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Volume 9 Issue 5

JOURNAL FOR

U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

PEER REVIEWED

Healthcare Research in United Arab Emirates

A Decade of Biosimilars Have Expectations Been Met?

Collaborating with Patients for Better Trial Design

Driving by Data

A Faster, Better Road to Market

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Contents

JOURNAL FOR

4

Your Resource for Multisite Studies & Emerging Markets

6

U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker MANAGING EDITOR Maria Dominici maria@pharmapubs.com EDITORIAL ASSISTANT Virginia Toteva virginia@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH&CIRCULATION MANAGER Evelyn Rogers info@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.jforcs.com Journal by Clinical Studies - ISSN 1758-5678 is published bi-monthly by PHARMAPUBS

FOREWORD

WATCH PAGES Everything Old is New Again: Bacteriophage Therapy

Bacteriophages are viruses that can be found inside plants and animals and in soil, rivers, oceans, and even sewers. Phages invade bacterial cells and inject their DNA into the bacterial target. The intentional application of phages to destroy bacteria is known as bacteriophage therapy. Julie Odland of Clarivate Analytics discusses the goals that the FDA identified towards the scientific and regulatory considerations for bacteriophage therapies. 8

Health Informatics Data: Connecting Patients to Investigators

From the perspective of a clinical trial, a rare disease suggests the available patient and site population is quite small and distributed diffusely. Likewise, any challenge related to study logistics, competitive landscape or patient recruitment is magnified as compared to trials in other indications. Kamila Subaieva and Earl Seltzer, at INC Research/inVentiv Health, discuss how major regulatory agencies encourage the development of treatments for patients with rare diseases. 10 How can Modelling and Simulation Fuel the Clinical Development of Biosimilars? The relatively low cost to enter the “generic” market and the size of the biologic drug market make entry attractive. However, the failure rate for biosimilars is deemed high, due to the complex manufacturing process and the high variability expected for biologics. Bernardo de Miguel Lillo and Daniel Röshammar at SGS Exprimo discuss why there is a high risk-cost relationship in the establishment of clinical biosimilarity. 12 Clinical Trial’s Role in Compliance and Patient Safety Although James Lind conducted the first controlled clinical trial back in 1747, it wasn’t until the Nuremberg Code in 1947 and the Declaration of Helsinki in 1964 that patient safety in clinical trials became paramount. Catherine Maidens of Clinical Professionals shows how investigators and sponsors comply with all these rules to ensure that patient safety is protected. REGULATORY 14 A Decade of Biosimilars: Have Expectations Been Met?

The opinions and views expressed by the authors in this magazine are not neccessarily those of the Editor or the Publisher. Please note that athough care is taken in preparaion of this publication, the Editor and the Publisher are not responsible for opinions, views and inccuracies in the articles. Great care is taken with regards to artwork supplied the Publisher cannot be held responsible for any less or damaged incurred. This publication is protected by copyright. Volume 9 Issue 5 Sept 2017 PHARMA PUBLICATIONS

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Innovator companies have employed a variety of multipronged strategies to counter biosimilar competition. These include development of ‘biobetter’, gaining regulatory approval for additional indications and new formulations. Karen Lipworth, Jill Dawson, Raymond A. Huml, and Nigel R. Rulewski, of QuintilesIMS, discuss why these products have potential to improve drug access for patients while cutting healthcare costs. MARKET REPORT 20 Healthcare Research in United Arab Emirates The UAE has rapidly transformed its healthcare sector in the past decade. Adhiti Sharad Kumar explains the UAE’s 2021 Vision, which states that the UAE will invest continually to build world-class Journal for Clinical Studies 1


Contents healthcare infrastructure, expertise and services to fulfil citizens’ growing needs and expectations. THERAPEUTICS 24 Potential Therapies in the R&D Pipeline for Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral MD, likely the most prevalent form of MD, currently has no cure, but several factors point to the potential for successful development of a disease-modifying FSHD treatment in the near future. Raymond A. Huml, Lucie Undus, Meredith L. Huml, and Margaret Dean discuss how the number of interventional trials to treat FSHD is increasing sharply. 32 Augmenting Clinical Development of Heart Failure Therapies There are currently a number of pharmaceutical or device-based heart failure therapies in clinical use, with numerous promising candidates under development. Bobby Stutz and Dr Winter of AtCor Medical, Inc discuss how PWA assessments have the ability to streamline and optimise HF drug development by increasing programme efficiency, shortening project timelines, and enhancing post-market activities.

52 Early-stage Development, Xcelodose & Clinical Phases The pharmaceutical industry’s ongoing demand to shorten drug development times, thus making significant cost savings, is driving technological advances forward at the same time as there are major changes happening in the research and development of highvalue and often potent speciality medicines. David O’Connell at PCI Pharma Services explains the effectiveness of Xcelodose® technology, utilising the latest equipment for the processing of potent molecules. CLINICAL SUPPLIES 56 Seeing Beyond the Label: Transforming the Management of Customer Materials Integration and increased automation are transforming the way life sciences companies manage much of their operational and regulatory information. Labelling and packaging content – so critical to market acceptance and patient safety – remain subject to very separate, manual processes, leaving organisations open to unacceptably high risk of error. Romuald Braun of AMPLEXOR discusses better ways. SPECIAL SECTION

36 Three Respiratory Trial Strategies that Won’t Leave You Breathless

60 Patient-centricity: A Progressive Prescription for Modern Healthcare

The biopharmaceutical industry invests billions of dollars annually into clinical research to address a range of debilitating respiratory conditions. Phil Lake at ERT discusses how the active management of data quality reduces variability in the outcomes, as well as bringing greater confidence in the drug’s effect, ability to identify the true responders, and faster drug development.

A revolution is happening in the healthcare industry. Societal pressure to improve our health, technological advances, and market forces are all driving forward a novel patient-centric approach to healthcare. Tim Davis of ERT discusses how putting the patient first can achieve the best experience and outcome for that person and their family.

40 Clinical Development in Challenging Cancers: Primary Bone Sarcomas

64 Collaborating with Patients for Better Trial Design

Primary bone sarcomas are cancers of mesenchymal, non-epithelial derivation, originating from bone cells or their precursors. Kelechi K. Olu MD, MSc, Vijayanand Rajendran and Mohamed El Malt at Europital explain the pathways which are expected to lead to identification of specific target genes that could represent novel treatment options for these tumours.

Modern patients are taking control of their own healthcare, from sharing information with one another to approaching industry organisations with their concerns. Tarquin Scadding-Hunt at mdgroup discusses how, in order to appeal to this new wave of patient-consumers, clinical trial organisers are having to reconsider key components of trial design, to ensure adequate enrolment.

TECHNOLOGY 44 Enrolment Compliance and Study Data The current concept of clinical trial conduct is a balance between benefits from treatment (efficacy) and risks that this treatment may have (risk). Maxim Kosov, Tatiana Dumpis, Alexey Maximovich, John Riefler and Maxim Belotserkovskiy, at PSI-CRO, discuss how the eligibility review is an essential part of risk-based monitoring and allows mitigation of enrolling non-eligible patients. 48 Driving by Data: A Faster, Better Road to Market The clinical development path is rife with complexity that can stall or stop a drug’s journey to market. Paul Evans, Jetendra Rao and Abigaile Betteridge at PAREXEL International explain that, while there is no single transformative solution to streamline clinical development, biopharmaceutical companies can take common sense steps to mitigate risks, control costs, improve efficiency, and gain competitive advantage. 2 Journal for Clinical Studies

Volume 9 Issue 5


Foreword The National Human Genome Research Institute (NHGRI) announced recently that it will provide more than $240 million over the next four years to fund research into the genomic variation underlying common diseases. NHGRI Director, Eric Green, says that the time is right for a very large-scale human genome sequencing programme, in order to understand the genetic and environmental causes of common diseases. The kind of information that can come out of this is overwhelmingly medically important. To spearhead the project, NHGRI has launched the Centers for Common Disease Genomics (CCDG), which will focus on diseases including diabetes, autism, and heart disease. Researchers at four funded centres associated with universities and colleges across the US will sequence tens of thousands of genomes from individuals with and without the diseases in order to identify underlying genomic causes and correlations. The National Heart, Lung, and Blood Institute will provide an additional $20 million for the CCDG centres, according to the NHGRI press release. Meanwhile, funding of $40 million from NHGRI has been secured for the Centers for Mendelian Genetics (CMG)—a complementary programme established in 2011. This programme will continue its work on the genomic causes of rare diseases, including cystic fibrosis and muscular dystrophy. In the last four years, the centres have identified more than 740 genes associated with Mendelian diseases and have sequenced the protein-coding regions of over 20,000 genomes, said NHGRI. I started my foreword with this little piece of information because finding cures for rare diseases is becoming more and more important. In the Watch Pages, Earl Seltzer, Director – Global Feasibility at INC Research/inVentiv Health, discusses why clinical trials in rare diseases are so challenging today. Amongst other interesting Watch Pages, the one I would like to highlight here is the editorial by Julie Odland of Clarivate JCS – Editorial Advisory Board

Analytics, where she discusses the goals that the FDA identified towards the scientific and regulatory considerations for bacteriophage therapies. Our Market Report is on the United Arab Emirates. Adhiti Sharad Kumar explains the UAE’s 2021 Vision which states that the UAE will invest continually to build world-class healthcare infrastructure, expertise and services to fulfil citizens’ growing needs and expectations. The Therapeutic Section contains an article by Bobby Stutz and Dr Winter of AtCor Medical, Inc where they discuss how PWA assessments have the ability to streamline and optimise HF drug development. Kelechi K. Olu MD, MSc, Vijayanand Rajendran and Mohamed El Malt at Europital explain the pathways which are expected to lead to identification of specific target genes that could represent novel treatment options for primary bone sarcoma tumours. Patient-centric healthcare and patient-centricity in clinical trials are the current buzzwords in the industry. Tim Davis of ERT discusses how putting the patient first can achieve the best experience and outcome for that person and their family, and Tarquin Scadding-Hunt at mdgroup discusses how, in order to appeal to this new wave of patient-consumers, clinical trial organisers are having to reconsider key components of trial design, to ensure adequate enrolment. We have approached that time of the year when major exhibitions and conferences are ahead. JCS and all our team will be attending ICSE/CPHI at Frankfurt, and also Partnership in Clinical Trials in Amsterdam. Please visit our stand at CPHI/ICSE – Hall 4, 1N22. I hope you enjoy this issue, and my team and I look forward to bringing you more interesting features in the next issue. Maria Dominici, Managing Editor • Hermann Schulz, MD, Founder, PresseKontext

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

• Jerry Boxall, Managing Director, ACM Global Central Laboratory

• Bakhyt Sarymsakova – Head of Department of International

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

• Catherine Lund, Vice Chairman, OnQ Consulting

• Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

• Mark Goldberg, Chief Operating Officer, PAREXEL International

Cooperation, National Research Center of MCH, Astana, Kazakhstan

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

IDM Pharma.

Corporation

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

• Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson

• Rabinder Buttar, President & Chief Executive Officer of ClinTec

• Elizabeth Moench, President and CEO of Bioclinica – Patient

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

Reuters

Recruitment & Retention

• Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

• Francis Crawley, Executive Director of the Good Clinical Practice

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

• Georg Mathis, Founder and Managing Director, Appletree AG • Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

4 Journal for Clinical Studies

International

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

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

• Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) • Stefan Astrom, Founder and CEO of Astrom Research International HB • Steve Heath, Head of EMEA – Medidata Solutions, Inc • T S Jaishankar, Managing Director, QUEST Life Sciences Volume 9 Issue 5


Live & On Air

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The First Interactive Guidance Management System (IGMS) in the Clinical Research Industry Find out more at penthu.com www.jforcs.com

Journal for Clinical Studies 5


Watch Pages

Everything Old Is New Again: Bacteriophage Therapy According to conventional wisdom, if you let children play in the dirt, they get sick less frequently. As is often the case, science appears to back up this homespun theory. Now that many disease-inducing pathogens are developing antibacterial resistance, scientists and medical professionals are looking for answers that may literally be beneath their feet. Bacteriophages (or “phages”) are viruses that can be found inside plants and animals and in soil, rivers, oceans, and even sewers. Phages invade bacterial cells and inject their DNA into the bacterial target. Some phages can disrupt bacterial metabolism and cause the bacterium to disintegrate. The intentional application of phages to destroy bacteria is known as bacteriophage therapy. Because phages attack bacteria and are strain-specific, they are thought to be harmless to humans. An added benefit of the strainspecific nature of phages is that they do not disrupt the natural flora that are beneficial in the body. Bacteriophages were discovered independently by Frederick W. Twort in Great Britain (1915) and Félix d'Hérelle in France (1917). Phage use, research, and development lapsed in the 1940s when antibiotics became standard treatment for bacterial infections. Interest in phage therapy has resurged in recent years: They are seen as a possible therapy against antibiotic-resistant strains of many pathogenic bacteria (Duckworth and Gulig, 2002). The Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) held a two-day public workshop in July 2017 to exchange information with the medical and scientific community about the regulatory and scientific issues associated with bacteriophage therapy. The workshop brought together government agencies, academia, industry, and other stakeholders involved in research, development, and regulation of bacteriophages intended for therapeutic use in humans. The goals that the FDA identified for the workshop were to: 1. discuss the scientific and regulatory considerations for bacteriophage therapies, 2. provide a forum for the exchange of information and perspectives, and 3. facilitate development and rigorous clinical assessment of bacteriophage therapy products. Previously, in September 2014, the White House released the National Strategy for Combating Antibiotic-Resistant Bacteria. The strategy’s three priorities are to: • Prevent, detect, and control outbreaks of resistant pathogens recognised by the Centers for Disease Control and Prevention (CDC) as urgent or serious threats. • Ensure continued availability of effective therapies for treatment of bacterial infections. 6 Journal for Clinical Studies

• Detect and control newly-resistant bacteria that emerge in humans or animals. Following the 2014 National Strategy, the White House issued a five-year National Action Plan for Combating AntibioticResistant Bacteria (CARB). The plan, released in March 2015, outlined interrelated goals for the federal government to address in collaboration with partners in healthcare, public health, veterinary medicine, agriculture, food safety, and academic, federal, and industrial research. Among the goals of CARB are accelerating basic and applied research and development for new antibiotics, other therapeutics and vaccines, and improving international collaboration. Although bacteriophages are not currently an FDA-approved therapy for humans, the FDA allows so-called compassionate use of phage therapy. At the 2017 workshop, CBER’s Scott Stibitz said that the FDA is committed to facilitating the testing of phage therapy in clinical trials. Clinical trials are currently proceeding under FDA oversight in the investigational new drug (IND) programme. CBER may authorise emergency-use expanded access for single patients within hours of the request. Recent case studies include successful phage therapy treatment against multidrug resistant (MDR) Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa). Because phage research has been compiled for more than a century, researchers have a breadth of knowledge about phage genome sequences, lifestyle, transduction potential, host range, complementation, frequency of resistance, and genetic engineering. The pharmaceutical industry, in turn, holds more than a century of antimicrobial development knowledge and experience in a range of areas, including drug discovery, pharmacokinetic/ pharmacodynamic (PK/PD) modelling, toxicology, manufacturing, regulatory issues, and clinical trial design. Stibitz acknowledged that there are novel chemistry, manufacturing, and controls (CMC) considerations for bacteriophage products. Bacteriophages are diverse: For most bacterial hosts, there are many phages in the environment and an “inexhaustible” supply of natural products to treat infections, Stibitz said. Yet every bacteriophage/bacterial host pair is unique, so drawing a priori conclusions about their characteristics is problematic, he said. The specificity of bacteriophage is another consideration in phage therapy. Unlike antibiotic drugs that work in a more generalised manner, phage therapy usually requires identification of the infectious agent prior to treatment. Gene expression and replication are other specificity factors, Stibitz said. A third consideration is immunogenicity. Mammalian hosts are likely to have an adaptive immune response to bacteriophage, Volume 9 Issue 5


Watch Pages

Phages that attack Vibrio cholera, the bacterium that causes cholera, can be found in the Ganges River. The ancient practice of bathing in the Ganges to ward off illness and promote health can be said to have scientific validity.

which may limit the length of use or re-use of phages, Stibitz said. Few published studies address immunogenicity, so it is unclear what safety concerns may arise, he said. Doran Fink of CBER mentioned additional safety considerations for phage therapy. Although phages are directly active only against specific target bacteria and are presumed to be inert with respect to human cells and tissues, researchers will need to determine whether certain human tissues (e.g., airways) might be sensitive to certain components of phage material, Fink said. In clinical trials, phages have been introduced intravenously and directly at the infection site. There can be potential toxic effects of product excipients or impurities (e.g., residual endotoxin) or the device/matrix used to administer the product, he said. As is the case with other types of medical treatments, FDA licensure of phage therapy products requires demonstration of efficacy, safety, purity, potency, and consistency of manufacture. These requirements, Stibitz noted, are not likely to hinder the approval of sponsors’ products. Stibitz added that regulatory officials, scientists, and product developers have shared goals and need to work together. “Communication is vital” through the phage therapy development process, Stibitz said. Through efforts such as the 2017 workshop, members of the regulatory community, industry, and science show that they are interested in bridging these gaps to add phage therapy to the medical toolkit. www.jforcs.com

REFERENCES 1. Duckworth D, Gulig P. Bacteriophages: potential treatment for bacterial infections. BioDrugs. 2002;16(1):57-62. 2. The White House National Strategy for Combating AntibioticResistant Bacteria, September 18, 2014. Available at: https:// obamawhitehouse.archives.gov/sites/default/files/docs/ national_action_plan_for_combating_antibotic-resistant_ bacteria.pdf 3. The White House National Action Plan for Combating Antibiotic-Resistant Bacteria, March 2015. Available at: https:// www.cdc.gov/drugresistance/pdf/national_action_plan_for_ combating_antibotic-resistant_bacteria.pdf

Julie Odland A writer and editor with more than two decades of experience in publishing. She recently joined Clarivate Analytics and specialises in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin. Email: julie.odland@clarivate.com

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Watch Pages

Health Informatics Data: Connecting Patients to Investigators Why are Clinical Trials in Rare Diseases Challenging Today? From the perspective of a clinical trial, a rare disease suggests the available patient and site population is quite small and distributed diffusely. Likewise, any challenge related to study logistics, competitive landscape or patient recruitment is magnified as compared to trials in other indications. The paucity of sites and patients is an ongoing theme in rare disease trials beyond simply locating sites to participate in a trial. There may also be local patient treatment differences, particularly in children, that vary by region and country, which can further complicate any feasibility effort. The current regulatory landscape in rare disease research is another area to consider. Major regulatory agencies encourage the development of treatments for patients with rare diseases, which, while accomplishing that larger goal, can also result in greater research competition for populations being studied. Site and Patient Identification in Rare Disease Clinical Trials: Every Patient Matters When planning rare disease trials, one must first understand the patients, then use this knowledge as a roadmap to identify and characterise the sites and countries where these patients live. The mechanisms by which this can be done are many, but the central theme is the same: when every patient matters, knowing the right investigators is essential. Collectively, these objectives have driven the development of physician and patient networks, consortia, and advocacy groups focused on individual diseases, as well as on classifications of disease, which are key collaborators in defining the pathway for success in rare disease clinical trials. Such networks are often critical partners in the conduct of rare disease trials, and early engagement with them can carry substantial benefits with regard to study conduct. It cannot be overstated that finding patients, sites and countries are intertwined and in the majority of cases, separating each pillar from the other can potentially jeopardise study delivery. Operational efficiency becomes more difficult to balance with the realities of enrolment and feasibility in rare disease trials. This is because there are generally more sites required to achieve enrolment in a reasonable timeframe, particularly in larger trials. Objectively, this is inefficient from a trial delivery perspective but must be accepted as an outcome of feasibility. But what ultimately drives the development of a rare disease trial delivery strategy? The answer is multi-dimensional, considering the treatment landscape, site feedback, standards of care, competitive landscape, individual population’s availability for a clinical trial, and most importantly, investigator and patient/family engagement in the clinical trial enrolment process. Lastly, the advent of health informatics data has shown the potential to revolutionise the recruitment of trial participants in general, but in particular for rare diseases. There are a number of organisations accessing de-identified patient records, lab results, medical claims and prescription data, which have potential to generate site and patient efficiencies by removing uncertainty from the site and patient availability equation. However, many of the 8 Journal for Clinical Studies

sources are largely unproven in the clinical trial space, and they are localised to the United States for the time being. Future Challenges in Rare Disease Site Selection and Patient Recruitment Moving deeper into the 21st century and beyond, site identification in rare disease clinical trials is likely to increase in complexity for several reasons, including: • The rate of innovation in personalised medicine and novel techniques such as gene therapy, and certainly soon, CRISPR will further warrant a highly-specialised site identification strategy that extends beyond the simple matching of potential patients to potential sites. • Assuming the regulatory landscape remains consistent, more developers will enter the rare disease space – not only addressing conditions without current treatment, but also to improve upon existing therapies in indications. Further specificity in cancer and other indications to identify specific gene mutations and expression patterns effectively create hyper-personalised targets for new treatments. In this way, many cancers will become rare diseases, and the identification of these patients in clinical studies may precede clinical practice patterns because of the early development of new diagnostic modalities. Ultimately, identifying patients and sites with appropriate patient access is likely to undergo a paradigm shift in order to accommodate these innovations. Although the future may see additional complexities, there are undoubtedly going to be even more opportunities to utilise health informatics data connecting patients to investigators. The path forward to success is bright, and one must embrace this innovation and understand that while the potential exists, challenges will accompany our collective journey to enhance our ability to effectively plan and recruit rare disease clinical trials.

Kamila Subaieva

Senior Global Feasibility Analyst at INC Research/inVentiv Health, started her career as a medical doctor, specializing in psychiatry, forensic psychiatry and medical psychology. Her experience working as a doctor, scientist and investigator has given her an opportunity to gain a deeper understanding of the patient environment.

Email: kamila.subaieva@incresearch.com

Earl Seltzer

Director of Global Feasibility at INC Research/ inVentiv Health, has approximately 12 years of industry experience working at both CROs and clinical investigator sites. Since joining the CRO space, Earl’s area of expertise focused on rare disease and pediatric clinical trials while working in global feasibility across many different indications as well as in therapeutic strategy.

Email: earl.seltzer@incresearch.com Volume 9 Issue 5


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How Can Modelling and Simulation Fuel the Clinical Development of Biosimilars? The relatively low cost to enter the “generic� market and the size of the biologic drug market make entry attractive. However, the failure rate for biosimilars is deemed high, due to the complex manufacturing process and the high variability expected for biologics. Considering that the associated cost for developing a biosimilar is estimated at US$100 million, there is a high riskcost relationship in the establishment of clinical biosimilarity.1 It is therefore of great interest to investigate the possibility to optimise the design of clinical trials of biosimilars in order to increase the studies’ efficiency (e.g., robust results, shorter duration, fewer patients, reduced cost). Because these studies have a great regulatory impact, they must be executed in accordance with regulatory guidelines for the evaluation of biosimilarity.2,3 Modelling and simulation (M&S) has been used in the pharmaceutical industry for more than two decades, and can be of competitive advantage for drug sponsors seeking to improve their drug development process and decision-making. The use of M&S for evaluating pharmacokinetic/pharmacodynamic (PK/ PD) relationships can support a biosimilar programme, and offers high regulatory impact. In principle, regulators have accepted that PK/PD, dose-response and longitudinal analyses are more sensitive methods than clinical outcome analysis at a single fixed time-point to detect differences between the originator and biosimilar.4 Although traditional statistical methods are commonly

10 Journal for Clinical Studies

used for the primary evaluation of pivotal clinical trial data, modelbased simulations are increasingly used to optimise the design of clinical PK, PK/PD and outcome studies for biosimilars, by leveraging quantitative knowledge of the new product against the originator.5 Additionally, the FDA acknowledges that M&S can be useful when designing studies, for example, when determining dose selection and defining the acceptable limits for PD similarity. Through the efficient use of available public domain data and information on the new product, study design decisions can be made to increase the probability of a successful outcome. By integrating information across dose levels, using longitudinal PK/ PD and disease-progression models, uncertainty can be reduced in the estimated PK, PD, efficacy and safety endpoints. The models allow variability within, and between, subjects to be estimated, and it is also possible to simultaneously account for multiple factors to explain variation in exposure and response across individuals, including the formation of anti-therapeutic antibodies. Using the models for subsequent clinical trial simulation, various study designs can rapidly be explored in silico (doses, sample size, study duration, reduced sampling schedules, inclusion/ exclusion criteria, and choice of statistical evaluation method). By simulating multiple virtual clinical studies and calculating the outcome for each study in accordance with regulatory guidelines, the probability of concluding PK/clinical similarity can be explored under various scenarios. The influence of an expected difference between the originator and new product (e.g. 0, 1, 3, 5 or 10%) on

Volume 9 Issue 5


Watch Pages the required sample size can easily be calculated, and the most cost-effective design with a sufficient probability of a successful outcome can then be chosen. These methods are also applicable for bridging results across study populations and therapeutic indications. Case Study: Adalimumab Biosimilar PK Study When developing biosimilars, clinical trials demonstrating PK and PD similarity of the new product against the approved drug are required, and an insufficient sample size can jeopardise the study outcome. For adalimumab, an anti-TNF-alpha antibody used to treat a variety of autoimmune diseases, PK similarity trials often involve a higher-than-normal number of subjects, as high variability in the PK between patients is anticipated. To explore whether the sample size of such studies can be reduced, a model-based approach was employed. The optimal number of subjects required for demonstrating PK similarity between a proposed biosimilar and the originator was studied using available literature information on the adalimumab originator, against in-house data on the new biosimilar candidate. A population PK model for adalimumab in rheumatoid arthritis patients following a 40 mg subcutaneous injection of the EU and US approved formulations was implemented in the clinical trial simulation software Simulo. The effect of patient body weight was also incorporated into the model, along with the influence of antiadalimumab antibodies. Various study designs, with varying sample sizes, were simulated 1000 times. For each simulated clinical trial, the differences in the maximal drug concentration (Cmax) and the area under the drug concentration-time curve (AUC) between the new product and the reference were evaluated using traditional statistical bioequivalence testing methods. The overall likelihood of having a successful study outcome was eventually predicted for the various simulated study design scenarios. The analysis indicated that studies including more than 150 subjects did not give any significant improvement in the probability of showing bioequivalence when compared with studies in smaller cohorts. It also showed that a difference in anti-adalimumab antibodies of 15% is likely to decrease the likelihood of successful results being achieved for all pairwise comparisons. By using this model-based simulation approach, accounting for already available adalimumab data, the number of subjects required to demonstrate PK similarity could be reduced by 40–60%, compared to the originally proposed design. This demonstrated the advantages of using such methods to assist in the design of pivotal PK studies to cut cost and save time. The methodology can also easily be applied for PD markers and clinical outcome endpoints. REFERENCES 1. Blackstone E.A. and Fuhr J.P. The Economics of Biosimilars. Am Health Drug Benefits. 2013;6(8):469-478 2. EMA. Guideline on Similar Biological Medicinal Products, London, 30 Oct 2005. CHMP/437/04 3. FDA draft guidance on Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. 2014. 4. 2013 activity report of the Modelling and Simulation Working Group (MSWG) EMA/303848/2014 5. Dodds M., Chow V., Marcus R., Perez-Ruixo J.J., Shen D. and Gibbs M. The Use of Pharmacometrics to Optimize Biosimilar Development. J Pharm Sci 2013: 3908-14 6. Simulo. www.exprimo.com/simulo www.jforcs.com

Bernardo de Miguel Lillo A Modelling and Simulation Consultant at SGS Exprimo and, Bernado holds a PhD in Pharmacokinetic and Pharmacodynamic Population Modelling from the University of Valencia. He has over 15 years’ experience in drug development, and before joining SGS in 2015, held posts at AC Nielsen, PRA Health Sciences and PharmaMar. He has provided PK/PD modelling support across multiple therapeutic areas with a special focus on new anticancer agents. Recently he has worked with several biological and biosimilar drugs such as adalimumab, pegfilgastrim, rituximab, bevacizumab, palivizumab and trastuzumab.

Daniel RĂśshammar Managing Director of SGS Exprimo NV since 2016. He obtained his MSc Pharm from Uppsala University, and Daniel holds a PhD in Medical Sciences from the Sahlgrenska Academy at Gothenburg University. He previously held numerous expert and management positions in the pharmaceutical industry, including at AstraZeneca, Ferring Pharmaceuticals and Servier. He has worked across a range of therapeutic areas (infectious diseases, cardiovascular, respiratory, urology, oncology, intensive care, and reproductive health) and has contributed to the filing and subsequent approval of several new drug applications.

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Watch Pages

Clinical Trial’s Role in Compliance and Patient Safety Although James Lind conducted the first controlled clinical trial back in 1747, it wasn’t until The Nuremberg Code in 1947 and The Declaration of Helsinki in 1964 that patient safety in clinical trials became paramount. We now have a whole assortment of guidelines and regulations for clinical trials across the world. How can investigators and sponsors comply with all these rules to ensure that patient safety is protected? Good Clinical Practice (GCP) was an initiative developed by The International Conference on Harmonization (ICH) back in 1990. Compliance with GCP provides assurance that the rights, safety and wellbeing of trial subjects are protected. It also ensures the clinical trial has credible data, hopefully resulting in a marketable drug at the end (having worked in pharmacovigilance for a few years I sometimes forget the end goal!). The new ICH GCP E6 (R2) Addendum released in November 2016 gives the investigator more responsibility for clinical trial oversight. The investigator can delegate tasks but they are ultimately responsible for supervision. The investigator or sub-investigator must also be a qualified physician. GCP R2 has a new quality risk management section requiring early identification of processes and data integral to patient safety. Many countries have adopted GCP principles as laws and regulations. The ICH GCP principles are embedded in clinical trials legislation of the UK, European Union, Japan and the United States. So, not only do site staff and sponsors need to get to grips with GCP; they also have to comply with their local regulations too! The sponsor is responsible for ongoing safety evaluation of the investigational drug. They must notify investigators, regulatory authorities and ethics committees of issues that could affect subject safety. Maintaining safety information and reporting adverse events are critical to ensure that the welfare and safety of human subjects is protected. Each clinical trial will also have its own set of risks and considerations associated with patient safety. Clinical trial protocols need to be well designed and identify all potential risks to patient safety and include ways to minimise them. Compliance with the protocol is essential for keeping trial subjects protected. Some of the challenges facing compliance include facilities, equipment, data storage, inexperienced personnel and training. Such challenges are often more common in resource limited countries being used more and more in clinical trials. So, What Tools do we Have to Ensure there is Compliance to Protect Patient Safety? Compliance can be measured by checking documents and systems. Inspections and audits of sponsors and sites conducted by individuals independent of the clinical trial also assess compliance. But probably the most important players are the clinical research associates (CRAs). Monitoring of study sites by CRAs involves overseeing the progress of the clinical trial to ensure it is 12 Journal for Clinical Studies

conducted in accordance with the protocol, GCP and all regulatory requirements. And if it isn’t documented somewhere, it didn’t happen! If non-compliance is detected, prompt action is needed. If required by local regulations, the sponsor must notify regulatory authorities when the non-compliance is a serious breach of GCP or trial protocol – this can result in a trial being halted. New to GCP R2 is the need to implement appropriate corrective and preventative actions, and to incorporate these during trial design and protocol development. Planning is key to identifying processes and data critical to ensure compliance and protect patient safety… and of course to execute a successful clinical study!

Catherine Maidens Catherine has six years of clinical research experience in pharmacovigilance and project management. She completed a PhD at the Department of Microbiology at University of Reading, going on to be a Clinical Trial Coordinator for Investigator Initiated Studies at the same University. Catherine then moved from academia to work in a number of CROs with roles within drug safety / pharmacovigilance. With her passion for mentoring and coaching she joined Clinical Professionals as Hosted Employee and Academy Manager in June 2017. Email: catherine@clinicalprofessionals.co.uk

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Regulatory

A Decade of Biosimilars: Have Expectations Been Met? Since the European Union approved the first biosimilar, Sandoz's biosimilar recombinant human growth hormone  somatropin, in 2006,1,2 with marketing commencing in 2007,3 a total of 35 biosimilars have been approved in the EU.4Five biosimilars have been approved in the United States.5 Such products have potential to improve drug access for patients while cutting healthcare costs. Yet how much of this potential has been realised? The biologics sector is an attractive one. Six of the top eight drugs by revenue in 2016 were biologics,6 and the market share of biotech products is forecast to increase from 24% in 2015 to 29% in 2022. EvaluatePharma estimates that biotech product sales totaled $220 billion in 2017, compared with $453 billion for conventional pharmaceuticals. The company predicts that, in 2022, 50% of the value of the top 100 products will come from biologics.7 With increasing numbers of patent expiries, the global biosimilars and follow-on biologics market is expected to grow at a compound annual growth rate (CAGR) of 38.8% in the first half of the period from 2017–2027, and 11.3% in the second half of the forecast period, according to Visiongain.8 Estimated at $5.31bn in 2016, the biosimilars market is predicted by Visiongain to reach $41.07bn by 2027. Potential for Cost Savings While discounts on biosimilars cannot match those of small molecule chemical generics due to the level of investment required for their development, regulatory approval and manufacturing, they are still expected to generate significant savings owing to the high unit costs of their originators. A small molecule generic typically takes two to three years and $2–5 million to develop, while biosimilars take up to five years and $40–300 million to develop, according to CVS.9 A May 2017 report from QuintilesIMS,10,11 ‘The Impact of Biosimilar Competition in Europe’, shows a consistent average price reduction in therapy areas where biosimilars have been introduced. Increased biosimilar competition affects not only the price for the directly comparable product, but for the whole product class. Other observations in the report include: the entrance of just one biosimilar into the market can be sufficient to lower prices across the class; in some therapeutic classes, lowering the price of the reference product can limit the market penetration of the biosimilar; there is a first-to-market advantage in biosimilar markets; and overall, biosimilar competition contributes to increased patient access of the whole market. Pricing discounts as high as 45% and 72% (Norway) have been seen for biosimilars in Europe.12,13 14 Journal for Clinical Studies

Experience to date is limited in the US, but CVS Health Corp (a major US pharmacy benefit manager) has predicted biosimilar price discounts of 20–30%.14 In June 2017, the Galen Institute estimated that biosimilars could reduce spending on biologics in the United States by $44 billion over the next decade, based on a RAND Corporation study.15,16 The Galen Institute notes a Congressional Budget Office prediction that biosimilars could yield savings of $25 billion for patients and taxpayers over 10 years. When the first approved biosimilar in the US, Sandoz’s filgrastim-sndz (now filgrastim-bflm), was launched in 2015, its list price was 15% lower than that of the originator biologic; sales of the originator then decreased from approximately $1 billion in 2015 to $765 million in 2016.17 According to the Association for Accessible Medicines (formerly GPhA) CEO, Chip Davis, biosimilars have been deemed the top growth driver for the pharmaceutical industry in 2017.18 Stakeholder education to build confidence in these products remains a primary goal for the industry. In addition, the complexity of the legal landscape and the payer system, especially in the US, will remain key challenges. In a move that favours biosimilar manufacturers, the US Supreme Court ruled on June 12, 2017, that biosimilar companies will not have to give originator manufacturers an additional 180 days’ notice after US Food and Drug Administration (FDA) approval before launching their newly approved biosimilars. Switching and Interchangeability On the strength of accumulating real-world evidence, any biosimilars are now deemed ‘medically switchable’ in the eyes of regulators, academic medical societies and clinicians. Interchangeability is a more sensitive issue. The EMA currently makes no specific recommendation on the interchangeability of the biosimilars it approves, leaving that decision to EU member states. However, several national regulatory authorities, including the Dutch Medicines Evaluation Board (MEB), the Finnish Medicines Agency (Fimea), the Irish Health Products Regulatory Authority, Healthcare Improvement Scotland, and Germany’s Paul Ehrlich Institute, have taken national positions endorsing the interchangeability of biosimilars under the prescriber’s supervision.19 The US FDA, in contrast, invites biosimilar applicants to specifically apply for an interchangeability designation – a step up from approval as a biosimilar – and has recently defined the criteria by which it will judge such applications.20,21 The draft guidance recommends that sponsors aiming to have a biosimilar approved as interchangeable with a reference product should carry out one or more switching studies, designed to show that patients can alternate between the two products safely and without diminished efficacy.

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Driving quality and integrity in scientific research and development

2,300 members located in 58 countries worldwide As a not-for-profit association we have around 2,300 members of which 44% are based outside of the United Kingdom and located in 58 countries worldwide, with many of our members working in an international environment and to international standards.

We continue to meet the needs of our members by: • Promoting quality standards in scientific research and development • Facilitating knowledge sharing through events, publications and networking • Liaising with regulatory agencies in the development and interpretation of regulations and guidance • Offering professional development opportunities • Working in partnership/cooperation with other organisations.

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Regulatory FDA definition of interchangeability: “Interchangeable products are both biosimilar to an FDAapproved reference product, and can be expected to produce the same clinical result as the reference product in any given patient. An interchangeable product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. In addition, for a biological product that is administered more than once to an individual, the risk in terms of safety or efficacy of alternating or switching between the biological product and the reference product will not be greater than the risk of using the reference product without alternating or switching.”22

Evolving Opinions In light of this accumulating real-world evidence, several leading academic medical societies now support biosimilar use. The positions taken by a selection of US and European organisations are summarised below:

• Across Europe, nearly 90% of doctors know what biosimilar medicines are and nearly 60% have already prescribed them • EMA-approved biosimilars have generated more than 400 million patient days of positive clinical experience, “accompanied by massively increased access to modern biological medicines” • Between 2006 and 2014, biosimilar medicines increased patient access by 44% overall within the EU-5 countries.

• American Society for Clinical Oncology (ASCO): Included biosimilar versions of filgrastim in its guidelines for use of white blood cell growth factors, published in 201537 • US National Comprehensive Cancer Network (NCCN): Has suggested that biosimilars should be prescribed as an alternative to the originator product38 • European League Against Rheumatism (EULAR): Has stated that “the advent of biosimilars provides potential for reduction of pressure on healthcare budgets”39 • American College of Rheumatologists (ACR): In response to the FDA approval of biosimilar infliximab, ACR stated that the organisation “welcomes the introduction of biosimilars to the US healthcare system and is hopeful that the decrease in cost resulting from the availability of safe and effective biosimilars in the US will increase our patients’ access to life-changing therapies and improve their overall health”40 • European Crohn’s and Colitis Organisation (ECCO): Following publication of the results of NOR-SWITCH, ECCO issued a statement that “switching from the originator to a biosimilar in patients with IBD is acceptable”41 • American College of Physicians (ACP): Stated that “unresolved policy issues need to be addressed to ensure maximum utilisation of biosimilars by patients and physicians” as one of its recommendations on ways to stem the escalating cost of US prescription drugs42, 43 • European Society for Medical Oncology (ESMO): Advocated biosimilars as ‘must-have weaponry’ in financially sustaining healthcare systems on a global scale44

Numerous real-world studies support the safety and efficacy of licensed biosimilars compared with originators. Key examples published in 2016 and 2017 are listed in Table 1.

Prescriber surveys in the US and Europe also reflect the growing confidence in biosimilars. A 2016 survey of members of the European Crohn's and Colitis Organization (ECCO) found that 44.4% of 118

Real-world Evidence for the Safety and Efficacy of Biosimilars The most compelling evidence for the clinical performance of biosimilars comes from Europe, which has led the way in this field. In 2017, the EMA announced that, over the last 10 years, the EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicines.23 In 2016, marking the 10th anniversary of the launch of the first biosimilar in Europe in 2006, Medicines for Europe stated that:24

• A real-world prospective study in 1400 patients with chemotherapyinduced febrile neutropenia confirmed the clinical similarity of biosimilar filgrastim to the originator Neupogen®25 • A Johns Hopkins Bloomberg School of Public Health systematic review of 19 studies reported that TNF-α inhibitor biosimilars for the treatment of rheumatoid arthritis and other autoimmune diseases appear to be as effective and safe as their branded equivalents26,27 • The NOR-SWITCH Study, a non-commercial switching study sponsored by the Norwegian government, was a Phase III randomised trial of 482 patients at 40 sites who were on stable treatment with originator infliximab (Remicade®) for at least six months. Participants were randomised to either continue Remicade® or switched to the biosimilar, and followed up for 52 weeks.28 Switching to biosimilar infliximab was found to be safe and non-inferior to continued treatment with Remicade® across multiple indications • The triple-switch EGALITY study was a randomised, double-blind trial involving 531 patients with moderate to severe plaque psoriasis that compared biosimilar etanercept with the originator product, Enbrel.®29,30,31 Patients underwent three switches back and forth between the originator and biosimilar, with no clinically meaningful differences in safety and efficacy • At the annual European League Against Rheumatism (EULAR) congress, data were presented on patients transitioned from

originator etanercept (n=254) and infliximab (n=396) to their biosimilar counterparts.32 In both cases, there were no treatmentemergent safety or immunogenicity issues, and efficacy was sustained for up to two years Delegates at the annual European Crohn’s and Colitis Organisation (ECCO) congress heard that 10 real-world studies involving nearly 600 patients with inflammatory bowel disease all showed comparable efficacy and safety following a switch to biosimilar infliximab from the originator33 A meta-analysis of results from 11 published real-world studies including 829 patients showed that biosimilar infliximab has “excellent clinical efficacy and safety” in patients with Crohn’s Disease or ulcerative colitis34 One-year outcomes from the Danish DANBIO registry reported sustained efficacy and safety after 802 patients with inflammatory arthritis were switched within routine care from Remicade® to biosimilar infliximab (CT-P13, Remsima®) without a prescriber-led decision in each case35 A study in patients with breast cancer receiving neoadjuvant myelosuppressive chemotherapy (n=218) showed that switching back and forth between originator filgrastim (Neupogen) and biosimilar filgrastim (Zarxio) (5 µg/kg/day) over six cycles of treatment was no less effective or well tolerated than receiving either Neupogen or Zarxio throughout all six cycles36

Table 1: Examples of real-world biosimilar studies published in 2016–17 16 Journal for Clinical Studies

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Regulatory respondents considered biosimilars to be interchangeable with the originator product, up from 6% in 2013.45 Only 19.5% of respondents said they had little or no confidence in the use of biosimilars, down from 63% in 2013. In addition, a 2016 survey by Industry Standard Research found that two-thirds of biopharma companies with a biologics offering currently market, or plan to market, biosimilars, including companies with no internal manufacturing capabilities.46 This figure is up from 46% the previous year. Barriers to Biosimilar Uptake Innovator companies have employed a variety of multipronged strategies to counter biosimilar competition. These include development of ‘biobetter’ and/or follow-on biologic medicines, gaining regulatory approval for additional indications and new formulations, patent extensions and litigation, reducing prices and launching new patient assistance programmes.47 Among these, patent extensions and litigation can be particularly effective in helping delay the introduction of biosimilars. However, most such strategies are unlikely to have a significant long-term impact on the approval, launch and uptake of biosimilars. Although much progress has been made to date, education is still needed to quell physician and patient doubts about biosimilars. In conclusion, the biosimilar sector has seen significant progress over the past decade, with the EMA leading the way in establishing regulatory pathways.48 The regulatory environment for biosimilars continues to evolve, based on advances in technology and analytical methods, and the availability of new targets for biosimilar development. The second half of 2017 is likely to see an expansion of product classes of biosimilars in both the EU and US, with additional guidance from regulatory agencies as to what is needed to obtain approval of biosimilars in these classes.49 Expectations have probably been met in Europe, including glimmers of large discounts such as those in the Scandinavia region, though in some EU countries and other ICH regions, like the US, are still trying to play catch-up with regard to cost savings – for both payers and patients. Looking ahead, resolution of the uncertainty around interchangeability and the patent log-jam will further advance the biosimilar market, helping to deliver on the promise of improved cost-effectiveness and patient access to this powerful category of therapies. REFERENCES 1. http://www.medicinesforeurope.com/wp-content uploads/2016/ 04/6.-Biosimilar-Medicines_On-Biosimilar-Medicines.pdf, accessed July 6, 2017. 2. http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003956.pdf, accessed July 6, 2017. 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031732/, accessed July 6, 2017. 4. http://www.gabionline.net/Biosimilars/General/Biosimilarsapproved-in-Europe, accessed July 6, 2017. 5. Brennan Z. FDA Approves 5th Biosimilar, 2nd for Remicade. Regulatory Affairs Professionals Society (RAPS) Focus. April 21, 2017.http://raps.org/Regulatory-Focus/ News/2017/04/21/27390/FDA-Approves-5th-Biosimilar-2ndfor-Remicade/, accessed July 6, 2017. 6. http://www.genengnews.com/the-lists/the-top-15-best-sellingdrugs-of-2016/77900868, accessed July 6, 2017. 7. http://info.evaluategroup.com/rs/607-YGS-364/images/wp16. pdf, accessed July 6, 2017. www.jforcs.com

8. https://www.aboutpharma.com/blog/2017/05/15/globalbiosimilars-and-follow-on-biologics-market-2017-2027/, accessed July 6, 2017. 9. http://investors.cvshealth.com/~/media/Files/C/CVS-IR-v3/ reports/biosimilars-prospect-050316.pdf, accessed July 6, 2017. 10. http://ec.europa.eu/growth/tools-databases/newsroom/cf/ itemdetail.cfm?item_id=9146, accessed July 6, 2017. 11. http://www.raps.org/RegulatoryFocus News/2017/05/09/27509/ Biosimilars-in-the-EU-New-IMS-Report-Shows-SavingsThrough-Competition/, accessed July 6, 2017. 12. http://www.reuters.com/article/pharmaceuticals-biosimilarsidUSL5N0YV0LR20150609, accessed July 6, 2017. 13. http://www.gabionline.net/Biosimilars/General/Huge-discounton-biosimilar-infliximab-in-Norway, accessed July 6, 2017. 14. http://galen.org/2017/biosimilar-drugs-offer-promise-for-drugprice-savings-but-risks-remain/, accessed July 6, 2017. 15. https://www.rand.org/content/dam/rand/pubs/perspectives/ PE100/PE127/RAND_PE127.pdf, accessed July 6, 2017. 16. https://www.healio.com/hematology-oncology/practicemanagement/news/online/%7Bbad90186-64cc-40c0-ac7782c64ee8b0a3%7D/supreme-court-ruling-acceleratesavailability-of-biosimilars, accessed July 6, 2017. 17. https://www.lifescienceleader.com/doc/why-is-the-year-towatch-biosimilars-0001, accessed July 6, 2017. 18. http://www.raps.org/Regulatory-Focus/News/2017/03/31/27240/ Are-Biosimilars-Interchangeable-in-the-EU-A-NewPerspective/#sthash.2CM5FcLR.dpuf 19. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugsgen/documents/document/ucm537135.pdf, accessed July 6, 2017. 20. http://www.raps.org/Regulatory-Focus/ews/2017/01/17/26624/ FDA-Issues-Long-Awaited-Biosimilar-InterchangeabilityGuidance/, accessed July 6, 2017. 21. https://www.fda.gov/drugs/developmentapprovalprocess/ howdrugsaredevelopedandapproved/approvalapplications/ therapeuticbiologicapplications/biosimilars/ucm241719.htm, accessed July 6, 2017. 22. http://www.ema.europa.eu/docs/en_GB/document_library/ Leaflet/2017/05/WC500226648.pdf 23. http://www.biosimilarnews.com/10-years-of-biosimilar-medicinesin-europe-transforming-healthcare, accessed July 6, 2017. 24. Gascón P, Aapro M, Ludwig H et al. Treatment patterns and outcomes in the prophylaxis of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim (the MONITOR-GCSF study). Support Care Cancer (2016) 24:911–925. 25. Semedo D. Generic biologic drugs appear comparable to brandname counterparts. Rheumatoid Arthritis News, 5 August 2016. https://rheumatoidarthritisnews.com/2016/08/05/genericbiologic-drugs-comparable-brand-name-counterparts/, accessed July 6, 2017. 26. http://www.jhsph.edu/news/news-releases/2016/genericbiologic-drugs-appear-comparable-to-brand-namecounterparts.html, accessed July 6, 2017. 27. http://thelancet.com/journals/lancet/article/PIIS01406736(17)30068-5/abstract, accessed July 6, 2017. 28. https://www.novartis.com/news/media-releases/innovativestudy-three-treatment-switches-confirms-sandoz-biosimilaretanercept, accessed July 6, 2017. 29. Griffiths C et al. The EGALITY study: A confirmatory, randomised, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, versus the originator product in patients with moderate to severe chronic plaque-type psoriasis. Br J Dermatol. 30. Griffiths EM et al. GP2015, a proposed etanercept biosimilar, has equivalent efficacy, safety and immunogenicity to etanercept Journal for Clinical Studies 17


Regulatory originator product in patients with chronic plaque-type psoriasis: 12 week results from the phase 3 EGALITY study. Poster presented at the Psoriasis 2016, 5th Congress of the Psoriasis International Network (PIN), July 07, 2016 (e-poster P222) 31. Amgen press release: New Data Presented at the Annual European Congress of Rheumatology (EULAR 2016) Demonstrate Safety and Efficacy of Biogen’s Anti-TNF Biosimilars Portfolio. June 9, 2016. 32. http://media.biogen.com/press-release/biosimilars/new-datapresented-annual-european-congress-rheumatology-eular2016-demons, accessed July 6, 2017. 33. Business Wire: Celltrion Healthcare: Switching to Remsima® (infliximab) from originator has no negative effect on safety or efficacy in 10 real-world studies. March 18, 2016 http://www. businesswire.com/news/home/20160318005262/en/CelltrionHealthcare-Switching-Remsima%C2%AE%E2%96%BCinfliximab-originator-negative, accessed July 6, 2017. 34. http://newsroom.wiley.com/press-release/alimentarypharmacology-therapeutics/biosimilar-costly-inflammatorybowel-disease-ther, accessed July 6, 2017. 35. http://ard.bmj.com/content/early/2017/05/04/annrheumdis2016-210742, accessed July 6, 2017. 36. http://abstracts.asco.org/199/AbstView_199_191748.html, accessed July 6, 2017. 37. https://www.asco.org/about-asco/press-center/news-releases/ asco-updates-guideline-use-white-blood-cell-growth-factors, accessed July 6, 2017. 38. http://www.ajmc.com/conferences/nccn-2016/nccn-has-faithin-the-potential-of-biosimilars, accessed July 6, 2017. 39. http://ard.bmj.com/content/annrheumdis/early/2017/03/17/ annrheumdis-2016-210715.full.pdf, accessed July 6, 2017. 40. https://www.rheumatology.org/About-Us/Newsroom/PressReleases/ID/737/Rheumatology-Community-Responds-toFDA-Approval-of-Inflectra-infliximab-dyyb-a-Biosimilar-toRemicade, accessed July 6, 2017. 41. http://www.bigmoleculewatch.com/2016/12/14/europeancrohns-and-colitis-organisation-supports-switch-tobiosimilars/, accessed July 6, 2017. 42. https://www.acponline.org/acp-newsroom/new-policy-paperrecommends-ways-to-stem-the-rising-cost-of-prescriptiondrugs, accessed July 6, 2017. 43. http://annals.org/aim/article/2506848/stemming-escalatingcost-prescription-drugs-position-paper-american-collegephysicians, accessed July 6, 2017. 44. http://www.esmo.org/Press-Office/Press-Releases/ Biosimilars-Create-Opportunities-for-Sustainable-CancerCare, accessed July 6, 2017. 45. https://www.ncbi.nlm.nih.gov/pubmed/27112706, accessed July 6, 2017. 46. http://www.marketwired.com/press-release/two-thirdsbiopharma-sponsors-surveyed-currently-sell-plan-sellbiosimilar-products-2125816.htm, accessed July 6, 2017. 47. Manaktala C, Huml R, Rulewski N. Strategies Adopted by Innovator Companies in Response to Biosimilars Competition. Regulatory Focus. April 2017. Regulatory Affairs Professionals Society. http://www.raps.org/Regulatory-Focus/ Features/2017/04/10/27307/Strategies-Adopted-by-InnovatorCompanies-in-Response-to-Biosimilars-Competition/, accessed July 6, 2017. 48. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440034/, accessed July 6, 2017. 49. http://www.lexology.com/library/detail.aspx?g=fc078702ccce-4274-a8fe-1bd22631def0, accessed July 6, 2017. 18 Journal for Clinical Studies

Karen Lipworth UK-based medical writer and scientific communications professional with over 25 years’ experience in the global healthcare and pharmaceutical industries. Since 2012, she has worked closely with QuintilesIMS’s Biosimilars Center of Excellence on narrative development, internal and external training programmes, news updates and diverse communications on biosimilars for all audiences from specialist to lay.

Jill Dawson PhD, has worked as a consultant to the QuintilesIMS Corporate Communications team for more than 10 years, collaborating across the organisation to develop and execute external and internal initiatives. Areas of expertise include directing all aspects of corporate communications, including major pharmaceutical programmes, social and traditional media relations, writing and editing. Jill holds a BSc and PhD in Life Sciences from Imperial College London (UK).

Raymond A. Huml MS, DVM, RAC is Vice President of QuintilesIMS’s Biosimilars Center of Excellence and Head of Global Biosimilars Strategic Planning. He works with QuintilesIMS experts to provide an end-toend biosimilars solution to the biopharmaceutical industry. Dr Huml has more than 27 years of experience in the healthcare industry and formerly led the Global Due Diligence group for Quintiles Corporate Development. Dr Huml earned his Doctor of Veterinary Medicine at North Carolina State University, his Master of Science degree in Biology from East Stroudsburg University and his US Regulatory Affairs Certification from the Regulatory Affairs Professionals Society. Email: raymond.huml@quintiles.com

Nigel R. Rulewski He holds an MB and BS from St Bartholomew’s Medical School, University of London, a Diploma in Child Health from the Royal College of Physicians and a Diploma from the Royal College of Obstetricians and Gynecologists. Dr Rulewski has over 30 years of experience in drug development and regulatory affairs in both large and small pharmaceutical companies and has worked in venture capital and pharmaceutical business development. Dr Rulewski currently serves as Head of QuintilesIMS’s Global Biosimilars Center of Excellence.

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Market Report

Healthcare Research in United Arab Emirates Expansion is the buzzword for the UAE healthcare industry to meet the increasing healthcare needs as life expectancy grows, population rises, awareness increases and technology advances. The UAE has rapidly transformed its healthcare sector in the past decade. This has been further helped by the favourable government policies such as mandatory health insurance for its expatriates, tie-ups with foreign hospitals, along with government spending on healthcare. Urbanisation has been an important driver of healthcare services in the country. The UAE has also been actively promoting itself as a medical tourism destination that provides medical care that is of international standards. The country is also striving to lower the prevalence of diabetes and hypertension — both risk factors for cardiovascular disease. The UAE’s 2021 Vision states that “the UAE [will] invest continually to build world-class healthcare infrastructure, expertise and services to fulfil citizens’ growing needs and expectations.”

The healthcare structure in the UAE is different to that of its neighbours in Abu Dhabi and Dubai, and they have their own healthcare regulators. There are four regulators in the UAE: • • • •

The Ministry of Health (MOH) Health Authority Abu Dhabi (HAAD) Dubai Health Authority (DHA) Dubai Healthcare City Free Zone (DHCC)

The Ministry of Health (MOH) The mission of MOH is to enhance community health by providing comprehensive, innovative and fair healthcare services as per international standards, as well as to perform its role as a regulator and a supervisor of the healthcare sector through a modern and integrated health legislative system. Health Authority Abu Dhabi (HAAD) The Health Authority – Abu Dhabi (HAAD) is the regulatory body of the healthcare sector in the Emirate of Abu Dhabi and ensures excellence in healthcare for the community by monitoring the health status of the population. In addition, HAAD shapes the regulatory framework for the health system, inspects against

Dubai Health Authority (DHA)

20 Journal for Clinical Studies

Volume 9 Issue 5


Market Report regulations, enforces standards, and encourages adoption of worldclass best practices and performance targets by all healthcare service providers in the Emirate.

a health and wellness destination. This free zone comprises two phases. Phase 1, dedicated to healthcare and medical education, and Phase 2, which is dedicated to wellness.

Dubai Healthcare City Free Zone (DHCC) Dubai Healthcare City (DHCC) is a free zone committed to creating

The table below shows the current trends in UAE: -

Indicator

Definition

Source

Results

1

Average Healthy Life Expectancy

An indicator that measures the average number of years that a person can expect to live in full health.

World Health Organization

68.3 years (2016)

Ministry of Health and Prevention

2

Prevalence of Smoking any Tobacco Product

An indicator that measures the daily consumption of cigarettes and tobacco products among different segments of society of different ages.

Ministry of Health and Prevention

21.6% among men 1.9% among women (Ministry of Health 2010)

Ministry of Health and Prevention

3

Percentage of Accredited Health Facilities

An indicator that measures the share of public and private hospitals adhering to national or internationally recognised standards (NKPI specific to UAE)

Ministry of Health and Prevention

68.25% (2016)

Ministry of Health and Prevention

4

Number of Deaths from Cardiovascular Diseases per 100,000 Population

An indicator that measures the deaths from cardiovascular disease per 100,000 population.

World Health Organization

297.6 deaths per 100,000 population (2012 figure published in the 2014 report)

Ministry of Health and Prevention

5

Prevalence of Diabetes

An indicator that measures the number of people between the age of 20 and 79 with diabetes in the UAE, as a proportion of the total population. (This age group is aligned with the age group used by the International Diabetes Federation.)

International Diabetes Federation

19.3%(2015)

Ministry of Health and Prevention

6

Prevalence of Obesity amongst Children

An indicator that measures the proportion of children between the ages of 5 and 17 who are considered obese out of the total children of the same age group. The definition of obesity in children is where BMI is > +2 standard deviations regarding the relevant Z-score chart regarding BMI-for-age.

Ministry of Health and Prevention

13.54%(2016)

Ministry of Health and Prevention

7

Number of Deaths from Cancer per 100,000 Population

An indicator that measures the deaths from malignant tumours per 100,000 population.

World Health Organization

99 deaths per 100,000 population (2012 figure published in 2014 report)

Ministry of Health and Prevention

8

Healthcare Quality Index

An indicator that measures the quality of healthcare from (3) perspectives: basic health outcomes, health infrastructure and preventative care, and physical and mental health satisfaction.

Legatum Prosperity Indicator

Rank 28(2016)

Ministry of Health and Prevention

9

Number of Physicians per 1000 Population

An indicator that measures the average number of physicians per 1000 population (including general practitioners and all specialities except dentistry).

World Health Organization

2.53 physicians per 1000 population (2007-2013 average published in 2015 report)

Ministry of Health and Prevention

10

Number of Nurses per 1000 Population

An indicator that measures the average number of nurses per 1000 population.

World Health Organization

3.16 nurses per 1000 population (2007-2013 average published in 2015 report).

Ministry of Health and Prevention

www.jforcs.com

Key Sponsor

Journal for Clinical Studies 21


Market Report

The medical insurance in Dubai has been explained in the image below: -

• Improving the customer experience and the overall perception of healthcare. • Attracting highly-skilled healthcare professionals. • Development of healthcare services in the private sector. The country’s improved healthcare infrastructure, alongside its existing profile as a tourism hub, has led to the development of

The medical tourism market is currently on a rise in UAE. And Dubai has been actively working towards making it a global destination for medical tourism.

medical tourism within the GCC. Dubai is becoming a popular medical tourism destination as patients look to combine leisure time with affordable yet high-quality medical services.

In 2016, Dubai launched the world’s first comprehensive electronic medical tourism portal: www.dxh.ae, Dubai Health Experience, that promises to provide all health, travel, hospitality and visa services at the click of a button. Medical packages will include procedures such as wellness, cosmetic and dental services, ophthalmology, orthopaedics and physiotherapy and specialised medical tests, etc. The initiative has a target of over 500,000 international medical tourists by 2020. Given these figures, the DHA estimate of 500,000 international medical tourists is conservative and is likely to far exceed the target.

Dubai attracted 260,000 medical tourists in the first half of 2015, up 12% from the same period a year ago, generating Dh1 billion in revenues. The Dubai Health Authority aims to grow the number of medical tourists by around 12% annually and to generate Dh2.6 billion in revenue by 2020.

With medical insurance being mandatory in UAE, this has helped the residents to be more aware about their health and conditions, and go for frequent check-ups, and there is 98% coverage in Dubai.

Six million people travel for medical treatment from one country to another, and if you add in those who travel some distance within a country, it exceeds 10 million a year. Medical tourism is a key area for developing the healthcare sector in the UAE. The benefits of medical tourism to the overall health sector are numerous. Among others, they include: • Higher quality of healthcare service provision due to the need for international competitiveness. 22 Journal for Clinical Studies

Regional dynamics play a crucial role in the trends of medical tourism, as a large volume of travellers prefer regional locations over long-distance travel. In Dubai, for example, Asian tourists accounted for 33% of the total, followed by 27% from Europe, and 23% from GCC and other Arab countries in the first half of 2015. Future of Healthcare Market As healthcare providers increasingly integrate their services with electronic infrastructure, the big volumes of valuable data generated are expected to pose several analytical opportunities for the UAE in the years to come. The UAE Government is liberalising policies to attract foreign investments, to improvise the healthcare standard and boost the healthcare industry. Volume 9 Issue 5


Market Report This holistic research and analysis depicts that the healthcare market of UAE will grow at a CAGR of around 7% during the forecast period 2015 to 2020.5

Dubai Government has 15 ambitious strategic programs 2016–2021 • Care Model Innovation • Prevention & Healthy Lifestyle • Public Health & Safety • Primary Care • Oral & Dental Care • Mental Health • Chronic Disease Management: • Centers of Excellence • Medical Tourism • Excellence & Quality • Governance (Regulation and Service Delivery) • Workforce & Medical Education • Medical Informatics & Technology • Health Insurance & Financing • Investment & Partnerships This would help Dubai to boost its healthcare economy. Along with this, the other Emirates are also working on to boost up their economy. REFERENCE 1. https://www.dha.gov.ae/Documents/Dubai_Health_ Strategy_2016-2021_En.pdf 2. http://www.isahd.ae/content/images/pillars-to-isahd-3.png 3. https://www.vision2021.ae 4. http://gulfnews.com/business/sectors/tourism/500-000medical-tourists-to-dubai-in-2015-1.1597133 5. https://www.researchandmarkets.com/reports/3275275/uaehealthcare-sector-outlook-2020 www.jforcs.com

Adhiti Sharad Kumar She has been working for a clinical research organisation for the past four years, and has been involved in the quality management and regulatory functions. She is also the Coordinator for the Gulf Chapter of the Association of Clinical Research Professionals – ACRP. This group is focused on promoting clinical research around the Gulf, and is involved in training sessions, networking events, etc. Email: adhitisoni@gmail.com

Journal for Clinical Studies 23


Therapeutics

Potential Therapies in the R&D Pipeline for Facioscapulohumeral Muscular Dystrophy At no time in the history of facioscapulohumeral muscular dystrophy (FSHD) has the future looked brighter for the successful development of a disease-modifying treatment. For example, in 2015, there were only seven clinical studies listed on the US-based Clinicaltrials.gov website (using the search term “FSHD”). With now (as of 21 June 2017) over 30 studies listed in the US – some involving pharmaceutical treatments and some involving interventions – the stage is set for positive change. More groundwork is needed, however, such as the conduct of natural history studies, establishment of more global patient registries and completion of additional genetic and molecular studies, to better understand FSHD and to identify promising targets. Establishing relevant outcome measures and/or biomarkers of disease progression is crucial as well. Indeed, it has historically proven difficult to find preclinical and animal models of FSHD; however, a newer generation of mouse models appears to be encouraging in regard to reflecting human FSHD pathology. Because it is critically important for the pharmaceutical industry to find suitable patients for their FSHD trials quickly, a brief discussion of patient registries is also included. Several promising approaches to the treatment of FSHD include: intramuscular transplant of muscle-derived and adiposederived mesenchymal cells (e.g., myoblast transfer), histidyl-tRNA ligase modulation, myostatin inhibition and DUX4 modulation, in addition to protein supplementation and muscle imaging. This paper will provide a very brief overview of FSHD (for more details, see our paper entitled, “Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates” published in Volume 9, Issue 3 of the Journal for Clinical Studies), discuss the challenges associated with the lack of a unified FSHD registry and discuss select promising pharmaceutical interventions in the pipeline. A brief overview describing protein supplementation will also be provided, but imaging will not be discussed. As ongoing FSHD studies are completed, it is hoped that the mechanism of disease will become better elucidated, more targets will be identified, and more biopharmaceutical companies will be willing to invest in clinical trials. Background1 FSHD is a complex muscle disease that affects the entire body; but it is typically referenced as a single clinical phenotype affecting the face (facio), scapula (scapulo), and humerus (humeral) muscles. It appears to have varying molecular and genetic determinants with commensurate differences in disease progression. 24 Journal for Clinical Studies

FSHD has only recently attracted attention from the pharmaceutical industry, largely due to advances in our understanding of the genetic mechanisms of disease, including overexpression of a protein called double homeobox 4 or DUX4. There is currently no disease-modifying treatment or cure for FSHD. Most treatments proposed to “treat” FSHD have not yet been tested in randomised clinical trials. According to the University of Massachusetts Medical School’s Wellstone Center of FSHD, FSHD is the most prevalent hereditary muscular dystrophy affecting men, women and children and is more prevalent than any of the other types of muscular dystrophy. A conservative estimate of incidence for FSHD1, the most common type, is 1 in 14,286 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be as high as 1 in 7500. Accessing Patients A patient registry is a collection of secondary data related to FSHD patients (and therefore may include family members). Registries can vary in sophistication from simple MS Excel spreadsheets that can only be accessed by a small group of physicians, to very complex databases that are accessed online across multiple institutions. Because of the large unmet need to identify disease-modifying and curative treatments – coupled with greater elucidation of the mechanism of action of certain types of MD (like Duchenne MD [DMD], Becker’s MD [BMD] and FSHD) – pharmaceutical companies and third-party capital investors are increasingly willing to invest in drug development. Registries are needed to help pharmaceutical companies rapidly identify FSHD patients for global trials, protect patients’ rights, meet patient expectations, and expedite drug development. Due to the small number of patients with FSHD, it is important to identify these individuals quickly in order to share rapidly evolving scientific advances with them, advocate for them, and provide opportunities to advance our scientific knowledge so that, ultimately, viable treatment options can be found. Registries can play multiple roles, including identifying FSHD patients for scientific research, clinical trials, and later, as products/drugs are approved for the treatment of FSHD, in the post-marketing surveillance of pharmaceuticals. Registries can also send reminders to healthcare providers (or even patients) to undergo certain tests in order to reach treatment quality goals. Registries are less complex and simpler to set up than an electronic medical record, which keeps track of all the patients a doctor follows, while a registry only keeps track of a small sub-population of patients with a specific condition. Volume 9 Issue 5


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Therapeutics Currently, many registries are only offered in one geographic area or for just one or two types of MD. The Muscular Dystrophy Association (MDA) – the world’s leading non-profit dedicated to finding treatments and cures for muscular dystrophy, amyotrophic lateral sclerosis (ALS) and other neuromuscular diseases – is attempting to remedy this disparity by working with QuintilesIMS and patient advocacy groups to provide a world map of people with myopathies. The MDA is not currently developing a registry of patients with FSHD.

the effects of vitamins and protein supplements. For the purposes of this paper, the authors will focus on the four main therapeutic treatments just below, but will comment on our literature review of protein supplementation.

Because there are multiple registries, it can be confusing for both the newly diagnosed patient and the caregiver. In general, for those who are unfamiliar with a certain type of MD, most patient advocacy groups provide links and post information for patients and their caregivers. Some groups, such as the US-based FSH Society, is attempting to plug the gap for a unified global FSHD patient registry and recently announced its intention to establish such a registry in collaboration with a dozen other organisations and government agencies around the world.3

Cell Therapies Different cell therapy strategies using various types of cells have been tested in chronic muscle disorders.5-9 There are many challenges in developing robust and efficacious muscle disease cell therapies. An ideal therapeutic candidate will have the following attributes: 1) cells which are easily obtainable in sufficient quantities, 2) robust and rapid isolation and cellular amplification, 3) significant myogenic potential, 4) proper homing, 5) genetically modifiable (if applicable), and lastly 6) the ability to restore the pool of satellite cells in order to amplify the therapeutic effect in subsequent rounds of regeneration.10 The majority of this work has been done in muscular dystrophy animal models and in patients with DMD. This research, when paired with recent advances in cell therapeutics, gives promising insights into what the difficulties will be and how to overcome them when developing an efficacious therapeutic.

Funding In the past three years, there has been a shift in the funding source for clinical studies in FSHD, as listed on clinicaltrials.gov, with 35% of studies started from 2014 through 2016 receiving primary funding from industry. See Figure 1 below for a summary of industry and non-industry sponsors of FSHD trials, by percentage, since 1993. Additionally, regardless of the sponsor, 71% of studies during this time were interventional in nature. These trends provide optimism of future approved treatments for FSHD. As a point of reference, industry sponsored trials became a significant portion of Duchene muscular dystrophy (DMD) development beginning in 2008, and in 2016 the first treatment for DMD was approved by the FDA.

Figure 1 – Industry and Non-industry Sponsors of FSHD Trials Since 1993

Pharmaceutical Treatments The World Health Organization4 defines a “clinical trial” as: • “For the purposes of registration, a clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc.” Therefore, studies listed on certain regulatory-mandated websites, like Clinicaltrials.gov, may include observational studies to study natural history progression, imaging trials to determine the differences between muscle groups and studies to examine 26 Journal for Clinical Studies

1. Cell therapies, including myoblast transfer therapy 2. Histidyl tRNA synthetase stimulation 3. Myostatin inhibition; and 4. DUX4 modulation

Myoblast transfer therapy, in which allogenic myoblasts were given via multiple intramuscular injections, was originally proposed for the treatment of DMD; however, the clinical effects were minimal and disappointing. Multiple factors contributing to the treatment failure were subsequently identified.11 According to Skuk and Tremblay, it is now widely believed that the inefficiency of myoblast transfer therapy derives from the poor survival and insufficient migration of transplanted myoblasts, as well as their rejection by the recipient’s immune system.12 It was estimated in animal models that 90–99% of myoblasts die after the injection, primarily within the first 12 hours post-injection. These results indicate that a stem-cell like sub-population is responsible for the persistent cells.13 For myoblasts to be an efficacious therapeutic, this sub-population must be significantly enriched and amplified. Poor dispersion of the injected cells was another factor which negatively impacted the myoblast transfer therapies.14 While much of the prior research has focused on DMD, the selective muscle involvement in FSHD and OPMD has directed scientists’ interest toward autologous myoblast transfer as a potentially feasible treatment option for these disorders.15 In DMD, the muscle pathology is spread across most muscles as opposed to diseases such as FSHD and OPMD, where affected and nonaffected muscles typically coexist. Vilquin et al. have explored proliferation and in vitro and in vivo differentiation of myoblasts from FSHD-unaffected vastus lateralis muscle and found that large-scale production of myoblasts is possible, with no morphological aberrations compared to the controls. This was in contrast to the finding of another study, where morphological changes were found.16 Nevertheless, the investigated myoblasts also had a high proliferative capacity.17 Based on their results, it was hypothesised that myoblasts expanded from unaffected FSHD muscles may be suitable candidates for autologous cell transplantation in FSHD. It is important to note that genetic and epigenetic changes due to cell passaging, best exemplified using induced pluripotent stem cells (iPSCs)18, is of concern, and so cellular amplification should be minimised. Volume 9 Issue 5


Therapeutics Mesoangioblasts and muscle-derived CD133+ stem/progenitor cells have been tested in boys with DMD. Human mesoangioblasts differentiate into skeletal muscle under a variety of conditions, with the highest efficiency when exposed to human normal myoblast-conditioned medium.19 Studies have shown that intraarterial injection of mesoangioblasts restored muscle morphology in muscular dystrophy animal models.20 Mesoangioblasts can be efficiently isolated from FSHD patient muscle biopsies and expanded ex vivo to an amount necessary to have efficacy in animal models, but the disease state of the muscle of origin is important. Proliferating mesoangioblasts differentiated into skeletal muscle to differing extents, correlated with the overall disease severity and the degree of involvement of the muscle of origin as assessed by clinical, MRI, and histopathology examination.21 While promising, the extent of differentiation necessary and the cell numbers required for efficacy in patients can only be determined in clinical trials. Mesoangioblasts from the unaffected muscles differentiate into morphologically normal myotubes, whereas those from affected FSHD muscles show myogenic differentiation block.22 In vivo studies in mice followed and confirmed these observations. Mesoangioblasts from apparently normal muscles were able to integrate and efficiently participate in muscle regeneration, whereas mesoangioblasts obtained from affected muscles presented differentiation defects.23 While a number of challenges will need to be resolved for the successful clinical development of a cellular therapeutic for muscle diseases, recent developments, including the identification of the potential hurdles and possible approaches, show that cell-based treatments for muscular dystrophy have significant promise. Histidyl tRNA Synthetase Stimulation Several decades ago, it was discovered that RNA synthetase has roles outside of translation; later, aberrant or mutant tRNA synthetases were linked to the pathogenesis of disease, ranging from cancer to peripheral neuropathies.23 Recombinant tRNA synthetase is currently being tested in different types of muscular dystrophies, investigating cytokinelike capabilities of histidyl tRNA synthetase which might present an effective treatment of myopathies with an inflammatory component. The compound, Resolaris (ATYR1940), is a physiocrinebased protein that modulates immune responses in skeletal muscle preclinically, and is identical to substantially all of human histidyl tRNA synthetase, a protein that is released from skeletal muscle. In vitro T-cell modulation experiments have demonstrated that at 100 pM, Resolaris results in significant reduction of T-cell activation in muscle, as shown by reduced expression of T-cell activation markers.24 This compound has received orphan drug designation from both US Food and Drug Administration (FDA) and European Medicines Agency (EMA), as well as fast track status for FSHD from the FDA.25 The route of administration of Resolaris is intravenous. Last year, data from a randomised, double-blind, placebocontrolled, multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics, immunogenicity and biological activity of ATYR1940 in adult FSHD patients were published, and supported the advancement of ATYR1940 for further clinical development in FSHD.26 www.jforcs.com

At the end of 2016, the company announced interim results from an ongoing Phase Ib/II trial in patients with early onset FSHD (003 trial), results from a trial in patients with adult FSHD (005 trial) and results from a Phase Ib/II trial in adult patients with limbgirdle muscular dystrophy and FSHD (004 trial). Forty-four patients received Resolaris at the time of data analysis, which was generally well-tolerated, adverse events were mild to moderate intensity and no serious adverse events were reported. According to an aTYR press release, overall individualised neuromuscular quality of life (INQoL) questionnaire scores were stable in all FSHD patients in the 004 trial and in five of eight patients, a small decrease in disease burden was demonstrated. In study 003, the INQoL scores were relatively stable and three of four patients demonstrated improved muscle strength. The 005 trial did not demonstrate worsening or improvement in INQoL or manual muscle testing.27 It is important to highlight that the press release did not list any figures related to statistical significance. Myostatin Inhibition Myostatin is an endogenous negative regulator of muscle growth. Neutralising antibody to myostatin, MYO-29, was tested in Phase I/II double-blind, placebo-controlled, randomised study in different types of muscular dystrophies including FSHD (NCT00104078). The compound failed to improve muscle strength in patients, measured by manual muscle testing, quantitative muscle testing, and timed function tests. The study, however, was not powered for efficacy. Bioactivity of MYO-029 was supported by a trend in a limited number of subjects towards increased muscle size using dualenergy X-ray absorptiometry and muscle histology assessments.28 ACE-083, a locally acting muscle agent which increases muscle strength and function in an animal model, is another compound in development for the treatment of FSHD. ACE-083 works by binding to and inhibiting select proteins in the Transforming Growth Factor beta (TGF-beta) protein superfamily that negatively regulate muscle growth, such as activins and myostatin.29 TGF-beta causes fibrosis and promotes inflammation in skeletal muscles.30 Increased TGF-beta signalling has also been associated with inherited and acquired muscle disorders, including muscular dystrophies and neuromuscular diseases such as ALS.31,32 Besides its effect on induction of muscle atrophy and fibrosis, TGF-beta also decreased muscle fibre size and dramatically reduced maximum isometric force generation in mice.33 A Phase I study investigating ACE-083 in healthy volunteers demonstrated that ACE-083 produced substantial dose-dependent increases in muscle volume, with the highest dose level generating a 14.5% increase in muscle volume.34,35 A Phase II study in FSHD patients with muscle weakness in musculi tibialis and anterior biceps brachi has been initiated. DUX4 Modulation Both FSHD types (FSHD1 and FSHD 2) have a common downstream mechanism of aberrant expression of DUX4, which causes a toxic gain of function. DUX4 has therefore become an interesting target for potential FSHD therapeutics. Possible therapeutic approaches include increasing methylation in the D4Z4 region, knocking down or inhibiting expression DUX4 or targeting downstream targets of DUX4.36, 37, 38 Multiple preclinical studies have been carried out or are underway. In 2012, a group of scientists led by Wallace used adenoassociated viral vector (AAV) to deliver micro mRNA targeting Journal for Clinical Studies 27


Therapeutics DUX4, and managed to correct DUX4-associated myopathy in mice model by DUX4 gene silencing.39 The main issue with Wallace’s work was that the delivery system using AAV could trigger an immune response. Ansseau later used different antisense oligonucleotides (AOs), against the DUX4 mRNA and was able to knock down DUX expression in an in vitro model of FSHD and demonstrated the promise of antisense strategies to treat FSHD.40 Further work has been published on AOs that are targeting DUX4 mRNA to prevent or downregulate its translation to the toxic protein, and also to decrease the aberrant expression of genes downstream of DUX.41 This study used a new AO-based therapeutic approach for FSHD using phosporodiamidate morpholino oligomers (PMOs), targeting the key elements of 3’ end processing of the DUX transcript, which are believed to bring certain advantages over classic AOs. A recent study showed that in primary human myoblasts from FSHD patients and unaffected controls, DUX4-targeted AOs suppress the atrophic myotube FSHD phenotype but do not improve the disorganised FSHD myotube phenotype. It is hypothesised that the latter may be caused by overexpression of DUX4c. DUX4c is a protein identical to DUX4 except for the end of the carboxyl terminal domain, is expressed at a low level in healthy muscle cells and up-regulated in FSHD, and therefore might be another suitable therapeutic target in FSHD.42, 43, 44 Another possible therapeutic approach is the use of CRISPR/ dCas9-based genome editing technology. Himeda and colleagues demonstrated that the CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly-repetitive FSHD macrosatellite array and can repress expression of DUX4 full-length protein and downstream targets in primary FSHD myocytes. The last approach we would like to mention is antisense RNA therapy to eliminate the polyadenylation signal on the 4qA allele so that DUX4 is not translated. In other words, it means that the 4gA allele is converted to the 4qB allele.45 Further progress in DUX-targeted therapeutic approaches for FSHD is warranted prior to moving into clinical trials involving patients. Protein Supplementation An earlier, non-randomised clinical study by Anderson et al. suggested that protein-carbohydrate supplements might improve protein balance in patients with MD46, including those with FSHD; however, later, randomised studies involving only patients with FSHD did not show any further improvement to the training effects alone.47 The 2015 study, a randomised, double-blind placebo study conducted in Denmark, found that while regular endurance training does improve fitness, walking speed and self-assessed health in patients with FSHD without causing muscle damage, the proteincarbohydrate supplement (consisting of 23 grams of whey protein and 17 grams of carbohydrates) did not offer any improvements. Although creatine is frequently in the news as a popular performance-enhancing supplement, Evangeliou et al. conclude that while it may help, “there is a lack of double-blind clinical trials in humans and undoubtedly, further research is required.”48 Therefore, the authors concluded that there is little evidence that protein supplementation provides any significant positive effects in patients with FSHD. Because FSHD varies in its effects on targeted anatomical regions of the body in each individual, larger-scale clinical trials, 28 Journal for Clinical Studies

facilitated by FSHD-targeted registries, are needed in order to obtain a greater understanding of how protein supplements affect the bodies of patients. Summary Facioscapulohumeral MD, likely the most prevalent form of MD, currently has no cure, but several factors point to the potential for successful development of a disease-modifying FSHD treatment in the near future. First, the number of interventional trials to treat FSHD is increasing; second, the amount of capital for FSHD investment has increased; and third, industry sources of capital are increasing sharply. We reviewed four main therapeutic approaches in clinical development: cell therapies, histidyl tRNA synthetase stimulation, myostatin inhibition, and DUX4 modulation. The majority of work on cell therapies has been done in muscular dystrophy animal models and in patients with DMD. A number of challenges exist – such as poor survival of the myoblasts, insufficient migration, rejection by the recipient’s immune system and variability with proliferation – that will need to be resolved for the successful clinical development of a cellular therapeutic for FSHD. Recent advances, including the identification of the potential hurdles and possible approaches, show that cell-based treatments for FSHD have significant promise. Resolaris is the most advanced recombinant tRNA synthetase currently being tested in FSHD. Its administration appears to significantly reduce certain types of inflammatory responses. Initial results from a randomised, double-blind, placebo-controlled, multiple ascending dose study, interim results from an ongoing Phase Ib/II study in patients with early onset FSHD, and results from a Phase Ib/II study in adult patients with FSHD all appear encouraging, but the clinical development is not yet complete and it is important to highlight that that the press releases did not list any figures related to statistical significance. Myostatin was tested in a Phase I/II double-blind, placebocontrolled, randomised study in patients with FSHD. Although the safety and tolerability was favourable, the compound failed to improve muscle strength in patients, as measured by manual muscle testing, quantitative muscle testing, and timed function tests. ACE-083, a locally-acting muscle agent that increased muscle strength and function in an animal model, is also in development for the treatment of FSHD. Early studies produced substantial, dosedependent increases in muscle volume and appear encouraging. A Phase II study in FSHD patients has been initiated. DUX4 has become an interesting target for potential FSHD therapeutics. Possible therapeutic approaches include increasing methylation in the D4Z4 region, knocking down or inhibiting expression of DUX4 or targeting downstream targets of DUX4. Multiple preclinical studies have been carried out and are underway. Antisense oligonucleotides are being used to alter DUX4 expression in animal models, though there remains a concern about immunogenicity. Other models, including the use of CRISPR geneedited technology, appear promising, but further progress in DUXtargeted therapeutic approaches for FSHD will be required prior to moving to clinical trials in patients. Regarding protein supplementation, few well-controlled, randomised clinical studies are available for review. Earlier studies appeared promising, but later studies were inconclusive or showed no clear benefit. Volume 9 Issue 5


Therapeutics As FSHD becomes better understood, the current interest from the pharmaceutical interest can be expected to build. Hopefully, ongoing and future clinical trials will soon result in an approved, disease-modifying or curative treatment for patients with FSHD. REFERENCES 1. Huml RA, Undus L, Dean M, Huml ML. Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates, Journal for Clinical Studies, Volume 9, Issue 3; pp 1214, 16 and 18, https://issuu.com/mark123/docs/jcs_may_web, accessed 07 June, 2017. 2. https://www.cancer.gov/publications/dictionaries/cancerterms?cdrid=538640, accessed 07 June, 2017. 3. https://www.fshsociety.org/?s=registry, accessed 06 April, 2017. 4. http://www.who.int/topics/clinical_trials/en/, accessed 16 June, 2017. 5. Maffioletti 2014 - https://www.ncbi.nlm.nih.gov/pubmed/25054157, accessed 05 June, 2017. 6. Benedetti 2013 - https://www.ncbi.nlm.nih.gov/pubmed/23387802, accessed 05 June, 2017. 7. Negroni 2015 - https://www.ncbi.nlm.nih.gov/pubmed/25405809, accessed 05 June, 2017 8. Morosetti 2011 - https://www.ncbi.nlm.nih.gov/pubmed/21176400, accessed 05 June, 2017. 9. Mouly 2005 - https://www.ncbi.nlm.nih.gov/pubmed/16550930, accessed 05 June, 2017. 10. Ibid #6. 11. Ibid #8. 12. Skuk 2014- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC 4015228/, accessed 07 June, 2017. 13. Beauchamp 1999 - https://www.ncbi.nlm.nih.gov/pubmed/25054157, accessed 07 June, 2017. 14. Skuk – 2003 https://www.ncbi.nlm.nih.gov/pubmed/14569201,

www.jforcs.com

accessed 07 June, 2017. 15. https://www.ncbi.nlm.nih.gov/pubmed/23831596, accessed 07 June, 2017. 16. Winokur - https://www.ncbi.nlm.nih.gov/pubmed/12868502, accessed 07 June, 2017. 17. Vilquin 2005 - https://www.ncbi.nlm.nih.gov/pubmed/15973444, accessed 07 June, 2017. 18. Liang 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3760008 19. Sampaolesy – 2006 https://www.ncbi.nlm.nih.gov/pubmed/17108972, accessed 07 June, 2017. 20. Morosetti 2007 - https://www.ncbi.nlm.nih.gov/pubmed/17761758, accessed 07 June, 2017. 21. Morosetti 2007 - https://www.ncbi.nlm.nih.gov/pubmed/17761758, accessed 07 June, 2017. 22. Morosetti 2007 - https://www.ncbi.nlm.nih.gov/pubmed/17761758, accessed 07 June, 2017. 23. Morosetti 2011 - https://www.ncbi.nlm.nih.gov/pubmed/21176400, accessed 07 June, 2017. 24. Becker 2016 - http://www.nature.com/nm/journal/v22/n5/ full/nm0516-452.html, accessed 07 June, 2017. 25. http://www.prnewswire.com/news-releases/atyr-pharmareceives-ema-orphan-drug-designation-for-the-treatment-oflimb-girdle-muscular-dystrophy-with-resolaris-300417615.htm, accessed 07 June, 2017. 26. http://www.nmd-journal.com/article/S0960-8966(16)30586-7/ abstract, accessed 07 June, 2017. 27. Gershman 2016 - http://www.nmd-journal.com/article/S09608966(16)30586-7/abstract, accessed 07 June, 2017. 28. http://investors.atyrpharma.com/news-releases/news-releasedetails/atyr-pharma-reports-promising-signals-clinicalactivity-multiple, accessed 07 June, 2017. 29. Wagner 2008 - https://www.ncbi.nlm.nih.gov/pubmed/18335515, accessed 07 June, 2017.

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Therapeutics 30. http://acceleronpharma.com/product-candidates/ace-083/, accessed 07 June, 2017. 31. https://www.ncbi.nlm.nih.gov/pubmed/14982854, accessed 07 June, 2017. 32. https://skeletalmusclejournal.biomedcentral.com/ articles/10.1186/2044-5040-1-19, accessed 07 June, 2017. 33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574401/, accessed 07 June, 2017. 34. https://www.ncbi.nlm.nih.gov/pubmed/22190307, accessed 07 June, 2017. 35. https://clinicaltrials.gov/ct2/show/NCT02257489, accessed 07 June, 2017. 36. https://musculardystrophynews.com/2017/05/10/fshdtherapy-ace-083-phase-2-trial-doses-first-patient-acceleronannounces, accessed 07 June, 2017. 37. Statland 2016 - https://www.ncbi.nlm.nih.gov/pubmed/27922500, accessed 07 June, 2017. 38. Bao 2016 - https://www.ncbi.nlm.nih.gov/pubmed/27672539, accessed 07 June, 2017. 39. Ansseau 2013 – http://www.probram.be/index.php/probram/ article/view/58, accessed 07 June, 2017. 40. Wallace 2012 - https://www.ncbi.nlm.nih.gov/pubmed/22508491, accessed 07 June, 2017. 41. Ansseau 2013 – http://www.probram.be/index.php/probram/ article/view/58, accessed 07 June, 2017. 42. Marsollier 2016 - https://www.ncbi.nlm.nih.gov/pubmed/26787513, accessed 07 June, 2017. 43. Ansseau 2016 - http://journals.plos.org/plosone/article?id=10.1371/ journal.pone.0146893, accessed 07 June, 2017. 44. Ansseau 2017 - https://www.ncbi.nlm.nih.gov/pubmed/28273791, accessed 07 June, 2017. 45. https://www.ncbi.nlm.nih.gov/pubmed/?term=26420234, accessed 12 June, 2017. 46. Anderson, G, Orngreen MC, Preisler N, Jeppesen TD, Krag TO, Haurslev S, van Hall G, Vissing J. Protein-carbohydrate supplements improve muscle protein-balance in muscular dystrophy patients after endurance exercise: a placebocontrolled cross-over study, Am J Physicol Regul Integr Comp Physiol 308: R123-R130, 19 November 2014 47. Anderson G, Prahm, Dahlvist JR, Citirak G, Vissing J. Aerobic training and postexercise protein in facioscpaluohumeral muscular dystrophy (RCT Study); Neurology, 85, 4 August, 2015; pp.396-403. 48. Evangeliou A, Vasilaki K, Karagianni P, Nikolaidis. Clinical Applications of Creatine Supplementation on Paediatrics, Current Pharmaceutical Biotechnology; 2009; 10; 683-690. Acknowledgments The authors would like to thank Drs Joseph J. Higgins, MD, FAAN, Medical and Laboratory Director, Neurology, Athena & Quest Diagnostics, for his editorial contributions and insights and Jill Dawson, PhD, consultant to QuintilesIMS, for her editorial contributions and support.

George Smith PhD, MBA is the Integrated Program Lead for the QuintilesIMS Stem Cell Center. He has 20 years of experience in discovery, development and programme strategy for cell therapies, biologics and small molecules across a wide variety of therapeutic areas. Dr Smith has a PhD in Biology and an MBA from the University of California at San Diego.

30 Journal for Clinical Studies

Raymond A. Huml MS, DVM, RAC is Vice President of QuintilesIMS Global Biosimilars Strategic Planning. Dr Huml has a personal interest in FSHD and works with the QuintilesIMS/ Muscular Dystrophy Association (MDA) team on their national patient registry. Dr Huml is a member of the FSH Society and has presented at FSH Society’s Biennial “FSHD Connect” meeting. Dr Huml is co-founder and member of the NC Chapter of the FSH Society. He is a member of MD STARnet’s North Carolina Advisory Committee representing the interests of patients with FSHD. In 2015, Dr Huml edited and wrote or co-wrote eight chapters for the Springer book, Muscular Dystrophy: A Concise Guide, which covers all types of MD.

Lucie Undus MD, is a board-certified neurologist with over a decade of experience in clinical medicine and clinical trials and seven years of industry experience both in the EU and the US. Dr Undus has a special interest in neuromuscular disorders, holds neuromuscular sub-specialisation and EMG licences, and has been working with mainly adult neuromuscular patients including patients with muscular dystrophies. Dr Undus further subspecialises in neurological orphan indications and movement disorders. She received her MD from the Charles University in Prague, Czech Republic, and trained further in neurology in Perugia, Italy and Toulouse, France.

Meredith L. Huml She is a case worker for the Alliance of Disability Advocates, located in Wake County, North Carolina. She was diagnosed with FSHD in 2003 at Duke University Hospital. She authored Chapter 13, “Patient Advocacy,” for the book Muscular Dystrophy: A Concise Guide, published by Springer in 2015, and co-authored the articles titled, “The Growing Case for the Rapid Identification of Patients with Muscular Dystrophy for Clinical Trials” and “Facioscapulohumeral Muscular Dystrophy: Clinical, Therapeutic and Regulatory Updates”; both published in the Journal for Clinical Studies.

Margaret Dean MBA, has 15 years of healthcare experience, with roles in clinical development and commercialisation. As Deputy Head of the Rare Disease Center of Excellence at QuintilesIMS, she leverages an analytical approach to understanding best practice trends in rare disease development. Margaret has a BS in Chemistry from the University of Richmond and an MBA from University of North Carolina – Chapel Hill’s Kenan-Flagler School of Business.

Volume 9 Issue 5


www.jforcs.com

Journal for Clinical Studies 31


Therapeutics

Augmenting Clinical Development of Heart Failure Therapies Pulse Wave Analysis Provides Valuable Insights into Therapeutic Development for More Efficient Trials & Earlier Indications of Success There are currently a number of pharmaceutical- or devicebased heart failure (HF) therapies in clinical use1 with numerous promising candidates under development. Available therapies range from established drug classes such as beta-blockers, angiotensinconverting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, and nitrates to the more recently approved first-inclass angiotensin receptor-neprilysin inhibitor.2 We have also seen the potential off-target benefits of a sodium glucose co-transporter-2 (SGLT2) inhibitor, an anti-diabetic agent that was shown to reduce hospitalisations for heart failure.3 Heart failure-focused trials of this drug are currently underway and expected to complete in 2020.4 Meanwhile, there are several novel HF therapies currently in Phase III studies. These include myosin activators,5 guanyl cyclase stimulators,6 gene transfer therapies,7 and a baroreflex activation system,8 to name a few. Recently, however, there has been criticism of how clinical trials for novel heart failure therapies are designed and interpreted.9 Clinicians, researchers, regulators, and industry have collectively pointed out that current approaches have led to initial enthusiasm followed by disappointment in some candidate compounds, discontinuation of other potentially promising therapies, and a general decline in the investment in the development of heart failure therapeutics. This criticism has led to several specific recommendations on how to improve future heart failure trials.9,10 These include: • • • •

identifying new patient and disease improvement markers tailoring end point selection to mechanism of action comprehensive assessment of multidomain data, and considerations for population enrichment

One such clinical measurement that is particularly wellsuited to address these recommendations is the analysis and interpretation of the central arterial pressure waveform (pulse wave analysis – PWA). PWA provides insights about an individual’s current cardiovascular condition and has demonstrated greater prognostic capabilities than other standard clinical measurements.11 Improvements in the central pressure waveform with therapy are directly related to functional improvements in heart failure patients.12 Changes in pressure waveform contour differ with different therapies13 and in different patients with similar therapies.12 Through analysis of the entire pressure waveform contour, and not just the extremes (i.e. systolic and diastolic blood pressure), PWA assessments allow for a more comprehensive understanding of the effects an intervention has on ventricularvascular interactions14 and, given its independent relationship with cardiovascular outcomes,15 allows for identification of patients with a greater likelihood of experiencing an event. 32 Journal for Clinical Studies

One parameter available from PWA that recent research has identified as important in heart failure is pulse pressure amplification (PPA), in which reflections of the pressure pulse from distal reflections sites result in the amplification of the pulse pressure from the heart to the brachial artery.14 As the pressure pulse created by the ejecting left ventricle propagates distally from the ascending aorta to the peripheral arteries, there is a gradual increase in the systolic and pulse pressures, an increase that ranges from 2 to more than 30 mmHg and varies significantly between individuals.16 Of course, office blood pressure is measured at the brachial artery so that the individual variability of PPA can lead to individual variability of the ascending aortic pressure, resulting in an unknown variability in the effect of blood pressure on ventricular afterload. PWA can significantly reduce this variability, leading to a simple and more precise indication of this load. Besides variations in pulse pressure amplification, variations in wave reflections (as well as arterial stiffness) result in changes to the contour of the pulse waveform. As the incident/forward travelling pressure wave generated by the left ventricle propagates through the arterial system, it encounters numerous discontinuities (e.g. geometric and elastic tapering, changes in vessel structure, bifurcations, and arterial/ arteriolar interfaces).16 These discontinuities act as reflection sites in that some portion of the incident wave is reflected back towards the left ventricle. These multiple reflected waves merge with the incident wave so that the measured pressure wave in the arteries then is the sum of these incident and reflected waves. The timing of the interaction between the incident and reflected waves controls the contour of the measured pressure wave. If, for example, an individual’s arterial stiffness is substantially increased due to disease, the reflected waves arrive in the ascending aorta before the aortic valve closes. This leads to an increase in left ventricular afterload, an important consideration in assessing heart failure and the effects of heart failure therapies. As mentioned above, the difference between brachial and aortic systolic pressure varies widely between individuals, so much so that two individuals with identical brachial systolic pressures may have aortic systolic pressures that differ by as much as 30 mm Hg or more.16 As a consequence, aortic pressure cannot be inferred from standard brachial cuff blood pressure measurements. Furthermore, aortic pressure changes following therapy do not necessarily mirror the changes in brachial blood pressure. Numerous investigations have shown that interventions with non-significant differences on cuff pressure can have significantly different effects on aortic pressure.13,17 Not surprisingly, it is aortic pressures that have been shown to be a stronger stimulus to left ventricular hypertrophy18 and better correlated to LV structural improvements with therapy.19 These differential aortic pressure effects are also known to explain the difference in outcomes between treatment arms in major CV trials.20 With left ventricular unloading a cornerstone of HF management,1 understanding central BP effects of a compound early in the clinical development process can be markedly informative. Volume 9 Issue 5


FOR BETTER TRIAL DECISIONS With 30+ years of expertise, sponsors trust Bioclinica to provide HIGH

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Therapeutics

As noted, increased arterial stiffness leads to arrival of reflected waves in mid-to-late systole, while the aortic valve is still open. A healthy left ventricle is able to compensate for and overcome this increased afterload so that wave reflections manifest as a late systolic boost in aortic pressures (i.e. increased augmentation pressure – the additional pressure that results from wave reflections and increased arterial stiffness). Chronic exposure to this increased afterload, however, leads to decompensation and a weakened ventricle which becomes highly sensitive to pressure changes. As a result, instead of presenting as increased augmentation pressure, reflected waves abbreviate ejection and decrease flow because the pressure-sensitive left ventricle is unable to overcome this additional load.21 Multivariable analysis in large population studies have shown measures of wave reflections to be strong and independent predictors of the development of congestive heart failure.11 In patients with established heart failure, prospective trials have found that baseline measures of wave reflections are able to differentiate between responders and nonresponders to vasoactive therapy12 and predict adverse outcomes (re-hospitalisation for HF, non-fatal myocardial infarction, non-fatal stroke, and death) during long-term follow-up.22 Finally, responders, as measured by improvements in functional status, demonstrate significantly greater reductions in central pressure measures of wave reflection and pulsatility than non-responders.12 PWA assessments offer the opportunity to identify HF subjects at greater risk of experiencing an adverse event (population enrichment), provide novel markers for predicting disease improvement, and more fully understand mechanisms driving outcomes – all valuable insights as a candidate moves through the clinical development process. 34 Journal for Clinical Studies

Finally, modification of the central pressure waveform does not necessarily require prolonged periods of intervention exposure. Depending on the mechanism of action of the drug, it is possible to observe significant changes in waveform variables in only a few minutes.23 Thus, lengthy trials may not be necessary to determine the effects a compound has on central pressure parameters. The value that PWA assessments can bring to a heart failure clinical development programme is substantial and multi-faceted. Through an understanding of central haemodynamics, and the effects of a therapy on the aortic pressure waveform, it is possible to: • 1) gain greater confidence earlier about a drug’s likelihood of success when transitioning through the clinical development phases, thus facilitating better-informed project decisions; • 2) identify potential safety issues early in the development process; • 3) aid in recruiting an enriched patient population, • 4) provide insight into the mechanistic actions of an intervention • 5) facilitate drug differentiation PWA assessments have the ability to streamline and optimise HF drug development by increasing programme efficiency, shortening project timelines, and enhancing post-market activities. With the advent of well-validated, established, cuff-based technologies,24 these assessments can be conducted in any out-patient facility, without the need for highly-specialised trained personnel, making PWA assessments an attractive, easily incorporated, substantially valuable addition to any ongoing or future HF therapy clinical trial. Volume 9 Issue 5


Therapeutics At a time when there is a need to improve HF clinical trials, PWA assessments, backed by a robust supporting literature, are uniquely positioned to provide researchers, clinicians, regulators, and industry members with significant and relevant data to augment the clinical development of HF therapies. REFERENCES 1. Yancy, CW et al. (2013 Oct 15). 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol, 62(16), e147-239. 2. Yancy, CW et al. (2017 Apr 25). 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Card Fail, S1071-9164(17)30107-0. 3. Fitchett, D. et al. (2016 May 14). Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J, 37(19), 1526-34. 4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT03057977, EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced); 2016 Feb 16 [cited 2017 July 31]; [6 pages]. Available from 7977?term=empagliflozin&recrs=a&cond=heart+failure&rank=2 5. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT02929329, Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction (GALACTIC-HF); 2016 Sept 30 [cited 2017 July 31]; [5 pages]. Available from https://clinicaltrials.gov/ct2/show/ NCT02929329 6. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT02861534, A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-001) (VICTORIA); 2016 Aug 5 [cited 2017 July 31]; [5 pages]. Available from https:// clinicaltrials.gov/ct2/show/NCT02861534 7. RT-100 (AC6 GENE TRANSFER): Renova Therapeutics Website. (cited 31 July 2017). Retrieved from http://renovatherapeutics. com/therapies/rt-100-congestive-heart-failure/ 8. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT00957073, Rheos HOPE4HF (Health Outcomes Prospective Evaluation for Heart Failure With Ejection Fraction (EF) ≥ 40%) Trial (HOP4HF); 2009 Aug 10 [cited 2017 Aug 3]; [6 pages]. Available from https:// clinicaltrials.gov/ct2/show/NCT00957073?term=rheos&rank=4 9. Butler, J et al. (2017 Apr). Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations. Circ Heart Fail, 10(4). 10. Cowie, MR et al. (2017 Jun). New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment. Eur J Heart Fail, 19(6), 718-727. 11. Chirinos, JA et al. (2012 Nov 20). Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol, 60(21), 2170-7. 12. Wohlfahrt, P et al. (2017 Feb). Aortic Waveform Analysis to Individualize Treatment in Heart Failure. Circ Heart Fail, 10(2). 13. Protogerou, AD et al. (2009). The Effect of Antihypertensive Drugs on Central Blood Pressure Beyond Peripheral Blood Pressure. Part II: Evidence for Specific Class-Effects of Antihypertensive Drugs on Pressure Amplification. Curr Pharm www.jforcs.com

Des, 15(3), 272-89. 14. Nichols, WW, O’Rourke, M, Vlachopoulos, C. (2011). McDonald’s blood flow in arteris: theroteicalo, experimental and clinical principles, 6th Edition. Hodder Arnold. 15. Roman, MJ et al. (2009 Oct 27). High central pulse pressure is independently associated with adverse cardiovascular outcome the strong heart study. J Am Coll Cardiol, 54(18), 1730-4. 16. O’Rourke, MF, Pauca, A and Jiang, XJ. (2001 Jun). Pulse Wave Analysis. Br J Clin Pharmacol, 51(6), 507-22. 17. Boutouyrie, P et al. (2010 Jun). Amlodipine-valsartan combination decreases central systolic blood pressure more effectively than the amlodipine-atenolol combination: the EXPLOR study. Hypertens, 55(6), 1314-22. 18. Roman, MJ et al. (2010 Feb). Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study. J Hypertens, 28(2), 384-8. 19. Kampus, P et al. (2011 Jun). Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension, 57(6), 122-8. 20. Williams, B et al. (2006 Mar 7). Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circ, 113(9),1213-25. 21. Denardo, SJ et al. (2010 Jan). Pulse wave analysis of the aortic pressure waveform in severe left ventricular systolic dysfunction. Circ Heart Fail, 3(1), 149-56. 22. Sung, SH et al. (2012 Dec). Excessive wave reflections on admission predict post-discharge events in patients hospitalized due to acute heart failure. Eur J Heart Fail, 14(12), 1348-55. 23. Kelly, RP et al. (1990 Feb). Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery. Eur Heart J, 11(2), 138-44. 24. Hwang, MH et al. (2014 Aug). Validity and reliability of aortic pulse wave velocity and augmentation index determined by the new cuff-based SphygmoCor Xcel. J Hum Hypertens, 28(8), 475-81.

Bobby Stutz Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. where he is responsible for Clinical Trial Services Business Development. Mr. Stutz has spent the last ten years in the medical device industry after earning his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C. E-mail: b.stutz@atcormedical.com

Dr Winter Dr Dean Winter is currently the Senior Consultant – Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial tonometry. Dr. Winter is an internationally recognised expert in physiological fluid mechanics, biomechanics and medical device development. E-mail: d.winter@atcormedical.com

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Therapeutics

Three Respiratory Trial Strategies that Won’t Leave You Breathless The biopharmaceutical industry invests billions of dollars annually into clinical research to address a range of debilitating respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and idiopathic pulmonary fibrosis, as well as non-respiratory indications with lung safety and disease progression endpoints. Clinical trials that collect respiratory endpoints are among the most expensive to conduct.1 In such a competitive environment where recruiting patients is increasingly difficult and costly, data from all patients need to actively contribute to the overall success of the study and development programme. Lung function data are regarded by regulators as a key biomarker for clinical efficacy. However, measurements are inherently variable, and this variability drives the need for greater patient numbers to demonstrate a treatment effect which increases the time and cost of development. This variability also reduces the ability to determine responder patients and can actively reduce the magnitude of observed treatment effect in some situations. There are many examples of excessive variability undermining study outcomes, which result in repeated pivotal programmes. At an earlier stage, high variability increases the chance of a type I or type II error and can impact go/no-go development decisions. The fact that routine clinical care does not require high-quality data, and that patients often find it easier to generate suboptimal data contributes to this problem. Attempts to reduce variability culminated in the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidance published by Miller in 2005.2 Despite this guidance, a post-hoc analysis of specialist respiratory tertiary care sites in Belgium revealed that 57% of data failed to meet core ATS/ERS standards and that the majority of respiratory technicians used the highest FEV1 data suggested by the spirometer, without critical appraisal.3 This level improves when equipment is standardised and sites are provided basic training at the study start. However, in a recent study, where approximately 3.3 million lung function assessments were analysed, approximately 11% of the tests submitted by investigators still had errors. When inappropriate test data were deselected and more appropriate test results were selected, the average change in FEV1 was approximately 112 mL4 (Figure 1).

Sources and Results of Variability Variability in lung function testing can originate from many areas. The improper performance of spirometry tests or the inclusion of patients who are unable to master the technique represents the largest source of variability, which can exceed 50% of the test value. This patient-based variability can preferentially occur at the start of any clinical research, as the patient is not sufficiently experienced at generating spirometry data. Suboptimal efforts can also (counterintuitively) inflate, rather than underestimate, lung function values. Improvements in patient technique due to practice can then actively reduce the lung function values, which counters the potential benefits from treatment and thus underestimates true treatment effect. Variability at any time point will increase the standard deviation of the treatment effect, which reduces statistical power and confounds the determination of a true mean treatment effect. A good example of this technique-based variation can be found in COPD patients. Within the young healthy lung, as forced expiration occurs, inter-attachments within the lung support the airways and hold these open, allowing the air to escape quickly. As the lung ages, there is a natural destruction of lung parenchyma, which impacts these attachments. This decline is accelerated with advancing pathology and increased levels of inflammation driven by infection or underlying abnormal immune responses as seen in asthma or COPD. In this altered state, the pressures placed on the lung compress the lung and start to collapse the airways. This results in a pressure-dependent collapse of the airways which restricts the flow of exhaled air. In this instance, a good effort will massively restrict the amount of forced exhaled air in one second (FEV1). A failure to exhale forcefully will reduce the level of pressure-dependent airway collapse and actually increase the FEV1. As patients do not like the experience of collapsing their airways and restricting their airflow, their technique is often poor at the start of a trial. Gradual improvement in technique will drive loss of FEV1. This process does not generate just acceptable or unacceptable data at two extremes but a continuum of effort-dependent collapse. It is possible for patients to generate repeatable but still suboptimal data and as such, even when the exhalation meets minimum standards established by the ATS/ERS criteria, it is possible to inflate FEV1 data twice the level seen within a normal treatment effect. A core technique to counter this issue is for sites to focus on the flow loop geometry for each patient to ensure that this is consistent between visits. To address variability within the data, it is necessary to adhere to few basic steps: 1) Assure Quality Before First Patient In Standardise devices. Standardising equipment across investigative sites minimises the variability originating from different equipment models. Sites use a variety of equipment for clinical use, resulting in an inability to determine the level of adherence to ATS/ERS minimum standards, sensor accuracy and calibration. Without standardisation, sites can adopt varying approaches to configuring

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Therapeutics devices and recording patient data; variability in test results will increase. Increased numbers of outliers will undermine trust in the data during regulatory review. Apply best practices. The most effective clinical trials follow ATS/ ERS standards as a baseline and then apply additional best practices to reduce other areas of variability that can influence data quality and reliability. These practices can include software workflow reinforcement for study protocols, checks for inclusion/exclusion criteria, alerts to highlight out-of-range values or data acceptability, and even reminders to check if patients have adhered to restrictions on highly-caffeinated drinks or tobacco prior to testing. Consistently train. The core objective for site training is the generation of higher-quality research-grade data. While it is possible to provide overread feedback based on deviation, this only allows the ability to select the best efforts based on data that has already been generated. New, more optimal data cannot be generated once the patient has left the site. Also, it is not possible to remove suboptimal data from the primary analysis in most studies. It is critical that sites understand what drives variability and actively manage the patient to ensure that the primary data generated is optimal for each patient visit. Effective education and training needs to move beyond hardware and software operation, so that sites understand how variability in data quality occurs and what the impact of this will be on the study outcome. Without this, sites are more likely to return to the standards followed in normal clinical practice. While training may add incremental time and expense to trial start-up, the benefits are potentially significant – a greater percentage of acceptable data can be collected, resulting in an array of downstream benefits. Require device proficiency testing. A proficiency verification step serves to assess the site staff’s core understanding of the equipment and data transfer process. Software and hardware should restrict access to those staff who have met these basic requirements. Because of patient consent issues, the certification process is normally performed on fellow research staff rather than patients with underlying pathology; therefore, certification does not ultimately test the suitability of staff to adequately test research patients. As a result, early critical assessment of the first patients analysed provides the best opportunity to assess competency and address remaining training issues. It is important to link each test procedure to a specified technician to drive optimal quality. Password control of spirometry systems does not prevent different technicians from progressing with testing once the initial sign-in process is complete. A fingerprint sensor with verification prior to each test is a quick and efficient way to allocate each test to a specific technician. Select sites based on past performance. Future site performance related to data quality can largely be predicted from past performance. Core data which look at the percentage of various QC grades in recent studies give a good indication around the overall level of proficiency of a specific site. More enhanced algorithms can be generated to use a combination of technical quality indicators along with behavioural and performance data that score a site’s historical performance. This can give an indication around both the quality of data and the core abilities of the site to meet recruitment and operational responsiveness targets. This evidence-based risk approach allows the implementation of mitigation strategies and the selection of sites that are most suited to specific study requirements. www.jforcs.com

2) Optimise Data Collection During the Study Enforce minimum acceptability standards. Minimum ATS/ ERS standards regulate equipment performance criteria and measurement procedures (e.g., environmental restrictions, patient position, instruction and coaching) to ensure reliability and consistency. Following these standards ensures that a minimum quality standard is reached. Moving beyond minimum data standards is possible if sites ensure that data is optimal for each patient. A core concept of this is the focus on flow loop geometry. The flow loop geometry represents the underlying lung pathophysiology and acts in some respects like a fingerprint for each patient. Flow loop geometry should not change between visits in most circumstances. Significant changes in flow loop geometry are normally driven by poor technique, which act as a marker for excessive variability. Sites should review the flow loop geometry prior to patient testing so that they start the session with an understanding of what the patient is capable of achieving. It is only then that techniquebased variability will be captured whilst a patient is still at site and there is time to influence the quality of data. In addition, any unexplained jumps in lung function values should be explored with an open question to the patient around any changes in their normal routine since the last assessment. This can often uncover issues which the patient has forgotten to mention, which allows for rescheduling of assessments, if appropriate. Conduct calibration checks. Many forms of equipment require calibration at the start of each test session to adjust measurements to ambient pressure humidity and temperature and to improve the measurement accuracy of the spirometers. The introduction of pre-calibrated sensors on spirometry devices can reduce site burden and remove potential variability based on poor calibration. These devices also offer the benefit of automated sensors that adjust for temperature, pressure and humidity conditions, further reducing variability and site burden. Perform ongoing best test review overread. Review by qualified and intra-/inter-reader variability tested respiratory specialists identifies noncompliant values to the ATS/ERS guidance and deselects them. This allows the selection of the highest technically acceptable effort, reducing the level of unacceptable data to 1-2%. Errors contribute to overall variability, reduce study power to show a mean drug effect and can potentially change the responder status of individual patients. 3) Centralise Data Analysis and Risk-Based Monitoring Perform centralised data quality review. Checking and correcting data against minimum ATS/ERS standards will drive improvements in variability and enable greater determination of the drug effect; however, levels of variability often remain that are not initially detected by focusing on each assessment in isolation. Review of changes in lung function data over time helps to validate the appropriateness of individual data points by comparing these with repeat measures. This process allows the assessor to consider what optimal data quality looks like for a patient and to discover transitions in lung function data that are biologically implausible. Review of outliers based on the transition from baseline parameters at each visit helps to identify potential errors with either the baseline data or subsequent test sessions. The magnitude of the outlier determination needs to focus on the likely drug effect being tested and the specific indication under assessment. Once outlier limits are set, any change in lung function above this level should Journal for Clinical Studies 37


Therapeutics

Figure 2: Comparison of Monthly Respiratory Data Quality in Two Studies

prompt a review of all test sessions regarding the transition in numerical parameters and flow loop geometry. This process identifies early detection of specific site issues and allows for early remedial action. Engage in quality risk management and risk-based monitoring. With new regulatory guidance, sponsors and CROs are increasingly engaging in quality risk management and risk-based monitoring (RBM) strategies for maximum programme quality and efficiencies.5 Studies show that RBM can reduce source data verification and monitoring costs, which account for an estimated 25–50% of overall trial costs.6,7 An effective risk management programme includes an endpoint-specific monitoring plan for the investigative site that assesses the initial protocol risks, needs and metrics and then analyses the endpoint data in near real time to identify potential data quality risks. Such a programme enables sponsors and CROs to proactively focus their resources on those sites that need support or retraining to enhance data quality. These centralised study data can also be integrated into electronic data capture (EDC) and other eClinical systems for enhanced trial oversight. Part of this approach requires the upfront determination of risk for each site and a variable approach to identify risk trends to allow intensification of oversight. Vendors with detailed site feasibility data allow historical quality metrics to be assessed for individual sites to help focus the initial risk assessment. Certification of site staff and bespoke training at study start permit some level of baseline risk determination. Central reporting of current and historical quality helps to identify outliers and determine the current risk of endpoint data generation. More focused training and oversight can be implemented and current or recent quality metrics can be compared with historical performance since trial onset. As an example, in Figure 2, two different respiratory studies are compared, one with active quality risk management to identify sites with poor data quality, and one with no active risk management. Data quality improved by 4% with enhanced oversight and retraining of targeted sites. Move from acceptable to optimal data Since the introduction of the combined guidance in 2005, the standardisation of spirometry systems and use of centralised overread services have significantly improved lung function quality and reduced variability. However, variability still exists with the minimum standards in the ATS/ERS criteria and can 38 Journal for Clinical Studies

reduce the ability to identify patients who respond to therapy. A move to optimal research-grade data can increase the determination of the true drug effect; however, focused training and proactive management are required to achieve optimal results. Conclusion Active management of data quality should reduce variability in the outcomes, producing greater confidence in the drug effect, greater ability to identify the true responders, faster drug development, enhanced potential for approval and reimbursement and potentially greater first-line drug use. Adhering to these three strategies will help sponsors cut the time and cost of their trials while improving data quality – and that may just give them the edge they need to gain a competitive advantage in this market. REFERENCES 1. https://aspe.hhs.gov/report/examination-clinical-trial-costsand-barriers-drug-development 2. https://www.thoracic.org/statements/resources/pfet/PFT2.pdf 3. Dieriks, B., Use of spirometry software in two major Belgium hospitals, European respiratory journal Vol28 S50 2006; 202S, P1215 4. https://www.ert.com/standards-risk-based-monitoringexecuting-successful-spirometry-trial/ 5. http://www.appliedclinicaltrialsonline.com/preparing-ich-e6r2-addendum-3-part-series-0 6. http://www.ncbi.nlm.nih.gov/pubmed/15864237 7. Redfearn S. Risk-Based monitoring slow to catch on with industry. CenterWatch Monthly, May 2012, Vol 19(5).

Phil Lake, PhD

Respiratory Solutions Architect, ERT Phil Lake has held a variety of roles in drug development for nearly 20 years, predominantly focused on respiratory trials. Prior to ERT, Phil held positions at SmithKline Beecham and GlaxoSmithKline where he worked on a number of anti-inflammatory agents, dual and triple combination therapies, monoclonal antibody studies, antiinfectives and some of the largest mechanistic studies looking at biomarkers within sputum and biopsy samples. For the last 10 years, he has concentrated extensively on rare respiratory diseases, including Cystic Fibrosis and Idiopathic Pulmonary Fibrosis, covering a variety of drug mechanisms and medical devices.

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Therapeutics

Clinical Development in Challenging Cancers: Primary Bone Sarcomas Primary bone sarcomas are cancers of mesenchymal, nonepithelial derivation, originating from bone cells or their precursors. As shown in Figure 1, the most common forms include osteosarcoma, chondrosarcoma, and Ewing sarcoma (EW) (35%, 25% and 16%, respectively)1. These are rare malignancies and account for less than 0.2% of all reported new cancer cases in adults2,3. They represent however, roughly 5% of all childhood cancers, with osteosarcoma accounting for 50% and EW for approximately 45% of primary cancers of the bone in children and young adults3. Chondrosarcoma, in contrast, is more commonly diagnosed in adults and typically occurs between the fifth and seventh decades of life.

Figure 1 – Primary Bone Sarcomas

Front-line therapy for these cancers consists of a combined approach of systemic chemotherapy and local treatment by surgery (osteosarcoma), and/or radiotherapy (EW)4,5,6. In fact, when compared with surgery alone, a multimodal approach in the treatment of high-grade osteosarcoma increases survival from only 10–20% to around 60%7,8,9. Standard treatment for chondrosarcomas, however, consists mainly of surgery, as these cancers are relatively resistant to both chemotherapy and radiation therapy10. Survival data obtained from the National Cancer Data Base of the American College of Surgeons suggest that the relative five-year survival rate is approximately 53.9%, 50.6%, and 75.2% for osteosarcomas, Ewing’s sarcoma and chondrosarcoma, respectivelyviii, as shown in Figure 2. For patients with poor response to chemotherapy and patients presenting metastatic disease, reported outcomes are far worse, with survival at <50% and <30% respectively12,13.

Figure 2 – Relative 5-Year Survival Rate 40 Journal for Clinical Studies

Treatment outcome for bone sarcomas has remained at a standstill over the last decade, though new treatment interventions have been successfully tested14. Prognosis for these patients has been closely linked to histological diagnoses of the cancers15. Since bone sarcomas are known to exhibit highly heterogenous histologic and molecular profiles, it would be unlikely that a single target treatment approach would be able to address all, or even a majority of patients16,17. An urgent need, therefore, arises for new and effective therapeutic strategies. Recent advances in the understanding of the genetic abnormalities that underscore the pathogenesis of these tumours have led to a genetic classification of sarcomas into two groups; tumours with recurrent molecular changes, including EW. These generally have tumour-specific chromosomal aberrations that result in the expression of an oncogenic chimeric transcription factor, or a coactivator for transcription. The second group consists of tumours with complex karyotypes and variable genetic alterations, and includes osteosarcomas18,19. Common genetic alterations include disturbances in cell-cycle genes such as p53, RB1, and INK4A19,20. Thus, for the two most common primary bone sarcomas, Ewing’s sarcoma and osteosarcoma, these pathways are expected to lead to identification of specific target genes that could represent novel treatment options for these tumours. Targeting of Oncogenic Pathways Inhibition of EWS-FLI1: Anti-IGF-1R Monoclonal Antibodies EWS-FLI1 is a fusion protein resulting from chromosomal translocations, expressed in EW tumour cells, and has been identified as an ideal target for specifically treating EW without affecting healthy cells21. In fact, decreased expression of EWSFLI1 has been shown to inhibit several molecular pathways: IGFR, PDGFR, VEGFR, SHH, among others22,23. Binding of IGF to its receptor IGF-1R leads to activation of the PI3K/Akt/mTOR pathways, with subsequent triggering of tumour growth and angiogenesis through augmented secretion of HIF-1α and VEGF24,25. In xenograft models of OS and EW, anti- IGF-1R targeted drugs have shown ant-tumour effects26,27, and several anti-IGF-1R monoclonal antibodies have been investigated in Phase I clinical studies in EW patients with relapsed or refractory disease, where subjects achieved stable disease28. R1507, an anti-IGF-1R monoclonal antibody, was administered to 115 patients with Ewing sarcoma family of tumours (ESFT) at a weekly dose of 9mg/kg for 109 patients, and 27 mg/kg every three weeks for six patients. For all patients, the overall response rate Volume 9 Issue 5


Therapeutics was 10% (95% CI, 4.9% to 16.5%). A single complete response and ten partial responses were also observed, with a median survival of 7.6 months (95% CI, 6 to 9.7 months)29. Figitumumab is another monoclonal antibody targeting IGF-1R studied in a Phase I trial that included 16 patients with EW. Two of the patients obtained objective response, one complete response, and one partial response30. Low response rates, however, have been observed for these agents, despite their promising potential. An explanation for this may be the development of alternate pathways for growth in these tumours. In their study on patients with progression following initial response to IGF-1R antibody, Thomas et al. observed an upregulation of p-Akt and p-m-TOR, with a subsequent response to combined IGF1R inhibition with m-TOR inhibitionxviii. This could imply that multiple pathways may need to be inactivated for more durable responses31,32. Strategies simultaneously targeting the IGF-1R/PI3K/AKT/ mTOR pathway have also been evaluated. A Phase I study of EW patients combining cixutumumab, an anti-IGF1-R antibody, and temsirolimus, an mTOR inhibitor, showed regression of the tumour of over 20% in five patients out of 17. Complete response was also observed in one out of six patients, who had previously developed resistance to a different IGF-1R inhibitor antibody33. Targeting the Bone Microenvironment Bone sarcomas are typically characterised by an imbalance in the physiological turn-over of the bone tissue, mediated between osteoclasts (bone resorption) and osteoblasts (synthesis of new bone). The majority of bone sarcomas secrete osteoclast-stimulating cytokines, which promote bone resorption by osteoclasts. RANK and its ligand RANKL are key mediators of osteoclast differentiation, function, and survival. Bisphosphonates, such as zoledronic acid, not only induce osteoclast apoptosis but also inhibit osteosarcoma, Ewing’s sarcoma and chondrosarcoma cell proliferation in vitro and tumour progression in vivo34. Based on preclinical data for the anti-tumour effect of zoledronate in osteosarcoma, zoledronic acid, in combination with 1st-line methotrexate or adriamycin/platinum/ifosfamidebased CT, was studied in the French randomised Phase III trial, OS200635. However, after enrolment of 318 patients, the study was discontinued due to futility, as this treatment regimen did not improve event-free survival at three years [63.4% (55.2-70.9) for the control group and 57.1% (48.8–65.0) for the zoledronate arm]35. Immune Therapies The rationale for the clinical development of immunotherapies for primary bone sarcomas is strongly supported by the clinical results obtained by the use of cytokine therapies in other forms of sarcoma. In OS patients, the most significant prognostic factor is the development of lung metastases, which, more often than not, are already present at the time of diagnosis36,37. Efforts are currently being made to target the programmed cell death checkpoint pathway (PD-1/PD-L1) in OS patients with lung metestases38. Nivolumab, a PD-1 inhibitor, appears to be a promising therapeutic agent in this regard, and several trials are currently investigating this in patients with non-small cell lung cancer (NSCLC), both in monotherapy and in combination with chemotherapeutic agents. However, recently published reports from an open-label Phase III study (CheckMate 026 study) indicate that nivolumab was not www.jforcs.com

able to extend progression-free survival in patients with NSCLC39. Although nivolumab presented a more favourable safety profile, median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% CI, 0.91 to 1.45; P=0.25). Median overall survival reported for nivolumab was 14.4 months versus 13.2 months for chemotherapy (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30)39. Conclusions In the wake of the unsatisfactory results obtained to date, it appears that the therapies described above have been unable to demonstrate significant improvements in overall survival, or any distinct clinical advantage for these patients. Particularly discouraging are the incongruences between results obtained in clinical studies and preclinical data that prompt these trials. Given the rarity of these tumours, greater efforts should perhaps be directed at collaborative studies between institutions, particularly with regard to the molecular profiling of tumours for identification of tumour markers, as these represent an emerging approach in guiding treatment decisions. REFERENCES 1. Howard D Dorfman and Bogdan Czerniak, “Bone Cancers,” Cancer 75, no. S1 (1995): 203–10. 2. National Cancer Intelligence Network (NCIN), “Bone Sarcoma: Incidence and Survival Rates in England. Tumours Diagnosed between 1985 and 2009.,” October 2012 Data Briefing, accessed July 14, 2017, http://www.ncin.org.uk/publications/data_briefings/bone_sarcoma_ incidence_and_survival_rates_in_england_october_2012. 3. C.A Stiller, A.W Craft, and I Corazziari, “Survival of Children with Bone Sarcoma in Europe since 1978,” European Journal of Cancer 37, no. 6 (n.d.): 760–66, doi:10.1016/S0959-8049(01)00004-1. 4. Ruth Ladenstein et al., “Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial,” Journal of Clinical Oncology 28, no. 20 (2010): 3284–91, doi:10.1200/JCO.2009.22.9864. 5. K. Scotlandi, P. Picci, and H. Hovar, “Targeted Therapies in Bone Sarcomas,” Current Cancer Drug Targets 9, no. 7 (November 1, 2009): 843–53, doi:10.2174/156800909789760410. 6. Nathalie Gaspar et al., “Bone Sarcomas: From Biology to Targeted Therapies,” Sarcoma 2012 (2012): 301975, doi:10.1155/2012/301975. 7. Craig Gerrand et al., “UK Guidelines for the Management of Bone Sarcomas,” Clinical Sarcoma Research 6, no. 1 (May 4, 2016): 7, doi:10.1186/s13569-016-0047-1. 8. Robert J Grimer, “Surgical Options for Children with Osteosarcoma,” The Lancet Oncology 6, no. 2 (n.d.): 85–92, doi:10.1016/S1470-2045(05)01734-1. 9. Ian J. Lewis et al., “Improvement in Histologic Response But Not Survival in Osteosarcoma Patients Treated With Intensified Chemotherapy: A Randomized Phase III Trial of the European Osteosarcoma Intergroup,” JNCI: Journal of the National Cancer Institute 99, no. 2 (January 17, 2007): 112–28, doi:10.1093/jnci/djk015. 10. Hans Gelderblom et al., The Clinical Approach Towards Chondrosarcoma, vol. 13, 2008, doi:10.1634/theoncologist.2007-0237. 11. Timothy A Damron, William G Ward, and Andrew Stewart, “Osteosarcoma, Chondrosarcoma, and Ewing’s Sarcoma: National Cancer Data Base Report.,” Clinical Orthopaedics and Related Research 459 (2007): 40–47. 12. Gaetano Bacci et al., “Prognostic Factors for Osteosarcoma of the Extremity Treated with Neoadjuvant Chemotherapy,” Cancer 106, no. 5 (2006): 1154–61. 13. P A Meyers et al., “Chemotherapy for Nonmetastatic Osteogenic Sarcoma: The Memorial Sloan-Kettering Experience.,” Journal of Clinical Oncology 10, no. 1 (January 1, 1992): 5–15, doi:10.1200/ JCO.1992.10.1.5. Journal for Clinical Studies 41


Therapeutics 14. Annemiek M. van Maldegem et al., “Comprehensive Analysis of Published Phase I/II Clinical Trials between 1990-2010 in Osteosarcoma and Ewing Sarcoma Confirms Limited Outcomes and Need for Translational Investment,” Clinical Sarcoma Research 2, no. 1 (January 27, 2012): 5, doi:10.1186/2045-3329-2-5. 15. Bacci et al., “Prognostic Factors for Osteosarcoma of the Extremity Treated with Neoadjuvant Chemotherapy.” 16. Dominique Heymann and Francoise Redini, “Bone Sarcomas: Pathogenesis and New Therapeutic Approaches,” IBMS BoneKEy 8, no. 9 (September 2011): 402–14, doi:10.1138/20110531. 17. David S Geller and Richard Gorlick, “Osteosarcoma: A Review of Diagnosis, Management, and Treatment Strategies,” Clin Adv Hematol Oncol 8, no. 10 (2010): 705–18. 18. Lee J. Helman and Paul Meltzer, “Mechanisms of Sarcoma Development,” Nat Rev Cancer 3, no. 9 (September 2003): 685–94, doi:10.1038/nrc1168. 19. Katia Scotlandi et al., “Insulin-like Growth Factor I Receptor-Mediated Circuit in Ewing’s Sarcoma/Peripheral Neuroectodermal Tumor: A Possible Therapeutic Target,” Cancer Research 56, no. 20 (1996): 4570–4574. 20. Jay S Wunder et al., “Opportunities for Improving the Therapeutic Ratio for Patients with Sarcoma,” The Lancet Oncology 8, no. 6 (June 1, 2007): 513–24, doi:10.1016/S1470-2045(07)70169-9. 21. Gaspar et al., “Bone Sarcomas: From Biology to Targeted Therapies.” 22. Hayriye V. Erkizan, Vladimir N. Uversky, and Jeffrey A. Toretsky, “Oncogenic Partnerships: EWS-FLI1 Protein Interactions Initiate Key Pathways of Ewing’s Sarcoma,” Clinical Cancer Research 16, no. 16 (2010): 4077–4083, doi:10.1158/1078-0432. CCR-09-2261. 23. Scotlandi et al., “Insulin-like Growth Factor I Receptor-Mediated Circuit in Ewing’s Sarcoma/Peripheral Neuroectodermal Tumor: A Possible Therapeutic Target.” 24. Erkizan, Uversky, and Toretsky, “Oncogenic Partnerships: EWS-FLI1 Protein Interactions Initiate Key Pathways of Ewing’s Sarcoma.” 25. W. D. Tap et al., “AMG 479 in Relapsed or Refractory Ewing’s Family Tumors (EFT) or Desmoplastic Small Round Cell Tumors (DSRCT): Phase II Results.,” Journal of Clinical Oncology 28, no. 15_suppl (May 20, 2010): 10001–10001, doi:10.1200/jco.2010.28.15_ suppl.10001. 26. Maria C. Manara et al., “Preclinical In Vivo Study of New Insulin-Like Growth Factor-I Receptor–Specific Inhibitor in Ewing’s Sarcoma,” Clinical Cancer Research 13, no. 4 (2007): 1322–1330, doi:10.1158/10780432. CCR-06-1518. 27. E. Anders Kolb et al., “Initial Testing (Stage 1) of a Monoclonal Antibody (SCH 717454) against the IGF-1 Receptor by the Pediatric Preclinical Testing Program,” Pediatric Blood & Cancer 50, no. 6 (2008): 1190–1197, doi:10.1002/pbc.21450. 28. David Olmos et al., “Safety, Pharmacokinetics, and Preliminary Activity of the Anti-IGF-1R Antibody Figitumumab (CP-751,871) in Patients with Sarcoma and Ewing’s Sarcoma: A Phase 1 Expansion Cohort Study,” The Lancet Oncology 11, no. 2 (n.d.): 129–35, doi:10.1016/S14702045(09)70354-7. 29. Alberto S. Pappo et al., “R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study,” Journal of Clinical Oncology 29, no. 34 (December 1, 2011): 4541–47, doi:10.1200/ JCO.2010.34.0000. 30. Heribert Juergens et al., “Preliminary Efficacy of the Anti-Insulin–Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma,” Journal of Clinical Oncology 29, no. 34 (December 1, 2011): 4534–40, doi:10.1200/JCO.2010.33.0670. 31. David Thomas et al., “Denosumab in Patients with Giant-Cell Tumour of Bone: An Open-Label, Phase 2 Study,” The Lancet Oncology 11, no. 3 (n.d.): 275–80, doi:10.1016/S1470-2045(10)70010-3. 32. Charles Forscher, Monica Mita, and Robert Figlin, “Targeted Therapy for Sarcomas,” Biologics: Targets & Therapy 8 (2014): 91–105, doi:10.2147/ BTT.S26555. 42 Journal for Clinical Studies

33. Aung Naing et al., “Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors,” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 18, no. 9 (May 1, 2012): 10.1158/1078-0432.CCR-120061, doi:10.1158/1078-0432. CCR-12-0061. 34. Heymann and Redini, “Bone Sarcomas: Pathogenesis and New Therapeutic Approaches.” 35. Sophie Piperno-Neumann et al., “Zoledronate in Combination with Chemotherapy and Surgery to Treat Osteosarcoma (OS2006): A Randomised, Multicentre, Open-Label, Phase 3 Trial,” The Lancet Oncology 17, no. 8 (n.d.): 1070–80, doi:10.1016/S1470-2045(16)30096-1. 36. Yulia A. Savitskaya et al., “Serum Tumor Markers in Pediatric Osteosarcoma: A Summary Review,” Clinical Sarcoma Research 2, no. 1 (March 23, 2012): 9, doi:10.1186/2045-3329-2-9. 37. Geller and Gorlick, “Osteosarcoma: A Review of Diagnosis, Management, and Treatment Strategies.” 38. Pooja M. Dhupkar et al., “Immune Modulation through Targeting PD-1/PDL-1 Signaling Pathway for the Treatment of Osteosarcoma Lung Metastastasis,” Journal for ImmunoTherapy of Cancer 3, no. 2 (November 4, 2015): P218, doi:10.1186/2051-1426-3-S2-P218. 39. David P. Carbone et al., “First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer,” New England Journal of Medicine 376, no. 25 (June 21, 2017): 2415–26, doi:10.1056/NEJMoa1613493.

Kelechi K. Olu MD, MSc. Clinical Research Physician, Europital. Pharmaceutical physician and clinical epidemiologist, with considerable experience in clinical research, including various stages of clinical drug development and post-marketing surveillance. Experienced in medical monitoring of clinical trials, therapeutic areas include immunology, rheumatology, oncology, hematology. Email: info@europital.com

Vijayanand Rajendran MD, Senior Clinical Research Physician, Europital. Qualified physician with over ten years of clinical and research experience. Hands-on experience in safety monitoring of Phase I-IV trials in a variety of therapeutic areas including oncology, haematology, respiratory, gastroenterology and the musculo-skeletal system. Email: info@europital.com

Mohamed El Malt MD, PhD, Chief Medical Officer, Europital. Oncology surgeon and expert scientific researcher with more than 32 years of experience as a medical doctor, including 18 years of clinical research and drug development experience in academic medical centres, pharma and CRO as investigator, project leader and medical director, in addition to 15 years of experience as general and oncology surgeon. Email:info@europital.com

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Journal for Clinical Studies 43


Technology

Enrolment Compliance and Study Data

The current concept of clinical trial conduct is a balance between benefits from treatment (efficacy) and risks that this treatment may have (risk), which is defined as a “risk-based monitoring” approach. This approach combines a thorough assessment of factors that have the potential to influence safety of study subjects and integrity of study data, with a centralised review of patients’ data1. However, being a standard practice of clinical trials, the regulations do not give a definite answer how to conduct this monitoring. It is recommended to design a study-specific monitoring plan tailored to specific risks of a particular trial1. Such a plan includes factors that are critical for the study conduct. There are several factors in a successful clinical trial, but we consider two of them to be key – enrolment within the projected timelines and collection of reliable data. The estimation of the accrual period of a clinical trial has dramatic practical, scientific, and economic consequences2. The major players in the estimation of the accrual period are the feasibility group and project management. The fact that a study has enrolled patients within the expected timelines does not automatically mean success. To produce quality and scientifically valid data, the study population has to be consistent with the protocol criteria, and those already enrolled should be followed up for a minimal required time period to meet the study endpoints3. The preferred approach to statistical analysis is intent-to-treat (ITT) analysis, which includes all enrolled patients in the groups to which they were assigned, regardless of their adherence with the entry criteria, compliance with the protocol requirements (protocol deviations), premature withdrawal, and availability for a follow-up 4. ITT is considered the standard statistical approach in randomised clinical trials. The wide acceptance of the approach is due to its main advantage: as the data are analysed, exactly as randomised, no bias or confounding – either from known or unknown sources – is likely to occur. Disadvantages of the ITT analysis are: inclusion of ineligible patients (e.g. enrolled by mistake), patients who were discontinued prior to the initiation of study treatment, patients with treatment non-compliance, and those who had been lost to follow-up data and thus the study endpoints were evaluated with a significant degree of approximation. To eliminate these issues, a per-protocol (PP) analysis is used. It guarantees relatively clean data for the analysis, but sacrifices the above-mentioned property of the ITT approach – bias due to selective exclusion of patients from the analysis becomes a concern. Even considering that FDA recommends use of ITT as the primary statistical analysis, the situations of a significant difference of ITT vs PP groups may make interpretation of study results less obvious. If, for example, a significant number of patients with violation of inclusion and/ or exclusion criteria is enrolled, and they will be excluded from the PP analysis, a study could be insufficiently powered to demonstrate a statistically significant difference between treatment groups, and it will subsequently raise a question as to whether the correct population had been chosen for the study5. In addition, in noninferiority trials, PP statistical analysis plays a more important role 6. 44 Journal for Clinical Studies

As stated, one of the major components of a “homogenous” ITT population is enrolment of patients who fit the protocol inclusion and exclusion criteria. Herein, we discuss the role of the medical monitor in the process of enrolment of eligible patients. The primary responsibility in enrolling only eligible patients lies with the investigator. The main reasons for enrolment of ineligible patients are misinterpretation of the study protocol requirements, “overuse” of medical judgement vs the protocol criteria, and substitution of key screening procedures due to unavailability of the ones required by the protocol, as well as the human factor, or mistakes. To minimise the chance of erroneous enrolment, the industry-wide accepted practice is review of patient eligibility prior to randomisation, which is done either by a CRO, or a sponsoring company medical monitor. Based on our experience, we highly recommend using a pre-randomisation eligibility review and approval procedure, and such an approach ensures enrolment of 98-100% of compliant patients. One may ask – why not always 100%? This is mostly due to the study sites providing incomplete information. We do not consider intentional sending of wrong, or fraudulent information – this is a topic for a separate talk – but situations when investigators underestimate a patient’s condition or laboratory data. Our standard approach is to develop a study-specific eligibility checklist, which includes the key inclusion and exclusion criteria, and equally important – a detailed step-by-step procedure, which indicates the exact steps, responsible persons, communication pathways and timelines, but still is not too long and does not take too much time to fill in. Such a procedure is normally a part of the study-specific medical monitoring plan, and all members of the clinical team, as well as the study sites, receive comprehensive training in this procedure. It is obvious that the contents of the eligibility checklist will vary depending on the therapeutic area, screening procedures, and design of the study protocol. It is important to take into account that a protocol can have up to several dozen inclusion and exclusion criteria, all having equal importance for the decision, as if a subject does not meet a single criterion, s/he is considered not eligible and should be a screen failure. However, the difference exists and is determined by the objectivity of assessment and complexity of these criteria. We can distinguish the following groups of eligibility criteria: 1. Objective criteria, which could be easily verified and confirmed with applicable administrative, clinical, and laboratory data: demographics (age and gender), criteria related to the disease under study (clinical signs, pathology/histology diagnosis), various laboratory and additional data (e.g. radiology), and laboratory parameters. 2. Subjective criteria that frequently include a statement about an investigator’s clinical judgement, most typically include wording such as “medical or psychiatric condition that, in the opinion of the investigator, would make study drug administration hazardous”. 3. Historical criteria – medical history, previous and concomitant Volume 9 Issue 5


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Journal for Clinical Studies 45


Technology medications. Quality of this data depends on the availability of information at the time of screening, and there might be situations when additional, disqualifying information is discovered after the patient had already started study treatment. When elaborating a study-specific eligibility checklist, objective criteria should be recorded in a precise manner, rather than simply checking a “yes/no” checkbox: complete diagnosis, laboratory values (with normal ranges!), ECG or cardiac ultrasound parameters, etc. In some situations, especially those involving pathological and immunohistochemistry diagnosis, it may be reasonable to make the corresponding report a part of the eligibility package. Even if inclusion criteria are obvious and seem straightforward, for example, solid tumours’ protocols usually have a requirement of at least one measurable lesion per RECIST 1.1 criteria, or revised response criteria for malignant lymphomas in lymphoma trials. There may still be a mistake in characteristics of nodal and extranodal lesions (different axes are used for defining if the lesion is measurable), besides which, patients may be stratified in accordance with the number or/and location of nodal and extra-nodal lesions, which also require verification. A typical workflow of eligibility verification at PSI includes the following steps: 1. After completion of all screening procedures, the site will provide completed eligibility review checklist and copies of local screening laboratory and other reports, if applicable, to the PSI Medical Monitor at Study Code_MedicalMonitor@psi-cro.com. Such an email domain includes all medical monitors assigned to the study, project manager, senior clinical research associates (CRAs), and the project coordinator. 2. The PSI medical monitor will review the documents to ensure the patient meets all inclusion and does not meet any exclusion criteria. 3. If the PSI MM considers that additional data are necessary to confirm a patient’s eligibility, or the submitted documents require clarification, s/he will contact the site as soon as possible and ask for clarification, or request additional data. 4. The timelines for eligibility review and confirmation are established on a study-by-study basis, but typically will not exceed 48 hours. It could be done on an expedited basis (within 1–2 hours), if requested by the study site in a case of an urgent randomisation, but it will require a perfectly prepared eligibility package and availability of the site team for resolution of medical monitor’s queries, if necessary. 5. Once the PSI medical monitor confirms the patient’s eligibility, s/he will sign the appropriate section of the eligibility review checklist and send to the study site and/or the clinical team for randomisation processing. 6. Original eligibility checklist with investigator’s signature, and a copy of the checklist with medical monitor’s signature and approval are filed in the on-site site file. All correspondence with the site, PSI clinical team, and the sponsor is filed by the responsible member of the PSI team in the appropriate section of the project master file. Our experience of eligibility review in 30 Phase II-III randomised clinical trials within the last five years allowed us to identify the following categories of mistakes made by clinical investigators. 1.

Incorrect assessment of the previous treatment of the disease under study; most typically in oncology trials it will be miscalculation of previous lines of chemotherapy, incorrect understanding of refractory disease definition, and the previous treatment of the disease that does not fit the protocol criteria.

46 Journal for Clinical Studies

In a Phase III study of Diffuse Large B-Cell Lymphoma, patients who progressed within 12 weeks after completion of the first line of chemotherapy were not allowed to enter the study, as well as those considered to have primary refractory disease. A patient was receiving the first line chemotherapy and was diagnosed with stable disease at re-staging after the 4th cycle. Due to that, he was switched to another regimen. Progression of lymphoma was revealed significantly after 12 weeks after initiation of the first line of chemotherapy. The investigator considered the patient eligible, based on more than 12 weeks from start of therapy to progression. However, the patient was rejected by the medical monitor, based on the primary refractory condition, which is defined as no response to the initial therapy, and includes not only progression of disease, but also stable disease7. And actually, lack of objective response led to administration of the second line of chemotherapy. 2. Use of unallowed previous, or concomitant medications. The majority of study protocols have at least one medicationbased exclusion criterion. It could be exclusion of certain medications (e.g. prior pemetrexed may be not allowed in NSCLC study), or a group pf drugs (e.g. prior and concomitant 5-HT3 receptors antagonists in study of chemotherapy-induced nausea and vomiting (CINV)), or exclusion is based on metabolic pathways (e.g. inhibitors of CYP3A4 or CYP2D6 enzymes). Obviously, tracking the last category of prohibited medications is more complicated and, to make it easier, as much as possible a comprehensive list of medications under question should be either included in the study protocol as an appendix, or provided to study sites as a separate document. Another matter to consider is that previous therapies for the disease under study are easier to identify and handle, as these medications are normally thoroughly tracked, and a mistake may occur as a result of an oversight. A typical example – in Phase II NSCLC study topoisomerase I inhibitors were not allowed prior to randomisation and while on study. The eligibility review form indicated that the patient had recently received topotecan, and this patient was not enrolled. A more complex situation is with concomitant medications. Needless to say, almost 100% of patients enrolled in oncology clinical trials use concomitant medications. The study sites should be instructed to methodically and accurately collect information about all concomitant medications used by the study subject within the protocol-specified timelines; for example, during the past 30 or 60 days. Particular attention should be paid to dietary supplements and over-the-counter medications, as sometimes patients do not mention them, especially when these are common medications to treat allergy or common cold signs. 3. Screening procedures performed not in accordance with the protocol. From our experience, radiology assessments are the most frequently violated or misinterpreted at the screening stage. They include: incorrect radiology modality, performing procedure without contrasting in situations where the contrast is required, incomplete scanning, and misinterpretation of the lesions’ dimensions. 4. Overuse of medical judgement, especially with the criteria that do not foresee any possible deviations. There are a number of inclusion criteria that require an investigator’s medical judgement per se, for example certain medical conditions, if not considered clinically significant by the investigator. Such criteria may need additional discussion between medical monitor and the investigator, considering the term of “judgement”. Volume 9 Issue 5


Technology All these inconsistences had been identified by medical monitors during review of eligibility, and these patients were screened out. At the same time, we have to admit that even a detailed and thorough review of eligibility does not guarantee 100% compliance. The main reason is unavailability of the complete set of information at the time of review. It may occur either by mistake, due to limited timelines, or, again, through misinterpretation of the protocol by the study investigator. Sometimes such situations are not straightforward. In a Phase II study of advanced gastric and oesophageal carcinoma, “intolerance to chemotherapy used in this study” was exclusionary. When the medical monitor was reviewing the clinical database, as a part of a periodic review, he revealed that the patient who had been considered eligible after a thorough review of eligibility was started on the study at a dose decreased by 30%. The investigator explained that the patient “was not fit enough to receive a full dose of chemotherapy”. As a result, the patient was treated with a significantly reduced dose and died due to disease progression four months after initiation of the study therapy. This is below a median survival for this disease (nine months). The primary objective of the study was progression-free survival, and secondary objectives – overall survival and survival rate at 12 months. Thus, enrolment of this non-eligible patient had a potential to influence study objectives and statistical analysis. Conclusion Eligibility review is an essential part of risk-based monitoring and allows mitigation of enrolling non-eligible patients, ensuring safety of study subjects and providing reliable study data. We recommend using eligibility review, performed by CRO or/and sponsors’ medical monitors, in every clinical trial. Depending on the complexity of inclusion and exclusion criteria and screening procedures, it may be either a simple check of investigators’ statements confirming eligibility, or a detailed review of the eligibility packet, which may include pathology, radiology, laboratory and other reports. The process of eligibility review should be described in minor detail in the study-specific medical monitoring plan, and a review of patients’ eligibility is to be performed by qualified medical monitors. REFERENCE 1. Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations – a risk-based approach to monitoring. Aug 2015. Available from: https://www.fda.gov/ downloads/Drugs/Guidances/UCM269919.pdf 2. Carter R, Sonne S, Brady K. Practical considerations for estimating clinical trial accrual periods: application to a multi-center effectiveness study. BMC Medical Research Methodology. 5, 11 (2005) DOI: 10.1186/1471-2288-5-11 3. Gupta S. Intention-to-treat concept: a review. Perspect Clin Res. 2, 109-112 (2011) DOI: 10.4103/2229-3485.83221 4. Fisher I, Dixon D, Herson J et al. Intention to treat in clinical trials. In: Peace K. editor. Statistical issues in drug research and development. New York: Marcel Dekker; 1990, 331-350 5. Ranganathan P, Pramesh C, Aggarwal R. Common pitfalls in statistical analysis: intention-to-treat versus per-protocol analysis. Perspect Clin Res. 7, 144-146 (2016) DOI: 10.4104/22293485.184823 6. Schumi J, Wittes J. Through the looking glass: understanding non-inferiority. Trials. 12, 106 (2011) DOI: 10.1186/1745-6215-12106 7. B-cell lymphomas, NCCN guideline, version 3. 2017 – March 27, 2017. Available from: https://www.nccn.org/professionals/ physician_gls/pdf/b-cell.pdf www.jforcs.com

Maxim Kosov MD, PhD, is Director, Medical Monitoring & Consulting at PSI CRO AG (USA). He is a board-certified physician in paediatrics and anaesthesiology and intensive care. Maxim has more than 20 years of experience in both the medical and clinical research industry and has experience across a broad range of indications. He is also the author/co-author of more than 40 publications. Email: maxim.kosov@psi-cro.com

Tatiana Dumpis MD, is Medical Officer, Medical Monitoring & Consulting at PSI CRO AG (Russia). She is a board-certified physician in oncology and anaesthesiology and intensive care. Tatiana has more than 20 years of experience in the medical industry and 10 years of experience in clinical research as investigator and medical monitor. She is a Fellow, Russian Society of Clinical Oncologists (RUSSCO), and Fellow, European Society of Medical Oncologists (ESMO). Email: tatiana.dumpis@psi-cro.com

Alexey Maximovich MS, is Group Leader, Biostatistics at PSI CRO AG (Russia). He is an expert in data analysis in clinical trials with over eight years of experience in the clinical research industry and has experience across a broad range of indications and analysis techniques. He is also the author/co-author of 11 publications. Email: alexey.maximovich@psi-cro.com

John Riefler MD, MS, is Director, Medical Monitoring & Consulting at PSI CRO AG (USA). His MS is in microbiology and his clinical training is in internal medicine and infectious diseases. He is a Fellow, Infectious Disease Society of America (FIDSA) and Fellow, American Heart Association (FAHA). He has 27 years’ experience in clinical development in big pharma and CROs. He is also the author/ co-author of 22 publications. Email: john.riefler@psi-cro.com

Maxim Belotserkovskiy MD, PhD, MBA is Head of Medical Affairs at PSI CRO AG. He is a boardcertified physician in internal medicine, rheumatology, anaesthesiology and intensive care, and haemodialysis, and a Certified Associate Professor of Pathological Physiology. He has more than 20 years of experience in clinical research as investigator and clinical research professional. He is also the author/co-author of more than 130 publications. Email: maxim.belotserkovsky@psi-cro.com

Journal for Clinical Studies 47


Technology

Driving by Data: A Faster, Better Road to Market The clinical development path is rife with complexity that can stall or stop a drug’s journey to market. Trial timelines are lengthening, partly due to the increasing complexity of study protocols that also produce higher costs, lower enrolment rates, and time-consuming, unplanned protocol amendments. While there is no single transformative solution to streamline clinical development, biopharmaceutical companies can take common sense steps to mitigate risks, control costs, improve efficiency, and gain competitive advantage. Clinical trials are taking longer to complete, imposing unwelcome costs on companies and delaying the delivery of drugs to patients who need them. An analysis of industry benchmark data showed that studies initiated between 2014–2016 had an average cycle time (start-up through treatment phase) of 75.1 weeks. That’s a 37% increase from the average of 41.5 weeks for trials launched between 2003 and 2005.1 A disproportionate amount of the overall timeline for a clinical trial increasingly is spent in the start-up stage due to several factors: • The volume of studies in complex indications is rising – these protocols typically include more procedures, more data collection, and longer set-up times (by sites and at the regulatory level); • Selecting sites has become increasingly challenging and timeconsuming due to an increased number of competitor trials and fast-changing local laws and regulatory requirements; • Getting contracts and budgets negotiated is difficult because increasingly complex protocols place higher demands on investigative sites, yet companies still need to control costs; and • The prevalence of targeted therapies, genomic medicine and orphan disease drugs means more trials are seeking smaller subsets of patients, requiring sophisticated outreach and logistics. Then there are self-inflicted problems that contribute to the trend of longer trials and higher costs. In the planning stages, too many companies are choosing countries, sites, or investigators based on anecdotal evidence rather than objective quality and performance data. Companies too often set up trials with independent operations teams that focus on their own spreadsheets, to-do lists, and deadlines, with little sense of the big picture and insufficient coordination. For example, a team charged with getting site contracts signed will operate separately from a team tasked with site initiations, yet these two activities cannot be effectively pursued independently. Protocols may be scientifically rigorous, but are frequently not vetted at investigational sites for practicality, nor designed with the patient in mind. Once committed, protocol design errors can affect a study’s entire life-cycle from start-up to patient recruitment to 48 Journal for Clinical Studies

data analysis. As design flaws reveal themselves, protocols undergo multiple amendments, increasing costs, lengthening timelines, aggravating sites, and generating reams of paperwork. To improve the conduct of trials from study feasibility and planning through investigator and patient recruitment and through to completion, companies need integrated trial management methodologies and enabling systems. While there is no single transformative solution to these problems, the following process improvements can help companies steer a faster, straighter path to market. Optimise for Practical, Patient-centric Protocol Design To be operationally sound, a protocol must account for projected recruitment rates, clinical demands at sites, and the realities of patients’ lives. Reviewing available data sources can ensure a protocol defines a realistically large population, and increases the chance of successful recruitment. For example, electronic health records (EHRs) and/ or recruitment rates reported in previous studies of similar patient populations can guide adjustments to inclusion/exclusion criteria (within the bounds of the scientific rationale for the study) to maximise the available population. Not every therapeutic area lends itself to this type of analysis – for example, it won’t help when entry criteria require extensive use of unstructured data in the notes section (e.g., tumour type) rather than straightforward structured data like blood pressure measurement. However, for the right protocol and with the right data source, a comprehensive review can inform changes that save time and prevent costly protocol amendments. Gathering feedback from investigational sites, medical experts and patients also will optimise study design and data collection. The driving factor behind many slow start-ups is a protocol that investigators don’t like, yet sponsors rarely conduct a systematic assessment of investigator interest until the site identification phase of a study, which is too late. A simple fix is administering pre-study surveys to assess investigators’ motivation and potential barriers to participation. Too often, the impact of study participation on patients is poorly researched. A patient burden analysis can highlight problems from a patient’s perspective and identify protocols with overly long or demanding procedures. The average study collects over one million data points, yet less than a third of those are used in assessing the primary endpoint. Protocols must be pruned to collect what’s needed without placing needless burdens on patients and investigators. Use Data More Effectively to Select Countries and Sites Picking the right countries and sites is crucial to trial success because it can impact the setup time, recruitment rates, data quality, and regulatory viability of the results. Traditionally, countries have been selected based on anecdote and past experience. But we now have access to data to make more informed decisions, as well as Volume 9 Issue 5


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Technology sophisticated technologies to visualise and interpret that data. It’s critical to consider all relevant financial, clinical, medical, and regulatory risks and benefits before finalising a country list. For example, differences between countries in standard of care, transportation infrastructure, availability of advanced equipment, or regulatory paperwork requirements can throw off trial timelines in disastrous fashion. Data-based due diligence can mitigate these risks. Gathering country-specific data on multiple parameters allows companies to analyse the most important factors and produce an optimised country footprint. Sometimes, factors such as strategic marketing considerations will take precedence over a purely data-driven list of optimal countries (e.g., a country may need to be included because it’s required for launching a product at a targeted reference price). But that will work only if most other countries on your list have been chosen wisely, and if discussions about additions/deletions occur in the context of objective data. Even in cases where it’s too late to modify a pre-specified country list, data can help quantify the magnitude of risks and suggest mitigations. After selecting countries, trial planners must identify and choose investigative sites. Again, without comprehensive and upto-date site intelligence, selection is often subjective, which can lead to omitting or rejecting sites that may be key to reaching the right patients. Rushing to start up sites that then perform poorly is of little value. Each site should be evaluated on: 1) its ability to produce quality data (i.e., data that stands up to verification); and 2) its ability to recruit patients at the target rate. These two data points cannot be decoupled, as high enrolment means nothing if the data are poor. Patient recruitment in previous studies is a simple measure and a good indicator of future performance, yet there is remarkably little solid data available, since many organisations are surprisingly poor at maintaining records, let alone seeking external sources that could enhance the reliability of their own data. Prior performance in start-up can be measured by clinical site agreement (CSA) and site regulatory package (SRP) cycle times (among other metrics), and are credible indicators of future performance. Even after a site has made the short list of preferred sites, further due diligence is required. Final scoring and tiering of sites should be based on (among other things) the commitment of lead investigators, local institutional review board (IRB) procedures and suitability (for example, an otherwise wonderful site may not be well-suited for a trial studying an ultra-rare genetic disease). Again, technology allows us to be much more scientific and systematic about the way we continue to score sites so we can take some of the softer decision-making out of the process. Leveraging site knowledge and relationships is key. Sites with strong ties not only prioritise and expedite their own internal start-up processes, but they can advocate to speed processing and administrative aspects of local start-up within their respective countries. Strong site relationships can shave about 10% off study start-up (SSU) cycle times and boost patient recruitment by as much as 50% versus traditional sites. While no country or site selection algorithm is perfect, companies that invest in data-driven methodologies can reap significant downstream time- and cost-savings. 50 Journal for Clinical Studies

Translate Strategies Into Integrated Operational Plans Securing early study milestones is critical to the overall success of a study. The key drivers of successful study start-up are strategy, integrated planning, and coordinated, cross-functional execution. To accelerate study launch, there needs to be an immediate mobilisation of resources, aligning and coordinating the translation of the strategy into coordinated operational plans (not just for startup, but for the entire life-cycle of the project). Continuity of strategy is key; ensuring consistent application of the strategy throughout all planning, alignment to the same goals and ultimately, successful and timely study launch and quality-bydesign-based project life-cycle management. Drive Start-up and Manage Activities to the Critical Path There are many moving parts to a clinical trial, and during start-up the number and interdependency of these increase exponentially. Traditionally siloed teams can’t accurately prioritise interdependent activities (e.g., furiously chasing a site for a CSA when IRB approval is not expected for six weeks). Prioritising tasks and anticipating bottlenecks boosts efficiency because small setbacks or narrowly missed deadlines at the site level can snowball into big delays for the entire study. Aligning the discrete (and often concurrent) activities of start-up and managing them on a critical path is mission-critical to efficient and expedited start-up. Industry benchmarking data suggest that application of critical path management techniques can cut up to 21% off industry average cycle times for final protocol approval (FPA) to first site initiated (FSI), and 12% off FPA to last site initiated (LSI) overall.2 Like air-traffic control, centralised oversight and risk management decreases confusion and promotes consistency, especially if there are multiple partners and vendors involved, which is common in large, multinational trials. Using effective and disciplined critical path management, we were recently able to achieve significant acceleration of start-up cycle times for a large, multinational Phase IIIb study in oncology (4000 patients, 150 sites, 19 countries). FSI was accomplished in only three weeks from time of site selection, with clinical site agreements (CSAs) fully executed in just two weeks. The first subjects were screened within five weeks of site initiation. Monitor Metrics and Risk Indicators in Real Time Tracking the workflow of a multinational clinical trial requires sophisticated, intelligent, automated systems that can detect problems early and guide users to mitigate risks. Dynamic analytics based on real-time data should be used to drive informed decisions. Supplying teams with technology to visualise, identify, and manage risks according to their criticality helps ensure that everyone is on the same roadmap to meet milestones and targets. Leading metrics, risk indicators, and first-time-quality flags are all essential to successful proactive management of start-up and operational execution. There are many types of leading metrics (including quality, cycle times, and budgets) that are available in real time and trackable via systems software that can alert you when a trial is not proceeding as it should. Visualisation, analytics, and reporting solutions should enable management of start-up tasks from the macro (i.e., portfolio, project, country) to the micro (i.e., site, investigator) level. Aided by technology, teams can drill into daily management of activities on the critical path to deliver site activation targets. It is essential that technology solutions enable the user to quickly identify the Volume 9 Issue 5


Technology fierce, getting them right the first time can be the difference between success and failure – for new drugs and for companies. Inefficiencies and mismanagement cause delays, which can add significant incremental costs, loss of competitive edge for the product, and frustrate both sites and patients. The costs of investing in feasibility studies, protocol optimisation, start-up strategies, and disciplined critical path management are negligible compared to the expense and risk of delays and rework. Proper planning, management, and execution can help companies avoid these delays and costs, while easing the burden on sites and patients and maintaining the competitive advantage their science confers. specific area of a bottleneck (whether on a study/process level or a specific site progress level). Studies using fit-for-purpose tools have delivered up to a 30% reduction in cycle time from FPA to site initiation visit (SIV). If a problem with an ongoing trial has been identified and characterized with real-time analytics, it can be fixed before it derails the study. The intervention required may be small and targeted, or large and comprehensive, but either way a problem tackled early is easier to fix than one that has festered. Engage With and Educate Patients Recruiting patients is the most important part of getting a trial completed on time, yet, by necessity, it’s often pursued by investigators and sites on a part-time basis. In the rush of optimism, and the frenzy of planning for a new study, patient recruitment and retention tactics are often an afterthought, sometimes viewed as an unnecessary expense – until enrolment lags, jeopardising the study. Therefore, companies must commit to supporting sites in educating and engaging patients. The number one reason only about 10% of patients take part in clinical studies is a lack of awareness about their options, according to the ECRI Institute’s definitive study.3 Other reasons can include cumbersome informed consent procedures and inconvenient study designs with unrealistic data collection demands. Targeted, patient-centric interventions can accelerate and sustain enrolment in a trial, allowing sponsors to complete studies in timely fashion even in a shifting therapeutic and reimbursement landscape. The key is that such interventions are a planned part of the overall study strategy and not a bolted-on response to a failing study. For example, a recent Phase III oncology trial faced an enrolment slump because halfway through the trial a competing product was approved for national reimbursement and quickly became the gold-standard treatment. Patients, naturally, were less motivated to enroll in a research protocol. The solution was threefold: 1) An outreach programme to better engage patient advocacy groups (PAGs) through social media and to leverage the PAG-run disease education programmes at the point of care; 2) a minor protocol amendment, devised by statisticians, to loosen the trials’ overly strict prescription for follow-up visits and enable sites to adhere to a more realistic, practical schedule; and 3) bolstering physician referral systems by establishing relationships with key opinion leaders in the field. Better Planning and Start-up Prevents Costly Inefficiencies & Delays Clinical trials are staggeringly expensive, and with designs growing more complex, and competition for sites and patients increasingly www.jforcs.com

REFERENCES 1. KMR Group. (2017). Proprietary data on Main Cycle Times, Q42016-2017 (All Phases). [online] Available at: https:// kmrgroup.com [Accessed 8 Aug. 2017]. 2. KMR Group. (2017). Proprietary data. [online] Available at: https://kmrgroup.com [Accessed 8 Aug. 2017]. 3. ECRI Institute (2002). Patients’ Reasons for Participation in Clinical Trials and Effect of Trial Participation on Patient Outcomes. ECRI Evidence Report. Plymouth Meeting, PA: ECRI Health Technology Assessment Information Service.

Paul Evans Corporate Vice President Global Site Solutions, PAREXEL International Dr Paul Evans has 25+ years of industry experience in global CROs and SMOs, a broad range of therapeutic experience, and is an acknowledged industry expert on patient recruitment methodologies and site management. Dr Evans serves on the Board of the Association of Clinical Research Professionals. Email: paul.evans@parexel.com

Abigaile Betteridge Director, Global Study Start-up Office, PAREXEL International Abigaile Betteridge has 15+ years of experience in the pharmaceutical/CRO industry, holding varied roles in clinical development, from planning/design through marketing authorisation. As Director of the Global Study Start-up at PAREXEL, she is focused on the optimisation of planning and execution through lean processes, innovative technologies, and critical path management. Email: abigaile.betteridge@parexel.com

Jeetendra Rao Director, Business Analytics & Opti-mization, PAREXEL International Jeetendra Rao has 15+ years of experience across technology and CRO industry, transforming business performance through analytics, process improvement and holistic enterprise-wide data-driven management. In his current role, he is focused on driving faster start-up times through real-time analytics and dynamic risk identification along the start-up critical path. Email: jeetendra. rao @parexel.com

Journal for Clinical Studies 51


Technology

Early-stage Development, Xcelodose & Clinical Phases Following the acquisition of Penn Pharma, PCI’s comprehensive pharmaceutical development and clinical trial service includes the production of drug in capsule (DIC) using Xcelodose® technology, utilising the latest equipment for the processing of potent molecules. The pharmaceutical industry’s ongoing demand to shorten drug development times, thus making significant cost savings, is driving technological advances forward at the same time as there are major changes happening in the research and development of high-value, and often potent, speciality medicines. Currently, more than half of research projects from pre-clinical to late clinical development fall into this category. In the past, pharmaceutical companies have competed on the grounds of product innovation. Taking into account the high cost of R&D, coupled with the economic and political pressures for better end product pricing, finding ways to reduce overall costs becomes critical. But it is not just cost which is at the forefront of development – the size, timescales and complexity of clinical trials are all putting pressure on the industry to shorten the drug development process. Research and development within the industry has the potential to transform patient care across a wide range of diseases through the use of an ever-increasing range of new chemical entities (NCEs). Since the supply and cost of these new chemical entities are of high value, the importance of accelerating the supply of drug product into the clinic for initial Phase I, first-in-man clinical trials becomes crucial.

costs do not take into account the cost of delivering the actual clinical trial. The ability of pharmaceutical companies to remain commercially competitive depends on transforming new chemical entities into clinical products and on to commercial launch. Filling an active pharmaceutical ingredient (API) directly into a capsule is potentially the quickest and preferred option for entering earlyphase clinical trials. Manufacturing drug in capsules (DIC) can reduce time and financial investment at the early stage of the drug development process. It can minimise the use of costly API and reduce the amount of formulation and analytical development necessary to support an investigation new drug (IND) application or investigational medicinal product dossier (IMPD). As such, the timeframe for completion to early-phase clinical manufacture can be reduced to approximately four to six months

But the traditional product development route of a formulated solid oral drug for Phase I clinical trials involves a range of complex activities. These include the initial compatibility studies; analytical method development; prototype development; short-term stability; process/formulation refinement; Phase I method validation; stability manufacture and finally clinical manufacture. This process can take in excess of nine months to complete and with significant cost for product development alone – and such

52 Journal for Clinical Studies

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CIDP, the innovative clinical partner for your success story Our global presence provides you with a strategic link to a wide and competent network of investigators for conducting trials, and meet your project objectives. • Project Management • Medical Writing • Monitoring • Pharmacovigilance • Clinical Supplies Management • Regulatory Affairs • Biostatistics & Data Management

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Journal for Clinical Studies 53


Technology – potentially halving the time taken by the traditional product development route. The associated cost savings can be as much as 70 per cent, though once again this is dependent on the cost of the API and does not include the cost of the actual clinical trial. However, as the biological activity and the specificity of the API increases, the dosage strengths are decreasing, making the APIs more potent in terms of occupational handling for drug product manufacture.

The new technology ensures safety and prevents operator exposure to potent products by the installation of a Xceloprotect isolator. The high levels of containment afforded by this equipment ensures an occupational exposure limit (OEL) down to ˂0.1µg/m3 over an eight-hour time weighted average, meeting the intended regulations for Safebridge 3 and 4 applications.

Therefore it is not suitable to use methods of manufacture such as hand filling, semi-automatic filling and traditional automatic encapsulation for the accelerated development pathway of DIC for low dosage strengths. Such processes may also lead to inconsistent capsule filling, and are often time-consuming and inefficient in terms of cost.

“By involving our experts early in the strategic development of a client’s new product, we can assist in optimising the process, ensuring that regulatory hurdles are minimised and that the most efficient routes to clinic are delivered.”

Automated powder precision dosing at very low powder fill weights, less than 50mg, was not possible until recently. Manual hand filling using human operators was very time-consuming, requiring an enormous amount of concentration to accurately weigh such low fill weights. Xcelodose® technology was first introduced into PCI in 2010 with the installation of the Xcelodose® 120S – a semi-automated process. This required capsules to be manually separated and loaded into the dial plate; filling was automatic and acceptable capsules would be manually capped and closed. In December 2015, PCI invested in the latest Xcelodose® 600S microdosing system. This new technology has the capability to fill amounts as low as 100 µg at speeds of more than 600 capsules an hour, and is fully automated and controlled by a programmable logic control (PMC) system. The system does away with the need for initial formulation screening and associated stability testing, enabling faster times to first-in-man, and informs the key go/no-go decision point of Phase I clinical studies for the development of new molecules. Capsules are loaded into the feed hopper and a dispense head is selected and fitted on to the system. Drug powder is placed into the dispense head, or the operator can use the integral high throughput unit for longer runs and greater fill weights. Once product batch data is entered into the control PMC, the system auto handles and fills the capsules, separating and then realigning the base and cap before closure. The capsules are then checked for length and sorted automatically. The fully programmable system provides exceptional levels of accuracy and precision. There is very little waste of expensive drug product and batch production is recorded, allowing traceability of samples that meet GMP requirements. As the industry continues to focus on products to treat more specialist disease areas, the trend will be towards the development of more potent, expensive molecules, putting even greater pressure on the need for greater cost-effectiveness and shorter development and production timescales. There is a distinct lack of early toxicity data available when initiating the DIC process. Potent compound development therefore requires a focus on safety through the use of contained processing. Potent compounds include drugs aimed at oncology, immunosuppressants, antivirals and opioid-based analgesics. www.jforcs.com

David O’Connell, PCI’s Director of Scientific Affairs, said:

All new project enquiries are based on the principles of lean manufacture, and follow a process which examines safety, quality, delivery and cost (SQDC). An initial questionnaire is issued to potential clients to assist with this process. Only when all elements of this process are fulfilled will a proposal be prepared and sent to the client. If a project is subsequently awarded, a second questionnaire is completed to further inform the process, following which each molecule is awarded a ‘potent passport’. During the production cycle, all information is constantly reviewed and updated during the product development and clinical trial lifecycle. During the process, health and safety is a primary driver; great attention is given to on-site security and safety with four levels of secure access to the containment facility, with only qualified staff being permitted in the production unit. With the pharmaceutical industry targeting more specialist niche medicines with ever-increasing potency, PCI is able to offer clients a state-of-the-art facility and the latest contained technology, adhering to industry guidelines for the processing of potent molecules, delivering contained manufacturing which offers speed-to-market of the highest quality.

David O’Connell Director of Scientific Affairs at PCI Pharma Services, an integrated full-service provider expertly delivering a seamless transition from development to commercialisation. After graduating from Glasgow Caledonian University with a Bachelor of Science degree in applied bioscience, David spent seven years as a Supervisory Scientist working for Aptuit in Edinburgh, before moving to Penn Pharma as Head of Formulation Development in 2009. Here he played a vital part in the design of the potent Contained Manufacturing Facility (CMF), which won the ISPE Facility of the Year award for Facility Integration (2014). In 2013, David took on the role of Director, Pharmaceutical Development at the PCI site in Tredegar, South Wales. In his current role, David aids clients with formulation development, technical transfer and scale-up of solid oral, oral liquid and semi-solid products for clinical trials and/or commercialisation. Email: sales@pciservices.com

Journal for Clinical Studies 54


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Clinical Supplies

Seeing Beyond the Label: Transforming the Management of Customer Materials Integration and increased automation are transforming the way life sciences companies manage much of their operational and regulatory information. So it seems odd that labelling and packaging content – so critical to market acceptance and patient safety – remains subject to very separate, manual processes, leaving organisations open to unacceptably high risk of error as well as considerable inefficiency. There must be a better way, says AMPLEXOR’s Romuald Braun As long as product labelling is treated as a distinct, manuallydriven process, life sciences organisations will continue to leave themselves open to the risk, not to mention a level of inefficiency they can ill afford. Mislabelling is one of the leading causes of costly product recall,1 and a particularly frustrating one given that it is so easily preventable. So it is probably no bad thing that increasingly strict regulatory requirements and the imminence of IDMP are causing regulatory and quality teams to review their processes and systems for managing content. It was in this context that labelling management came up as a prominent topic at AMPLEXOR’s recent annual customer conference. The Bigger Picture As life sciences organisations start to think more laterally about regulatory information and greater efficiency in how they respond to new demands, they are beginning to realise that the only real way to manage this in a sustainable way is by creating and drawing from a definitive master data repository that is capable of supporting multiple applications. Instead of starting from scratch each time there is new content (such as new labelling) to create, regulatory teams and those responsible can simply call up approved content from a central resource. This approach becomes a natural one as organisations move towards a more holistic, next-generation regulatory/product information management strategy. This is the vision advocated by Steve Gens, founder of Gens & Associates, one of the leading authorities on regulatory information management (RIM). He maintains that RIM should be as wide-ranging in scope as possible, encompassing dossier management, submission planning and tracking as well as manufacturing, change control, safety reporting, master data management, and labelling and document management. As long as such activities take place separately, each served by standalone systems and processes, companies risk repeatedly reinventing the wheel and introducing inconsistencies with each new content preparation task. If a company has procured systems for each distinct process from a series of different vendors, integration can be an issue and data’s dominion may be unclear: which is the authoritative, correct version of content and how is this determined and controlled? 56 Journal for Clinical Studies

Do it Once and Do it Well Next-generation RIM needs to facilitate a seamless, reliable end-toend process – from data/content collection to submission tracking and reporting. To further maximise the benefits, companies should be extending this same systematic process of content management to all important product data across a drug’s lifecycle. If this, rather than a targeted application of the data, becomes the core resource, it becomes possible to derive maximum efficiencies each time that content is repurposed for a particular use case. So ideally, any master data management initiative should start with a product master data object model, of which regulatory intelligence is a part. The regulatory factors may not fit generic system data fields, being the proprietary IP of each company. But if the information is structured, it can still be reflected in the main product information system, contributing to that holistic, 360-degree resource which caters for all information needs. Combining product master data with regulatory intelligence makes it possible to automate more processes – including labelling management. Suddenly more becomes viable, and the need for heavy manual work is reduced each time there is a new contentrelated requirement. In the next-generation scenario, whether the result is new labelling or an IDMP-related submission, the output is ultimately just an expression of the company’s product data, in a particular format. Taking a master data/complete product profile approach means all of the correct content for accurate, compliant labelling can be called up quickly and easily for the given use. In addition to ingredients and manufacture information, it should be possible to call up detail for all authorised medicinal products alongside all the respective countries’ procedures, health authority organisation information and marketing authorisation programmes and processes. Labelling processes, change requests, sequences and templates should all be possible to manage in a clear and structured way. Intelligent Grouping of Common Content Assets Proper provision for labelling, to reduce risk and improve efficiency, should include the ability to select approved content elements as self-contained label ‘objects’ or assets. These might include the name of a medicinal product or its clinical particulars, pharmaceutical particulars or pharmaceutical form. Some elements might be market-specific; others could be global/core content. But using an object-based master data management approach, grouping fields becomes very easy to do, linking components as appropriate to the various applications – for example a particular artwork, or at a global level the company core data sheet or the core package insert. All of these fuller objects are referenced but the components are sourced from master data. Volume 9 Issue 5


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Clinical Supplies The clever part, where content is linked logically using metadata, is that by selecting one object it becomes possible to see at a glance the relationships to all the other objects, and therefore the knockon effect of any changes to the content. So the impact and risk assessment of any changes becomes a natural part of the design. When content ‘fragments’ are used in several places in several documents, the master data and object-based approach means that if something fundamental needs to be changed, the ripple effect of those changes can be seen at a glance and the changes automatically reflected wherever this is needed, with full traceability. So, for instance, the user might create the fragment name of a medicinal product once and then re-use it in multiple documents. As this is reflected in the master data, it can be referenced by other documents. Each element is managed in the same way teams manage documents already, and creating the labelling structure is similar to the way teams create a submissions structure. It is a virtual document with all the respective sections: listed are the core company data sheet, a cover page, a table of contents and the name of the medicinal product, below which are the text fragments. The real leap is that those authorised to do so can now alter labelling elements fragments in a virtual document environment, and whole steps can be automated because the correct data will be applied automatically. Preparation is Everything Once all of the necessary text elements have been input into the structure, it’s then just a case of deciding what to do. Similar to publishing, the submission structure is created independently from the published output. In this case, it’s possible to transform the content to the desired format according to rules that have been pre-set. An ability to preview the document is desirable too, for instance as a complete PDF. The underlying enabler is the data-centric, object-oriented model, which allows labels and related documents to be created and amended using approved master data. Automated creation of labelling documents becomes something teams can do with confidence. And where regulatory intelligence is also reflected in the system, label creation can be done in accordance with the specific country requirements. By seeing the bigger picture around data management, life sciences firms open themselves to a range of new possibilities – to reduce complexity, cost and risk, while improving productivity, accuracy and speed. Reducing complexity begins with reducing the number of systems in use for different tasks, the number of interfaces and, as a consequence, the number of manual interactions (and associated risk factors, and inefficiencies – i.e. as it becomes easier to re-use approved content and automate the editing and creation of new materials). It goes without saying that there need to be important safeguards, controls and checks – especially where affiliates are part of the process. But ideally these checks will be built in to the core system, ensuring compliance and building confidence and, as an extension of this, user acceptance. It has taken time to get there but quantifiable simplification and de-risking of labelling management is now within reach in life sciences, a day many across the industry have been greatly anticipating because of the many practical challenges it can now overcome with a palpable ROI. REFERENCES 1. Characteristics of FDA drug recalls: A 30-month analysis, US National Library of Medicine/National Institutes of Health, 2016: https://www.ncbi.nlm.nih.gov/pubmed/26843501 58 Journal for Clinical Studies

When Labelling Lets Companies Down The rules around pharma labelling are becoming stricter all the time, as authorities internationally strive to improve patient safety and increase the burden of responsibility placed on drug companies. The European Medicine Agency’s Good Practice Guide on Risk Minimisation and Prevention of Medication Errors provides two pages of guidance on the information that must appear and where, the recommended use of language, and colour. One estimate suggests that up to 25% of all medication errors are attributed to name confusion and 33% to packaging and labelling confusion. Where companies make errors which could affect patient safety, the cost to manufacturers in product recalls, lost revenue and market confidence can be substantial. Yet year after year, labelling errors feature as the reason for numerous product recalls. Among those most recently listed on the FDA drug recall web pages are Astrazeneca’s physician samples of BRILINTA (ticagrelor) 90mg tablets, which actually contained another medicine; Truxton Inc’s Amitriptyline HCL Tablets, USP 50mg and Phenobarbital Tablets, USP 15mg, 30mg, 60mg, 100mg, which were subject to a ‘labelling mixup’; Impax Laboratories Inc’s Lamotrigine, removed from the market due to ‘incorrect labelling of blister cards’. Translations/provisions for the special requirements of other countries or regions are a common cause of labelling issues, too. Keeping track of the different requirements for each market can be an onerous task, especially given the frequency with which these are reviewed, updated and expanded. The precise wording, meaning and other factors such as use of colours, fonts and their sizes, the position and prominence of warnings and safety symbols, are likely to be subject to strict controls or recommended guidance which will affect the acceptance of a product or its vulnerability to recall in a given market. And of course, the issues may not end with the cost of the product recall. Drug recalls may also trigger a range of expensive product liability claims, especially if there is a chance that patient safety was put at risk due to inadequate warnings or errors contained in the packaging or labelling information. Country-by-country requirements are listed here: https://uk.practicallaw.thomsonreuters.com/Browse/Home/ International/LifesciencesGlobalGuide?transitionType= Default&contextData=(sc.Default)

Romuald Braun Vice President Strategy, Life Sciences, AMPLEXOR. Since 1992, Romuald has worked in roles related to compliance, document management and content management in the life sciences industry. Romuald has taken roles on the client side and in consulting, in delivery, in sales, in project roles and in line responsibility. He has also worked in client server and in cloud environments, in both Europe and in the US. Romuald holds a Master’s degree in Drug Regulatory Affairs, in addition to his Engineer diploma in Data Technology. Email: romuald.braun@amplexor.com

Volume 9 Issue 5


PATIENTS ARE TAKING A MORE ACTIVE ROLE THAN EVER IN THE CARE THEY RECEIVE

IN THE AGE OF INFORMATION, PATIENTS ARE NO LONGER SATISFIED WITH TAKING A BACK SEAT

www.patientprimary.com


Special Section

Patient-Centricity: A Progressive Prescription for Modern Healthcare A revolution is happening in the healthcare industry. Societal pressure to improve our health, technological advances, and market forces are all driving forward a novel patient-centric approach to healthcare: that is, putting the needs of the patient first and designing services or solutions around them. As such, modern pharmaceutical organisations are becoming increasingly engaged in dialogue with patients at every twist and turn of their treatment journeys, from beginning to end. Listening to the patient’s voice is increasingly helpful to assigning added value to new drugs, providing healthcare decisionmakers such as sponsors, regulators, payers and physicians with rich real-world data (RWD) that traditional clinical trials alone cannot provide. This patient-generated RWD feeds into a wider real world evidence (RWE) base, which has the potential to generate significant ROI for pharmaceutical companies in major areas across the product lifecycle. Despite the substantial benefits to patient care and the valuable insights for regulatory and reimbursement decisions, adoption of patient-centric approaches in the biopharmaceutical industry has been unexpectedly low. One of the key barriers to success is the burden that RWD capture places on both program sponsors and patients, as well as the perceived costs and logistical difficulties involved with implementing such an approach. New technological advances are promising to overcome these challenges, emphasising that innovative solutions must be developed and implemented to combat barriers to success. As the ultimate end consumer of new medicines, the patient’s voice must be heard in order to progress patient-centric healthcare decisionmaking and disease management. Patient-Centricity: What Is it and Why Is it Important? Healthcare stakeholders are currently converging on the idea of patient-centricity, which involves improving the lives of patients by acquiring a deeper understanding of their specific diseases, treatment experiences, requirements and priorities to enhance the research and development of biopharmaceutical products and disease management. It’s now becoming essential for the biopharmaceutical industry to partner with patients throughout the entire product lifecycle – including discovery, research, development, distribution, and access to medicines – to bring about outcomes that are meaningful to patients, foster innovation, and support the development of novel therapeutics. Although we currently lack a clear definition of patient-centricity, since its emergence there have been concerted efforts to formalise one common definition. Based on collaborative input from key stakeholders, including patients, healthcare providers and payers, 60 Journal for Clinical Studies

it has recently been suggested that patient-centricity should be defined as: “Putting the patient first in an open and sustained engagement of the patient to respectfully and compassionately achieve the best experience and outcome for that person and their family.”1 Patient-centricity means that the traditional approach of physicians and pharma deciding what is best for the patient is becoming obsolete. Instead, informed, technology-driven patients are becoming more involved — and empowered — in managing their own health and well-being, with the internet opening up a wealth of information and community engagement. Patients can now educate themselves about their illnesses, find the best practitioners, and play a direct role in improving their health. This approach can potentially create self-propagating benefits in every segment of the healthcare system, such as improving patient health, reducing costs to payers, informing reimbursement and regulatory decisions, and ensuring that clinical trials are safe and effective. For example, patient-centric initiatives can improve treatment compliance2 boost satisfaction in patientphysician interactions 3 and secure profitability for pharmaceutical companies.4 The Importance of Patient Voice in Healthcare A crucial aspect of a patient-centric approach is listening to the patient’s voice throughout their treatment journey to obtain robust RWD that can be used to inform healthcare initiatives. Indeed, as a “listening ear” in dialogue with patients, stakeholders can quickly and easily obtain information about patients’ treatment journeys that can be incorporated into patient engagement initiatives and healthcare decision-making. This information includes outcomes that are important to patients; reasons why patients make certain decisions, such as why they adhere to treatments; practical input into future study design and successful study execution; and patients’ experiences of illness and care that physicians and program coordinators would not otherwise hear about. Patient-centric services and solutions can then be built around this patient-generated RWD to improve patients’ experiences and outcomes. As such, pharma companies are increasingly using technologies to run contests and competitions to gather ideas and feedback on trial designs, informed consent forms (ICFs) and protocols. Seeking input from patients on their understanding of protocols can help to build patient-friendly protocols and ICFs to improve patient retention, which is key to the success of the overall project5. Moreover, companies are actively using social listening techniques to analyse what patients are discussing online to drive better patient participation and relationships.5 The FDA released draft guidance on social media usage in June 2014, reflecting its growing importance in the industry.6 Volume 9 Issue 5


Special Section As this patient-generated RWD feeds into a wider RWE base, this information not only informs healthcare services and solutions, but it can also advise key processes throughout a new product’s lifecycle from drug development to launch, and finally to the inmarket stage. As a result, companies that invest in collecting patient-generated RWD are starting to enjoy significant commercial benefits from the RWE that it generates. For example, Quintiles IMS estimates that RWE could produce up to $1 billion for a top-10 pharmaceutical product when it is applied collectively in six key areas: informing clinical development, demonstrating product safety and value, facilitating initial product pricing and market access, enabling productivity and cost-savings, improving product launch planning and tracking, and enhancing commercial spend effectiveness (Figure 1).7 Overall, patient-generated RWD can inform patient-centric approaches to not only enhance healthcare decisions, reduce costs to payers and improve future clinical studies and product profitability, but it can also ensure that patients receive effective treatments while living their normal everyday lives. However, capturing robust patient-generated RWD is far from straightforward, and is one challenge that could hinder the success of patient-centric initiatives. Dismantling the Barriers to Patient-Centricity According to Quintiles IMS, only a third of companies who have

attempted patient-centric initiatives have reported any success, citing their inability to uncover real patient insights as one of four key barriers to success8. One challenge of capturing robust patient-generated RWD is the use of paper data recording methods, which can create logistical and administrative problems, introduce the likelihood of human error, and place significant burden on patients, which in turn generates ethical and regulatory concerns. A way to overcome these problems is to implement new technological solutions, such as electronic data capture platforms, that give patients the opportunity to input data and engage in community discussions on their own devices. Not only are methods like these easily integrated into patients’ everyday lives to give them a more positive, autonomous experience and to encourage their continued participation, but they can better ensure the integrity of the data and reduce many of the manual logistical tasks for program organisers that paper recording methods demand. They also enable patient interactions – with other patients as well as with healthcare practitioners and programme sponsors – which can enhance health outcomes, better educate patients, and facilitate discussions among patients and care providers. Other innovative solutions like these must therefore be developed to dismantle all the barriers to implementing successful patient-centric healthcare. This includes clearer measures of success

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SAFETY AND VALUE DEMONSTRATION

RWE PRODUCTIVITY AND COST SAVINGS

LAUNCH PLANNING AND TRACKING

CLINICAL DEVELOPMENT

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Journal for Clinical Studies 61


Special Section and ROI; establishing patient-centric organisational structure and processes, and forming guidelines on privacy protection and other regulations. Continuing the push toward patient-centricity in healthcare therefore depends on several changes taking place. This includes recognising companies for their patient-centric efforts, which requires measuring outcomes that matter most to patients (rather than to pharma and clinicians) and rewarding companies if they are successful. Agreement on a clear definition of patient-centricity is also important to generating common understanding, actions and outcomes. These changes rely on continued public policy initiatives to improve health services and solutions, such as public contributions into future study design and structure; carefully listening to the patient’s voice to gain insight and feedback on new treatments in real-world settings, and enabling individual participation, so that the patients themselves regain control of their own healthcare. Conclusion Patient-centric healthcare means putting patients’ needs first, so listening to the patient’s voice is essential to realising the full potential of this approach. Capturing patient-generated RWD can bring considerable benefits to the healthcare industry, such as improving patient care, reducing costs to payers, informing reimbursement and regulatory decisions, and enhancing clinical study design and execution. Uncovering real patient insights can be difficult, and can consequently hinder the success of companies’ patient-centric initiatives. Therefore, technological solutions must be implemented to ensure that today’s ‘digital patient’ can easily generate robust RWD that can be efficiently captured and used. Indeed, solutions must be put in place to dismantle all the barriers to patient-centric healthcare. In this way, we can gain an increased understanding of what matters most to the patient while they live their normal lives, and apply those learnings across the product lifecycle – to drug discovery and development to distribution from new medicines. Patient-centricity makes patients more accountable for their own health and well-being, ensuring their autonomy and personal involvement in their own healthcare. To reap the many rewards of such an approach and continue to improve patient outcomes, healthcare providers and pharmaceutical companies must ensure that patients’ voices are not only heard, but acted upon and integrated into future healthcare practices. REFERENCES 1. Yeoman, G., Furlong, P., Seres, M. et al. (2017). Defining patient centricity with patients for patients and caregivers: a collaborative endeavour. Health IT, systems and process innovations, 3, 76-84. 2. Cross, N., Hanna, D., Stafkey-Mailey, D., Eaddy, M. and Suryavanshi., M. (2016). Impact of a patient-centered support program on treatment compliance among patients with multiple myeloma. Blood, 128, 2389. 3. October, T.W., Hinds, P.S., Wang, J., Dizon, Z., Cheng, Y.I. and Roter, D.L. (2016). Parent satisfaction with communication is associated with physicians’ patient-centered communication patterns during family conferences. Pediatric Critical Care Medicine, 17, 490-497. 4. Burmann, C., Meurer, J. and Kanitz, C. (2011). Customer centricity as a key to success for pharma. Journal of Medical Marketing: 62 Journal for Clinical Studies

Device, Diagnostic and Pharmaceutical Marketing, 11, 49-59. 5. Sharma, N.S. (2015). Patient centric approach for clinical trials: Current trends and new initiatives. Perspectives in Clinical Research, 6, 134-138. 6. https://www.fda.gov/aboutfda/centersoffices/ officeofmedicalproductsandtobacco/cder/ucm397791.htm 7. Hughes, B., Kessler, M. and McDonell, A. (2014). Breaking New Ground with RWE: How Some Pharmacos are Poised to Realize a $1 Billion Opportunity. A White Paper from IMS Health, pp. 1-24. Accessed 26/05/2017: www.imshealth.com:90/files/web/ Global/Services/Services%20TL/rwes_breaking_new_ground_ d10.pdf. 8. Quintile IMS. The idea of Patient Centricity is becoming a significant strategic focus across all healthcare stakeholders. But what does this term really mean? What does success look like? And are life science companies succeeding? Accessed 26/05/2017: https://www.imshealth.com/files/web/Global/ Services/Strategy%20&%20Management%20Consulting/ Consulting%20Group%20TL/IMS_Patient_Centricity.pdf 

Tim Davis Vice President, Digital Patient Solutions, ERT Tim is responsible for ERT’s Digital Patient initiative, which focuses on product development on phase IV clinical development through commercialization. Tim has more than 20 years of experience identifying new markets in the clinical technology industry, including mobile health, branded prescription product services, and patient social networks. Tim was CEO and Co-founder of Exco InTouch, acquired by ERT in 2016, and previously held positions at CRF, Procter and Gamble Pharmaceuticals and PAREXEL.

Volume 9 Issue 5


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Journal for Clinical Studies 63


Special Section

Collaborating with Patients for Better Trial Design 88% of American patients would be willing to share their personal information online for the sake of improving care and treatment options.1 Modern patients are taking control of their own healthcare, from sharing information with one another to approaching industry organisations with their concerns. Thomas P Sellers, Senior Director of Patient Advocacy at The Takeda Oncology Company outlined the emergence of the modern patient-consumer, eager to learn about and contribute to the processes that affect their healthcare: “In the past, industry viewed doctors as the customer and patients as the subjects, but that has begun to change with the emergence of patient thought leaders in the community who could talk about the science and about clinical trial designs.”2 Thomas P Sellers As a result of readily available online healthcare information and united patient advocacy groups, patients are taking a more active role than ever in the care they receive, researching treatments and weighing up the pros and cons of trial participation for themselves. Support online and offline allows patients to reach out to one another, compare their experiences, and recommend or raise concerns about trials. In order to appeal to this new wave of patient-consumers, clinical trial organisers are having to reconsider key components of trial design to reflect these concerns and ensure adequate enrolment. Rather than simply monitoring patients’ potential barriers to participation, however, the time has come to go straight to the source and involve patients in trial design from the very beginning. Why Should Patients be Incorporated? In the age of information, patients are no longer satisfied with taking a back seat, demanding a more active role in not only their own healthcare decisions, but in the research process itself. Far from being a hindrance to the trial process, this active patient-partner role can provide a significant incentive for trial involvement. 56% of patients participating in a retinal health trial at the Sydney Eye Hospital claimed that they joined due to a wish to contribute to medical science, compared to just 10% who joined because they wanted free treatment.3 As major stakeholders in both the short- and long-term results of a study, patients are unlikely to join or remain involved in studies that they feel aren’t working for them. However, the reasons patients give for non-participation often differ significantly from physician-perceived barriers. For example, oncologists considered fear of placebo to be a significant reason why patients might hesitate or refuse to join a trial, with 67% suggesting it as a major reason. However, in actuality, only 10% of patients surveyed agreed with this.3 We can’t afford to make assumptions when it comes to the needs and concerns of patients. Rather than wasting time and money on trial designs based purely on physicians’ suppositions, we need to put patients at the centre of clinical trials. 64 Journal for Clinical Studies

While patient support often focuses on practical ways to make the trial experience easier and more engaging, for patients the heart of the matter remains emotional. From logistical issues, such as transport and accommodation, to building relationships with physicians, we are dealing directly with the concerns of critically ill people, their families, and their carers. Whereas the goal of putting life-enhancing drugs on the market is common to all trial stakeholders, the potential barriers to patient involvement are far more personal and varied. Some patients may worry about spending long periods of time away from their children, while others may be more concerned about the accumulating costs of regular hospital visits during their time away from work. Each individual case stands to offer a unique perspective of the burdens associated with trial participation, and an opportunity to improve trial design. Where Are We Missing the Mark? Integrating patient perspective into regulatory decision-making has become a key point for FDA development, with the organisation’s Patient Representative Program4 seeking input on drugs and devices as well as wider regulations. However, expanding these practices across private sector companies relies on a more general shift in the dialogue between patients and researchers. A survey conducted by the Clinical Trials Transformation Initiative and the Drug Information Association found that only about 45% of large pharmaceutical companies actively engage with patient groups, with 41% claiming that they had no immediate plans to do so. Furthermore, many respondents that did reference patient engagement did so late in the process, often only during Phase III trials.5 This highlights how, despite incorporating patient-centric measures, researchers tend to heed the patient voice too late in the process, resulting in less-than-ideal solutions at a significant cost in both time and money. By neglecting the practical and emotional concerns of the patient populations at an early stage, sites and CROs are spending time and money developing recruitment plans and trial protocols that are irrelevant or retrograde to the needs of the patients themselves. The first step in accelerating enrolment and retention should be open, active listening. Clinical trial organisers need to understand the language patients use to discuss their own illnesses and experiences and incorporate this into their own messaging, creating an equal and accessible dialogue devoid of medical jargon. How Can Patients be Incorporated? Modern patients expect choice and control in all aspects of their treatment and trial experience, and an initial request for informed consent is no longer enough. Instead, trial participation needs to be an ongoing conversation, starting from the ground up. Rather than simply offering patients materials and resources to guide them through the trial process, we should allow them input in creating those resources, giving them wider opportunities to ask questions, suggest changes, and define their own experiences. Volume 9 Issue 5


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Special Section

Offering patients opportunities to join or form advisory boards, give structured feedback, and take a key role in furthering medical research, could improve both enrolment and retention rates, changing the overarching rhetoric around clinical trials into a more active and appealing concept. Advisory Boards and Focus Groups Whether focused around in-person meetings or online discussions, advisory boards and focus groups can facilitate a two-way conversation. Firstly, they serve to educate patients more fully about the risks and benefits of trial participation, allowing patients to actively debate and discuss these rather than simply reading resources. This goes a long way to gaining patient trust, ensuring they have answers to all their questions before the trial begins. At the same time, this involvement stands to inform clinical trial organisers of potential issues and improvements at every level of trial design, including finding an appropriate trial venue, transport, accommodation, food, drug delivery and other logistical issues. While healthcare staff follow protocols to keep the patient's best interests at heart, the patients themselves have wider considerations still – their families and caregivers. By listening to patients’ perspectives on the wider implications of trial participation, we can engage with the wider community of people invested in combatting illness, and ensure that the trial experience is supportive and empowering to all. When engaging patients at this level, it’s important to keep in touch with your legal and compliance departments, maintaining transparency about hard regulations and ensuring you don’t mistakenly offer patients something you can’t legally or logistically deliver. It is vital that patients see their suggestions being duly considered and actioned, otherwise they will consider their participation in trial design to be a mere token gesture, and not worthy of their time. 66 Journal for Clinical Studies

Consider maintaining a central online hub, via which patients can check the status of their feedback and the progress of any patient-focused projects they’re involved with. This will not only reassure patients that their points are being taken seriously, but also allow patients, caregivers, physicians and trial organisers to stay on the same page across the trial experience. The Role of Technology The easy accessibility of online patient support groups is giving patients a new voice when it comes to the trial changes they want to see. A questionnaire of 528 online patient support group members found that respondents felt significantly ‘better informed’ and experienced ‘enhanced social wellbeing’ as a result of such groups.7 Combined with the accurate and real-time insight patients are given into their own conditions and treatments via big data, health wearables and designated trial apps, these online communities allow patients to put forward better-informed ideas than ever about their own trial experiences. It falls to clinical trial organisers to take advantage of these platforms, or to create bespoke trial-specific patient communication hubs, where feedback can be offered and responded to in real time across the trial period. Services such as mdgroup’s patientprimary app, allow for patient feedback pertaining to the wider trial experience. As well as allowing patients to access important trial information, make appointments and book transport and accommodation, the app offers a space for patients to review the services and make special requests, ensuring that their changing needs are taken into account.7 A bespoke patient advisory app could go one step further, allowing patients to make qualitative notes about their experience alongside clearly-presented quantitative information taken from wearable devices. This will give both patients and physicians a fuller picture of the patient’s experience. The information could Volume 9 Issue 5


Special Section be uploaded to a portal, from which researchers could compare feedback from all patients across the trial, and base objectives on this. Furthermore, giving patients ready app-based access to information about the trial, specific data on their condition, and a dictionary to help them decipher medical jargon will empower them to understand and speak out about their trial experience, feeling like active partners in the research, rather than helpless guinea pigs. This could be combined with space for a trial-specific support group chat, accessible via the app. This way, patients can compare notes, raise queries, and represent themselves throughout the trial, emboldened by conversations with fellow patients. Social Monitoring Data mining gives another interesting option for discovering and responding to patient opinions – particularly those that may not be shared in a formal setting. Companies such as Treato9 algorithmically monitor public conversations on Facebook, Twitter and patient forums, capturing real-time commentary and analysing it for particular patient language. The trends captured give healthcare staff and patients alike a global overview of the big conversations in relation to specific conditions. Clinical trial organisers could use this information to monitor public opinions of trials and treatments, anticipating patients’ expectations in order to exceed them. Connectivity and Communication In order for researchers and physicians to communicate with patients and translate their requirements into the trial process, efforts must also be made to ease administrative burdens, freeing time, resources and expertise to be spent on improving the patient experience. Here, too, technology is opening more options than ever before. With the global wireless health market projected to grow from $39 billion in 2015 to $110 billion by 2020,10 connected hospitals and trial environments will soon rely on automation for routine processes such as retrieving patient files, inputting and analysing data, and filling prescriptions, allowing staff to invest more in forming relationships with patients. These advances could benefit clinical research in more ways than simply boosting retention rates. By being seen as an active and personable presence throughout the trial experience, staff can improve the level of open and empowered feedback they receive, ensuring more accurate qualitative data and allowing for further patient input into future trial design. Trial Technology Challenges Before launching patients into a world of apps and online forums, researchers should consider the fact that many patients are still uncomfortable with the use of certain technology, for both cultural and practical reasons. Older patients may struggle to keep up with digital processes, while those with demobilising conditions may struggle to scroll through their phones.

functionalities for the physically, visually and hearing impaired into an app could go a long way to make collaborative trial design accessible to all. The First Steps While it will take time to change the paradigms around clinical trials universally, we can start by reaching out to patients and offering them a safe, supportive space to make their voices heard, and to find out how they want to be involved in the rest of the trial design process. Kick-start the trial enrolment process with a meeting for all potential stakeholders, including healthcare staff, researchers, patients, their carers, and representatives from patient support and advocacy groups. Involve patients who can’t attend in person by live-streaming the meeting online. Make sure that you come to the meeting with some specific ideas of what patient advisors can help to address. Getting the ball rolling with a few practical questions can get patients comfortable discussing a wider range of ideas in the long term. An unstructured and uncentred meeting, on the other hand, could put patients off future involvement. Leave time for patients and staff to get to know one another, both online and in person, ensuring a comfortable starting point for future conversations. Bear in mind that not all patients will have the time, energy or inclination to take on the full responsibilities of advisory board members, but their opinions could still be instrumental to creating patient-centric processes. It’s therefore important to express that suggestions made at any point will be welcomed and taken seriously. True patient collaboration is not a set endpoint but a constant discussion, requiring refinement for individual differences and changing patient needs. While finding the balance takes dedication, the reward is multifold: a patient-centric trial will not only cut the time and cost taken to bring a drug to the market, but also create an accessible dialogue around disease, treatment and clinical research that will change the face of clinical trials. REFERENCES 1. http://www.makovsky.com/news/fifth-annual-pulse-ofonline-health-survey-2/ 2. https://conquer-magazine.com/including-the-patient-voicein-clinical-trials-design/ 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511246/ 4. https://lillypad.lilly.com/entry.php?e=7100 5. https://www.fda.gov/forpatients/about/ucm412709.htm 6. https://www.ctti-clinicaltrials.org/files/pgctexpertmtgsummary-2015-02-24.pdf 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483925/ 8. https://mdgroup.com/en/services/patientprimary/ 9. https://treato.com/ 10. http://www.marketsandmarkets.com/Market-Reports/ wireless-healthcare-market-551.html

It’s important to approach patient feedback in a flexible patientcentric manner, giving every trial participant an equal chance to offer their thoughts and feedback, and adapting processes on a caseby-case basis.

Tarquin Scadding-Hunt

For example, a workshop introducing trial apps to patients who are unfamiliar with mobile technology could make them feel more confident and involved in the process, while incorporating

Email: tarquin.scadding-hunt@mdgroup.com

www.jforcs.com

CEO at mdgroup, a full-service agency with a focus on the life sciences industry.

Journal for Clinical Studies 67


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Journal for Clinical Studies 69


Preview

ICSE Preview: The Contract Services Industry Returns to Frankfurt Welcome to the 28th CPhI Worldwide!

women to share their experiences, exchange expertise, and discuss effective leadership strategies.

“The event returns in a year where global growth across the pharmaceutical industry is flourishing and it is a particularly strong time for outsourcing & ingredients, as well as an incredibly buoyant time for the contract manufacturing and clinical trials supply industry. Perhaps most exciting of all, we have seen 23 drugs approved by the FDA in just the first six months of 2017, which shows how clinical trials are becoming more productive again after a relatively quiet 2016.” Orhan Caglayan, Brand Director Europe, UBM

This year’s CPhI Pre-Connect Congress will take place on the 23rd of October, the day prior to CPhI Worldwide, and offers its most exciting and comprehensive agenda to date. This platform gathers experts and thought leaders from the entire pharmaceutical supply chain to provide insights into the latest developments. In particular, the first keynote will feature Samsung Biologics President & CEO, Dr Tae Han Kim. He will provide an in-depth presentation addressing uncertainty in the industry, as well as the future outlook for pharma.

Event Overview CPhI Worldwide and ICSE will take place on 24 – 26 October 2017 at the Messe Frankfurt, Germany. After last year’s record-breaking event, the world’s most prominent pharma executives are ready to gather again for three days of collaboration, information dissemination, and discussions that will define the future of the industry. The 2016 CPhI Worldwide event in Barcelona saw an all-time record attendance of over 42,000 people, with 2550+ exhibitors from 156 countries. Building on this success, CPhI Worldwide 2017 will host over 20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma, machinery, and many more.

The conference also includes a presentation from Jim Miller entitled ‘Contract Manufacturing Industry Outlook’, featuring a snapshot of the performance within the CMO industry, an understanding of the major trends and growth drivers shaping the sector, and a forecast of the outlook for CMOs in the next 2–5 years.

Running concurrently with the pharmaceutical ingredients halls are four other nearby brands, helping visitors quickly identify the right event for their business’s needs. These include InnoPack, P-MEC Europe, and Finished Dosage Formulation (FDF), but most notably, ICSE, an outsourcing-focused event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs, bringing the contract community together under one roof. Beyond the exhibition, the CPhI Pharma Insight Briefings will offer participants the chance to access a diverse range of content through succinct 45-minute sessions, with 24 confirmed tracks in ICSE alone. These in-depth seminars on specialist topics and regional updates will take place throughout the course of CPhI Worldwide. As well as the many free-to-attend industry seminars, the Innovation Gallery will feature some of CPhI’s most exciting new products, including a combined ICSE and InnoPack showcase located in hall 4.2. Moreover, in collaboration with ICSE, Pharma Publications will present visitors with the opportunity for guided Innovation Tours for the first two days of CPhI Worldwide. Most exciting of all, Journal for Clinical Studies’ very own Mark Barker will be hosting some of the tours.

The CPhI Annual Report also launches its 5th edition, and will provide thought leadership on the industry’s hottest topics and issues. In particular, a contract services overview comes from Gil Roth of the PBOA, and several of the papers will explore issues and trends in clinical trials supply and development. Finally, in recognition of pharma excellence, the vastly expanded CPhI Pharma Awards return to the show for its 14th year, awarding an impressive 20 commendations in celebration of the most successful and innovative pharma achievements, including a dedicated category in ‘Contract Services and Outsourcing’. The expanded awards have been created to give wider recognition to all the great advances and technologies coming out of the pharma industry, and all submissions are free to enter. At the event, remember to use the official CPhI mobile app, providing exhibitors and attendees with a timetable of the day’s activities, a list of exhibitors and their hall location. Held in the heart of Europe’s largest pharma market, this year’s event is an unmissable opportunity to network with existing contacts, learn, and engage vital new customers that will be invaluable in moving your business to the next level. Register now for CPhI Worldwide 2017 at: www.cphi.com/ europe/

The Women in Leadership Forum will take place on the second day of CPhI Worldwide and provides an opportunity for female executives to meet with their peers and hear from senior executives on promoting diversity in the workplace. It serves as a space for 70 Journal for Clinical Studies

Volume 9 Issue 5


contract services Mix with the world of pharma, products, people & solutions

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Journal for Clinical Studies 71


Ad Index Page 33

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Corporate Translations Dora Wirth Languages Ltd

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Durbin PLC

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Greens Ltd. ICSE Expo

Page 9 Marken Page 59 mdgroup Page 25

MLM Medical Labs GmbH

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Ophthalmic Drugs Conference (SMi Group)

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Partnerships in Clinical Trials Europe

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Pharmaceutical Microbiology East Coast Conference (SMi Group)

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Pharmaworld.TV

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Qualogy Ltd.

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Replior AB

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Research Quality Association Ltd

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SGS S.A.

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Synevo Central Labs

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SYNLAB International GmbH

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Worldwide Clinical Trials

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

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