives. Providing annual reviews on IDMP progress has proved painful in recent years because momentum has not always been where it should be, due to shifting timescales and fluctuating focus and alignment among the various stakeholders. But 2019 has seen some decent progress, particularly at a substance level, as well as a crystallisation of ideas about what needs to happen next. Common Substance Definitions: A Proof of Concept One of the important developments in 2019 has been the demonstration of the impact shared definitions of substances can have internationally, via a proof-of-concept project led by the Dutch regulator (Medicines Evaluation Board) on behalf of the European regulatory network. This considered the benefits of data continuity in a substances context, from a scientific point of view. Specifically, it explored how agreed descriptions/coding for complex molecules would help in cross-border medicines management – for instance in scenarios where a patient loses their medication on holiday, or needs a new prescription, and a healthcare provider needs to check the active ingredients, and identify any contraindications or allergy implications. The proof-of-concept study is currently demonstrating that describing molecules in a consistent, agreed way, with common mapping, would provide significant support for data and process interoperability. Instead of individual professionals having to sift through dossiers to confirm the constituent ingredients of equivalent products, they could simply exchange the agreed identifier – much as people use their social security number to identify themselves as individuals to different government organisations. Here, the primary benefit is reduced risk of wrong medicines being issued (though the efficiency gains for all stakeholders, and the accelerated speed of decision-making, are clear sub-benefits). This is just one of up to 20 use cases making up the business case for IDMP – that is, for having a common method of identifying medicines. Interestingly, in the US, a project has been underway for some time looking at incorporating images of drugs into a central medicines database, with potential benefits for elderly or vulnerable patients or their carers, who have reference to only limited information, such as the known colours of pills. The aim of that particular project is to capture images of every tablet on the market, so that medication can be identified visually – as a further dimension to the common descriptions being captured. The Rise of the Veterinary Regulatory Agenda IDMP developments in relation to substances are not yet being matched by developments around product-level descriptions. 10 Journal for Clinical Studies

And there have been some concerns that momentum might once again be lost here, at least in relation to human medicines, as measures to address veterinary medicine data come into central focus. Standardising veterinary medicines information was always part of the EU/EMA plan, and a team is now championing the cause with January 2022 now designated as a hard deadline for compliance with standardised identifiers. Some in the human medicines industry fear that advances with product-level data will now take a back seat, causing new delays to progress with IDMP implementation. Yet there is no reason why the two streams of work should not happen in parallel. Indeed, they could both feed off and help drive the other, as there will be considerable commonality between most of the process requirements – and one of the big points of IDMP is to foster greater efficiency/replication of proven success. Veterinary implementations of data standards will put pressure on affected industry stakeholders to establish target operating models for product and substance data, which is something all medicines companies now need to do anyway. So if veterinary work streams move along at a slightly faster pace now, this could even help accelerate or boost the business case for broader/human medicines data transformation efforts. Certainly there is no need for working parties with interests in human and veterinary medicines to plan their projects sequentially. Parallel planning makes much more sense, especially if the respective work parties can learn from each other and accelerate overall progress. The target go-live date for human medicines/IDMP compliance is 2023, and it is in everyone’s interests that we keep to this deadline. So if we can harmonise the process, rather than create two sets of definitions, vocabularies and so on, so much the better for everyone concerned. With a concerted effort, I believe we can all hit our deadlines, and in 2020 it would be immensely encouraging to see all industry stakeholders – regulator, industry and technology vendors – come together to drive progress against SPOR data standards1, whichever angle they are coming from. Patient Representation: Championing Electronic Product Information In the context of human medicines, something else we very much need to see in 2020 is greater and more prominent representation of the patient voice in discussions and developments. It is ironic that, despite the public being the ultimate intended beneficiaries of IDMP medicinal data standards, this important stakeholder group currently has no seat at the table. It has long been accepted that few patients bother to open up and read the lengthy advice leaflets included with drugs, with their microscopic print and overly-thorough detail with a strong legal leaning. To address this, in due course patients will increasingly have access to more fit-for-purpose ‘instructions for use’ (IFU) content, and potentially broader product information, through a choice of media and distribution channels. Volume 12 Issue 1

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Audio instructions, video explanations and pictograms, delivered via websites or mobile platforms, are among the planned options. So, wherever patients are, and whatever their ability to comprehend the information, they will have a more accessible means of learning about the products on offer to them, how to get the best from them and when and how NOT to take them. Again, it cannot be overstated that the interpretation of the source information across different media is heavily dependent on having common data standards, reducing the risk of meaning or accuracy being lost in translation. But currently the rollout of these initiatives feels too far off, and it doesn’t help that there is no one specifically campaigning on patients’ behalf for these innovations to happen sooner; for a deadline for at least a first iteration of a new IFU format. As medicines become increasingly complex in their make-up, and as treatments become more personalised, the role of user-friendly content will only become more important, too. Again, standardised approaches to data are central to progress here, not least because companies need a way to govern and trace all of the information they are putting out into the market. A common set of definitions will allow both the pharmaceutical industry and the regulator to have an agreed understanding of the product, in whatever communication may follow. Cooperation & Mutual Support is the Answer in 2020 My hope for 2020 is that it will be a year of decisive action. Stakeholders from across the life sciences industry should look at the encouraging progress and development of use cases for

substance data, and accept veterinary medicine data developments as additional blocks they can build on for human medicines data developments under IDMP. In the meantime, all stakeholders need to work together to prioritise and drive the patient agenda. This involves demanding more work towards common definitions and process flow, so that a standardised European approach to electronic patient information can take shape – and a deadline for compliance can be set. People pay their taxes for this kind of thing: it’s time the industry delivered. REFERENCES 1.

Substance, product, organisation and referential (SPOR) master data, European Medicines Agency

Frits Stulp Frits Stulp is Managing Director of Iperion Life Sciences Consultancy, and a prominent mover in IDMP circles. He was Program Manager of the first completed IDMP implementation program and is a member of the EMA ISO IDMP Task Force. Email:

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Merger and Acquisition in Healthcare

Mergers and acquisitions (M&A) is a broad term used to refer to the partnership of companies or assets through various types of financial transactions, including mergers, acquisitions, associations, tender offers, purchase of assets and management acquisitions. The term mergers and acquisitions (M&A) refers to the process of one company combining with another. A merger is the combination of two firms, which subsequently form a new legal entity under the banner of one corporate name. In an acquisition, one company purchases the other outright. The acquired firm does not change its legal name or structure but is now owned by the parent company. Merger and Acquisition in the Healthcare Industry Healthcare mergers and acquisitions have been the cause of extensive debate across the medical industry, calling into question the tools and scale necessary to thrive in current care models in healthcare. But as industry professionals consider the business case for mergers and acquisitions, it is essential to also understand how these events impact the patient experience. There are two types of consolidation occurring in the healthcare industry. Vertical integration occurs when consolidation occurs between two companies producing different goods or services for one specific finished product, and horizontal consolidation occurs between firms who operate in the same space, often as competitors offering the same goods or services. Declining reimbursements and the need for capital, especially to invest in technology, also play a role in the increase in consolidation. The use of technology is almost essential for healthcare organisations that want to compete with other providers that utilise value-based payment.1 Advantages Publicised benefits of consolidation in the healthcare industry include: • Improved care management • Decreased repetition of clinical services • Enhanced clinical integration and management • Reduced operating costs in acquired hospitals • Increased local access to acute care services • Reduced organisational costs Disadvantages Challengers of consolidation cite the following disadvantages: • Increased average price of hospital services by 6−18 per cent • Reduced competition • No measured impact on quality • Limited patient benefits • Higher health insurance premiums, even with insurers paying less to providers Healthcare deal-making involves more players with different goals and new business models than ever before. It is a disservice to refer to healthcare M&A with the same vocabulary as in decades 12 Journal for Clinical Studies

past. Tried and true language still serves a purpose but does not express the aims and diversity of mergers and acquisitions in healthcare today. Merger and Acquisition in the Healthcare Industry in the GCC Region Business confidence in the healthcare sector in the GCC and the broader Middle East and North Africa (MENA) region is understandably buoyant. Since the beginning of 2015, the GCC region has witnessed a cycle of clear growth in the healthcare sector, a testament to growing consumer demand. This period of evolution in the sector coupled with a push by healthcare providers to broaden services, diversify and seek higher margin business has resulted in a surge in mergers and acquisitions (M&A) activity. As these providers enter a phase of consolidation, this M&A movement will continue. The surge in M&As has been especially notable in the UAE and Saudi Arabia, with the former alone seeing more than a dozen major healthcare acquisitions. Firstly, the region has witnessed substantial demographic shifts in recent years with the GCC population expected to reach 59.2 million people by 2020, up from 52.6 million last year. The second driver can be assigned to lifestyle. The GCC, unfortunately, is one of the global leaders in lifestyle-related, non-communicable diseases: more than half of the region’s population can be considered overweight. The final key factor has been the introduction of compulsory health insurance in the region. This provides residents with easier access to healthcare services and this therefore will increase demand. These market drivers have created a chance for growth that the healthcare sector is eager to pursue. An increased curiosity is noted in longer-term healthcare strategic assets, with PE investors focusing on value-building deals that possibly offer exit strategies after five years. In addition, a growing number of investors are seeking to create regional valuefor-money healthcare firms aimed at a wider population. Lastly, deal-making opportunities are moving from the competitive UAE to KSA, where the healthcare market remains largely untapped and there are upcoming opportunities as the government seeks to privatise a number of healthcare holdings. The region’s high projected growth rate is partly because of relatively low levels of investment currently. At just 4.9 per cent of gross domestic product (GDP), Bahrain’s spending on healthcare is the highest in the GCC, with Saudi Arabia and the UAE spending only 3.2 per cent. Globally, the average is 10 per cent of GDP.4 According to reports, the Middle East healthcare sector is expected to attract $200 billion in the next five years. Currently, opportunities for investors are abundant in the Middle East healthcare sector. As a result of this positive outlook for growth, investors are active in the sector and there has been an increase in investment activity. Recent deals include Aster DM Healthcare’s purchase of Volume 12 Issue 1

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a 57 per cent stake in Sanad Hospital in Riyadh for $245.1m; South Africa-based Mediclinic International’s acquisition of Al Noor Hospitals Group for $2.2bn in 2016; NMC Health’s acquisition of four healthcare companies in the UAE since 2015, including the fertility clinic Fakih IVF, which it picked up for $189.5m.4 Merger and Acquisition in the Healthcare Industry in UAE The UAE healthcare market is experiencing an astonishing and dramatic growth with the rising government initiatives. That is due to the sedentary lifestyle of the Emirates population  and the region's rising medical tourism. The UAE government is  also expanding and upgrading its healthcare system extensively  to develop strong, world-class healthcare infrastructure. The government also promotes and supports the involvement of the private sector to upgrade existing infrastructure and suit the service level quality provided in developed countries. In addition, the government of UAE is also liberalising policies to attract foreign investment to improvise the standard of healthcare and boost the healthcare sector.5 UAE has witnessed many merger and acquisition deals and strategic alliances between healthcare companies, both public and private. The government is also encouraging greater private participation in the UAE’s healthcare sector. The healthcare sector across the UAE has seemingly adopted a similar path to that witnessed at a regional level. There has been a substantial increase in the number of hospitals in the Emirates, especially between 2013 and 2017, where the total number of hospitals grew from 107 to 137. In 2018 the UAE government contributed a mammoth 66% towards the total expenditure of the country on healthcare, which amounted to a whopping USD 15 billion.6 A rapidly growing market through market transformation combined with a drive by different providers from the healthcare sector in order to diversify and gain higher margins has automatically seen a surge in mergers and acquisitions activity across the United Arab Emirates. NMC Health’s Royal Hospital at Khalifa City in Abu Dhabi was developed on land provided by the government and still cost a

projected $200m. The year before NMC Health purchased Al Zahra Hospital in 2016, the facility is reported to have made $38.8m in revenue. With a reported acquisition price of $560m, the priceearnings ratio (the share price relative to its per-share earnings) is projected at a high 14.5. So far, the performance of the region’s healthcare companies seems to justify these lofty estimates. UAEheadquartered Aster DM Healthcare, which operates 18 hospitals, as well as medical clinics and pharmacies, has plans to open five more hospitals in the GCC and India. Aster has confirmed plans to sell a stake through an initial public offering in India, with the chance of raising $234m. UAE’s expenditure when it comes to healthcare is expected to reach $2.4 billion in 2025 and $3.6 billion by 2030. And, according to the market reports, UAE’s healthcare expenditure has grown at a compound annual growth rate of 8.8 per cent between 2011 and 2019.6 Because of multiple factors like medical tourism, mandatory insurance, etc., there is increased spending in the country, and this contributes to a more integrated health system. Increases in healthcare spending from private and public sources are the most significant drivers, closely followed by the rapid market and infrastructural growth. REFERENCES 1. 2.

3. 4. 5. 6. witnessed_significant_MA_deals_in_Medical_Insurance_and_ Education_in_Q1_2018-ZAWYA20180409074226/ UAE-Healthcare-Sector-Outlook-2019-2023---Mergers

Adhiti Sharad Kumar Adhiti has over eight years of widespread experience in clinical research and market research. In clinical research, she has had experience handling different studies for multiple therapeutic areas. Adhiti also has experience in market research within industries such as Healthcare, FMCG and the Government sector across the MENA region. Email:

Journal for Clinical Studies 13

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The Use of Modelling and Simulation Studies in Early-phase Clinical Trials Improving experimental drug success rate and accelerating clinical development are top priorities for pharmaceutical and biotech companies. Careful and considered decision-making is essential early on in the process to minimise development time, manage a project’s costs and improve the probability of commercial success. The use of modelling and simulation tools can be a very useful strategy to mitigate such risks and make better-informed decisions. Modelling and simulation has been used in the pharmaceutical industry for over twenty years and has numerous advantages for drug sponsors. Its use in drug development involves modelling drug compounds, their mechanisms and disease-level data based on historical observations and existing real-life data. Computer simulations are run on these models to generate information that can be used to predict outcomes, thereby improving the quality, efficiency and cost-effectiveness of decision-making, both for internal and regulatory purposes. Modelling and simulation studies the effects of a drug in a “virtual patient population” using mathematical models that incorporate information on physiological systems. Simulations can be used to test assumptions, improve predictability, better characterise risk, and identify opportunities to optimise outcomes by observing the effects of different model inputs. For example, an understanding of the full range of potential outcomes can be cultivated by observing the effects of more extreme model inputs than have been observed in real-world patients. In this way, modelling and simulation can help drug developers to improve the planning and design of clinical trials by exploring and quantifying risks prior to their start. Physiologically-based pharmacokinetic (PBPK) modelling and simulation integrates prior knowledge and data generated through the research and development process to inform decisions for the next step of compound development, focusing on an understanding and a prediction of a drug’s absorption, distribution, metabolism and excretion (ADME) properties on targeted, “virtual” populations. PBPK modelling allows the investigation of various drug concentrations at the site of action that may mechanistically drive pharmacodynamic effects. From a regulatory standpoint, the U.S. Federal Drug Administration, European Medicines Agency, Japanese Pharmaceuticals and Medical Devices, as well as other global agencies encourage the use of modelling and simulation. It is considered an important drug development tool that enhances product and process understanding, with the ultimate goal of ensuring consistent performance once a drug is launched on the market. Modelling and simulation can assist in several areas of drug development, and answer the following questions: •

Can the starting dose of a first-in-human trial be optimised by extrapolating non-clinical data?

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• • •

Is it possible to accurately estimate complex drug-drug interaction profiles of a compound in silico and explore its potential effects on, for example, cytochrome P450 enzyme? Could the inhibitor effect at the site of metabolism (gut, liver, or any tissue) be predicted? Can drug behaviour in paediatric patient populations be predicted to support a paediatric investigation plan, based on existing adult data?

Case Study 1: Epilepsy Drug Development During the clinical development of an epilepsy drug, developers were looking to quantify the relationship between exposure monotherapy and seizure probability, and to simulate the effect of changing the dose regimen. Data from adult patients newly diagnosed with epilepsy and experiencing focal or generalised tonic–clonic seizures participating in a trial was used to create a structural time-to-event model for dropouts (not because of a lack of efficacy) and seizures. These dropout and seizure models could then be used for simulating the effect of changing the initial target dose on seizure freedom, allowing the drug’s developer to determine that the baseline disease severity was the most important predictor of seizure probability. Further simulations suggested that an adaptation of initial target dose could potentially benefit patients with greater disease severity, and this outcome was used to support the continued development of the drug product. Case Study 2: Accelerating Clinical Development by Bridging Phase I and II Studies A compound in a paediatric orphan indication had undergone a Phase I trial and modelling and simulation was proposed as a method to bridge to the Phase II study. Following a successful Phase I healthy volunteer study, modelling and simulation used data to predict the proposed dose for a paediatric population, upon which the Phase II trial was to be conducted. Using a cross-discipline team, including PK experts, medical directors and regulatory specialists, the Phase II trial was designed and integrated in the clinical development plan. With the data collected from the modelling and simulations, the paediatric investigational plan was developed and agreed with the necessary regulatory agencies, allowing for a rapid initiation of the Phase II trial.

Bruno Speder Bruno Speder is Head of Clinical Regulatory Affairs & Consultancy at SGS Clinical Research. He is a pharmaceutical engineer and has over 10 years of experience in drug development. He is also a member of the advisory board of several biotech companies and a guest lecturer on clinical research in the honours programme of Ghent University. Email:

Volume 12 Issue 1



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Journal for Clinical Studies 15


The Biggest Regulatory Moments of 2019 & How They’ll Impact 2020 2019 saw many noteworthy changes across the world in the regulatory industry. This article serves to provide the reader with a snapshot of a selection of the changes that have impacted the industry last year and will continue to do so, although it is by no means an exhaustive listing of all the changes globally. FDA Updates In the US, following on from a few changes at the FDA that were set in place from Scott Gottlieb’s resignation in March last year, Dr. Stephen Hahn was confirmed by the Senate in December. Dr. Hahn has taken over from Dr Brett Giroir, an interim commissioner who took over after the previous acting commissioner, Dr. Ned Sharpless, left. Dr. Hahn’s prior position was chief medical executive at the University of Texas MD Anderson Cancer Center. At the beginning of this year, the FDA published its annual list of “novel” drugs.1 The list of 48 “novel drugs” includes new drug applications (NDAs), biologic license applications (BLAs) and other incidental categories. 2018’s total was 59, however the level of activity is still trending higher than the 10-year average of 36. This demonstrates the positive environment for drug research and development in addition to the uptake of the variety of expedited pathways that FDA have in place. In fact 29 of the 48 drugs (60) had one or more of the expedited review categories (Fast Track, Breakthrough, Priority Review, and/or Accelerated Approval). Twenty-one of them received orphan-drug designation (which gives some added benefits to the drug developer) and 33 of the novel drugs (69%) received their first global approval in the US. In April 2019, the FDA announced changes in the FDA’s Office of New Drugs (OND)2 that would create enhanced review zones that would intersect disease areas and divisions, to maximise access to more focused and innovative areas of regulatory expertise. The changes increased the number of OND offices overseeing product reviews from six to eight, and increased the number of specific clinical review divisions from 19 to 27. The intent is to provide greater consistency and nimbleness. OND’s Implementation of the Reorganisation The changes to the structure of OND occur in four phases, as described below. Phase I: October/November 2019 •

The Office of New Drug Policy (ONDP), Office of Program Operations (OPO), Office of Drug Evaluation Sciences (ODES), and the immediate offices of Office of Regulatory Operations (ORO) and Office of Administrative Operations (OAO) will be “stood up”.

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Phase II: November/December 2019 The Office of Antimicrobial Products (OAP) will become the Office of Infectious Diseases (OID) • • • •

Division of Anti-Infective Products (DAIP) will become the Division of Anti-Infectives (DAI) Division of Anti-Viral Products (DAVP) will become the Division of Antivirals (DAV) Division of Pharm/Tox For Infectious Diseases (DPT-ID) will be formed from Pharm/Tox personnel currently in the OAP divisions A Division of Regulatory Operations for Infectious Diseases (DRO-ID) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO

The Office of Hematology and Oncology Products (OHOP) will become the Office of Oncologic Diseases (OOD) • Division of Oncology Products I & II (DOP I & II) will be split into three divisions (DO I, II, & III) • Division of Hematology Products (DHP) will be split into Division of Hematologic Malignancies I & II (DHM I & II) • Division of Hematology Oncology Toxicology (DHOT) will keep the same name in the new Office of Oncologic Diseases (OOD) • A Division of Regulatory Operations for Oncologic Diseases (DRO-OD) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO The Office of Neuroscience (ON) will be formed from select divisions in the Office of Drug Evaluation I, II • Division of Neurology Products (DNP) will split into Division of Neurology I & II (DN I & II) • Division of Psychiatry Products (DPP) will become Division of Psychiatry (DP) • Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) will become Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP) • Division of Pharm/Tox for Neuroscience (DPT-N) will be formed from Pharm/Tox personnel currently in divisions forming ON • A Division of Regulatory Operations for Neuroscience (DRO-N) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO Phase III: December 2019/January 2020 The Office of Nonprescription Drugs (ONPD) will be formed from the Division of Non-prescription Drug Products in the Office of Drug Evaluation IV Volume 12 Issue 1

Regulatory • • •

Division of Non-prescription Drug Products (DNDP) will be split into two divisions (DNPD I and DNPD II) A Division of Regulatory Operations for Non-prescription Drugs (DRO-NPD) will be comprised of regulatory staff from the corresponding clinical divisions and will report to ORO Non-clinical staff for ONPD will report to the immediate office of ONPD

The Office of Specialty Medicine (OSM) will be formed from divisions in the Office of Antimicrobial Products (OAP), and the Office of Drug Evaluation IV • Select staff from the Division of Transplant and Ophthalmology Products (DTOP) will transition to the Division of Ophthalmology (DO) • Division of Medical Imaging Products (DMIP) will become the Division of Medical Imaging and Radiation Medicine (DMIRM) • The newly created Division of Pharm/Tox of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (DPTRPURM) will also provide Pharm/Tox support to the Office of Specialty Medicine once ORPURM is stood up in Phase IV. Non-clinical staff will remain with their original supervisors from original divisions until Phase IV. • A Division of Regulatory Operations for Specialty Medicine (DRO-SM) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO Phase IV: February/March 2020 The Office of Cardiology, Hematology, Endocrinology, & Nephrology (OCHEN) will be formed from divisions in the Office of Drug Evaluation I, II, III, and the Office of Hematology and Oncology Products • • • •

Division of Cardiovascular and Renal Products (DCRP) will become the Division of Cardiology and Nephrology (DCN) Division of Non-Malignant Hematology (DNH) will be formed as a new division with personnel from the Division of Hematology Products (DHP) Select staff from the Division of Metabolism and Endocrinology Products (DMEP) will become the Division of Diabetes, Lipid, Disorders, and Obesity (DDLO) Select staff from the Division of Bone, Reproductive, and Urologic Products (DBRUP) and Division of Metabolism and Endocrinology Products (DMEP) will become the Division of General Endocrinology (DGE) Division of Pharm/Tox for Cardiology, Hematology, Endocrinology, and Nephrology (DRO-CHEN) will be formed from Pharm/Tox personnel currently in Divisions forming OCHEN A Division of Regulatory Operations for Cardiology, Hematology, Endocrinology, & Nephrology, (DRO-CHEN) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO

The Office of Immunology and Inflammation (OII) will be formed from divisions in the Office of Drug Evaluation II, III and the Office of Antimicrobial Products • Select staff from the Division of Transplant and Ophthalmology Products (DTOP) and the Division of Pulmonary, Allergy, Rheumatology Products (DPARP) will form the Division of Rheumatology and Transplant Medicine (DRTM) • Select staff from the Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) will become the Division

• • •

of Pulmonology, Allergy, and Critical Care (DPACC) Select staff from the Division of Gastroenterology and Inborn Errors Products (DGIEP) will form the Division of Gastroenterology (DG) and the Division of Hepatology and Nutrition (DHN) Division of Dermatology and Dental Products (DDDP) will become the Division of Dermatology and Dentistry (DDD) Division of Pharma/Tox for Immunology and Inflammation (DPT-II) will be formed from Pharm/Tox personnel currently in divisions forming OII A Division of Regulatory Operations for Immunology & Inflammation (DRO-II) will be comprised of regulatory staff from the corresponding clinical Divisions in this Office and will report to ORO

The Office of Rare Diseases, Pediatrics, Urologic, & Reproductive Medicine (ORPURM) will be formed from divisions in the Office of Drug Evaluation III, IV • Division of Pediatrics and Maternal Health (DPMH) will be aligned to ORPURM in the new structure • Select staff from the Division of Gastroenterology and Inborn Errors Products (DGIEP) will form the Division of Rare Diseases and Medical Genetics (DRDMG) • Select staff from the Division of Bone, Reproductive, and Urologic Products (DBRUP) focused on Urologic, Obstetric and Gynecologic Products will form the new Division of Urology, Obstetrics, and Gynecology (DUOG) • Division of Pharm/Tox of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (DPT- RPURM) will be a newly formed division with shared P/T support to OSM • Division of Regulatory Operations for Rare Diseases, Pediatrics, Urologic, and Reproductive Medicine (DRORPURM) will be comprised of regulatory staff from the corresponding clinical divisions in this office and will report to ORO FDA Guidance Documents Over the past year, the FDA issued several new draft guidance documents as well as finalising guidance documents that have been in draft. It is important to note that the guidance describes FDA’s current thinking on a topic and are to be viewed as recommendations. Finalised Guidance Documents from the FDA Include but are not Limited to the Following: Guidance: Considerations for the Inclusion of Adolescent Patients in Adult Oncology Trials3 was published to facilitate industry with the recommendation of the inclusion of adolescent patients (ages 12 to 17) in relevant adult oncology clinical trials that are disease and target-appropriate, to enable earlier access to investigational and approved drugs for adolescent patients with cancer. The guidance gives appropriate criteria for the inclusion of adolescent patients in adult oncology trials, dosing and pharmacokinetic (PK) evaluations as well as safety and ethical requirements. Guidance: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products4 was finalised “to assist industry in developing enrichment strategies that can be used… to demonstrate the effectiveness of drug and biological products. Enrichment is the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population. Although this guidance focuses on enrichment directed at improving the ability of a study to detect a drug’s effectiveness, similar strategies can be used in safety assessments.” Journal for Clinical Studies 17

Regulatory Guidance: Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment Guidance for Industry5 has been finalised to assist sponsors in the clinical development of drugs and biological products for the treatment of amyotrophic lateral sclerosis (ALS). It provides insight into FDA’s current thinking regarding the clinical development for drugs to support an indication for the treatment of ALS. This guidance focuses on specific clinical drug development and trial design issues that are unique to the study of ALS. Guidance: Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry6 provides guidance “to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic”. It describes “important principles for designing, conducting, and reporting the results from an adaptive clinical trial” advising “sponsors on the types of information to submit to facilitate FDA evaluation of clinical trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design”. Guidance: Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products7 provides recommendations for the use of placebos and blinding in randomised controlled clinical trials in development programmes for drug or biological products to treat haematologic malignancies and oncologic diseases. Guidance: Adaptive Designs for Clinical Trials of Drugs and Biologic8 sets out FDA’s recommendations on adaptive trial design principles and the information the FDA will review from adaptive studies submitted as part of investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs) and supplemental applications. In addition to minor editorial changes, the guidance also clarifies FDA’s recommendations for Bayesian adaptive designs and its expectations for the extent of pre-specification required for governing adaptations to studies.   FDA has Issued the Following New Draft Guidance Documents: Guidance: Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients9 gives recommendations “regarding minimum age eligibility criteria and addresses specific situations

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in which the inclusion of children (aged 2–12) and adolescents (aged 12 to 17 years) is appropriate in cancer trials (i.e., based on disease biology and clinical course, molecular target of the investigational drug, and/or its molecular mechanism)”. Guidance: Rare Diseases: Natural History Studies for Drug Development.10 The focus of this guidance is rare diseases; however, recommendation 22 in the guidance may be applicable to drug development for non-rare diseases. This guidance describes the broad potential uses of a natural history study in all phases of drug development for rare diseases, the strengths and weaknesses of various types of natural history studies, data elements and research plans, and a practical framework for the conduct of a natural history study. This guidance also discusses some considerations for aligning the study design with study objectives and for enhancing the interpretability of study results; patient confidentiality and data protection issues in natural history studies; and potential interactions with FDA related to these studies. Guidance: Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics11 is intended to encourage “sponsors and applicants who are using real-world data (RWD) to generate real-world evidence (RWE) as part of a regulatory submission to FDA to provide information on their use of RWE in a simple, uniform format. RWD are data relating to patient health status and/or the delivery of health care that are routinely collected from a variety of sources. RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD”. Guidance: Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs12 proposes ways to increase patient diversity in clinical trials. Previously the focus has been to promote enrolment practices; however, this guidance has focused on having sponsor companies to include more historically underserved populations in clinical trials such as women, the elderly and minorities.   Guidance: Non-alcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment13 provides much welcomed guidance on “the enrollment criteria, trial design, efficacy endpoints, and safety considerations for phase 3 trials.” It also identifies “knowledge gaps that represent important challenges in the development of drugs for this indication.”

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Revised Guidance: Rare Pediatric Disease Priority Review Vouchers14. This revised guidance to industry is to clarify the process and reflect changes as a result of the Advancing Hope Act of 2016. The vouchers (potentially lucrative because they are transferable) can be used to reduce the time of an FDA new drug approval review to six months from ten months. Companies have sold them for as much as $350 million and as little as $80.6 million. The revisions include a new definition for rare pediatric disease, to define the pediatric population as from birth through to 18 years. FDA previously considered the pediatric population as from birth to 16 years. The guidance also explains how the rare pediatric disease PRV program shows how the FDA will not be able to designate products for the rare pediatric disease priority review voucher program after September 2020, and the agency cannot award any rare pediatric review vouchers after September 30, 2022.   Guidance: Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products15 is a guidance, for comment only, providing guidance to sponsors and applicants on “interacting with the FDA on complex innovative trial design (CID) proposals for drugs or biological products. FDA is issuing this guidance to satisfy, in part, a mandate under section 3021 of the 21st Century Cures Act (Cures Act).” The guidance “discusses the use of novel trial designs in the development and regulatory review of drugs and biological products, how sponsors may obtain feedback on technical issues related to modeling and simulation, and the types of quantitative and qualitative information that should be submitted for review.”      Qualification Process for Drug Development Tools Guidance for Industry and FDA Staff16 is a draft guidance explaining its

qualification process for drug development tools (DDTs) in line with the 21st Century Cures Act. It provides a detailed overview of the general concepts surrounding the DDT qualification programme, a discussion of each of the three stages of the qualification process and explains how qualified DDTs may be modified or rescinded.   EMA Updates Early last year EMA published a questions-and-answers (Q&A) document on the preparatory work that European Union authorities were undertaking to prevent medicine shortages due to the United Kingdom’s withdrawal from the EU.17 The EMA also relocated from London to Amsterdam18 and reported that Brexit Costs EMA Almost €60M in 2019.19 In the same manner as the FDA, the EMA is keen to support drug developers and issued a report on the previous year’s workshop that was attended by regulators from the EU’s national competent authorities, EMA, the FDA and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), as well as industry representatives. The aim of the workshop was “to discuss scientific and regulatory approaches to address quality and manufacturing challenges encountered during the development of medicines under early access… such as the PRIority MEdicines scheme (PRIME)20 in the European Union and the Breakthrough Therapy designation21 in the United States”. The report contains recommendations from participants on next steps and areas to be further explored by both the EMA and the FDA.22 EMA took note of the European Ombudsman recommendations on avoiding bias.23,24 In addition, EMA issued a Guide on Consistency of Indication Wording25 on factors reviewers should Journal for Clinical Studies 19

Regulatory consider to ensure the wording of therapeutic indications is consistent across products. “Stakeholders, who rely on this information for their work, have raised concerns that therapeutic indications may be worded inconsistently and can contain varying levels of detail,” EMA writes, noting that more consistent and detailed indications can benefit healthcare professionals, health technology assessment (HTA) bodies and payers. The EMA finalised a Clinical Development Guideline for New Gout Treatments.26 Within the guideline, EMA provided recommendations for patient selection, safety and efficacy assessments and clinical trial design, in addition to discussing further considerations for studies in elderly, paediatric and renally impaired patients. However, EMA points out that “the study design, inclusion criteria, primary endpoints and trial duration largely depend on the treatment goal and mode of action of the new drug.” The EU’s clinical trial regulation was adopted and entered into force in 2014, but its application is contingent on a functional clinical trials information system, which is determined via an independent

20 Journal for Clinical Studies

audit. The European Commission (EC) recently updated guidance27 on the incoming clinical trials regulation, with new questions and answers (Q&As) on requests for information (RFIs), how assessment reports will be made public and the sponsor’s responsibilities regarding changes to a clinical trial that are not substantial modifications but are relevant for supervising the trial. Regulatory Agency News •

The EMA offered line-by-line comments and edits on the FDA draft guidance on comparative analytical assessments for biosimilars.28

ICH E8(R1) General Considerations for Clinical Studies draft guideline29 was released for public consultation. The guideline focuses on designing quality into clinical studies, considering the diversity of clinical study designs and data sources used to support regulatory and other health policy decisions.

The FDA launched the Expanded Access Pilot ‘Project Facilitate’. Under Project Facilitate30, FDA has set up a call

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Regulatory centre to serve as a single point of contact for oncologists to reach out to for assistance with completing and submitting expanded access requests for single patient investigational new drug (IND) applications. •

FDA undertook its first action under a new international collaboration, Project Orbis, with Australia and Canada, designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma (31), within a couple of months. FDA announced Project Orbis may expand to Singapore and Switzerland.32

Towards the end of the year, the FDA proposed to withdraw four NDAs after the companies failed to submit annual reports.33

Summary 2019 proved to be another year of change within the industry. Drug developers are in a dynamic environment with a constant change within the regulatory landscape. We expect further changes in 2020, but also some stability for agencies as they settle into another routine of what is expected of them as regulators and as what they will expect from drug developers. REFERENCES 1.

FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, Advancing Health Through Innovation: New Drug Therapy Approvals 2. 3. Considerations for the Inclusion of Adolescent Patients in Adult Oncology Trials (finalised 03/12/2019) GuidanceComplianceRegulatoryInformation/Guidances/UCM609513. pdf 4. Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products (finalised 03/14/19) https://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM332181.pdf 5. Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment Guidance for Industry (published 23 Sep 2019) media/130964/download 6. Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry (published 29 Nov 2019) download 7. Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug and Biological Products Guidance for Industry (published 28 Aug 2019) 8. FDA Finalizes Guidance on Adaptive Trial Designs (published 02 Dec 2019) 9. Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients (03/12/19) ComplianceRegulatoryInformation/Guidances/UCM633138.pdf 10. Rare Diseases: Natural History Studies for Drug Development (03/22/19) Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM634062.pdf 11. Guidance: Submitting Documents Using Real-World Data and RealWorld Evidence to FDA for Drugs and Biologics (published 08 May 2019) 12. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry (published 06 Jun 2019) 13. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry (published 06 Jun 2019) 14. Guidance: Rare Pediatric Disease Priority Review Vouchers (published

XXXX) 15. Guidance: Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products (published 20 Sep 2019) https://www. 16. Qualification Process for Drug Development Tools Guidance for Industry and FDA Staff (published 13 Dec 2019) media/133511/download 17. 18. 19. 20. prime-priority-medicines 21. 22. Supporting medicine developers in generating quality data packages in early access approaches (PRIME and breakthrough therapies): workshop report published (published 31 Jul 2019) en/news/supporting-medicine-developers-generating-quality-datapackages-early-access-approaches-prime 23. 24. 25. EMA Guide on Consistency of Indication Wording (published 21 Oct 2019) 26. guideline-clinical-investigation-medicinal-products-treatment-goutfirst-version_en.pdf 27. EC Offers Further Clarity on Clinical Trial Regulation (12 Nov 2019) regulation5362014_qa_en.pdf 28. 29. ICH E8(R1) General Considerations for Clinical Studies draft guideline was released for public consultation (31 Jul 2019) media/129527/download 30. 31. 32. FDA’s Project Orbis May Expand to Singapore and Switzerland (published 12 Nov 2019) 33.

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

Journal for Clinical Studies 21


Rescue Trials – When Should You Call for Help? Although previously very rare, more and more trials are becoming in need of 'rescue' as competition for resources means less experienced staff are left to manage unforeseen problems or ensure projects keep to their timelines. The timeline is moving way off schedule. Site activation is much slower than was forecast and subject enrolment is delayed as well. At this rate the last patient in may be 12 months late and the budget 30% higher due to delays. No one seems sure how to deal with all the delays and the CRO is beginning to run out of ideas. Trust is breaking down and the working relationship is becoming fractious. The sponsor team is now looking at all options to correct this situation. If any of this sounds familiar, then it's almost certainly time to shout for help. In the past, the great majority of clinical trials never reached this point, and although there are always likely to be a few unforeseen circumstances, these should be eminently solvable if there is good rapport between the sponsor, CRO, and investigators. Now, with more trials than ever taking place for a more diverse range of pharma and biotech sponsors, it is a scenario that is becoming far more common. In some cases, the problems are so great that the only answer is to 'bite the bullet' and call in someone who can 'rescue' the study. This may be in the form of a sr. consultant or another CRO who can remedy the situation. Before dealing with what to look for in, and how to construct, a 'rescue package', it is useful to review some of the scenarios that typically cause a tipping point to be reached. This is important if only to ensure these can be identified early on and, hopefully, help stop the study reaching a crisis point. Avoiding the need to switch CROs in a rescue scenario is always preferable, but it is also good to know when to make a change for the better. At the onset of a project, one of the most obvious risks is patient enrolment failing to meet its targets. In many cases, this could be down to not enough careful thought going into exactly how and where patients are going to be recruited, or that the right sites were not selected. For example, institutional sites can often run the IRB approval process a lot slower than private clinics and delay opening. Alternatively, it could be failing to get patients involved and retained within the study or finding too many patients who do not meet the protocol-specified inclusion criteria. Even with the right sites, it could be that not enough personnel have been deployed who have the depth of knowledge required to deal with very complex feasibility and start-up activities needed to help sites manage enrolment effectively. However, in many cases the problems stem from three main causes: money, experience, and attention — or rather a lack of them. In order to win the business, it's not unusual for a vendor to go in with a low budget. This usually spells trouble right from the start, as it will be impossible to allocate the level of resources needed to 22 Journal for Clinical Studies

meet the timelines. Lack of resources leads to lack of attention or energy devoted to the trials and leads to disorder or entropy, as it is commonly called. Even if the budget is adequate, then problems can still arise because the CRO may have over-stretched themselves and has no option but to allocate some less experienced staff to the team. As mentioned earlier, with more trials taking place there is likely to be competition for staff with proper 'hands-on' experience in a particular therapeutic area. If things run smoothly, this may be fine. But, if problems crop up, it may take a lot longer to resolve them satisfactorily with the sponsor and investigators. With more competition, and with other sponsors running similar trials at the same sites, hands-on experience is imperative to detect this and evolve a counter strategy to enroll subjects. A third common cause of dissatisfaction is a lack of attention and scrutiny by senior staff responsible for the project. The expectation is that more management attention is given to large, high-profile projects, typically with large sponsors with a large amount of business. This means that smaller and medium-sized customers, with smaller overall trial commitments, can sometimes be seen as a lower priority. Big, high-profile studies tend to get the biggest available resources. Ways of working can also cause problems. While controlled processes are imperative for successful study execution, some commonly used processes can leave little room for flexibility. So, when problems arise, it may be very hard, if not impossible, to deviate from these processes in order to offer an effective solution to a sponsor’s acute needs. This can be especially true if this requires outside of the box thinking and execution. This 'strait jacket' can certainly lead to an inability to act nimbly, either for budgetary reasons, or just an inherent aversion to making the necessary changes needed to meet the sponsor's needs within the required timeline. It takes a long time to turn a large ship 180 degrees. If things go awry, and do not look like they will ever get back on track, then the sponsor’s study director and leadership will have a very difficult decision to make; "Is it time to pull the plug and appoint a new CRO to rescue the study or throw more money at the situation and hope the incumbent will turn things around?" Typically, his or her project manager and staff have probably confided that, "I’ve done everything I can to work with the CRO to fix the situation and still the results day after day remain unsatisfactory." But, any switch will have major budget implications, not only due to the appointment of a new CRO, but also because some of the work that has already been completed may need to be repeated, and done to the sponsor's original requirements. However, in many ways, the financial aspect is actually of secondary importance. The overriding priority at this stage is to avoid making the same mistake with partner selection again. This leads to the inevitable conclusion that any 'rescue' partner must be a known entity, and one in which the sponsor can have complete trust, with a track record of turning challenging studies around. That's why they should concentrate their attentions on two potential sources for Volume 12 Issue 1

Regulatory help: 1) companies they have worked with in the past that deliver; 2) and suppliers who may have missed out in the original selection process. An alternative, which may be the best solution, is to seek a CRO known to have rescued many studies that understands these challenges. Usually the sponsor will have a pretty clear idea of what the problem is, otherwise, there would not be a trigger to do something different. At this stage, they may recognise that a proposal they rejected was, in hindsight, a far better solution. Or, they may feel that, based on previous relationships and working experience, a known partner is more capable of solving the problems that have arisen. In both circumstances, trust is the vital element, which is why a CRO that meets these two requirements, and has a track record of successfully rescuing trials, is seen as the safest option. Once appointed, the main challenges facing the new 'rescue' CRO are adhering to strict deadlines during and after the transition period and keeping the costs in line. They may have to deliver some bad news about extended deadlines, but it is important to manage expectations realistically right from the start. To some extent, time pressures should already be well defined, as they are often the key driver for a rescue. So the proposed solution should also be made clear, at least in concept, in the joint agreement between the new CRO and the sponsor to take on the rescue. The details regarding how the new plan can be executed should then be agreed. These may vary from one study to another, but there are certain activities that every project requires: the transfer of the existing information, tools and processes to address the issues that caused the rescue situations, and renewed communications with the study sites to confirm the commitment of the project team to support them. The investigators and coordinators will have to start working with a new team and, possibly, change their processes. So, it is vitally important to get them 'on board' as soon as possible by discussing the underlying issues. Here, being proactive and interactive should allow the rescue team and the investigators to work collaboratively to identify and solve whatever bottlenecks have precipitated the need for a rescue mission. Again, establishing trust between the sponsor, investigator team, existing service providers, and the new CRO is crucial. The handover process itself can be very labour-intensive initially, but will depend on the nature of the rescue. If it's a complete study handover then that’s one thing, but sometimes it may be more of a 'tidy up' or facilitation. For example, a company recently rescued a project at the very end of enrolment in a Phase III trial where they were brought in alongside the incumbent CRO to ensure timely data cleaning, collection and entry. They provided additional resources with focused expertise in data management. As a result, this intervention ultimately allowed the sponsor to meet their deadlines with high quality data to support their trial. On another occasion, a CRO was called in to support a very specialised study that was outsourced to a niche CRO that, while being very good with this specific indication, lacked experience in monitoring and specifically on study closeout activities. The sponsor approached the new CRO to help them do a second round of monitoring and ensure the necessary source documentation was being accurately checked and documented at the site, and consistent with findings that surfaced post data review. They also dedicated a rescue data management team to help the sponsor sort through their queries, review their data, and execute on the delivery of high-quality data.

So, what is likely to happen when a carefully selected 'rescue team' is called in? Obviously, they will need a consultation period to review the project and current situation to see: how far it has progressed; what problems have been encountered that triggered the need for a switch; and what solutions, if any, have been already tried. Typically, it may take between three and four weeks to really understand the situation. Based on the needs, a dedicated rescue team would be then assembled, made up of appropriately skilled experts, who can start working on potential solutions. This may take a further week to ten days, by which time a strategic proposal can be submitted to the sponsor. Once approved, the team can immediately start chipping away at specific issues and offer more comprehensive solutions to get the study back on track. Conclusion By securing the right level of support and experience, it is often possible to get a problematic trial back on track, albeit with potential impacts on the timeline and the budget. No one really wants to shout for help, particularly if this means having to admit they chose the wrong partner initially. But reliable and experienced support is out there and ready to step in quickly and efficiently. To avoid making the same mistake again, sponsors should always consider: CROs who they have worked with well in the past; those who, in hindsight, might have submitted a more appropriate plan of action (even if it was not the fastest or cheapest option); and those who have a track record of stepping in and successfully rescuing other trials. Sometimes, it can of course simply come down to bad chemistry, therefore trust in any partner is an underestimated factor that can be the difference between a difficult trial’s success or a potential rescue.

David Ng David Ng, PhD., is Vice President of Biometrics at WuXi Clinical. David has over 25 years of experience in biostatistics, data management, and strategic management. David's clinical development experience covers drugs, biologics, and devices and has extensive experience in a wide range of therapeutic areas, including oncology, heart disease, central nervous system, immunology, and infectious diseases. David has successfully designed the proof-of-concept endpoints and research, and the project he was in charge of has been approved after it was submitted to the FDA. David is committed to establishing data management services in Asia and has been involved in the development of data management systems and processes for more than 25 years. Email:

Leslie Jones Leslie Jones is the Executive Director of Clinical Operations US for WuXi Clinical. She has over 25 years of clinical research experience, ranging from working in a Phase 1 unit, to performing GCP site audits, to managing clinical and data teams on large-scale Phase 2 and Phase 3 trials. She has a great ability to unify internal and external resources and provides focus to the teams to achieve client goals and outcomes. She has been with WuXi Clinical for over a decade and is based in Austin, TX. Email:

Journal for Clinical Studies 23

Market Report

Ensuring Effective Financial Management in Sponsored Research in Malaysia The principles of developing, conducting, analysing and subsequently reporting clinical research are widely known.1–3 However, the success of a clinical trial goes beyond these principles. It also requires a structured, viable and businesslike management of the whole process, without which trials may fail.4 A critical part of managing clinical trials is a solid, well thought out clinical trial budget.5 A successful budget to ensure a good quality clinical trial should not only entail careful detailing of costs that are in line with the trial protocol, but should also include a financial management system that executes this budget in an efficient, timely and transparent manner. Some issues and challenges in formulating clinical trial budgets could be applicable when managing the finances during conduct of the trials. Examples include how to maintain audit trails and being abreast of billing processes, ensuring all costs have been encountered for, and management of residual monies. Though ultimately the responsibility of the principal investigators, the detailed construction of a clinical trial budget and its management places a huge burden on physicians (or researchers) who have to juggle clinical practice while overseeing the running of multiple clinical trials. Reducing the Burden of Principal Investigators Established in 2012, the main objectives of Clinical Research Malaysia (CRM) are to effectively increase the speed, reliability and quality in delivery of outcomes of clinical trials conducted within the country. This is in line with the Malaysian government’s vision to enhance the country’s placing among other clinical trial hubs as a preferred global destination for clinical research.6 CRM, therefore, is also equipped to manage the financial aspects of clinical trials and is currently used extensively by principal investigators, investigators, contract research organisations (CRO) and sponsors conducting clinical trials in Ministry of Health facilities. CRM’s financial management services extend throughout the trial process, i.e. from prior to study initiation to its close. Legal services are also included during the initial process to support the management of clinical trial agreements (CTAs), parallel with negotiations and refining of the trial budget. CRM reviews and endorses the study budget for the CTA within seven working days (from the last feedback date received from the relevant party involved in the budget negotiation). CRM takes on full financial and administrative duties that include initial budget negotiation with sponsors/CROs and investigators, keeping track of the trial progress, budget and invoicing, receipt of funds from sponsors/ CROs and payments to various stakeholders involved. CRM also prepares statements of account for the principal investigators 24 Journal for Clinical Studies

on a monthly basis to facilitate better planning of clinical trial activities. Facilitating Initiation of Clinical Trials Involvement of the finance team starts just prior to initiation of the clinical trial in collaboration with the legal department, principal investigators, CROs and sponsors. This is crucial, as CROs, sponsors and investigators each bring expertise required for the conduct of specific types of trials, whilst the finance team contributes with their experience working on the financial aspect of clinical trials across the board. The legal team facilitates the process by ensuring that the CTA meets local requirements. The finance team also supports CROs, sponsors and investigators when negotiating and finalising the trial budget with approval from these parties. The timeframe for this process is expedited by a dedicated team handling the details of the negotiations and preparation of the approved final budget for submission, though it is still dependent on response time from CROs, sponsors and investigators. Financial Management During Trial Conduct CRM’s involvement in the management of the clinical trial budget is to reduce payment time through a standardised financial process by prompt issuing of invoices and providing efficient disbursements of payments. This ensures that the financial management of clinical trials conducted by investigators at their respective clinical trial sites has a proper audit trail and is executed in an efficient and transparent manner. Prior to the establishment of CRM, all financial transactions to and from government linked facilities were routed via established local medical societies or the clinical research arm of the Ministry of Health (Clinical Research Centre). Between 2012 and March 2015, payments to investigators had to go through a trust account under the purview of the Director of Kuala Lumpur Hospital. Due to red-tape processes, payments could take at least a month. However, from April 2015, CRM’s role expanded to making payments out directly to investigators and study team members (specifically government-employed staff affiliated with Ministry of Health facilities) and similarly reduced the timelines to within two weeks. With the advancement of online banking facilities in Malaysia, these timelines have further reduced. In 2018, the total value of trial budget managed by CRM was RM 39.5 million, compared to 2015 which was only about RM8.3 million, translating to more than four times in the growth of the budget management. In addition, CRM’s responsibilities encompass ensuring there are enough funds available for the smooth running of a clinical trial by keeping track of the budget and communicating with sponsors so that payments are as scheduled in the trial budget Volume 12 Issue 1

Market Report

and CTA. If, for any undue reasons, receipt of funds from sponsors is delayed, CRM steps in to guarantee timely payments to vendors and study subjects, ensuring that trials are on track. All receipts and disbursements of funds are carefully tracked, and monthly statements of account are sent to the principal investigators for review. All financial processes performed by CRM are also audited by internal and external auditors, which include the National Audit Department and the Ministry of Health. During the close of a trial, CRM provides an added service of negotiating the best price for archiving trial-related documents from third-party vendors. This enables cost savings in a clinical trial budget as well as more efficient conduct during clinical trial study closure. Conclusion CRM in essence acts as an account manager with in-house expertise in clinical trial budget management. Its focus is to streamline the processes for all clinical trials conducted in Ministry of Health facilities and involving Ministry of Health staff. CRM facilitates the clinical trial process from the budget negotiation stage, receipt and disbursement of study funds and lastly, archiving services upon study closure. REFERENCES 1.

European Medicines Agency. ICH Topic E8: General considerations for clinical trials – Step 5 (CPMP/ICH/291/95). March 1998. 2. National Pharmaceutical Regulatory Agency, Ministry of Health Malaysia. Malaysian guideline for good clinical practice. Fourth edition. 2018. 3. Chew BH. Planning and conducting clinical research: the whole process. Cureus 2019;11(2): e4112. DOI: 10.7759/cureus.4112. 4. Farrell B, Kenyon S, Shakur H. Managing clinical trials. Trials 2010;11:78. Available at Accessed October 2019. 5. Hatfield E, Dicks E, Parfrey P. Budgeting, funding and managing clinical research projects. In: P. Parfrey and B. Barrett, editors. Methods of

Molecular Biology, Clinical Epidemiology, vol. 473. Totowa, New Jersey: Humana Press, 2009; 299-311. 6. Ooi AJA, Khalid KF. Malaysia’ clinical research ecosystem. Applied Clinical Trials 2017. Available at http://www.appliedclinicaltrialsonline. com/malaysia-s-clinical-research-ecosystem. Accessed October 2019.

Audrey Ooi Audrey Ooi is currently the Acting Head of Business Development at Clinical Research Malaysia. She graduated from Monash University with a Bachelor of Medical Science and went on to obtain a Master’s Degree in Medical Science from the University of Malaya. She has extensive experience in various fields within the healthcare and clinical research industry including medical writing, corporate communication, project management and stakeholder engagement. Email:

Yau Yit Huan Yau Yit Huan completed his professional accountancy qualification from the Association of International Accountants (AIA), in the United Kingdom. He has 18 years of experience in accounting and auditing. Mr Yau joined CRM as Finance Manager in 2013 before being promoted to the position of Senior Finance Manager and subsequently as Head of Finance & IT. Email:

Journal for Clinical Studies 25


Exploring the Limb Girdle Muscular Dystrophy Clinical Trial Landscape With the recent advent of adeno-associated, virus-based gene therapy treatments, limb girdle muscular dystrophy (LGMD) is currently attracting the attention of the biopharmaceutical industry, especially with the goal of restoring full or partial proteins that are otherwise dysregulated. Because of the multiplicity of LGMD subtypes (greater than 35 subtypes identified to date – each with a number and unique letter to identify it), is it likely that not all subtypes will be targeted simultaneously for drug development in the short term. For example, in contrast to Duchenne muscular dystrophy (DMD), where a dysregulation of the protein dystrophin is deemed to be the mechanism of action, LGMD presents as a complex of multiple subtypes of disease with sarcoglycan and dysferlin as the primary dysregulated proteins. Several sponsors are developing potential gene therapies for LGMD patients. Therefore, LGMD patients have a choice of clinical trials, which can raise new challenges for recruitment. Additionally, trial sites are selected based on a myriad of factors, which may include sponsor choice (for an individual company’s business purposes or rapid enrolment considerations), the physical location of the clinical sites (based on feasibility and capability), the site’s principal investigator, regional marketing considerations, and ease of patient access. These complexities must be balanced against the risk of conducting trials in countries/regions that may lack the ability, expertise, or capacity to participate. This article describes the results of a proactive, global LGMD feasibility study conducted by IQVIA in 2019, including insights from investigators currently providing LGMD patient care. The feasibility study asked 32 questions about physician interest in and motivation for LGMD clinical trial participation and solicited data regarding the investigatorestimated numbers of LGMD patients available for clinical trials by age group and for subtypes of LGMD identified by Nigro and Savarese. Over 200 investigators were polled in 48 countries with a response from 116 investigators across 36 countries. Overview of the Muscular Dystrophies and US Impact Muscular dystrophies (MD) comprise a group of multi-systemic diseases caused by defects in genes for the production of muscle proteins. These diseases manifest clinically as progressive muscle weakness, with associated loss of mobility, agility and body movements. Ongoing elucidation of the proteins and structures involved in certain disease processes has boosted the number of potential pharmaceutical targets, with significantly heightened interest in investment, partnership and collaboration as a result. The research community could benefit from tools to identify where 26 Journal for Clinical Studies

patients are eligible and willing to participate in clinical research and where trial sites have adequate experience and resources to conduct the complex protocols that will be forthcoming. Although the muscular dystrophies are rare in terms of individual disorders, when combined with other neuromuscular disorders, they have a significant influence on the global economy. For example, the IQVIA Institute estimates that, collectively, the neuromuscular disorders impact 250,000 patients and their caregivers in the US alone. Analysis of healthcare charges using IQVIA real-world data indicates that total annual charges across all neuromuscular patients in the US exceed $46 billion.1 Overview of the Limb Girdle Muscular Dystrophies The LGMD group contains heterogeneous autosomal muscular dystrophies under the phenotype of progressive proximal weakness at the hip and shoulder girdles. There are multiple forms of LGMD due to mutations in different genes (such as CAPN3, DYSF, SGCA, SGCB, SGCG, SGCD, TTN and ANO5).2 Determinants of specific diagnoses include the distribution of weakness; ethnicity; family history; age at onset; rate of disease progression; presence of contracture, rigidity, rippling muscle, muscle hypertrophy or atrophy; and systemic involvement including cardiac, pulmonary, and skin complications.3,4 By definition, the term “limb girdle muscular dystrophy” usually excludes other defined types of muscular dystrophies such as Duchenne and Becker MD, myotonic dystrophies, and facioscapulohumeral muscular dystrophy.5 Ethnicity and family history may reveal recessive vs. dominant variants endemic to certain regions, e.g., LGMD 2A in southern Europe. In some families, the inheritance pattern and the exact gene mutation cannot be determined. Complicating the diagnostic process are substantial overlaps, as mutations in different proteins that share similar cellular functions can result in almost identical clinical phenotypes. There is no standard of care for patients with LGMD,6 though as with Duchenne MD, physicians often prescribe corticosteroids. In addition, supportive therapy is often prescribed for those patients with cardiopulmonary issues and cognitive issues. Many LGMD patients take various vitamin supplements, although little is known or proven about vitamin supplementation in patients with LGMD.7 Increasing Number of Clinical Trials in LGMD In addition to the heterogeneity of LGMD, the ultra-rare characteristics of each subtype add to clinical trial recruitment challenges. This article addresses the global LGMD landscape for a better understanding of patient distribution, aimed at overcoming these challenges. Volume 12 Issue 1

Therapeutics LGMD clinical trial success relies upon site selection, which may include sponsor choice (for business purposes or rapid enrolment considerations, based on feasibility and capability), advice from patient advocacy groups specific for the subtype (e.g., Jain Foundation, Coalition to Cure Calpain 3, Family Group of Beta-sarcogylcanopathy, etc.), locations of natural history studies (e.g., Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy or GRASP study),6 the physical location of the clinical site, the site’s principal investigator’s speciality, regulatory requirements, marketing considerations and ease of access. These complexities must be considered when considering conducting trials in countries/regions that may lack the ability, expertise, capacity or willingness to implement LGMD studies. It is worth highlighting that some sponsors of LGMD treatments hesitate to work in certain markets and geographies because of access and reimbursement challenges. Also, some sponsors are hesitant to partner with trial sites outside of traditional and known facilities, which could be due to long start-up timelines (e.g., in Eastern Europe and Latin America), lack of knowledge of the local environment and lack of previous rare disease clinical trial experience, especially when conducting first-in-human (FIH) clinical trials. According to, a database of privately and publicly funded clinical studies conducted around the world, a total of 33 current trials mention the term “limb girdle muscular dystrophy” as of December 3, 2019 – although some are specified by the exact subtype (e.g., 2E, 2C, 2 and 2B). This compares with 266 DMD trials (search term “Duchenne muscular dystrophy”). Some of the postings on reflect the fact that LGMD clinical trial development is at an early stage, such as those seeking to identify clinical trial endpoints as well as those seeking to understand the natural history of a specific LGMD subtype. The number of LGMD clinical trials is expected to increase with cell and gene therapy development on the rise. This paper will describe the results of a proactive LGMD feasibility study which was conducted by IQVIA (a leading provider of advanced analytics, technology solutions and contract research services to the life sciences industry) in the second half of 2019 with the objective of obtaining unique and current insights from global investigators currently providing LGMD patient care. Methods Our 32-question survey for LGMD clinical trial “readiness” – defined here as physician interest/motivation in LGMD clinical trial participation – was sent to more than 200 physicians treating LGMD patients across 48 countries.

years and older], subtype, and how patients are identified), diagnosis and treatment, and site experience and logistics. The main physician specialities this survey interviewed were neurologists, paediatric neurologists, neuromuscular specialists, and paediatric neuromuscular specialists (see Figure 1). The survey was launched in two phases: the first survey was distributed to treating physicians in 12 countries (the US, France, Italy, Spain, UK, Germany, Denmark, Finland, Malaysia, Korea, Japan and Brazil); while the second phase included physicians in 36 additional countries (Argentina, Belgium, Bulgaria, Czech Republic, Hungary, India, Mexico, New Zealand, Poland, Romania, Turkey, South Africa, Australia, Bosnia, Canada, Chile, China, Colombia, Costa Rica, Croatia, Greece, Israel, Latvia, Lithuania, Netherlands, Norway, Peru, Philippines, Portugal, Russia, Serbia, Slovakia, Slovenia, Sweden, Taiwan and Ukraine). Responses were summarised descriptively and by region. Results IQVIA received completed surveys from 166 investigators across 36 countries (see Figure 2) over a three-month period. There was no difference in the response rate between the two phases of the survey. In terms of general interest in participating in LGMD trials, a majority (70%) of physicians responded positively (see Figure 3). More than 50% of the physicians, identified largely as neurologists or paediatric neurologists, who had expressed their interest to participate in a LGMD trial, were found to be associated with an academic hospital (see Figure 4). Sites in the United States, Canada, Brazil, Russia, Portugal, Ukraine, China and Spain were among those having the largest numbers of interested physicians. It is important to note that physician interest may not necessarily imply that there is the ability to conduct a clinical trial or the capacity to enroll patients.

Figure 2 – Total Number of Survey Responses by Country

The objective was to evaluate investigator access to LGMD patients, research experience, and challenges in recruiting and treating the LGMD patient population, and to gain an awareness of access to equipment and diagnostic capabilities in different geographies. The broad categories of questions included: investigator interest, patient population (including age [3–6 years old, 7–17 years old, 18

Figure 3 – Number of Interested Physicians by Country

Figure 1 – An Overview of the Physician Specialities Responding

Investigator Descriptions of Patients Investigators who responded to the survey believe patients and caregivers treated in the last six months across all three age groups (3–6 years old, 7–17 years old, and ≥ 18 years of age) would be interested in being enrolled in LGMD clinical trials, with the largest Journal for Clinical Studies 27


Figure 7 – Regional Distribution of Patients by Source of Identification Figure 4 – Interested Investigators’ Practice Setting

number of patients coming from the adult (≥ 18 years) age group (see Figure 5 for country-by-country tallies). In the 3-6-years age group, investigators from Russia, India, Ukraine and US reported the highest patient volume who may be interested in participating in a trial for LGMD. In the age group of 7-17 years, investigators from Russia, Ukraine, Germany and India reported a higher volume. In the adult population, investigators from countries like Spain, Brazil, Russia and US have estimated ≥100 LGMD patients may be interested in participating in an upcoming LGMD trial (see Figure 5).

Figure 5 – Physician Estimates of Numbers of Patients Willing to Participate in LGMD Trials Based on Age Group – By Country

Figure 8 – Distance Travelled by Patients to Reach the Site

It was also noted across regions that there was a variance in the distance travelled by the LGMD patients to reach their treating physician. In some regions, LGMD patients travelled long distances, some up to 75 miles (or more) to reach their treating physician (see Figure 8).

Figure 9 – Classes of Medications Used as Supportive Care for LGMD

Figure 10 – LGMD Standard of Care by Country

Figure 6 – Number of Patients Estimated by Physicians to be Willing to Participate in LGMD Trials Based on Age Group – By Region

Figure 6 illustrates that investigators predict that a large number of LGMD patients would be willing to participate in an LGMD trial from Western Europe, followed by Eastern Europe, Latin America, Asia Pacific and North America. Regions/countries seeing a relatively smaller number of total / interested LGMD patients is mainly due to lack of access to appropriate genetic testing to confirm diagnosis and a lack of trial-ready infrastructure. Across all regions, investigators reported that most of the patients in their clinical trials were identified through self-referral (34%), followed by patient registries / databases (23%) (see Figure 7). “Registries” referred to investigators’ own patient databases, local registries or national/international neuromuscular disease registries. 28 Journal for Clinical Studies

Only one LGMD treatment guideline exists within the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) countries. Dated 2014,5 this states that any experimental treatment offered to patients with LGMD (e.g., myostatin, gene therapy, etc.) should be administered only within the clinical trial setting. Figure 9 shows supportive care for LGMD under treatment by the responding investigators. Figure 10 summarises the types of treatments used as “standards of care” by country. Some regions are currently conducting clinical trials either for LGMD or other types of muscular dystrophies as seen in Figures 11 and 12. Antisense oligonucleotides (ASOs), such as nusinersen, inotersen and drisapersen) were the most commonly used class of drugs for trials in treatment of LGMD globally (24%), followed by small Volume 12 Issue 1

Therapeutics molecules such as edasalonexent and risidiplam (20%), others (which include enzyme replacement and adrenocorticotropic hormone or ACTH therapy) (19%), gene therapies (14%) and monoclonal antibodies (14%).

gene therapies using AAV vector technology). Although advanced / precision therapy use is currently a small part of the LGMD treatment regimen, this is expected to increase considerably in importance if disease-modifying therapies are approved.

Most investigators started LGMD treatment before the motor function plateaued, with some preferring to start the treatment when the motor function begins to decline.

As the pathology of each of the subtypes becomes more elucidated, additional targets will be available for study. As the number of clinical trials rises, so will the need for patients with certain subtypes. Given the small size of the clinical trials, as shown in the postings, concierge services (including reimbursement for travel costs, and vouchers for meals and accommodations) and language support services (e.g., a translator) should be considered to ease patient and caregiver burden after enrolling in a clinical trial and to ensure compliance.

Figure 11 – Site Experience with Investigational Products for LGMD and Other Muscular Dystrophy Clinical Trials

The speciality of principal investigators for LGMD clinical trials is typically neurology; although other specialities are either already part of the LGMD medical care team (respiratory pathologist, cardiologist, physical therapist, speech pathologist, etc.) or may be added to the patient’s management team as the disease progresses. Based on all global investigator feedback received, the authors believe that while LGMD patient enrolment will be challenging in certain geographies (such as the US and Europe), other regions are not yet fully explored (including Eastern Europe, Latin America, China and India).

Figure 12 – Site Experience in Terms of Treatment Modalities: Regional Distribution

Conclusions In summary, responses to the global proactive feasibility study from 116 investigators treating LGMD patients in 36 countries yielded the following findings: • • •

• • • •

In terms of general interest in participating in LGMD trials, a majority (70%) of physicians responded positively. The typical speciality of principal investigators for LGMD clinical trials is neurology. More than half of the physicians – identified largely as neurologists or paediatric neurologist – who had expressed their interest in participating in a LGMD trial, were found to be associated with an academic hospital. Sites in the United States, Brazil, Russia, Portugal, Ukraine, China and Spain were among those having the largest numbers of interested physicians. There is an opportunity to enroll more LGMD patients in global clinical trials, beyond North America and Western Europe. Investigators rely on self-referral, LGMD patient registries and site databases to identify patients for clinical trials. Travel distance for LGMD patients may be an important barrier for recruitment.

LGMD is one of the most severe forms of muscular dystrophy with currently no available cure and no approved disease-modifying treatments. Since LGMD can be life-threatening and severely debilitating due to progressive muscle weakness, new diseasemodifying therapies aiming to slow or halt disease progression – as well as curative treatments – are desperately needed. LGMD in all of its forms represents a formidable challenge for drug developers. Due to the disparity of subtypes, some forms might not be amenable to all types of currently proposed therapies (e.g.,

As clinical research is still at an early stage in LGMD, some expert sites have never participated in industry-sponsored clinical trials, especially in FIH studies. LGMD clinical trial expertise and knowledge could be provided to investigative trial sites by the pharmaceutical companies and/or designee, directly. Once a trial has been identified and initiated, LGMD training should be provided from the early stages and throughout the study. It is hoped that with further LGMD feasibility analyses, we will gain a better grasp on investigator interest and experience with the potential to allow all patients with LGMD – regardless of subtype or geography – to enroll in a clinical trial to explore products that could provide desperately needed disease-modifying treatments or a cure. Diagnostic Approach to LGMD The diagnosis of limb girdle muscular dystrophy is often challenging because of significant disease heterogeneity. Historically, the muscular dystrophies were classified as either type 1 (dominant) or type 2 (recessive) depending on the mode of inheritance. According to Nigro and Savarese (2014), there are currently eight subtypes of autosomal dominant (type 1) limb girdle muscular dystrophy. Calpainopathies or LGMD type 2A, are the most common form of LGMD, and are caused by mutations in CAPN3. LGMD type 2B, also known as dysferlinopathies, are caused by mutations in the DYSF gene. While sarcoglycanopathies, also known as LGMD types 2D, 2E, 2C, and 2F are caused by mutations of the following genes: SGCA, SGCB, SGCG, and SGCD genes. Mutations of the ANO5 gene cause type 2L LGMD. Several other gene mutations cause LGMD forms called dystroglycanopathies, including types 2I, 2K, 2M, and 2N. The disorders are labelled alphabetically according to when the individual genes were identified. The main classes of proteins involved in these conditions include extracellular matrix and external membrane proteins, enzymes or proteins

Journal for Clinical Studies 29

Therapeutics with putative enzymatic function, sarcolemma-associated proteins, nuclear membrane proteins, and sarcomeric proteins. The differential diagnosis of limb girdle muscular dystrophy is broad which, at least in the past, has led to misdiagnoses. For example, the authors have met several patients with LGMD who had previously been diagnosed with DMD or another dystrophy before their LGMD and specific subtype diagnosis. The differential diagnosis spectrum includes other muscular dystrophies such as congenital muscular dystrophies, myotonic dystrophy, facioscapulohumeral muscular dystrophy, and Emery-Dreifuss muscular dystrophy, as well as congenital myopathies, myofibrillar myopathies, distal myopathies, metabolic myopathy (such as Pompe or lipid storage disease), channelopathies, inflammatory myopathies, neurogenic disorders, and neuromuscular junction transmission disorders. Similar to other muscular dystrophies, the approach to LGMD requires a detailed history, a thorough physical examination, and measurement of a serum creatine kinase level. Other genetic and acquired causes of proximal muscular weakness should be excluded. The diagnosis may be confirmed by

30 Journal for Clinical Studies

molecular genetic testing, muscle biopsy, or a combination of both. Muscle biopsy will typically reveal the characteristic dystrophic features; further immunostaining may demonstrate the presence or absence of specific muscle proteins such as dystrophin, dysferlin, sarcoglycans, emerin, collagen VI, merosin, and glycosylated alpha-dystroglycan. The future of molecular testing may shift away from targeted genetic analysis toward whole genome or exome sequencing that will allow rapid and cost-efficient confirmation of the diagnosis. General treatment principles include offering genetic counselling for affected individuals and families; connecting them with patient organisations and disease registries; providing rehabilitation through multidisciplinary clinics to maximise function; supporting education, career, social, and financial needs; screening and treating the associated complications; and evaluating new treatment options for specific diseases when available. Acknowledgment The authors wish to thank the entire IQVIA Feasibility Team, which was supported by Marie Trad, MD, Vice President and Therapeutic Area Head, CNS, at IQVIA Biotech, for the design of the survey.

Volume 12 Issue 1

Therapeutics REFERENCES 1.


3. 4.

Understanding Neuromuscular Disease Care: Current State and Future Prospects; Institute Report, October 30, 2018; insights/the-iqvia-institute/reports/understanding-neuromusculardisease-care, accessed November 12, 2019. Nigro V, Savarese M. Genetic Basis of Limb-Girdle Muscular Dystrophies: the 2014 Update. Acta Myol. 2014 May; 33(10):1-2; https://www.ncbi.nlm., accessed November 27, 2019. Mercuri E, Muntoni F. Muscular Dystrophies. Lancet. 2013; 381:845-60. Mah JK. Chapter 5: An Overview of the Other Muscular Dystrophies: Underlying Genetic and Molecular Mechanisms in Muscular Dystrophy:

Raymond A. Huml Raymond A. Huml, MS, DVM, RAC is Vice President and Head of IQVIA’s Global Biosimilars Center of Excellence, has a personal interest in MD and works with the IQVIA/ Muscular Dystrophy Association (MDA) team on their national patient registry. Dr. Huml is a member of the FSH Society, co-founder and member of the North Carolina Chapter of the FSH Society, and a member of MD STARnet’s NC Advisory Committee. He edited and co-wrote eight chapters for the Springer book, “Muscular Dystrophy: A Concise Guide (2015). Email

Siddharth Aras Siddharth Aras, MS is a Clinical Planning Strategist and the Global Feasibility Manager at IQVIA. Some of his key responsibilities include overseeing and analyzing business requests for designing, developing and delivering analytical solutions to support and enhance IQVIA R&D and RWI solutions opportunities and trial programs. Siddharth has 12 years of industry experience in the areas of regulatory affairs and global feasibility. Email:

Marie Trad Marie Trad, MD is Vice President and Head of IQVIA’s CNS Biotech division. Dr. Trad has over 30 years of CNS experience, including 11 years as a clinical Neurologist/Neuroradiologist and 19 years of pharmaceutical industry experience as a Clinical Research Specialist/Consultant. She also has 19 years of CNS drug development and clinical trial management experience, providing medical, clinical and global strategic support to neurology and psychiatry trials in: epilepsy (both monotherapy and add-on therapy), idiopathic Parkinson’s disease (early and advanced), Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), chronic and acute pain, including diabetic neuropathic pain and post herpetic neuralgia, migraine, major depressive disorder, schizophrenia, bipolar disorders, generalized anxiety disorder, traumatic brain injury and stroke. She has significant experience in neuroradiology, including magnetic resonance imaging, magnetic resonance angiography, and computed tomography (e.g., scans of head, neck and spine). Email:

A Concise Guide (Huml RA, Editor), Springer Publishing (ISBN 978-3319-17361-0), Copyright 2015. 5. Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, et al. Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: Report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 2014;83:1453-63. 6. Evidence Based Guideline: Diagnosis and Treatment of Limb-Girdle and Distal Dystrophies; American Association of the Neuromuscular & Electrodiagnostic Medicine (AANEM) group: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine at Guidelines/home/GetGuidelineContent/672, accessed November 20, 2019. 7. Life Extension: The Source of a Healthier Life at https://www., accessed November 27, 2019. 8. Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD) (GRASP);, accessed November 20, 2019.

Tiffany Chow Tiffany Chow, MD is Director and Medical Strategy Lead for IQVIA’s CNS Center of Excellence. A neurologist by training, she is an experienced industry physician with over 20 years of clinical research in both academic neuroscience and research on elucidating the neurobiology of neurodegenerative disorders, applying PET imaging and functional neuroimaging methods, neuropsychiatric assessments and genomic testing in order to develop clinically meaningful therapies. Email:

Olja Tanjga Olja Tanjga, MD is Director of IQVIA’s CNS Biotech solution. Dr. Tanjga is a neurologist with 17 years combined industry and clinical research experience. Dr. Tanjga a boardcertified neurologist with a special interest in MS, neuromuscular diseases, extrapyramidal disorders, stroke and pain with experience in many other neurology indications. She has served as both medical and scientific advisor on over 40 clinical trials including the following indications: multiple sclerosis, Parkinson’s disease, Alzheimer’s Disease, ALS, epilepsy, stroke, acute/chronic pain (headache, low lumbar pain, neurogenic, herpetic pain, diabetic neuropathy, trigeminal neuralgia), and myasthenia gravis. Email:

Jill Dawson Jill Dawson, PhD, is a medical writing consultant to IQVIA, and a co-author of multiple papers on muscular dystrophy, biosimilars, celiac disease and other topics. She has a BSc and a PhD in Life Sciences from Imperial College London. Email:

Journal for Clinical Studies 31


Emerging Treatments for Spinal Cord Damage Injuries to the spinal cord can cause permanent paralysis and even lead to death, with little or no hope of regaining lost functions once the trauma has occurred. News of my spinal cord research first came to prominent public awareness in the 1980s with a front-page story in The New York Times entitled, “Rat Nerves Repaired and Rejoined with Spine” which chronicles our presentation at the annual Society for Neuroscience meeting, the first time crushed peripheral nerves were successfully regenerated back into the spinal cord. Regeneration of the nerves inside the spinal cord itself after injury, a far more complex challenge, is coming closer to fruition as a Canadian company I have partnered with is tasked with developing my discoveries with the goal of conducting human clinical trials. My team at Case Western Reserve University medical school and I are working to understand why nerves that are damaged through spinal injury don’t regenerate and to identify non-invasive, easy-to-administer strategies that can promote robust functional recovery. Can Damaged Nerves Regrow? My research began by investigating whether it was even possible for an adult nerve cell to regrow within the environment of the damaged adult spinal cord. It had long been thought that this was impossible. Nerve cells consist of elaborate long extensions (axons) that grow out from the main cell body. It is these axons that make the connections called synapses with other nerve cells, and it is the axons within the spinal cord that are severed when the bony spine is impelled into the cord when it is violently broken. Axons can be incredibly lengthy, some reaching almost the entire span of our bodies. One challenge for researchers working in the field of spinal injury was to determine whether damaged axons have the intrinsic capacity (i.e., a strong enough growth motor) so that, in principle, they had at least the potential to replace the damaged ones. My team and I found that this was possible, even long after the damage had occurred. To demonstrate this, we conducted a simple experiment. First, we purified in cell culture, fully adult nerve nells that were genetically prelabelled with a fluorescent protein so that the cells could be easily visualised. The first step served not only to harvest the nerve cells but also to cut all the axons away from the cell bodies that, nevertheless, remain alive. Next, we collected the axon-less nerve cell bodies and very gently re-implanted them into the pre-lesioned spinal cord of an unlabelled adult host animal so as not to create any damage or scarring at the implant site. It was a huge surprise to the scientific community when we found that axons could, indeed, grow robustly in the spinal cord and reach out quickly over long distances. However, we also found that when the new axons reached the area of severe lesion damage and scarring, they stopped growing abruptly and started to deteriorate. We suspected that there was some sort of chemical produced by the scar tissue around the break itself that was hostile to axons and stops even exuberantly growing new ones from extending further. 32 Journal for Clinical Studies

Understanding Scar Tissue Inflammatory damage to the spinal cord after the initial injury can continue to spread outward from the lesion epicentre into surviving tissue to cause further loss of function. The development of scar tissue encases the lesion core and plays an important role in the protection of the healthy nerve cells from further harm. However, it is now clear that once the important task of protection is complete, the same structure that offered protection soon after the injury then develops into a barrier to the regrowth of the cut axons. My team and I set out to identify the culprit in the scar that was stopping axon regrowth, and then see what we could do to reduce or overcome the growth inhibitory effect of the scar, once it had mitigated the danger of the initial injury. As we had already shown that axons can regrow once past or through the scar, we understood that this could be the key to returning or improving function to the injured area. We found a particular family of potently inhibitory molecules that were being produced in the scar tissue, and that when newly regenerating axons encountered them, it caused the growing tips of the axons to become so tightly stuck (similar to a fly on flypaper) that they could no longer move forward. These sticky molecules are known as chondroitin sulphate proteoglycans (CSPGs). Bridging the Scar Tissue and Repairing the Nerve Damage Having identified the culprit that stops the growth of axons near the scar tissue, our next step was to find a way to selectively eliminate CSPGs. My team and I investigated the use of a special enzyme (chondroitinase) that consumes the CSPGs once injected into the cord, stopping them from having such detrimental effects. Using these enzymes, we found success in re-growing axons and improving function in animals that had problems with their limbs, bladder and diaphragm (which was hampering them from breathing). As these are common and potentially fatal conditions in humans following paralysis, the improvements in these areas were especially promising. The use of enzymes to break down CSPGs has been widely investigated, with researchers attempting to optimise various factors, including the timing of administration and appropriate amount of targeted physical therapy. Benefits have been shown in many different animal models, including non-human primates and at long chronic timepoints post-injury. However, problems still exist as the enzyme is of bacterial origin, must be injected directly into the spinal cord, and acts only over a very short distance. Supplementary treatments may also be required to ensure optimal spread of the enzyme and that the regrown axons go on to make the right connections. Studies are ongoing by a variety of research teams around the world to overcome these challenges. To overcome the need to directly inject a molecule into the spinal cord, my colleagues and I tested a novel systemic approach to see what effect it would have on axon regrowth. We identified a receptor molecule called protein tyrosine phosphatase sigma (PTPσ) on the axons that acted as a ‘helper’ to cause CSPGs to be overly adhesive. This newly discovered PTPσ receptor provided a way for the axons Volume 12 Issue 1


to detect CSPGs, signalling them to stop and become entrapped. We developed a molecule that negates this signal, allowing the regenerating axons to ignore and bypass CSPGs. When the molecule, known as intracellular sigma peptide (ISP), was administered non-invasively via injections under the skin, it interfered with the CSPG/receptor signalling within the spinal cord, allowing for robust axon regrowth, resulting in greatly improved bladder function and improved locomotion in animal models of spinal cord injury. Beyond Spinal Cord Injuries In working to understand what controls the regrowth of axons after spinal cord injury, we also discovered several medical conditions involving nerve injury where scarring also occurs and CSPGs impact axon regrowth. Axons that are severed in the peripheral nerves, such as those found in the arms and legs, do have a limited capacity to regrow. However, when the lesion is severe and closer to the body, a CSPGladen scar also hinders recovery because damaged peripheral axons also upregulate the same PTPσ receptor. My team and I were able to show that ISP can help heal injuries to peripheral nerves by speeding up the growth of injured nerves across and beyond the scar to the muscles they control. Multiple sclerosis (MS) is an inflammatory mediated nervous system disease that affects both the brain and the spinal cord. It damages the myelin, the material that wraps and insulates the nerve cells. The loss of myelin slows down or blocks the electrical message that travels between the brain and the body, leading to MS. Again, CSPG-filled scar-like plaques that form in the damaged areas play a critical role in preventing recovery by blocking migration of immature, potential myelin-forming stem cells that exist in huge numbers within the central nervous system. In animal models, we

recently found that ISP promotes the migration of the stem cells into the lesion with return of the myelin sheath leading to functional recovery. We also teamed up with investigators who study scars that form after heart attack. When a heart attack occurs, sympathetic axons that control the heart rate are damaged in the vicinity of the forming scar. Just like in the spinal cord, these cut axons die back away from the lesion core and their regenerating tips become entrapped within the outer edges of the scar, causing irregular heartbeats known as arrhythmias, which can be lethal. In animal models of heart attack, systemic treatment with ISP promoted new growth of the damaged axons back into the scar, stopping the arrhythmias. My team and I are creating innovative solutions for the treatment of nerve damage. Together, we have identified an ISP analogue known as NVG-291 to treat human patients. It is our hope that this technology can improve the lives of the many people living with debilitating nerve damage.

Dr. Jerry Silver Dr. Jerry Silver is the co-inventor and scientific advisor to NervGen Pharma, a company that is creating innovative solutions for the treatment of nerve damage. Dr. Silver is the Professor of Neurosciences at Case Western Reserve University’s School of Medicine and adjunct Professor in the Department of Neurosurgery at the Cleveland Clinic Foundation. Email:

Journal for Clinical Studies 33


Chronic Lymphocytic Leukaemia: Current and Emerging Treatment Options With the advent of new targeted and cellular therapies, the treatment landscape for patients with chronic lymphocytic leukaemia (CLL) has considerably changed in the last years. Current CLL management is based on updated risk stratification strategies considering demography, fitness level, genetic aberrations, previous treatments, as well as disease relapse, in addition to the clinical stage. While the CLL treatment paradigm was changed in the last decade due to approval of novel targeted therapies, disease relapse rates are still high. Additional clinical trials are needed to answer outstanding questions or provide alternatives for further improvements of long-term efficacy and safety/tolerability in the overall CLL population and specifically in patients with high-risk CLL. This article describes contemporary CLL management, with a focus on current and emerging therapies in first-line disease and subsequent settings. Introduction Chronic lymphocytic leukaemia (CLL), the most common form of leukaemia in the Western hemisphere1,2, is a lowgrade lymphoproliferative disease characterised by progressive accumulation of cluster of differentiation (CD)5+/CD19+ B lymphocytes in the peripheral circulation, bone marrow, and lymphoid tissues3. CLL has an annual age-adjusted incidence of 3-5 per 100,000 persons4 and mostly arises in patients ≥65 years. Typically, CLL has an indolent disease progression and is preceded by monoclonal B-cell lymphocytosis (MBL)5, present in 5% of healthy individuals older than 40 years6,7. While a relatively long survival is observed in the majority of patients with CLL, treatment-resistant disease is typically encountered in high-risk patient subsets8. For decades, treatment of patients with CLL, including high-risk subsets, was conservative and non-curative, focusing on purine analogues and alkylating agents. This became secondary with the emergence of novel targeted therapies, which led to significant changes in CLL therapy programmes. Current Treatment Programs for CLL Present-day CLL management programmes follow the International Workshop on CLL (IWCLL) criteria published in 20189. These programmes are divided into three categories: for patients who do not meet criteria for therapy, for patients who meet criteria for therapy and have untreated CLL, and for patients who meet criteria for therapy and present with relapsed/refractory CLL. For all patients, a risk stratification strategy is initially applied using the CLL-International Prognostic Index (CLL-IPI)10, which classifies patients into four risk groups based on five factors (Table 1) that have been shown to be independently associated with overall survival (OS). Additionally, assessment of minimal residual disease following CLL therapy is recommended by the IWCLL guidelines, 34 Journal for Clinical Studies

to help predict time to and individualise subsequent treatment phases (e.g. consolidation, maintenance)9. The majority of patients have MBL (B cell count <5 x 109/L) or early-stage CLL (B cell count ≥5 x 109/L) at diagnosis and do not meet criteria to initiate therapy10. The NCCN and IWCLL guidelines recommend a “wait-and-watch” approach, including close follow-up, for these patients4,9. For patients who meet criteria for therapy (e.g. advanced stage, progressive disease, significant disease-related symptoms), typical factors determining treatment approaches additional to those indicated by CLL-IPI are fitness level and untreated vs relapsed/refractory disease. Currently, there are 509 clinical trials planned or ongoing that assess various therapies for CLL (GlobalData; Figure 1A), with the majority of trials in Phase II-II/III. This, together with the high number of drugs and drug combinations being evaluated in the preclinical and early clinical phases (Figure 1B), indicates that the field of CLL therapy remains to undergo significant developments. While historical CLL treatment was composed of chemotherapy agents, the development of new therapies led to the introduction of small molecules, cell therapies, immunotherapy, proteins, antibodies and other compounds in the treatment armamentarium of CLL. As opposed to chemotherapy agents, these new compounds rely on specific target inhibition or dysregulation of signalling pathways (Figure 1C). Based on recommendations from the IWCLL9 and NCCN guidelines4 and the aforementioned CLL treatment landscape, a summary of CLL management modalities can be found in Figure 2. The team at CATO SMS summarised the current treatment approaches and emerging CLL therapies, including their modes of action and targets, below. First-line Treatment Options for CLL Anti-CD20 Monoclonal Antibodies A significant step forward in changing the CLL treatment paradigm was the development and subsequent approval of the anti-CD20 antibody rituximab (Table 2). Humanised chimeric monoclonal antibodies targeting CD20 induce killing of CD20+ cells by direct effects, such as complement-mediated and antibody-mediated cytotoxicity (ADCC), or indirect effects pertaining to structural changes, cell sensitisation to chemotherapy, and apoptosis. According to NCCN guidelines4, the chemoimmunotherapy regimen fludarabine-cyclophosphamide-rituximab (FCR) is part of the current first-line SoC for patients aged <65 years without del17p/TP53 mutations and significant comorbidities (Figure 2). The approval of rituximab as part of this first-line SoC (Table 2) was based on the pivotal Phase III trial CLL8, in which FCR vs FC significantly improved the objective and complete response rates (ORR and CRR, Table 3), as well as the three-year median progression-free survival (PFS) and overall survival (OS) in 817 previously untreated, physically fit patients11. Updated analyses reported FC therapy, TP53 mutations, del17p, and non-mutated IGHV as primary predictors of shorter OS/PFS12 (Table 3). An alternative to FCR is bendamustine-rituximab (BR), recommended for treatment of genetically similar patient populations to those receiving FCR, but presenting with significant comorbidities4. Volume 12 Issue 1

Therapeutics Prognostic factor


Additional information

TP53 mutation or del17p* presence


Patients with TP53 mutation experienced shorter time to first therapy, PFS, and OS53,54,55,56,57,58 Increasing OS per patient group59: 

Del17p13: OS~3 years

Del11q23: OS~6.5 years

Trisomy 12: OS~9.2 years

Negative FISH: OS~9.5 years

Del13q14: OS~14 years

No IGHV mutation


Serum β2 microglobulin >3.5 mg/L Clinical stage (Binet B-C or Rai stage I-IV) Age ≥65 years


Independent predictor of PFS and OS63,64


Used for >4 decades as backbone for prognostication in clinical practice/trials, as well as for the decision on treatment initiation65,66 Prognostic factor for OS, independent of cytogenetic or molecular genetic factors67,68,69,70,71


Higher OS in patients with mutated vs non-mutated IGHV (NR vs 10 years [60]; 24.4 vs 7.9 years61; >20 vs 8 years62)

*As determined by FISH. Abbreviations: CAR: chimeric antigen receptor; CLL: chronic lymphocytic leukaemia; del: deletion; FISH: fluorescence in situ hybridisation; IGHV: immunoglobulin heavy chain variable region gene; IPI: International Prognostic Index; NR: not reached; OS: overall survival; PFS: progression-free survival; TP53: tumour protein 53.

Table 1. The CLL-International Prognostic Index: independent prognostic factors, cumulative score, and limitations10.

This recommendation could potentially be explained by the better patient tolerance of BR versus FCR13, while response and survival rates remained similar (Table 3). Other anti-CD20 monoclonal antibodies used as monotherapy for CLL are obinutuzumab and ofatumumab. In pivotal Phase III trials, both compounds showed significant improvements in ORR and PFS versus chlorambucil plus rituximab (Table 3), while maintaining a tolerable safety profile14,15,16. Combination therapy recommended for patients with del17p/ TP53 mutations includes obinutuzumab administered together with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, the BTK inhibitor acalabrutinib or chlorambucil4,14,15,16 (Table 2 and Figure 2).

Figure 1. Summary of the current clinical trial landscape for CLL. Depicted are: A) Numbers of CLL clinical trials by phase, B) Numbers of therapies under evaluation for CLL by stage of development, and C) Top ten targets by drugs. Abbreviations: BCL-2: B-cell lymphoma 2; BTK: Bruton’s tyrosine kinase; CD: cluster of differentiation; CLL: chronic lymphocytic leukaemia; DNA: deoxyribonucleic acid; ROR1: neurotrophic tyrosine kinase, receptor-related 1; PI3K: phosphoinositide 3-kinase.

Bruton’s Tyrosine Kinase (BTK) Inhibitors Ibrutinib and acalabrutinb are currently the only small-molecule BTK targeted therapies approved by the Food and Drug Administration (FDA) for first-line treatment of CLL (Table 2). Similar to other BTK inhibitors, ibrutinib covalently binds to and ultimately inhibits the BTK enzyme, thus impairing the rate of abnormal B-cell multiplication and subsequent CLL development. Initially, ibrutinib was approved for relapsed/refractory patients and subsequently for treatment-naïve patients with and without del17p/TP53 mutations.

Figure 2. Summary of current CLL management and treatment programmes4,9. *Approximately 75% of patients, with a median time to first therapy of approx. seven years. **Approximately 25% of patients, with a median time to first therapy of approx. two years10. Abbreviations: BR: bendamustine rituximab; CAR-T: chimeric antigen receptor T cell; CLL: chronic lymphocytic leukaemia; del: deletion; FCR: fludarabine cyclophosphamide rituximab; FISH: fluorescence in situ hybridisation; IGHV: immunoglobulin heavy chain variable region gene; IPI: International Prognostic Index; SCT: stem cell transplant; TP53: tumour protein 53; yrs: years.

Journal for Clinical Studies 35

Therapeutics Drug

Mechanism of action


Ofatumumab Anti-CD20 mAbs

Initial approval

Current approval indications

FDA: Feb 2010 EMA: Feb 2009

FDA:  In combination with fludarabine and cyclophosphamide (as FCR), for treatment of patients with previously untreated and previously treated CD20+ CLL EMA:  In combination with chemotherapy, for treatment of patients with previously untreated and relapsed/refractory CLL FDA and EMA:  In combination with chlorambucil, for treatment of previously untreated patients with CLL and contraindications to fludarabine-based therapy  For treatment of patients with CLL refractory to fludarabine and alemtuzumab  In combination with FC, for treatment of patients with relapsed CLL. FDA:  In combination with chlorambucil, for treatment of patients with previously untreated CLL EMA:  In combination with chlorambucil, for treatment of adult patients with previously untreated CLL and comorbidities contraindicating fludarabine-based therapy FDA:  For treatment of patients with B-cell CLL, as a single agent EMA:  For treatment of patients with B-cell CLL for whom treatment combinations including fludarabine are not appropriate FDA and EMA:  As monotherapy, for treatment of patients with previously untreated CLL (±del17p) or relapsed/refractory CLL to at least one prior therapy

FDA: Oct 2009 EMA: Apr 2010

FDA: Nov 2013 EMA: July 2014



Anti-CD52 mAb

FDA: May 2001 EMA: July 2001


BTK inhibitors

FDA: Feb 2014 EMA: Oct 2014

FDA: Nov 2019 EMA: FDA: Jul 2014 EMA: Sep 2014

Acalabrutinib Idelalisib


PI3K inhibitors

FDA: Sep 2018 EMA: -


Bcl-2 inhibitor

FDA: Apr 2016 EMA: Dec 2016

FDA:  For treatment of adults with CLL or small lymphocytic lymphoma FDA and EMA:  In combination with an anti-CD20 monoclonal antibody (rituximab/ofatumumab), for treatment of adult patients with previously untreated CLL and del17p/TP53 mutations or patients with relapsed/refractory CLL to at least one prior therapy, and ineligible for other therapies FDA:  Relapsed/refractory CLL after at least two prior therapies FDA:  For treatment of adult patients with relapsed/refractory CLL to at least one prior therapy, with/without del17p EMA:  As monotherapy, for treatment of patients with CLL, but no genetic changes, who failed on chemoimmunotherapy and ibrutinib/idelalisib or with CLL and genetic changes (del17p, TP53 mutation) who failed on ibrutinib/idelalisib  In combination with rituximab, for treatment of adult patients with relapsed/refractory CLL to at least one prior therapy

*In August/September 2012, alemtuzumab was withdrawn from the markets in the United States and Europe, to prevent off-label use for treatment of multiple sclerosis and to prepare for a relaunch with a different dosage and trade name, aimed for treatment of multiple sclerosis. Abbreviations: BTK: Bruton’s tyrosine kinase; CD: cluster of differentiation; CLL: chronic lymphocytic leukaemia; CR: complete response; del: deletion; EMA: European Medicines Agency; FC: fludarabine cyclophosphamide; FCR: fludarabine cyclophosphamide rituximab; FDA: Food and Drug Administration; IV: intravenous; PI3K: phosphoinositide 3-kinase; PR: progressive response; TP53: tumour protein 53. Table 2. Overview of approved targeted agents for treatment of CLL.

These approvals were based on the demonstrated efficacy of single-agent ibrutinib in treatment-naïve17,18 and relapsed/ refractory CLL patients19 (Table 3). Subsequent trials demonstrated a five-year sustained efficacy in these patient populations, with response rates and tolerability improving over time20 (Table 3). Acalabrutinib is a second-generation BTK inhibitor with superior selectivity as compared to ibrutinib21. This, and its efficacy similar to that of ibrutinib (Table 3) make acalabrutinib a suitable treatment alternative for previously untreated and relapsed/refractory CLL. On the basis of the Phase III clinical trial ELEVATE TN22, which reported higher OS rates in treatmentnaïve patients receiving acalabrutinib alone or combined with obinutuzumab versus obinutuzumab plus chlorambucil (85% and 94% vs 79%, Table 3), while maintaining a tolerable safety, acalabrutinib monotherapy received FDA approval for treatment of adult patients with CLL in November 2019 (Table 2). As a result, NCCN guidelines included acalabrutinib, alone or in combination therapies, as a preferred regimen for CLL treatment4. Treatment Options for Relapsed/Refractory CLL According to the CLL-IPI10, patients with relapsed/refractory CLL 36 Journal for Clinical Studies

should undergo restaging/restratification prior to assignment to any new therapies (Figure 2). The specific therapies to be used will be based on fitness level, presence of comorbidities, and intolerance to previous treatments. Anti-CD20 Monoclonal Antibodies In addition to their use in the first-line setting, anti-CD20 monoclonal antibodies are among the recommended options for treatment of relapsed/refractory CLL4 (Table 2) in elderly (≥65 years) patients without del17p/TP53 mutations, but presenting with coexisting comorbidities that make these patients ineligible for purine analogs-based therapies4,14,15,16 (Figure 2). BTK Inhibitors The pivotal Phase III trial RESONATE demonstrated significant benefits of ibrutinib versus ofatumumab in patients with relapsed/refractory CLL, including clinically relevant improvements in haematologic function and patient-reported outcomes19,23. Improved efficacy and similar safety profiles were observed in the Phase III HELIOS trial comparing ibrutinib versus placebo, upon combination with bendamustine-rituximab24. Lastly, results of a recent cross-trial Volume 12 Issue 1

Therapeutics Drug

CLL type

Treatment arms

Trial name/ phase



Median OS/ OS rate

Median PFS/ PFS rate

Anti-CD20 mAbs Rituximab


Previously untreated (young and fit pts)

FCR vs FC (6 courses)

CLL8 (Phase III)11,12

90% vs 80% (p<0.0001)

44% vs 22% (p<0.0001)

At 3 yrs: 87% vs 83% (HR, 0.67; 95% CI, 0.48–0.92; p=0.012)

At 3 yrs: 65% vs 45% (HR, 0.56; 95% CI, 0.46-0.69; <0.0001)

Previously untreated (young pts with lower fitness level or old pts)


CLL10 (Phase III)13

96% vs 95% (p=1.0)

40% vs 31% (p=0.034)

In pts <65 yrs: 95% vs 98% (p=0.096)

In pts <65 yrs: 41% vs 30% (p=0.022)

At 3 yrs: 91% vs 92% (HR, 1.034; 95% CI, 0.620–1.724; p=0.897)

55.2 vs 41.7 mths (HR, 1.643; 90.4% CI, 1.308–2.064; p=0.0003)

In pts ≥65 yrs: 97% vs 92% (p=0.164)

In pts ≥65 yrs: 36% vs 32% (p=0.648)

In pts <65 yrs: 53.6 vs 38.5 mths (95% CI, 33.1–44.8; p=0.0004) In pts ≥65 yrs: NR vs 48.5 mths (95% CI, 34.6–52.0; p=0.172)

Previously untreated pts not eligible for fludarabine-based therapy due to older age/ comorbidities

OC vs C


82% vs 69% (OR, 2.16; 95% CI, 1.36–3.42, p=0.001)

14% vs 1% (p value not mentioned)

At 3 yrs: 85% vs 83% (HR, 0.91; 95% CI, 0.57–1.43; p=0.666)

22.4 vs 13.1 mths (HR, 0.57; 95% CI, 0.45–0.72; p<0.0001)

Maintenance in R/R CLL

Ofatumumab maintenance or observation


29.4 vs 15.2 mths (HR 0.50; 95% CI, 0.38–0.66; p<0·0001)


Treatment-naïve pts ≥65 years with coexisting comorbidities

OC vs RC vs C

CLL11 (Phase III)14

At 3 mths after EOT: 77.3% vs 65.7% vs 31.4% (p<0.001)

At 3 mths after EOT: 22.3% vs 7.3% vs 0% (p<0.001)

• OC vs C: 91% vs 80% (HR, 0.41; 95% CI, 0.23-0.74; p=0.002) • RC vs C: 85% vs 80% (HR, 0.66; 95% 0.39–1.11; p=0.11)

• OC vs C: 26.7 vs 11.1 mths (HR 0.18; 95% CI, 0.13–0.24; p<0.001) • RC vs C: 16.3 vs 11.1 mths (HR 0.44; 95% CI, 0.34–0.57; p<0.001)


R/R CLL with prior exposure to rituximab

Ublituximab (single arm)

Phase I38





Ublituximab + ibrutinib (single arm)

Phase II39



Previously untreated or R/R CLL with del17p and TP53 mutations

Ibrutinib (single arm)

Phase II17

At 24 months: • Treatment-naïve pts: 97% • R/R CLL: 80%

No CRs observed

At 24 months: • All pts: 80% (95% CI, 68–94) • Treatment-naïve pts: 84% (95% CI, 72–100) • R/R CLL: 74% (95% CI, 57–100)

At 24 months: • All pts: 82% (95% CI, 71–94)

Treatment-naïve and R/R CLL

Ibrutinib (single arm)

PCXYC-1102 and PCYC-1103 (Phase II)20

At the 5-yr follow-up: • Treatment-naïve pts: 87% • R/R CLL: 89%

At the 5-yr follow-up: • Treatmentnaïve pts: 29% • R/R CLL: 10%

Median OS: • Treatment-naïve pts: NR • R/R CLL: NR

Median PFS: • Treatment-naïve pts: NR • R/R CLL: 51 mths

At the 5-yr follow-up: • Treatment-naïve pts: 92% • R/R CLL: 60%

At the 5-yr follow-up: • Treatment-naïve pts: 92% • R/R CLL: 44%

BTK inhibitors Ibrutinib



Ibrutinib vs ofatumumab


63% vs 4.1% (OR, 2.16; 95% CI, 8.1–37.3; p<0.001)

No CRs observed in either group

42.6% vs 4.1% (p<0.001)

Median follow-up of 9.4 mths: NR vs 8.1 mths (p<0.001)

Previously untreated pts ≥65 years

Ibrutinib vs chlorambucil

RESONATE-2 (Phase III)18

86% vs 35% (HR, 0.09; 95% CI, 0.04–0.17; p<0.001)

4% vs 2%

At 24 mths : 98% vs 85% (HR, 0.16; p<0.001)

Median follow-up of 18.4 mths: NR vs 18.9 mths (HR, 0.28; 95% CI, 0.09-0.28; p<0.001)


Ibrutinib + BR vs placebo + BR

HELIOS (Phase III)24

82.7% vs 67.8%

10.4% vs 2.8%

Median OS: NR (HR, 0.628; 95% CI, 0.385– 1.024; p=0.0598)

At the 18-month follow-up: 79% vs 24% (HR 0.203, 95% CI 0.150–0.276; p<0·0001)

Relapsed CLL

Acalabrutinib (single arm)

Phase I/II21

At the 14.3-month follow-up: 95%

No CRs observed



Pts with R/R CLL and intolerant to ibrutinib

Acalabrutinib (added cohort of the open-label Phase II doseexpansion)

Phase I/II72



Median PFS: NR • 1-year PFS: 83.4% (95% CI, 64.5–92.7) • 2-year PFS: 75.0% (95% CI, 54.2–87.4)

Treatment-naïve CLL

Acalabrutinib alone (A) vs A + obinutuzumab (A + O) vs OC


• A: 85% • A + O: 94% • OC: 79%

A: One patient had CR A + O and OC: No CRs

Median OS: • A + O vs OC: NR vs NR (HR, 0.47, 95% CI, 0.21–1.06, p=0.0577) • A vs OC: NR vs NR (HR 0.60, 95% CI 0.28–1.27, p=0.1556)

Median PFS: • A + O vs OC: NR vs 22.6 mths (HR, 0.10, 95% CI, 0.06–0.18, p<0.0001) • A vs OC: NR vs 22.6 mths (HR 0.20, 95% CI 0.13–0.31, p<0.0001)

Relapsed/refractory CLL

A vs rituximab + idelalisib (IDR)/BR

ASCEND (Phase III)26

81% vs 75% (p=0.22)

At 12 mths: 94% vs 91%

At 12 mths: 88% vs 68% Median follow-up of 16.1 mths: NR vs 16.5 mths (HR, 0.31, 95% CI, 0.20–0.49, p<0.0001)

Table 3. Efficacy overview of approved and emerging targeted agents for CLL – Part 1

Journal for Clinical Studies 37

Therapeutics Drug

CLL type

Treatment arms

Trial name/ phase



Idelalisib + rituximab vs rituximab

Phase III27


Idelalisib + ofatumumab vs placeboofatumumab




Median OS/ OS rate

Median PFS/ PFS rate

81% vs 13% (OR, 29.92; p<0.001)

At 12 mths: 92% vs 80% (HR, 0.28; 95% CI, 0.09–0.86; p=0.02)

NR vs 5.5 mths (HR, 0.15; 95% CI, 0.08–0.28; p<0.001)

Phase III28

75.3% vs 18.4%

<1% (1 pt) vs 0%

NR (HR, 0.75; 95% CI, 0.48–1.18; p=0.27)

16.3 vs 8.0 mths (0.27, 95% CI 0.19–0.39, p<0·0001)

Duvelisib (single arm)

Phase I42




Duvelisib vs ofatumumab

DUO (Phase III)43

73.8% vs 45.3% (p<0.0001)

PR: 72.5% vs 44.7% CR: 0.6% vs 0.6%

NR in either treatment arm

13.3 vs 9.9 mths (HR, 0.52; p < 0.0001)


Duvelisib + BR vs duvelisib + R

Phase I44

75.0% vs 88.9%

0% vs 0%


NR vs 22.1 mths (95% CI 13.7-NA)



Umbralisib (single arm)

Phase I45




Relapsed CLL

Venetoclax (single arm)

Phase I30



At 15 mths: 66% (95% CI, 51–77)

R/R CLL and del17p

Venetoclax (single arm)

Phase II31

79.4% (95% CI, 70.5–86.6)


At 12 mths: 86.7% (95% CI, 78.6-91.9)

At 12 mths: 72% (95% CI, 61.8–79.8)


Venetoclax + rituximab vs bendamustine + rituximab


93.3% vs 67.7%

26.8% vs 8.2%

At 2 yrs: 91.9% vs 86.6% (HR, 0.48; 95% CI, 0.25-0.90)

At 2 yrs: 84.9% vs 36.3% (HR, 0.17; 95% CI, 0.11–0.25, p<0.x001)

PI3K inhibitors


Bcl-2 inhibitors

Anti-CD37 mAbs Otlertuzumab

Untreated pts ineligible for standard chemotherapy due to age and comorbidities

Otlertuzumab + rituximab

Phase Ib35



16 months

Relapsed CLL

Otlertuzumab + bendamustine vs bendamustine

Phase II36

69% vs 39% (p=0.025)

9% vs 3%


15.9 vs 10.2 months (p=0.0192)


Relapsed and transformed (Richter) CLL

Pembrolizumab (single arm)

Phase II46

Relapsed CLL: 0% RT: 11%

• All pts: 10.7 mths (95% CI, 4.4-NR) • Relapsed CLL: 11.2 months (95% CI, 2.8-NR) • RT: 10.7 mths (95% CI, 4.4-NR)

• All pts: 3.0 mths (95% CI, 2.1-5.6) • Relapsed CLL: 2.4 months (95% CI, 1.2-3.3) • RT: 5.4 mths (95% CI, 2.8-12.2)


Multiple R/R CLL

CD19-directed CAR-T alone

Pilot Phase I48



• Median OS: 29 mths • Estimated 18-mth OS rate: 71% (95% CI, 40.6-88.2)

• Median PFS: 6 mths • Estimated 18-mth PFS rate: 28.6% (95% CI, 8.8-52.4)

R/R high-risk CLL

Liso-cel CD19directed CAR-T alone





CD19-directed CAR-T + ibrutinib vs CAR-T alone

Phase I/II50

88% vs 56%, p=0.06)

Not reported

Not reported

Not reported

High-risk CLL

Autologous vs allogeneic SCT

Long-term follow-up trial51

Not reported

Not reported

At 6 years: 58% vs 55% (HR, 0.98; 95% CI, 0.53-1.83; p=0.96)

At 6 years: 30% vs 24% (HR, 0.62; 95% CI, 0.39-0.98; p=0.04)

Purine analog refractory pts

RIC vs myeloablative allogeneic SCT

Long-term follow-up trial52

Not reported

Not reported

At 5 years: 83% vs 47%, p=0.003

At 5 years: 64% vs 47%, p=0.15

Anti-PD1 mAbs • Relapsed CLL: 16% (95% CI, 0.05-0.36) • Richter’s transformation (RT): 44% (95% CI, 0.14-0.79)

Cellular therapies


Abbreviations: A: acalabrutinib; BTK: Bruton’s tyrosine kinase; C: chlorambucil; CAR-T: chimeric antigen receptor T cell; CD: cluster of differentiation; CI: confidence interval; CLL: chronic lymphocytic leukaemia; CR: complete response; CRR: complete response rate; EOT: end of treatment; FC: fludarabine cyclophosphamide; FCR: fludarabine cyclophosphamide rituximab; HR: hazard ratio; IGHV: immunoglobulin heavy chain variable region gene; mAb: monoclonal antibody; MRD: minimal residual disease; NR: not reached; O: obinutuzumab; OC: obinutuzumab chlorambucil; OR: odds ratio; ORR: objective response rate; OS: overall survival; PD1: programmed cell death protein 1; PI3K: phosphoinositide 3-kinase; PFS: progression-free survival; PR: partial response; pts: patients; R/R: relapsed/refractory; RC: rituximab chlorambucil; RIC: reduced intensity conditioning; SCT: stem cell transplant.

Table 3. Efficacy overview of approved and emerging targeted agents for CLL – Part 2

comparison of pivotal Phase III CLL trials (CLL8, CLL10, CLL11, COMPLEMENT, RESONATE-2) demonstrated that ibrutinib versus chemoimmunotherapy led to longer PFS in the overall analysed population and in high-risk (e.g. advanced/bulky disease, del11q, unmutated IGHV) patients25. Similarly, in older patients with comorbidities, ibrutinib reached an OS longer than chemoimmunotherapy, but comparable to that reached with FCR/ BR in younger patient populations25. Based on these data, ibrutinib is currently one of the preferred and guideline-recommended treatment options for relapsed/refractory patients with CLL4 (Figure 2). 38 Journal for Clinical Studies

In the recent Phase III ASCEND trial, the median PFS rate at 16.1 months follow-up was not reached with acalabrutinib versus 16.5 months with the investigator’s choice (rituximab-idelalisib or rituximab-bendamustine) (Table 3), representing a 69% reduction in the risk of progression or death26. Based on the positive results from this trial, acalabrutinib has become an alternative for treatment of relapsed/refractory CLL in patients intolerant to ibrutinib4. PI3K Inhibitors Due to their capacity to modulate the PI3K/AKT/mTOR signalling Volume 12 Issue 1

Therapeutics pathway involved in cellular growth control, metabolism, and translation initiation, PI3K inhibitors are investigated for treatment of various cancers. In alignment with the rising trend of combination therapies for CLL to improve outcomes, combined therapy of the PI3K inhibitor idelalisib and rituximab substantially improved efficacy (ORR: 81% vs 13%, p<0.001; Table 3) and safety of relapsed/refractory CLL patients versus rituximab monotherapy27. Similar results were observed upon combination of idelalisib with ofatumumab versus ofatumumab alone28 (Table 3). BCL-2 Inhibitors The selective BCL-2 inhibitor venetoclax, a guidelinerecommended treatment option for relapsed/refractory CLL4, was shown to promote rapid apoptosis in CLL cells by selectively mimicking the action of antitumoural BH3-only proteins and antagonising the activity of BCL-2 pro-survival proteins29. In patients with relapsed/refractory CLL, single-agent venetoclax achieved ORR rates >75%30,31 (Table 3). However, despite the demonstrated efficacy, venetoclax was reported to lead to grade 3–4 neutropenia and tumour lysis syndrome (TLS), if dose adjustments are not performed30. Adjusting the venetoclax dose when combined with rituximab was shown to account for potential TLS32, while simultaneously improving outcomes and eradicating minimal residual disease33 as compared to other therapies32 (Table 3). Based on this data, venetoclax received FDA approval for treatment of patients with relapsed/refractory CLL (Table 2). Emerging Treatment Programmes for CLL Despite the gradual introduction of the aforementioned targeted therapies, new treatment strategies efficacious for patients ineligible for/unresponsive to these therapies are still required. These new strategies should ideally overcome disease relapse and circumvent compound-specific safety challenges. Emerging treatment options include new compounds aimed for both untreated and relapsed/refractory CLL and combination therapies of existing compounds that extend single-agent efficacy in specific high-risk patient populations. A member of the tetraspanin superfamily of cell surface antigens, CD37 has been suggested to offer advantages over CD20 as a treatment target because it is selectively expressed by most B-cell malignancies34. The humanised anti-CD37 antibody otlertuzumab triggers caspase-independent apoptosis of malignant cells and induces ADCC. In treatment-naïve CLL patients with comorbidities, combination of otlertuzumab with rituximab led to a 54% ORR (Table 3), lower than that typically observed with the SoC FCR or BR, but almost no grade 3–4 AEs35. Addition of otlertuzumab to bendamustine was shown to improve efficacy (Table 3), while maintaining a safety profile similar to that of bendamustine alone36. Another novel therapy is the next-generation anti-CD20 monoclonal antibody ublituximab, which binds to an epitope on the CD20 antigen distinct from rituximab, ofatumumab, and obinutuzumab, and that has been glycoengineered to achieve ADCC superior to that of rituximab37. Initial Phase I and II trials have shown that ublituximab is able to achieve high ORR, either as single-agent in patients previously exposed to rituximab (67%)38 or in combination with the SoC ibrutinib (88%)39. Other promising combination regimens with ublituximab are currently being evaluated (Table 3). A novel inhibitor of the delta and gamma PI3K isoforms active in the presence of BTK mutations40,41, duvelisib alone achieved a

55% ORR in a heavily pretreated patient population42 (Table 3). In the pivotal Phase III DUO trial, duvelisib vs ofatumumab significantly improved PFS and ORR43 (Table 3). Furthermore, combined therapy of duvelisib with SoC bendamustine-rituximab led to similar results in patients with relapsed/refractory CLL44. While duvelisib has recently been approved by the FDA for treatment of relapsed/refractory CLL after at least two prior therapies (Table 2), EMA approval is still pending. Another PI3K gamma inhibitor currently under investigation for treatment of patients with relapsed/refractory CLL is umbralisib, which led to a 94% ORR in a Phase I dose-escalation trial45 (Table 3). While preliminary data indicates a low incidence of grade 3–4 AEs45, the tolerability profile of umbralisib still needs to be completely defined. Other treatment modalities currently under development in Phase I–II clinical trials include checkpoint inhibitors and cellular therapies. The most commonly employed checkpoint inhibitor is the anti-PD-1 antibody pembrolizumab, already approved for clinical use in various solid tumours. In the first Phase II trial to demonstrate the efficacy of single-agent pembrolizumab in patients with transformed CLL who relapsed after ibrutinib treatment, the observed ORR was 44%46 (Table 3). Considering that most common (>20%) AEs observed with pembrolizumab were drug-related46, improving its safety profile in this patient population by potential use of lower doses in combination therapies is an approach currently under investigation (Table 3). While experience with chimeric antigen receptor (CAR)-T cell therapy for CLL treatment is limited47, preliminary results reported a 57% ORR in heavily pretreated patients48 (Table 3). In the ongoing Phase I/II TRANSCEND trial in relapsed/refractory CLL patients previously treated with ibrutinib and venetoclax and presenting with TP53 alterations, treatment with the liso-cel CD19-directed CAR-T cell product led to a 75% ORR49 (Table 3). Cytokine release syndrome (CRS), a common AE typical for CAR-T cell therapy, was encountered in 80% of patients, but was categorised as grade 1–2 and managed with the interleukin-6 receptor antibody tocilimumab49. Combination of CAR-T cell therapy with an established treatment might help diminish CRS severity, as reported in a recent Phase I/II trial50. Another emerging option for patients with high-risk CLL is stem cell transplantation (SCT). Initial results demonstrated long-term efficacy of both autologous and allogeneic SCT, with autologous SCT leading to a significantly longer PFS51 (Table 3). Subsequent approaches focused on reduced intensity conditioning SCT (RIC SCT), due to lower incidences of non-relapse mortality than with myeloablative SCT (9.5% vs 46%)52. Conclusions Despite the recent progress made by targeted therapies, approaches that consistently address CLL relapse, aim to improve safety/tolerability, and enhance efficacy in high-risk patient populations are still required. Emerging findings with combination therapies allowing for more patient-tailored approaches indicate a promising therapeutic outlook for CLL. REFERENCES 1. 2.

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Oscier, D.G., Rose-Zerilli, M.J., Winkelmann, N., Gonzalez de Castro, D., Gomez, B., Forster, J., Parker, H., Parker, A., Gardiner, A., Collins, A., Else, M., Cross, N.C., Catovsky, D. & Strefford, J.C. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 121, 468–475 (2013). 59. Döhner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Kröber, A., Bullinger, L., Döhner, K., Bentz, M. & Lichter, P. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 343, 1910–1916 (2000). 60. Damle, R.N., Wasil, T., Fais, F., Ghiotto, F., Valetto, A., Allen, S.L., Buchbinder, A., Budman, D., Dittmar, K., Kolitz, J., Lichtman, S.M., Schulman, P., Vinciguerra, V.P., Rai, K.R., Ferrarini, M. & Chiorazzi, N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 94, 1840–1847 (1999). 61. Hamblin, T.J., Davis, Z., Gardiner, A., Oscier, D.G. & Stevenson, F.K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 94, 1848–1854 (1999). 62. Juliusson, G., Oscier, D.G., Fitchett, M., Ross, F.M., Stockdill, G., Mackie, M.J., Parker, A.C., Castoldi, G.L., Guneo, A., Knuutila, S., Elonen, E. & Gahrton, G. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N. Engl. J. Med. 323, 720–724 (1990). 63. Hallek, M., Wanders, L., Ostwald, M., Busch, R., Senekowitsch, R., Stern, S., Schick, H.D., Kuhn-Hallek, I. & Emmerich, B. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progressionfree survival in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma. 22(5-6), 439–47 (1996). 64. Molica, S., Levato, D., Cascavilla, N., Levato, L. & Musto, P. Clinico-prognostic implications of simultaneous increased serum levels of soluble CD23 and beta2-microglobulin in B-cell chronic lymphocytic leukemia. Eur J Haematol. 62(2), 117–22 (1999). 65. Rai, K.R., Sawitsky, A., Cronkite, E.P., Chanana, A.D., Levy, R.N. & Pasternack, B.S. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219–234 (1975). 66. Binet, J.L., Auquier, A., Dighiero, G., Chastang, C., Piguet, H., Goasguen, J., Vaugier, G., Potron, G., Colona, P., Oberling, F., Thomas, M., Tchernia, G., Jacquillat, C., Boivin, P., Lesty, C., Duault, M.T., Monconduit, M., Belabbes, S. & Gremy, F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 48, 198–206 (1981). 67. Wierda, W.G., O'Brien, S., Wang, X., Faderl, S., Ferrajoli, A., Do, K.A., Cortes, J., Thomas, D., Garcia-Manero, G., Koller, C., Beran, M., Giles, F., Ravandi, F., Lerner, S., Kantarjian, H. & Keating, M. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 109(11), 4679–4685 (2007). 68. 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Manero, G., Cortes, J., Thomas, D., Koller, C.A., Burger, J.A., Lerner, S., Schlette, E., Abruzzo, L., Kantarjian, H.M. & Keating, M.J. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 29(31), 4088–4095 (2011). Haferlach, C., Dicker, F., Weiss, T., Schnittger, S., Beck, C., Grote-Metke, A., Oruzio, D., Kern, W. & Haferlach, T. Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters. Genes Chromosomes Cancer. 49(9), 851–859 (2010). Cramer, P. & Hallek, M. Prognostic factors in chronic lymphocytic leukemiawhat do we need to know? Nat Rev Clin Oncol. 8(1), 38–47 (2011). Pflug, N., Bahlo, J., Shanafelt, T.D., Eichhorst, B.F., Bergmann, M.A., Elter, T., Bauer, K., Malchau, G., Rabe, K.G., Stilgenbauer, S., Döhner, H., Jäger, U., Eckart, M.J., Hopfinger, G., Busch, R., Fink, A.M., Wendtner, C.M., Fischer, K., Kay, N.E. & Hallek, M. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 124(1), 49–62 (2014). Awan, F.T., Schuh, A., Brown, J.R., Furman, R.R., Pagel, J.M., Hillmen, P., Stephens, D.M., Woyach, J., Bibikova, E., Charuworn, P., Frigault, M.M., Hamdy, A., Izumi, R., Linghu, B., Patel, P., Wang, M.H. & Byrd, J.C. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Advances. 3,1553–1562 (2019). van der Velden, A.M., Mulder, A.H., Hartkamp, A., Diepersloot, R.J., van VelzenBlad, H. & Biesma, D.H. Influenza virus vaccination and booster in B-cell chronic lymphocytic leukaemia patients. Eur J Intern Med. 12(5), 420–424 (2001). Pasiarski, M., Rolinski, J., Grywalska, E., Stelmach-Goldys, A., KoronaGlowniak, I., Gozdz, S., Hus, I. & Malm, A. Antibody and plasmablast response to 13-valent pneumococcal conjugate vaccine in chronic lymphocytic leukemia patients--preliminary report. PLoS One. 9(12), e114966 (2014). Solomon, B.M., Chaffee, K.G., Moreira, J., Schwager, S.M., Cerhan, J.R., Call, T.G., Kay, N.E., Slager, S.L. & Shanafelt, T.D. Risk of Non-hematologic Cancer in Individuals with High Count Monoclonal B-Cell Lymphocytosis (MBL). Leukemia. 30(2), 331–336 (2016). Strati, P., Jain, N. & O’Brien, S. Chronic Lymphocytic Leukemia: Diagnosis and Treatment. Mayo Clin Proc. 93(5), 651–664 (2018). Mansfield, A.S., Rabe, K.G., Slager, S.L., Schwager, S.M., Call, T.G., Brewer, J.D. & Shanafelt, T.D. Skin Cancer Surveillance and Malignancies of the Skin in a Community-Dwelling Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia. J Oncol Pract. 10(1), e1–e4 (2014). Dohner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Krober, A., Bullinger, L., Dohner, K., Bentz, M. & Lichter, P. Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia. N Engl J Med. 343, 1910–1916 (2000).

Oana Draghiciu Oana Draghiciu, PhD, is a medical writer at CATO SMS, where she develops clinical trialrelated documentation in the oncology and immuno-oncology fields. Oana obtained her PhD in immuno-oncology at The University Medical Center Groningen (The Netherlands) and has over 5 years of experience in publication/development and medical writing in oncology, immuno-oncology, and hematology, and a background in pharmaceutical sciences. Email:

Inka Pawlitzky Inka Pawlitzky, PhD, is director of oncology drug development affairs at CATO SMS, where she provides expert advice on the design and implementation of oncology trials. Inka obtained her PhD in immunology at Tufts Medical School (US) and conducted two postdoctoral fellowships at the Max-Planck Institute for Immunobiology and Epigenetics (Germany) and the Netherlands Cancer Institute (The Netherlands). Email:

Volume 12 Issue 1

Corporate Profile Ramus Corporate Group

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

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

• • • • • • • • • • •

Medical Centre Ramus with Phase I Unit

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

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

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

• • • •

Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

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

Others: • • • • •

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

Medical Diagnostic Laboratory Ramus Ltd

26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Tel/Fax: +359 2 944 82 06 email:

Ramus Medical Ltd Tu

to Cito


e re

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

Dimitar Mihaylov Marketing Director

Journal for Clinical Studies 43


Unified Trial Governance: Why CTMS is the Jewel in the Crown In today’s extremely regulated and progressively global life sciences marketplace, managing clinical trials can be exceptionally challenging. It requires an end-to-end system that offers oversight into trial costs and regulatory risks, while being flexible and compatible with other technologies. This is where clinical trial management systems (CTMSs) play a part. A CTMS is primarily about knowledge and integrating data from disparate sources to help people make proactive and informed decisions. Admittedly, in the past that has not always been the case. Yet historical challenges of poor usability, legacy applications, lengthy implementation cycles, slow innovation and costly maintenance can be overcome by CTMS systems grounded in modern agile engineering practices like continuous validation and continuous integration. These days, innovative CTMS systems are engineered for change and offer extensive automation to deliver new features in a regulated industry, faster than current products. Intuitive systems that utilise flexible cloud architecture allow biopharmaceutical and medical device companies of all sizes to leverage affordable enterprise technology to fit their particular organisation model. This article will highlight that by using CTMS to its best ability, it is possible to extract value from a process-intensive and procedure-orientated industry, ensuring increased governance on trials. Which is ultimately what everyone is striving for. Technology is evolving at a rapid pace, and how users interact with it in their everyday lives is as well. It makes sense that clinical trial systems should evolve in that way too. Introduction The early to mid-1990s saw the introduction of clinical trial management systems (CTMSs), where they played a part in managing clinical trials in clinical research within the biotechnology and pharmaceutical industries. An often-misunderstood software system, numerous smaller organisations view CTMS as a discretionary tool, its value overlooked and not quite recognised. Yet it is a system that can do so much: store centralised contact information and subject data, manage enrolment, track milestones and statuses; and maintain and manage planning and monitoring activities, performance and reporting functions, along with payment tracking – essentially the crown jewels of a clinical trial. Surely it is time for organisations to find a way to harness the value of CTMS. Indeed, market research suggests that CTMS is set to play a fundamental role in the clinical software ecosystem, especially as the number of clinical trials continues to grow and regulations continue to evolve.1 Markets such as Asia Pacific continue to invest heavily in clinical research.2 China CTMS industry revenue is forecast to 44 Journal for Clinical Studies

produce more than USD 270 million by 2024.1 Government initiatives to establish research centres along with high spending on research activities across pharmaceuticals, life sciences, and clinical research sectors will drive regional growth. Furthermore, there is anticipated growth of mobile optimisation in aspects of CTMS solutions, such as analytics, business intelligence and site monitoring. In addition, continued changes in regulations affecting both biopharma and medical device companies will have an impact on the CTMS market. The new MDR legislation3 could increase the number of trials in the medical device market, potentially increasing CTMS adoption in this segment. Enhanced regulations are also impacting the CTMS industry, especially in terms of good clinical practice. For instance, the regulatory landscape has evolved with increased requirements for risk management plans, and risk evaluation and minimisation strategies. For example, with ICH GCP E6 R2 necessitating a “systematic, prioritised, risk-based approach to monitoring clinical trials” the need for an intuitive monitoring solution has never been greater. Responding to Challenges Over the years, CTMS has promised to ease the challenges of managing a clinical trial by providing increased visibility and data insights so that problems can be addressed, progress can be made, and new possibilities uncovered. However, many have failed to deliver as they are not supportive of users that are in the field. Historically, CTMSs have had their challenges, being complex, difficult to implement and set up, and deficient in integration. Classic systems can be heavy, clunky and slow, lack intuitiveness and focus too much on manual data entry and rekeying of data that exists in other systems. Other operational systems can be used instead of CTMS, including spreadsheets and in-house developed systems, however they can often be burdensome to manage and lack compatibility. Disparate systems, non-standardised processes, siloed information and organisational boundaries all obstruct clinical trial management.

Image 1: Design Sprint Process Volume 12 Issue 1


Image 2: Full Visibility of Clinical Trials

CTMS solutions will continue to form a fundamental part of an ecosystem of clinical and operational systems that a company will have. As such, the market is ripe for change, and inventive approaches using modern technologies are beginning to emerge. As the healthcare industry evolves, companies demand a smarter CTMS designed to simplify the management and control of clinical trials. The evolution of clinical trial management has come a long way, from paper, to spreadsheets, to on-premise systems (spreadsheets on a server), to hosted systems (the negative view being spreadsheets in a â&#x20AC;&#x2DC;systemâ&#x20AC;&#x2122; wrapper that someone will host for you) and now to a world of true SaaS solutions that are trying to change the way clinical trials are managed. Evolution is not just about doing the same thing and just hosting it differently. CTMS systems have been rightly considered as expensive, monolithic systems that are costly to both implement and maintain. Through improvements in technology, this has begun to change with SaaS offerings. The continued growth and adoption of SaaS technology solutions especially for CTMS will be a key industry trend in the coming years. This is especially true for SME companies striving to reduce the cost and overhead of either home-grown or hosting their own solutions. Further, with the continued focus on data collection and analysis, companies are adopting CTMS solutions to eradicate the inefficiencies of spreadsheets and other manual tools. With regard to data collection, CTMS systems are increasingly positioning themselves in the middle of an ecosystem of inbound and outbound data, reducing the amount of manual data entry and increasing the transparency of data for reporting and informed decision-making. CTMS Design Considerations It is important that clinical operations executives at life sciences companies address clinical trial management issues proactively and thoroughly to enable successful product development. Yet many organisations face a dilemma when it comes to selecting a CTMS

solution to manage clinical trials. To choose an existing approach/ solution or explore alternative options? This is where CTMS design plays a crucial role. CTMS design needs to be considered from several perspectives; technically, functionally and identifying what the USPs are going to be right up front. As with any other enterprise software, building a CTMS requires some up-front design to ensure that the foundations are scalable and maintainable as the product grows over time. Not putting in strong foundations will increase the costs of adding features and maintaining the software over time. Then there is interoperability â&#x20AC;&#x201C; CTMS systems should be designed to be able to exchange data with a variety of other systems using mechanisms that can reduce the need for custom point-to-point integration. Functionally, usability needs to be at the core. Legacy systems have failed as their focus has been on capturing the data rather than the outcomes that the end user needs to achieve from utilising the technology. Other key factors are configurability, ease of adoption through data standards and pre-configurations to reduce the overhead to implement the system. Agile flow-based engineering practices can also be applied to CTMS, benefiting the validation process. Software validation is an important consideration for biopharmaceutical organisations, CROs and medical device companies. The time and cost of validation can cause version lock, delay time to value, and reduce agility. While validation is required in a regulated industry, some approaches allow users to increase the pace of innovation in a controlled way. For instance, a CTMS that utilises 100% test automation would accelerate innovation and new features, giving clients greater trust, reliability and confidence that any issues will have already been identified. CTMS systems designed and developed utilising agile engineering practices with extensive automation could help ensure that validation assets can be generated with higher accuracy and quality utilising a continuous validation framework. Journal for Clinical Studies 45


Image 3: Business Intelligence

Integration is Crucial To properly manage clinical trials, it is vital to understand the role of information within different technologies across all clinical trials and this is where CTMS comes into its own, seamlessly integrating with eClinical applications. CTMS is one of many systems that can be integrated with other technologies, such as electronic data capture (EDC), electronic trial master files (eTMF) and interactive response technology (IRT) systems, enabling multiple technologies to be utilised within a clinical trial, streamlining workflows and improving productivity. Interoperability is a crucial factor of CTMS. The import/export capabilities must be flexible to accelerate set-up and allow users to perform additional data processing, and reduce manual data entry and reconciliation. This can all help improve clinical trial transparency to simplify registration with public registries such as

value does not start and end with each individual trial. The ability to deliver enterprise control across a portfolio of clinical trials is invaluable. CTMS can provide powerful business intelligence through features such as embedded dashboards and system reports across study management, site monitoring and issue management. The ability to track study progress including enrolment, milestones and essential documents, maintain organisations and associated contacts including global investigators and manage GCP oversight across flexible supply chains, provides the foundation for a corporate knowledge base. This master hub of information can be mined to track performance across clinical trials, and organisations can use the metrics to learn from and improve future studies. The ability to select and filter reports across study, country and site generates a searchable, user-friendly audit trail which supports regulatory compliance.

CTMS forms a cornerstone product across the lifecycle of a clinical trial, from initial budgeting and planning, to protocol development, compliance with government regulations, project management, financials, patient management and recruitment, investigator management and site monitoring and issue management. The objective is visibility into operational metrics and strategic management of clinical trials, with the goal of getting studies up and running quickly and smoothly and increasing the likelihood of success.

Extending the Benefits A CTMS should be adaptable enough to adjust to specific circumstances. With a flexible CTMS, it is possible to improve internal and external communication and enhance supply chain management. Using a CTMS that is adaptive, both functionally and technically, can benefit a company in a multitude of ways. Adaptive CTMSs improve the ability to manage more complex trials and can substantially reduce the cost and time spent by eliminating duplicative or unnecessary tasks. Furthermore, they can improve interaction and increase collaboration across multiple stakeholder groups, providing greater insights into clinical trial data, thus reducing inefficiencies that have previously existed with siloed business processes.

If the appropriate CTMS solution is chosen and implemented in the right way, then the impact of data access and collection should be hugely positive. A good CTMS solution should increase the capture of structured data and reduce the need for data duplication through both inbound and outbound integration capabilities. This streamlines processes and speeds up data collection. It also increases data access for a wide range of stakeholders wishing to have insights into various aspects of the clinical trial portfolio. Knowledge is King While having oversight of a specific clinical trial is crucial, the 46 Journal for Clinical Studies

CTMS can also help to mitigate costs. Adopting a SaaS CTMS system in replacement of an existing hosted solution or even just to replace home-grown solutions is the common way to mitigate some costs of trial management spend. But just replacing the system is not the only way to mitigate costs; adopting standards, increasing collaboration with a single system and streamlining processes which a CTMS implementation requires all can help reduce the cost pressures. Volume 12 Issue 1


Conclusions Todayâ&#x20AC;&#x2122;s enterprise technology needs to be much more affordable, much more accessible, easier to use, quicker to implement and deliver real value to those running clinical trials. Now, CTMS can no longer be viewed as a discretionary system, especially with regulators asking for increased governance of clinical trials and additional guidelines to follow such as ICH E6 R2. Organisations engaging in global clinical trials can benefit from the enhanced levels of real-time communication that come from using a collaborative CTMS that works seamlessly with other clinical solutions, helping researchers realise the benefits of their global trials. There are still challenges to address. Designing and agreeing the future state business processes to help realise the ROI on a CTMS is a key challenge to overcome. CTMS supports multiple groups within a sponsor or CRO and different roles at varying levels within these companies. Each will have different requirements and goals, as well as different priorities. Other challenges include the lead time required for setup and configuration, and in some cases unfortunately customisation, which increase the cost and time of implementation. However, with a CTMS it is possible to demonstrate every touchpoint of a clinical trial (CRO, suppliers, provider, external organisations) all captured within the system to fully demonstrate regulatory compliance. The value of CTMS as a tool for unified trial governance is rising.




Ricky Lakhani Ricky is a Product Management Professional with more than a decade of global experience, specialising in understanding customer requirements and developing products that are valuable, innovative and successful in supporting pharmacovigilance and clinical operations for Life Science Organisations. They are responsible for managing the entire product lifecycle from product strategy, planning and definition through to development and delivery. Email:

Journal for Clinical Studies 47


The New Healthcare, Digital by Design

Our healthcare is becoming increasingly interconnected as technologies allow us to be more connected to our devices, to other people and healthcare services and providers. Our healthcare footprint is now part of our digital footprint. Our digital footprint is now part of a larger digital ecosystem that promises to enable better patient care through better insights. The challenge is to enable while also maintaining individual privacy and data security. Increasingly, there are standards to enable better integration, better data integration and better data security. The patient journey is now enabled through the EMR data allowing patients and doctors to be connected, livestreaming across time, geography, condition and treatment through direct patient-centricity. The Healthcare and Life Sciences Mission • Improving patient care and outcomes should be the overarching goal of any technology and digital engagement in healthcare and life sciences. •

The common goal of improving patient care and outcomes is a unifying theme that connects life science research and therapeutic development with direct patient care, treatment as well as care value and reimbursement. Digital capabilities represent significant enablement throughout the life science and healthcare ecosystem toward better therapeutic discovery, development, patient treatment, experience and journey as well as outcomes including both healthcare metrics and cost.

Introduction “Digital Healthcare” has become a recent buzzword representing the application of digital or data technologies to healthcare, from patient engagement to apps and digital media, from connected medical devices and biomarker metrics through to IoT (Internet of Things), from patient data and insights to digital records. Electronic health records (EHRs) or electronic medical records (EMRs) are the key capture and integration layer for digital patient data and represent documented data of the patient’s journey through healthcare, from diagnosis, to treatment, to outcome. At the same time, EHRs/EMRs are currently limited to clinical case data only and contain both structured and unstructured data. Increasingly, the demand from digital healthcare is for more structured data and more granular patient detail, including genetic test results or other ongoing values such as EKG, hypertension metrics or blood sugar levels that may not be structured or captured between clinical appointments. As an additional concern, while there is more demand for data, there is greater sensitivity to patient privacy, security and higher thresholds to ensure data compliance in GDPR, HIPAA and the new CCPA (California Consumer Privacy Act) legislation. 48 Journal for Clinical Studies

The Patient Digital Journey Increasingly, patients are looking for closer engagement in their own treatment and responding favourably to the use of smart devices and other technologies they are familiar with to understand and manage their own care.1 At the same time, pharmaceutical companies want to better understand and identify patents where the treatment can be most efficacious as well as be able to track outcomes and mitigating factors. Care providers want to improve patient outcomes and reduce re-occurrence and readmission risks that affect their reimbursement bottom line. From a patient perspective, the patient-centric message must be that we are focused on treating you, the patient, not just the disease. Traditionally, pharmaceutical companies and treatment providers grouped patients and treated them as broad categories, not as individuals. If you are a breast cancer patient, traditionally your treatment would be the same, within parameters (size, hormoneresponsive or not, peripheral migration or not), as for any other breast cancer patient with the same metrics. This is changing with personalised health care and precision medicine, and with things such as companion diagnostics and other genetic technologies that enable improvements in an individual patient's diagnosis and definition of the best course of treatment. As treatments become more individualised, patients expect and want an individualised experience. The power of digital technologies/data connectivity is to change the patient's perception from not just being a category but into having an individual experience and engagement with their treatment, even if the back-end platform (or handheld device) is the same. Allowing the patient to create their own engagement has been shown to be extremely effective as in chronic disease management such as diabetes,2 addiction and neurology3. The future of medicine is about the patient's individual journey and staying connected, engaged and in control, each step, and one day at a time. The Digital Data Problem Relative to Healthcare The amount of data and relevance of data to patient healthcare and improving care metrics is exploding. The main challenges are data relevance to patient care, quality and interoperability. What data is important to treating patients, how is it important, how should it be structured, shared and prioritised? One effort to meet these challenges is FAIR,4 a data modeling standard, that posits the principles that data should be (F)indable, (A)accessible, (I)nteroperable and (R)eusable by both humans and machines. The challenges of big data are the 4 Vs: volume, velocity, variety and veracity – and healthcare data is no exception. As mentioned, EMR data is the electronic clinical record of a patient’s journey from condition to diagnosis and treatment. The data is as multi-dimensional as the patient’s interactions throughout their healthcare system. Structured information elements, including demographics, diagnoses, procedures, medications and laboratory tests, tell the chronology of the patient journey. EMR data also includes unstructured data elements such Volume 12 Issue 1

Technology as medical images, EKGs, genetic test results and physician notes (including pathology reports and discharge reports) that cannot readily be queried but are extremely relevant to patient condition and care metrics. The goal is “meaningful use”, i.e. that electronic exchange of health information should enable improvements in quality of care. The concept of meaningful use rests on five pillars of health outcomes policy priorities5: 1. Improve quality, safety and efficiency, and reduce health disparities 2. Engage patients and families in their health 3. Improve care coordination 4. Improve population and public health 5. Ensure adequate privacy and security protection for personal health information The additional challenge is data privacy and ownership. Who owns a patient’s data if not the patient? How can a patient’s data be collected and shared within their healthcare network and with their attending physicians to guide and facilitate the patient’s care while also protecting personal and private information and conforming to new healthcare data regulations? There are several new business ventures and cooperatives around healthcare data exchanges, where the patient owns their own healthcare, lifestyle and environmental data, and can embellish and selectively share it. The bet is that patients will have increasingly more access to and control of their own personal healthcare data. Collaboration Patient healthcare is increasingly a collaborative process between different healthcare services, both inpatient and outpatient care, different physician specialities, care centres and testing services which are no longer exclusively managed through a single point of contact (traditionally, the family or primary care physician). Increasingly, with the advent of greater patient travel capability and telemedicine services into rural areas, it is not uncommon for patients to be seen in different care settings and in different contexts and as they search out different speciality care options. From a healthcare perspective and with the purpose of treating patients with more context to their entire journey, there are numerous efforts between hospitals, within systems and across systems, to be able to share patient data in order that redundant procedures and treatments, and perhaps even misdiagnoses, are prevented. In Massachusetts, the Massachusetts Health Information Highway (MASS HIWAY) is a secure statewide network that facilitates the transmission of healthcare data and health information among providers, hospitals, and other healthcare entities as allowed by applicable state and federal laws. In New York City, in the EPIC Together Program,6 several hospitals are combining efforts using EPIC’s cloud-based EMR system to combine inpatient and outpatient charts, as well as allow patients to share their records with other institutions. More broadly, the eHealth Exchange (formerly the NHIN) is seeking to bring all US data together.7 In Switzerland, where the writer is based, the SPHN (Swiss Personalized Health Network) has several initiatives to enable teaching hospitals to share data and understand care metrics across the country. Most recently, the partnership8 in the US between Google and the medical system, Ascension, to store and analyse the data of millions of patients, could have huge reach. Ascension operates 150 hospitals in 20 states and the District of Columbia. Under the arrangement, the data of all Ascension patients could eventually be uploaded to Google’s cloud computing

platform. In Korea, the Korea University Medical Center is leading national efforts to enable big data analysis of patient outcomes and support the development of personalised medicine and artificial intelligence in healthcare by sharing data across sites in a cloud-based, Blockchain-protected system, the Precision-Hospital Information System (P-HIS).9 Back in Europe, the HONEUR collaboration10 has the goal of accelerating the development of new cancer treatments and the improvement of patient outcomes by bringing together data from multifarious institutions across the continent that have large data sets of patients diagnosed with haematological malignancies. And in the Netherlands, where there is an average of 43 isolated medical records per person, the Connect2healthconsumer programme is just being launched to unify the data under one data model, to ease reuse of data and the personalisation of health advice and interventions. The point of all of this is that healthcare has become collaborative and there is no longer a single point of care for most patients. Data integration is critical to improving patient care and outcomes from the levels of their existing care, but standards of data integration, interoperability, data security and standards for data anonymisation from personal and private patient data are critical for success. Data Standards Data standards have become as critical as the access to the data itself. Much like the diplomatic courtier language of the Middle Ages, what should the “lingua franca” be in the realms of healthcare data and patient records? How can disparate systems create an overall patient journey profile? There are several data standards. SDTM11 is used for submission of clinical data to the FDA. HL-7’s FHIR provides guidelines and standards for data exchange.12 OHDSI & EHDEN’s OMOP brings observational data into the mix. OHDSI13 is a community effort to standardise healthcare data into a common data model and vernacular called OMOP. The OMOP common data model (CDM) is designed for EMR data as well as administrative insurance claims data, allowing users to generate insights from a wide variety of data sources, both within and outside the United States. The intent is that once data sources have been converted to the OMOP CDM format, that several open source analytical tools are available to generate standardised queries and insights. What does this translate into for patients and actual patient care? A common data model and vernacular means that regardless of when and where a patient is seen and for whatever test, treatment or diagnosis, that the patient’s records and charts can be viewed and made available in totality in one context, and not as disparate or fragmented clinical records and insurance claims. Although OMOP currently works with structured EMR data, there are numerous efforts14,15 to also extend this to unstructured EMR data using natural language processing (NLP), a form of AI. The intent is enabling queries across structured and unstructured data that enable better patient-centricity, stratification, care metrics and patient models such as relevant cohorts. The Healthcare Network Healthcare is changing; it is becoming multi-dimensional through greater connectivity between patients and care-givers and enabling digital technologies. Patient metrics are no longer limited to individual clinical settings and doctor’s visits but can now be facilitated through IoT technologies that enable metrics Journal for Clinical Studies 49

Technology recording for virtual clinical trials as well as apps and messaging that engage the patient between doctor visits. Healthcare is now delivered through a network of care-givers and services. At the same time, patients and their data are also part of their own patient network: the ecosystem of patients and their data represented within a healthcare system, hospital network, primary care consortium, or combination of any of these across country and geographic areas. The power of these networks to improve patient care is immense. Not only can individual patients be cared for holistically through the entirety of their digital experience, but a better understanding of care metrics, care efficacy as well as epidemiology can be derived by looking at care within and across different settings.

Figure 1: EMR patient network can used to more rapidly identify potential patients than traditional outreach methods, allowing more time for extra outreach and patient validation.

“Value for care” is now the mantra in healthcare: to be able to demonstrate treatment and therapeutic effectiveness. Patient networks are critical to being able to trace a patient’s treatment and outcomes and to examining the effectiveness of therapeutics in different settings and as part of different treatment regimens. A patient’s journey is not alone but part of thousands, if not millions, of steps by other patients also on their own paths. We learn from each other Figure 2: Total patients found by EMR-data-driven solution was significant in many therapeutic areas and enable better outcomes, as although we are each where relevant data is digital, and many patients are only identifiable by the digital method an N of 1, we have, in aggregate, the ability to better in comparison to traditional outreach methods. understand disease, develop treatment options and Use Case: Real-world Data Performance Insights better deliver individualised patient care. It all arises from being Use of an EMR-based solution offers a combination of multiable to predict a patient`s journey by having access to models dimensional query definition, real-time search across multiple based upon longitudinal data, “Precisely practicing medicine with networked electronic health record systems made interoperable by a trillion points of data”, as evoked by Dr. Atul Butte of Stanford the use of semantic and ontology methods, and a highly scalable University.16 hybrid cloud- and federated local installation-based platform. Users can thereby identify relevant anonymised patient data for a given protocol through automated screening of EMRs, using real-time Clinical Trials, Integrated Research Partnerships data. This enables optimisation of study protocols, more efficient and Real-world Data site selection and faster patient search as well as anonymised RWD The merger of digital healthcare and patient data networks has also collection options. This can bring the following applications and increased partnership and synergy in a number of areas of patient use cases: care, but in clinical trials, especially between sponsors and CROs to better identify patients and accurately recruit patients specific • Synthetic control arms: using longitudinal data to create virtual to the clinical research and study design.17 As EMR data is the control groups is helping reduce clinical trial enrolment, cost most accurate resource of clinical patient data, access to patient and needless duplication of patient treatment groups for networks of EMR data is critical to clinical research. Not only is which treatment data already exist. Additionally, using EMR EMR data critical for understanding where actual patients are, but data to develop and test synthetic cohort models is critical to also for effective study design and site selection. The anonymised epidemiology and disease progression modelling20. data is also invaluable for retrospective studies, studying treatment • Predictive modelling: data scientists can use the time series regimens and developing surrogate cohorts. EMR data is a highly information to predict the number of new patients for a accurate source for RWD18 to understand trends and care and specific indication in the future. Those predictions could help differences geographically and within care centres. in clinical trials to model incidence/prevalence of specific condition of interest for a site. Below, we outline cases for both areas. • Therapeutic insights: health researchers can show insights into frequency and volume of use of medications and procedures Use Case: EMR data for Patient Identification for Clinical Trials and changes therein over time. They can also monitor from and Clinical Research which date new medications/procedures get prescribed to Keyla Deucher, Managing Director of BIOSERV SMO, has run patients – and if new prescriptions decrease the usage of other recruitment for trials at the Hospital São Vicente de Paulo, Brazil. medications/procedures. The results19 show that the use of the EMR-data-driven solution: • Healthcare market insights: create market segmentation reports, e.g. monitoring the frequency and volume of • Allows trial staff to spend more time on patient outreach and prescriptions for medication across pharmaceutical companies. screening. (Figure 1) • Finds patients not otherwise findable. (Figure 2) • Compound-specific usage statistics: 50 Journal for Clinical Studies

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Technology •

“How many patients with the diagnosis X receive compound Y within Z weeks of diagnosis? • “How did the number of treatments with compound Y change during the last two years and is it gradually replaced by a competitor?” • “Is the compound mostly administered in an in- or outpatient setting?” (i.e. one-day hospital visits or inpatient). Adverse effects / events reporting: • “What are the top-10 diagnoses within two months after administration of X or procedure Y?” • “What is the median time to re-admission after administration of X or procedure Y in comparison with Z?” Demographic treatment algorithms: • “What is the preferred (i.e. most prescribed) treatment for illness X in the age group 18–28?”

Anonymised EMR data can be used for longitudinal retrospective studies based upon various cohorts such as disease diagnosis and treatments. As an example, multiple myeloma patients diagnosed in 2018, as found by searching patient EMRs on Clinerion’s Patient Network Explorer, could be analysed to show demographics, Charlson comorbidity risk scores21 and Bortezomib treatment regimens. (Figure 3).

Figure 3c: Bortezomib treatment regimens in multiple myeloma-identified 2018-firstinstance Patient Network Explorer patients in Turkey.

4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14.

15. 16.

17. Figure 3a: Patient demographics in multiple myeloma-identified 2018-first-instance Patient Network Explorer patients in Turkey.

18. 19. 20.


Visit Visit Visit Visit Singer N, Wakabayashi D, Google to Store and Analyze Millions of Health Records, The New York Times, 11 November, 2019, available at www.nytimes. com/2019/11/11/business/google-ascension-health-data.html Visit First look at cloud-based medical records, Nature Research, ref.: doi: 10.1038/ d42473-019-00098-4 Visit Visit Visit Liu S, Wang Y, Wen A, Wang L, Hong N, Shen F, Bedrick S, Hersh W, Liu H (2019). CREATE: Cohort Retrieval Enhanced by Analysis of Text from Electronic Health Records using OMOP Common Data Model, 10.2196/preprints.17376. Si Y, Weng C, An OMOP CDM-Based Relational Database of Clinical Research Eligibility Criteria, Stud Health Technol Inform. 2017; 245: 950–954. Butte A, Precisely practicing medicine with a trillion points of data, TEDxSanFrancisco, 31 october, 2017, available at watch?v=fbZZ_1Jbm6w Integrated research partnerships build momentum, 1 July, 2015, Centerwatch, available at Research Operations for Secondary Use of Clinical Sites, EMR Fall 2019, Evidera white paper Rentsch I, Deucher K, How EHR driven patient recruitment supports patient centricity, presented at MAGI Clinical Research Conference, October 27, 2019. Goldsack J, Synthetic control arms can save time and money in clinical trials, STAT, February 5, 2019. Available at synthetic-control-arms-clinical-trials Charlson ME, Pompei P, Ales KL, MacKenzie CR, A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation, Journal of Chronic Diseases, Volume 40, Issue 5, 1987, Pages 373-383

Douglas Drake

Figure 3b: Charlson Comorbidity Index scores for multiple myeloma-identified 2018-firstinstance Patient Network Explorer patients in Turkey.




Boissy A, The Digital Experience Must Also Be a Human(e) Experience, NEJM Catalyst, 21 November, 2017, available at Dobson R, Carter K, Whittaker R, Diabetes Text-Message Self-Management Support Program (SMS4BG): A Pilot Study, JMIR Mhealth Uhealth, 2015 JanMar; (3.1): e32, available at Visit

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

Journal for Clinical Studies 51

Logistics & Supply Chain Management

Temperature Challenges in Clinical Supply: Examining the Cold Chain to Ensure the Efficacy of IMPs and Patient Safety Supply chains for investigational medicinal products (IMPs) are becoming more complex. As clinical trials change rapidly, maintaining product integrity and quality at every stage is challenging. Additional demands are being created by the growing development of biologic and orphan drugs, as well as cell and gene therapies. These temperature-sensitive products are subject to more stringent stability profiles, with strict temperature ranges having to be adhered to. This myriad of challenges calls for the entire cold chain network to be reexamined and potential packaging, labelling, storage and distribution requirements to be considered early in a study’s planning. With this in mind – how can you be sure that the medication is safe to give to the patient? This article looks at the temperature challenges associated with biologic products and addresses how emerging cold chain management solutions are helping sponsors ensure specified temperatures are maintained throughout the supply chain. Today’s Changing Clinical Trial Landscape The precision medicine market has witnessed remarkable growth, augmented by a surge in investment into more targeted and patientcentric medicines. Driven by the increasing prevalence of cancer and rare diseases, and ongoing advancements in genome mapping and molecular diagnosis, the global market is expected to reach $216.75 billion by 2028. Translating developments in precision medicine into treatments is helping to mature the biologics sector, with this market expected to touch $399.5 billion by 2025.3 As these therapies become relevant to more disease areas, many sponsors are choosing to populate their drug pipelines through investment opportunities in biologic products and biotech capabilities. A record number of drug approvals in 2018 saw 59 novel treatments reaching the US market, with almost two-thirds being patented by biopharma companies.4 The shift towards greater clinical development of biologics and cell and gene therapies has a resulting impact on clinical trials, with completion timelines, costs, resources, and the likelihood of study success, all being affected. Additional complexities are also being introduced by these products, including the need for more frequent re-test dates, changing handling requirements, limited bulk availability, short stability data, and, perhaps, the biggest challenge of all – the complex process of managing cold chain supply. The globalisation of clinical trials dictates that products travel greater distances, crossing numerous climates and environments, all while maintaining strict temperature controls. By 2020, it is projected that eight of the top 10 pharmaceutical products will require cold chain handling.5 This has led many sponsors to look to outsourced service 52 Journal for Clinical Studies

providers to deliver clinical trial materials to investigative sites, while supporting supply planning and forecasting. Establishing efficient supply chain logistics is critical to avoid delayed or failed trials and there is a need for vendors that can achieve this, particularly with mounting concern over costs and patient safety. Rising need for cold chain logistics calls for packaging and monitoring technologies that offer lower-cost solutions, including reusable packaging and phase change materials that allow cooling for more specific temperature ranges.6 Industry Perspectives A snapshot of industry perspectives pertaining to cold chain management has been captured by a survey of individuals working within pharmaceutical companies, contract research organisations and biotech companies.7 The survey found that 47% of respondents value reliability as the primary driver for cold chain logistic decisions. This was more than double the percentage of respondents who chose cost (21%) and ten times more than those who selected ease-of-use (5%). Regarding cold chain management, 71% of respondents stated that their companies either outsource exclusively or do a combination of outsourcing and in-house management. The survey also found that biotech companies are more inclined to outsource certain functions than pharmaceutical companies. 60% of biotech respondents stated that all manufacturing, packaging, storage and distribution functions were outsourced. For pharmaceutical companies, the corresponding figure was 7%. Implications for Labelling and Packaging of Cold Chain Products Failure to consider potential packaging and labelling challenges at a study’s planning phase has the potential to compromise the timing, safety and success of a trial. As a result of increased demand for cold chain management capabilities for temperature-sensitive products, new hidden challenges have emerged within the cold chain substream, adding to the existing challenges which apply to all forms of clinical labelling and packaging. Selection of the right packaging design to withstand and maintain a product within specific limits is critical to ensure stability and integrity within the supply chain. Sponsors should consider several elements prior to defining a packaging and labelling configuration. These include storage and shipping criteria (frozen, ultra-low or cryogenic), ability to have time out of conditions for labelling, blinding requirements, expiration dates, the likelihood of product re-work due to information updates, depot and site storage availability, home storage and patient/physician handling. Storage criteria will influence how a product is packaged. Biologic products typically sit within three temperature ranges (refrigerated: 2°C to 8°C, frozen: -25°C to -15°C and ultra-low: -25°C and below). The packaging design requirements for 2°C to 8°C products are akin Volume 12 Issue 1

Logistics & Supply Chain Management The amount of time that a product spends out of stipulated temperature conditions will be dependent on the processes involved, the complexity of packaging and the assembly time. If time out of conditions is necessary, then it is advisable to make the best use of this and consider any potential for rework of material or expiry date updates. If time out of conditions is completely prohibited, insulated containers may be necessary for transportation of material between areas. Alternatively, products can be packaged directly in 2°C to 8°C and -25°C to -15°C conditions, or even processed directly out of a freezer for materials stored below -25°C.

to those used for ambient medicinal products and usually include solid bleach sulfate (SBS) for the carton material. While cartons for product stored in frozen conditions require a stronger material to prevent damage from moisture, polyethylene one-sided coating is commonly used. Label design is also influenced by temperature, with consideration required for both processing and storage conditions. When a product is stored below -25°C, the integrity of paper labels becomes threatened. In this case, a single-panel label is usually the best option over a booklet. The correct label adhesive is fundamental as glues behave differently based on the temperature they are applied at, the temperature they are stored at (and for how long), and the material to which they are applied. If materials are stored in frozen or ultra-low temperatures, cryogenic label stock is necessary.

Choosing the Most Appropriate Manufacturing Process for Temperature-sensitive Products Development of biologic and precision medicines means the industry needs to work in non-traditional ways to mitigate the supply-based risks that these trials pose. There are several methods of manufacturing, packaging and labelling which can be adopted for different demands. Standard batch manufacturing involves a drug product being made, packaged, labelled and added to inventory to produce a set demand. Favoured for small molecule drugs, this approach can cope with uncertain demand forecast as operations can start and stop as required. While overheads are reduced as one production line can be used for multiple products, lack of flexibility makes the approach unsuitable for biologics and precision medicines. Lean manufacturing offers a systematic method of minimising waste without compromising productivity. Unlabelled products

Journal for Clinical Studies 53

Logistics & Supply Chain Management held in inventory are packaged and labelled in smaller batches in accordance with short-term forecast. Offering the ability to respond quickly to last-minute scheduling, lean operations can help mitigate the risks of stock-outs, especially in trials where patient enrolment and drug demand forecasts are uncertain. However, the model supports little flexibility as supplies are made in advance.

Temperature Management Solutions for Cold Chain Products The complexity of clinical trials is driving the need for reliable data management across the supply chain. To ensure products are fit for patients, it is imperative that sponsors are equipped with the ability to track and trace the journey of their IMP, identify issues at the first opportunity and make informed decisions.

Just-in-time labelling services offer partial late-stage customisation of clinical kits at the time of distribution. Kits are packaged and labelled in advance of standard batch or lean manufacturing operation. Once a distribution order is placed, kits can be modified with the application of an auxiliary label. This approach can improve efficiency, decrease waste and reduce cost by removing the need for labelling rework.

Single databases are being introduced that enable temperature data to be tracked from product manufacture right through to the point of patient administration. This not only means that temperature data is held in one place, but also enables a history to be built for every product as it passes through the supply chain, demonstrating that IMPs have been stored within specified temperature limits. Using this type of technology readily alerts sponsors to any pending temperature excursions, enabling preventative action to be taken.

Just-in-time manufacturing solutions permit the assembly of finished patient kits based on demand. As well as supporting the need for greater flexibility, sponsors are finding that storage costs can be reduced if kits are assembled closer to the point of use. Subsequent changes to study design are also simplified since pre-labelled material is not sitting in inventory. This provides a solution to support patientcentric dosing, which is common in trials involving temperaturecontrolled medicines. The benefits of just-in-time manufacturing were realised by an organisation running a Phase Ib trial for a rare paediatric disease which required varied patient dosing. Strict temperature conditions of -70°C +/-10°C were necessary throughout the drug’s lifecycle and the product was able to withstand only an extremely limited time out of conditions. To overcome the challenges, a custom process was established to enable full late-stage customisation of kits. This condensed the lead-time from the point of drug order to receipt of the shipment at the clinical site from six to eight weeks, to two weeks.

54 Journal for Clinical Studies

Advances in temperature-controlled shippers are also ensuring the integrity of IMPs in transit. They represent a move away from traditional bulky shippers featuring water-based refrigerants, instead utilising new technology including phase change material and vacuum insulation panels. With the ability to maintain temperature for 96 hours, these shippers bring the flexibility to ship IMPs at any point in the week, as well as mitigating risks associated with potential delays. The shippers can hibernate when stored in an environment that matches their required temperature, effectively ‘stopping the clock’ and no longer losing the validation period. Reusability also means that the carbon footprint associated with traditional solutions is reduced, as too is the site burden of managing disposal. An example cold chain distribution which benefited from temperature-controlled shippers involved an IMP that needed to be maintained below -60°C, with orders processed and shipped

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Logistics & Supply Chain Management

within 24 hours. By using new shipper designs, when a drug order is received the shipper is prepared with dry ice and stored in a -70°C freezer for approximately 12 hours. Temperature monitors for -70°C and colder shipments are inventoried in a -20°C walk-in freezer then moved to a -70°C mobile freezer when the material is picked. The material is verified and packed into the pre-conditioned shipper, and the temperature monitor is activated. The sealed shipper is placed back into the -60°C freezer until courier pick-up. The whole preconditioning process has eliminated all front-end excursions. Final Thought The packaging, storage and transportation of temperature-sensitive IMPs demands constant monitoring to ensure their stability and viability. Managing product integrity at every point of transfer from manufacture to distribution is imperative in safeguarding patients. As more temperature-sensitive biologic drugs enter the supply chain, innovative solutions are helping to optimise the complex task of tracking temperature excursions. By having a complete picture of an IMP’s temperature profile as it progresses through the cold chain, sponsors can have confidence that their product has been maintained within temperature constraints and therefore meets the compliance requirements essential for safe and successful supply. REFERENCES 1. 2. 3. 4.

Frost & Sullivan: Biologics Report 2016 5. 6. 7. Clinical Supply Chain Survey Report: SCORR Marketing and Applied Clinical Trials

Anthony Mistretta Tony has over 25 years of experience in the pharmaceutical industry including production, warehouse, training, and distribution. Tony and his logistics team have provided customers with sound logistics solutions based upon their many years of experience in the clinical supply chain. Tony is passionate about providing excellent customer service throughout the entire supply chain process, from order receipt to drug shipment delivery, on-time and within specification. Tony is well versed in working closely with customers, third party organizations, and the appropriate departments within Almac, to deliver comprehensive logistics solutions for the clinical supply chain. Email:

Bryan Thompson Bryan Thompson has worked in a manufacturing capacity with Almac Clinical Services for the last 11 years. He is responsible for the development and management of 200+ staff across a three-shift clinical packaging operation. Bryan has the additional responsibility of overseeing the generation of a complex production schedule, review of Project specific generated batch documentation, and quotation generation. At Almac, Bryan has gained extensive knowledge of the processes, equipment, and materials utilized in clinical trials packaging, and is a subject matter expert on cold room packaging. Email:

Journal for Clinical Studies 55

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