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Volume 9 Issue 4

Volume 9 Issue 4


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets

Journal for Clinical Studies

Accelerating Clinical Research in Brazil

Initial Findings of Immunostimulating Interstitial Laser Thermotherapy Of solid tumors

Doing More with Clinical Trial Business Data Adopt a Data Warehouse

Big Data’s Role in Patient Centric Care

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U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITOR Orsolya Balogh EDITORIAL ASSISTANT Maria Dominici DESIGNER Jana Sukenikova RESEARCH ASSISTANT Virginia Toteva 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: Journal by Clinical Studies - ISSN 1758-5678 is published bi-monthly by PHARMAPUBS


WATCH PAGES Recent Trends and Innovations in Outcomes and Design of Clinical Trials in Respiratory Drug Development Part 2: Design of Clinical Trials

For the second part of his series on respiratory drug development, Robert Lins, Respiratory Project Director at SGS, focuses on clinical trial strategy and study design. The goal of adaptive trials is to increase the efficiency of randomised clinical trials, which have the potential to both reduce costs and enhance the likelihood of finding a true patient benefit. The emphasis in exploratory trials is on finding safe and effective doses, assigning a larger proportion of patients to treatments with a relevant effect, and to select the most relevant doses for confirmatory trials. 10 Chronic Cholestatic Liver Diseases: PBC and PSC Clinical Complexity and Appropriate Medical Management In this article, Hans-JĂźrgen Gruss, MD, PhD and Robert Riccio, PhD of INC Research, discuss how cholestasis is the hallmark feature of chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholestasis can lead to chronic progressive liver disease, which finally leads to cirrhosis, liver failure and death. The goals of treatment are a reduction in disease progression rate and/or alleviation of the bothersome symptoms (such as pruritus/itching). Liver transplantation is presently the only curative, life-saving procedure. Several new molecules are in clinical evaluation for PBC and PSC, with the goal of extending the therapeutic options to manage affected patients. REGULATORY 12 Breaking New Ground: How Industry Collaboration is Transforming Clinical Trials In this piece, Jennifer Goldsmith, Senior Vice President of Veeva Vault Strategy, illustrates how an increasingly complex clinical trial landscape is driving the life sciences industry to support broad collaborations to define and implement common approaches that make running a trial easier. These collaborations are becoming a strategic priority for many companies hoping to create greater efficiencies in the race to deliver innovative therapies, drugs, and medicines to market faster. The industry is working together to collectively define approaches that could create greater efficiencies in trial processes, especially as sponsors increasingly outsource their research and development work to CROs. MARKET REPORT

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 4 July 2017 PHARMA PUBLICATIONS

14 Accelerating Clinical Research in Brazil Clinical research is underdeveloped in Brazil, although the country has the requisite expertise and infrastructure. Luis Magalhaes and Le Vin Chin of Clinerion Ltd examine the situation and trends in South America and Brazil. In particular, they look at two developments which promise the acceleration of clinical research in Brazil. First, the approval in the Senate of the PLS 200 law, which gives a framework for making clinical trials approvals more efficient. Second, the initiatives for digitisation of health data, which permits the use of new patient data analytics technologies. Journal for Clinical Studies 1

Contents 18 Clinical Market in Russia More than six years have passed since the federal law ‘On Circulation of Medicines’ came into effect, replacing the law ‘On Medicines’. The adoption of the new legislation has significantly impacted the pharmaceutical market in Russia as a whole, and the clinical trials sector in particular. The business had to be largely rebuilt according to the new rules of the game. Today, looking back on the past few years, Svetlana Zavidova, Executive Director of the Association of Clinical Trials Organizations (ACTO) says that the regulatory system has been completed now, and the clinical trials market in Russia has moved into a stable phase. 22 Contract & Budget Management of Industry-sponsored Clinical Trials in Turkey In industry-sponsored clinical trials, as the sponsors are for-profit companies, contract negotiations with the trial sites can be difficult and complex. The smooth management of this process mandates an understanding of the local country processes and considering these from the very beginning of the study management. This paper, by Duygu Koyuncu Irmak, Esin Bayir, Ebru Acar Altunsac, Begul Perincek, Ozge Ozmeral of INC Research Turkey, is to contribute to the literature by clarifying the budget preparation and contract management procedures in Turkey. Emphasis has been placed on the specific procedures of different institutions and some key factors, in order to achieve the ultimate goal of execution of the planned study deliverables for the industry. THERAPEUTICS 28 Initial Findings of Immunostimulating Interstitial Laser Thermotherapy of Solid Tumours Immunostimulating interstitial laser thermotherapy (imILT) is a treatment protocol for solid tumours developed to destroy the tumour at the treatment site while simultaneously inducing an immunologically mediated systemic response against the treated tumour type. In this article, Jakob Axelsson, Cristina Pantaleone and Stefan Åström of Clinical Laserthermia Systems AB define how previously clinical treatment data of the method has been presented, and in this progress report a broader array of indications are described. It details the initial findings of the clinical study programme designed to evaluate the safety and usability of the equipment.

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32 Panel Recommends Device While Questioning Clinical Trial Change The US Food and Drug Administration (FDA) allows for some flexibility related to changes in clinical trial protocols—for example, with adaptive trials. However, certain changes can lead to some pointed questions from agency officials. Elizabeth Hollis, writer and editor at Clarivate Analytics, explains how the FDA has also provided its thinking on adaptive trials in joint guidance, titled Adaptive Designs for Medical Device Clinical Studies, from the Center for Devices and Radiological Health and Center for Biologics Evaluation and Research. The guidance notes that an adaptive design allows for prospectively planned modifications as data are collected without weakening the study’s integrity and validity. 34 Rise of Paediatric Diabetes in Mauritius In this paper, Laure Lam Hung PhD, Project Manager and Clinical Research Associate at CIDP and Dr Tarkeswarnath Bachoo MBBS, MD (Paediatrics), Consultant Paediatrician at Flacq Hospital, give a detailed insight into the health situation in Mauritius, which has seen a switch from infectious diseases to non-communicable disease, namely diabetes, heart disease, cancers and chronic respiratory diseases. The death rate due to chronic diseases has increased, with diabetes the leading cause of death. Alarmingly, the T2D and obesity epidemics have spread to children and adolescents. Although the public healthcare system provides treatments and support free of charge to diabetic children and adolescents, preventive measures have been set up to tackle obesity and consequently T2D in children and adolescents. TECHNOLOGY 38 How Functional Service Provision can Directly Impact Clinical Trials Success – Crucial Factors to Select the Right Model In this paper, Chris Hamilton, Chief Commercial Officer at CROS NT, analyses how it is important to delve into the challenges when trying to achieve 'sustained' quality. Sustained quality begins with picking the right model and exploring myriad critical areas to safeguard its success: planning, training, cultural fit, staff retention, technology, communication, agility, sponsor participation, performance indicators, expectations management, etc. It’s also

Volume 9 Issue 4

OFFERING DEEP INSIGHTS INTO KEY AREAS OF CLINICAL DEVELOPMENT Bioclinica is specifically structured to create clarity in the clinical trial process — so you can make better decisions.

eHEALTH SOLUTIONS eClinical Solutions Randomization & Trial Supply Management Safety & Regulatory Solutions Financial Lifecycle Solutions

GLOBAL CLINICAL RESEARCH Research Network Patient Recruitment & Retention Post-Approval Research

MEDICAL IMAGING & BIOMARKERS Medical Imaging Cardiac Safety Molecular Marker Laboratory

Contents important to consider the crucial success factors involved in order to mitigate the risks that can disrupt a clinical trial losing time, effectiveness and potentially damaging the sponsor/vendor relationship. 44 Doing More with Clinical Trial Business Data: Adopt a Data Warehouse Pharmaceutical companies have been working for years on leveraging their clinical research data in more efficient ways, but other sectors of the research industry have been slower to follow. A data warehouse serves as a valuable tool that should be considered as a source for near-real-time business data that can foster enhanced business operations, leading to simplified research processes and more advanced reporting. This article by Kyle Ricketts Marketing Manager at Bio-Optronics, Inc. strives to explain the reasons for utilising a data warehouse in a clinical trials management setting and discusses the benefits these organisations gain from implementing this technology. 50 Big Data’s Role in Patient-centric Care The healthcare industry needs a fully connected IT infrastructure, integrating information from multiple systems to ease administrative workloads, facilitate patient-provider collaboration, and improve quality of care. In this sense, big data can be seen as part of a wider movement toward patient-centric connectivity, enhancing the overall patient experience both directly and indirectly. This calls for an in-depth analysis of how big data is currently affecting the industry, affirms Tarquin ScaddingHunt, CEO at MD Group, and how we can build on this to place a patient-centric data system at the core of big pharma business strategy. 54 Clinical Precision: What Does AI Offer Life Sciences? Where information overload has started to slow innovation and efficiency in medicinal markets, could artificial intelligence and machine learning help – by pinpointing what’s important and suggesting better ways of doing things? Elvis Paćelat, Executive Vice President, Life Sciences at AMPLEXOR, ponders the bigger picture. In life sciences, start-ups are already using machine learning algorithms to reduce drug discovery times; AI promises to make clinical trials cheaper, faster and more targeted, offering a way to find and keep teams focused on what’s important – from what’s being said in the market, to how drugs are designed and developed. CLINICAL SUPPLIES 58 Patient-centricity – A Winning Formula There has been considerable discussion around the concept of patientcentricity in the pharmaceutical community. The industry has taken a collective pause in an effort to re-evaluate and rethink longstanding approaches to drug development and commercialisation, with attention being recalibrated on the ultimate goal; making it easier for the patient to reach improved health outcomes. Justin Schroeder, Executive Director, Marketing, Business Development & Design at PCI Pharma Services, says this perspective is underpinned by the recognition that what is best for the patient will lead to beneficial outcomes for all stakeholders, including the drug company, the healthcare provider, and the supporting community of associated service providers. 4 Journal for Clinical Studies

Volume 9 Issue 4

Foreword Clinical research describes many different elements of scientific investigation. Simply put, it involves human participants and helps translate basic research into new treatments and information to benefit patients. Clinical trials as well as research in epidemiology, physiology and pathophysiology, health services, education, outcomes and mental health can all include under the clinical research topic, which is developing fast. Journal for Clinical Studies welcomes the readers to the Summer time of 2017. Immunostimulating interstitial laser thermotherapy is a treatment protocol for solid tumors developed to destroy the tumor at the treatment site while simultaneously inducing an immunologically mediated systemic response against the treated tumor type. Jakob Axelsson, Cristina Pantaleone and Stefan Åström at Clinical Laserthermia Systems AB define how previously clinical treatment data of the method has been presented and in this progress report a broader array of indications are described. We are happy to announce that the second part of the previously published “Recent Trends And Innovations In Outcomes And Design Of Clinical Trials In Respiratory Drug Development“ has now arrived by Robert Lins, Respiratory Project Director at SGS, where he focuses on Clinical trial strategy and study design. The goal of adaptive trials is to increase the efficiency of randomised clinical trials, which have the potential to both reduce costs and enhance the likelihood of finding a true patient benefit. The emphasis in exploratory trials is on finding safe and effective doses, assigning a larger proportion of patients to treatments with a relevant effect, and to select the most relevant doses for confirmatory trials. Brazil, officially the Federative Republic of Brazil is the largest country in both South America and Latin America. As the world's fifth-largest country by both area and population, it is the largest country to have Portuguese as an official language and the only one in the Americas. In this edition, JCS focuses on the south American area,

JCS - Editorial Advisory Board

with Luis Magalhaes and Le Vin Chin of Clinerion Ltd who examine the situation and trends in South America and Brazil. Pharmaceutical companies have been working for years on leveraging their clinical research data in more efficient ways, but other sectors of the research industry have been slower to follow. Kyle Ricketts, Marketing Manager at Bio-Optronics explaines the reasons for utilizing a data warehouse in a clinical trials management. There has been a lot of activity in the healthcare sector, as hospitals and healthcare providers are adopting electronic health records, and are increasingly engaging in HealthIT initiatives. With this changing infrastructure, biopharmaceutical enterprises can leverage these innovations in order to execute studies more efficiently, widen patient access, and enhance patient centricity. In this issue of JCS, Jennifer Goldsmith Senior Vice President of Veeva Vault Strategy illustrates how an increasingly complex clinical trial landscape is driving the life sciences industry to support broad collaborations to define and implement common approaches that make running a trial easier. These collaborations are becoming a strategic priority for many companies hoping to create greater efficiencies in the race to deliver innovative therapies, drugs, and medicines to market faster. The industry is working together to collectively define approaches that could create greater efficiencies in trial processes, especially as sponsors increasingly outsource their research and development work to CROs. The healthcare industry needs a fully connected IT infrastructure, integrating information from multiple systems to ease administrative workloads, facilitate patient-provider collaboration, and improve quality of care. In this sense, big data can be seen as part of a wider movement toward patient-centric connectivity, enhancing overall patient experience both directly and indirectly. Tarquin ScaddingHunt, CEO at MD Group focuses on how to build a patient-centric data system at the core of big pharma business strategy. I Hope you enjoy this issue, and look forward to bringing you more fantastic features in the September 2017 issue. Orsolya Balogh, Managing Editor

• Hermann Schulz, MD, CEO, Synlab Pharma Institute

• 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.


• 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


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

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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 4


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Journal for Clinical Studies 7

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Recent Trends and Innovations in Outcomes and Design of Clinical Trials in Respiratory Drug Development Part 2: Design of Clinical Trials In part 1 of our “Trends and Innovations in Outcomes in Respiratory Drug Development Journey,” we concluded that recently, a great number of new and/or more relevant outcomes have been put forward, but further validation is needed before they can be accepted as primary outcomes. Clinical trial strategy and study design are therefore key to success. Potential Improvements in the Design of Studies a) Adaptive trial design The goal of adaptive trials is to increase the efficiency of randomised clinical trials, which have the potential to both reduce costs and enhance the likelihood of finding a true patient benefit. The emphasis in exploratory trials is on finding safe and effective doses, assigning a larger proportion of patients to treatments with a relevant effect, and to selecting the most relevant doses for confirmatory trials. In confirmatory trials, changes to the course of an ongoing trial are planned prospectively, and executed based on a blinded or unblinded interim analysis, without undermining the validity of the study. There are four major categories of adaptations:

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1. Seamless Phase II-III designs 2. Sample-size re-estimation 3. Group sequential designs 4. Population-enrichment designs As an example, it was possible in a seamless Phase II–III design for a COPD study (INHANCE trial) to select some doses, and enrol many more patients in a study group of primary interest, after an early readout of end-point data.1 In this scenario, the planning of the trial needed to be meticulous, with detailed dose-selection criteria, a communication plan for interim results, a hypothesistesting strategy, and detailed simulations of the operating characteristics. b) Decreased variability between multicentre sites Variability between sites can be reduced by supporting site staff, using one type of equipment for measuring important outcomes, electronic recording of data through one software system, and using one set of standard operating procedures. Using the SGS satellite network, multiple sites in various geographic locations were able to act as a virtual “monocentric” site. This was based on the SGS clinical pharmacology unit’s expertise, services and procedures, combined with dedicated SGS clinical trial coordinators, study nurses, lab technicians, pharmacy support, and training staff. Strongly motivated local hospital staff

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collaborated with SGS, driven by a hospital policy of strategic development. c) Precision medicine Personalised, or precision medicine, is an evolving field, in which treatments are tailored to the individual patient. Much of the current focus involves developing drugs for cancer and other diseases. Increased attention to precision medicine has emerged in literature and public health, and was further enforced by the precision medicine initiative (PMI) in the United States. Enthusiasm has been heightened by a recent reduction in the cost of highthroughput genomic sequencing, and a dramatic increase in the identification of potential molecular targets for therapy. Biomarker tests help to select the most effective therapy and avoid ineffective or harmful treatments. One advancement in the evolution of precision medicine in asthma was recently demonstrated in a study with a monoclonal antibody, dupilumab, which inhibits some of the key drivers of type-2-mediated inflammation. d) Pragmatic trials Many current trials may not adequately inform practice because they have been performed with small sample sizes. Run by experienced investigators and highly selected participants, benefits have been overestimated and risks underestimated. Therefore, more pragmatic trials, designed to show the real-world effectiveness (RWE) of a treatment in broad patient groups, are required. In some cases, informed consent is a barrier to recruitment and would need to be waived. It is also easier to implement an intervention randomly at group level than at an individual level, using cluster randomisation. A variety of investigators, with a mix of experience, need to be included. Focusing outcomes on major events, such as death and emergency admissions, and on pragmatic end points, important to patients, should minimise bias. The recently published Salford Lung Study in patients with COPD used an innovative design, showing a decrease in the rate of moderate or severe exacerbations in a real-world setting. The study took place in an urban area, with all treatment carried out by the primary care-givers, connected through an electronic healthcare record (EHR), with simultaneous, remote monitoring of patients.2 RWE is driven by a patient-centric approach, with increasing use of outcomes relevant to patients, Big Data derived from EHR and registries, patient’s own devices (bring your own device BYOD), electronic patient-reported outcomes (ePRO), and electronic clinical outcome assessment (eCOA).

Conclusion There is a clear need for a patient-centric approach with increasing patient engagement through all stages of clinical development for respiratory diseases. This represents an evolution from classical randomised clinical trials with low external validity and delays, which will remain necessary for regulatory submission, to more efficient and adaptive designs which will be seen in the future. This evolution from undefined targets to a more targeted approach will lead us closer to precision medicine. Finally, appropriate techniques need to be applied for the collection of real-world evidence, moving away from a researcher-centric approach, to a real patient-centric approach. REFERENCES 1.

Donohue JF, Fogarty C, Lötvall J et al. “Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease. Indacaterol versus Tiotropium.” Am J Respir Crit Care Med 2010; 182: 155-162 2. Vestbo J, Leather D, Diar Bakerly N, New J, Gibson M et al. “Effectiveness of Fluticasone Furoate–Vilanterol for COPD in Clinical Practice. Salford Study.” N Engl J Med 2016; 375: 1253-1260.

Dr Robert Lins Project Director, Respiratory Diseases at SGS Clinical Research. He is an MD and certified specialist in internal medicine, nephrology and hypertension, and holds a PhD in medical sciences from the University of Antwerp, and is also a Fellow of the Belgian College of Pharmaceutical Physicians. He began his career over 35 years ago, working in animal clinical pharmacology at the Heymans Institute in Ghent, Belgium, and has since been continuously active in the field of human clinical pharmacology. He first studied renal patients and later founded the SGS Clinical Pharmacology Unit in Antwerp, Belgium, where many innovative human pharmacology models were developed for the study of cardiovascular, metabolic, CNS, infectious and most recently respiratory drugs. These include bronchial challenge methods, a local bronchial PK model and sputum induction. Dr Lins has published many articles about clinical pharmacology in these different areas of research.

Journal for Clinical Studies 9

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Chronic Cholestatic Liver Diseases: PBC and PSC Clinical Complexity and Appropriate Medical Management Cholestasis is the hallmark feature of chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholestasis can lead to chronic progressive liver disease, which finally leads to cirrhosis, liver failure and death. The underlying mechanism is the hepatic accumulation and retention of hydrophobic and potentially toxic bile acids, causing structural and functional liver damage. Goals of treatment are the reduction in disease progression rate and/or alleviation of the bothersome symptoms (such as pruritus/itching). Liver transplantation is presently the only curative, life-saving procedure. Several new molecules are in clinical evaluation for PBC and PSC, with the goal of extending the therapeutic options to manage affected patients. PBC PBC is an autoimmune-mediated, chronic progressive liver disease of the intrahepatic bile ducts, which predominantly affects middle-aged women. Initial clinical symptoms of PBC are most often pruritus and jaundice. In addition to increased levels of cholestasis markers, such as alkaline phosphatase (AP) and γ-GT, is the positive detection of anti-mitochondrial antibodies (AMAs). Histologically, chronic destructive cholangitis is seen in the intrahepatic small bile ducts. Histological features for PBC patients indicate a heterogeneous spotty damage across the whole liver. Key differential diagnosis includes autoimmune hepatitis, PSC and drug-induced chronic cholestasis, which need to be excluded for a PBC diagnosis. Around 70–80% of PBC cases are asymptomatic at the point of diagnosis and do not progress over the next 10 years.

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PSC PSC is a more rare idiopathic, heterogeneous and progressive chronic cholestatic liver disease of unknown etiology. PSC is characterised by inflammatory and fibrotic processes affecting intra- and extrahepatic bile ducts, which lead to obliterations, strictures and dilatations of bile ducts, causing obstruction or interruption of bile flow from the liver (cholestasis). The male to female ratio is approximately 2:1 with a mean age of diagnosis around 40 years. Of interest, 60–80% of PSC patients have a concomitant inflammatory bowel disease, particularly ulcerative colitis. The diagnosis of PSC is made by unexplained elevated serum cholestasis markers (AP, γ-GT) plus imaging studies showing typical bile duct changes. Around 50% of PSC patients are symptomatic at first presentation and will have, on average, a liver transplantation within 12 to 15 years. Symptoms include pruritus, abdominal pain, fatigue, weight loss and episodes of fever/ chills. Hepatomegaly and splenomegaly are also common clinical findings. New Treatment Options Ursodeoxycholic acid (UDCA), a dihydroxy bile acid, is the oldest and first-line approved drug since the late 1980s for the treatment of PBC, and has been shown to be therapeutically beneficial in PSC. Recommended doses are in the range of 13–15 mg/kg/ day to induce clinical (e.g. pruritus), biochemical (e.g. alkaline phosphatase/AP) and histological (e.g. fibrosis) improvements. Disease progression will result in severe fibrosis/cirrhosis in PBC and PSC patients requiring liver transplantation, as the only presently available curative therapy approach.

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Watch Pages PBC has currently no curative medical treatment, but URSO is the first-line treatment, as it effectively delays disease progression and the need for liver transplantation. Patients with a biochemical response to URSO have a similar survival rate compared to the general population. On the other hand, up to 40% of PBC patients do not achieve an adequate response to URSO and indicate the persistent medical need for new therapies. In 2016, several regulatory authorities, including the FDA and EMA, have approved obeticholic acid (OCA), a farnesoid X receptor agonist, in combination with URSO – or alone if URSO is not tolerated in patients with PBC – as second-line therapy based on significant AP normalisation rates (46% OCA versus 10% placebo). As summarised in Figure 1, numerous additional newer agents are presently tested in Phase II studies to verify the biological target and demonstrate efficacy for the underlying mode of action. It is expected that several of the tested molecules will enter Phase III clinical evaluation in the next two years. Therefore, it is predicted that medical treatment options for PBC will be further enhanced in the next few years.

The rapid advance in medical treatment options for chronic liver diseases has reached conditions such as PBC and PSC with a clear medical need.

Figure 1

Pre Clinical

E6011 (Eisai) CFTR Inhibitor (Vanda) Microbiome Therapeutics (MetaboGen)

GKT-137831 (Genkyotex)

Saroglitazar (Zydus)

Ustekinumab (Janssen) A4250 (Albiero)


NGM282 (NGM)

Table: Comparison of clinical and pathological features of PBC and PSC

APD334 (Arena) MBX-8025 (CymaBay Therapeutics)

LUM001 (Shire) LJN452 (Novartis) FFP-104 (PanGenetics)

RGLS5040 (Regulus)

Phase 3

Phase 2

Phase 1

GS-9674 (Gilead)

Obeticholic Acid (Intercept) UDCA (Dr. Falk)

GSK2330672 (GSK) Elafibranor (Genfit)

Figure 1: Summary on current development pipeline for PBC (Status: June 2017)

PSC has presently no established effective medical treatment to delay or halt the disease progression. Treatment is directed toward the observed clinical symptoms or complications. There are several new medications currently in Phase II clinical trials for the treatment of PSC. One of the tested molecules is obeticholic acid (OCA), recently licensed and launched in US and Europe for the treatment of PBC due to its effects on bile acid homeostasis and reduced bile acid synthesis. Furthermore, cenicriviroc is an oral, once-daily chemokine receptor antagonist to suppress the inflammatory and fibrogenic downstream signalling pathways. NGM282 is an FGF-19 analog reducing the biosynthesis of bile acids. LUM001 interrupts the circulation of bile acids at the intestinal luminal level to control cholestasis. GS-9674 is another farnesoid X receptor agonist. Norursodeoxycholic acid is a homolog of URSO with biological effects on sclerosing cholangitis features. Overall, all the indicated molecules therapeutically aim to interfere with the bile acid homeostasis. The ongoing development pipeline for new drugs in PSC is summarised in Figure 2. In summary, several newer agents are on the horizon to provide a needed proven medical treatment for PSC. Confirmatory Phase III studies are required.

Hans-Juergen Gruss MD, PhD Vice President, Gastroenterology/Hepatology, provides medical and operational leadership for INC Research’s development projects in gastroenterology and hepatology. He has over 25 years of medical and clinical research experience. Email: Website:

Robert Riccio PhD, Vice President, Clinical Development, General Medicine, leads INC Research’s clinical development programmes for gastrointestinal and hepatic disease products all the way through to marketing approval. He has 25 years of medical and clinical research experience. Figure 2: Summary on current development pipeline for PSC (Status: June 2017)


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Breaking New Ground: How Industry Collaboration is Transforming Clinical Trials An increasingly complex clinical trial landscape is driving the life sciences industry to support broad collaborations to define and implement common approaches that make running a trial easier. These collaborations are becoming a strategic priority for many companies hoping to create greater efficiencies in the race to deliver innovative therapies, drugs, and medicines to market faster.

A centralised model of information exchange, such as the TransCelerate SIP, is a good example of how the life sciences industry is transforming the clinical model in four key areas: 1. Creating a universal and flexible operating model 2. Enabling a collaborative clinical ecosystem 3. Gaining better insight from metrics and measurement 4. Shifting to modern, unified systems

TransCelerate BioPharma, Inc., a non-profit organisation whose members consist of some of the world’s most successful biopharmaceutical companies, has played a significant role in bringing the industry together to accelerate research and development efforts.

Standardising on a Common Operating Model Creating a common framework that standardises trial processes, while still enabling flexibility to support individual study needs, will help to eliminate the rework that takes place with each new trial and reduce the time to full study optimisation.

The importance of such industry collaborations is increasing as the complexity of clinical trials rises dramatically. The industry is working together to collectively define approaches that could create greater efficiencies in trial processes, especially as sponsors increasingly outsource their research and development work to CROs. With more stakeholders in the mix, as well as different processes and systems used across the clinical trial ecosystem, the ability to share information and make timely decisions has become burdensome. For example, study teams regularly use manual processes to manage documents and data – often sharing information via email – which limits collaboration, creates redundant work, and significantly lengthens trial timelines.

To date, rigid information systems have exacerbated the challenges in embracing a common model because they limit the flexibility of a business process and force people to find workarounds to complete their tasks at hand. For example, today’s trials require more data collection and protocol amendments, and include novel therapeutic areas and multiple partnerships. Clinical study teams often must adjust to mid-study changes, and if the systems they work within are not flexible enough to easily accommodate change of any sort, people revert to managing activities and tasks outside the system, creating manual processes and information silos, and ultimately extending the duration of a trial.

To address some of these challenges, TransCelerate introduced the Shared Investigator Platform (SIP) initiative, with the aim of providing the industry with a centralised platform focused on collaborating with investigational sites that is interoperable with various clinical solutions. The SIP’s goal is to streamline communications between investigators and sponsors and reduce duplicate information requests during trials. As part of this effort, TransCelerate recently announced it will integrate a cloud-based content management solution, Veeva Vault SiteExchange, with the SIP to enable clinical teams to easily access and exchange information with sites before, during, and after trial execution. The cloud application will help sites consolidate studydocument requests, alerts, and notifications in the TransCeleratesponsored SIP, allowing sites to spend less time on tedious administrative tasks and focus more on clinical research. Centralising information-sharing and establishing an easy, consistent process for document access and information exchange, sites, and sponsors has the potential to dramatically reduce administrative burden in trials and increase operational efficiency. In addition, companies gain visibility across all of their studies, and investigator sites can have a consolidated view across multiple trials with multiple sponsors. This level of visibility hasn’t been possible before within SIP. 12 Journal for Clinical Studies

A common industry process for exchanging documents and information can drive significant operational improvements in running trials and ultimately speed time to market. With sponsors, partners, investigators, and others working on one centralised platform, the need to seek non-standard workarounds is greatly reduced. Investigator sites no longer need to log in and out of multiple systems to share important information with sponsors. And sponsors gain a complete view across all their studies, and can post and retrieve documents quickly and easily. Improving Collaborative Processes Operational and information silos between functional areas, as well as sponsors and partners, have historically made collaboration difficult. As clinical trials expanded in scope and complexity, sponsors built dedicated teams internally, with specialised functions to handle specific parts of trials. Over time, these functions developed their own organisational structures, processes, and systems. Teams drove toward efficiency in their areas of specialisation, with limited visibility into end-to-end trial processes and inability to conduct effective handoffs between groups. Similar challenges exist between sponsors and partners. Each commonly has its own processes and systems in place, which makes information harder to share and difficult to access. Functional and operational silos have created barriers to effective trial collaboration. Volume 9 Issue 4

Regulatory Creating a more collaborative ecosystem requires a cultural shift. Companies must be willing to move away from specialised and siloed processes to ones that fit into a common framework across all trial activities. The growing call for information to be shared across both company and geographic lines is driving the need to collaborate and contribute information that can be easily accessed and disseminated. In TransCelerate’s example of site-document exchange, investigator sites have a channel to exchange information across multiple sponsors and trials, instead of working in one way with one sponsor and another way with another. Sites can simply log in once and find out exactly what tasks are outstanding and what tasks need attention, across multiple trials. Communication is streamlined and the administrative burden is greatly reduced. Linking all stakeholders together on a common platform provides greater visibility across the end-to-end trial process. Enabling realtime access to information, and the ability to transfer knowledge more easily, engenders trust that all parties are working towards the same goals and outcomes – which, in turn, fosters greater collaboration. Enabling Better Metrics and Measurement Visibility into how trials are performing relative to other studies is another common challenge among investigators, sponsors, and CROs. Lack of comparable data makes it tough to judge what is working or how to improve trial performance. Increasingly, sponsors and CROs want to have single, consolidated views of their clinical trials across their portfolios, regardless of which specialised providers have participated in contributing data or documents to trials. But inconsistent metrics and varying means of measurement often make it impossible to harmonise the data to gain the insight they need. Investigators typically deal with multiple sponsors and requests for documentation and information that they manually track. When the collection of documents and the data around these documents is easier to manage and track, sponsors can better understand the progression of their trials and where delays may be occurring. Sponsors can also benchmark their trials as they relate to the timeliness and quality of how sites are executing. Setting common operational metrics and measurements is an important aspect of a more unified, collaborative clinical landscape. With a standard set of metrics and measures, the ability to extract quality insight and identify trends across the industry is greatly improved. For example, a clinical team can determine whether a problem is isolated to one study, one site, one therapeutic area, or another common denominator. This type of information then becomes a strategic asset to perform predictive analysis across multiple sites and studies, using real-world evidence and historical operational metrics to better inform trials moving forward. Modernising and Unifying Information Systems Limitations in available technology created the silos that companies are now trying to eliminate. Systems were implemented to support specific functional activities, not end-to-end trial processes. As a result, most clinical teams work in many different systems, and often without the benefit of direct collaboration between teams, either internally or externally. The systems also have very different purposes. While one system may manage content, another manages the data being produced. Therefore, content and data are collected

and managed from multiple sources, even though the information is all associated with the same study. Now life sciences companies are bringing together previously disparate systems in the cloud to support the end-to-end trial process. Open APIs, standards, and emerging native cloud solutions allow companies to better support a unified clinical environment and sustain collaboration among internal and external partners. In addition, next-generation cloud applications can manage both content and data to eliminate information and process silos. Clinical information systems that are inherently integrated by leveraging a single platform will be essential in propelling the industry toward a unified clinical environment. Groups such as TransCelerate BioPharma Inc. are also establishing approaches to facilitate better engagement and collaboration between sponsors and their partners by using technology platforms. Now clinical and other functional groups can access much of the same information and data throughout the drug development lifecycle with cloud technologies and sharing tools, helping to foster more collaborative working processes. The flexibility and collaborative nature of next-generation clinical systems creates an environment where people are enabled to work within their processes, as well as ensure information can be traced and viewed across the trial. Industry Collaboration and the Patient Effect Cultural barriers, organisational structures, and functional and operational siloes still exist across life sciences – but the boundaries for collaboration between companies and their partners are expanding. Collaborations are building greater understanding among clinical trial stakeholders and the industry is focused on finding new ways of working together for the benefit of the patient. With a common framework supported by technologies designed to enable greater sharing and information exchange, collaboration among sponsors, CROs, IRBs, investigator sites, and others in the trial process becomes easier. Cloud technology is helping to drive the transition from traditional operating models to more efficient, agile, and collaborative processes – empowering life sciences to innovate faster and accelerate new drugs, targeted therapies, and speciality medicines to market. For the industry – and for patients – that’s a breakthrough.

Jennifer Goldsmith Senior Vice President of Veeva Vault Strategy. She leads the Vault initiative for Veeva Systems, overseeing the product vision, implementation, and marketing. She has honed her skills for regulated content management over the last 15 years by working with clients such as Johnson and Johnson, Pfizer, Shire, BMS and Roche, and has created strategies and solutions in business areas across the life sciences value chain, including research and development, regulatory submissions, manufacturing and promotional materials. Following the launch of Veeva Vault in 2011, PharmaVOICE named Goldsmith one of the top 100 most inspirational leaders in life sciences and, in 2015, was invited to serve on the editorial advisory board of RAPS Regulatory Focus.

Journal for Clinical Studies 13

Market Report

Accelerating Clinical Research in Brazil Clinical research is underdeveloped in Brazil, although the country has the requisite expertise and infrastructure. We examine the situation and trends in South America and Brazil. In particular, we look at two developments which promise the acceleration of clinical research in Brazil. First, the approval in the Senate of the PLS 200 law, which gives a framework for making clinical trials approvals more efficient. Second, the initiatives for digitisation of health data, which permits the use of new patient data analytics technologies. Introduction To use a boxing analogy, in the area of clinical research, South America as a whole, and Brazil in particular, do not punch in their weight class. With a population of 418 million people1, South America is home to 5.7% of the world’s population, and yet only runs 3.5% of the currently open trials on clinicaltrials.gov2. Brazil, itself, is underdeveloped for clinical trials, with a population that is 2.8% of the world’s, yet it only runs 2% of the trials. Brazil runs three times as many trials as Argentina, but its neighbour operates slightly above the world average for trials per capita, while Brazil, and South America as a whole, lag way behind. Table 1 shows the relevant numbers for the countries of South America.

The Broader Context Global Clinical Research Trends One key trend in global clinical research is the transition of all healthcare information into digital format. The HIMSS Electronic Medical Record Adoption Model (EMRAM) provides an eightstage roadmap and evaluation system that allows healthcare organisations around the world to measure their degree of digitisation. It is a long, slow process, but the “paperless hospital” will allow huge efficiency gains, transparency of patients, hospitals and treatments; and data from trials to be mapped and made comparable. In South America, health digitisation is moving forward in the largest countries like Mexico, Chile, Argentina, and Colombia. In Brazil, at least 50% of the hospitals have electronic health records (EHR). The trend of digitisation is not an end in itself, but to support the recording, storage and analysis of patient health data. The importance of the availability and use of good, structured data is paramount in the high-cost process of developing a new drug, alongside good practices. Prof. Dr Carlos Kiffer, founder and researcher in infectious diseases at the GC-2 Lab, points out that the development of a new drug could cost up to $13 billion, and: “it is only possible to put together the pieces of the puzzle that make the process of developing a drug, better, cost-effective and safer for the patient, by using robust data and good practices.” 3 Good practices in drug development are, of course, essential. Adopting a “quality by design” principle and using standard Good Lab Practices (GLP), Good Clinical Practices (GCP) and Good Manufacturing Practices (GMP) should make processes more robust, prevent waste of time and effort and improve cost-effectiveness of the drug development process, without compromising quality.

Table1: Population and clinical trials by country in South America.

What this means is that patients and physicians in South America are currently not receiving all the access they might need to cutting-edge medical treatments. It also means that Brazil, as a country with a large population and that clearly has infrastructure and expertise to run clinical trials, has the strong potential to develop its clinical research capacity further. Of course, it’s not that simple. In this paper, we will attempt to outline some overall trends in clinical research worldwide and examine their possible impact in Brazil. We will look at features of Brazilian clinical research and tease out how particular issues – such as the approval of the PLS 200 bill – will change the landscape in the country. 14 Journal for Clinical Studies

Another key trend is the requirement to ensure clinical testing is done for Hispanic and Latin populations, which are underrepresented in trials done in North America, Europe and China2. The USA Food & Drug Administration (FDA), for example, sees this as important because Hispanics make up 16% of the US population, but only 1% of clinical trial participants 4. Jonca Bull, M.D., director of the agency’s Office of Minority Health (OMH) explains: “there are biological differences in how people process drugs. For example, variations in genetic coding can make a cancer treatment more toxic in one ethnic group than it would be in another ... Getting more data on these differences is essential for FDA to truly know that a medical product will truly work and be safe for all patients.”5 It also follows here that there is little research conducted on diseases found primarily in developing countries and, consequently, the ability to diagnose and treat these diseases is significantly impaired. Meanwhile, precision medicine is gaining momentum. Recent reports put the market on a growth track to reach USD 65–75 billion Volume 9 Issue 4

Market Report by 2021, with an estimated average growth rate of 10–12%6. The clearest case for more personalised medicine comes in the treatment of cancers, where treatments are most effective when focussing on tumour genotype. But the advantages presented by precision medicine can also be seen in the treatment of rare diseases, where the new next-generation sequencing techniques can play a pivotal role. There are an estimated 7000 rare diseases, afflicting as many as 350 million people around the world, and of which 80% involve a genetic component7. According to a Mapi report, there are a potential 40 million rare disease patients in countries in Latin America4.

launch sales in 201210,11, suggesting that while sales are correlated to population size (Brazil is also the fifth most populous country), access to innovative medicine lags far behind.

South America Latin America’s population is growing at roughly the global growth rate, but its pharma market is growing above the global rate, with a CAGR of 6.3% compared to the global 4.8%. The region has large, urban populations of patients, who have both common and special disease profiles, but are still drug-naïve. It has good healthcare systems and highly involved and experienced investigators, following strict regulations at USA- and EC-equivalent medical standards4. The region has 16,000 hospitals 8. Why then are clinical trials lagging?

The downside of this strong regulatory control is that Brazil has been one of the countries that takes the most time to authorise clinical research: authorisation takes up to 18 months, a process that, in the rest of the world, would take only three to six months. As reported by CenterWatch, the delay is partly caused by the multiple layers of approval at both local and national ethics committee levels that must be obtained before the National Health Surveillance Agency (ANVISA) gives its final approval12.

The first problem is the lengthy approvals processes in the region. A European Society of Medical Oncology (ESMO) workgroup has pointed out that Latin America has one of the longest timelines globally from application for a clinical trial until regulatory approval 9. It has not helped that the regulatory landscape in the region is fragmented, with no centralised or harmonised procedure for drug registration, although the Pan American Health Organization (PAHO) is trying to align individual countries via the Pan American Network for Drug Regulatory Harmonization (PANDRH) and most of the countries do follow WHO GMP requirements 4. Related to this is also the lack of infrastructure – many Latin American countries still do not have reliable disease registries. A second problem is the lack of education in both patients and physicians. The low patient acceptance of being recruited for trials (due, for example, to the fear of being a “guinea pig”) is directly correlated to low educational levels. Meanwhile, while there are many excellent investigators of high quality in the region, there are still insufficient numbers of them. This relates to a third problem, that of investment. Latin America has a low level of investment in development and research compared to developed countries. Government authorities give clinical research a low priority, and this leads to a lack of resources, supplies and technologies for diagnosis and treatment 9. The Situation in Brazil Pharma Trends On first sight, the discrepancy seems particularly incongruous in Brazil, a large, wealthy country with an educated population. The country has over 40 per cent of Latin America’s 16,000 healthcare establishments (more than the US) 8. Of the ones which do clinical research, there are 40 university hospitals and 60 private hospitals. Some of these are considered the best hospitals in their field of specialisation in Latin America. At the same time, all the big pharmaceutical companies and CROs are also present and active in Brazil. The country accounted for roughly 43% of Latin America’s pharmaceutical sales between 2013 and 2017 8. According to an IMS report, the Brazilian pharma market was on track to grow 12.7% per year between 2012 and 2017, and Brazil became the fifth largest pharma market in the world in 2016. Interestingly, Brazil only contributed 1.1% of global

Clinical Research in Brazil Again, on paper, Brazil is doing well in terms of setting up a conducive infrastructure for clinical research. Of the seven regulatory authorities in the Americas qualified as Level 4 category (for competence and efficiency) by the WHO, Brazil’s was certified among the earliest, in 2010. The country sets GMP certification as mandatory for product registration approval 4.

This delay discourages new research coming to the country, which leaves Brazil out of the theatre of relevant studies and advances in medicine. It is this bureaucracy which has caused a downward trend in Brazilian clinical research over the past eight years, as tracked by CenterWatch, making Brazil responsible for less than 2% of new clinical research around the world. “We would like to run more trials, but prospective clients are running away because of our long regulatory timelines,” explains Douglas Andreas Valverde, CEO of Techtrials12. The growing requirement for digitisation of healthcare operations has also taken root in Brazil. According the iHealth Group, an EHR supplier in the country, at least 50% of the hospitals have EHR systems. However, there is still an issue of standardisation among these solutions. “There are five to 10 different systems running, and they are not integrated very well,” says Valverde12. This is relevant for the success, or failure, of clinical research, because trial recruitment often depends on the ability to find patients. “In Brazil, at least 40% of all clinical trials fail due to low patient recruitment. Patients want to participate in clinical trials, but, for various reasons, they cannot be found,” reports Bruno Oliveira, CEO of iHealth Group. Solutions: The New Regulatory Environment – the PLS 200 Law On March 18, 2014, the first debates started in the Brazilian Senate regarding changing and simplifying the clinical research laws in Brazil. The initiative aimed to optimise the regulatory framework for the analysis and registration of new drugs in the treatment of diseases. It aims, above all, to debureaucratise the system and speed up the release of new tests, removing Brazil from the uncomfortable position of being one of the slowest countries for the approval of research studies, and bringing modern medicines to Brazil, improving health outcomes and saving more lives of Brazilian patients13. On March 15, 2017, the new law, now called PLS 200, was sent from the Senate to the Brazilian Parliament for approval – the final stretch for its implementation13. What PLS 200 does is expedite regulatory approvals, in Brazil. The biggest difference is in the registration and evaluation process for a clinical trial. It creates an accreditation process for research ethics committees under the CONEP (Comissão Nacional de Ética em Pesquisa – the national research ethics committee), coordinated Journal for Clinical Studies 15

Market Report by the Secretariat for Science, Technology and Strategic Inputs (SCTIE), of the Ministry of Health. It also creates a procedure for analysing study protocols for risk, standardising and setting deadlines. Minimum to low risk protocols can be fast-tracked, medium to high risk protocols would go on to the ethics committee approval process14. The new law contains provisions aimed at protecting the health of the patient by guaranteeing medical assistance by qualified personnel throughout the execution of the study. It also provides a guarantee of access to the experimental drug, post-study, if it proves to be most beneficial and indispensable for the continuity of treatment of the patient after the end of the research. “These changes should improve the regulatory environment significantly,” says Valverde. “We hope to see the number of clinical trials jump from the current level of 1.5% to 3.5–4%.”12. “We can already see a strong influence on the number of clinical research studies, which has increased since the law was approved in the senate,” says Dr Charles Schmidt of Aliança (the Brazilian association for Clinical Research)13. Solutions: Patient Data Analytics to Accelerate Recruitment “According to existing regulations on data privacy, when the identity of the patient is not revealed to third parties and the norms are followed, there is nothing blocking the use of technological tools to improve and accelerate the recruitment of patients for clinical trials,” says Dr Antônio João Nocchi Parera, a legal expert in Brazil 15. A moderately structured EHR represents a rich source of patient information which allows queries to be made to a patient database. With EHR-based patient recruitment, electronically sending a protocol in the form of a query to multiple sites enables trial sponsors to evaluate numbers of patients fitting a protocol’s complex criteria across all linked sites, nearly instantaneously, and removing the subjective element from the process. With such a system, a trial’s primary investigator starts a study with an exhaustive list of potential candidate patients who fit the trial protocol criteria to screen, cutting down search and recruitment time. Depending on how they are configured, electronic patient recruitment systems may screen for patients on a continuous basis and identify eligible patients in near real time. This offers important advantages where trials are time-sensitive, or for capturing eligible candidates directly when they enter an emergency room. Conclusion: An Optimistic Future for Brazilian Clinical Research The development of new drugs is risky and expensive, taking time and much investment. However, in these two developments in the country, we can see clear movements which will support Brazil, a country which has the resources and the will to take a more prominent seat at the table in the area of clinical research in the world. In the words of Professor Yagiz Üresin, president-elect of the International Clinical Trial Center Network (ICN), who recently spoke at a seminar in São Paulo on Accelerating Clinical Research in Brazil, ”Brazil has much to offer to the global community of clinical research and we would like to see, in the near future, Brazilian academic institutions sitting side-by-side with the best research centers of the world as members of a reputable group, helping to change and improve the lives of more Brazilian patients.”

2. 3. Carlos Kiffer, The role of central labs and the importance of structured data in clinical research, proceedings from “Accelerating Clinical Research in Brazil” seminar, May 15, 2017 4. Silvia Bendiner, Fernando Ferrer, Pharma Strategies in Latin America Keys to Success, Mapi, March 15, 2016 5. Clinical Trials Shed Light on Minority Health, FDA ( ForConsumers/ConsumerUpdates/ucm349063.htm), April 26, 2013 6. Precision Medicine Market Size By Technology (Big Data Analytics, Gene Sequencing, Drug Discovery, Bioinformatics, Companion Diagnostics), By Application (Oncology, CNS, Immunology, Respiratory), Industry Analysis Report, Regional Outlook (U.S., Canada, Germany, UK, France, Scandinavia, Italy, Japan, China, India, Singapore, Mexico, Brazil, South Africa, UAE, Qatar, Saudi Arabia), Application Potential, Price Trends, Competitive Market Share & Forecast, 2016 – 2023, Global Market Insights, July 2016 7. Heather Gartman, What “Precision Medicine” Means for Rare Diseases,, Mar 03, 2016 8. Guillaume Corpart, Latin America: ripe potential for pharma, Pharmaphorum, May 15, 2015 9. Christian Rolfo, Christian Caglevic, Denisse Bretel, David Hong, Luis E Raez, Andres F Cardona, Ana B Oton, Henry Gomez, Urania Dafni, Carlos Vallejos, Christoph Zielinski, Cancer clinical research in Latin America: current situation and opportunities. Expert opinion from the first ESMO workshop on clinical trials, Lima, 2015, ESMO Open 2016; 1(4): e000055, 2016 Jun 17 10. Graham Lewis, Outlook 2018: The Current and Future Direction of the Pharma Industry, DCAT Connect, August 3, 2015 11. Charlotte Pineau, Charles Rink, White Paper: Pharmerging markets. Picking a pathway to success, IMS Health, ©2013 12. Marilyn Fenichel, Clinerion enters an improved clinical trials market in Brazil, CenterWatch Weekly, January 16, 2017 13. Charles Schmidt, Clinical Research in Brazil – PLS 200/15, proceedings from “Accelerating Clinical Research in Brazil” seminar, May 15, 2017 14. Wanda Dobrzanski, Anibal Calmaggi, Latin America: Challenges & Opportunities in Clinical Research, Medpace 15. Antônio João Nocchi Parera, Panorama Jurídico da Pesquisa Clínica no Brasil e a Possibilidade de Utilização de Solução Tecnológica para Recrutamento de Pacientes, proceedings from “Accelerating Clinical Research in Brazil” seminar, May 15, 2017

Luis Magalhaes International Sales Manager at Clinerion, with a background in business, administration and marketing. In the last 15 years, he has participated in several healthcare projects in geographies like the Sub-Sahara region, Latin America and the Middle East, involving the public and private sectors. Email:

Le Vin Chin


Head of Marketing and Communications at Clinerion and has been working in communications and marketing for 20 years, in a wide variety of industries, including software and services.



United Nations, Department of Economic and Social Affairs, Population Division. World Population Prospects: The 2015 Revision

16 Journal for Clinical Studies

Volume 9 Issue 4

You are the person

Who engaged the expert

Who managed the supply chain

Across 20 different countries

For the multi-centre trial

That led to this vital new drug launch.

With our global network of audited and approved suppliers, total quality focus and worldwide distribution capabilities, you can trust Clinigen to make your trial a success. To trial Clinigen CTS, contact: Email: Web:

Trust our chain reaction

Journal for Clinical Studies 17

Market Report

Clinical Market in Russia

The Overall Picture of the Last Several Years More than six years have passed since the Federal Law ‘On Circulation of Medicines’ came into effect, replacing the Law ‘On Medicines’. The adoption of the new legislation has significantly impacted the pharmaceutical market in Russia as a whole, and the clinical trials sector in particular. The business had to be largely rebuilt according to the new rules of the game. Today, looking back on the past few years, we can say that the regulatory system has been completed now, and the clinical trials market in Russia has moved into a stable phase. We briefly remind readers of the novel innovations that the new law brought to the clinical trials. First and foremost, this was of course the requirement for registering medicines to present data from clinical trials, some of which were conducted in Russia. Some market players found a certain new hope among this clearly destructive new regime. They hoped that it would increase the number of multinational clinical trials (MCTs) in Russia. However, as we will see below, this requirement did not lead to a significant change in the number of MCTs in Russia. In addition to the rules on local data, the law brought in a lot of new regulations about how to conduct clinical trials. The regulator itself changed – whereas previously, approval to conduct clinical trials was issued by Roszdravnadzor, with the new law this authority was transferred to the Ministry of Healthcare (MoH). Within a short span of time, more than fifteen by-laws were adopted, covering various aspects of the clinical trials process. New rules were brought in regarding insurance for clinical trial subjects, accreditation of clinical sites, importing IMPs, and exporting biological samples. On the whole, we can say that between 2010 and 2012, the clinical trial sector went through quite a number of serious challenges, and was able to adapt to the new rules of the game with relative ease (at least as compared to the commercial market). The bigger damage that hit the MCT market in Russia was perhaps most as a result of the changing geopolitical situation in 2014. The swift deterioration in relations between Russia and Ukraine undoubtedly led to withdrawals of a number of MCTs from both countries. This was to be expected – the unstable situation scared off several sponsors. The ‘fright’ affected smaller sponsors more strongly, likely because the risk of losing some of their data due to possible problems in a given country would be relatively more damaging for them. Larger sponsors, especially those with representation in Russia, remained quite unflappable. As ACTO’s1 2014 survey of its members demonstrated, changes in Russia’s global geopolitical position in the overwhelming majority of cases did not have any impact on MCTs conducted by Big Pharma. And, as the latest crash in the ruble shows, they even reaped some minor economic benefits. In Diagram 1, we see the dynamics of the clinical trials market for the period 2004–2016. Up to 2009, we see a steadily growing market. The slight drop in the number of trials in 2009 was most likely connected with the effects of the global economic crisis, 18 Journal for Clinical Studies

when a similar decline was seen in many countries. In 2010 came a ‘crash’ with a very clear explanation – in the last quarter of 2010 the approval system was practically not functioning. This was due to the transition of authority for issuing approvals for clinical trials, from Roszdravnadzor to MoH. In 2011 the market adapted. Further, we see rapid growth. Unfortunately, as is evident looking at the structure, this growth was as a result of increased local trials and bioequivalence studies. There are several reasons for this. First, the already-discussed requirement to present local data when registering drugs in Russia. This first of all explains the growth in the number of bioequivalence studies with foreign sponsors. The significant increase in the number of studies by Russian sponsors was in large part a result of the general state policy of support for local manufacturers, import substitution programmes, and so on. Unfortunately, there was no significant growth in the number of MCTs. On the contrary, in 2014 we saw the aforementioned ‘geopolitical’ drop. Although in the past two years the number of MCTs has been growing, albeit slowly.

Diagram 1: Data from

Structural Market Changes The past few years have seen serious structural changes to the clinical trials market in Russia. And whereas before the adoption of the new law, MCTs accounted for 60% of the total number of trials conducted, in the past three years, thanks to the rapid growth in the number of local and bioequivalence studies, today MCTs account for just 35% of market share. About 50% are for generics (bioequivalence studies plus socalled ‘therapeutic equivalence studies’). The remaining 15% are local studies of everything else (brand name drugs, biosimilars, new combinations of well-established substances, herbal medicines etc.). In this way, unfortunately, we can’t help but conclude that at present, the Russian market for clinical trials has clearly shifted towards generics. It is noteworthy that, located in a single space, the Russian clinical trials market has apparently divided into two independent and almost completely distinct parts – MCTs and local trials (including bioequivalence). This regards both market players (sponsors and CROs) and also, apparently, the quality of the trials conducted. And this is also readily explained – the tasks for MCTs Volume 9 Issue 4

Market Report and local trials are different. In the first case, the issue is fulfilling all the requirements of strict regulators such as the FDA and the EMA, and about precisely conforming to all GCP requirements. In the second case, the issue is meeting exclusively local tasks – to give the MoH certain data obtained in limited trials, conducted with a lack of control. The Russian watchdog – Roszdravnadzor – has extremely limited resources for inspections, in addition to which there are practically no real sanctions that it can impose for violations. And very often, local trials sponsors simply do not set a goal of obtaining quality data. Regulatory Environment In trying to characterise the current regulatory climate in the MCT sector, it would probably be most accurate to refer to it as positiveneutral. And that is, possibly, the best conditions possible today for foreign business in Russia, taking into account the current fashion for import-substitution and an aversion to all western things. It’s not a secret to anyone that Russia is a rather heavily bureaucratised country, where business comes up against a large quantity of administrative barriers. And clinical trials have not avoided their share. But despite all the bureaucratic hurdles, what’s most important is that the MCT industry is not today meeting any opposition from either the government or society. Perhaps the MoH bureaucrats are not applying particular efforts in order to ease the workings of the industry. But publicly they love to talk about how important it is for the country to participate in international projects, and that Russia is extremely interested in increasing the number of MCTs. Today, no one is blaming business for using Russia ‘like a test-range for western drugs’, and treating Russian citizens like ‘guinea pigs’, although just ten years ago these sorts of slogans were seen frequently in the Russian media. There are several reasons for this rather loyal behaviour on the part of the government. First, the current Healthcare Minister, Veronika Skvortsova, undoubtedly plays a positive role, as she has first-hand knowledge of MCTs and previously worked in them herself as an investigator. Second, strange as it may seem, the law on mandatory local clinical data – justifiably criticised for its anachronistic standards – in this case does fulfil a protective role. How can society blame business for ‘conducting experiments on Russian citizens’, when the law directly requires this, in fact requiring companies to conduct repeat, unnecessary trials?

additional questions from the experts, and 123 days in the event of experts’ questions. Approval to import IMPs took an average of 14 days and to export biosamples, 18 days. The not-quite-fast process of obtaining approval, by the way, is often compensated for by subsequent quick enrolment of patients. And that brings us to Russia’s strong side – a large number of patients who want to take part in MCTs. There are two main factors influencing this. The first is the relatively large population – 146.5 million. The second is the unfortunately poor quality of the healthcare system overall. It is well-known that in Russia it’s often easy to find ‘naïve’ patients. Access to medication on the whole is poor. And the chance to get expensive, advanced treatment is extremely attractive for bringing people into MCTs. It is rather difficult to find open sources of information on enrolment in Russia. But if we consider the planned number of subjects for enrolment (and these data are publically accessible), then on average in 2016 each MCT in Russia had about 103 participants. This figure was highest in cardiology and cardiovascular disease – with an average of 492.5 patients per MCT. Then come drugs used in pulmonology (220 participants per trial), and then analgesics and NSAIDs (209 participants). What is Being Studied? As we remember from Diagram 1, 302 MCTs were approved in Russia in 2016. 210 were Phase III trials (69.5%). 62 MCTs (20.5%) were in Phase II, 7 trials (2.3%) in Phase I, and 9 (3%) in Phase IV. A further 14 trials were in in-between phases – I/II, II/III, and so on. In Diagram 2, we present a breakdown of 2016 MCT approvals by therapeutic areas. The biggest share (67 MCTs or 22.2%) was in oncology. The separately-accounted-for category of oncohaemotology had a further 18 approved MCTs (6%). In second place after oncology was rheumatology (11.9%). In third place was neurology (9.3%).

Procedure and Timeframes to Obtain Approval The process to obtain approval for an MCT works on the ‘one window’ principle: documents are submitted to the MoH, which sends them to two expert review organisations – the FSBI and the Ethics Council. Based on the results of these two expert reviews, the MoH makes either a positive or a negative decision. In the process of expert review, the expert organisations can request additional data, and then the wait period is stopped. A refusal for the trial can be overcome, but to do this it is necessary to submit all the documents again, and pay the submission fee again. The fee to apply for an MCT is currently 210,000 rubles (about $3,500). In addition to obtaining approval to conduct a trial, it is necessary to obtain approval to import medicines, and to export biological samples. Furthermore, in order to begin a trial in a clinical site, it should be approved by the local ethics committee. Wait periods to obtain approvals have never been one of Russia’s strong suits. But on the whole, they can probably be considered acceptable. By law, the timeframe to obtain approval for a clinical trial is 40 working (57 calendar) days. In practice, the average timeframe to obtain approval in 20162 was 66 days, if there are no

Diagram 2: Data from

Geographical Distribution Russia is a large country. And in this sense, sponsors have a wide choice. But of course, the distribution of MCTs across the country is uneven, and is primarily concentrated in four regions – the Central Federal District (Moscow, Yaroslavl, Smolensk), the NorthWest Federal District (St Petersburg), the Volga Federal District Journal for Clinical Studies 19

Market Report (Tatarstan, Saratov, Nishny Novgorod), and the Siberian Federal District (Novosibirsk, Tomsk, Kemerevo, Omsk). The Urals are also fairly active. This geographical distribution of MCTs is the product of a number of factors. These include the population density of a given region, as well as logistical factors – the need to organise timely delivery of biosamples to central laboratories dictates that trial sites must be located reasonably close to international airports. In Diagram 3, we present the Top 10 regions of the Russian Federation in terms of number of MCTs approved in 2016. The leader, as we can clearly see, was Moscow (266 MCTs), followed by St Petersburg (263 MCTs) and Tatarstan (99 MCTs). And in Diagram 4, we present the same data, but in proportion to population per 1 million. And it gives us quite a different picture. In first place is the Yaroslavl region (61.3 MCTs per 1 million people), second is St Petersburg (50.3), third is the Smolensk region (50.1). Remarkably, Moscow doesn’t even make it into the Top 10 in this ranking, coming just 12th with 21.6 MCTs per 1 million people.

Diagram 3: Data from

trials. First place in the ranking for 2016 was Dr Reddy’s Lab. (14 trials), next was Hetero Labs Limited and Teva, with 10 trials each. Diagram 5 also shows when trials were conducted by the companies themselves, versus when they were conducted with the assistance of a CRO. Here, though, we need to say that we based this information on the MoH’s register of approvals issued for trials, and this does not always reflect the participation of CROs. On the whole, according to the MoH’s data, 47% of MCTs were conducted by sponsors using the resources of their own local offices, and 53% used CROs. Among the ranking of CROs in 2016, we see the following breakdown. First place (30 MCTs approved) was QuintilesIMS. Second place was PPD (16 MCTs), and third was PRA Health Sciences (15 MCTs). Rounding out the top five were Parexel and INC Research (13 and 12 MCTs respectively).

Diagram 5: Data from

Data Quality Russia has historically been proud of the quality of its MCT data. In order to avoid accusations of subjectivity, we turn to an outside source, namely, the publicly accessible results of FDA inspections. It would seem that no one can accuse this organisation of any undue loyalty to Russian investigators. In Table 1, we present the results of FDA inspections in a number of countries from 1995 to the present time.3

Diagram 4: Data from

Logistics As we have already mentioned, to begin a trial in Russia it’s not enough to get it approved. You also need to obtain approval to import IMPs and export biosamples. In addition, in a number of situations it is necessary to undergo special procedures to arrange importing medical equipment, electronic devices, and so on. Unfortunately, importing IMPs is a separate and rather weighty expenditure. The sponsor has to pay 10% VAT. In addition, the logistics, taking into account the size of the country and the need to organise prompt dispatch and delivery of goods, mean that the task is not always simple or cheap. By the way, the recent drop in the ruble has enabled a degree of optimisation of these expenses. Market Leaders Diagram 5 shows the Top 10 sponsors of MCTs by approvals obtained in 2016. The first, as it was in the previous year, was Novartis with 21 trials, next was Merck (18) and then GSK (16). To demonstrate the previously-mentioned market breakdown, we present data by leaders on conducting local and bioequivalence 20 Journal for Clinical Studies

Data from index.cfm?fuseaction=Search.ShowAdvancedSearchForm

Of course, for a more accurate comparison of data, we need to take into account the total number of inspections in a given country. The more inspections there are, the more accurate the picture they reflect of the quality of trials conducted in that country. We can see that despite one inspection with an OAI result (this event was in 2006), Russia performs at least as well, in fact often better, than many developed countries on the NAI figure. Volume 9 Issue 4

Market Report

General Conclusions Of course, Russia is not the leader in conducting MCTs. And here it is difficult to compete with the developed markets – the US and EU countries. However, the weaknesses (particularly the tricky bureaucratic processes and the sometimes less-than-ideal approval timeframes) are fully compensated for by the strong points – a large number of patients, rapid enrolment, and the high quality of data. Regarding the economic perspective, it is probably not accurate to call the country the cheapest in which to conduct MCTs. However, low prices for oil, connected with the ruble exchange rate, may keep the costs of conducting MCTs in Russia at a reasonably accessible level for the time being. REFERENCES 1. Association of Clinical Trials Organisations, Russia 2. According to data from ACTO wait time monitoring 3. The FDA began its first inspections of Russian investigators in 1995.

Svetlana Zavidova Executive Director of the Association of Clinical Trials Organizations (ACTO) since its establishing in 2007. ACTO is a non-commercial organization of sponsors (pharmaceutical companies) and CROs engaged in clinical trials in Russia. Svetlana is a lawyer by education and has more than 20 years’ experience in non-commercial sector and more than 15 years in clinical trials market. She specialized in analysis of regulation of pharmaceutical market, has a broad experience in the elimination of harmful administrative barriers. Email: Website:

Journal for Clinical Studies 21

Market Report

Contract & Budget Management of Industry-sponsored Clinical Trials in Turkey

In industry-sponsored clinical trials, as the sponsors are for-profit companies, contract negotiations with the trial sites can be difficult and complex. These agreements are designed to address a large number of issues such as scope of work, budget, payment terms, intellectual property rights, confidentiality, publication rights, indemnification and termination rights1, 2 The requirements of each country participating in an international trial have to be considered individually according to each country’s healthcare policies, public healthcare system, legal framework ruling the hospitals’ financial management and investigator payment procedures, in order to achieve a smooth and complete trial budget and contract management process in the given country.

General Procedure In all countries, a sponsor develops a high-level draft study budget covering the services to be purchased from the hospital and investigator grant and releases a clinical trial agreement (CTA) template to be negotiated. During the site identification and qualification process and/ or feasibility evaluation of potential clinical sites, the financial procedures at that site are assessed. In Turkey, a study budget that includes the amounts for the hospital and investigator fees and grants is required for the initial study application. This study budget has to be prepared in a sitespecific manner by the sponsor/authorised clinical research organisation (CRO). The final budget needs to be integrated into the research budget form template generated by the Turkish regulatory authority (RA), the Ministry of Health Turkish Medicines and Medical Devices Agency (TMMDA), and is expected to be submitted as part of the initial application binder to the ethics committee (EC) and the RA. Thus, the site-specific budget document is one of the key documents evaluated by the regulatory bodies during the review of the initial study application. On the other hand, clinical trial agreements (CTAs) do not need to be submitted to or reviewed by the EC or RA in Turkey. The CTA template provided by sponsor is shared with the clinical site institution (hospital) management and the principal investigator (PI). For some sites, there are site-specific CTA templates. The sponsor or site template, or a combination of these two templates as agreed by all parties, can be negotiated. The RA approved budget needs to be incorporated in the CTA. In Turkey, separate CTAs with the PIs (two-party agreements) are not allowed, thus the CTAs are designed as tripartite (sponsor/ CRO, institution, PI) documents. The language of the CTA needs to be bilingual (Turkish – English) as solely English CTAs are not legally valid in Turkey. As per the local legal framework, Turkish language within the CTA prevails over the English4. The clinical study budget and the CTA can be amended during the course of the trial in cases such as protocol amendments or subject number increases requiring budget change. The timelines for budget and the CTA process during the study start-up, execution and close-out at clinical sites are illustrated in Figure 1.

With its unique geographical location creating a physical, cultural and commercial bridge between East and West, Turkey has been displaying an exponential growth in the number of sponsored clinical trials3. The clinical trial budget preparation and the trial agreement finalisation at Turkish sites is a process that needs to be proactively planned and requires a fully knowledgeble sponsor or contract research organisation (CRO) authorised by the sponsor to manage to activate the Turkish sites and start with subject enrolment within planned timelines. The main aim of this paper is to contribute to the literature by clarifying the budget preparation and contract management procedures in Turkey. Emphasis has been placed on the specific procedures of different institutions and some key factors to achieve the ultimate goal of execution of the planned study deliverables for the industry, as well as for the clinical teams worldwide that are planning or conducting clinical trials in Turkey.

Figure 1: Schematic demonstration of the clinical trial budget preparation and clinical trial agreement process timelines in Turkey.

In industry-sponsored clinical trials, as the sponsors are forprofit companies, contract negotiations with the trial sites can be difficult and complex. The smooth management of this process mandates understanding the local country processes and considering these from the very beginning of the study management. This paper is intended to contribute to the literature by clarifying the budget preparation and contract management procedures in Turkey. Emphasis has been placed on the specific procedures of different institutions and some key factors in order to achieve the ultimate goal of execution of the planned study deliverables for the industry, as well as for the clinical teams worldwide that are planning or conducting clinical trials in Turkey. Introduction Operational aspects of the conduct of sponsored clinical trials consist of a number of steps, such as trial application to independent ethics committees or independent review boards (IECs/IRBs) to get approvals, collection of essential documents, planning and organisation of the study logistics, and managing the budget and contract (clinical trial agreement) process. Among the major challenges in this process are the preparation of the trial budget per country requirements and finalisation of the site contract.

22 Journal for Clinical Studies

Volume 9 Issue 4

Market Report Clinical Trial Budget Preparation As per the regulatory process in the country, once the sites are selected and confirmed by the sponsor, one of the participating investigators is selected and allocated as national coordinating investigator (NCI). The initial aplication is done as a parallel submission to the NCI site’s ethics committee (EC) and to the RA. The EC reviews all the sites’ information together with the study core documents; the RA reviews the study application as a whole. The clinical trial budget theoretically has three levels, including study level, institution/investigator level, and subject level. The sponsor provides the country budget to start negotiations with the site. The country budget is split into institution- and investigatorlevel, as per the institution’s requirements. The study-level budget, which is high-level and compiled at the very beginning of the trial planning, generally includes financial figures for each study visit, including assessment fees and investigator grant together. All of the budget elements need to be carefully determined and implemented in the CT budget. These elements can be lined up as shown in Table 1 as general estimated figures that are received from sponsors, and their customisation aspects as per Turkish sites and for the country.

Investigator-level payments consist of the items other than the procedures listed in the institution budget. These are the assessments directly performed by the investigator at the study site (e.g. ICF collection, questionnaires, data entry) as well as the per-visit investigator fee determined in the budget. Investigator fee payments are made to the institution, and the institution distributes the amount to the investigator after the hospital deductions are made. Additionally, the Turkish Government has introduced new legislative incentives and support mechanisms for research and development activities. In accordance with the 16 February 2016 Amendment Law to the Law Supporting Research and Development Activities (Law No 6676)8, the earnings arising from research and development activities in the scope of universityindustry cooperation are collected in a separate account, and 85% of the earnings are paid to the investigator with no deduction and exempted from income tax. However, in order to apply these provisions to the research projects, university management approval upon investigator application is required. Therefore, there is no standard implementation of this amendment in clinical trials. Universities have different approaches and procedures for the application and evaluation of research and development activities.

Table 1: General Budget Elements and those of customised budget elements for clinical sites in Turkey.

The items in the institution budget consist of fees for those tests and assessments that are performed using the hospital facilities. These procedures include, but are not limited to, physical examination, local laboratory assesments, imaging services, etc. Assessment fees are non-negotiatable and listed in the price tarriff of each institution. The price tarriffs may vary between sites as listed below: • Hospital Special Prices (e.g. Kocaeli University, Trakya University, Public and Private Hospitals5) • Social Security Institution Health Implementation Declaration (SUT-Sağlık Uygulama Tebliği)6 • Public Health Services Sales Tarriff (used by the majority of university hospitals)7 • Turkish Medical Association Price Tarriff.

Management of the Clinical Trial Contract with the Clinical Sites The applicable legislations that rule and regulate the management of contracts in clinical trials are summarised in Table 2. Clinical trial agreements covering the responsibilities of the parties are signed as tripartite agreements between the sponsor/ CRO, institution and PI, and have to be bi-lingual (Turkish and English). These agreements need to be signed by the institution unless the institution has a different procedure. Depending on the type of institution and study, there may be further signatories. Once all signatures are completed in a contract, a stamp tax should be paid in accordance with the applicable law. The tax will be calculated depending on the contract content. This requirement has to be discussed with the sponsor at the beginning of the study. Journal for Clinical Studies 23

Market Report

Table 2: Applicable local regulations applicable to clinical trials contracts execution

A contract review fee is requested by some sites prior to them accepting to review the CTA. This has to be clarified during the site selection phase. Ege University (Prokom), Istanbul University Clinical Trials Excellence Application and Research Center (IUKAMM), Çukurova University (DAP Unit), and Dokuz Eylul University (DAP Unit) request a contract review fee. The majority of the sites agree to negotiate and sign the sponsor or CRO contract template. Some of the sites, however, have sitespecific contracts/agreements. In such cases, both sponsor/CRO and site-specific contracts have to be executed for full activation of the site, as usually the site-specific contract only covers budgetary items and not necessarily all other items. The contract template can be a sponsor or CRO template. If a sponsor template will be used in a clinical trial conducted by a CRO, the responsible project team member will review the site contract for relevant terms ensuring consistency with the contract between CRO and sponsor (“sponsor contract”), payment terms and general CRO obligations. If the sponsor prefers to use a CRO template, the current existing contract template is provided by the CRO for sponsor review and facilitates any sponsor-required changes to the template. The final site contract template(s) must be mutually agreed upon between CRO and sponsor before beginning negotiations with the site. A site budget template is also provided along with the parameters. After completion of the template development step, the project team member who is delegated for contract negotiation needs to generate the contracts incorporating the approved study budget figures in accordance with country and site-specific requirements. Once the negotiation is completed, it can be signed by all parties. CTA Negotiation and Execution Process Clinical trial agreement components include, but are not limited to: 24 Journal for Clinical Studies

• • • • •

Parties of the contract Protocol number and protocol title Sponsor and/or CRO details Reference to the protocol and applicable local laws Obligation of parties, conduct of the trial, terms of termination, confidentiality, indemnity/insurance, trial data, inspections, publications, intellectual property/inventions, equipment retention, if any • Budget exhibit including EC/RA approved figures, payment terms and payee information • Tax information including stamp tax payment Unless a site-specific process is applicable, the following steps are needed for contract/budget negotiations: 1. Budget and contract template is received from the project team 2. Assessment fees of the institution are obtained and budget is split between PI and institution 3. Turkish RA budget form is completed and submitted to EC/ MoH as part of the initial submission package 4. Budget and contract template is sent to PI for review and approval 5. Site contract template including the budget table is sent to the institution for review after PI approval 6. Institution approves the template or asks for revisions 7. Any institution revisions are escalated to the project team member and contract is finalised and quality controlled for signature University Hospitals Prokom (Ege University): Ege University has a clinical trials unit that reviews and approves the site budgets and contracts; this is Prokom (Project and Special Services Coordination Center). This site accepts sponsor template contracts, but has a site-specific supplemental agreement template that must also be used. Volume 9 Issue 4

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Journal for Clinical Studies 25

Market Report A submission is made to Prokom for budget and contract review and approval. The submission file is reviewed in the committee meeting held bi-weekly. The submission file includes the following documents: application letter, Ege University budget form, study procedures request form prepared by PI, study stamp, Prokom review fee payment receipt9, a copy of EC initial submission file, EC/RA approvals (can be presented afterwards if not obtained at the time of submission to Prokom), contract and supplemental agreement template. The negotiation process is as follows: 1 2 3 4

Prokom Submission File is sent for review Prokom provides feedback two weeks after the meeting, via e-mail Revisions are made and missing documents (including EC/RA approvals) are provided to Prokom Contract is executed

Budget presented to Prokom needs to be compliant with the study protocol as the committee reviews the budget versus the protocol. The legal department in Prokom does not approve any reference to other countries’ laws and regulations. Although as mentioned previously, submission to Prokom can take place prior to having EC/RA approvals, and Prokom will only proceed with approval for signature after EC and RA approvals are provided. A site-specific supplemental agreement needs to be signed along with the site contract. Stamp tax declaration and payment receipt shall be sent to Prokom after the stamp tax payment is performed. Istanbul University Clinical Trials Excellence Application and Research Center (IUKAMM): IUKAMM is the clinical trials unit of the following Istanbul University institutions: Istanbul University Istanbul Medical Faculty, Istanbul University Cerrahpaşa Medical Faculty, Istanbul University Cardiology Institute, Istanbul University Oncology Institute and Istanbul University Pharmacy Faculty. Contract/ budget negotiations, contract execution and site payments are performed through IUKAMM. There is an electronic system called Clinical Trial Database, where the contract templates, including the budget, are uploaded for review and approval. 1 2 3 4 5 6

The process differs slightly between Çukurova University and Dokuz Eylül University as summarised in Table 3.

RA approval is received and contract review fee payment is performed10 Contract template is uploaded to IUKAMM’s Clinical Trials Database along with RA approval and payment receipt IUKAMM reviews and approves the contract template or asks for revisions Any institution revisions are escalated to the project team member and contract is finalised/quality controlled for signature Contract is executed Review process is completed in 3–4 weeks and the status can be tracked through IUKAMM’s Clinical Trials Database

Dokuz Eylul University Research Projects With Sponsor (DAP) Unit and Cukurova University: Dokuz Eylül University and Çukurova University have DAP units reviewing site contracts and organising site payment procedures. Contract review and execution process are as follows: 1 Contract template and local agreement template is sent to DAP unit for review 2 Any site revisions are escalated to the project team member and contract is finalised/quality controlled for signature 3 Site agreement is sent to site for signature along with supporting documents (EC/RA approvals should be in place to start the signature process) 4 Contract is executed 26 Journal for Clinical Studies

Table 3: The CTA process differences between Çukurova University and Dokuz Eylül University.

Uludağ University: There is no specific contract execution meeting at this institution. A copy of the initial EC submission file needs to be sent to Uludag University Medical Faculty EC in addition to EC and RA approvals of the trial for review and signature process of the CTA. Stamp Tax Payment Procedure for the Fully Executed CTAs Stamp tax is a consumption tax levied on papers, which are prepared with intent to execute the transactions regarding transfer of goods, services and wealth appearing in the chain extending from production to consumption legally, and paid for each party. Stamp tax is regulated under Stamp Tax Law numbered 488 and dated July 1, 1964 (the “Stamp Tax Law”). The sponsor/CRO is obliged to make the stamp tax payments. Stamp tax declaration is made monthly (declared by the 23rd of the following month). Some of the institutions are requesting proof of the stamp tax payment in order to complete all steps of site activation. Public (State) Hospitals Every public hospital is affiliated to a Public Hospitals Union General Secretariat based on their location. Public Hospitals Union General Secretariats are connected to the Public Hospitals Institute located in Ankara. In order to execute a contract in public hospitals, the below described process should be completed in accordance with the Directive on Procedures and Principles for Trials conducted within the scope of a Revolving Fund Enterprise by Sponsor request (Directive number 1488 dated 20 February 2013). 1 2 3 4 5 6 7

Study is submitted to Public Hospitals Union (PHU) General Secretariat for pre-approval PHU gives pre-approval for the study Budget form and pre-approval letters are submitted to Public Hospitals Institute (PHI) for approval PHI requests a review fee and determines prices in committee meeting Final budget is signed by PHI and sent to sponsor/CRO Site agreement, including final budget, is sent to site for signature along with supporting documents Contract is executed after RA approval

A pre-approval application file consists of the pre-approval form and protocol synopsis in the local language. Some Hospital Union Secretariats may request additional documents. The application requirements should be confirmed during the application file preparation with the respective Secretariat. Volume 9 Issue 4

Market Report If there are multiple public hospitals in a study, all pre-approvals will need to be be collected in order to perform budget submission to PHI. There is no fixed price tarriff for the procedures. The prices are determined in the meeting performed by PHI for the study. The submitted initial budget to PHI is prepared in accordance with the Public Health Services Sales Tarriff. PHI either sends a counteroffer after reviewing the budget, or approves the budget without any revisions. Conclusions and Key Success Factors Clinical trial budget preparation and the clinical trial agreement finalisation process at Turkish sites is a complex and timeconsuming process. There are various contract procedures which change per site in addition to local requirements in Turkey. Planned work, familiarisation with the site-specific procedures and thorough communication with sponsor and project team members play a significant role in finalising the contract execution and managing Turkish sites’ activation in a timely manner. Key success factors include the following: a) There is a study code activation in each hospital/clinical site’s finance department. After CTA is signed, this code activation needs to be managed pre-SIV or during the SIV for the site to be ready to enrol a patient. This code activation process varies amongst the sites, e.g. Hacettepe University Medical Faculty requests a site-specific form in addition to EC/RA approval letters, stamp tax payment receipt and fully executed CTA b) Expertise of local legal requirements and site-specific procedures is of key importance c) Good level of knowledge of the study-specific assessments and implementation to local requirements d) Project team member/sponsor should be informed about local requirements and site-specific requirements at the very beginning of the study, so that all steps are followed without any disruption. The main processes (country- and site-specific) and legal framework ruling and shaping the preparation of the clinical trials budget and CTA procedures have been elaborated in this paper. Having these in mind in combination with real-time experience, we believe these will serve as a useful tool for all stakeholders involved in clinical operations in Turkey. REFERENCES 1.

2. 3. 4. 5. 6.


8. 9. 10.

Office of Research, Office of Sponsored Programs. Accessible at: http://osp. Access date: 26 Sep 2016 The New England Journal of Medicine, Conflict-of-interest policies for investigators in clinical trials, V:343 No: 22, Nov 2000 Clinical Trials Journey of Turkey-Long and Thin Road, J Clin Trials 2015, 5:2, Ilbars, et al. Law on Mandatory Usage of the Turkish Language for Corporations (Law No:805), dated 22 April 1926 Health Implementation Declaration, available at: http://www.resmigazete. and the amendment to the declaration, available at: 10/20161007-12.htm The current Public Health Services Sales Tarriff, available at: http://,ek-2-kamu-saglik-hizmetleri-satistarifesi2016062914073-.xlsx?0

Duygu Koyuncu Irmak Dr. Irmak has been working in the clinical research industry more than 14 years. She currently serves as an Associate Director at INC Resarch, leading clinical operations in Turkey and the Middle East-North Africa region. Irmak is a member of INC’s Rare Disease Consortium and contributes to rare disease research and orphan drug development on a global level. She earned her Master of Science and her PhD and has co-authored numerous scientific publications. Email:

Esin Bayır Esin Bayir is a Site Start Up & Regulatory Specialist at INC Research and is responsible of contract negotiations and ethics/regulatory submission. She holds a bachelor’s and a master’s degree in Political Science. Bayir has six years of clinical research experience in global CROs with specialization in contracts and budget negotiation. Email:

Ebru Acar Altunsac Ebru Acar Altunsac is a Senior Site Start Up & Regulatory Specialist at INC Research. Her clinical research experience spans more than 10 years in local and global CROs and pharmaceutical companies.  Acar Altunsac earned her biology degree from Istanbul University Faculty of Science, where she studied oncology, hematology, cardiology (both in adults and pediatric) endocrinology, infection diseases and chest diseases. Email:

Begul Perincek Begul Perincek is a Senior Site Start Up & Regulatory Specialist at INC Research. She holds a bachelor’s degree in biology and two Master’s degrees, one in science and the other in education. Perincek started her career in the CRO industry in 2007 as a CRA and worked as a senior CRA for more than six years in Turkey before joining INC in September 2015. Email:

Ozge Dalmis Ozge Dalmis is a Senior Site Start Up & Regulatory Specialist at INC Research. After graduating from Canakkale Onsekiz Mart University in Turkey with a degree in biology, she earned a master’s degree from Istanbul Technical University in molecular biology, genetics and biotechnology. Dalmis began her career in the CRO industry in 2013 as a Regulatory Affairs Associate before joining INC in May 2016. Email:

Journal for Clinical Studies 27


Initial Findings of Immunostimulating Interstitial Laser Thermotherapy of Solid Tumours Immunostimulating interstitial laser thermotherapy (imILT) is a treatment protocol for solid tumours developed to destroy the tumour at the treatment site while simultaneously inducing an immunologically mediated systemic response against the treated tumour type. Previously clinical treatment data of the method has been presented and in this progress report, a broader array of indications are described. It details the initial findings of the clinical study programme designed to evaluate the safety and usability of the equipment. Thus far, twelve patients exhibiting a wide variety of solid tumours are included in the programme and are described. These early indications point to a satisfactory safety profile and important user feedback from the treatment sessions. Introduction Local control of cancer is very important, especially in early stages of the disease, and is standard practice in treatment of many tumour types. Local destruction of tumour tissue is available using a wide range of different modalities such as radiotherapy and thermotherapies. Many, if not all, of these local techniques have been shown to induce immunologically mediated systemic anti-cancer effects, abscopal effects. This provides a potential treatment option for metastases at distant sites, even for the micro-tumours that are not yet visible to the radiologist. Interstitial laser thermotherapy, heat generated by laser light, has proven to be both a safe and a very controllable modality to achieve tissue destruction. Aiming to maximise the chances of abscopal effects, a low-temperature laser thermotherapy protocol was developed. This protocol, called Immunostimulating Interstitial Laser Thermotherapy (imILT), has been and is being thoroughly studied pre-clinically in vivo and is currently under investigation in a multicentre clinical study programme. A laser unit capable of keeping the exterior of the targeted tumour at constant temperature was developed. The construction of the system consists of a laser generator providing laser light to a silica optical fibre, which is inserted into the tumour, causing heat as the light is absorbed by the tumour tissue. A temperature probe connected to the laser unit is placed in the periphery of the tumour and regulates the laser output, keeping the temperature at the rim of the tumour constant (Figure 1).

Figure 1 Overview of the imILT system. A. Graphical representation of the feedback system of the TRANBERG Thermal Therapy System. B. Placement of optical fibre applicator delivering laser light and temperature probe measuring the temperature within the targeted tumour tissue. 28 Journal for Clinical Studies

Pre-clinical experiments showed that temperatures of 46°C in the periphery of the tumour induced more powerful abscopal effects than higher temperatures1 and lower temperatures were unable to cause complete tumour destruction at reasonable treatment times. Ensuring total tissue destruction at the chosen temperature requires a prolonged exposure time2, 30 minutes, compared to other ablative techniques. Technical Specifications The TRANBERG Thermal Therapy System is a medical device developed specifically for imILT. The novelty with this system is the automatic tissue temperature control achieved with a feedback system that adjusts the light dose according to the temperature measured in the tissue. The energy source is a built-in laser diode that emits light at a wavelength of 1064 nm up to 25 W continuous wave. The wavelength used by this system is in the near infrared region and is commonly used for laser ablation procedures because of its deeper penetration capabilities. The light is delivered to deeply situated tissues in a minimally invasive way by means of a laser applicator; specifically a non-cooled radial-emitting or diffusortipped optical fibre with a construction tailored to enhance its thermal and mechanical stability. The radial emitting fibre creates spherical ablation volumes and the diffusor tipped fibre results in ellipsoid ablation volumes3. (Note: please note that the lengths and widths in the tables of original reference are reversed.) This type of laser applicator was used to supply between 1 W and 8 W optical power to the treatment site for the cases presented in this publication. The insertion of the applicator in the target is performed using an introducer by computed tomography (CT) or ultrasound image guidance. Throughout the imILT treatment, the temperature is measured using an external temperature probe positioned at the edge of the targeted tumour volume. The probe communicates the temperature directly to the laser unit to control the treatment and the resulting outcome in terms of ablation size. The temperature reached in the tissue varies depending on the position of the temperature measurement, the distance from the laser applicator, the treatment stage and the tissue type and condition2. While the tumour border is kept at a temperature around 46°C, the tissue closer to the applicator reaches temperatures higher than 100°C during warm-up, when the laser is continuously running. Immunological Response Local ablation has been shown to induce immunologically driven anti-cancer using a wide range of modalities4–6. This has been experimentally shown to be partly dependent due to the release of cancer antigens6. imILT was developed to optimise the immunological events evoked by thermal therapy by operating at a low temperature believed to coagulate less antigens and disturbance to surrounding tissue. imILT treatment results in immediate local tissue destruction and cell activation7. Subsequent immunological Volume 9 Issue 4

Therapeutics events include abscopal, or out-of-field, effects in the pre-clinical setting using a rat model of colorectal cancer in the liver8. Delayed anti-tumour effects suggesting an “in situ vaccination”, have been demonstrated9 and also a decreased degree of metastasis when compared to surgery1,8. These treatment effects are accompanied with intra-tumoral infiltration of cytotoxic T lymphocytes and macrophages of distant tumours in rats subjected to imILT treatment9. Antigen presentation cells are recruited and activated after imILT, as demonstrated in a clinical study of breast cancer patients10. However, in a follow-up study, these findings could not be correlated to clinical outcome11. In conclusion, these findings suggest the following mechanism to be of major importance for the immunological mediated anticancer effects of imILT (Figure 2).

Previous Clinical Experience and Current Clinical Study Programme Prior to the initiation of the currently ongoing clinical programme, 72 patients were treated using the imILT protocol but using a prototype of the currently developed equipment. The malignancies included breast, liver, lymph nodes and pancreas 15, 16. To retrieve data for safety and feasibility of the imILT treatment, a clinical programme is currently being implemented at six university clinics in Europe. The individual studies cover a variety of solid malignancies of the breast, pancreas, liver, lymph nodes and melanoma. The current data comprises data from the first twelve patients that have been treated within the clinical programme. The clinical programme was initiated in 2015 and is expected to be concluded in December 2017. All studies are performed according to GCP-ICH and have been approved by local ethics committees at the respective study site. On-site monitoring is performed on a regular basis by external, qualified monitors. Study protocols all have an open, non-randomised design with descriptive statistics. Study specifics are summarised in Table 1. For a full list of participating investigators and clinics, please see acknowledgements.

Table 1. Studies included in the study programme.

Figure 2: Overview of the proposed mechanism of action. 1. Hyperthermia induces cell rupture and cytokine release (yellow triangles). 2. This recruits antigen presenting cells (APCs), such as immature dendritic cells (iDCs) to the tumour. 3. APCs take up tumour cells/antigens (red circles) and are activated. 4. Activated APCs travel to draining lymph nodes (dLN) and cross-present tumour antigens to T lymphocytes, in turn activating and turning them into cytotoxic T lymphocytes (CD8+ T cells). 5. CD8+ T cells traffic through the circulation and attack unheated tumour cells.

Laser light is absorbed in the tissue and in turn generates heat. The higher temperatures closer to the laser fibre cause cell membranes to rupture and proteins to coagulate, resulting in instant necrosis of the affected tissue. The temperature closer to the temperature probe is lower and is causing a rim of apoptotic cells called the transition zone, which is known to generate immunogenic cell death12. Ultimately, over the course of hours to a few days, these changes result in complete destruction of the targeted tissue13. But more importantly for the immunological response, the dying cells release chemokines and different kinds of molecular danger signals recruiting different immune cells. Tumour specific antigens are released from the site and are picked up by activated antigen presenting cells6,14. These cells present the tumour antigens on their cell surfaces to T lymphocytes, which in turn are activated and their T cell receptors are made specific to the tumour antigen. These highly-specific T lymphocyte clones then proliferate15 and return to the bloodstream in large numbers. When encountering tumour cells, anywhere in the body, the cytotoxic T lymphocytes make contact with the tumour cell and kill it.

Inclusion criteria common for all studies within the study programme include patients; ≥ 18 years of age, have histologically confirmed solid tumour, ECOG performance status ≤ 2, stable hematologic, renal and hepatic functions and informed verbal and written consent to participation in the trial. Common exclusion criteria include: known HIV positive patients, active autoimmune disease, systemic corticosteroid medication, bleeding disorders or anticoagulant medication and pregnancy. Clinical Findings Study Population Patient demographic data and tumour types treated have been summarised in Table 2. Data cutoff was June 6, 2017. Total number of patients in the study programme was 12, of which eight were male and four were female. The patients were between the age of 41 and 83 years at the time of imILT treatment. The performance status (ICOG) of the patients were either 0 (n=5, 63%) or 1 (n=3, 38%). All patients included in this report were treated using the TRANBERG Thermal Therapy System and radial emitting fibres. The tumour types subjected to imILT treatment include primary breast cancer (n=1), breast cancer metastasis (n=1), colon cancer metastasis (n=2), malignant melanoma metastasis (n=2), pancreatic carcinoma (n=1) and primary pancreatic carcinoma (n=5). All tumour types except pancreatic cancer were treated percutaneously, while the primary pancreatic carcinoma were imILT treated in open surgery. The treatment sites included pancreas, liver, subcutaneous soft tissue, breast and abdominal lymph nodes. Due to comorbidity, the patients included in this study programme have had numerous prior treatments. Two of the malignant melanoma patients had undergone immunotherapy before receiving imILT treatment but not during the study period (Table 2). Journal for Clinical Studies 29

Therapeutics Average age (range) Gender1Gender1     ECOG performance status2ECOG

62 (41-83) Male Female  

performance status2

  Most common tumor types1Most common tumor types1

      Most common treatment sites1Most common treatment sites1               Prior immunotherapy   SAE  

  8 (67 %) 4 (33 %)   0 6 (67 %) 1 3 (33 %)  

Pancreatic Malignant melanoma Breast Colorectal

6 (67 %) 2 (22 %) 2 (22 %) 2 (22 %)

Pancreas Liver Subcutaneous Breast Abdominal lymph nodes Total   2 (22 %)   1 (11%)

5 (56 %) 3 (33 %) 2 (22 %) 1 (11 %) 1 (11 %) 9 (100%)      

Radiology Radiological evaluation using CT and/or MR was performed before imILT, in close proximity after treatment and at follow-up visits in all studies. A typical example of the result of ablation can be seen in Figure 4, of imILT treatment of primary pancreatic cancer. Tumours less than 30 mm in diameter, which have been possible to treat radically, were treated successfully. Larger tumours, which were not possible to ablate radically, were initially treated as well but showed continued growth after treatment.

Table 2: Study population. Baseline characteristics of patients of all sponsor-initiated studies (n=9). 1. The gender, total number of patients included in the study, tumour types and treatment sites are given for the total study population (n=12). All other data refer to data derived from the sponsor-initiated studies (n=9). 2. At the time of inclusion in the study.

Safety and Usability of Equipment One serious adverse event (SAE) has been reported to CLS (Table 2) within sponsor initiated studies, which is 11% of the total number of patients (n=9). The usability data of the TRANBERG Mobile Laser unit during imILT treatment has been summarised in Figure 3. A score of 1 = easy and a score of 4 = difficult. No statistical analysis is possible yet due to the low number of subjects, but a tendency toward different scores between the study sites can be seen. The initial interpretation is that removal, handling of disposables and sterile access are seen as less complicated while placement of fibres and probes is perceived as more difficult. The feedback of the handling of the laser unit is more variable and needs further analysis to evaluate.

Figure 4: A. Preprocedural axial CT image. Metal stent is visible in the common hepatic duct adjacent to the tumour in the head of pancreas (white arrow). B. Post-procedural axial CT image demonstrates low attenuation, indicating tumour destruction, within the tumour area (white arrow) nine days after treatment.

Summary and Conclusions In summary, it can be concluded that the imILT can be performed safely and reasonably accurately. The frequency of SAEs and other complications is not higher than what can be expected based on previous knowledge of laser ablation17 and other local ablative techniques18. A major drawback in evaluating the current data set is the limited number of study subjects. Therefore, no statistical analysis of the data was performed but merely compiled and reported. Taking this into account, preliminary safety data and user feedback is very relevant and a requirement for larger, data-driven conclusive proof-of-concept studies.

Figure 3: Assessment of imILT equipment usability. Score of 1 = easy and a score of 4 = difficult. 30 Journal for Clinical Studies

Acknowledgements Principal investigators of the studies were: Dr Kristjan Skuli Asgeirsson (Nottingham University Hospital, Nottingham, United Kingdom), Dr Belarmino Goncalves (Portuguese Oncology Institute of Porto, Porto, Portugal), Prof Johan Hansson (Karolinska Volume 9 Issue 4

Therapeutics University Hospital, Stockholm, Sweden), Dr Salvatore Paiella (General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona, Verona, Italy), Dr Olivier Turrini (Institut J. Paoli et L. Calmettes, Marseille, France), Prof. Thomas J. Vogl (University Hospital Frankfurt, Frankfurt, Germany). Radiology evaluations were performed locally at each study site as well as centrally by Dr Inger Keussen (Lund University and Skåne University Hospital, Lund, Sweden). REFERENCES 1.















1. Möller, P.H., Ivarsson, K., Stenram, U., Radnell, M. & Tranberg, K.G. Comparison between interstitial laser thermotherapy and excision of an adenocarcinoma transplanted into rat liver. British Journal of Cancer 77, 1884-92 (1998). Möller, P.H., Ivarsson, K., Stenram, U., Radnell, M. & Tranberg, K.G. Interstitial laser thermotherapy of adenocarcinoma transplanted into rat liver. The European Journal of Surgery = Acta chirurgica 163, 861-70 (1997). Pantaleone, C., Dymling, S. & Axelsson, J. Optical fiber solutions for laser ablation of tissue and immunostimulating interstitial laser thermotherapy - Product development in the network of developers, industry and users. Photonics and Lasers in Medicine 5, 69-75 (2016). Isbert, C., Boerner, A., Ritz, J.-P., Schuppan, D., Buhr, H.J. & Germer, C.-T. In situ ablation of experimental liver metastases delays and reduces residual intrahepatic tumour growth and peritoneal tumour spread compared with hepatic resection. The British Journal of Surgery 89, 1252-9 (2002). Yantorno, C., Soanes, W.A., Gonder, M.J. & Shulman, S. Studies in cryoimmunology. I. The production of antibodies to urogenital tissue in consequence of freezing treatment. Immunology 12, 395-410 (1967). den Brok, M.H.M.G.M., Sutmuller, R.P.M., van der Voort, R., Bennink, E.J., Figdor, C.G., Ruers, T.J.M. & Adema, G.J. In situ tumor ablation creates an antigen source for the generation of antitumor immunity. Cancer Research 64, 4024-9 (2004). Ivarsson, K., Myllymäki, L., Jansner, K., Bruun, A., Stenram, U. & Tranberg, K.-G. Heat shock protein 70 (HSP70) after laser thermotherapy of an adenocarcinoma transplanted into rat liver. Anticancer Research 23, 370312 (2003). Tranberg, K.G., Myllymäki, L., Möller, P.H., Ivarsson, K., Sjögren, H.O. & Stenram, U. Interstitial laser thermotherapy of a rat liver adenocarcinoma. Journal of X-ray Science and Technology 10, 177-85 (2002). Ivarsson, K., Myllymäki, L., Jansner, K., Stenram, U. & Tranberg, K.G. Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response. British Journal of Cancer 93, 435-40 (2005). Haraldsdóttir, K.H., Ivarsson, K., Jansner, K., Stenram, U. & Tranberg, K.-G. Changes in immunocompetent cells after interstitial laser thermotherapy of breast cancer. Cancer Immunology, Immunotherapy: CII 60, 847-56 (2011). Haraldsdóttir, K.-H., Ingvar, C., Stenram, U. & Tranberg, K.-G. Longterm Follow-up After Interstitial Laser Thermotherapy of Breast Cancer. Anticancer Research 35, 6147-52 (2015). Chu, K.F. & Dupuy, D.E. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nature reviews. Cancer 14, 199208 (2014). Wheatley, D.N., Kerr, C. & Gregory, D.W. Heat-induced damage to HeLa-S3 cells: correlation of viability, permeability, osmosensitivity, phase-contrast light-, scanning electron- and transmission electron-microscopical findings. Int J Hyperthermia 5, 145-62 (1989). Isbert, C., Ritz, J.-P., Roggan, A., Schuppan, D., Rühl, M., Buhr, H.J. & Germer, C.-T. Enhancement of the immune response to residual intrahepatic tumor tissue by laser-induced thermotherapy (LITT) compared to hepatic resection. Lasers in Surgery and Medicine 35, 28492 (2004). Tranberg, K.-G. Laser tumor thermotherapy: Is there a clinically relevant effect on the immune system? Proceedings of SPIE - The International

Society for Optical Engineering 6087, 60870B-60870B-12 (2006). 16. Tranberg, K.-G., Möller, P., Hannesson, P. & Stenram, U. Interstitial laser treatment of malignant tumours: initial experience. Eur J Surg Oncol 22, 47–54 (1996). 17. Vogl, T.J., Straub, R., Eichler, K., Woitaschek, D. & Mack, M.G. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology 225, 367-377 (2002). 18. Paiella, S., Salvia, R., Girelli, R., Frigerio, I., Giardino, A., D’Onofrio, M., De Marchi, G. & Bassi, C. Role of local ablative techniques (Radiofrequency ablation and Irreversible Electroporation) in the treatment of pancreatic cancer. Updates in Surgery, 2-6 (2016).

Dr Jakob Axelsson research manager at Clinical Laserthermia Systems AB, a company developing and marketing Immunostimulating Interstitial Laser Thermotherapy (imILT). Dr Axelsson holds a Master of Science degree in Biochemistry from Lund University, Lund, Sweden and a Ph.D. in experimental medicine, Lund University, Lund, Sweden. Dr Axelsson is a researcher in the field of translational research performing basic research and applying results from in vivo and in vitro studies in clinical trials. Research focus is inflammation with special attention to immuno-oncology. Email:

Cristina Pantaleone received a Master of Science in Physics Engineering specialised in nanooptics and photonics from Politecnico di Milano, and a Master of Science in Physics Engineering specialised in medical engineering from Lund University, Faculty of Engineering as part of the Top Industrial Managers for Europe programme. She has experience in development of medical devices, expertise in light-tissue interaction and a deep understanding of CLS technology and product range. She is responsible for product design, specifications definition and product verification and testing of CLS products. She also provides technical training and support during clinical trials. Email:

Dr Stefan Astrom Vice President of Clinical Operations at Clinical Laserthermia Systems AB. Dr Astrom has a Bachelor of Dental Surgery from The University of Lund, followed by a Bachelor of Biochemistry from University of Stockholm and a Ph.D. in Physiology, University of Stockholm. Dr Astrom is a serial entrepreneur within the CRO industry and the founder of one of Sweden’s longest-running independent CROs. He is active within management of clinical research Phases I – IV in Europe and China. Email:

Journal for Clinical Studies 31


Panel Recommends Device While Questioning Clinical Trial Change The US Food and Drug Administration (FDA) allows for some flexibility related to changes in clinical trial protocols—for example, with adaptive trials. However, as one sponsor has found out, certain changes can lead to some pointed questions from agency officials. TransMedics, Inc, an Andover, Massachusetts-based device company, is waiting for a decision from the FDA on the potential approval for its Organ Care System (OCS)-Lung. This portable monitoring system, which the company has said would mark a step forward in terms of organ preservation, aims to maintain donor lungs in a near physiologic state ahead of transplantation. It also is intended to enable surgeons to perfuse and ventilate the organ between the donor and recipient sites. TransMedics has said OCS-Lung should offer a beneficial alternative to cold static storage, the current standard of care (SOC), by allowing for the following: • Reducing ischemic injury; • Optimising the lung condition; and • Allowing for ex vivo functional assessment of the donor lung during preservation and prior to transplant. On May 17, 2017, the Gastroenterology-Urology Devices Panel of the Medical Devices Advisory Committee heard from both the FDA and the sponsor about the system. Ultimately, members voted 11 to 2 in favor of the device’s safety. In addition, members determined that the sponsor had demonstrated that the system was effective (8 to 5) and the benefits outweighed its risks (9 to 4). The FDA is not obligated to follow the voting recommendation of the advisory committee, but it may do so once all information is considered.

32 Journal for Clinical Studies

Despite these votes, panel members had reservations about the sponsor’s decision to change the primary effectiveness endpoint during the pivotal INSPIRE study. One member even cautioned the sponsor never to conduct such a change during future clinical trials—an admonition with which TransMedics agreed. Broadly, studies of devices posing significant risk to the health, safety, or welfare of a subject require both FDA and institutional review board (IRB) approval. To request an FDA sign-off, sponsors must submit an investigational device exemption (IDE) application, and the agency should issue a positive or negative decision within 30 calendar days. The agency’s decision process is outlined in the guidance document titled “FDA Decisions for Investigational Device Exemption Clinical Investigations.” After a review, it may issue one of the following decisions: • Approval—study may begin upon IRB approval; • Approval with conditions—study may begin upon IRB approval, but sponsor must respond to issues identified by the FDA within 45 days; or • Disapproval—study may not begin until issues identified by the FDA have been addressed. During its briefing, the FDA noted that it cannot disapprove an IDE application if it believes that the study design is not adequate enough to support a future premarket approval application, 510(k) submission, humanitarian device exemption application, or de novo classification. That said, it may discuss aspects of the trial with the sponsor. As the FDA noted in its briefing documents, the agency approves IDEs for clinical studies based on the safety of study subjects. It added that if changes to study endpoints do not have an impact on safety of the subjects, a new protocol may be approved, even if the agency has concerns. The FDA would address these concerns in approval letters.

Volume 9 Issue 4

Therapeutics The multinational INSPIRE study included 407 subjects, randomised to receive either OCS-Lung (n = 208) or SOC (n = 199). That figure represents the intent-to-treat (ITT) population. Screening failure, resulting in exclusion of patients, occurred in the OCS arm (21%) and SOC arm (7.5%). The changes left a modified ITT population of 349 randomised subjects. No results were collected from the excluded patients. In addition, the FDA initially approved a composite endpoint of “patient survival at day 30 post-transplantation, and absence of 2005 International Society for Heart and Lung Transplantation (ISHLT) Primary Graft Dysfunction (PGD) grade 3 at 72 hours post-transplantation.” However, TransMedics changed that endpoint to “survival at day 30 post-transplantation and absence of ISHLT PGD3 within the first 72 hours post-transplantation.” The agency advised against the change, as it could “jeopardize the integrity of the study and may invalidate the data collected thus far,” according to briefing documents posted ahead of the meeting. The sponsor did not take this advice. As a result of the change, the sponsor changed the primary analysis population from modified ITT to per protocol (PP). The FDA regarded the modified ITT population as primary and the PP as the secondary analysis population. The agency said the PP population is susceptible to selection bias. During its presentation at the meeting, the FDA noted that it had statistical concerns for the modified endpoint, particularly relating to good clinical trial design. The agency said that primary endpoints and hypotheses should be pre-specified before any medical device clinical trial begins. In addition, the FDA noted that prior to the primary endpoint change, the sponsor had access to unblinded outcome data and 227 of 320 subjects had been transplanted. Access to data related to these subjects, the FDA hypothesised, might have led to the endpoint change. In addition, excluding patients after randomisation potentially could weaken the comparability of the study arms produced by randomisation. Further, inferences based on random or ad hoc subgroups present challenges regarding interpretation and generalisation. It remains to be seen how the FDA will decide on OCSLung. However, the FDA does not discourage sponsors from making changes. A sponsor may modify the device or clinical protocol without approval of a new IDE application or supplement if it meets certain criteria. Examples include emergency use to protect the life of a subject and certain developmental changes in the device that do not constitute a significant change in the design or basic principles of operation. In these cases, the sponsor must provide notice to the FDA within five working days either of learning of the emergency or making the changes. The FDA also has provided its thinking on adaptive trials in joint guidance, titled "Adaptive Designs for Medical Device Clinical Studies," from the Center for Devices and Radiological Health and Center for Biologics Evaluation and Research. The guidance notes that an adaptive design allows for prospectively planned modifications as data are collected without weakening the study’s integrity and validity. The guidance offers other tips, including what factors should be taken into consideration when choosing an adaptive design.

Elizabeth Hollis Writer and editor who has covered the medical device and pharmaceutical sectors for a decade. She started at Clarivate Analytics in January, focusing on FDA drug/device advisory committee meetings and drug approvals for Cortellis and the AdComm Bulletin. Email:

Journal for Clinical Studies 33


Rise of Paediatric Diabetes in Mauritius Mauritius is a small island (1864 km2) located in the Indian Ocean, about 2000 km east of Madagascar. The resident population was 1,236,817 according to the 2011 “Mauritian” census and is estimated to be 1,348,242 by the US Bureau of the Census (ranking 156th in the world)1. It has a multi-ethnic population, consisting of Indians (68%), Creole (27%), Chinese (3%) and French (2%)1. Mauritians are the wealthiest in Africa with an average wealth of US$25,700 per person, still lower than the global average of US$27,0002. Mauritius is a welfare state, providing free education and healthcare (primary to tertiary). The healthcare system is equitably distributed in terms of availability and access to care. At the end of 2015, it had five regional hospitals, two district hospitals, one psychiatric hospital and three other specialised hospitals and one cardiac centre. At the primary level, there are two community hospitals, five mediclinics, 18 area health centres (AHC) and 116 community health centres (CHC). Additionally, 17 private health institutions with a total of 647 beds were present3. The health situation in Mauritius has seen a switch from infectious diseases, including malaria, tuberculosis, poliomyelitis, pneumonia, maternal conditions and malnutrition, to noncommunicable disease, namely diabetes, heart disease, cancers and chronic respiratory diseases. The death rate due to chronic diseases has increased from 467 in 2007 to 527 per 100,000 population in 20153. Diabetes is the leading cause of death (24.1%), followed by heart diseases (19.9%), cancers and other tumours (13.3%) and diseases of the respiratory system (9.2%) in 20153. Diabetes is a group of metabolic diseases characterised by hyperglycaemia, resulting from defects in insulin secretion, insulin action, or both. In diabetics, the chronic hyperglycaemia is associated with long-term damage, dysfunction and failure of various organs, including the eyes, kidneys, nerves, heart and blood vessels. Generally, it can be classified as: Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes mellitus and other specific types of diabetes4. Table 1 shows the clinical characteristics of type 1, type 2 and monogenic diabetes in children and adolescents.

Table 1: Clinical characteristics of type 1, type 2 and monogenic diabetes in children and adolescents5. CGK: Glucokinase; NDM: neonatal diabetes mellitus. 34 Journal for Clinical Studies

Type 1 Diabetes Type 1 diabetes (T1D) is caused by pancreatic β-cell destruction and usually leads to absolute deficiency of insulin secretion. The T1D immune-mediated form (previously known as insulin-dependent diabetes or juvenile-onset diabetes) accounts for 5–10% of those with diabetes and results from a cellular-mediated autoimmune destruction of the β-cells. The known markers are islet cell autoantibodies, autoantibodies to insulin, autoantibodies to GAD (GAD65) and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. Invective and environmental triggers remain mostly unknown but start the process of β-cell destruction months to years before the clinical symptoms manifest5. In the T1D idiopathic form, the antibodies are absent but the clinical presentation is similar4,5. Collaborative initiatives, including the WHO DIAMOND Project, develop population-based, standardised registries of new T1D cases worldwide6. Nonetheless, large differences in the incidence and prevalence of T1D were reported, ranging from under 0.5 to over 60 cases annually per 100,000 children aged under 15 years. T1D was most common in Scandinavian populations, Sardinia and Kuwait and much less common in Asia and Latin America in the WHO DIAMOND project study sites7. In high-income countries, the annual incidence has been increasing steadily by about 3% for the past few decades. However, data for sub-Saharan Africa and Latin America remain scarce8-10. In Mauritius, from 1986–1990, the T1D age-standardised average incidence was 2.1 per 100,000 children aged ≤ 14 years of age and was similar amongst Mauritians of Asian Indian, Chinese and Creole origin11. In contrast, from 2004–2008, it was reported that the age-standardised average incidence was 4.94/100,000/year12. In 2012, the number of children classified as Type 1 diabetes in the five regional hospitals was 125 (<18 years old) and in 2017 this number is 155 (≤16 years old) (National Coordinator, personal communication and unpublished results). Figure 1 shows the number of children classified as having Type 1 diabetes at the five regional hospitals and % of those children with % HbA1c > 7.5 and > 10 at the five regional hospitals in 2017. Volume 9 Issue 4

Therapeutics and adolescents with T2D but those cases are now encountered more often at the public hospitals. Furthermore, there has been an increase in the number of adolescents that have been identified as potentially pre-diabetic and diabetic (HbA1C of > 6) during the screening at secondary schools carried out by the Ministry of Health and referred to the public hospitals.

Figure 1: (A) Number of children classified as having Type 1 Diabetes at the five regional hospitals. (B) % of T1D children having % HbA1c > 7.5 and > 10 at the five regional hospitals in 2017.

Type 2 Diabetes Type 2 diabetes (T2D) accounts for ~90-95% of those with diabetes and was previously known as non-insulin-dependent diabetes or adult-onset diabetes. Individuals with T2D have insulin resistance and usually have relative insulin deficiency4. Therefore, T2D is usually associated with other features of the insulin resistance syndrome, namely hyperlipidaemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, and non-alcoholic fatty liver disease (NAFLD)13.

Obesity Most patients with Type 2 diabetes are obese, and obesity also causes some degree of insulin resistance4. Obesity is commonly defined as having an excess of body weight due to a chronic caloric imbalance, with less calories being expended than consumed each day19. The Body Mass Index (BMI) is a measure derived from the weight and height of an individual which is then compared to age and gender percentile-based norms to classify individuals as underweight, normal weight, overweight or obese19. The Global Burden of Disease (GBD) 2015 Obesity Collaborators estimated that 107.7 million children and 603.7 million adults were obese. The prevalence of obesity in both children and adults has increased, with the rate of increase in childhood obesity greater than that of adult obesity in many countries20. It is estimated that approximately 43 million preschool-aged children worldwide are overweight or obese, with 92 million considered to be at risk21. In the US, approximately 17% of children are considered obese and one-third of children are overweight or obese22, with African American and Hispanic children at an increased risk23. In Mauritius, the prevalence of obesity in 2015 has increased compared to that measured in 2009. In 2015, it was 45.5%: 50.6% for women and 39.4% for men and the prevalence of overweight was 23.1%: 20.9% in women and 26.7% in men using the ethnicspecific BMI cutpoints. It is alarming that 68.6% of participants were either overweight or obese (rate of 66.0% for men and 70.1% for women)18. The 2011 Global School-based Student Health Survey on 2168 students aged between 13 and 15 years in Mauritius showed that 21.2% students were overweight, whilst 6.2% of students were obese24. In 2006, the prevalence of overweight and obesity in 9-10-year-old boys was 15.8% and 4.9%, respectively, and in girls was 18.9% and 5.1%, respectively. Urban children had a slightly higher mean BMI than rural children but were twice as likely to be obese25. The high percentage of overweight and obese children and adolescents in Mauritius indicates that Type 2 diabetes in these age groups is, and will become, more common than previously expected.

The World Health Organisation (WHO) estimated that in 2014, 422 million adults had diabetes (the majority with T2D), and approximately half of the diabetics live in WHO South-East Asia and Western Pacific Regions14. The global prevalence had increased from 4.7% in 1980 to 8.5% in 2014 (NCD Risk Factor Collaboration)15. The prevalence had increased faster in low- and middle-income countries than in high-income countries, with the WHO Eastern Mediterranean Region showing the greatest increase and highest prevalence (13.7%)14. Similarly, T2D in children and adolescents has increased rapidly worldwide in recent years16. Epidemiologic studies have shown that the prevalence of T2D in children and adolescents varies between different ethnic groups, with the highest prevalence for Pima Indians (50.9/1000)17. The U.S. SEARCH study calculated an incidence of 8.1/100,000 and 11.8/100,000 for 10–14 years old and 15–19 years old, respectively, with the highest rate among Native American Indians and the lowest rate among non-Hispanic white youth10.

Other Types of Diabetes Monogenic diabetes is another form of diabetes diagnosed in children and adolescents and include genetic defects of the β-cell function4. These are commonly characterised by the onset of hyperglycaemia at an early age (usually before 25 years old) and are called maturity-onset diabetes of the young (MODY). They are inherited in an autosomal dominant pattern and are characterised by impaired insulin secretion with no or minimal defects in insulin action4. On the other hand, neonatal diabetes is diagnosed in the first six months of life and is distinct from the autoimmune T1D, and can be either transient or permanent4.

In Mauritius, a survey conducted in 2015 revealed that the age and sex standardised prevalence of diabetes in 18–74 years old was 19.5%: 18.7% in men and 19.5% in women and prevalence of pre-diabetes (impaired glucose tolerance or impaired fasting glycaemia) to be 19:4%: 20.2% for women and 18.5% for men in adults aged 25–74 years18. The incidence of diabetes in men and women was estimated to be 21.2 and 19.7 per 1000 person-years, respectively18. Unfortunately, there is no official number of children

Diagnosis of Diabetes The presenting symptoms of the child with diabetes are classical: polyuria (excessive or abnormally large production or passage of urine), polydipsia (excessive thirst), nocturia (excessive urination at night), enuresis (involuntary urination), polyphagia (excessive hunger or increased appetite), blurred vision, weight loss and failure to thrive, especially among 0–3 years5. In severe cases, the child may present acute symptoms of ketoacidosis or non-ketotic

Journal for Clinical Studies 35

Therapeutics hyperosmolar syndrome: extreme weakness, dehydration, vomiting, stupor, coma which can lead to death without immediate and intensive clinical intervention5. For immediate diagnosis, routine laboratory tests such as urea, electrolyte, blood sugar, acid base gas and screening for infection are carried out, and a diagnosis is made in order to start an appropriate treatment. In addition, it is mandatory to obtain the family history of the patient so as to proceed for additional tests: antibody detection (GAD, IAA, IAD) for type 1 diabetes and genetic testing for maturity onset diabetes of the young (MODY). With the available information, the diagnosis is confirmed and the most appropriate treatment is given to the patient and also the clinical course of the disease can be predicted. In Mauritius, it is important to note that the following laboratory tests: GAD antibodies, serum insulin level and C-peptide level are now available and accessible to the treating practitioner in public healthcare. The majority of the clinical cases of diabetes in children or adolescents are being treated by a paediatrician or a doctor who has a special interest in diabetes in public hospitals. The treatment is given in a shared care approach with the involvement of doctors, diabetic nurses, social workers, psychologists and parents. A major constraint in the management of diabetes in children and adolescents is the non-availability of genetic testing and MODY cases are therefore misdiagnosed as T1D or T2D. The treating doctor fails to predict the clinical course of the disease and give the most appropriate treatment. Treatments Special diabetic clinics for children and adolescents have been set up in all five regional hospitals in Mauritius, and are run by a multidisciplinary team consisting of medical specialists or community physicians, diabetic nurses and nutritionists, with the patient at the centre. The family is also involved in the treatment of the patient. Paediatric diabetes patients have frequent appointments with their doctors; the frequency depends on the glycaemic control and can be as often as weekly, and the diabetic nurses maintain constant contact with the patient by phone. Additionally, there is a retinal screening unit and a diabetic foot clinic which are annexed to each diabetic clinic. Patients under the age of 16 are provided with rapidacting and long-acting drugs such as insulin glulisine (Apidra®) and glargine (Lantus®) and determir (Levemir®) and insulin pens at no cost. Moreover, glucometers and glucose strips are provided free of charge to diabetics of all ages at the hospital. Treatment in all five centres is delivered according to the International Society of Pediatric and Adolescent Diabetes (ISPAD) guidelines so that uniformity in the management of diabetes can be achieved in all five centres. Intensive therapy with multiple-dose insulin and regular self-monitoring of blood glucose (SMBG) are required to attain the optimal glycaemic control. A target of HbA1c < 7.5% without succumbing into episodes of severe hypoglycaemia is recommended by both the ISPAD and ADA26,27. Unlike adults, paediatric patients have to live with the disease longer. The onset of the diabetes at an early age increases the risk of micro- and macro-vascular complications as there is an increased duration of exposure to hyperglycaemia and other metabolic abnormalities28. In addition, there is rapid growth and development of the body from infancy to adolescence. Any deviation from the normal homeostasis of the internal environment has deleterious effect on the normal course of growth and development. In patients under six years old, the caregivers are able to maintain good glycaemic control. Pre-teen patients under parental guidance are 36 Journal for Clinical Studies

also able to achieve acceptable glycaemic control. However, there is a real challenge for adequate glycaemic control in adolescents, who are very different physiologically and cognitively from the younger group. Nevertheless, acute complications of diabetes, namely hypoglycaemia and diabetic ketoacidosis, are rare, but there have been some cases recorded at the accident and emergency department. The latent period for chronic complications including retinopathy, neuropathy and nephropathy is 5–10 years. In Mauritius, acute and chronic complications of diabetes are both reduced by: 1. Free and accessible healthcare; 2. Encouragement of parental involvement; 3. Good monitoring of blood glucose levels and frequent HbA1c testing (once every three months); 4. Continuous education of parents and patient; 5. Positive doctor-patient relationship; 6. User-friendly technology, (e.g. glucometers) and provision of drugs and insulin pens. Prevention Preventive strategies are being coordinated from a public health approach in the country. Screening programmes are carried out in secondary schools among 11–17 years old (pubertal) students and measurements, namely weight, height, BMI and blood pressure are taken, and eye and laboratory tests including HbA1c and blood glucose are carried out. From January 2006 to May 2009, 13,294 out of 62,407 students screened have been referred to appropriate health institutions for further management and treatment29. Students with BMI above 85% percentile are referred to hospital for investigation, counselling and follow-up. Community physicians (CPs) of different regions and health caravans carry out talks to sensitise students in primary and secondary schools30. In addition, several non-governmental organisations (NGOs) provide assistance in the management of diabetes by running diabetic camps, carrying out home visits and school screening programmes and providing education and support to diabetic children and their family. However, it is a known fact that no intervention has been shown to delay or prevent T1D30. In genetically susceptible individuals, some environmental factors such as congenital rubella and enteroviral infections cause destruction of the islet β-cells30. Unlike T1D, T2D can be delayed or prevented by adopting a healthy lifestyle and by maintaining an optimum weight, practising regular physical exercise, eating healthily and not smoking. In Mauritius, the sale of soft drinks, and sugary and fatty foods, are banned on the premises of educational institutions: pre-, primary, secondary and pre-vocational schools30. Additionally, two periods of physical education (PE) per week are carried out in all secondary schools and PE has gradually been implemented, although not accessed in primary schools30. Overall, the patients have to be reminded by healthcare providers that they have to lead a healthy lifestyle throughout their life. Conclusion Diabetes is a substantial public health problem with an enormous global burden. In 2012, it caused 1.5 million deaths and higherthan-optimal blood glucose caused 2.2 million deaths by increasing the risks of other disease, including cardiovascular diseases14. The situation is as bleak in Mauritius: diabetes is the number one killer and the NCD 2015 survey has shown moderately poor metabolic control of diabetes (33% of diabetic patients had HbA1c ≥9.0%), Volume 9 Issue 4

Therapeutics ominous of very high risk of developing diabetic complications. Alarmingly, the T2D and obesity epidemics have spread to children and adolescents. Although costly, the public healthcare system provides treatments and support free of charge to the diabetic children and adolescents. Screening programmes are carried out in secondary schools to detect undiagnosed diabetes in students and preventive measures have been set up to tackle obesity, and consequently T2D, in children and adolescents. However, type 2 diabetic registries for children and adolescents are still lacking and genetic testing for monogenic diabetes is not available at the hospitals, therefore patients are misdiagnosed and not given the appropriate treatment. It remains a priority to effectively and urgently address diabetes in Mauritius and this can only be achieved using whole-of-government and whole-of-society approaches. REFERENCES 1 Central Intelligence Agency. The World Factbook. Available at: mp.html#Issues. Last accessed: 01 July 2017. 2 AfrAsia Bank. Africa Wealth Report 2017. (2017). 3 Ministry of Heatlh and Quality of Life. Health Statistics Report. (2015). 4 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes care 37 Suppl 1, S81-90, doi:10.2337/dc14-S081 (2014). 5 Craig, M. E. et al. ISPAD Clinical Practice Consensus Guidelines 2014. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatric diabetes 15 Suppl 20, 4-17, doi:10.1111/pedi.12186 (2014). 6 Diamond Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. Diabetic medicine : a journal of the British Diabetic Association 23, 857-866, doi:10.1111/j.1464-5491.2006.01925.x (2006). 7 Tuomilehto, J. The emerging global epidemic of type 1 diabetes. Current diabetes reports 13, 795-804, doi:10.1007/s11892-013-0433-5 (2013). 8 Patterson, C. C. et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 373, 2027-2033, doi:10.1016/S01406736(09)60568-7 (2009). 9 Gale, E. A. The rise of childhood type 1 diabetes in the 20th century. Diabetes 51, 3353-3361 (2002). 10 Writing Group for the Search for Diabetes in Youth Study Group et al. Incidence of diabetes in youth in the United States. Jama 297, 2716-2724, doi:10.1001/jama.297.24.2716 (2007). 11 Tuomilehto, J. et al. Incidence of IDDM in Mauritian children and adolescents from 1986 to 1990. Diabetes care 16, 1588-1591 (1993). 12 Guness, P. & Chan Sun, M. Epidemiology of Type 1 Diabetes Mellitus in Mauritius. American Journal of Health Research 1, 32-35 (2013). 13 Miller, J., Silverstein, J. H. & Rosenbloom, A. L. Type 2 diabetes in the child and adolescent. . Paediatric Endocrinology edn, Vol. 1 169-188 (Marcel Dekker, 2007). 14 World Health Organization. Global report on diabetes. (2016). 15 NCD Risk Factor Collaboration. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387, 1513-1530, doi:10.1016/S0140-6736(16)00618-8 (2016). 16 Chen, L., Magliano, D. J. & Zimmet, P. Z. The worldwide epidemiology of type 2 diabetes mellitus--present and future perspectives. Nature reviews. Endocrinology 8, 228-236, doi:10.1038/nrendo.2011.183 (2011). 17 Fagot-Campagna, A. et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. The Journal of pediatrics 136, 664-672 (2000). 18 Ministry of Health and Quality of Life. The Trends in Diabetes and Cardiovascular Disease Risk in Mauritius. The Mauritius Non Communicable Diseases Survey 2015., (2015). 19 Pulgaron, E. R. & Delamater, A. M. Obesity and type 2 diabetes in children: epidemiology and treatment. Current diabetes reports 14, 508, doi:10.1007/

s11892-014-0508-y (2014). 20 GBD Obesity Collaborators. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. The New England journal of medicine, doi:10.1056/NEJMoa1614362 (2017). 21 de Onis, M., Blossner, M. & Borghi, E. Global prevalence and trends of overweight and obesity among preschool children. The American journal of clinical nutrition 92, 1257-1264, doi:10.3945/ajcn.2010.29786 (2010). 22 Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of obesity and trends in body mass index among US children and adolescents, 19992010. Jama 307, 483-490, doi:10.1001/jama.2012.40 (2012). 23 Kumanyika, S. & Grier, S. Targeting interventions for ethnic minority and low-income populations. The Future of children 16, 187-207 (2006). 24 Ministry of Health and Quality of Life. Global School-based Student Health Survey 2011. Country Report. Republic of Mauritius. (2013). 25 Caleyachetty, R. et al. Prevalence of overweight, obesity and thinness in 9-10 year old children in Mauritius. Globalization and health 8, 28, doi:10.1186/1744-8603-8-28 (2012). 26 Chiang, J. L., Kirkman, M. S., Laffel, L. M., Peters, A. L. & Type 1 Diabetes Sourcebook, A. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes care 37, 2034-2054, doi:10.2337/dc14-1140 (2014). 27 Rewers, M. J. et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatric diabetes 15 Suppl 20, 102-114, doi:10.1111/pedi.12190 (2014). 28 Amutha, A. & Mohan, V. Diabetes complications in childhood and adolescent onset type 2 diabetes-a review. Journal of diabetes and its complications 30, 951-957, doi:10.1016/j.jdiacomp.2016.02.009 (2016). 29 Ministry of Health and Quality of Life. Available at: http://health. Last accessed: 01 July 2017. 30 Chan Sun, M. F. & Jeetun, N. University of Mauritius Research Journal 18B (2012).

Laure Lam Hung PhD, Project Manager and Clinical Research Associate at CIDP. Laure has a PhD in molecular biology from the University of Cambridge (Wellcome Trust Sanger Institute four-year PhD studentship). She has been responsible for the management of dermatological and pharmaceutical clinical trials since 2015 and monitoring of multiple sites of two global multi-centric Phase III clinical trials in paediatric patients with type 2 diabetes. Email:

Dr Tarkeswarnath Bachoo MBBS, MD (Paediatrics), Fellowship (Paediatric Endocrinology). Consultant Paediatrician at Flacq Hospital. He graduated with an MBBS from Goa University, India in 1999, an MD from Benaras Hindu University, India in 2005 and undertook a fellowship (paediatric endocrinology) in Nairobi, Kenya. Dr Bachoo has been working in paediatry at the Mauritius Government since 2006, and acts as an investigator in studies in the paediatric population with type 2 diabetes. Email:

Journal for Clinical Studies 37


How Functional Service Provision can Directly Impact Clinical Trials Success Crucial Factors to Select the Right Model It has become quite evident for pharmaceutical companies that their approach to the implementation of a functional service provision (FSP) directly impacts how successful those FSP teams will be. This is why, before any pharmaceutical company makes that decision, it should fully understand how to utilise its CRO or CROs to attain the best possible results with FSP teams. In outlining a modest roadmap, it is important to delve into the challenges when trying to achieve 'sustained' quality. Sustained quality begins with picking the right model and exploring myriad critical areas to safeguard its success: planning, training, cultural fit, staff retention, technology, communication, agility, sponsor participation, performance indicators, expectations management, etc. It is also helpful to clearly understand the four models (uncapped T&M, capped T&M, fixed fee and ring-fenced FTEs) and the key advantages and disadvantages they bring, based on clinical trial requirements and actual real-life experience. In doing so, it’s important to consider the crucial success factors involved in order to mitigate the risks that can disrupt a clinical trial losing time, effectiveness and potentially damaging the sponsor/vendor relationship. Through the feedback from people who have worked within an FSP team, we have uncovered what works best from the standpoint of those involved operationally. The first of two main trends in outsourcing is the project-based model. The difficulty with such a model for big pharma that are accustomed to in-house groups is that they typically have a steady stream of questions going to the study teams. This is because they are used to initiating changes and utilising internal resources to address often-changing requirements. Often, when this approach is deployed with a CRO, they run into taking on change orders and then become dissatisfied. The second trend encompasses managed, full-time equivalent (FTE) pools, otherwise known as functional service provision (FSP). Typically, medium or large companies take interest in these because they quite often have internal teams, but have the need to supplement them for fixed periods, managing peaks and valleys to keep employee overhead down. The four main delivery models for FSP are as follows: • Uncapped time and materials (T&M) – This often entails using the systems and SOPs of the pharmaceutical company. It can be low-profit work if the CRO does not achieve the correct blend of senior to junior resources, or higher cost regions to low cost regions. However, it is a straightforward delivery model and 38 Journal for Clinical Studies

agreeing on change orders is less contentious. Price increases tend to be inflation-linked and usually work on a two- or even three-year pricing model. • Fixed fee – Generally performed using the CRO’s own systems and SOPs, less commonly using the pharmaceutical company’s infrastructure. Pricing can be difficult to get right when delivery is on the pharmaceutical company’s systems as it involves processes of which the CRO has no experience at first. Pharmaceutical companies should allow time for learning, followed by efficiency gains over the period of the contract. Fixed fee FSP can include lengthy projects and can be of high complexity. For the CRO, defining the complexity levels during or after the bid process is key to avoid making a financial loss on high-complexity work. This model can cause conflict within the pharmaceutical company – pitching procurement needs against the requirements of the operations department. This potential risk needs active management. The CRO needs to fit in with both the pharmaceutical company’s procurement team and operations team and needs to be strict on working to contract as change orders are difficult to obtain. The CRO is often treated as part of the pharmaceutical company’s own delivery team; the FSP manager is therefore key to this relationship and the customer procurement team will expect pushback if their operations team start requesting work outside of contract. The CRO is expected to police the scope to ensure what is delivered is within it, and to ensure change orders are managed up front and prior to work being completed. The pricing of hours required to deliver units has to be correct or the profit margin slips away very quickly. Creating a pricing model that the pharmaceutical company can use before allocating the work will help build confidence and trust; change orders may then be more easily accepted. Fixed fee usually operates on a three-year pricing model. • Capped T&M – This often entails using the systems and SOPs of the pharmaceutical company. The key is to manage caps very carefully using percentage complete versus hours worked. Capped T&M can first appear to be quite profitable for the CRO. The risk is that caps are hit before the work is completed and no change orders have been agreed in advance. The CRO may have to write off hours that cannot be charged. The CRO must review and monitor project performance constantly. It also needs to manage the workload, not take on too much or commit too many employees to the contract as the work can suddenly disappear. This applies to all delivery models. Typically, capped T&M also operates on a three-year pricing model. • FTE or ring-fenced – This is a T&M model, fundamentally, but the pharmaceutical company buys 100% of the resources’ time. They, therefore, pay for the resource whether they use Volume 9 Issue 4

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SGS is a leading life sciences CRO providing clinical research and bioanalytical testing services. Delivering solutions in Europe and in the US, SGS offers Phase I to IV clinical trial services encompassing clinical project management and monitoring, biometrics, PK/PD modeling & simulation and regulatory & medical affairs consultancy. Clients benefit from our a wealth of expertise in regulatory and exploratory trials, viral challenge testing, complex PK/PD and biosimilars studies with a high patients therapeutic focus in Infectious Diseases, Vaccines, Oncology and Respiratory. Stay ahead in your drug development plan, contact us for reliable and adaptive clinical trial solutions.





Journal for Clinical Studies 39

Technology them or not. The pricing is often annual and linked to inflation. The model is again often used working on the pharmaceutical company’s systems and SOPs. It is usually low-profit as the pricing is restricted due to the pharmaceutical company comparing the cost to that of contractors or in-house resource, forgetting that the FTE is managed by the CRO. There can be a risk that the CRO cannot ramp up, as the price is too low for the salaries required to recruit the level of staff the customer wants. Staff may be required on customer site at times and the customer will want senior staff as often they expect them to manage/interact with their own employees. Often the work is not complex and this leads to boredom and a high staff turnover. From real-world experience and feedback from the field, we have come to realise just how important it is to anticipate the risks of each model and assurance of measures to be implemented to ensure sustainable quality, customer satisfaction and staff retention. Building Long-term Relationships For CROs there are a few critical success factors to consider to reach a long-term sponsor/vendor relationship. The vendor needs to guarantee 'sustained' quality. It is not acceptable to deliver ten good people (who are perhaps more expensive) and then, in an effort to get to a target margin, reduce the quality of the next ten by buying in cheaper resources and repeat that again with the next ten. Any plan needs to deliver an agreed margin, which may be lower than the vendor wants but will unlock more work in the medium/long term. The CRO needs to conduct ongoing pre-selection of candidates to avoid rushing and recruiting sub-optimal resource. Culture Assessment The cultural fit between the pharmaceutical company and individuals in the FSP team is important. The pharmaceutical company must be able to screen to ensure there is a cultural fit with the person and not just technical suitability. Character profiling is often overlooked in the heat to meet demand. It is important that individuals can work to the values of the pharmaceutical company.

40 Journal for Clinical Studies

Getting the pharmaceutical company involved to some extent in the CRO’s HR processes can be beneficial in aligning expectations and building trust with the selected CRO. Communication and Transparency Communication and transparency are crucial. Therefore, if KPIs can be agreed in the area of communication, both parties can agree on their expectations. Typically, the team will be located in different offices and different countries. This can be acceptable to a pharmaceutical company in the knowledge that they may get the necessary blend of high/low cost with some team leads that are local to their own for regular communication. For example, the mix could be 40% high cost, 20% medium, 40% low, and the geographical spread may enable the appointment of more experienced resource in each country. Time zone is important to achieve essential dayto-day communications to get the work done.   Technology and Effective Training Technology-wise, it is often most efficient for the CRO team to access the pharmaceutical company’s technology environment remotely and work within it. One person or a small group can be trained directly by the sponsor who, in turn, can train others as needed. This is known as the “Train the Trainer” model. The CRO should deploy internal management to monitor quality and productivity. KPIs should be monitored in this respect and shared with the pharmaceutical company at regular governance meetings. The FSP manager at any given location is critical to the relationship. Typically, the pharmaceutical company and vendor can agree on a ratio of one FSP manager to a particular number of resources.   Retaining the Team Team attrition can be a big factor in achieving an ongoing quality service. If the team is located in an unattractive location, attrition can be higher. In addition, the team lead plays an important role in keeping individuals motivated and happy in their place of work. Salary is, of course, a key factor, so if the CRO has agreed to a fiveyear price deal that is unsustainable due to demand and salary increases for a particular skill set, then attrition only increases as

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employees are lured to higher-paid positions in other companies. Sponsors have often found that CROs who are good at delivering fixed fee projects are not good at delivering FSP and vice versa. FSP is a very different mind-set and modus operandi. Sponsors and vendors need to be aware of this if trying out FSP for the first time. Oftentimes it works best where the sponsor supplies the team leads and the CRO employees are treated as an extension of the sponsor’s own in-house team. Agility and Scalability An important factor in evaluating a vendor is to see some evidence of their ability to ramp up to meet the pharmaceutical company’s work plan. A typical question is how many resources does the CRO have in the particular functional area. The answer may be a high or a low number, but whatever the case, it does not bear any relation to the number of resources available to the sponsor. No CRO has idle staff in great numbers, so the sponsor has to expect a ramp-up period. The CRO needs to have a credible ramp-up plan, preferably with some previous track record of success. It should be transparent to the sponsor how many resources will be existing employees and how many will be recruited. Experience and Expertise Having testimonials is helpful to support a bid. The bid documents themselves need to be very well defined, and fully aligned with the needs of the pharmaceutical company in terms of timescale, skill levels, pricing, workload and communication. Competitive Pricing On the subject of pricing, a blend of low-cost resources with medium-/high-cost ones ensures a competitive overall price, but it is important to build in inflation if the pricing is to last more than a year. If the bid is via an online reverse auction, 42 Journal for Clinical Studies

robust models will need to be built to quickly calculate margin at different prices. The downside of this procurement method is the significant risk to sustainable quality if the price is driven too low. It can become impossible to recruit the right level of resource so the vendor fails and the sponsor is left with an urgent problem to solve, to avoid pushing out study end dates. In Summary Overall, sponsors who already have experience with FSP should evaluate what aspects are working and which are not, as there may be a better model available. They should also make sure that the contract details are going to be sustainable for the CRO because they will ultimately be affected by resource constraints or team turnover. CROs need to evaluate if they can really meet the experience levels, resource numbers and pricing sought by the sponsor. A realistic ramp-up plan should be agreed between both parties to align expectations.

Chris Hamilton Chief Commercial Officer, CROS NT Over the past 27 years, Chris has worked in the pharma, CRO and publishing sectors. He is currently Chief Commercial Officer with CROS NT – a data-driven, full-service CRO with offices in Europe, the USA and India. Chris leads an international team and works in a consultative manner with sponsors who seek more strategic outsourcing practices. Email:

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Doing More with Clinical Trial Business Data: Adopt a Data Warehouse Healthcare is notorious for creating exorbitant amounts of data. The clinical research sector of the healthcare market is, by far, no exception to this trend. Pharmaceutical companies have been working for years on leveraging their clinical research data in more efficient ways, but other sectors of the research industry have been slower to follow. One solution for these businesses is to implement a data warehouse to derive trends and other actionable information to reduce costs and streamline research timelines. For the providers and the sites conducting and managing clinical trials, a data warehouse also serves as a valuable tool that should be considered as a source for near-real-time business data that can foster enhanced business operations, leading to simplified research processes and more advanced reporting. Whatâ&#x20AC;&#x2122;s more, data warehousing, and similar resources such as data marts and data repositories, can have expanded scope to incorporate data from other applications utilised in other areas of a business to derive even more valuable business insights. This article strives to explain the reasons for utilising a data warehouse in a clinical trials management setting, and discuss the benefits these organisations gain from implementing this technology. Understanding Data Warehousing A data warehouse is a database that is designed for query, analysis and reporting, rather than for transaction processing. It usually contains historical data that is derived from transaction data, but it can include data from other sources5. Unfortunately, the industry has created ambiguity when attempting to understand the concept of data warehousing. A data warehouse is a highlyorganised collection of standardised data that can be utilised to drive business intelligence or to pull large reports for specific purposes1. Business intelligence software can be utilised to analyse this data, and the data can also be grouped into subsets of the larger warehouse, referred to as data marts. For example, a health system can create a data mart surrounding sponsor/CRO invoicing data related to clinical trials that specific individuals can access and report on without being impeded by other financial data within the data warehouse. Both the entire data warehouse and the related data marts differ vastly from rudimentary data repositories, which store large amounts of data and are difficult to manipulate1. Who Benefits from Data Warehousing? A data warehouse provides value to many organisations conducting and managing clinical trials. Those facilities conducting a large number of ongoing trials (regardless of the number of physical trial locations at those facilities), in addition to those who have a large archive of trials that have closed out, have a strong need for a data warehouse. For these organisations, such as hospitals, health systems, academic research organisations (AROs), independent research sites or site management organisations (SMOs), leveraging their data in an unstructured way, rather than from a relational database within a specific research application, offers a multitude of efficiencies. 44 Journal for Clinical Studies

Furthermore, organisations with multiple research systems are ideally set up to gain unparalleled business insights from data warehousing. Clinical research requires a variety of systems to both conduct and manage a trial in a compliant manner that is also conducive to profitability and quality patient care. Research organisations that leverage applications such as a clinical trial management system (CTMS), electronic medical record (EMR) system, interactive web response system (IWRS), electronic data capture (EDC) system or biospecimen management tool (just to name a few) afford themselves the ability to relate data from multiple systems in new ways to derive further information about the research business that does not reveal itself easily, even when these systems are integrated together. As organisations look to grow and evolve how clinical research is factored into their overall business, business leaders would be remiss to forego the additional leverage that they can extract from their existing trial-related data that comes with a data warehouse. When is Data Warehousing Used? For research businesses, there are several reasons to utilise a data warehouse, and the matter with which they utilise the data warehouse varies for each use in order to gain the most from the data entered into the data warehouse. Business-wide Reporting Utilising Multiple Systems While research systems integrate to streamline research workflows and eliminate duplicate data entry, all of the information from the separate systems is not located in every system. When the data from these systems is entered into the data warehouse, it is no longer stored in a cumbersome, relational data model2. Rather, the unstructured configuration of a data warehouse allows for a business intelligence interface to relate information from multiple systems and generate accurate, standardised reports that are actionable, and provide relevant analysis with minimal effort in data gathering. Data Standardisation At a large research organisation conducting clinical trials in multiple departments or locations, the likelihood of multiple systems (i.e. multiple EMR systems at different hospitals within a single health system) is high. At a central research office, if researchers are attempting to identify their pool of potential patients for a clinical trial across their health system, pulling patient demographics from multiple EMR systems can be daunting, considering the fact each systems report fields differently (e.g. DOB vs. date of birth). This can make aggregating data manually extremely inefficient or entirely prohibitive4. A data warehouse allows for one-time standardisation of data between the multiple systems, and any reports generated through the data warehouse yield consistent, accurate data very quickly. Large Reports that a Single Research Application Cannot Handle Sometimes, the data in a single research application (e.g. CTMS) is so large, that pulling one report from a single, relational Volume 9 Issue 4

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database can result in timeouts or maximum report sizes, both of which make it ineffective for the individuals looking for the data (e.g. all sponsor invoices generated within a site network over the last seven years). The same data can be entered into the data warehouse and pulled with a business intelligence application to provide a complete report in a short amount of time. When You Require Multiple Data Marts If an organisation has teams throughout the business looking to analyse different cohorts of data related to clinical research, a data warehouse can make it simple to leverage specific sets of data within the single data warehouse through data marts. For example, an organisation can create data marts for reporting on clinical trials at a specific location, of a specific therapeutic area, or associated with a specific sponsor1. These specific subsets eliminate unnecessary data that might slow the ability to create reports or add unnecessary clutter. Oftentimes, a research has multiple reasons for adopting a data warehouse, and the flexibility of this tool allows for a multitude of teams to derive value at all levels of the business. 46 Journal for Clinical Studies

What Value Does Data Warehousing Provide? At research organisations looking to better leverage their research data, the freedom to analyse the data in several different ways benefits individuals throughout the business hierarchy. Managers and executives derive trends and predictive metrics that help move the business forward, while role-specific users can gather unparalleled depth into a specific area of the clinical trial process. As a result, these individuals can optimise their workflows to address areas of weakness or capitalise on strengths. More than simple reporting, a data warehouse can positively other impact areas of the business: Trial Budget Negotiation A reasonable and fair budget is essential for research organisations when running trials for a sponsor. If they are not able to negotiate the funds they need, they might have to forego conducting a trial in order to maintain profitability. While a CTMS can allow users to reference past trial data and reference old budgets and costs for procedures, a data warehouse can further this analysis; a data warehouse can allow sites to compare data in different ways (e.g. organised by therapeutic area, sponsor, or procedure) in order to justify budget amounts based on thorough, accurate data. Volume 9 Issue 4


Journal for Clinical Studies 47

Technology Assessing Trial Feasibility A data warehouse can efficiently determine a potential patient population, even when multiple EMR applications are in use. This is a difficult component in determining whether or not to accept a trial, and this data also allows for further negotiation on enrolment goals. When paired with the CTMS tools for budget feasibility, sites can attain greater confidence in determining if a trial will bring revenue to the business or not. Improved Subject Enrolment It has already been discussed how a data warehouse can better assess the potential patients for a clinical trial, but that efficiency in potential patient identification can also transcend to benefit the enrolment of trial patients. The Boston Medical Center conducted an analysis of their research assistants’ ability to enroll patients before and after implementing data warehousing within their organisation. What they found was, when conducting manual chart audits, their research assistants were able to assess 1500 charts in 1440 hours. This effort ultimately enrolled 50 subjects into a clinical trial. Post-implementation of the data warehouse, the team at the Boston Medical Center re-analysed the performance of their research assistants. The data warehouse allowed the research assistants to search for the overarching requirements of a trial and pull the patients with those qualifying characteristics. From there, the research assistants at the Boston Medical Center could begin screening patients, eliminating the manual process of looking through charts of unqualified patients. What they found was that number of chart audits reviewed improved 147% to 3700, while the time it took to review the charts decreased by an astounding 91% to 120 hours total. Ultimately, the research assistants at the Boston Medical Center were able to utilise the data warehouse to be more efficient, and boost their enrolment by 240%, from 50 to 1704. Better Responses to Audits and Other Inquiries Time is critical when responding to inquiries related to audits, or if reports are required for regulatory submissions. The standardised data in a data warehouse ensures that an organisation can pull the necessary data quickly. Moreover, the data warehouse removes the dependencies the data is associated with when pulled from other systems, and this has further positive impacts on the speed of reporting2. Risk Reduction At higher levels of the organisation, data warehousing, and the data standardisation that comes with it, allows business leaders to more quickly identify opportunities for improvement within the research components of the business and beyond. The value of this decisionmaking capability is heightened by the quality and efficiency with which the data is able to be aggregated3. When paired with business intelligence software, the business leaders of a research organisation can establish recurring reports that consistently provide proactive guidance that propels the business forward, while also streamlining research processes and improving patient care. Conclusion With the increasing complexity of clinical research at all levels, the importance of successfully maximising the capability for a research organisation to leverage its data is greater than ever before. For those conducting research, a data warehouse streamlines some of the tedious tasks associated with enrolling patients and providing complex reports on other facets of the research process. When paired with other research tools such as CTMS and EDC, 48 Journal for Clinical Studies

researchers have an end-to-end technology suite that streamlines their workflows and minimises risks that compromise data quality. For the managers of research, a data warehouse provides the necessary insights to better determine the feasibility of clinical trials. This predictability offers the opportunity to make clinical research a more profitable business unit. The ability to leverage this data also makes these research organisations more attractive partners for sponsors and CROs, as they have a better understanding of the characteristics of their patient population. What’s more, the aggregation of data from multiple systems allows for unique reports to be produced related to research financial data, which can be used during negotiations with sponsors and CROs. This data ensures sites conducting research have the support and resources they need to successfully enroll patients and conduct research in a quality and compliant manner. For the business leaders, a data warehouse provides a comprehensive understanding of their business through standardised data. Leaders’ ability to make decisions are not limited by the capabilities of systems to provide necessary data; rather, the unstructured nature of the database in a data warehouse allows for the combination of data originated in separate systems to derive trends and actionable insights that can be utilised to instill proactive changes at all levels of the business. Over time, expect to see the research industry continue to adopt data warehousing at all levels and at organisations of all sizes. While there might be significant effort in setting up these tools, the power of quality data will continue to prompt research organisations to implement everything they can in order to maximise the value of their data and positively position the company for long-term growth. REFERENCES 1. 2. 3.

4. 5., visited on 15 May 2017, visited on 15 May 2017 Evans, R. Scott, Lloyd, James F. and Pierce, Lee A. “Clinical Use of an Enterprise Data Warehouse.” AMIA Annual Symposium Proceedings 2012 (2012): 189–198. Print., visited on 15 May 2017, visited on 15 May 2017

Kyle Ricketts is the Marketing Manager at Bio-Optronics, Inc., the makers of Clinical Conductor CTMS, the clinical trial management system utilised by over 2000 research organisations worldwide, and several other software applications serving various sectors in healthcare. Kyle coordinates the creation of print and digital marketing materials for the research industry, and strives to provide the community with value-added information that shares best practices and elevates the clinical research community. Kyle received his MBA at the Rochester Institute of Technology in 2013. Email:

Volume 9 Issue 4


Big Data’s Role in Patient-centric Care

Effective use of big data could reduce healthcare expenditure by 8%, making $300 billion in savings every year, according to a study from the McKinsey Global Institute.1 There’s no doubt that healthcare’s digital transformation makes sound business sense, cutting down on administrative and clinical inefficiency. According to analysis from Accenture, digitisation will fuel almost one-third of growth and 40 per cent of profitability in the pharmaceutical market by 2020.2 However, as the NHS moves ever further into the digital sphere with a commitment to paper-free, cloud-based systems and a greater investment in AI and data analysis, it’s important to ask how the rise of big data will affect patients themselves. Thanks to constant technological innovation, patients have more involvement than ever in the care they receive. Technologies such as mobile healthcare apps and wearables have granted patients greater access to information about their own illnesses and care, changing their expectations about diagnosis, treatment and disease management. This same technology also offers a cost-effective and less intrusive method of monitoring health, with patients’ questions about their conditions answered in real time. To meet these expectations, the healthcare industry needs a fully connected IT infrastructure, integrating information from multiple systems to ease administrative workloads, facilitate patient-provider collaboration, and improve quality of care. In this sense, big data can be seen as part of a wider movement toward patient-centric connectivity, enhancing the overall patient experience both directly and indirectly. Healthcare staff need to corroborate data meaningfully via cutting-edge analytics technologies, pre-emptively spotting new opportunities for adding value to the patient experience and demonstrating transparency and trust via 24/7 personalised care. This calls for an in-depth analysis of how big data is currently affecting the industry, and how we can build on this to place a patientcentric data system at the core of big pharma business strategy. What is Big Data? The term ‘big data’ refers to large and complex data sets that require specialist processing software to store and analyse. Over the last few years, we’ve become accustomed to generating data in almost everything we do, from shopping to travelling to interacting online. In fact, 90% of the world’s data has been created over the past two years, showing the exponential rate at which our records are growing.3 As advances in technology allow us to collect and analyse data more efficiently, this information can be used by businesses and healthcare professionals to understand the needs of their audience and improve their service offering. Big data also uses inductive statistics, inferring laws and relationships between sets of data and allowing analysts to predict outcomes and behaviours, pre-emptively responding to consumers’ needs. The healthcare sector currently deals with an estimated 50 petabytes of data, predicted to grow to 25,000 petabytes by 2020.4 With organisations increasingly turning to online data storage, this information can be analysed on a global scale, helping practitioners 50 Journal for Clinical Studies

to prevent epidemics, avoid preventable deaths, and improve quality of life for patients. Big data allows us to view patients as consumers and analyse the decisions they make when it comes to their treatment. With healthcare data being generated about individuals from the moment of their birth, analysts are now keen to understand as much about patients as possible, picking up on potential illnesses at an earlier and more easily treatable stage, and personalising care at every step of the way. How Has Big Data Transformed the Clinical Process? Big data already plays a significant part in drug discovery, with researchers relying on AI systems to select the most promising drug candidates from a library of millions of molecules. Leo Barella, Global Head of Enterprise Architecture for AstraZeneca, went as far as to suggest that data-driven AI will be the primary tool for drug discovery by 2027.5 Once an appropriate drug is discovered, big data is consulted once again in the design process, with patients’ trending preferences in the shape, size and amount of pills taken into account. This ensures that patients’ expectations are being met, down to even the most aesthetic details of their treatment. Clinical trials also benefit from the prevalence of big data. The increasing amount of available information on applicants allows researchers to pick the most appropriate subjects for their studies, and monitor them more closely throughout the trial process. With 85% of clinical trials failing to retain enough patients, personalising processes is a pressing concern, with the potential to save millions by getting drugs on the market sooner. Big data lends itself to collaboration as well, with key pharmaceutical players sharing data between organisations in order to speed up research and development processes and make new breakthroughs. In fact, in 2013 publically available data from FDA-approved drugs led Stanford researchers to discover that the antidepressant desipramine had potential to cure small-cell lung cancer, for which there had previously been few reliable treatment options.6 Researcher Atil Butte commented on the relative time and cost efficiency with which the discovery was made, saying “We are cutting down the decade or more and the $1 billion it can typically take to translate a laboratory finding into a successful drug treatment to about one to two years and spending about $100,000.”7 All of these factors indirectly improve patient experience, making more effective treatments more accessible than ever before. Big data can go one step further, however, directly changing the way we approach patient care. Personalised Care While big data allows us to analyse trends on a massive scale, it also offers us unique insights into individuals. By tapping into the data generated by patients’ mobile devices, wearables and web searches, researchers are able to see the wider context of each patient’s story. This can lead to highly personalised care, improving relationships between patients and practitioners, offering bespoke data-driven advice, and making sure treatment fits into patients’ lifestyles as seamlessly as possible. Volume 9 Issue 4

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.

Research Quality Association 3 Wherry Lane, Ipswich Suffolk IP4 1LG UK T: +44 (0)1473 221411 E:

Our membership caters for professionals including managers, scientists, auditors, inspectors and practitioners concerned with the quality and compliance of research and development. Our members focus on the safety and efficacy of pharmaceuticals, biologicals, medical devices, agrochemicals and chemicals in man, animals and the environment. More information on all of our first class services and products can be viewed on our website.

Journal for Clinical Studies 51

Technology Clinical trials likewise benefit from analytical systems, with apps and portals drawing on data from social media to engage with patients and track results. Despite the ready availability of this data, it’s important for researchers to consider the fact that online interaction varies drastically depending on the age of each patient, and the stage and severity of their illnesses. As the current digitallydriven generation outlives its predecessors, however, this is likely to change, making social data a key indicator of patients’ lifestyles and needs across the board. This makes it more important than ever to raise awareness about the benefits of big data in healthcare. Many patients may be hesitant to consent to their data being used, yet the more data physicians have access to, the more informed diagnoses they can make. By being entirely transparent about data use and privacy, practitioners can help shift patients’ perceptions about big data, improving and accelerating healthcare’s digital revolution. Connected Hospitals Patients are rapidly becoming accustomed to having their day-today lives and preferences recorded in real time – and this doesn’t stop when it comes to hospital care. The Internet of Things (IoT) is responsible for a significant growth in ‘smart’ devices and sensors that communicate with one another, gathering information and instantly reacting to it. This technology is driven by data, with devices comparing patient input to statistical norms in order to help physicians make decisions. However, smart sensors and devices also generate data as they go, logging readings from each individual in order to create a streamlined, patient-centric experience. This level of connectivity means that sensors placed on patients’ bodies can seamlessly communicate with life-support systems and hospital infrastructures alike, recording vital signs and alerting caregivers about any changes in condition. Connecting hospitals means connecting patients, giving them access to the very latest information about their conditions, and allowing them to participate in decisions about their care. Connected medical devices can send regular updates to patient apps, allowing them to monitor their own vital signs and ask practitioners informed questions should any concerns arise. This level of patient involvement could have a significant effect on healthcare costs, avoiding unnecessary readmissions and helping practitioners to spot irregularities and pre-emptively combat issues before they become more serious and costly. Perhaps more importantly, wearable sensors and IoT devices offer caregivers a chance to interact with patients in innovative, convenient and consistent ways, developing meaningful relationships even when face-to-face care is not possible or necessary. In fact, a survey conducted by the American Academy of Family Physicians found that the overall majority of patients preferred home-based care to hospital care, citing comfort and convenience as well as relationships with physicians as key factors for their decision.8 For example, apps and wearables trialled on in-home monitoring of chronic obstructive pulmonary disease patients4 were able to accurately track weight changes in patients as they went about their day-to-day lives, notifying them and their caregivers of any unusual fluid retention. This allowed patients to remain at home during treatment, learning to manage their own diseases with the assistance of trustworthy data-driven reminders. Likewise, caregivers were able to cut down on hospital costs while nonetheless closely monitoring patients’ conditions, administering preventative care and treatment before hospitalisation was necessary. 52 Journal for Clinical Studies

Value-based Care Healthcare costs are a significant concern for patients at any stage of illness, and it’s important for healthcare staff to work together to offer as much value as possible to patients’ experiences. Big data can assist caregivers in this mission by ensuring coordinated and consistent care, based on the latest trends and information available. US insurers and public health systems such as Medicare and Medicaid are already promoting value-based and datadriven healthcare10, through compensation systems that reward meaningful use of electronic health records. Research shows that 44% of healthcare providers consider this a significant driving factor in investing in big data.11 In order to meet these conditions, healthcare practitioners are required to reassess their reporting, data management, and process automation to ensure that their patient care is top-quality and cost-effective. This will affect patients directly, ensuring complete transparency in healthcare delivery and billing, and ensuring that care is efficient and price-conscious. US insurers’ move away from fee-for-service compensation will hopefully set a precedent for global healthcare providers to invest in digital solutions and capitalise on big data while improving patient outcomes. Facilitating Big Data in Healthcare With the amount of healthcare data growing at 48% per year,7 healthcare providers need access to the most cutting-edge analytics capabilities, in order to translate this wealth of data into valuable insights about patient care and engagement. This requires significant updates to IT infrastructures, making them more powerful and scalable, anticipating continued growth in the amount of data processed. This is a significant challenge in the implementation of clinical data analysis, with 45% of organisations surveyed claiming that combining different types of data had caused them problems, and 37% citing difficulties in effectively managing volumes of data.13 Taking cues from the wider business world, healthcare professionals could benefit from the emerging trend of data lakes, which provide powerful architecture in which vast quantities of both raw and transformed data can be stored in a single location in multiple formats. This would not only reduce the number of data silos across healthcare organisations, leading to inefficient analysis and potential for lost or misinterpreted information, but would also allow for effective and efficient cross-data analysis. By interconnecting data from a number of trusted external sources such as wearables, fitness devices, and medical devices on the IoT, data lakes will allow clinical teams to amass rich pools of data for each patient under their care, reducing complications in care, delivering personalised treatments, and improving the safety of clinical trials. Open source data storage and analysis application, Hadoop, was developed by Yahoo, based on research by Google.14 Using powerful algorithms, it automatically divides large data queries into many more manageable parts, processing these individually via different nodes, and then combining the results for analysis. This will give researchers across the globe access to data sets that were previously impossible for their infrastructures to handle, opening up entire new research domains for exploration. This functionality will also allow analytics to become more forwardfocussed and accurate in their predictions, helping healthcare providers to create a continuous learning environment that reacts to every trend and innovation. Safeguarding One of the most significant concerns about healthcare’s growing reliance on big data regards safeguarding. As medical data is amongst an individual’s most personal information, researchers Volume 9 Issue 4

Technology need to ensure that this information is only seen by those whom patients have agreed to share it with. Medical data is highly valuable to cyber thieves, who reportedly make more money from stealing and abusing health data than they do from credit card details.15 In 2015 alone, 750 medical data breaches occurred,16 including the theft of 80 million patient records from healthcare insurer Anthem.17 While this attack focussed on gleaning identity data from patients rather than exposing data on illnesses and treatments, patients are understandably concerned about the digitisation of their medical information – and putting patients’ minds at ease about their privacy is a significant part of providing patient-centric care. Currently, an approximate 91% of cyber attacks come from phishing emails,18 luring professionals into clicking links and downloading compromising viruses. Healthcare professionals therefore need thorough training in computer literacy, with a particular focus on security. Spreading this knowledge and regularly updating training as cyber crime trends develop will pre-emptively counter further attacks of this nature. The FDA has also issued new guidelines on data security over the past two years, updating them to reflect the diversity of medical devices and apps. As well as calling for tighter security measures on connected devices and apps before they come to market, the guidelines focus on developing stronger channels of communication between device manufacturers and the practitioners who use them, ensuring that vulnerabilities discovered later down the line can be quickly fixed. In fact, greater levels of communication can be seen as a crucial aspect of healthcare’s digital transformation, pairing innovation with complete transparency to ensure that the risks of big data don’t outweigh the benefits it offers the world of healthcare. Conclusion Already, research from CDW Healthcare19 shows that 82% of organisations that have implemented big data analytics have reported improved patient care, while 63% report reduced admission rates and 62% claim improved overall health outcomes. With such significant yields already being seen, the big data revolution doesn’t seem to be slowing down. We can look at the Electronic Medical Records programme in Denmark20 for a glance at future successes: this nationally-implemented big data model has grown exponentially since its introduction in 2007, amassing 1.2 million entries by 2011, a significant proportion of which were supplied by patients themselves. This has provided a solid foundation for decision-making, and provided patients with easy and empowering access to their own health information. As much as these trends provide encouragement for healthcare organisations experiencing their own digital transformations, it’s the future we must focus on now: as patients become accustomed to the use of apps, wearables and IoT devices in their day-to-day lives, they will directly feed into their own patient care, and to the improvement of outcomes across the system. By becoming more involved in their own healthcare decisions, patients can actively contribute their experiences to the ongoing pool of information used by physicians across the globe to diagnose illnesses, plan and execute treatments, and offer patients extra value. Big data doesn’t just put patients at the centre of their own healthcare experiences. It puts them at the heart of the entire industry. REFERENCES 1.








9. 10.


12. 13. 14.



17. 18. 19. 20.

business-functions/digital-mckinsey/our-insights/big-data-the-nextfrontier-for-innovation Pharmaceutical companies that digitize grow more” retrieved from Big Data, for better or worse: 90% of world's data generated over last two years”, 2013, retrieved from releases/2013/05/130522085217.html Accelerating the evolution of human care”, retrieved from http://www. Robots and Research: The Future of Drug Discovery”, retrieved from A. Azvolinsky, “Antidepressants Could Treat Small-Cell Lung Cancer” retrieved from K. Conger, “Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study” retrieved from http://scopeblog.stanford. edu/2013/09/27/big-data-big-finds-clinical-trial-for-deadly-lungcancer-launched-by-stanford-study/ Patients Prefer Home vs. Hospital Care for Acute Illness” 2006, retrieved from afp/2006/1215/p2109.html B. Celler, N. Lovell, J. Basilakis, “Using information technology to improve the management of chronic disease”, 2003, retrieved from https:// Medicare & Medicaid EHR Incentive Program”, retrieved from https:// D. Mareco, “How to optimise patient care: the growth of big data in healthcare”, retrieved from how-to-optimize-patient-care-the-growth-of-big-data-in-healthcareinfographic R. Leventhal, “Report: Healthcare Data is Growing Exponentially, Needs Protection”, 2014, retrieved from com/news-item/report-healthcare-data-growing-exponentially-needsprotection D. Mareco, “How to optimise patient care: the growth of big data in healthcare J. Crapo, “Hadoop in Healthcare: A No-nonsense Q and A”, retrieved from C. Humer, J. Finkle, “Your medical record is worth more to hackers than your credit card”, 2014, retrieved from us-cybersecurity-hospitals-idUSKCN0HJ21I20140924 Why Data Security is The Biggest Concern of Health Care”, retrieved from B. Herman, “Details of Anthem's massive cyberattack remain in the dark a year later”, 2016, retrieved from article/20160330/NEWS/160339997 A. Savvas, “91% of cyberattacks begin with spear phishing email”, 2012, retrieved from D. Mareco, “How to optimise patient care: the growth of big data in healthcare Ehealth in Denmark”, retrieved from Filer%20-%20Publikationer_i_pdf/2012/Sundheds-IT/Sundheds_IT_ juni_web.ashx

Tarquin Scadding-Hunt CEO at mdgroup, a full-service agency with a focus on the life sciences industry. Email:

J. Manyika et al, “Big data: The next frontier for innovation, competition, and productivity”, 2011, retrieved from

Journal for Clinical Studies 53


Clinical Precision: What does AI Offer Life Sciences? Where information overload has started to slow innovation and efficiency in medicinal markets, could artificial intelligence and machine learning help – by pinpointing what’s important and suggesting better ways of doing things. AMPLEXOR’s Elvis Paćelat ponders the bigger picture. It would be easy to assume that the more adventurous end of technological innovation belongs to markets other than life sciences. To those with more direct contact with the public, and which are less bound by red tape – from retail to hospitality and travel, even banking. Yet ignoring the potential of digital disruption could put companies on the back foot1 as their own market starts to transform itself around them.

In an age of data overload, AI offers a way to find and keep teams focused on what’s important – from what’s being said in the market, to how drugs are designed and developed. AI’s Role So what is it that AI does differently, and how broad is its potential in life sciences? AI takes automation and makes it smart. Where robots in factories excelled at doing repetitive, mundane tasks efficiently and tirelessly, with precision, AI can be programmed to carry out more complex tasks (e.g. robotics taking measurements in hostile environments which would be too risky for humans to go into, and where there are lots of variables).

Just look at the impact artificial intelligence (AI) and machine learning are expected to have on healthcare, in accelerating and transforming patient diagnoses, for instance. Investments in healthcare-focused AI start-ups have more than tripled in recent years2. In life sciences, the opportunities are not dissimilar: startups are already using machine learning algorithms to reduce drug discovery times3.

Machine learning improves upon that, allowing AI-based systems to find better ways of doing things5. Rather than humans having to foresee every possibility and programme a system for every eventuality, AI-based systems can learn and adapt from what they know to create effective and powerful shortcuts – as though they are ‘thinking’ and problem-solving using their own intelligence and reasoning. (What they’re really using are complex algorithms or clever maths.)

AI promises to make clinical trials cheaper, faster and more targeted. Last November, British AI startup, BenevolentAI, announced that its technology – which offers to speed up late-stage development of drugs and provide richer clinical data – would be tested under exclusive licence for a series of novel clinical stage drug candidates with Janssen Pharmaceutica, part of Johnson & Johnson, this year4.

If they’re faced with a deluge and range of data that would tie up a human team for days or months, machine learning systems can perform analyses and distil subtle trends that humans might overlook. In the context of pharmacovigilance, they can help scour the internet for relevant patient feedback about life sciences products, or identify unmet needs or gaps in the market. Operationally, such tools can help companies navigate routine

54 Journal for Clinical Studies

Volume 9 Issue 4


processes more promptly, thoroughly and economically, freeing up teams to use their skills where they will add greater value. Cutting Through Compliance Demands An obvious area where AI and machine learning can help here is in managing matters of regulatory compliance – where requirements are multiplying and changing all the time. Not only does this increase the burden on regulatory affairs and quality teams; it also potentially slows companies’ time to market. Moves towards international standards, and deployment of sophisticated content management systems, go a long way towards alleviating the additional work involved and maintaining data quality. Yet, with each new regulatory initiative or submissions hoop that companies need to jump through, the business agility and creativity they are aiming for appears to become further out of reach. In everyday life, AI has begun to transform the way people interact with diverse information and achieve end results. Over breakfast, thanks to AI-enabled ‘personal assistants’, they can check their various message sources, get a precis of the news, peruse their diary, search for travel options and make bookings, without touching a keypad or mouse. They simply speak their requests to a voice-enabled user interface (Siri, Alexa, Google Assistant or Cortana), and an AI-enabled ‘assistant’ does the rest – instantly interacting with all the different applications and performing the various analyses and transactions, returning its results before the user has taken a second bite of their toast. It may feel like a leap now, but there is no reason to suppose regulatory affairs teams couldn’t enjoy a similarly unencumbered user experience when managing health authority submissions. The ideal is that their product lifecycle content systems will make it

more intuitive to manage data changes, document authoring and reviews, quality control, and submission. Currently much of this is managed via comprehensive rules, templates and workflow which help to streamline processes and ensure that the right data is used in support of the given requirement. But what if AI and machine learning could promote reliable shortcuts, and issue red flags or suggestions if rogue actions are taken, the wrong master data is used, or someone tries to alter approved ISO IDMP-compliant source content? René Kasan, a visionary speaker from IT consultancy NNIT, outlined his own personal take on AI’s potential as part of regulatory information management at AMPLEXOR’s recent annual conference. He explored how it might help transform companies’ ability to consume and harness vast volumes of complex data, and unprecedented inter-connections between different data sources and systems – without compromising the integrity of the content, and with significant benefits to speed and reliability. And without time limits, because AI doesn’t get tired or slow down. As well as freeing up skilled people’s time to do more satisfying and productive work, AI could also reduce the risk of dependence on a single person’s knowledge of how things are done. (If a highly skilled team member moves on, there is usually a productivity gap as their replacement gets up to speed.) It’s easy to see how companies would benefit: it is getting harder to attract experienced skills for important regulatory roles6 as demand increases, yet the pressures of the job take their toll. Could Alexa Automate Regulatory Information Preparation? Life sciences firms are already harnessing more automation to streamline regulatory information processes: annual surveys by Gens & Associates repeatedly show increasing sophistication in Journal for Clinical Studies 55

Technology the industry’s approach to regulatory information management. Although exploiting AI in particular is something that is only now appearing on their radar, AI and machine learning have become hot topics, and events and conference sessions on the theme are well attended. We can speculate about a number of ways AI could transform regulatory information and submissions management transformation – improving the process of planning, structuring, authoring, publishing and archiving content. Example scenarios might include using AI to monitor and determine which content elements of a submission are routinely included, so that they become a structural component in their architecture. AI could also help ensure referential integrity, so that the correct, approved master content is reliably drawn on every time, and that protected sources (e.g. ISO IDMP data) cannot be tampered with, without a formal change request. Document and dossier authoring and reviews could be streamlined as AI capabilities learn to spot content that has been changed frequently in the past. Drawing on this knowledge, the system could propose changes as a document is being put together, saving rounds of redrafting. Alternatively, the user could ‘ask’ the system what the implications would be if they made a particular change to content, and have the Alexa-style voice interface list all the ramifications. An intuitive, user-friendly interface combined with smart, machine-based deductions could save a lot of clicks, system navigation and time. AI could reinforce compliance and content quality along the supply chain, too, helping to restrict what country affiliate representatives are able to do with content. Where there have been quality violations, AI could provide the analysis and insight so teams can act and prevent repeated issues. Related to this, the technology could help identify and avoid common submission queries, to prevent delays in getting products approved. Similarly, it might support strategic decisions about which health authorities/ markets to target first. Crossing the Digital Divide As organisations start to make the connection and understand the role artificial intelligence could have in transforming their operations, new opportunities may begin to present themselves – for example, the potential to improve R&D by sharing ‘learning’ back along the product lifecycle. In the meantime, there are associated issues companies will need to consider. For example, how might AI use affect the compliance processes, especially if checks have previously relied on conditions remaining static (rather than continuously tweaked and adjusted, as AI finds scope for improvement)? If the AI capability is becoming an additional reviewer or actor in the workflow associated with creating regulated or regulatory content, how does this change the auditing requirements and where does responsibility lie? Finally, if knowledge management and retention comes to rely more heavily on machines rather than skilled individuals, what is the migration plan if technology moves on? None of these details are a reason to dismiss AI’s potential; they merely need to be factored into the design plan. It’s all part of understanding the technology’s potential in the context of the challenges life sciences organisations are trying to overcome – and at this stage nothing should be ruled out. 56 Journal for Clinical Studies

Returning to the example of BenevolentAI, the British AI startup has bold ambitions for the way drugs are developed and brought to market – and it plans to do this itself, within as short a timeframe as four years7. It envisages a world where, thanks to AI’s ability to cut to the chase, it is possible to provide “first-in-class and best-in-class stratified medicines to help patients with high unmet needs”. At a recent conference in London, the company hosted a session exploring how digital, data and technology developments are disrupting clinical trials and the big leap the life sciences industry now needs to make if it is to prepare itself for a brave new future. The drivers for change are very clear – from the inefficient management and strategic use of operational data, to the high cost of developing medicines and preparing them for market. Now all companies need to do is clear the way for a new approach. Because if they don’t, someone else will. REFERENCES 1.




5. 6.


Digital disrupters take big pharma ‘beyond the pill’, Financial Times, April 2017: From Virtual Nurses To Drug Discovery: 106 Artificial Intelligence Startups In Healthcare, CB Insights, February 2017: blog/artificial-intelligence-startups-healthcare/ Top Artificial Intelligence Companies in Healthcare to Keep an Eye On, Medical Futurist, September 2016: Exclusive license agreement with Janssen for clinical stage drug candidates, BenevolentAI news announcement, November 2016: http:// Machine learning versus AI: what's the difference?, Wired, December 2016: Compliance Key to Business Expansion for the Life Sciences Sector, Fresh Business Thinking, April 2015: http://www.freshbusinessthinking. com/compliance-key-to-business-expansion-for-the-life-sciencessector/ A British tech unicorn is trying to cure Alzheimer's and ALS with artificial intelligence, Business Insider UK, April 2017: http://uk.businessinsider. com/benevolent-ai-ceo-ken-mulvany-interview-2017-4?r=UK&IR=T

Elvis Paćelat Executive Vice President, Life Sciences, AMPLEXOR. Elvis is a business and technology executive with more than two decades of international experience in the life sciences market. With detailed technical understanding and expertise in compliance and regulatory content management solutions for Life Sciences, Elvis is a specialist in business impact analysis. At AMPLEXOR, he is responsible for driving the corporate strategy and market success of the AMPLEXOR Life Sciences business. Elvis is committed to delivering benefit for clients, partners and shareholders, whilst supporting client-centric strategies and spearheading groundbreaking innovations. Email:

Volume 9 Issue 4

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Journal for Clinical Studies 57

Clinical Supplies

Patient-Centricity – a Winning Formula

There has been considerable discussion around the concept of patient-centricity in the pharmaceutical community. The industry has taken a collective pause in an effort to reevaluate and rethink longstanding approaches to drug development and commercialisation, with attention being recalibrated on the ultimate goal; making it easier for the patient to reach improved health outcomes. This perspective is underpinned by the recognition that what is best for the patient will lead to beneficial outcomes for all stakeholders, including the drug company, the healthcare provider, and supporting community of associated service providers. There is a famous quote from former United States Surgeon General, C. Everett Koop: “Drugs don’t work in people who don’t take them.” It is estimated that less than one-third of all prescriptions written are actually filled at the pharmacy by patients. Wide-ranging studies have shown medication adherence rates for life-threatening diseases including diabetes, heart disease and oncology can be as low as 30–40 per cent. With the benefit of interventional techniques and developing technologies, adherence rates have been shown to improve – however, these programmes are not broadly adopted within industry with scale, and have not had significant impact on decreasing the overall cost of healthcare, nor benefitted large populations. Patients may be non-adherent for a variety of reasons, some conscious and some unconscious. Certainly, we are all admittedly forgetful when it comes to taking our medicine on time or being diligent about timely refills of those prescriptions. Cost can also be a significant factor, whereby patients will consciously stretch their medication supply or simply go off therapy. In either instance, doing so will hamper the health impact of their prescribed therapy or worse, in an example such as taking a drug holiday while prescribed an anticoagulant, potentially put their life in jeopardy.

58 Journal for Clinical Studies

Other considerations may be unwanted side-effects or a lack of understanding about how to optimally take the medication, such as taking with food, or alternatively avoiding food for some period of time, resulting in reduced effectiveness. Fear or general lack of understanding can also inhibit the path to improved health, by affecting the patient’s perception of the medication and their willingness to be compliant. Likewise, the patient may not physically experience the benefit of the drug, and in some instances may have a negative perception due to the unwanted side-effects. Hypertension is the classic example, where a patient may have high blood pressure, but generally not feel the effects of their disease – however they may experience considerably unpleasant side-effects as a result of their course of treatment. Furthermore, a similar scenario plays out in popular cholesterol-lowering medications. By scale, these two examples are noteworthy, as in the US, with a population of more than 300 million people comprising of 75 per cent of adults, it is estimated that one in every three adults has hypertension, while between 10 and 20 per cent of adults have high cholesterol. A large-scale patient-centric approach to benefit medication adherence would have significant positive health and economic impacts. Focusing Patient-Centricity in Clinical Trials In addition to challenges with patient adherence to medication in clinical trials, sponsors and study organisers are also constantly faced with hurdles, such as patient recruitment and patient retention. As the industry is tasked with further expediting drug development and decreasing clinical study duration, the FDA is increasingly requiring additional studies and data to prove long-term safety and comparative effectiveness, including postmarketing studies once the drug is commercially available in the market. This trend is coupled with an increasing percentage of drugs being brought to market for very specialised disease states and narrow therapeutic indications. This wave of specialised medicines and the ongoing need for treatment-naïve candidates, paired with cost pressures in the R&D sector more broadly, has increased the

Volume 9 Issue 4

Clinical Supplies

use of multi-national studies. These complex studies in turn create the requirement for multi-language labelling. This can result in the creation of IMP study materials that may contain upwards of 16â&#x20AC;&#x201C;20 languages on a single label. Clinical trial professionals are left to balance all of these demands and creatively identify initiatives to keep the focus on the patient. At a surface level, these competing priorities may seem to be in direct conflict. However, when looking at the situation from a broader perspective, the focus on patient-centricity clearly generates tangible value and outweighs the short-term inefficiencies created by not opting for a solution solely based on immediate speed or cost. Patient-Centricity in Package Design A practical example of patient-centricity in action can be found in package selection for an investigational study. When looking to initiate a clinical study, a sponsor company may be evaluating choosing a bottle or a unit dose blister in a calendarised format for their clinical study material. Looking simply at the short-term criteria of expediting material for study initiation, where a difference of weeks or days can be considerable, the path of selecting a bottle would be a logical solution. It is a cost-effective packaging option, it is relatively â&#x20AC;&#x2DC;off the shelfâ&#x20AC;&#x2122; in its availability, it can be hand-filled by a clinical packager with minimal startup costs, as well as having an acceptable stability profile for barrier properties, and is proven to be child-resistant. Conversely, when evaluating the development of a unit dose adherence package, there may be a longer lead time for development and it may be more costly to produce. If looking from a short-term perspective and the immediate pressures of cost and expediting, the choice leaves little room for debate. However, if the sponsor company is taking a holistic approach with a focus on patient-centricity, the broader economics absolutely point to use of a patient-centric package. Utilisation of a calendarised unit dose blister format, or compliance/adherence packaging, offers sponsor companies

considerable benefit in both addressing the needs of the patient and positively impacting the desire for better data, more efficient studies, and lower total delivered cost. The use of this style of package allows patients to take medication exactly as prescribed and track their usage, rather than a bulk approach in a bottle format. Physicians can capture vital information on the package, including the specific date to start the therapy and any other pertinent notes for the patient. With the returned package, the patient can physically demonstrate to clinical providers that they have taken the product as prescribed. Furthermore, technologies are available that can provide real-time tracking of patient dosing, allowing for clinical interventions to ensure proper adherence while the study is in progress. These technologies and principles extend to other delivery forms, such as injectables. The ability to prompt, monitor and even track real-time information is a powerful tool. Likewise, with the advent of Bluetooth and nearfield communication technologies, packages with integrated technology can capture real-time information about side-effects or other vital information, as patients take the medication over the course of treatment. Enhanced adherence leads to healthier patients and more valuable study data. Poor adherence can be rectified and corrected as it happens. Better information gathering can lead to improved patient retention, a significant cost in clinical trial administration and a persistent challenge in study duration. It is estimated that in the industry, clinical studies have a 30 per cent average dropout rate. With more adherent investigational study patients, health outcomes are improved and better retention is realised, translating into reduced total delivered cost, more valuable data generated, and studies executed more efficiently. Patient-Centricity in Clinical Supply Chain Logistics Another area of focus for realising patient-centricity in clinical trials is in the area of study design and administration. Considerable interest is being focused in direct-to-patient models, where patients may minimise, or in some instances avoid, the need to Journal for Clinical Studies 59

Clinical Supplies

come to a hospital or clinic to receive the study drug, as well as providing critical health feedback. In this scenario, patients are engaged by clinical trial or healthcare professionals in a home setting and the study drug is physically delivered to their home by a trained specialist. Clearly this model is not applicable for all studies and disease states, but for particular programmes, there can be considerable benefit to the patient and the study. In certain geographies, patients in a traditional clinical study may have to travel significant distances to participate, which can considerably hamper patient recruitment and retention. In a direct-to-patient model, the study effectively comes to them. This model may increase the cost of study administration for the sponsor company, however by executing the study in a more patient-focused approach, the sponsor company can realise significant benefit through patient recruitment and retention, again translating into better data, more efficient studies, and a faster path to completion. Patient-Centricity in a Global World One of the increasing challenges in taking a patient-centric approach to clinical study execution is the growth in multinational study execution. Often supplies are designed to pool so that multiple languages are provided and materials can be directed to individual countries as needed. This scenario forces sponsor companies to either manage a multitude of language-specific supplies, or focus on common supplies where they condense information due to the sheer amount of text being added, often squeezed into a multi-page booklet. Careful consideration must be paid to graphics common to all languages and cultures, to ensure patients can clearly comprehend considerably distilled opening instructions, dosing regimens and other key information. Rather than a traditional pooled supply approach, some companies have developed newer strategies for just-in-time labelling or late stage customisation logistics, whereby they label study materials according to country-specific requirements at the time of drug dispatch. This can reduce the complexity of a scenario where they 60 Journal for Clinical Studies

would be trying to accommodate many different languages on the same label in a multi-page booklet approach. This JIT strategy may decentralise supplies, but may bring other benefits in meeting the language and cultural needs of patients in their geography, as well as those of the study administration. Patient Focus Yields Powerful Results The pharmaceutical industry is in the infancy of its patientcentricity journey, but it is clear that with a focus on the patient, many tangible benefits are realised by drug companies in their development and commercialisation of life-saving medicines. With so many significant breakthroughs over the past decade, it is exciting to see where this patient-focused journey will lead as new patient breakthroughs are happening every day.

Justin Schroeder PCI Pharma Services Mr Schroeder is responsible for global marketing, creative package design and new account development with a focus on the development and commercialization of new products. Mr Schroeder has over 20 years of experience in outsourced pharmaceutical services in various roles including Engineering, Project Management, Marketing & Development. He holds a Bachelor of Science from the School of Packaging at Michigan State University and an MBA in Marketing from Northern Illinois University. Mr Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email:

Volume 9 Issue 4

SMi proudly present their 6th annual conference…

Cancer Vaccines Overcoming hurdles to cancer immune response: Cell therapies, vaccine development and combination therapies


SEPT 2017

Copthorne Tara Hotel, London, UK

Highlights in 2017: • Exploring personalising cancer vaccines, characterising and applying the outside in approach in cancer vaccine development • Maximising the therapeutic potential of cancer vaccines in combination with immune checkpoint inhibitors • In depth case study examples of peptide, DNA, neoantigen and MHC based vaccine development • Assessing the use of preclinical data for cancer vaccines

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PLUS ONE INTERACTIVE HALF-DAY PRE-CONFERENCE WORKSHOP Tuesday 26th September 2017, Copthorne Tara Hotel, London, UK

Biomarkers of immune response 12.30 – 16.00 Workshop Leaders: Rose-Ann Padua, Research Director, INSERM Antoine Toubert, Head, Alloimmunity, Autoimmunity, Transplantation, INSERM Eric Tartour, Head, Laboratory of Clinical Immunology, Hopital Europeen George Pompidou Sharam Kordasti, Honorary Senior Lecturer, Department of Haematological Medicine, Kings College London Zwi Berneman, Professor of Haematology, University of Antwerp Register online or fax your registration to +44 (0) 870 9090 712 or call +44 (0) 870 9090 711 ACADEMIC & GROUP DISCOUNTS AVAILABLE

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SMi Present the 7th Annual Conference on…

Orphan Drugs and Rare Diseases

Discussing strategies for patient engagement, market access and gene therapies to enhance rare disease and orphan drug research

HOLIDAY INN KENSINGTON FORUM, LONDON, UK FEATURED SPEAKERS: • Oliver Timmis, CEO, AKU Society • Stuart Hughes, Director, Head of Pharmacology, Vertex • Nadia Assenova, Senior Director Regulatory Affairs, EMEA, Alexion Pharma GmbH • Christine Lavery, Group Chief Executive, MPS Society • Hsin Loke, Director, Strategy, Operations and Finance, Rare Diseases Unit, GlaxoSmithKline • Olaf Ritzeler, External Innovation Lead, Sanofi • Stephen Marcus, CEO, Cantex Pharmaceuticals • Kei Kishimoto, Chief Scientific Officer, Selecta Biosciences Register online or call +44 (0) 870 9090 711




HIGHLIGHTS IN 2017: • Learn about new therapies for different rare diseases, and how these can successfully be applied to other diseases with similar attributes • Hear what opportunities and challenges come with working on rare diseases, as well as the development of the world’s first rare disease centre for children • Expand your knowledge on patient collaboration and patient-centric models with the stream on patient engagement, covering improvement strategies, patient-led trials, and much more • Gather further insight on drug approval and reimbursement with MAA, and how techniques for drug repurposing in the rare disease area can help treatment

Clinical Studies 61 #smiorphandrugs @SMIPHARM Journal for

The 15th Annual CTS East Coast event builds on last yearâ&#x20AC;&#x2122;s conference, Arenaâ&#x20AC;&#x2122;s biggest East Coast CTS event to date. To do this we have added a one day stream covering the emergence and adoption of innovative technology to fi nd solutions for your clinical trial supply problems, whilst also offering a larger variety of sessions covering all the essentials in clinical supply, from maximising forecasting software to managing a yo-yoing workforce and uncovering what is driving supply outsourcing.

Key agenda highlights 2017:

Key agenda highlights 2017: n




Exploring how working with preferred partners to establish development standards can improve your use of IRT Customizing current technologies to improve pharmaceutical supply chain management and improve efficiency Uncovering what is driving supply outsourcing; how and why are traditionally in-house capabilities being externalized Exploring what supply chain complexities arise from using biologics

n n n n n

Carla Reis, Senior Manager of IRT/ Randomization, Bristol-Myers Squibb Rey Bacchus, Clinical Trial Supply Manager, Janssen Rocco Barone, Associate Director Operations, Merck Brian Rogers, Packaging Project Management Head, Sanofi Anthony Orosz, Assistant Director, Pharmaceutical, Health and Chemical Center of Excellence and Expertise, US Customs and Border Protection

To register, please visit: and quote code: MK-ACAD or email us Journal for Clinical Studies 62

Partnerships in Clinical Trials Europe

28-29 November 2017 RAI Amsterdam co-located with

Early Clinical Development and Clinical Trial Supply


1000+ Attendees


Companies Represented


Influential Industry Speakers

STREAM 1: Partnerships and Collaboration

STREAM 5: Partnership Management

STREAM 2: Investigator and Industry: How Can They Work Together?

STREAM 6: Patients as Partners

STREAM 3: Mobile eHealth STREAM 4: Governance, Oversight and Quality

STREAM 7: Disruptive Innovation, Technology and Big Data STREAM 8: Small to Mid-Size Pharma and Biotech

To find out more about Partnerships in Clinical Trials Europe and book your pass please visit


Journal for Clinical Studies 63

For details of group booking rates please contact

Ad Index

Page 61

6th Annual Conference on Cancer Vaccines

Page 61

7th Annual Conference on Orphan Drugs and Rare Diseases

Page 3



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Partnerships in Clinical Trials Europe


PCI Pharma Services

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Qualogy Ltd.

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Research Quality Association Ltd

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Page 5

Synevo Central Labs

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SYNLAB International GmbH

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Worldwide Clinical Trials

Page 62

15th Annual Clinical Trial Supply East Coast 2017

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

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64 Journal for Clinical Studies

Volume 9 Issue 4

The Box is Just the Base! MLM Assembly Services™ Customized kit building Global supplies FDA/EMA-compliant central lab

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Flexible, scalable, full-service clinical supply services to take your study from Phase I to Phase IV. Our innovative solutions leverage our comprehensive services and expertise to create tailored clinical supply solutions that meet your needs, regardless of trial size or complexity. With 8 GMP facilities and 50+ strategically located depots worldwide, we have the local expertise to help speed your molecule to clinic and the global scale to handle virtually any clinical supply need.

Catalent. More products. Better treatments. Reliably supplied.™ us + 1 888 SOLUTION (765-8846) eu + 800 8855 6178

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